Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of diseases associated with PI3K modulation

Abstract

The present disclosure relates to compounds of Formula (I) or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, useful for treating diseases or disorders associated with PI3K modulation as allosteric chromenone inhibitors of phosphoinositide 3-kinases (PI3K), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, W, X, Y, s, and ring A are as described herein.

Description

[0001] SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on April 3, 2020, is named PEPH-012_00US SeqListing_ST25.txt and is 19 KB in size.

[0003] TECHNICAL FIELD

[0004] The present disclosure relates to allosteric chromenone inhibitors of phosphoinositide 3-kinases (PI3K) useful for treating diseases or disorders associated with PI3K modulation. The present disclosure relates to compounds and compositions that inhibit PI3K, methods of treating diseases or disorders associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and methods of using PI3K inhibitors in combination with one or more additional disorder or cancer therapies.

[0005] BACKGROUND

[0006] Cellular activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into and within cells to elicit an intracellular response is known as signal transduction. Over the past several decades, cascades of signal transduction events have been elucidated and discovered to play central roles in a variety of biological responses. Defects in various components of signal transduction pathways have been found to be responsible for a large number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).

[0007] Kinases represent an important class of signal transduction molecules. Kinases can generally be classified as protein kinases and lipid kinases, and certain kinases exhibit dual specificity. Protein kinases are enzymes that phosphorylate other proteins and / or themselves (i.e., autophosphorylation). Protein kinases can generally be divided into three major classes based on their substrate utilization: tyrosine kinases, which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine / threonine kinases, which predominantly phosphorylate substrates on serine and / or threonine residues (e.g., mTorCl, mTorC2, ATM, ATR, DNA-PK, Akt), and dual specificity kinases, which phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0008] Lipid kinases are enzymes that catalyze the phosphorylation of lipids within the cell. These enzymes and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. One particular group of lipid kinases includes the membrane lipid kinases, which are kinases that catalyze the phosphorylation of lipids contained in or associated with the cell membrane. Examples of such enzymes include phosphoinositide kinases (such as PI3-kinases, PI4-kinases), diacylglycerol kinases, and sphingosine kinases.

[0009] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the highest mutated systems in human cancer. PI3K signaling is involved in many other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.

[0010] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group of phosphatidylinositol or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001). Class I PI3Ks (pl lOa, pl lOβ, pl lOδ, and pl lOγ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt / PDK1 pathway, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0011] PI3K isoforms have been implicated in, for example, a variety of human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations leading to upregulation of PI3K isoforms are believed to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations clustered in several hotspots in the helical and kinase domains. Because of the high mutation rate of PI3K, targeting of this pathway can provide valuable therapeutic opportunities.

[0012] Genetic alterations in genes in PI3K signaling are believed to be involved in a range of cancers such as endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, Schwann cell tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibroblastic carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, kidney non-clear cell carcinoma, kidney clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and desmoplastic glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med. 2018 Nov 22;379(21):2052-2062).

[0013] The alpha isoform of PI3K has been implicated in, for example, a variety of human cancers. Angiogenesis has been shown to selectively require the alpha isoform of PI3K to control endothelial cell migration (Graupera et al., Nature 2008; 453; 662-6). Mutations in genes encoding PI3K alpha or mutations leading to upregulation of PI3K alpha are believed to occur in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in genes encoding PI3K alpha are point mutations clustered in several hotspots in the helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate of PI3K alpha, targeting of this pathway can provide valuable therapeutic opportunities. While other PI3K isoforms, such as PI3K delta or PI3K gamma, are primarily expressed in hematopoietic cells, PI3K alpha and PI3K beta are constitutively expressed.

[0014] Due to the central role of PI3Ka in regulating glucose homeostasis in the body, PI3K inhibition in patients often leads to hyperglycemia and / or hyperinsulinemia (Busaidy NL, et al., Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 2012;30:2919-28). High levels of circulating insulin can have mitogenic and / or anti-apoptotic effects on cancer cells, thereby counteracting the antiproliferative effects of PI3K inhibitors (Blouin M-J, et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013;73:4615).

[0015] In the case of cancers with mutated PI3Ka, one approach to overcome the problem of compensation in insulin and / or glucose upon systemic PI3Ka inhibition is to develop inhibitors that are more selective for the mutant PI3Ka than the wild-type PI3Ka. This would create an increased window for drug dosing to selectively inhibit the pathological signaling of mutant PI3Ka in cancer cells without affecting the wild-type PI3Ka in host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct;6(10): 1090-1105), thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target (Ariella B. Hanker, et al., Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 Apr;9(4): 482-491).

[0016] Currently, PI3Ka inhibitors are nearly equipotent for wild-type and mutant PI3Ka. Due to the distance of the PI3Ka mutation from the active site, mutant selective inhibitors have been elusive. Thus, inhibitors that target a second peripheral binding pocket near the known mutations (e.g., H1047R) can provide a pathway to selectively inhibit PI3Ka. Therefore, targeting the mutant peripheral binding pocket of PI3Ka can in turn provide a valuable therapeutic target for drug development.

[0017] Thus, kinases, for example lipid kinases such as PI3K, are major targets for drug development. The present disclosure provides a new class of kinase inhibitors.

[0018] SUMMARY

[0019] In one aspect, the disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0020]

[0021] wherein:

[0022] X is -NR 12 - or -O-;

[0023] Y is -C(R 11 )2-, -O-, -NR 11 - or -S-;

[0024] W is -N-, -O- or -S-, wherein when W is -O- or -S-, R1or R2is absent;

[0025] each R1and R2is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m - R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein said cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with one or more oxo, =NR 12 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , C3-C6cycloalkyl, aryl, heteroaryl, or R 15 ; or

[0026] R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, wherein said heterocycle is optionally substituted with one or more R 10 ; or

[0027] each R3, R4, R5, and R6is independently H, halogen, -CN, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S;

[0028] each R7and R8is independently H, halogen, -CN, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, or Ci-C6alkoxy;

[0029] R9is, at each occurrence, independently oxo, =NR 11 , halogen, -CN, -NO2, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 , -(CH2) m -CR 13 (OH)-R 12 , -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m -C(O)N(OH)R 12 , -(CH2) m -SO2R 12 , -(CH2) m -SO2-OR 12 , -(CH2) m -SO2N(R 12 )2, -(CH2)m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -P(O)(OR 13 )R 12 , -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 13 , -(CH2) m -C(O)O-(CH2CH2-O) r R 13 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 , -(CH2) m -S(O)(NR 12 )-R 13 , C3-C 10 cycloalkyl, aryl, heterocycle, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O, and S, wherein said Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, C3-C 10 cycloalkyl, aryl, heterocycle, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O, and S, wherein said Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, C3-C 10cycloalkyl, aryl, or heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the cycloalkyl, aryl, or heterocycle is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy;

[0030] R 10 independently at each occurrence is oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , -(CH2) n -O-(CH2CH2-O) r R 13 , C3-C 10 cycloalkyl, heterocycle, -(CH2) n -aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(CH2) n -SO2R 12 , -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , or -(CH2) n -C(O)N(R 12 )2, or

[0031] two R 10 , together with the atom to which they are attached, form a C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one or more oxo, =NR 12halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , C3-C6cycloalkyl, aryl, heteroaryl, or R 15 substituted;

[0032] R 11 is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl;

[0033] each R 12 and R 13 is, at each occurrence, independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) q -O-C(O)-(CH2) r -R 14 , -(CH2) q -NH-C(O)-(CH2) r -R 14 , -(CH2) q -O-C(O)-(CH2) r -OR 14 , -(CH2) q -NH-C(O)-(CH2) r -OR 14 , -(CH2) q -O-(CH2) r -R 14 , -(CH2) q -NH-(CH2) r -R 14 , -(CH2) q -O-(CH2) r -OR 14 , -(CH2) q -NH-(CH2) r -OR 14 , C3-C 10cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, -(CH2) q - aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy;

[0034] Ring A is C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O and S;

[0035] R 14 is ;

[0036] two R 15 , together with the atom to which they are attached, form a cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, or heteroaryl, wherein said cycloalkyl, aryl, heterocycle and heteroaryl are optionally substituted with one or more C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, or -(CH2) n -SO2R 12 ;

[0037] each n, m, q, r or s is independently, at each occurrence, 0, 1, 2, 3, 4, 5 or 6;

[0038] provided that when R1and R2, together with the nitrogen atom to which they are attached, form morpholine and:

[0039] i. when Y is -O-; R3, R4and R6are hydrogen; R7is methyl; X is -NR 12 - and Ring A is aryl; then R5is not -C(O)N(R 12 )2or C(O)OR 12 ;

[0040] ii. when Y is -O- or -NR 11; R3, R4, R6, and R8 are hydrogen; R7 is H or Ci-C6alkyl; X is -NR 12 - and ring A is phenyl or pyridyl; then R5 is not H, OH, OCH3, OCF3, F, Cl, CF3, Ci-C6alkyl, or -(CH2) m - aryl; or

[0041] iii. when R5 is -CH3, then (a) the morpholine is substituted or (b) ring A is not phenyl.

[0042] In one preferred embodiment of formula (I), s is at least 1 and at least one R9 is -C(O)OR 12 .

[0043] In another preferred embodiment of formula (I), W is -N-, and R1 and R2 together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 , and wherein the heterocycle is not optionally substituted morpholine.

[0044] In another preferred embodiment of formula (I), s is at least 1, at least one R9 is -C(O)OR 12 , W is -N-, and R1 and R2 together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 , and wherein the heterocycle is not optionally substituted morpholine.

[0045] In another aspect, the present disclosure relates generally to methods for treating cancer. These methods include administering to a subject in need thereof a therapeutically effective amount of a PI3K inhibitor (e.g., a PI3K a inhibitor or a PI3K A H1047R mutant inhibitor).

[0046] In certain embodiments, the PI3K inhibitor (e.g., a PI3K a inhibitor or a PI3K A H1047R mutant inhibitor) is a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (lh), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0047] In another aspect, the present disclosure provides compounds obtainable by or by a process for preparing a compound as described herein (e.g., a process comprising one or more steps described in the schemes).

[0048] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0049] In another aspect, the present disclosure provides an intermediate as described herein suitable for use in a method of making a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0050] In another aspect, the present disclosure provides a method of modulating the activity of a PI3K (e.g., PI3K a) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0051] In certain embodiments, the PI3K a sequence is associated with NCBI Reference Sequence: NP_006209.2. In certain embodiments, the PI3K b sequence is associated with NCBI Reference Sequence: NP_006210.1.

[0052] In certain aspects, the amino acid sequence encoding PI3K a comprises or consists of the following amino acid sequence:

[0053]

[0054] .

[0055] In certain aspects, the amino acid sequence encoding PI3K a with a H1047R mutation comprises or consists of the following amino acid sequence:

[0056]

[0057]

[0058] .

[0059] In certain aspects, the disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0060] In certain aspects, the disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0061] In certain aspects, the disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0062] In certain aspects, the disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0063] In another aspect, the disclosure provides a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for use in modulating (e.g., in vitro or in vivo) PI3K (e.g., PI3Ka) activity.

[0064] In another aspect, the disclosure provides a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for use in selectively inhibiting a mutant PI3Ka relative to wild-type PI3Ka.

[0065] In another aspect, the disclosure provides a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0066] In another aspect, the disclosure provides a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for use in treating a disease or disorder disclosed herein.

[0067] In another aspect, the disclosure provides use of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, in the manufacture of a medicament for modulating PI3K (e.g., PI3K a) activity (e.g., in vitro or in vivo).

[0068] In another aspect, the disclosure provides use of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0069] In another aspect, the disclosure provides use of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0070] In another aspect, the disclosure provides a method of making a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0071] In another aspect, the disclosure provides a method of making a compound, comprising one or more steps described herein.

[0072] Other features and advantages of the present disclosure will be apparent from the detailed description, and from the claims.

[0073] DETAILED DESCRIPTION

[0074] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which PI3K plays a role by administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor. The methods of the present disclosure can be used to treat a variety of PI3K-dependent diseases and disorders.

[0075] In certain embodiments, the disease or disorder is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In certain embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibroplastic carcinoma, hepatocellular carcinoma, diffuse gliomatosis, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, kidney non-clear cell carcinoma, kidney clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and wrapped glioma.

[0076] The specifics of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described below. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference herein in their entireties.

[0077] DEFINITIONS

[0078] The article "a" is used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0079] The term "and / or" is used in this disclosure, unless otherwise indicated, to mean "and" or "or".

[0080] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., alkyl) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety can contain other functional groups, but is not necessarily required to have any additional functional groups. Suitable substituents used in the optional substitution of the described groups include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(Ci-C6)alkyl, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -NHC(O)(Ci-C6)alkyl, -C(O)NH(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)NH(Ci-C6)alkyl, and -S(O)N((Ci-C6)alkyl)2. The substituents themselves can be optionally substituted. "Optionally substituted" as used herein also means substituted or unsubstituted, the meaning of which is described below.

[0081] The term "substituted" as used herein means that the designated group or moiety bears one or more suitable substituents, wherein the substituents can be attached to the designated group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group can indicate that the cycloalkyl group is attached to one atom of the aryl group either through a bond or by being fused to the aryl group and sharing two or more common atoms.

[0082] The term "unsubstituted" as used herein means that the designated group bears no substituents.

[0083] The term "aryl" means a cyclic aromatic hydrocarbon group having 1-3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl, unless specifically defined otherwise. In cases containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents (e.g., 1-5 substituents). Exemplary substituents include, but are not limited to, -H, -halogen, -0-(Ci-C6)alkyl, (Ci-C6)alkyl, -0-(C2-C6)alkenyl, -0-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -S(O)2-(Ci-C6)alkyl, -S(O)NH(Ci-C6)alkyl, and -S(O)N((Ci-C6)alkyl)2. The substituents themselves can be optionally substituted. Furthermore, when containing two fused rings, the aryl groups defined herein can have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems for these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthryl, phenalenyl, phenanthryl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzocycloalkenyl, and the like.

[0084] "Heteroaryl" means, unless specifically defined otherwise, a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Polycyclic aromatic radicals include two or more fused rings and can further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. "Fused" means, unless specifically defined otherwise, two rings that share two ring atoms. "Spiro-fused" means, unless specifically defined otherwise, two rings that share one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic radical, wherein the heteroatoms are selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as defined herein also means a tricyclic heteroaromatic radical containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as defined herein also means a tetracyclic heteroaromatic radical containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. The aromatic radical is optionally independently substituted with one or more substituents described herein.Examples of heteroaromatic groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiodiazole, indazol, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furano[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridinyl, furano[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furano[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein can have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, saturated or partially unsaturated rings can be further fused to the saturated or partially unsaturated rings described herein. In addition, when containing three or more fused rings, the heteroaryl groups defined herein can have one or more saturated or partially unsaturated rings that are spiro-fused. Any of the saturated or partially unsaturated rings described herein are optionally substituted with one or more oxo. Exemplary ring systems for these heteroaryls include, for example, indolinyl, indolinonyl, dihydrobenzo-thiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[l,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[l,2-a]indol-l(2H)-onyl, benzo[ c ][l,2]oxaborol-l( 3H )-yl (benzo[ c ][l,2]oxaborol-l( 3H )-olyl), 6,6a,7,8-tetrahydro-9 H -pyrido[2,3- b ]pyrrolo[l,2- d ][l,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-l,8'-pyrido[2,3- b ]pyrrolo[l,2- d ][l,4]oxazin]-9'-onyl.

[0085] Halogen or "halo" means fluoro, chloro, bromo, or iodo.

[0086] Alkyl means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of (Ci-C6)alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, neopentyl, and isohexyl.

[0087] "Alkoxy" means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms, containing a terminal "O", i.e., -0(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy.

[0088] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group can be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. The alkenyl group can be unsubstituted or substituted. The alkenyl group as defined herein can be straight chain or branched.

[0089] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. The alkynyl group can be unsubstituted or substituted.

[0090] The term "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups described above can become an alkylene by removing a second hydrogen atom from the alkyl group. The alkylene as defined herein can also be a C1-C6 alkylene. The alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0091] "Cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms, preferably 3-10 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0092] "Cycloalkylalkyl" refers to a monocyclic saturated carbocyclic ring containing 3-24 carbon atoms, preferably 3-10 carbon atoms, which is further substituted with a (C1-C6)alkyl group. In general, the cycloalkylalkyl groups described herein exhibit the following formula wherein m is an integer from 1 to 6 and n is an integer from 1 to 16. The cycloalkyl ring or carbocyclic ring can optionally be substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. The substituents themselves can optionally be substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decalinyl, octahydro-lH-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-l,4-dienyl, cyclohexa-l,3-dienyl, 1,2,3,4-tetrahydronaphthyl, octahydrocyclopenta-cenyl, 3a,4,5,6,7,7a-hexahydro-lH-indenyl, 1,2,3,3a-tetrahydrocyclopenta-cenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

[0093] "Heterocyclyl," "heterocycle," or "heterocycloalkyl" means a monocyclic or polycyclic ring having from 3 to 24 atoms, preferably 3 to 10 atoms, which includes carbon and one or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the ring is not aromatic. The heterocycloalkyl ring structure can be substituted with one or more substituents. The substituents themselves can optionally be substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0094] The term "aromatic" means a planar ring having 4 n + 2 electrons in a conjugated system. As used herein, "conjugated system" means a system of connected p-orbitals with delocalized electrons, and the system can include a lone pair of electrons.

[0095] As used herein, the term "haloalkyl" means an alkyl group as defined herein which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0096] The term "haloalkoxy" as used herein refers to an alkoxy group as defined herein, which is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0097] The term "cyano" as used herein refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond, i.e., C≡N or -CN.

[0098] "Spiroalkyl" or "spirocyclyl" refers to a carbobicyclic ring system in which two rings are connected by a single atom. The rings can differ in size and nature, or be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in the spirocycle can be fused to another ring, carbocyclic, heterocyclic, aromatic, or heteroaromatic. One or more carbon atoms in the spirocycle can be replaced by a heteroatom (e.g., O, N, S, or P). (C3-C 12 )spiroalkyl is a spirocycle containing 3 to 12 carbon atoms. One or more carbon atoms can be replaced by a heteroatom.

[0099] The term "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" is understood to mean a spirocycle in which at least one ring is a heterocycle (e.g., at least one ring is furanyl, morpholinyl, or piperidinyl).

[0100] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present disclosure, such a solvent can not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are commonly referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing variable amounts of water.

[0101] The term "isomer" refers to compounds having the same composition and molecular weight, but differing in physical and / or chemical properties. Structural differences can be in constitution (geometric isomers) or in the ability to rotate plane-polarized light (stereoisomers). With respect to stereoisomers, the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0102] The present disclosure also encompasses isotopically-labelled compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II) (e.g., having one or more atoms replaced by an isotope such as a deuterium (2H) or tritium (3H) atom). 2 H and 14those labeled with deuterium (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred. Furthermore, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and hence can be preferred in some circumstances. Isotopically-labeled compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II) can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent.

[0103] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0104] A "patient" or "subject" is a mammal, for example, a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. Preferably, the mammal is a human.

[0105] "Effective amount" when used in connection with a compound means an amount or a dose of such compound, which when administered to a patient, either as a single dose or as multiple doses, provides the desired effect in the patient receiving diagnosis or treatment. An effective amount can be determined by a person skilled in the art by using known techniques and by observing results obtained under analogous circumstances. In determining an effective amount for a patient, the attending diagnostician considers a number of factors, including, but not limited to: the species of the patient; its size, age, and general health condition; the specific disease or disorder involved; the degree or severity of the disease or disorder; the individual patient's response to treatment; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0106] The term "carrier" as used in the present disclosure encompasses carriers, excipients, and diluents, and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

[0107] The term "treatment" with respect to a subject includes inhibiting, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

[0108] The term“disorder” is used in the present disclosure to refer to the terms disease, condition, or illness and is used interchangeably therewith unless otherwise indicated.

[0109] The term“administering” as used in the present disclosure means either directly administering a disclosed compound or a pharmaceutically acceptable salt of a disclosed compound or composition to a subject, or administering to the subject a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition, which can form an equivalent amount of the active compound in the subject in vivo.

[0110] The term“prodrug” as used in the present disclosure means a compound that can be converted in vivo to a disclosed compound through metabolic processes (e.g., through hydrolysis).

[0111] The term“salt” refers to a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form an acid addition salt or by the addition of a pharmaceutically acceptable base to form a base addition salt. Salt can also be formed simultaneously upon deprotection of a nitrogen or oxygen. Pharmaceutically acceptable salts and common methodologies for preparing them are well known in the art (see, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use. (2nd Revised Edition. Wiley-VCH, 2011); S.M. Berge, et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19 (1977). Handbook of Pharmaceutical Salts: Properties, Selection and Use Journal of Pharmaceutical Sciences ​Volume 66, Issue 1, January 1977. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium edetate, camphorsulfonates, carbonates, chlorides, citrates, clavulanates, dihydrochlorides, edetates, ethanedisulfonates, etopoates, ethanesulfonates, fumarates, gluconate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexafluorophosphate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, iodides, isothiosulfates. (nate), lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pyrate, pantothenate, phosphate / bisphosphate, picrate, polygalacturonic acid ester, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, 8-chlorotheophylline salt, toluenesulfonate, triethyl iodide, and valerate.

[0112] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II) having, for example, an acidic functional group (such as a carboxylic acid functional group) with a base.

[0113] As used in this article, the term "regulation" refers to the inhibition and / or activation of the biological activity of PI3K by a compound or substrate.

[0114] As used herein, “PI3K inhibitor” refers to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II) that inhibits PI3K and / or a composition containing a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (II).

[0115] The amount of a compound or composition described herein required to achieve a therapeutic effect can be determined empirically using routine procedures for the particular purpose. Generally, for administration of a therapeutic agent (e.g., a compound or composition of Formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (lh), or (II) described herein (and / or an additional agent)) for therapeutic purposes, the therapeutic agent is administered in a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount that is sufficient to produce a desired physiological effect, particularly for treating a disorder or disease. As used herein, an effective amount will include an amount that is sufficient to, for example, delay the progression of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of a disease), reduce or eliminate one or more symptoms or manifestations of a disorder or disease, and reverse symptoms of a disorder or disease. For example, administration of a therapeutic agent to a patient suffering from a cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a reduction in the severity or duration of symptoms associated with the disease (e.g., reduction in tumor burden, reduction in circulating tumor cells, increase in progression-free survival). Therapeutic benefit also includes arresting or slowing the progression of the underlying disease or disorder, whether or not improvement is achieved.

[0116] Compounds of the disclosure

[0117] In one aspect, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0118]

[0119] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, W, X, Y, s, and ring A are as described in the SUMMARY for Formula (I).

[0120] In one preferred embodiment of Formula (I), X is -NR 12 - or -O-; Y is -C(R 11 )2-, -O-, -NR 11 - or -S-; WR1R2is a group of the formula:

[0121]

[0122] R 10 independently at each occurrence is oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , -(CH2) n -O-(CH2CH2-O) r R 13 , C3-C 10 cycloalkyl, heterocycle, -(CH2) n -aryl or heteroaryl, wherein the cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(CH2) n -SO2R 12 , -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , or -(CH2) n -C(O)N(R 12 )2, or two R 10 , together with the atom to which they are attached, form a C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N and S, or heteroaryl, wherein the cycloalkyl, aryl, heterocycle and heteroaryl are optionally substituted with one or more oxo, =NR 12 , halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , C3-C6cycloalkyl, aryl, heteroaryl or R15 substituted; R 10 independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 ; -L1- is absent, -(CH2)-, or -(CH2)2-; u is independently at each occurrence 0, 1, 2, 3, or 4; each R3, R4, R5, and R6is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S; each R7and R8is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; at least one R9is -C(O)OR 12 and each remaining R9is independently at each occurrence oxo, =NR 11 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 , -(CH2) m -CR 13 (OH)-R 12 , - (CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m-C(O)N(OH)R 12 , -(CH2) m -SO2R 12 , -(CH2) m -SO2-OR 12 , -(CH2) m -SO2N(R 12 )2, -(CH2) m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -P(O)(OR 13 )R 12 , -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 13 , -(CH2) m -C(O)O-(CH2CH2-O) r R 13 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 , -(CH2) m -S(O)(NR 12 )-R 13 , C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, C3-C 10cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, or two R9together with the atoms to which they are attached form a C3-C 10 cycloalkyl, aryl, or heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the cycloalkyl, aryl, or heterocycle is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R 11 is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; each R 12 and R 13 independently at each occurrence is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) q -O-C(O)-(CH2) r -R 14 , -(CH2) q -NH-C(O)-(CH2) r -R 14 , -(CH2) q -O-C(O)-(CH2) r -OR 14 , -(CH2) q -NH-C(O)-(CH2) r -OR 14 , -(CH2) q -O-(CH2) r -R 14 , -(CH2) q -NH-(CH2) r -R 14 , -(CH2) q -O-(CH2) r -OR 14 , -(CH2) q -NH-(CH2) r -OR 14 , C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, -(CH2) q- aryl, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; ring A is C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from N, O, and S, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S; R 14 is two R 15 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one or more C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, or -(CH2) n -SO2R 12 ; each n, m, q, or r is independently, at each occurrence, 0, 1, 2, 3, 4, 5, or 6; and s is 1, 2, 3, 4, 5, or 6.

[0123] In another preferred embodiment of formula (I), X is -NR 12 - or -O-; Y is -C(R 11 )2-, -O-, -NR 11 - or -S-; WR1R2is a group of the formula:

[0124]

[0125] R 10 is, independently at each occurrence, oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n-C(O)OR 12 -(CH2) n -C(O)N(R 12 )2 n -SO2R 12 -(CH2) n -O-(CH2CH2-O) r R 13 C3-C 10 cycloalkyl, heterocycle, -(CH2) n -aryl or heteroaryl, wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or -(CH2) n -SO2R 12 R 10 is independently at each occurrence halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or -(CH2) n -OR 12 ; -L1- is -(CH2)- or -(CH2)2-; u is independently at each occurrence 0, 1, 2, 3 or 4; each R3, R4, R5and R6is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N and S; each R7and R8is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl or C1-C6alkoxy; at least one R9is -C(O)OR 12 and each remaining R9is independently at each occurrence oxo, =NR 11halogen, -CN, -NO2, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 , -(CH2) m -CR 13 (OH)-R 12 , -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m -C(O)N(OH)R 12 , -(CH2) m -SO2R 12 , -(CH2) m -SO2-OR 12 , -(CH2) m -SO2N(R 12 )2, -(CH2) m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -P(O)(OR 13 )R 12 , -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 13 , -(CH2) m -C(O)O-(CH2CH2-O) r R 13 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) rR 13 -(CH2) m -C(O)-NR 12 -SO2R 13 -(CH2) m -SO2NR 12 -C(O)R 13 -(CH2) m -S(O)(NR 12 )-R 13 C3-C 10 cycloalkyl, aryl, heterocycle, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C 10 cycloalkyl, aryl, heterocycle, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C 10 cycloalkyl, aryl, or heterocycle comprising 1-4 heteroatoms selected from O, N and S, wherein said cycloalkyl, aryl, or heterocycle is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R 11 is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; each R 12 and R 13 are, at each occurrence independently, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) q -O-C(O)-(CH2) r -R 14 -(CH2) q -NH-C(O)-(CH2) r -R 14 -(CH2) q -O-C(O)-(CH2) r -OR 14 -(CH2) q -NH-C(O)-(CH2) r -OR 14 -(CH2) q -O-(CH2) r -R 14, -(CH2) q -NH-(CH2) r -R 14 , -(CH2) q -O-(CH2) r -OR 14 , -(CH2) q -NH-(CH2) r -OR 14 , C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, -(CH2) q -aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O, and S, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; ring A is C3-C 10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of N, O, and S, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O, and S; R 14 is each n, m, q, or r is independently, at each occurrence, 0, 1, 2, 3, 4, 5, or 6; and s is 1, 2, 3, 4, 5, or 6.

[0126] In another aspect, the present disclosure provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0127]

[0128] wherein R8is H and R7is not H, and R1, R2, R3, R4, R5, R6, R7, R9, W, X, Y, s, and ring A are otherwise described in the SUMMARY for Formula (I).

[0129] In another aspect, the present disclosure provides a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0130]

[0131] wherein R8is H and R7is not H, and R1, R2, R3, R4, R5, R6, R7, R9, W, X, Y, s, and ring A are otherwise described in the SUMMARY for Formula (I).

[0132] In another aspect, the present disclosure provides a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0133]

[0134] Wherein R7 is not H and R1, R2, R5, R7, R9, W, X, s and cycloa are as otherwise described in the summary for formula (I), and wherein R3 is a halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 2、-(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 2. C3-C 10 Cycloalkyl, aryl, heterocyclic rings containing 1-4 heteroatoms selected from O, N and S, or heteroaryl rings containing 1-4 heteroatoms selected from O, N and S.

[0135] In another aspect, this disclosure provides compounds of formula (Id) or pharmaceutically acceptable salts thereof, or prodrugs thereof, solvates, hydrates, isomers or tautomers:

[0136]

[0137] Where R7 is not H and R1, R2, R5, R7, R9, X, W, s and ring A are as described in the overview for equation (I).

[0138] In another aspect, this disclosure provides compounds of formula (Ie) or pharmaceutically acceptable salts thereof, or prodrugs thereof, solvates, hydrates, isomers or tautomers thereof:

[0139] (Ie)

[0140] Among them, R3, R4, R5, R6, R7, R8, R9, R 10 R 12 X, Y, and ring A are as described in the overview for formula (I), W is -N-, and R1 and R2 together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally surrounded by one or more R atoms. 10 The heterocycle is not a morpholine that is optionally substituted, and s is 1, 2, 3, 4, 5 or 6.

[0141] In yet another aspect, the present disclosure provides a compound of Formula (If) or a pharmaceutically acceptable salt thereof or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0142]

[0143] wherein R3, R5, and R9are as described in the SUMMARY for Formula (I), R 10 is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , s is 0 or 1, u is 0 or 1, J is C or N, and * indicates a stereocenter.

[0144] In yet another aspect, the present disclosure provides a compound of Formula (Ig) or a pharmaceutically acceptable salt thereof or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0145]

[0146] wherein R3, R5, R9, R 10 , s is 0 or 1, u is 0, 1, or 2, J is C or N, and * indicates a stereocenter.

[0147] In yet another aspect, the present disclosure provides a compound of Formula (Ih) or a pharmaceutically acceptable salt thereof or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0148]

[0149] wherein R3, R5, R9, R 10 , s is 0 or 1, u is 0, 1, or 2, J is C or N, and * indicates a stereocenter.

[0150] In yet another aspect, the present disclosure provides a compound of Formula (II):

[0151]

[0152] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

[0153] X is -NR 12 - or -O-;

[0154] Y is -C(R 11 )2-, -O-, -NR 11 - or -S-;

[0155] W is -N-, -O-, or -S-, wherein when W is -O- or -S-, R1or R2is absent;

[0156] each R1and R2is independently absent or H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl, or

[0157] R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 ;

[0158] each R3, R4, R5, and R6is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S;

[0159] each R7and R8is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy;

[0160] each R9is independently, at each occurrence, oxo, =NR 11 halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m -SO2R 12 , -(CH2) m -SO2-OR 12 , -(CH2) m -SO2N(R 12 )2, -(CH2) m -CON(R 12 )2, -(CH2) m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 13 , -(CH2) m -C(O)O-(CH2CH2-O) r R 13 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R13 -(CH2) m -SO2NR 12 -C(O)R 13 -(CH2) m -S(O)(NR 12 )-R 13 C3-C 10 Cycloalkyl, heterocyclic rings comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl rings comprising 1-4 heteroatoms selected from N, O, and S, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups, or

[0161] The two R9 atoms, together with the atoms they are attached to, form C3-C. 10 Cycloalkyl or a heterocycle comprising 1-4 heteroatoms selected from O, N and S, wherein the cycloalkyl or heterocycle is optionally substituted by one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy groups;

[0162] Each R 10 Each time it appears, it is independently of oxo, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2). n -OR 12 -(CH2) n -N(R 12 2、-(CH2) n -C(O)R 12 -(CH2) n -C(O)OR 12 -(CH2) n -C(O)N(R 12 2、-(CH2) n -SO2R 12 C3-C 10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy groups, or

[0163] two R 10 with the atom to which they are attached to form an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are optionally substituted with one or more oxo, =NR 12 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 ;

[0164] R 11 is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl;

[0165] each R 12 and R 13 is, at each occurrence, independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) q -O-C(O)-(CH2) r -R 14 , -(CH2) q -NH-C(O)-(CH2) r -R 14 , -(CH2) q -O-C(O)-(CH2) r -OR 14 , -(CH2) q -NH-C(O)-(CH2) r -OR 14 , -(CH2) q -O-(CH2) r -R 14 , -(CH2) q -NH-(CH2) r -R 14 , -(CH2) q -O-(CH2) r -OR 14 , -(CH2) q -NH-(CH2)r -OR 14 , C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O and S;

[0166] Ring A is C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of N, O and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O and S;

[0167] R 14 is and

[0168] each n, m, q, r or s is independently at each occurrence 0, 1, 2, 3, 4, 5 or 6,

[0169] provided that when R1and R2together with the nitrogen atom to which they are attached form a heterocycle, wherein the heterocycle is morpholine and R5is -CH3, then (a) the morpholine is substituted or (b) Ring A is not phenyl.

[0170] In preferred embodiment (1) of formula (I), (la), (lb) or (II), s is at least 1 and at least one R9is -C(O)OR 12 .

[0171] In preferred embodiment (2) of formula (I), (la), (lb) or (II), W is -N-, and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, wherein the heterocycle is optionally substituted with one or more R 10 , and wherein the heterocycle is not optionally substituted morpholine.

[0172] In preferred embodiment (3) of formula (I), (la), (lb) or (II), s is at least 1, at least one R9is -C(O)OR 12 , W is -N-, and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N and S, wherein the heterocycle is optionally substituted with one or more R 10 , and wherein the heterocycle is not optionally substituted morpholine.

[0173] It is understood that for a compound of formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (II), R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R13 , R 14 , X, Y, W, s, and ring A can each be selected from the groups described herein, and any group described herein for R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , any group described for any one of X, Y, W, s, and ring A can be combined with any group described herein for R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , any group described for the remaining one or more of X, Y, W, s, and ring A.

[0174] In one embodiment of a compound of Formula (I), (la), (lb), (le), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, Y is -O-.

[0175] In another embodiment of a compound of Formula (I), (la), (lb), (le), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is H.

[0176] In another embodiment of a compound of Formula (I), (la), (lb), (le), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole; more preferably, R3is -CN or C1-C3alkyl; most preferably, R3is -CN or methyl.

[0177] In another embodiment of a compound of Formula (I), (la), (lb), (le), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R4is H.

[0178] In another embodiment of the compound of Formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; more preferably, R5is H, halogen, methyl, or trifluoromethyl.

[0179] In another embodiment of the compound of Formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R6is H.

[0180] In another embodiment of the compound of Formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, and R4is H; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, and R4is H; more preferably, R3is -CN or C1-C3alkyl, and R4is H; most preferably, R3is -CN or methyl, and R4is H.

[0181] In another embodiment of the compound of Formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R4is H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3is -CN, C1-C3alkyl, -(CH2) m-OH, cyclopropyl or isoxazole, R4 is H, and R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; more preferably, R3 is -CN or C1-C3 alkyl, R4 is H, and R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; most preferably, R3 is -CN or methyl, R4 is H, and R5 is H, halogen, methyl or trifluoromethyl.

[0182] In another embodiment of a compound of formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or -(CH2). m -OR 12 -(CH2) m -C(O)R 12 C3-C 10 The aryl group is a cycloalkyl group, an aryl group, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein R4 and R6 are each H; preferably, R3 is -CN, C1-C3 alkyl, or -(CH2). m -OH, cyclopropyl or isoxazole, and R4 and R6 are each H; more preferably, R3 is -CN or C1-C3 alkyl, and R4 and R6 are each H; most preferably, R3 is -CN or methyl, and R4 and R6 are each H.

[0183] In another embodiment of a compound of formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or -(CH2). m -OR 12 -(CH2) m -C(O)R 12 C3-C 10 The R5 is a cycloalkyl, aryl, or 5-6 heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, and R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; preferably, R3 is -CN, C1-C3 alkyl, or -(CH2). m -OH, cyclopropyl or isoxazole, and R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; more preferably, R3 is -CN or C1-C3 alkyl, and R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; most preferably, R3 is -CN or methyl, and R5 is H, halogen, methyl or trifluoromethyl.

[0184] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, and R6is H; more preferably, R3is -CN or C1-C3alkyl, and R6is H; most preferably, R3is -CN or methyl, and R6is H.

[0185] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and R6is H; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and R6is H; more preferably, R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, and R6is H; most preferably, R3is -CN or methyl, R5is H, halogen, methyl, or trifluoromethyl, and R6is H.

[0186] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3and R4are each H.

[0187] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3and R4are each H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3and R4are each H, and R5is H, halogen, methyl, or trifluoromethyl.

[0188] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3, R4, and R6are each H.

[0189] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3is H, and R5is H, halogen, methyl, or trifluoromethyl.

[0190] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3and R6are each H.

[0191] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3and R6are each H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3and R6are each H, and R5is H, halogen, methyl, or trifluoromethyl.

[0192] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R4is H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R5is H, halogen, methyl, or trifluoromethyl.

[0193] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and R6is H; preferably, R5is H, halogen, methyl, or trifluoromethyl, and R6is H.

[0194] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and R4and R6are each H; preferably, R5is H, halogen, methyl, or trifluoromethyl, and R4and R6are each H.

[0195] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R4and R6are each H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R4and R6are each H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; more preferably, R3is -CN or C1-C3alkyl, R4and R6are each H, and R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl; most preferably; R3is -CN or methyl, R4and R6are each H, and R5is H, halogen, methyl, or trifluoromethyl.

[0196] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3, R4, and R6are each H, and R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R3, R4, and R6are each H, and R5is H, halogen, methyl, or trifluoromethyl.

[0197] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, X is -NR 12 -, preferably -NH-.

[0198] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7 is C1-C6 alkyl or C1-C6 haloalkyl. In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7 is C1-C3 alkyl (preferably methyl).

[0199] In another embodiment of the compound of Formula (I), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R8 is H.

[0200] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7 is C1-C6 alkyl or C1-C6 haloalkyl, and X is -NR 12 -, preferably -NH-. In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7 is C1-C3 alkyl (preferably methyl) and X is -NR 12 -, preferably -NH-.

[0201] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R8 is H and X is -NR 12 -, preferably -NH-.

[0202] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C6alkyl or C1-C6haloalkyl, and R8is H. In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C3alkyl (preferably methyl) and R8is H.

[0203] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C6alkyl or C1-C6haloalkyl, R8is H, and X is -NR 12 -, preferably -NH-. In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C3alkyl (preferably methyl), R8is H, and X is -NR 12 -, preferably -NH-.

[0204] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C3alkyl. In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C3alkyl, preferably R7is methyl.

[0205] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, each R9is, at each occurrence, independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m -SO2R 12 , -(CH2) m -SO2N(R 12 )2, -(CH2) m-CON(R 12 )2, -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 , C3-C m cycloalkyl, or tetrazole, and each R 12 and R m is, at each occurrence, independently H, C1-C6 alkyl, C1-C6 haloalkyl, or -(CH2) 12 -phenyl.

[0206] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, each R9is, at each occurrence, independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) m -C(O)OR 12 , -(CH2) m -SO2R 12 , -(CH2) m -CON(R 12 )2, -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 , C3-C 10 cycloalkyl, or tetrazole, and each R 12 and R 13 is, at each occurrence, independently H, C1-C6 alkyl, C1-C6 haloalkyl, or -(CH2) q -phenyl.

[0207] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R9is -C(O)OR 12 or -CON(R 12 )2, preferably -C(O)OH or -CONHR 12 , most preferably -C(O)OH.

[0208] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is phenyl, pyridine, pyridazine, pyrimidine, thiophene, furan, pyrazole, thiazole, imidazole, isoxazole, oxadiazole, indazole, benzothiophene, benzoxazole, benzoimidazole, isoindole, indene, or quinazoline; each of which is optionally substituted with (R9) s .

[0209] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is phenyl, pyridine, pyrimidine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s . In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is phenyl, pyridine, pyrimidine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OR 12 or -CON(R 12 )2, preferably -C(O)OH or -CONHR 12 , most preferably -C(O)OH.

[0210] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0211]

[0212]

[0213] wherein R 9a is, at each occurrence, independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C 10 cycloalkyl, v is 0, 1, 2, 3, or 4, w is 0, 1, 2, or 3, x is 0, 1, or 2, y is 0 or 1, z is 0, 1, 2, or 3, and R9is -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m-SO2R 12 -(CH2) m -SO2N(R 12 2、-(CH2) m -CON(R 12 2、-(CH2) m -C(O)-NR 12 -SO2R 13 -(CH2) m -SO2NR 12 -C(O)R 13 Or a heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups; preferably, R9 is -C(O)OR 12 or -C(O)NHR 12 Most preferably, R9 is -C(O)OH.

[0214] In another embodiment of a compound of formula (I), (Ia), (Ib), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the following formula:

[0215]

[0216] Where R 9a Each time it appears, it is independently a halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C 10 Cycloalkyl, v is 0, 1, 2, 3 or 4, w is 0, 1, 2 or 3, x is 0, 1 or 2, y is 0 or 1, z is 0, 1, 2 or 3, and R9 is -(CH2). m -C(O)OR 12 -(CH2) m -C(O)N(R 12 2、-(CH2) m -SO2R 12 -(CH2) m -SO2N(R 12 2、-(CH2) m -CON(R 12 2、-(CH2) m -C(O)-NR 12 -SO2R 13 -(CH2) m -SO2NR 12-C(O)R 13 , or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; preferably, R9is -C(O)OR 12 or -C(O)NHR 12 . Most preferably, R9is -C(O)OH.

[0217] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is phenyl, pyridine, pyrimidine, or benzothiophene, each of which is optionally substituted with (R9) s , preferably ring A is a group of the formula:

[0218]

[0219] wherein R9is -C(O)OR 12 ; R 9a is H, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, 2, 3, or 4, w is 0, 1, 2, or 3, x is 0, 1, or 2, y is 0 or 1, and z is 0, 1, 2, or 3; preferably, R9is -C(O)OH, R 9a is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2.

[0220] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0221]

[0222] wherein R9is -C(O)OR 12 ; R 9a is H, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, 2, 3, or 4, w is 0, 1, 2, or 3, x is 0, 1, or 2, y is 0 or 1, and z is 0, 1, 2, or 3; preferably, R9is -C(O)OH, R 9ahalogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2.

[0223] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0224]

[0225] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1.

[0226] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0227]

[0228] wherein R 9a is halogen or trifluoromethyl, preferably chloro.

[0229] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, W is -N-, and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with 0, 1, 2, 3, 4, or 5 R 10 , preferably 0, 1, 2, 3, or 4 R 10 .

[0230] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, W is -N-, and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 , and two R 10 together with the atoms to which they are attached form a C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with one or more oxo, =NR 12Halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 -(CH2) n -N(R 12 2、-(CH2) n -C(O)R 12 -(CH2) n -C(O)OR 12 -(CH2) n -C(O)N(R 12 2、-(CH2) n -SO2R 12 phenyl, C3-C6 cycloalkyl or R 15 replace.

[0231] In another embodiment of the compound of formula (I), (Ia), (Ib), (Ie), or (II), or its pharmaceutically acceptable salt, or its prodrug, solvate, hydrate, isomer, or tautomer, W is -N-, and R1 and R2 together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally surrounded by one or more R... 10 Replace, and both R 10 Together with the atoms they are attached to, they form a 4-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally bonded by one or more halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl, heteroaryl, or R. 15 replace.

[0232] In another embodiment of the compound of formula (I), (Ia), (Ib), (Ie), or (II), or its pharmaceutically acceptable salt, or its prodrug, solvate, hydrate, isomer, or tautomer, W is -N-, and R1 and R2 together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally surrounded by one or more R... 10 Replace; two Rs 10 Together with the atoms to which they are attached, they form aryl or heteroaryl groups, wherein the aryl and heteroaryl groups are optionally oxidized by one or more oxygen-, =NR 12 Halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 -(CH2) n -N(R 12)2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , phenyl, C3-C6cycloalkyl, or R 15 substituted, and optionally two R 10 together with the atom to which they are attached form an optionally substituted C3-C6cycloalkyl. n -OR 12 10 .

[0233] In another embodiment of the compound of Formula (I), (la), (lb), (Ie), or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0234]

[0235]

[0236] wherein R 10 independently at each occurrence is oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , -(CH2) n -O-(CH2CH2-O) r R 13 , C3-C 10 cycloalkyl, heterocycle, -(CH2) n ​-aryl or heteroaryl, wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or -(CH2) n -SO2R 12 substituted; R 10a independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, 2, 3 or 4. Preferably, R 10 is halogen, C1-C6alkyl, C1-C6haloalkyl or phenyl optionally substituted with halogen, -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1 or 2.

[0237] In another embodiment of the compound of Formula (I), (Ia), (Ib), (Ie) or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0238]

[0239] wherein R 10 independently at each occurrence is oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , -(CH2) n -O-(CH2CH2-O) r R 13 , C3-C 10 cycloalkyl, heterocycle, -(CH2) n- aryl or heteroaryl, wherein said cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy or -(CH2) n - SO2R 12 ; R 10a independently at each occurrence is halogen, -CN, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy or -(CH2) n - OR 12 ; -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, 2, 3 or 4. Preferably, R 10 is halogen, Ci-C6alkyl, Ci-C6haloalkyl or phenyl optionally substituted with halogen, -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1 or 2.

[0240] In another embodiment of the compound of Formula (I), (la), (lb), (Ie) or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0241]

[0242] wherein R 10 is independently at each occurrence halogen, Ci-C6alkyl, Ci-C6haloalkyl or phenyl optionally substituted with halogen; R 10 independently at each occurrence is halogen, -CN, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy or -(CH2) n - OR 12 , and -L1- is -(CH2)- or -(CH2)2-.

[0243] In another embodiment of the compound of Formula (I), (la), (lb), (Ie) or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0244]

[0245]

[0246] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0247] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C6alkyl or C1-C6haloalkyl; preferably, R7is C1-C3alkyl; most preferably methyl.

[0248]

[0249] R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and -X- is -NR 12 -; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and -X- is -NH-; more preferably, R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, C1-C3alkyl, and -X- is -NH-; most preferably, R3is -CN or methyl, R5is H, halogen, methyl, or trifluoromethyl, and -X- is -NH-.

[0250] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C6alkyl or C1-C6haloalkyl; preferably, R7is C1-C3alkyl; most preferably methyl.

[0251] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, and -X- is -NR 12 -; preferably, R3is -CN, C1-C3alkyl, -(CH2) m-OH, cyclopropyl or isoxazole, R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy, R7 is C1-C6 alkyl or C1-C6 haloalkyl, and -X- is -NH-; more preferably, R3 is -CN or C1-C3 alkyl, R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, R7 is C1-C3 alkyl, and -X- is -NH-; most preferably, R3 is -CN or methyl, R5 is H, halogen, methyl or trifluoromethyl, R7 is methyl, and -X- is -NH-.

[0252] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2) s s is at least 1 and at least one substituent R9 is -C(O)OR 12 or -CON(R 12 )2, preferably -C(O)OH or -CONHR 12 , most preferably -C(O)OH.

[0253] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy, R7 is C1-C6 alkyl or C1-C6 haloalkyl, -X- is -NR 12 and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s s is at least 1 and at least one substituent R9 is -C(O)OR 12 or -CON(R 12 )2; preferably, R3 is -CN, C1-C3 alkyl, -(CH2) m-OH, cyclopropyl or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH or -CONHR 12 ; more preferably, R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH; most preferably, R3is -CN or methyl, R5is H, halogen, methyl or trifluoromethyl, R7is methyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH.

[0254] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0255]

[0256] wherein R9is -C(O)OH, R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1.

[0257] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0258]

[0259] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1.

[0260] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0261]

[0262] wherein R 9a is halogen or trifluoromethyl; preferably R 9a is chloro.

[0263] In another embodiment of the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, and ring A is a group of the formula: 12

[0264]

[0265] wherein R9is -C(O)OH, R 9a is independently at each occurrence halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2; preferably R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, and ring A is a group of the formula:

[0266]

[0267] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1; more preferably R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH-, and ring A is a group of the formula:

[0268]

[0269] wherein R 9a is halogen or trifluoromethyl, preferably R​9a is chloro; most preferably, R3is -CN or methyl, R5is H, halogen, methyl or trifluoromethyl, R7is methyl, -X- is -NH- and ring A is a group of the formula:

[0270]

[0271] wherein R 9a is halogen or trifluoromethyl, preferably, R 9a is chloro.

[0272] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 , and two R 10 together with the atom to which they are attached form a 4-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, aryl, or heteroaryl, or R 15 .

[0273] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0274]

[0275]

[0276] wherein R 10 is, at each occurrence, independently halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , -(CH2) n -O-(CH2CH2-O)r R 13 , C3-C 10 cycloalkyl, heterocycle, -(CH2) n -aryl or heteroaryl, wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or -(CH2) n -SO2R 12 ; R 10a is independently at each occurrence halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2- and u is independently at each occurrence 0, 1, 2, 3 or 4. Preferably, R 10 is halogen, C1-C6alkyl, C1-C6haloalkyl or phenyl optionally substituted with halogen, -L1- is -(CH2)- or -(CH2)2- and u is independently 0, 1 or 2.

[0277] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0278]

[0279] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0280] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3is -CN, C1-C6alkyl, C1-C6haloalkyl, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10 cycloalkyl, aryl or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NR 12 - and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N and S, wherein said heterocycle is optionally substituted with one or more R 10 , and two R10 with the atom to which they are attached form a 4-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, aryl, heteroaryl, or R 15 ; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH- and WR1R2is a group of the formula:

[0281]

[0282] wherein R 10 independently at each occurrence is halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R 10 independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; most preferably, R3is -CN or methyl, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, -X- is -NH- and WR1R2is a group of the formula:

[0283]

[0284]

[0285] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0286] independently at each occurrence is halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R m -OR 12 , -(CH2) m -C(O)R 12 , C3-C 10cycloalkyl, aryl or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N and S, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NR 12 -, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s , where s is at least 1 and at least one substituent R9is -C(O)OR 12 or -CON(R 12 )2and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 , and two R 10 together with the atom to which they are attached form a 4-6 membered heterocyclic ring comprising 1-4 heteroatoms selected from O, N and S, wherein the heterocyclic ring is optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, aryl or heteroaryl or R 15 ; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s , where s is at least 1 and at least one substituent R9is -C(O)OH or -CONHR 12 ; and WR1R2is a group of the formula:

[0287]

[0288]

[0289] wherein R 10 is independently at each occurrence halogen, C1-C6alkyl, C1-C6haloalkyl or phenyl optionally substituted with halogen, R 10a is independently at each occurrence halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or -(CH2) n -OR 12, -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R3 is -CN or C1-C3 alkyl, R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R7 is C1-C3 alkyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9 is -C(O)OH and WR1R2 is a group of the formula:

[0290]

[0291] wherein R 10 is independently at each occurrence halogen, C1-C6 alkyl, C1-C6 haloalkyl, or phenyl optionally substituted with halogen, R 10a is independently at each occurrence halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2) n is -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; most preferably, R3 is -CN or methyl, R5 is H, halogen, methyl, or trifluoromethyl, R7 is methyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9 is -C(O)OH and WR1R2 is a group of the formula:

[0292]

[0293] wherein, -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0294] In another embodiment of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R3 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2) m is -OR 12 , -(CH2) m is -C(O)R 12 , C3-C 10 cycloalkyl, aryl, or 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, R7 is C1-C6 alkyl or C1-C6 haloalkyl, -X- is -NR12 - Ring A is a group of the formula:

[0295]

[0296] wherein R9is -C(O)OH, R 9a independently at each occurrence is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2 and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 independently at each occurrence is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2 and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 independently at each occurrence is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2 and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 15 ; preferably, R3is -CN, C1-C3alkyl, -(CH2) m -OH, cyclopropyl, or isoxazole, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, Ring A is a group of the formula:

[0297]

[0298] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1 and WR1R2is a group of the formula:

[0299]

[0300] wherein R 10 independently at each occurrence is halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R 10a independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R3is -CN or C1-C3alkyl, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH-, Ring A is a group of the formula:

[0301]

[0302] wherein R 9a is halogen or trifluoromethyl, preferably chloro, and WR1R2is a group of the formula:

[0303]

[0304] wherein R 10 independently at each occurrence is halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R 10a independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; most preferably, R3is -CN or methyl, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, -X- is -NH-, and ring A is a group of the formula:

[0305]

[0306] wherein R 9a is halogen or trifluoromethyl, preferably chloro, and WR1R2is a group of the formula:

[0307]

[0308]

[0309] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0310] In another embodiment of the compound of Formula (Id), or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0311]

[0312] wherein R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, and -X- is -NR 12 ; preferably, R5is H, halogen, methyl, or trifluoromethyl, and -X- is -NH-.

[0313] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R7is C1-C6alkyl or C1-C6haloalkyl; preferably, R7is C1-C3alkyl (most preferably methyl).

[0314] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, and -X- is -NR 12 ; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-.

[0315] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, and -X- is -NR s ; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-. 12 or -CON(R 12 )2; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-. 12 , most preferably -C(O)OH.

[0316] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, and -X- is -NR 12 ; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-. s or -CON(R 12 )2; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-. 12 In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, and -X- is -NR s ; preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; more preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, and -X- is -NH-. 12; more preferably, R5is H, halogen, C1-C6alkyl or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s ; most preferably, R5is H, halogen, methyl or trifluoromethyl, R7is methyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s ; most preferably, R5is H, halogen, methyl or trifluoromethyl, R7is methyl, -X- is -NH- and ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9)

[0317] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0318]

[0319] wherein R9is, at each occurrence, independently -C(O)OH, R 9a is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy or C3-C5cycloalkyl, v is 0, 1 or 2, w is 0, 1 or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1 or 2.

[0320] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0321]

[0322] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1.

[0323] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, ring A is a group of the formula:

[0324]

[0325] wherein R 9a is halogen or trifluoromethyl, preferably chloro.

[0326] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, and ring A is a group of the formula: 12 In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, and ring A is a group of the formula:

[0327]

[0328] wherein R9is, at each occurrence, independently -C(O)OH, R 9a is halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2; preferably, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH- and ring A is a group of the formula:

[0329]

[0330] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1; more preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH- and ring A is a group of the formula:

[0331]

[0332] wherein R 9a is halogen or trifluoromethyl, preferably chloro; most preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, -X- is -NH-, and ring A is a group of the formula:

[0333]

[0334] wherein R 9a is halogen or trifluoromethyl, preferably chloro.

[0335] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10Together with the atoms they are attached to, they form a 4-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally bonded by one or more halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl or heteroaryl, or R. 15 replace.

[0336] In another embodiment of the compound of formula (Id) or its pharmaceutically acceptable salt or its prodrug, solvate, hydrate, isomer or tautomer, WR1R2 is a group of the following formula:

[0337]

[0338] Where R 10 Each time it appears, it is independently a halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2). n -OR 12 -(CH2) n -N(R 12 2、-(CH2) n -C(O)R 12 -(CH2) n -C(O)OR 12 -(CH2) n -C(O)N(R 12 2、-(CH2) n -SO2R 12 -(CH2) n -O-(CH2CH2-O) r R 13 C3-C 10 Cycloalkyl, heterocyclic, -(CH2) n -aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -(CH2). n -SO2R 12 Replace; R 10a Each time it appears, it is independently a halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2). n -OR 12 -L1- is -(CH2)- or -(CH2)2-, and u is independently 0, 1, 2, 3, or 4 each time it appears. Preferably, R 10 It is a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a phenyl group optionally substituted with a halogen, R10a independently at each occurrence is halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently 0, 1, or 2.

[0339] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, WR1R2is a group of the formula:

[0340]

[0341] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0342] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, R7is C1-C6 alkyl or C1-C6 haloalkyl, -X- is -NH- and WR1R2is a group of the formula: 12 and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 together with the atom to which they are attached form a 4-6 membered heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, wherein the heterocycle is optionally substituted with one or more halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl, or heteroaryl or R 10 together with the atom to which they are attached form a 4-6 membered heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, wherein the heterocycle is optionally substituted with one or more halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl, or heteroaryl or R 15 In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, R7is C1-C6 alkyl or C1-C6 haloalkyl, -X- is -NH- and WR1R2is a group of the formula:

[0343]

[0344] wherein R 10 independently at each occurrence is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or phenyl optionally substituted with halogen, R 10a independently at each occurrence is halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2) n -OR 12, -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1 or 2; more preferably, R5is H, halogen, C1-C6alkyl or C1-C6haloalkyl, R7is C1-C3alkyl, and -X- is -NH-; most preferably, R5is H, halogen, methyl or trifluoromethyl, R7is methyl, -X- is -NH- and WR1R2is a group of the formula:

[0345]

[0346] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0347] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NR 12 , ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OR 12 or -CON(R 12 )2and W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 , and two R 10 together with the atom to which they are attached form a 4-6 membered heterocyclic ring comprising 1-4 heteroatoms selected from O, N and S, wherein the heterocyclic ring is optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, aryl or heteroaryl or R 15 ; preferably, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH or -CONHR 12 ; and WR1R2is a group of the formula:

[0348]

[0349] wherein R 10halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) 10a halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH and WR1R2is a group of the formula:

[0350]

[0351] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-. 10 halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) 10a halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH-, ring A is phenyl, pyridine, thiophene, pyrazole, benzothiophene, or benzoxazole, each of which is optionally substituted with (R9) s wherein s is at least 1 and at least one substituent R9is -C(O)OH and WR1R2is a group of the formula:

[0352]

[0353] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0354] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NR 12 , ring A is a group of the formula:

[0355] In another embodiment of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NR

[0356] wherein R9is independently at each occurrence -C(O)OH, R 9a halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, W is -N- and R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituents, and two R 10 together with the atom to which they are attached form a 4-6 membered heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, aryl, or heteroaryl, or R 15 ; preferably, R5is H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, R7is C1-C6alkyl or C1-C6haloalkyl, -X- is -NH-, ring A is a group of the formula:

[0357]

[0358] wherein R 9a is halogen or trifluoromethyl; v is 0 or 1; and w is 0 or 1 and WR1R2is a group of the formula:

[0359]

[0360] wherein R 10 is independently at each occurrence halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R 10a is independently at each occurrence halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; more preferably, R5is H, halogen, C1-C6alkyl, or C1-C6haloalkyl, R7is C1-C3alkyl, -X- is -NH-, ring A is a group of the formula:

[0361]

[0362] wherein R 9a is halogen or trifluoromethyl, preferably chloro, and WR1R2is a group of the formula:

[0363]

[0364] wherein R 10 independently at each occurrence is halogen, C1-C6alkyl, C1-C6haloalkyl, or phenyl optionally substituted with halogen, R 10a independently at each occurrence is halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -(CH2) n -OR 12 , -L1- is -(CH2)- or -(CH2)2-, and u is independently at each occurrence 0, 1, or 2; most preferably, R5is H, halogen, methyl, or trifluoromethyl, R7is methyl, -X- is -NH-, ring A is a group of the formula:

[0365]

[0366] wherein R 9a is halogen or trifluoromethyl, preferably chloro, and WR1R2is a group of the formula:

[0367]

[0368] wherein -L1- is -(CH2)- or -(CH2)2-, preferably -(CH2)2-.

[0369] In another embodiment of the compound of formula (If), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0370]

[0371] wherein R3is H or C1-C6alkyl, R5is halogen, C1-C6alkyl, or C1-C6haloalkyl, R9is halogen, R 10a is halogen, s is 0 or 1, u is 0 or 1, J is C or N, and the stereo center has the ( 10a )-configuration. R

[0372] In another embodiment of the compound of formula (Ig), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0373]

[0374] wherein R3is H or C1-C6alkyl, R5is halogen, C1-C6alkyl, or C1-C6haloalkyl, R9is halogen, R 10 ​independently halogen, -CN, C1-C6 alkyl or aryl, or two R 10 together with the carbon atom to which they are attached form a C3-C 10 cycloalkyl, s is 0 or 1, u is 0, 1 or 2, J is C or N, and the stereocenters have the (R)- 10 independently fluorine or methyl, or two R 10 together with the carbon atom to which they are attached form a cyclopropyl, s is 0 or 1, u is 0, 1 or 2, J is C or N, and the stereocenters have the (R)- R )-configuration.

[0375] In another embodiment of the compound of Formula (Ih), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof:

[0376]

[0377] wherein R3is H or C1-C6 alkyl, R5is halogen, C1-C6 alkyl or C1-C6 haloalkyl, R9is halogen, R 10 independently halogen, -CN, C1-C6 alkyl or aryl, or two R 10 together with the carbon atom to which they are attached form a C3-C 10 cycloalkyl, s is 0 or 1, u is 0, 1 or 2, J is C or N, and the stereocenters have the (R)- 10 independently methyl or aryl, or two R 10 together with the carbon atom to which they are attached form a cyclobutyl, s is 0 or 1, u is 0, 1 or 2, J is C or N, and the stereocenters have the (R)- R )-configuration.

[0378] In another embodiment of the compound of Formula (I), (la), (lb), (le) or (II), or a pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate, isomer, or tautomer thereof, the compound is selected from:

[0379]

[0380]

[0381]

[0382] wherein the bond at the * position represents .

[0383] Another embodiment is a compound of the formula

[0384] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0385] Another embodiment is a compound of the formula

[0386] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0387] Another embodiment is a compound of the formula

[0388] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0389] Another embodiment is a compound of the formula

[0390] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0391] Another embodiment is a compound of the formula

[0392] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0393] Another embodiment is a compound of the formula

[0394] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0395] Another embodiment is a compound of the formula

[0396] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0397] Another embodiment is a compound of the formula

[0398] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0399] Another embodiment is a compound of the formula

[0400] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0401] Another embodiment is a compound of the formula

[0402] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0403] Another embodiment is a compound of the formula

[0404] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0405] Another embodiment is a compound of the formula

[0406] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0407] Another embodiment is a compound of the formula

[0408] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0409] Another embodiment is a compound of the formula

[0410] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0411] Another embodiment is a compound of the formula

[0412] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0413] Another embodiment is a compound of the formula

[0414] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0415] Another embodiment is a compound of the formula

[0416] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0417] Another embodiment is a compound of the formula

[0418] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0419] Another embodiment is a compound of the formula

[0420] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0421] Another embodiment is a compound of the formula

[0422] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0423] Another embodiment is a compound of the formula

[0424] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0425] Another embodiment is a compound of the formula

[0426] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is a double bond. . In another embodiment, the bond at the * position is a double bond. .

[0427] Another embodiment is a compound of the formula

[0428] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0429] Another embodiment is a compound of the formula

[0430] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0431] Another embodiment is a compound of the formula

[0432] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0433] Another embodiment is a compound of the formula

[0434] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0435] Another embodiment is a compound of the formula

[0436] or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the bond at the * position is . In another embodiment, the bond at the * position is .

[0437] Embodiments in the following paragraphs refer to embodiments of compounds of Formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (lh), or (II), or a prodrug, solvate, enantiomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as applicable.

[0438] In certain embodiments, X is -NR 12 - or -O-. In certain embodiments, X is -NR 12 - In certain embodiments, X is -O-.

[0439] In certain embodiments, Y is -C(R 11 )2-, -O-, -NR 11 - or -S-.

[0440] In certain embodiments, Y is -C(R 11 )2-. In certain embodiments, Y is -O-. In certain embodiments, Y is -NR 11 - In certain embodiments, Y is -S-.

[0441] In certain embodiments, W is -O-, -N-, or -S-.

[0442] In certain embodiments, W is -O-. In certain embodiments, W is -N-. In certain embodiments, W is -S-.

[0443] In certain embodiments, each R1and R2is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) m - R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0444] In certain embodiments, each R1and R2is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) m - R12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0445] In certain embodiments, R1is absent or H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0446] In certain embodiments, R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0447] In certain embodiments, R1is absent.

[0448] In certain embodiments, R1is H.

[0449] In certain embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0450] In certain embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0451] In certain embodiments, R1is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0452] In certain embodiments, R1is C1-C6alkyl.

[0453] In certain embodiments, R1is methyl. In certain embodiments, R1is ethyl. In certain embodiments, R1is propyl. In certain embodiments, R1is n-propyl. In certain embodiments, R1is isopropyl. In certain embodiments, R1is butyl. In certain embodiments, R1is n-butyl. In certain embodiments, R1is isobutyl. In certain embodiments, R1is sec-butyl. In certain embodiments, R1is t-butyl. In certain embodiments, R1is pentyl. In certain embodiments, R1is hexyl.

[0454] In certain embodiments, R1is C2-C6alkenyl.

[0455] In certain embodiments, R1is C2alkenyl. In certain embodiments, R1is C3alkenyl. In certain embodiments, R1is C4alkenyl. In certain embodiments, R1is C5alkenyl. In certain embodiments, R1is C6alkenyl.

[0456] In certain embodiments, R1is C2-C6alkynyl.

[0457] In certain embodiments, R1is C2alkynyl. In certain embodiments, R1is C3alkynyl. In certain embodiments, R1is C4alkynyl. In certain embodiments, R1is C5alkynyl. In certain embodiments, R1is C6alkynyl.

[0458] In certain embodiments, R1is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0459] In certain embodiments, R1is C1-C6haloalkyl or C1-C6alkoxy.

[0460] In certain embodiments, R1is C1-C6haloalkyl.

[0461] In certain embodiments, R1is halomethyl. In certain embodiments, R1is haloethyl. In certain embodiments, R1is halopropyl. In certain embodiments, R1is halobutyl. In certain embodiments, R1is halopentyl. In certain embodiments, R1is halohexyl.

[0462] In certain embodiments, R1is C1-C6alkoxy.

[0463] In certain embodiments, R1is methoxy. In certain embodiments, R1is ethoxy. In certain embodiments, R1is propoxy. In certain embodiments, R1is butoxy. In certain embodiments, R1is pentoxy. In certain embodiments, R1is hexoxy.

[0464] In certain embodiments, R1is -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12, -(CH2) m -C(O)OR 12 or -(CH2) m -C(O)N(R 12 )2.

[0465] In certain embodiments, R1is -(CH2) m -R 12 , -(CH2) m -OR 12 or -(CH2) m -N(R 12 )2.

[0466] In certain embodiments, R1is -(CH2) m -R 12 . In certain embodiments, R1is -(CH2) m -OR 12 . In certain embodiments, R1is -(CH2) m -N(R 12 )2.

[0467] In certain embodiments, R1is -R 12 . In certain embodiments, R1is -CH2-R 12 . In certain embodiments, R1is -CH2CH2-R 12 . In certain embodiments, R1is -CH2CH2CH2-R 12 . In certain embodiments, R1is -CH2CH2CH2CH2-R 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2-R 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2-R 12 .

[0468] In certain embodiments, R1is -OR 12 . In certain embodiments, R1is -CH2-OR 12 . In certain embodiments, R1is -CH2CH2-OR 12 . In certain embodiments, R1is -CH2CH2CH2-OR 12 . In certain embodiments, R1is -CH2CH2CH2CH2-OR 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2-OR 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0469] In certain embodiments, R1is -N(R 12 )2. In certain embodiments, R1is -CH2- N(R 12 )2. In certain embodiments, R1is -CH2CH2- N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0470] In certain embodiments, R1is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0471] In certain embodiments, R1is -(CH2) m -C(O)R 12 . In certain embodiments, R1is -(CH2) m -C(O)OR 12 . In certain embodiments, R1is -(CH2) m -C(O)N(R 12 )2.

[0472] In certain embodiments, R1is -C(O)R 12 . In certain embodiments, R1is -CH2-C(O)R 12 . In certain embodiments, R1is -CH2CH2-C(O)R 12 . In certain embodiments, R1is -CH2CH2CH2-C(O)R 12 . In certain embodiments, R1is -CH2CH2CH2CH2-C(O)R 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2-C(O)R 12 . In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0473] In certain embodiments, R1is -C(O)OR 12 In certain embodiments, R1is -CH2-C(O)OR 12 . 在 In certain embodiments, R1is -CH2CH2-C(O)OR 12 In certain embodiments, R1is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R1is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R1is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0474] In certain embodiments, R1is -C(O)N(R 12 )2. In certain embodiments, R1is -CH2-C(O)N(R 12 )2. In certain embodiments, R1is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R1is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0475] In certain embodiments, R1is -CH2-C(O)NH2.

[0476] In certain embodiments, R1is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0477] In certain embodiments, R1is C3-C 10 cycloalkyl or heterocycle.

[0478] In certain embodiments, R1is aryl or heteroaryl.

[0479] In certain embodiments, R1is C3-C 10 cycloalkyl.

[0480] In certain embodiments, R1is monocyclic C3-C10 Cycloalkyl. In some embodiments, R1 is a polycyclic C3-C64 ring. 10 Cycloalkyl.

[0481] In some embodiments, R1 is a C5-C6 cycloalkyl group.

[0482] In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0483] In some implementations, R1 is a fused polycyclic C3-C 10 Cycloalkyl. In some embodiments, R1 is a bridged polycyclic C3-C... 10 Cycloalkyl. In some embodiments, R1 is C3-C. 10 Spirocycloalkyl.

[0484] In some implementations, R1 is a heterocyclic ring.

[0485] In some embodiments, R1 is a monocyclic heterocyclic ring. In some embodiments, R1 is a polycyclic heterocyclic ring.

[0486] In some embodiments, R1 is a 3-membered heterocyclic ring. In some embodiments, R1 is a 4-membered heterocyclic ring. In some embodiments, R1 is a 5-membered heterocyclic ring. In some embodiments, R1 is a 6-membered heterocyclic ring. In some embodiments, R1 is a 7-membered heterocyclic ring. In some embodiments, R1 is an 8-membered heterocyclic ring. In some embodiments, R1 is a 9-membered heterocyclic ring. In some embodiments, R1 is a 10-membered heterocyclic ring.

[0487] In some implementations, R1 is a 5-6 member heterocyclic ring.

[0488] In some implementations, R1 is a heterocycle containing 1, 2, or 3 heteroatoms.

[0489] In some embodiments, R1 is a heterocycle containing one, two, or three heteroatoms selected from N, O, and S.

[0490] In some embodiments, R1 is a heterocycle containing one, two, or three heteroatoms selected from N and O.

[0491] In some embodiments, R1 is a heterocycle containing one heteroatom selected from N and O. In some embodiments, R1 is a heterocycle containing two heteroatoms selected from N and O. In some embodiments, R1 is a heterocycle containing three heteroatoms selected from N and O.

[0492] In some implementations, R1 is an aryl group.

[0493] In some embodiments, R1 is a C6 aryl group (e.g., phenyl).

[0494] In certain embodiments, R1is heteroaryl.

[0495] In certain embodiments, R1is 5-6 membered heteroaryl.

[0496] In certain embodiments, R1is heteroaryl comprising 1, 2, or 3 heteroatoms.

[0497] In certain embodiments, R1is heteroaryl comprising 1, 2, or 3 heteroatoms selected from N, O, and S.

[0498] In certain embodiments, R1is heteroaryl comprising 1, 2, or 3 heteroatoms selected from N and O.

[0499] In certain embodiments, R1is heteroaryl comprising 1 heteroatom selected from N and O. In certain embodiments, R1is heteroaryl comprising 2 heteroatoms selected from N and O. In certain embodiments, R1is heteroaryl comprising 3 heteroatoms selected from N and O.

[0500] In certain embodiments, R1is ethyl, isobutyl, or -CH2-C(O)NH2.

[0501] In certain embodiments, R2is absent or H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0502] In certain embodiments, R2is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0503] In certain embodiments, R2is absent.

[0504] In certain embodiments, R2is H.

[0505] In certain embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0506] In certain embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0507] In certain embodiments, R2is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0508] In certain embodiments, R2is C1-C6alkyl (e.g., straight or branched chain).

[0509] In certain embodiments, R2is methyl. In certain embodiments, R2is ethyl. In certain embodiments, R2is propyl. In certain embodiments, R2is n-propyl. In certain embodiments, R2is isopropyl. In certain embodiments, R2is butyl. In certain embodiments, R2is n-butyl. In certain embodiments, R2is isobutyl. In certain embodiments, R2is sec-butyl. In certain embodiments, R2is t-butyl. In certain embodiments, R2is pentyl. In certain embodiments, R2is hexyl.

[0510] In certain embodiments, R2is C2-C6alkenyl.

[0511] In certain embodiments, R2is C2alkenyl. In certain embodiments, R2is C3alkenyl. In certain embodiments, R2is C4alkenyl. In certain embodiments, R2is C5alkenyl. In certain embodiments, R2is C6alkenyl.

[0512] In certain embodiments, R2is C2-C6alkynyl.

[0513] In certain embodiments, R2is C2alkynyl. In certain embodiments, R2is C3alkynyl. In certain embodiments, R2is C4alkynyl. In certain embodiments, R2is C5alkynyl. In certain embodiments, R2is C6alkynyl.

[0514] In certain embodiments, R2is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0515] In certain embodiments, R2is C1-C6haloalkyl or C1-C6alkoxy.

[0516] In certain embodiments, R2is C1-C6haloalkyl.

[0517] In certain embodiments, R2is halomethyl. In certain embodiments, R2is haloethyl. In certain embodiments, R2is halopropyl. In certain embodiments, R2is halobutyl. In certain embodiments, R2is halopentyl. In certain embodiments, R2is halohexyl.

[0518] In certain embodiments, R2is C1-C6alkoxy.

[0519] In certain embodiments, R2is methoxy. In certain embodiments, R2is ethoxy. In certain embodiments, R2is propoxy. In certain embodiments, R2is butoxy. In certain embodiments, R2is pentoxy. In certain embodiments, one R2is hexyloxy.

[0520] In certain embodiments, R2is -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0521] In certain embodiments, R2is -(CH2) m -R 12 , -(CH2) m -OR 12 , or -(CH2) m -N(R 12 )2.

[0522] In certain embodiments, R2is -(CH2) m -R 12 . In certain embodiments, R2is -(CH2) m -OR 12 . In certain embodiments, R2is -(CH2) m -N(R 12 )2.

[0523] In certain embodiments, R2is -CH2-R 12 . In certain embodiments, R2is -CH2CH2-R 12 . In certain embodiments, R2is -CH2CH2CH2-R 12 . In certain embodiments, R2is -CH2CH2CH2CH2-R 12 . In certain embodiments, R2is -CH2CH2CH2CH2CH2-R 12 . In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2-R 12 .

[0524] In certain embodiments, R2is -CH2-OR12 In certain embodiments, R2is -CH2CH2-OR 12 In certain embodiments, R2is -CH2CH2CH2-OR 12 In certain embodiments, R2is -CH2CH2CH2CH2-OR 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2-OR 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0525] In certain embodiments, R2is -CH2- N(R 12 )2. In certain embodiments, R2is -CH2CH2- N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0526] In certain embodiments, R2is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0527] In certain embodiments, R2is -(CH2) m -C(O)R 12 . In certain embodiments, R2is -(CH2) m -C(O)OR 12 . In certain embodiments, R2is -(CH2) m -C(O)N(R 12 )2.

[0528] In certain embodiments, R2is -CH2-C(O)R 12 . In certain embodiments, R2is -CH2CH2-C(O)R 12 . In certain embodiments, R2is -CH2CH2CH2-C(O)R 12In certain embodiments, R2is -CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0529] In certain embodiments, R2is -CH2-C(O)OR 12 In certain embodiments, R2is -CH2CH2-C(O)OR 12 In certain embodiments, R2is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R2is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0530] In certain embodiments, R2is -CH2-C(O)N(R 12 )2. In certain embodiments, R2is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R2is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0531] In certain embodiments, R2is -CH2-C(O)NH2.

[0532] In certain embodiments, R2is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0533] In certain embodiments, R2is C3-C 10 cycloalkyl, or heterocycle.

[0534] In certain embodiments, R2is aryl, or heteroaryl.

[0535] In certain embodiments, R2is C3-C 10 cycloalkyl.

[0536] In certain embodiments, R2is monocyclic C3-C 10 cycloalkyl. In certain embodiments, R2is polycyclic C3-C 10 cycloalkyl.

[0537] In certain embodiments, R2is C5-C6cycloalkyl.

[0538] In certain embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0539] In certain embodiments, R2is fused polycyclic C3-C 10 cycloalkyl. In certain embodiments, R2is bridged polycyclic C3-C 10 cycloalkyl. In certain embodiments, R2is C3-C 10 spirocycloalkyl.

[0540] In certain embodiments, R2is a heterocycle.

[0541] In certain embodiments, R2is a monocyclic heterocycle. In certain embodiments, R2is a polycyclic heterocycle.

[0542] In certain embodiments, R2is a 3-membered heterocycle. In certain embodiments, R2is a 4-membered heterocycle. In certain embodiments, R2is a 5-membered heterocycle. In certain embodiments, R2is a 6-membered heterocycle. In certain embodiments, R2is a 7-membered heterocycle. In certain embodiments, R2is a 8-membered heterocycle. In certain embodiments, R2is a 9-membered heterocycle. In certain embodiments, R2is a 10-membered heterocycle.

[0543] In certain embodiments, R2is a 5-6 membered heterocycle.

[0544] In certain embodiments, R2is a heterocycle comprising 1, 2, or 3 heteroatoms.

[0545] In certain embodiments, R2is a heterocycle comprising 1, 2, or 3 heteroatoms selected from N, O, and S.

[0546] In certain embodiments, R2is a heterocycle comprising 1, 2, or 3 heteroatoms selected from N and O.

[0547] In certain embodiments, R2is a heterocycle comprising 1 heteroatom selected from N and O. In certain embodiments, R2is a heterocycle comprising 2 heteroatoms selected from N and O. In certain embodiments, R2is a heterocycle comprising 3 heteroatoms selected from N and O.

[0548] In certain embodiments, R2is aryl.

[0549] In certain embodiments, R2is C6aryl (e.g., phenyl).

[0550] In certain embodiments, R2is heteroaryl.

[0551] In certain embodiments, R2is 5-6 membered heteroaryl.

[0552] In certain embodiments, R2is heteroaryl comprising 1, 2, or 3 heteroatoms.

[0553] In certain embodiments, R2is heteroaryl comprising 1, 2, or 3 heteroatoms selected from N, O, and S.

[0554] In certain embodiments, R2is heteroaryl comprising 1, 2, or 3 heteroatoms selected from N and O.

[0555] In certain embodiments, R2is heteroaryl comprising 1 heteroatom selected from N and O. In certain embodiments, R2is heteroaryl comprising 2 heteroatoms selected from N and O. In certain embodiments, R2is heteroaryl comprising 3 heteroatoms selected from N and O.

[0556] In certain embodiments, R2is ethyl, isobutyl, or -CH2-C(O)NH2.

[0557] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituents.

[0558] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a saturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituents. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituents.

[0559] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising 1 heteroatom which is N, wherein the heterocyclic ring is unsubstituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocyclic ring comprising one N heteroatom, wherein the heterocyclic ring is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 2 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 3 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted.

[0560] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 2 heteroatoms selected from O, N, and S, wherein the heterocycle is substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 3 heteroatoms selected from O, N, and S, wherein the heterocycle is substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a heterocycle comprising 4 heteroatoms selected from O, N, and S, wherein the heterocycle is substituted with one or more R 10 substituted.

[0561] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-10 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-9 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-8 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-7 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-6 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-5 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-10 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-9 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-8 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-7 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-6 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 4-5 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted.

[0562] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 5-6 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 5-7 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 5-8 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 5-9 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 5-10 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 6-10 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 6-9 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 6-8 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 6-7 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted.

[0563] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 7-8 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 7-9 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 7-10 membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted.

[0564] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted.

[0565] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted.

[0566] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3-15 membered saturated or partially unsaturated monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R

[0567] In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 3- to 10-membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R 10substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 12-membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 13-membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 14-membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted. In certain embodiments, R1and R2together with the nitrogen to which they are attached form a 15-membered saturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more R 10 substituted.

[0568] In certain embodiments, R3is H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, a heterocycle containing 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl containing 1-4 heteroatoms selected from O, N, and S.

[0569] In certain embodiments, R3is H.

[0570] In certain embodiments, R3is halogen, -CN, C1C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2)m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S.

[0571] In certain embodiments, R3is halogen. In certain embodiments, R3is F, Cl, Br, or I. In certain embodiments, R3is F, Cl, or Br. In certain embodiments, R3is F. In certain embodiments, R3is Cl. In certain embodiments, R3is Br. In certain embodiments, R3is I.

[0572] In certain embodiments, R3is -CN.

[0573] In certain embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S.

[0574] In certain embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0575] In certain embodiments, R3is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0576] In certain embodiments, R3is C1-C6alkyl (e.g., straight or branched chain).

[0577] In certain embodiments, R3is methyl. In certain embodiments, R3is ethyl. In certain embodiments, R3is propyl. In certain embodiments, R3is n-propyl. In certain embodiments, R3is isopropyl. In certain embodiments, R3is butyl. In certain embodiments, R3is n-butyl. In certain embodiments, R3is isobutyl. In certain embodiments, R3is sec-butyl. In certain embodiments, R3is t-butyl. In certain embodiments, R3is pentyl. In certain embodiments, R3is hexyl.

[0578] In certain embodiments, R3is C2-C6alkenyl.

[0579] In certain embodiments, R3is C2-C6alkenyl.

[0580] In certain embodiments, R3is C2-C6alkynyl.

[0581] In certain embodiments, R3is C2-C6alkynyl.

[0582] In certain embodiments, R3is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0583] In certain embodiments, R3is C1-C6haloalkyl or C1-C6alkoxy.

[0584] In certain embodiments, R3is C1-C6haloalkyl.

[0585] In certain embodiments, R3is halomethyl. In certain embodiments, R3is haloethyl. In certain embodiments, R3is halopropyl. In certain embodiments, R3is halobutyl. In certain embodiments, R3is halopentyl. In certain embodiments, R3is halohexyl.

[0586] In certain embodiments, R3is CH2F. In certain embodiments, R3is CHF2. In certain embodiments, R3is CF3.

[0587] In certain embodiments, R3is C1-C6alkoxy.

[0588] In certain embodiments, R3is methoxy. In certain embodiments, R3is ethoxy. In certain embodiments, R3is propoxy. In certain embodiments, R3is butoxy. In certain embodiments, R3is pentoxy. In certain embodiments, R3is hexyloxy.

[0589] In certain embodiments, R3is -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0590] In certain embodiments, R3is -(CH2) m -R 12 , -(CH2) m -OR 12 , or -(CH2) m -N(R 12 )2.

[0591] In certain embodiments, R3is -(CH2) m -R 12 . In certain embodiments, R3is -(CH2) m -OR 12 . In certain embodiments, R3is -(CH2) m -N(R 12 )2.

[0592] In certain embodiments, R3is -CH2-R 12In certain embodiments, R3is -R 12 In certain embodiments, R3is -CH2CH2-R 12 In certain embodiments, R3is -CH2CH2CH2-R 12 In certain embodiments, R3is -CH2CH2CH2CH2-R 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2-R 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2-R 12 .

[0593] In certain embodiments, R3is -OR 12 In certain embodiments, R3is -CH2-OR 12 In certain embodiments, R3is -CH2CH2-OR 12 In certain embodiments, R3is -CH2CH2CH2-OR 12 In certain embodiments, R3is -CH2CH2CH2CH2-OR 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2-OR 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0594] In certain embodiments, R3is -OR 12 wherein R 12 is H. In certain embodiments, R3is -OR 12 wherein R 12 is C 3-10 cycloalkyl. In certain embodiments, R3is .

[0595] In certain embodiments, R3is -N(R 12 )2. In certain embodiments, R3is -CH2- N(R 12 )2. In certain embodiments, R3is -CH2CH2- N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2CH2CH2- N(R 12)2. In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0596] In certain embodiments, R3is -N(CH3)2.

[0597] In certain embodiments, R3is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 or -(CH2) m -C(O)N(R 12 )2.

[0598] In certain embodiments, R3is -(CH2) m -C(O)R 12 In certain embodiments, R3is -(CH2) m -C(O)OR 12 In certain embodiments, R3is -(CH2) m -C(O)N(R 12 )2.

[0599] In certain embodiments, R3is -CH2-C(O)R 12 In certain embodiments, R3is -CH2CH2-C(O)R 12 In certain embodiments, R3is -CH2CH2CH2-C(O)R 12 In certain embodiments, R3is -CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0600] In certain embodiments, R3is -CH2-C(O)OR 12 In certain embodiments, R3is -CH2CH2-C(O)OR 12 In certain embodiments, R3is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R3is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R3is -CH2CH2CH2CH2CH2-C(O)OR 12In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0601] In certain embodiments, R3is -CH2-C(O)N(R 12 )2. In certain embodiments, R3is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R3is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0602] In certain embodiments, R3is -CH2-C(O)NH2.

[0603] In certain embodiments, R3is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0604] In certain embodiments, R3is C3-C 10 cycloalkyl or heterocycle.

[0605] In certain embodiments, R3is aryl or heteroaryl.

[0606] In certain embodiments, R3is C3-C 10 cycloalkyl.

[0607] In certain embodiments, R3is monocyclic C3-C 10 cycloalkyl. In certain embodiments, R3is polycyclic C3-C 10 cycloalkyl.

[0608] In certain embodiments, R3is C5-C6cycloalkyl.

[0609] In certain embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0610] In certain embodiments, R3is fused polycyclic C3-C 10 cycloalkyl. In certain embodiments, R3is bridged polycyclic C3-C 10 cycloalkyl. In certain embodiments, R3is C3-C 10 spirocycloalkyl.

[0611] In certain embodiments, R3is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0612] In certain embodiments, R3is a monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a polycyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0613] In certain embodiments, R3is a 3-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 4-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 5-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 6-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 7-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is an 8-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 9-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R3is a 10-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0614] In certain embodiments, R3is a 3-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 4-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 5-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 6-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 7-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is an 8-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 9-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 10-membered heterocycle comprising one N heteroatom.

[0615] In certain embodiments, R3is a heterocycle comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R3is a heterocycle comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R3is a heterocycle comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R3is a heterocycle comprising 4 heteroatoms selected from O, N, and S.

[0616] In certain embodiments, R3is aryl.

[0617] In certain embodiments, R3is C6aryl (e.g., phenyl).

[0618] In certain embodiments, R3is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0619] In some embodiments, R3 is a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from O, N and S.

[0620] In some embodiments, R3 is a 5-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, R3 is a 6-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, R3 is a 7-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, R3 is an 8-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, R3 is a 9-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, R3 is a 10-membered heteroaryl group containing 1-4 heteroatoms selected from O, N, and S.

[0621] In some embodiments, R3 is a heteroaryl group containing one heteroatom selected from O, N, and S. In some embodiments, R3 is a heteroaryl group containing two heteroatoms selected from O, N, and S. In some embodiments, R3 is a heteroaryl group containing three heteroatoms selected from O, N, and S. In some embodiments, R3 is a heteroaryl group containing four heteroatoms selected from O, N, and S.

[0622] In some embodiments, R3 is a monocyclic heterocyclic ring. In some embodiments, R3 is a 5-membered monocyclic heterocyclic ring. In some embodiments, R3 is... In some implementations, R4 is a 6-membered monocyclic heterocyclic ring. In some implementations, R3 is... .

[0623] In some embodiments, R4 is H, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -(CH2). m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 2、-(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 2. C3-C 10 Cycloalkyl, heterocyclic rings containing 1-4 heteroatoms selected from O, N and S, aryl, or heteroaryl rings containing 1-4 heteroatoms selected from O, N and S.

[0624] In certain embodiments, R4is H.

[0625] In certain embodiments, R4is halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0626] In certain embodiments, R4is halogen. In certain embodiments, R4is F, CI, Br, or I. In certain embodiments, R4is F, CI, or Br. In certain embodiments, R4is F. In certain embodiments, R4is CI. In certain embodiments, R4is Br. In certain embodiments, R4is I.

[0627] In certain embodiments, R4is -CN.

[0628] In certain embodiments, R4is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0629] In certain embodiments, R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0630] In certain embodiments, R4is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0631] In certain embodiments, R4is C1-C6alkyl (e.g., straight or branched chain).

[0632] In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is propyl. In certain embodiments, R4is n-propyl. In certain embodiments, R4is isopropyl. In certain embodiments, R4is butyl. In certain embodiments, R4is n-butyl. In certain embodiments, R4is isobutyl. In certain embodiments, R4is sec-butyl. In certain embodiments, R4is t-butyl. In certain embodiments, R4is pentyl. In certain embodiments, R4is hexyl.

[0633] In certain embodiments, R4is C2-C6alkenyl.

[0634] In certain embodiments, R4is C3-C6alkenyl. In certain embodiments, R4is C4-C6alkenyl. In certain embodiments, R4is C5-C6alkenyl. In certain embodiments, R4is C2-C5alkenyl. In certain embodiments, R4is C2-C4alkenyl. In certain embodiments, R4is C2-C3alkenyl. In certain embodiments, R4is C3-C4alkenyl. In certain embodiments, R4is C3-C5alkenyl. In certain embodiments, R4is C3-C6alkenyl. In certain embodiments, R4is C4-C6alkenyl. In certain embodiments, R4is C4-C5alkenyl. In certain embodiments, R4is C5-C6alkenyl.

[0635] In certain embodiments, R4is C2alkenyl. In certain embodiments, R4is C3alkenyl. In certain embodiments, R4is C4alkenyl. In certain embodiments, R4is C5alkenyl. In certain embodiments, R4is C6alkenyl.

[0636] In certain embodiments, R4is C2-C6alkynyl.

[0637] In certain embodiments, R4is C3-C6alkynyl. In certain embodiments, R4is C4-C6alkynyl. In certain embodiments, R4is C5-C6alkynyl. In certain embodiments, R4is C2-C5alkynyl. In certain embodiments, R4is C2-C4alkynyl. In certain embodiments, R4is C2-C3alkynyl. In certain embodiments, R4is C3-C4alkynyl. In certain embodiments, R4is C3-C5alkynyl. In certain embodiments, R4is C3-C6alkynyl. In certain embodiments, R4is C4-C6alkynyl. In certain embodiments, R4is C4-C5alkynyl. In certain embodiments, R4is C5-C6alkynyl.

[0638] In certain embodiments, R4is C2alkynyl. In certain embodiments, R4is C3alkynyl. In certain embodiments, R4is C4alkynyl. In certain embodiments, R4is C5alkynyl. In certain embodiments, R4is C6alkynyl.

[0639] In certain embodiments, R4is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0640] In certain embodiments, R4is C1-C6haloalkyl or C1-C6alkoxy.

[0641] In certain embodiments, R4is C1-C6haloalkyl.

[0642] In certain embodiments, R4is halomethyl. In certain embodiments, R4is haloethyl. In certain embodiments, R4is halopropyl. In certain embodiments, R4is halobutyl. In certain embodiments, R4is halopentyl. In certain embodiments, R4is halohexyl.

[0643] In certain embodiments, R4is CH2F. In certain embodiments, R4is CHF2. In certain embodiments, R4is CF3.

[0644] In certain embodiments, R4is C1-C6alkoxy.

[0645] In certain embodiments, R4is C1-C6alkoxy. In certain embodiments, R4is methoxy. In certain embodiments, R4is ethoxy. In certain embodiments, R4is propoxy. In certain embodiments, R4is butoxy. In certain embodiments, R4is pentoxy. In certain embodiments, R4is hexyloxy.

[0646] In certain embodiments, R4is -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0647] In certain embodiments, R4is -(CH2) m -R 12 , -(CH2) m -OR 12 , or -(CH2) m -N(R 12 )2.

[0648] In certain embodiments, R4is -(CH2) m -R 12 . In certain embodiments, R4is -(CH2) m -OR 12 . In certain embodiments, R4is -(CH2) m -N(R 12 )2.

[0649] In certain embodiments, R4is -R 12 . In certain embodiments, R4is -CH2-R 12 . In certain embodiments, R4is -CH2CH2-R 12 . In certain embodiments, R4is -CH2CH2CH2-R 12 . In certain embodiments, R4is -CH2CH2CH2CH2-R 12 . In certain embodiments, R4is -CH2CH2CH2CH2CH2-R12 In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2-R 12 .

[0650] In certain embodiments, R4is -OR 12 In certain embodiments, R4is -CH2-OR 12 In certain embodiments, R4is -CH2CH2-OR 12 In certain embodiments, R4is -CH2CH2CH2-OR 12 In certain embodiments, R4is -CH2CH2CH2CH2-OR 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2-OR 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0651] In certain embodiments, R4is -OR 12 wherein R 12 is H. In certain embodiments, R4is -OR 12 wherein R 12 is C 3-10 cycloalkyl. In certain embodiments, R4is .

[0652] In certain embodiments, R4is -N(R 12 )2. In certain embodiments, R4is -CH2- N(R 12 )2. In certain embodiments, R4is -CH2CH2- N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0653] In certain embodiments, R4is -N(CH3)2.

[0654] In certain embodiments, R4is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR12 or -(CH2) m -C(O)N(R 12 )2.

[0655] In certain embodiments, R4is -(CH2) m -C(O)R 12 In certain embodiments, R4is -(CH2) m -C(O)OR 12 In certain embodiments, R4is -(CH2) m -C(O)N(R 12 )2.

[0656] In certain embodiments, R4is -CH2-C(O)R 12 In certain embodiments, R4is -CH2CH2-C(O)R 12 In certain embodiments, R4is -CH2CH2CH2-C(O)R 12 In certain embodiments, R4is -CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0657] In certain embodiments, R4is -CH2-C(O)OR 12 In certain embodiments, R4is -CH2CH2-C(O)OR 12 In certain embodiments, R4is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R4is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0658] In certain embodiments, R4is -CH2-C(O)N(R 12 )2.In certain embodiments, R4is -CH2CH2-C(O)N(R 12 )2.In certain embodiments, R4is -CH2CH2CH2-C(O)N(R 12)2. In certain embodiments, R4is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R4is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0659] In certain embodiments, R4is -CH2-C(O)NH2.

[0660] In certain embodiments, R4is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0661] In certain embodiments, R4is C3-C 10 cycloalkyl or heterocycle.

[0662] In certain embodiments, R4is aryl or heteroaryl.

[0663] In certain embodiments, R4is C3-C 10 cycloalkyl.

[0664] In certain embodiments, R4is monocyclic C3-C 10 cycloalkyl. In certain embodiments, R4is polycyclic C3-C 10 cycloalkyl.

[0665] In certain embodiments, R4is C5-C6cycloalkyl.

[0666] In certain embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0667] In certain embodiments, R4is fused polycyclic C3-C 10 cycloalkyl. In certain embodiments, R4is bridged polycyclic C3-C 10 cycloalkyl. In certain embodiments, R4is C3-C 10 spirocycloalkyl.

[0668] In certain embodiments, R4is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0669] In certain embodiments, R4is a monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a polycyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0670] In certain embodiments, R4is a 3-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 4-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 5-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 6-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 7-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is an 8-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 9-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 10-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0671] In certain embodiments, R4is a 3-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is a 4-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is a 5-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is a 6-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is a 7-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is an 8-membered heterocycle comprising one N heteroatom. In certain embodiments, R4is a 9-membered heterocycle comprising one N heteroatom. In certain embodiments, R3is a 10-membered heterocycle comprising one N heteroatom.

[0672] In certain embodiments, R4is a heterocycle comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R4is a heterocycle comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R4is a heterocycle comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R4is a heterocycle comprising 4 heteroatoms selected from O, N, and S.

[0673] In certain embodiments, R4is aryl. In certain embodiments, R4is C6aryl (e.g., phenyl).

[0674] In certain embodiments, R4is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0675] In certain embodiments, R4is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0676] In certain embodiments, R4is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R4is a 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0677] In certain embodiments, R4is a heteroaryl comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R4is a heteroaryl comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R4is a heteroaryl comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R4is a heteroaryl comprising 4 heteroatoms selected from O, N, and S.

[0678] In certain embodiments, R4is a monocyclic heterocycle. In certain embodiments, R4is a 5-membered monocyclic heterocycle. In certain embodiments, R4is In certain embodiments, R4is a 6-membered monocyclic heterocycle. In certain embodiments, R4is .

[0679] In certain embodiments, R5is H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2)0-6OR5a, -(CH2)0-6 m -R 12 , -(CH2)0-6 m -OR 12 , -(CH2)0-6 m -N(R 12 )2, -(CH2)0-6 m -C(O)R 12 , -(CH2)0-6 m -C(O)OR 12 , -(CH2)0-6 m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0680] In certain embodiments, R5is H.

[0681] In certain embodiments, R5is halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S.

[0682] In certain embodiments, R5is halogen. In certain embodiments, R5is F, Cl, Br, or I. In certain embodiments, R5is F, Cl, or Br. In certain embodiments, R5is F. In certain embodiments, R5is Cl. In certain embodiments, R5is Br. In certain embodiments, R5is I.

[0683] In certain embodiments, R5is -CN.

[0684] In certain embodiments, R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S.

[0685] In certain embodiments, R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0686] In certain embodiments, R5is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0687] In certain embodiments, R5is C1-C6alkyl (e.g., straight-chained or branched).

[0688] In certain embodiments, R5is methyl. In certain embodiments, R5is ethyl. In certain embodiments, R5is propyl. In certain embodiments, R5is n-propyl. In certain embodiments, R5is isopropyl. In certain embodiments, R5is butyl. In certain embodiments, R5is n-butyl. In certain embodiments, R5is isobutyl. In certain embodiments, R5is sec-butyl. In certain embodiments, R5is t-butyl. In certain embodiments, R5is pentyl. In certain embodiments, R5is hexyl.

[0689] In certain embodiments, R5is C2-C6alkenyl.

[0690] In certain embodiments, R5is C2alkenyl. In certain embodiments, R5is C3alkenyl. In certain embodiments, R5is C4alkenyl. In certain embodiments, R5is C5alkenyl. In certain embodiments, R5is C6alkenyl.

[0691] In certain embodiments, R5is C2-C6alkynyl.

[0692] In certain embodiments, R5is C2alkynyl. In certain embodiments, R5is C3alkynyl. In certain embodiments, R5is C4alkynyl. In certain embodiments, R5is C5alkynyl. In certain embodiments, R5is C6alkynyl.

[0693] In certain embodiments, R5is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0694] In certain embodiments, R5is C1-C6haloalkyl or C1-C6alkoxy.

[0695] In certain embodiments, R5is C1-C6haloalkyl.

[0696] In certain embodiments, R5is halomethyl. In certain embodiments, R5is haloethyl. In certain embodiments, R5is halopropyl. In certain embodiments, R5is halobutyl. In certain embodiments, R5is halopentyl. In certain embodiments, R5is halohexyl.

[0697] In certain embodiments, R5is CH2F. In certain embodiments, R5is CHF2. In certain embodiments, R5is CF3.

[0698] In certain embodiments, R5is C1-C6alkoxy.

[0699] In certain embodiments, R5is C1-C6alkoxy. In certain embodiments, R5is methoxy. In certain embodiments, R5is ethoxy. In certain embodiments, R5is propoxy. In certain embodiments, R5is butoxy. In certain embodiments, R5is pentoxy. In certain embodiments, R5is hexyloxy.

[0700] In certain embodiments, R5is -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2. m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2.

[0701] In certain embodiments, R5is -(CH2) m -R 12 -(CH2) m -OR 12 -(CH2) m -N(R 12 )2.

[0702] In certain embodiments, R5is -(CH2) m-R 12 In some implementations, R5 is -(CH2). m -OR 12 In some implementations, R5 is -(CH2). m -N(R 12 )2.

[0703] In some implementations, R5 is -R 12 In some implementations, R5 is -CH2-R 12 In some implementations, R5 is -CH2CH2-R 12 In some implementations, R5 is -CH2CH2CH2-R 12 In some implementations, R5 is -CH2CH2CH2CH2-R 12 In some implementations, R5 is -CH2CH2CH2CH2CH2-R 12 In some implementations, R5 is -CH2CH2CH2CH2CH2CH2-R 12 .

[0704] In some implementations, R5 is -OR 12 In some implementations, R5 is -CH2-OR 12 In some implementations, R5 is -CH2CH2-OR 12 In some implementations, R5 is -CH2CH2CH2-OR 12 In some implementations, R5 is -CH2CH2CH2CH2-OR 12 In some implementations, R5 is -CH2CH2CH2CH2CH2-OR 12 In some implementations, R5 is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0705] In some implementations, R5 is -OR 12 , where R 12 It is H. In some implementations, R5 is -OR 12 , where R 12 It is C 3-10 Cycloalkyl. In some embodiments, R5 is... .

[0706] In some implementations, R5 is -N(R 12 2. In some implementations, R5 is -CH2-N(R 12 2. In some implementations, R5 is -CH2CH2-N(R 12)2. In certain embodiments, R5is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0707] In certain embodiments, R5is -N(CH3)2.

[0708] In certain embodiments, R5is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0709] In certain embodiments, R5is -(CH2) m -C(O)R 12 . In certain embodiments, R5is -(CH2) m -C(O)OR 12 . In certain embodiments, R5is -(CH2) m -C(O)N(R 12 )2.

[0710] In certain embodiments, R5is -CH2-C(O)R 12 . In certain embodiments, R5is -CH2CH2-C(O)R 12 . In certain embodiments, R5is -CH2CH2CH2-C(O)R 12 . In certain embodiments, R5is -CH2CH2CH2CH2-C(O)R 12 . In certain embodiments, R5is -CH2CH2CH2CH2CH2-C(O)R 12 . In certain embodiments, R5is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0711] In certain embodiments, R5is -CH2-C(O)OR 12 . In certain embodiments, R5is -CH2CH2-C(O)OR 12In certain embodiments, R5is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R5is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R5is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R5is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0712] In certain embodiments, R5is -CH2-C(O)N(R 12 )2. In certain embodiments, R5is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R5is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0713] In certain embodiments, R5is -CH2-C(O)NH2.

[0714] In certain embodiments, R5is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0715] In certain embodiments, R5is C3-C 10 cycloalkyl or heterocycle.

[0716] In certain embodiments, R5is aryl or heteroaryl.

[0717] In certain embodiments, R5is C3-C 10 cycloalkyl.

[0718] In certain embodiments, R5is monocyclic C3-C 10 cycloalkyl. In certain embodiments, R5is polycyclic C3-C 10 cycloalkyl.

[0719] In certain embodiments, R5is C5-C6cycloalkyl.

[0720] In certain embodiments, R5is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0721] In certain embodiments, R5is a fused polycyclic C3-C 10 cycloalkyl. In certain embodiments, R5is a bridged polycyclic C3-C 10 cycloalkyl. In certain embodiments, R5is a C3-C 10 spirocycloalkyl.

[0722] In certain embodiments, R5is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0723] In certain embodiments, R5is a monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a polycyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0724] In certain embodiments, R5is a 3-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 4-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 5-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 6-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 7-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is an 8-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 9-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is a 10-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0725] In certain embodiments, R5is a 3-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 4-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 5-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 6-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 7-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is an 8-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 9-membered heterocycle comprising one N heteroatom. In certain embodiments, R5is a 10-membered heterocycle comprising one N heteroatom.

[0726] In certain embodiments, R5is a heterocycle comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R5is a heterocycle comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R5is a heterocycle comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R5is a heterocycle comprising 4 heteroatoms selected from O, N, and S.

[0727] In certain embodiments, R5is aryl. In certain embodiments, R5is C6aryl (e.g., phenyl).

[0728] In certain embodiments, R5is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0729] In certain embodiments, R5is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0730] In certain embodiments, R5is 5 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is 6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is 7 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is 8 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is 9 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R5is 10 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0731] In certain embodiments, R5is heteroaryl comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R5is heteroaryl comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R5is heteroaryl comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R5is heteroaryl comprising 4 heteroatoms selected from O, N, and S.

[0732] In certain embodiments, R5is monocyclic heterocycle. In certain embodiments, R5is 5 membered monocyclic heterocycle. In certain embodiments, R5is In certain embodiments, R5is 6 membered monocyclic heterocycle. In certain embodiments, R5is .

[0733] In certain embodiments, R6is H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m-C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1 to 4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1 to 4 heteroatoms selected from O, N, and S.

[0734] In certain embodiments, R6is H.

[0735] In certain embodiments, R6is halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1 to 4 heteroatoms selected from O, N, and S, aryl, or heteroaryl comprising 1 to 4 heteroatoms selected from O, N, and S.

[0736] In certain embodiments, R6is halogen. In certain embodiments, R6is F, Cl, Br, or I. In certain embodiments, R6is F, Cl, or Br. In certain embodiments, R6is F. In certain embodiments, R6is Cl. In certain embodiments, R6is Br. In certain embodiments, R6is I.

[0737] In certain embodiments, R6is -CN.

[0738] In certain embodiments, R6is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m-C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S.

[0739] In certain embodiments, R6is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0740] In certain embodiments, R6is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0741] In certain embodiments, R6is C1-C6alkyl (e.g., straight or branched chain).

[0742] In certain embodiments, R6is methyl. In certain embodiments, R6is ethyl. In certain embodiments, R6is propyl. In certain embodiments, R6is n-propyl. In certain embodiments, R6is isopropyl. In certain embodiments, R6is butyl. In certain embodiments, R6is n-butyl. In certain embodiments, R6is isobutyl. In certain embodiments, R6is sec-butyl. In certain embodiments, R6is t-butyl. In certain embodiments, R6is pentyl. In certain embodiments, R6is hexyl.

[0743] In certain embodiments, R6is C2-C6alkenyl.

[0744] In certain embodiments, R6is C3-C6alkenyl. In certain embodiments, R6is C4-C6alkenyl. In certain embodiments, R6is C5-C6alkenyl. In certain embodiments, R6is C2-C5alkenyl. In certain embodiments, R6is C2-C4alkenyl. In certain embodiments, R6is C2-C3alkenyl. In certain embodiments, R6is C3-C4alkenyl. In certain embodiments, R6is C3-C5alkenyl. In certain embodiments, R6is C3-C6alkenyl. In certain embodiments, R6is C4-C6alkenyl. In certain embodiments, R6is C4-C5alkenyl. In certain embodiments, R6is C5-C6alkenyl.

[0745] In certain embodiments, R6is C2alkenyl. In certain embodiments, R6is C3alkenyl. In certain embodiments, R6is C4alkenyl. In certain embodiments, R6is C5alkenyl. In certain embodiments, R6is C6alkenyl.

[0746] In certain embodiments, R6is C2-C6alkynyl.

[0747] In certain embodiments, R6is C3-C6alkynyl. In certain embodiments, R6is C4-C6alkynyl. In certain embodiments, R6is C5-C6alkynyl. In certain embodiments, R6is C2-C5alkynyl. In certain embodiments, R6is C2-C4alkynyl. In certain embodiments, R6is C2-C3alkynyl. In certain embodiments, R6is C3-C4alkynyl. In certain embodiments, R6is C3-C5alkynyl. In certain embodiments, R6is C3-C6alkynyl. In certain embodiments, R6is C4-C6alkynyl. In certain embodiments, R6is C4-C5alkynyl. In certain embodiments, R6is C5-C6alkynyl.

[0748] In certain embodiments, R6is C2alkynyl. In certain embodiments, R6is C3alkynyl. In certain embodiments, R6is C4alkynyl. In certain embodiments, R6is C5alkynyl. In certain embodiments, R6is C6alkynyl.

[0749] In certain embodiments, R6is C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0750] In certain embodiments, R6is C1-C6haloalkyl or C1-C6alkoxy.

[0751] In certain embodiments, R6is C1-C6haloalkyl.

[0752] In certain embodiments, R6is halomethyl. In certain embodiments, R6is haloethyl. In certain embodiments, R6is halopropyl. In certain embodiments, R6is halobutyl. In certain embodiments, R6is halopentyl. In certain embodiments, R6is halohexyl.

[0753] In certain embodiments, R6is CH2F. In certain embodiments, R6is CHF2. In certain embodiments, R6is CF3.

[0754] In certain embodiments, R6is C1-C6alkoxy.

[0755] In certain embodiments, R6is C1-C6alkoxy. In certain embodiments, R6is methoxy. In certain embodiments, R6is ethoxy. In certain embodiments, R6is propoxy. In certain embodiments, R6is butoxy. In certain embodiments, R6is pentoxy. In certain embodiments, R6is hexyloxy.

[0756] In certain embodiments, R6is -(CH2) m -R 12 , -(CH2) m -OR 12 , -(CH2) m -N(R 12 )2, -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , or -(CH2) m -C(O)N(R 12 )2.

[0757] In certain embodiments, R6is -(CH2) m -R 12 , -(CH2) m -OR 12 , or -(CH2) m -N(R 12 )2.

[0758] In certain embodiments, R6is -(CH2) m -R 12 . In certain embodiments, R6is -(CH2) m -OR 12 . In certain embodiments, R6is -(CH2) m -N(R 12 )2.

[0759] In certain embodiments, R6is -R 12 . In certain embodiments, R6is -CH2-R 12 . In certain embodiments, R6is -CH2CH2-R 12 . In certain embodiments, R6is -CH2CH2CH2-R 12 . In certain embodiments, R6is -CH2CH2CH2CH2-R 12 . In certain embodiments, R6is -CH2CH2CH2CH2CH2-R12 In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2-R 12 .

[0760] In certain embodiments, R6is -OR 12 In certain embodiments, R6is -CH2-OR 12 In certain embodiments, R6is -CH2CH2-OR 12 In certain embodiments, R6is -CH2CH2CH2-OR 12 In certain embodiments, R6is -CH2CH2CH2CH2-OR 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2-OR 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0761] In certain embodiments, R6is -OR 12 wherein R 12 is H. In certain embodiments, R6is -OR 12 wherein R 12 is C 3-10 cycloalkyl. In certain embodiments, R6is .

[0762] In certain embodiments, R6is -N(R 12 )2. In certain embodiments, R6is -CH2- N(R 12 )2. In certain embodiments, R6is -CH2CH2- N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2- N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2CH2CH2- N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2- N(R 12 )2.

[0763] In certain embodiments, R6is -N(CH3)2.

[0764] In certain embodiments, R6is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR12 or -(CH2) m -C(O)N(R 12 )2.

[0765] In certain embodiments, R6is -(CH2) m -C(O)R 12 In certain embodiments, R6is -(CH2) m -C(O)OR 12 In certain embodiments, R6is -(CH2) m -C(O)N(R 12 )2.

[0766] In certain embodiments, R6is -CH2-C(O)R 12 In certain embodiments, R6is -CH2CH2-C(O)R 12 In certain embodiments, R6is -CH2CH2CH2-C(O)R 12 In certain embodiments, R6is -CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2-C(O)R 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0767] In certain embodiments, R6is -CH2-C(O)OR 12 In certain embodiments, R6is -CH2CH2-C(O)OR 12 In certain embodiments, R6is -CH2CH2CH2-C(O)OR 12 In certain embodiments, R6is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0768] In certain embodiments, R6is -CH2-C(O)N(R 12 )2.In certain embodiments, R6is -CH2CH2-C(O)N(R 12 )2.In certain embodiments, R6is -CH2CH2CH2-C(O)N(R 12)2. In certain embodiments, R6is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, R6is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0769] In certain embodiments, R6is -CH2-C(O)NH2.

[0770] In certain embodiments, R6is C3-C 10 cycloalkyl, heterocycle, aryl, or heteroaryl.

[0771] In certain embodiments, R6is C3-C 10 cycloalkyl or heterocycle.

[0772] In certain embodiments, R6is aryl or heteroaryl.

[0773] In certain embodiments, R6is C3-C 10 cycloalkyl.

[0774] In certain embodiments, R6is monocyclic C3-C 10 cycloalkyl. In certain embodiments, R6is polycyclic C3-C 10 cycloalkyl.

[0775] In certain embodiments, R6is C5-C6cycloalkyl.

[0776] In certain embodiments, R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0777] In certain embodiments, R6is fused polycyclic C3-C 10 cycloalkyl. In certain embodiments, R6is bridged polycyclic C3-C 10 cycloalkyl. In certain embodiments, R6is C3-C 10 spirocycloalkyl.

[0778] In certain embodiments, R6is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0779] In certain embodiments, R6is a monocyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a polycyclic heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0780] In certain embodiments, R6is a 3-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 4-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 5-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 6-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 7-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is an 8-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 9-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 10-membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0781] In certain embodiments, R6is a 3-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 4-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 5-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 6-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 7-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is an 8-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 9-membered heterocycle comprising one N heteroatom. In certain embodiments, R6is a 10-membered heterocycle comprising one N heteroatom.

[0782] In certain embodiments, R6is a heterocycle comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R6is a heterocycle comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R6is a heterocycle comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R6is a heterocycle comprising 4 heteroatoms selected from O, N, and S.

[0783] In certain embodiments, R6is aryl. In certain embodiments, R6is C6aryl (e.g., phenyl).

[0784] In certain embodiments, R6is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0785] In certain embodiments, R6is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0786] In certain embodiments, R6is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, R6is a 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0787] In certain embodiments, R6is a heteroaryl comprising 1 heteroatom selected from O, N, and S. In certain embodiments, R6is a heteroaryl comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, R6is a heteroaryl comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, R6is a heteroaryl comprising 4 heteroatoms selected from O, N, and S.

[0788] In certain embodiments, R6is a monocyclic heterocycle. In certain embodiments, R6is a 5-membered monocyclic heterocycle. In certain embodiments, R6is In certain embodiments, R6is a 6-membered monocyclic heterocycle. In certain embodiments, R6is .

[0789] In certain embodiments, each R7and R8is independently H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0790] In certain embodiments, each R7and R8is independently H.

[0791] In certain embodiments, each R7and R8is independently halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0792] In certain embodiments, R7is H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0793] In certain embodiments, R7is H.

[0794] In certain embodiments, R7is halogen. In certain embodiments, R7is F, CI, Br, or I. In certain embodiments, R7is F, CI, or Br. In certain embodiments, R7is F. In certain embodiments, R7is CI. In certain embodiments, R7is Br. In certain embodiments, R7is I.

[0795] In certain embodiments, R7is -CN.

[0796] In certain embodiments, R7is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0797] In certain embodiments, R7is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0798] In certain embodiments, R7is C1-C6alkyl (e.g., straight or branched chain).

[0799] In certain embodiments, R7is methyl. In certain embodiments, R7is ethyl. In certain embodiments, R7is propyl. In certain embodiments, R7is n-propyl. In certain embodiments, R7is isopropyl. In certain embodiments, R7is butyl. In certain embodiments, R7is n-butyl. In certain embodiments, R7is isobutyl. In certain embodiments, R7is sec-butyl. In certain embodiments, R7is t-butyl. In certain embodiments, R7is pentyl. In certain embodiments, R7is hexyl.

[0800] In certain embodiments, R7is C2-C6alkenyl.

[0801] In certain embodiments, R7is C2alkenyl. In certain embodiments, R7is C3alkenyl. In certain embodiments, R7is C4alkenyl. In certain embodiments, R7is C5alkenyl. In certain embodiments, R7is C6alkenyl.

[0802] In certain embodiments, R7is C2-C6alkynyl.

[0803] In certain embodiments, R7is C2alkynyl. In certain embodiments, R7is C3alkynyl. In certain embodiments, R7is C4alkynyl. In certain embodiments, R7is C5alkynyl. In certain embodiments, R7is C6alkynyl.

[0804] In certain embodiments, R7is C1-C6haloalkyl or C1-C6alkoxy.

[0805] In certain embodiments, R7is C1-C6haloalkyl.

[0806] In certain embodiments, R7is halomethyl. In certain embodiments, R7is haloethyl. In certain embodiments, R7is halopropyl. In certain embodiments, R7is halobutyl. In certain embodiments, R7is halopentyl. In certain embodiments, R7is halohexyl.

[0807] In certain embodiments, R7is CH2F. In certain embodiments, R7is CHF2. In certain embodiments, R7is CF3.

[0808] In certain embodiments, R7is C1-C6alkoxy.

[0809] In certain embodiments, R7is methoxy. In certain embodiments, R7is ethoxy. In certain embodiments, R7is propoxy. In certain embodiments, R7is butoxy. In certain embodiments, R7is pentoxy. In certain embodiments, R7is hexyloxy.

[0810] In certain embodiments, R8is H, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0811] In certain embodiments, R8is H.

[0812] In certain embodiments, R8is halogen. In certain embodiments, R8is F, Cl, Br, or I. In certain embodiments, R8is F, Cl, or Br. In certain embodiments, R8is F. In certain embodiments, R8is Cl. In certain embodiments, R8is Br. In certain embodiments, R8is I.

[0813] In certain embodiments, R8is -CN.

[0814] In certain embodiments, R8is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0815] In certain embodiments, R8is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0816] In certain embodiments, R8is C1-C6alkyl (e.g., straight-chained or branched).

[0817] In certain embodiments, R8is methyl. In certain embodiments, R8is ethyl. In certain embodiments, R8is propyl. In certain embodiments, R8is n-propyl. In certain embodiments, R8is isopropyl. In certain embodiments, R8is butyl. In certain embodiments, R8is n-butyl. In certain embodiments, R8is isobutyl. In certain embodiments, R8is sec-butyl. In certain embodiments, R8is t-butyl. In certain embodiments, R8is pentyl. In certain embodiments, R8is hexyl.

[0818] In certain embodiments, R8is C2-C6alkenyl.

[0819] In certain embodiments, R8is C2alkenyl. In certain embodiments, R8is C3alkenyl. In certain embodiments, R8is C4alkenyl. In certain embodiments, R8is C5alkenyl. In certain embodiments, R8is C6alkenyl.

[0820] In certain embodiments, R8is C2-C6alkynyl.

[0821] In certain embodiments, R8is C2alkynyl. In certain embodiments, R8is C3alkynyl. In certain embodiments, R8is C4alkynyl. In certain embodiments, R8is C5alkynyl. In certain embodiments, R8is C6alkynyl.

[0822] In certain embodiments, R8is C1-C6haloalkyl or C1-C6alkoxy.

[0823] In certain embodiments, R8is C1-C6haloalkyl.

[0824] In certain embodiments, R8is halomethyl. In certain embodiments, R8is haloethyl. In certain embodiments, R8is halopropyl. In certain embodiments, R8is halobutyl. In certain embodiments, R8is halopentyl. In certain embodiments, R8is halohexyl.

[0825] In certain embodiments, R8is CH2F. In certain embodiments, R8is CHF2. In certain embodiments, R8is CF3.

[0826] In certain embodiments, R8is C1-C6alkoxy.

[0827] In certain embodiments, R8is methoxy. In certain embodiments, R8is ethoxy. In certain embodiments, R8is propoxy. In certain embodiments, R8is butoxy. In certain embodiments, R8is pentoxy. In certain embodiments, R8is hexoxy.

[0828] In certain embodiments, at least one R9is oxo, =NR 11 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 , -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2, -(CH2) m -SO2R 12 , -(CH2) m -SO2-OR 12 , -(CH2) m -SO2N(R 12 )2, -(CH2) m -CON(R 12 )2, -(CH2) m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 12 , -(CH2) m -C(O)O-(CH2CH2-O) r R 12 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R13 -(CH2) m -SO2NR 12 -C(O)R 13 -(CH2) m -S(O)(NR 12 )-R 13 C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) 10 C3-C6cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, aryl, or 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from the group consisting of N, O, and S.

[0829] In certain embodiments, at least one R9is oxo, =NR 11 halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) m -N(R 12 )2, -(CH2) m -OR 12 -(CH2) m -C(O)R 12 -(CH2) m -C(O)OR 12 -(CH2) m -C(O)N(R 12 )2, -(CH2) m -SO2R 12 -(CH2) m -SO2-OR 12 -(CH2) m -SO2N(R 12 )2, -(CH2) m -CON(R 12 )2, -(CH2) m -P(O)(OR 12 )2, -(CH2) m -P(O)(R 12 )2, -(CH2) m -B(OH)2, -(CH2) m -B(R 12 )2, -(CH2) m -O-(CH2CH2-O) r R 13 -(CH2) m -NR 12 -(CH2CH2-O) r R 13 -(CH2) m -C(O)-(CH2CH2-O)r R 12 , -(CH2) m -C(O)O-(CH2CH2-O) r R 12 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 , -(CH2) m -S(O)(NR 12 )-R 13 , C3-C 10 cycloalkyl, heterocycle, aryl, or 5-6 membered heteroaryl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. 10 cycloalkyl, heterocycle, aryl, or 5-6 membered heteroaryl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0830] In certain embodiments, at least one R9is oxo, =NR 11 , halogen, -CN, or -NO2.

[0831] In certain embodiments, at least one R9is oxo.

[0832] In certain embodiments, at least one R9is =NR 11 .

[0833] In certain embodiments, at least one R9is halogen. In certain embodiments, at least one R9is F, Cl, Br, or I. In certain embodiments, at least one R9is F, Cl, or Br. In certain embodiments, R9is F. In certain embodiments, R9is Cl. In certain embodiments, R9is Br. In certain embodiments, R9is I.

[0834] In certain embodiments, at least one R9is -CN.

[0835] In certain embodiments, at least one R9is NO2.

[0836] In certain embodiments, at least one R9is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0837] In certain embodiments, R9is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0838] In certain embodiments, R9is C1-C6alkyl (e.g., straight or branched chain).

[0839] In certain embodiments, R9is methyl. In certain embodiments, R9is ethyl. In certain embodiments, R9is propyl. In certain embodiments, R9is n-propyl. In certain embodiments, R9is isopropyl. In certain embodiments, R9is butyl. In certain embodiments, R9is n-butyl. In certain embodiments, R9is isobutyl. In certain embodiments, R9is sec-butyl. In certain embodiments, R9is t-butyl. In certain embodiments, R9is pentyl. In certain embodiments, R9is hexyl.

[0840] In certain embodiments, R9is C1-C6alkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0841] In certain embodiments, R9is C2-C6alkenyl.

[0842] In certain embodiments, R9is C2alkenyl. In certain embodiments, R9is C3alkenyl. In certain embodiments, R9is C4alkenyl. In certain embodiments, R9is C5alkenyl. In certain embodiments, R9is C6alkenyl.

[0843] In certain embodiments, R9is C2-C6alkenyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0844] In certain embodiments, R9is C2-C6alkynyl.

[0845] In certain embodiments, R9is C2alkynyl. In certain embodiments, R9is C3alkynyl. In certain embodiments, R9is C4alkynyl. In certain embodiments, R9is C5alkynyl. In certain embodiments, R9is C6alkynyl.

[0846] In certain embodiments, R9is C2-C6alkynyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0847] In certain embodiments, R9is C1-C6haloalkyl or C1-C6alkoxy.

[0848] In certain embodiments, R9is C1-C6haloalkyl.

[0849] In certain embodiments, R9is halomethyl. In certain embodiments, R9is haloethyl. In certain embodiments, R9is halopropyl. In certain embodiments, R9is halobutyl. In certain embodiments, R9is halopentyl. In certain embodiments, R9is halohexyl.

[0850] In certain embodiments, R9is CH2F. In certain embodiments, R9is CHF2. In certain embodiments, R9is CF3.

[0851] In certain embodiments, R9is C1-C6haloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0852] In certain embodiments, R9is C1-C6alkoxy.

[0853] In certain embodiments, R9is methoxy. In certain embodiments, R9is ethoxy. In certain embodiments, R9is propoxy. In certain embodiments, R9is butoxy. In certain embodiments, R9is pentoxy. In certain embodiments, R9is hexyloxy.

[0854] In certain embodiments, R9is C1-C6alkoxy optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. In certain embodiments, at least one R9is -(CH2) m -N(R 12) 2. -(CH2) m -OR 12 、-(CH2) m -C(O)R 12 、-(CH2) m -C(O)OR 12 、-(CH2) m -C(O)N(R 12 )2、-(CH2) m -SO2R 12 、-(CH2) m -SO2-OR 12 、-(CH2) m -SO2N(R 12 )2、-(CH2) m -CON(R 12 )2、-(CH2) m -P(O)(OR 12 )2、-(CH2) m -P(O)(R 12 )2、-(CH2)<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0855] In certain embodiments, at least one R9is -(CH2) m -N(R 12 )2or -(CH2) m -OR 12 .

[0856] In certain embodiments, at least one R9is -(CH2) m -N(R 12 )2. In certain embodiments, at least one R9is -(CH2) m -OR 12 .

[0857] In certain embodiments, at least one R9is -CH2-N(R 12 )2.

[0858] In certain embodiments, at least one R9is -(CH2) m -C(O)R 12 , -(CH2) m -C(O)OR 12 , -(CH2) m -C(O)N(R 12 )2or -(CH2) m -CON(R 12 )2.

[0859] In certain embodiments, at least one R9is -(CH2) m -C(O)R 12 . In certain embodiments, at least one R9is -(CH2) m -C(O)OR 12 . In certain embodiments, at least one R9is -(CH2) m -C(O)N(R 12 )2. In certain embodiments, at least one R9is -(CH2) m -CON(R 12 )2.

[0860] In certain embodiments, at least one R9is -C(O)R 12 . In certain embodiments, at least one R9is -CH2-C(O)R 12 . In certain embodiments, at least one R9is -CH2CH2-C(O)R 12 . In certain embodiments, at least one R9is -CH2CH2CH2-C(O)R 12 . In certain embodiments, at least one R9is -CH2CH2CH2CH2-C(O)R 12In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2-C(O)R 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0861] In certain embodiments, at least one R9is -C(O)OR 12 In certain embodiments, at least one R9is -CH2-C(O)OR 12 In certain embodiments, at least one R9is -CH2CH2-C(O)OR 12 In certain embodiments, at least one R9is -CH2CH2CH2-C(O)OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0862] In certain embodiments, at least one R9is -(CH2) m -CON(R 12 )2.

[0863] In certain embodiments, at least one R9is -C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2-C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2-CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0864] In certain embodiments, at least one R9is -(CH2) m -SO2R 12, -(CH2) m -SO2-OR 12 or -(CH2) m -SO2N(R 12 )2.

[0865] In certain embodiments, at least one R9is -(CH2) m -SO2R 12 In certain embodiments, at least one R9is -(CH2) m -SO2-OR 12 In certain embodiments, at least one R9is -(CH2) m -SO2N(R 12 )2.

[0866] In certain embodiments, at least one R9is -SO2R 12 In certain embodiments, at least one R9is -CH2-SO2R 12 In certain embodiments, at least one R9is -CH2CH2-SO2R 12 In certain embodiments, at least one R9is -CH2CH2CH2-SO2R 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2-SO2R 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2-SO2R 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-SO2R 12 .

[0867] In certain embodiments, at least one R9is -SO2-OR 12 In certain embodiments, at least one R9is -CH2-SO2-OR 12 In certain embodiments, at least one R9is -CH2CH2-SO2-OR 12 In certain embodiments, at least one R9is -CH2CH2CH2-SO2-OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2-SO2-OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2-SO2-OR 12 In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-SO2R 12 .

[0868] In certain embodiments, at least one R9is -SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2-SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2-SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2-SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2-CH2CH2CH2CH2-SO2N(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-SO2N(R 12 )2.

[0869] In certain embodiments, at least one R9is -(CH2) m -P(O)(OR 12 )2, or -(CH2) m -P(O)(R 12 )2.

[0870] In certain embodiments, at least one R9is -(CH2) m -P(O)(OR 12 )2. In certain embodiments, at least one R9is -(CH2) m -P(O)(R 12 )2.

[0871] In certain embodiments, at least one R9is -P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2-P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2CH2-P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2-P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2-CH2CH2CH2CH2-P(O)(OR 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-P(O)(OR 12 )2.

[0872] In certain embodiments, at least one R9is -P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2-P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2CH2-P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2-P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2-CH2CH2CH2CH2--P(O)(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-P(O)(R 12 )2.

[0873] In certain embodiments, at least one R9is -(CH2) m -B(OH)2or -(CH2) m -B(R 12 )2.

[0874] In certain embodiments, at least one R9is -(CH2) m -B(OH)2. In certain embodiments, at least one R9is -(CH2) m -B(R 12 )2.

[0875] In certain embodiments, at least one R9is -B(OH)2. In certain embodiments, at least one R9is -CH2-B(OH)2. In certain embodiments, at least one R9is -CH2CH2-B(OH)2. In certain embodiments, at least one R9is -CH2CH2CH2-B(OH)2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-B(OH)2. In certain embodiments, at least one R9is -CH2- CH2CH2CH2CH2--B(OH)2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2-B(OH)2.

[0876] In certain embodiments, at least one R9is -B(R 12 )2. In certain embodiments, at least one R9is -CH2-B(R 12 )2. In certain embodiments, at least one R9is -CH2CH2-B(R 12)2. In certain embodiments, at least one R9is -CH2CH2CH2-B(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2-B(R 12 )2. In certain embodiments, at least one R9is -CH2- CH2CH2CH2CH2-B(R 12 )2. In certain embodiments, at least one R9is -CH2CH2CH2CH2CH2CH2.

[0877] In certain embodiments, at least one R9is -(CH2) m -O-(CH2CH2-O) r R 13 , -(CH2) m -NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-(CH2CH2-O) r R 13 , -(CH2) m -C(O)O-(CH2CH2-O) r R 13 , -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 , -(CH2) m -C(O)-NR 12 -SO2R 13 , -(CH2) m -SO2NR 12 -C(O)R 13 or -(CH2) m -S(O)(NR 12 )-R 13 .

[0878] In certain embodiments, at least one R9is -(CH2) m -O-(CH2CH2-O) r R 13 In certain embodiments, at least one R9is -(CH2) m -NR 12 -(CH2CH2-O) r R 13 In certain embodiments, at least one R9is -(CH2) m -C(O)-(CH2CH2-O) r R13 In certain embodiments, at least one R9is -(CH2) m -C(O)O-(CH2CH2-O) r R 13 In certain embodiments, at least one R9is -(CH2) m -C(O)NR 12 -(CH2CH2-O) r R 13 In certain embodiments, at least one R9is -(CH2) m -C(O)-NR 12 -SO2R 13 In certain embodiments, at least one R9is -(CH2) m -SO2NR 12 -C(O)R 13 In certain embodiments, at least one R9is -(CH2) m -S(O)(NR 12 )-R 13 .

[0879] In certain embodiments, at least one R9is -C(O)NR 12 -R 13 In certain embodiments, at least one R9is -C(O)NR 12 -CH2CH2-OR 13 In certain embodiments, at least one R9is -C(O)NR 12 -(CH2CH2-O)2R 13 In certain embodiments, at least one R9is -C(O)NR 12 -(CH2CH2-O)3R 13 In certain embodiments, at least one R9is -C(O)NR 12 -(CH2CH2-O)4R 13 In certain embodiments, at least one R9is -C(O)NR 12 -(CH2CH2-O)5R 13 In certain embodiments, at least one R9is -C(O)NR 12 -(CH2CH2-O)6R 13 .

[0880] In certain embodiments, at least one R9is -C(O)R 12 -R 13 In certain embodiments, at least one R9is -C(O)R 12 -CH2CH2-OR 13In certain embodiments, at least one R9is -C(O)R 12 -(CH2CH2-O)2R 13 In certain embodiments, at least one R9is -C(O)R 12 -(CH2CH2-O)3R 13 In certain embodiments, at least one R9is -C(O)R 12 -(CH2CH2-O)4R 13 In certain embodiments, at least one R9is -C(O)R 12 -(CH2CH2-O)5R 13 In certain embodiments, at least one R9is -C(O)R 12 -(CH2CH2-O)6R 13 .

[0881] In certain embodiments, at least one R9is C3-C 10 cycloalkyl, heterocycle, aryl, or 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the C3-C 10 cycloalkyl, heterocycle, aryl, or 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the C3-C

[0882] In certain embodiments, at least one R9is C3-C 10 cycloalkyl, wherein the C3-C 10Cycloalkyl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. In certain embodiments, at least one R9is aryl, wherein the aryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. In certain embodiments, at least one R9is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the 5-6 membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0883] In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl.

[0884] In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0885] In certain embodiments, at least one R9is monocyclic C3-C 10 cycloalkyl. In certain embodiments, at least one R9is monocyclic C3-C 10 cycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy. In certain embodiments, at least one R9is polycyclic C3-C 10 cycloalkyl. In certain embodiments, at least one R9is polycyclic C3-C 10 cycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0886] In certain embodiments, at least one R9is C5-C6cycloalkyl. In certain embodiments, at least one R9is C5-C6cycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0887] In certain embodiments, at least one R9is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. In certain embodiments, at least one R9is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0888] In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0889] In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with one substituent selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0890] In certain embodiments, R9is a 5-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0891] In certain embodiments, R9is a 5-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0892] In certain embodiments, R9is a 5-6 membered heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with one oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0893] In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with two substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0894] In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with three substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0895] In certain embodiments, at least one R9is a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with four substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0896] In certain embodiments, at least one R9is a heterocycle comprising 3 heteroatoms selected from N and S, which is optionally substituted with one or more oxo.

[0897] In certain embodiments, at least one R9is a 4-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is a 5-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is a 6-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is a 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is an 8-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is a 9-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo. In certain embodiments, at least one R9is a 10-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo.

[0898] In certain embodiments, at least one R9is .

[0899] In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0900] In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1 heteroatom selected from O, N, and S. In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1 heteroatom selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0901] In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 2 heteroatoms selected from O, N, and S. In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 2 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0902] In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 3 heteroatoms selected from O, N, and S. In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 3 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0903] In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, at least one R9is a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0904] In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S. In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0905] In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1 heteroatom selected from N, O, and S, optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl. In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 2 heteroatoms selected from N, O, and S, optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl. In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 3 heteroatoms selected from N, O, and S, optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl. In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 4 heteroatoms selected from N, O, and S, optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0906] In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, substituted with one oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0907] In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, substituted with two substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0908] In certain embodiments, at least one R9is a 5-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is substituted with three substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0909] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S.

[0910] .

[0911] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S. In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0912] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S. In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0913] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is substituted with one oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0914] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is substituted with two substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0915] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is substituted with three substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0916] In certain embodiments, at least one R9is a 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which is substituted with four substituents selected from oxo, halogen, -CN, -OH, -NH2, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0917] In certain embodiments, two R9together with the atom to which they are attached form a C3-C 10 cycloalkyl, or a 3-15 membered saturated or partially saturated heterocycle comprising 1-4 heteroatoms selected from O, N and S.

[0918] In certain embodiments, two R9together with the atom to which they are attached form a C3-C 10 cycloalkyl, or a 3-15 membered saturated or partially saturated heterocycle comprising 1-4 heteroatoms selected from O, N and S, wherein said cycloalkyl or heterocycle is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0919] In certain embodiments, two R9together with the atom to which they are attached form a C3-C 10 cycloalkyl.

[0920] In certain embodiments, two R9together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0921] In certain embodiments, two R9together with the atoms to which they are attached form a C3-C6cycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl. 10 cycloalkyl.

[0922] In certain embodiments, two R9together with the atoms to which they are attached form a C5-C6cycloalkyl.

[0923] In certain embodiments, two R9together with the atoms to which they are attached form a C5-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0924] In certain embodiments, two R9together with the atoms to which they are attached form a C3-C 10 cycloalkyl, which is substituted with one oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0925] In certain embodiments, two R9together with the atoms to which they are attached form a C3-C 10 cycloalkyl, which is substituted with two substituents selected from oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0926] In certain embodiments, two R9together with the atoms to which they are attached form a C3-C 10 cycloalkyl, which is substituted with three substituents selected from oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0927] In certain embodiments, two R9together with the atoms to which they are attached form a C3-C 10Cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0928] In certain embodiments, two R9together with the atom to which they are attached form a C3-C

[0929] In certain embodiments, two R9together with the atom to which they are attached form a C3-C 10 Cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0930] In certain embodiments, two R9together with the atom to which they are attached form a 3-15 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0931] In certain embodiments, two R9together with the atom to which they are attached form a 3-15 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0932] In certain embodiments, two R9together with the atom to which they are attached form a 3-15 membered saturated or partially unsaturated heterocycle comprising 1-4 heteroatoms selected from O, N, and S.

[0933] In certain embodiments, two R9together with the atoms to which they are attached form a heterocyclic ring comprising 1 heteroatom selected from O, N, and S, optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0934] In certain embodiments, two R9together with the atoms to which they are attached form a heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0935] In certain embodiments, two R9together with the atoms to which they are attached form a 5-6 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S.

[0936] In certain embodiments, two R9together with the atoms to which they are attached form a 5-6 membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo, halogen, -CN, -OH, -NH2, =NH, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0937] In certain embodiments, two R9, together with the atoms to which they are attached, form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo or =NH.

[0938] In certain embodiments, two R9, together with the atoms to which they are attached, form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S.

[0939] In certain embodiments, two R9, together with the atoms to which they are attached, form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo or =NH. In certain embodiments, two R9, together with the atoms to which they are attached, form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo. In certain embodiments, two R9, together with the atoms to which they are attached, form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more =NH.

[0940] In certain embodiments, two R9, together with the atoms to which they are attached, form a 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S.

[0941] In certain embodiments, two R9, together with the atoms to which they are attached, form a 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo or =NH. In certain embodiments, two R9, together with the atoms to which they are attached, form a 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more oxo. In certain embodiments, two R9, together with the atoms to which they are attached, form a 6-membered saturated or partially unsaturated heterocyclic ring comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more =NH.

[0942] In certain embodiments, two R9, together with the atoms to which they are attached, form a

[0943]

[0944] wherein “ ” represents the point at which the two R9are attached to different atoms of ring A.

[0945] In certain embodiments, two R9, together with the atoms to which they are attached, form a or wherein " indicates the point of attachment of two R9to different atoms of ring A.

[0946] In certain embodiments, at least one R 10 is oxo, halogen, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 , C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein said cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0947] In certain embodiments, at least one R 10 is oxo, halogen, or -CN.

[0948] In certain embodiments, at least one R 10 is oxo.

[0949] In certain embodiments, at least one R 10 is halogen. In certain embodiments, at least one R 10 is F, Cl, Br, or I. In certain embodiments, at least one R 10 is F, Cl, or Br. In certain embodiments, at least one R 10 is F. In certain embodiments, at least one R 10 is Cl. In certain embodiments, at least one R 10 is Br. In certain embodiments, at least one R 10 is I.

[0950] In certain embodiments, at least one R 10 is -CN.

[0951] In certain embodiments, at least one R 10 ​C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0952] In certain embodiments, at least one R 10 is C1-C6alkyl.

[0953] In certain embodiments, at least one R 10 is methyl. In certain embodiments, at least one R 10 is ethyl. In certain embodiments, at least one R 10 is propyl. In certain embodiments, at least one R 10 is n-propyl. In certain embodiments, at least one R 10 is isopropyl. In certain embodiments, at least one R 10 is butyl. In certain embodiments, at least one R 10 is n-butyl. In certain embodiments, at least one R 10 is isobutyl. In certain embodiments, at least one R 10 is sec-butyl. In certain embodiments, at least one R 10 is t-butyl. In certain embodiments, at least one R 10 is pentyl. In certain embodiments, at least one R 10 is hexyl.

[0954] In certain embodiments, at least one R 10 is C2-C6alkenyl.

[0955] In certain embodiments, at least one R 10 is C2alkenyl. In certain embodiments, at least one R 10 is C3alkenyl. In certain embodiments, at least one R 10 is C4alkenyl. In certain embodiments, at least one R 10 is C5alkenyl. In certain embodiments, at least one R 10 is C6alkenyl.

[0956] In certain embodiments, at least one R 10 is C2-C6alkynyl.

[0957] In certain embodiments, at least one R 10 is C2alkynyl. In certain embodiments, at least one R 10 is C3alkynyl. In certain embodiments, at least one R 10 is C4alkynyl. In certain embodiments, at least one R 10 is C5alkynyl. In certain embodiments, at least one R10 is C6alkynyl.

[0958] In certain embodiments, at least one R 10 is C1-C6haloalkyl or C1-C6alkoxy.

[0959] In certain embodiments, at least one R 10 is C1-C6haloalkyl.

[0960] In certain embodiments, at least one R 10 is C1-C6haloalkyl. In certain embodiments, at least one R 10 is halomethyl. In certain embodiments, at least one R 10 is haloethyl. In certain embodiments, at least one R 10 is halopropyl. In certain embodiments, at least one R 10 is halobutyl. In certain embodiments, at least one R 10 is halopentyl. In certain embodiments, at least one R 10 is halohexyl.

[0961] In certain embodiments, at least one R 10 is C1-C6alkoxy.

[0962] In certain embodiments, at least one R 10 is C1-C6alkoxy. In certain embodiments, at least one R 10 is methoxy. In certain embodiments, at least one R 10 is ethoxy. In certain embodiments, at least one R 10 is propoxy. In certain embodiments, at least one R 10 is butoxy. In certain embodiments, at least one R 10 is pentoxy. In certain embodiments, at least one R 10 is hexoxy.

[0963] In certain embodiments, at least one R 10 is -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2)​n -SO2R 12 .

[0964] In certain embodiments, at least one R 10 is -(CH2) n -OR 12 .

[0965] In certain embodiments, at least one R 10 is -OR 12 . In certain embodiments, at least one R 10 is -CH2-OR 12 . In certain embodiments, at least one R 10 is -CH2CH2-OR 12 . In certain embodiments, at least one R 10 is -CH2CH2CH2-OR 12 . In certain embodiments, at least one R 10 is -CH2CH2CH2CH2-OR 12 . In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2-OR 12 . In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2CH2-OR 12 .

[0966] In certain embodiments, at least one R 10 is -(CH2) n -N(R 12 )2.

[0967] In certain embodiments, at least one R 10 is -N(R 12 ). In certain embodiments, at least one R 10 is -CH2-N(R 12 ). In certain embodiments, at least one R 10 is -CH2CH2-N(R 12 ). In certain embodiments, at least one R 10 is -CH2CH2CH2-N(R 12 ). In certain embodiments, at least one R 10 is -CH2CH2CH2CH2-N(R 12 ). In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2-N(R 12 ). In certain embodiments, at least one R10 Yes-CH2CH2CH2CH2CH2CH2-N(R 12 ).

[0968] In some implementations, at least one R 10 It is -(CH2) n -C(O)R 12 .

[0969] In some implementations, at least one R 10 It is -C(O)R 12 In some implementations, at least one R 10 It is -CH2-C(O)R 12 In some implementations, at least one R 10 It is -CH2CH2-C(O)R 12 In some implementations, at least one R 10 It is -CH2CH2CH2-C(O)R 12 In some implementations, at least one R 10 It is -CH2CH2CH2CH2-C(O)R 12 In some implementations, at least one R 10 It is -CH2CH2CH2CH2CH2-C(O)R 12 In some implementations, at least one R 10 Yes-CH2CH2CH2CH2CH2CH2-C(O)R 12 .

[0970] In some implementations, at least one R 10 It is -(CH2) n -C(O)OR 12 .

[0971] In some implementations, at least one R 10 It is -C(O)OR 12 In some implementations, at least one R 10 It is -CH2-C(O)OR 12 In some implementations, at least one R 10 It is -CH2CH2-C(O)OR 12 In some implementations, at least one R 10 It is -CH2CH2CH2-C(O)OR 12 In some implementations, at least one R 10 It is -CH2CH2CH2CH2-C(O)OR 12 In some implementations, at least one R 10-CH2CH2CH2CH2CH2-C(O)OR 12 In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2CH2-C(O)OR 12 .

[0972] In certain embodiments, at least one R 10 is -(CH2) n -C(O)N(R 12 )2.

[0973] In certain embodiments, at least one R 10 is -C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2-C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2-C(O)N(R 12 )2. In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2CH2-C(O)N(R 12 )2.

[0974] In certain embodiments, at least one R 10 is -(CH2) n -SO2R 12 .

[0975] In certain embodiments, at least one R 10 is -SO2R 12 . In certain embodiments, at least one R 10 is -CH2-SO2R 12 . In certain embodiments, at least one R 10 is -CH2CH2-SO2R 12 . In certain embodiments, at least one R 10 is -CH2CH2CH2-SO2R 12In certain embodiments, at least one R 10 is -CH2CH2CH2CH2-SO2R 12 In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2-SO2R 12 In certain embodiments, at least one R 10 is -CH2CH2CH2CH2CH2CH2-SO2R 12 .

[0976] In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl.

[0977] In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0978] In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl. In certain embodiments, at least one R 10 is C3-C 10 cycloalkyl optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0979] In certain embodiments, at least one R 10 is monocyclic C3-C 10 cycloalkyl. In certain embodiments, at least one R 10 is monocyclic C3-C 10 cycloalkyl optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 10 In certain embodiments, at least one R 10 is polycyclic C3-C 10 cycloalkyl. In certain embodiments, at least one R 10 is polycyclic C3-C cycloalkyl optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0980] In certain embodiments, at least one R 10 is C5-C6cycloalkyl. In certain embodiments, at least one R 10 is C5-C6cycloalkyl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0981] In certain embodiments, at least one R 10 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. In certain embodiments, at least one R 10 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0982] In certain embodiments, at least one R 10 is fused polycyclo C3-C 10 cycloalkyl. In certain embodiments, at least one R 10 is fused polycyclo C3-C 10 cycloalkyl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. 10 is bridged polycyclo C3-C 10 cycloalkyl. In certain embodiments, at least one R 10 is bridged polycyclo C3-C 10 cycloalkyl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. 10 is C3-C 10 spirocycloalkyl. In certain embodiments, at least one R 10 is C3-C 10 spirocycloalkyl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0983] In certain embodiments, at least one R 10 is C3-C 10cycloalkyl. In certain embodiments, at least one R 10 is C3-C6cycloalkyl optionally substituted with C2-C6alkenyl. In certain embodiments, at least one R 10 cycloalkyl. In certain embodiments, at least one R 10 is C3-C6cycloalkyl optionally substituted with C2-C6alkynyl. In certain embodiments, at least one R 10 cycloalkyl. In certain embodiments, at least one R 10 is C3-C6cycloalkyl optionally substituted with C1-C6haloalkyl. In certain embodiments, at least one R 10 cycloalkyl. In certain embodiments, at least one R 10 is C3-C6cycloalkyl optionally substituted with C1-C6alkoxy. In certain embodiments, at least one R 10 cycloalkyl. In certain embodiments, at least one R 10 is C3-C6cycloalkyl optionally substituted with C1-C6haloalkoxy. In certain embodiments, at least one R 10 cycloalkyl.

[0984] In certain embodiments, at least one R 10 is a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S. In certain embodiments, at least one R 10 is a heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0985] In certain embodiments, at least one R 10 is a monocyclic heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S. In certain embodiments, at least one R 10 is a monocyclic heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a polycyclic heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S. In certain embodiments, at least one R 10 is a polycyclic heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0986] In certain embodiments, at least one R 10is a 3-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 4-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 5-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 6-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 7-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 8-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 9-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. In certain embodiments, at least one R 10 is a 10-membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0987] In certain embodiments, at least one R 10 is a 5-6 membered heterocycle containing 1-4 heteroatoms selected from O, N, and S. In certain embodiments, at least one R 10is a 5-6 membered heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0988] In certain embodiments, at least one R 10 is a heterocycle containing 1, 2, or 3 heteroatoms selected from N and O.

[0989] In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C1-C6alkyl. In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C2-C6alkenyl. In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C2-C6alkynyl. In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C1-C6haloalkyl. In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C1-C6alkoxy. In certain embodiments, at least one R 10 is a heterocycle containing 1-4 heteroatoms selected from O, N, and S, optionally substituted with C1-C6haloalkoxy.

[0990] In certain embodiments, at least one R 10 is aryl. In certain embodiments, at least one R 10 is aryl optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0991] In certain embodiments, at least one R 10 is C6aryl (e.g., phenyl). In certain embodiments, at least one R 10 is C6aryl (e.g., phenyl) optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0992] In certain embodiments, at least one R 10 is aryl optionally substituted with C1-C6alkyl. In certain embodiments, at least one R 10is aryl optionally substituted with C2-C6alkenyl. In certain embodiments, at least one R 10 is aryl optionally substituted with C2-C6alkynyl. In certain embodiments, at least one R 10 is aryl optionally substituted with C1-C6haloalkyl. In certain embodiments, at least one R 10 is aryl optionally substituted with C1-C6alkoxy. In certain embodiments, at least one R 10 is aryl optionally substituted with C1-C6haloalkoxy.

[0993] In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0994] In certain embodiments, at least one R 10 is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In certain embodiments, at least one R 10 is 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0995] In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C1-C6alkyl. In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C2-C6alkenyl. In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C2-C6alkynyl. In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C1-C6haloalkyl. In certain embodiments, at least one R 10 is heteroaryl comprising 1-4 heteroatoms selected from O, N, and S optionally substituted with C1-C6alkoxy. In certain embodiments, at least one R 10heteroaryl comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with C1-C6haloalkoxy.

[0996] In certain embodiments, at least one R 10 is .

[0997] In certain embodiments, two R 10 , together with the atom to which they are attached, form a C 6-10 aryl or heteroaryl. In certain embodiments, two R 10 , together with the atom to which they are attached, form a C 6-10 aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more oxo, =NR 12 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[0998] In certain embodiments, two R 10 , together with the atom to which they are attached, form an aryl. In certain embodiments, two R 10 , together with the atom to which they are attached, form an aryl, wherein the aryl is optionally substituted with one or more oxo, =NR 12 , halogen, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n-SO2R 12 substituted.

[0999] In certain embodiments, two R 10 , together with the atom to which they are attached, form a C6 aryl (e.g., phenyl). In certain embodiments, two R 10 , together with the atom to which they are attached, form a C6 aryl (e.g., phenyl), wherein the aryl is optionally substituted with one or more oxo, =NR 12 , halo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 substituted.

[1000] In certain embodiments, two R 10 , together with the atom to which they are attached, form an aryl, wherein the aryl is substituted with one oxo, =NR 12 , halo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 substituted.

[1001] In certain embodiments, two R 10 , together with the atom to which they are attached, form an aryl, wherein the aryl is substituted with two substituents selected from oxo, =NR 12halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1002] In certain embodiments, two R 10 together with the atoms to which they are attached form an aryl group, wherein said aryl group is substituted with three substituents selected from the group consisting of oxo, =NR 12 , halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1003] In certain embodiments, two R 10 together with the atoms to which they are attached form an aryl group, wherein said aryl group is substituted with four substituents selected from the group consisting of oxo, =NR 12 , halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR12 -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1004] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more oxo, =NR 12 , halogen, -CN, or -NO2.

[1005] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more oxo.

[1006] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more =NR 12 .

[1007] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more halogen. In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more F. In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more Cl. In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more Br. In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more I.

[1008] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, wherein the aryl group is optionally substituted with one or more -CN.

[1009] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more -NO2.

[1010] In certain embodiments, two R 10 , together with the atoms to which they are attached, form an aryl group, optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[1011] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more C1-C6alkyl groups.

[1012] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more C2-C6alkenyl groups.

[1013] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more C2-C6alkynyl groups.

[1014] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more C1-C6haloalkyl groups.

[1015] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more C1-C6alkoxy groups.

[1016] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 groups.

[1017] In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more -(CH2) n -OR 12 groups. In certain embodiments, two R 10 together with the atom to which they are attached form an aryl group, optionally substituted with one or more -OR 12 groups.

[1018] In certain embodiments, two R 10with the atom to which they are attached to form an aryl group optionally substituted with one or more -(CH2) n -N(R 12 )2. In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -N(R 12 )2.

[1019] In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -(CH2) n -C(O)R 12 . In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -C(O)R 12 .

[1020] In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -(CH2) n -C(O)OR 12 . In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -C(O)OR 12 .

[1021] In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -(CH2) n -C(O)N(R 12 )2. In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -C(O)N(R 12 )2.

[1022] In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -(CH2) n -SO2R 12 . In certain embodiments, two R 10 with the atom to which they are attached to form an aryl group optionally substituted with one or more -SO2R 12 .

[1023] In certain embodiments, two R 10with the atom to which they are attached form a heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In certain embodiments, two R 10 with the atom to which they are attached form a heteroaryl containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo, =NR 12 , halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1024] In certain embodiments, two R 10 with the atom to which they are attached form a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In certain embodiments, two R 10 with the atom to which they are attached form a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo, =NR 12 , halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1025] In certain embodiments, two R 10 with the atom to which they are attached form a heteroaryl containing 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo, =NR12 halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 -(CH2) n -C(O)OR 12 -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 substituted.

[1026] In certain embodiments, two R 10 together with the atom to which they are attached form a heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with one oxo, =NR 12 halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 -(CH2) n -C(O)OR 12 -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 substituted.

[1027] In certain embodiments, two R 10 together with the atom to which they are attached form a heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with two substituents selected from oxo, =NR 12 halo, -CN, -NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -OR 12 -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12, -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1028] In certain embodiments, two R 10 , together with the atoms to which they are attached, form a heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with three substituents selected from oxo, =NR 12 , halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1029] In certain embodiments, two R 10 , together with the atoms to which they are attached, form a heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is substituted with four substituents selected from oxo, =NR 12 , halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) n -OR 12 , -(CH2) n -N(R 12 )2, -(CH2) n -C(O)R 12 , -(CH2) n -C(O)OR 12 , -(CH2) n -C(O)N(R 12 )2, -(CH2) n -SO2R 12 .

[1030] In certain embodiments, two R 10together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo, =NR 12 , halogen, -CN, or -NO2.

[1031] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more oxo.

[1032] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more =NR 12 substituents.

[1033] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more halogen. In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more F.

[1034] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more Cl. In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more Br. In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more I.

[1035] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more -CN.

[1036] In certain embodiments, two R 10 together with the atoms to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, which is optionally substituted with one or more -NO2.

[1037] In certain embodiments, two R 10together with the atom to which they are attached form heteroaryl comprising 1-4 heteroatoms selected from O, N, and S, optionally substituted with one or more C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy.

[1038] In certain...

Claims

1. A compound of the formula: ###0001### or a pharmaceutically acceptable salt thereof, wherein: X is -NH; Y is -0-; WR1R2 is a group of the formula: ###0002### L1- is -(CH2)- or -(CH2)2-; u is independently at each occurrence 0, 1, 2, 3, or 4; R3 is H, or R3 is -CN or Ci-C6 alkyl; R4 is H, halo, Ci-C6 alkyl, or Ci-C6 haloalkyl; R5 is H, halo, methyl, or trifluoromethyl; R6 is H; R7 is Ci-C6 alkyl; R8 is H; at least one R9 is -C(O)OH and the other R9 is H, halo, Ci-C6 alkyl, or Ci-C6 haloalkyl; and ring A is phenyl, pyridine, pyrimidine, or benzothiophene; each n or m is independently at each occurrence 0, 1, 2, 3, 4, 5, or 6; and s is 1, 2, 3, 4, 5, or 6.

2. A compound according to claim 1 of the formula: ###0003### or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein R3 is hydrogen, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or claim 2, wherein R3 is -CN or Ci-C3 alkyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or claim 2, wherein ring A is a group of the formula: ###0004### or a pharmaceutically acceptable salt thereof. R 10 independently at each occurrence is oxo, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -(CH2) n -N(R 12 )2, -(CH2) n -C(O)N(R 12 )2, or phenyl; R 10a independently at each occurrence is halogen or -CN; 6. The compound according to claim 1 or claim 2, wherein ring A is a group of the formula: ###0005### or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 selected from the group consisting of: ###0006### or a pharmaceutically acceptable salt thereof.

8. A compound of the formula: ###0007### 10. A compound of the formula: ###0009### 12. A compound of the formula: ###0011### 14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

15. Use of a compound according to any one of claims 1-13 or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment of a disease associated with modulation of PI3K, wherein the disease associated with modulation of PI3K is breast cancer. ​ ​ each remaining R9is independently at each occurrence halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -(CH2) m -B(OH)2, or C3-C 10 cycloalkyl; or two R9together with the atom to which they are attached form a 5-6 membered heterocycle comprising 1-4 heteroatoms selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycle is optionally substituted with one or more oxo; each R is, independently at each occurrence, H or C1-C6alkyl; 12 independently at each occurrence, H or C1-C6alkyl; ​ ​ ​ ​ 。 ​ ​ ​ wherein R9is -C(O)OH, R 9a halo, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C3-C5cycloalkyl, v is 0, 1, or 2, w is 0, 1, or 2, x is 0 or 1, y is 0 or 1, and z is 0, 1, or 2. ​ wherein R 9a is halogen or trifluoromethyl; v is 0 or 1 ; and w is 0 or 1. ​ ​ ​ or a pharmaceutically acceptable salt thereof, wherein: R3is H or C1-C6alkyl, R5is halogen, C1-C6alkyl or C1-C6haloalkyl, R9is halogen, R 10a halogen, s is 0 or 1, u is 0 or 1, J is CH or N, and * indicates a stereocenter.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl, R5 is fluoro, methyl or trifluoromethyl, R9 is chloro, R 10a is fluoro, s is 0 or 1, u is 0 or 1, J is CH or N, and the stereocenters have the (R)-configuration. R )-configuration. ​ or a pharmaceutically acceptable salt thereof, wherein: R3is H or C1-C6alkyl, R5is halogen, C1-C6alkyl or C1-C6haloalkyl, R9is halogen, R 10 independently halogen, -CN, C1-C6alkyl or phenyl, or two R 10 together with the carbon atom to which they are attached form a C3-C 10 cycloalkyl, s is 0 or 1, u is 0, 1 or 2, J is CH or N, and * indicates a stereocenter.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl, R5 is fluoro, methyl or trifluoromethyl, R9 is chloro, R 10 is independently fluoro or methyl, or both R 10 form a cyclopropyl together with the carbon atom to which they are attached, s is 0 or 1, u is 0, 1 or 2, J is CH or N, and the stereocenters have the (R R )-configuration. ​ or a pharmaceutically acceptable salt thereof, wherein R3is H or C1-C6alkyl, R5is halogen, C1-C6alkyl or C1-C6haloalkyl, R9is halogen, R 10 independently halogen, -CN, C1-C6alkyl or phenyl, or two R 10 together with the carbon atom to which they are attached form a C3-C 10 cycloalkyl, s is 0 or 1, u is 0, 1 or 2, J is CH or N, and * indicates a stereocenter.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl, R5 is fluoro, methyl or trifluoromethyl, R9 is chloro, R 10 independently methyl or phenyl, or both R 10 form a cyclobutyl group together with the carbon atom to which they are attached, s is 0 or 1, u is 0, 1 or 2, J is CH or N, and the stereocenters have the (R) R )-configuration. ​ ​

Images