TEAD inhibitors and methods of use thereof

Abstract

Provided herein are compounds and methods for modulating or inhibiting TEAD. Further provided herein are pharmaceutical compositions comprising TEAD inhibitors and methods of treatment using the TEAD inhibitors or pharmaceutical compositions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of International Application No. PCT / CN2022 / 122654, filed September 29, 2022; International Application No. PCT / CN2023 / 078150, filed February 24, 2023; and International Application No. PCT / CN2023 / 112540, filed August 11, 2023, which are incorporated by reference in their entireties herein. [Background technology]

[0002]

[0002] The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. This pathway is thought to act as a tumor suppressor in mammals, and disruptions of this pathway have often been detected in human cancers. This pathway may be involved in and / or regulate the self-renewal and differentiation of stem and progenitor cells. In addition, the Hippo pathway may be involved in wound healing and tissue regeneration. Furthermore, the Hippo pathway crosstalks with other signaling pathways, such as Wnt, Notch, Hedgehog, and MAPK / ERK, potentially affecting a wide variety of biological events, and its dysfunction is thought to be involved in many human diseases in addition to cancer. The Hippo signaling pathway is conserved from Drosophila to mammals. The core of the pathway consists of a kinase cascade (Hippo-MST1-2, upstream of Lats1-2 and NDRI-2) that leads to the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ.

[0003]

[0003] The Hippo signaling pathway is involved in cancer development because it regulates animal growth, organ size, and stem cell function. In vitro, overexpression of YAP or TAZ in breast epithelial cells induces cellular transformation through the interaction of both proteins with the TEAD family of transcription factors. Increased YAP / TAZ transcriptional activity induces oncogenic properties, such as epithelial-mesenchymal transition (EMT). Furthermore, it has been shown to confer stem cell properties to breast cancer cells. In vivo, overexpression of YAP or genetic knockout of its upstream regulator MST1-2 in mouse liver leads to the development of hepatocellular carcinoma (HCC). Furthermore, inactivation of the tumor suppressor NF2 in mouse liver, along with concomitant inactivation of YAP, completely blocks HCC development.

[0004]

[0004] Deregulation of the Hippo tumor suppressor pathway is believed to be a key event in the development of a wide range of malignancies, including lung cancer, breast cancer, head and neck cancer, colon cancer, ovarian cancer, liver cancer, brain cancer, prostate cancer, mesothelioma, sarcoma, and leukemia.

[0005] Two of the core components of the mammalian Hippo pathway are Lats1 and Lats2, nuclear Dbf2-related (NDR) family protein kinases that are homologous to Drosophila Warts (Wts). Lats1 / 2 proteins are activated by binding to the scaffolding proteins Mob1A / B (Mps one-binder kinase activator-like 1A and 1B), which are homologous to Drosophila Mats. Lats1 / 2 proteins are also activated by phosphorylation by the STE20 family protein kinases Mst1 and Mst2, which are homologous to Drosophila Hippo. Lats1 / 2 kinase phosphorylates the downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with a PDZ-binding motif; WWTR1), which are homologous to Drosophila Yorkie. Phosphorylation of YAP and TAZ by Lats1 / 2 is a critical event in the Hippo signaling pathway. Lats1 / 2 phosphorylates YAP at multiple sites, with Ser127 phosphorylation being critical for YAP inhibition. YAP phosphorylation generates a protein-binding motif for the 14-3-3 protein family, which, upon binding of 14-3-3 proteins, results in the retention and / or sequestration of YAP in the cytoplasm. Similarly, Lats1 / 2 phosphorylates TAZ at multiple sites, with Ser89 phosphorylation being critical for TAZ inhibition. TAZ phosphorylation results in the retention and / or sequestration of TAZ in the cytoplasm. In addition, phosphorylation of YAP and TAZ is thought to destabilize these proteins by activating phosphorylation-dependent degradation catalyzed by ubiquitination of YAP or TAZ. Thus, when the Hippo pathway is "on," YAP and / or TAZ are phosphorylated, inactive, and typically sequestered in the cytoplasm. In contrast, when the Hippo pathway is "off," YAP and / or TAZ are unphosphorylated, active, and typically found in the nucleus.

[0006]

[0006] Unphosphorylated, activated YAP translocates to the cell nucleus, where its primary target transcription factors are the four TEAD domain-containing family proteins (TEAD1-TEAD4, collectively referred to as "TEAD"). YAP has been shown to cooperate with TEADs (or other transcription factors, e.g., Smad1, RUNX, ErbB4, and p73) to induce the expression of various genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Like YAP, unphosphorylated TAZ translocates to the cell nucleus, where it interacts with numerous DNA-binding transcription factors, e.g., peroxisome proliferator-activated receptor γ (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Many of the genes activated by the YAP / TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, YAP and / or TAZ act as oncogenes and the Hippo pathway acts as a tumor suppressor. Summary of the Invention

[0007]

[0007] Therefore, pharmacological targeting of the Hippo cascade through inhibition of TEADs is a valuable approach for the treatment of cancers with functional alterations of this pathway.

[0008]

[0008] Disclosed herein are compounds, or pharmaceutically acceptable salts, or stereoisomers thereof, that are TEAD inhibitors.

[0009] A compound of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] and wherein: however, [ka] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof, which is not:

[0010]

[0010] Also disclosed herein are pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients.

[0011]

[0011] A method for treating cancer in a subject in need of treatment, comprising the step of administering to the subject in need of treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0012] In some embodiments of the methods of treating cancer, the cancer is mesothelioma. In some embodiments of the methods of treating cancer, the cancer is NF2-deficient mesothelioma.

[0013]

[0013] In some embodiments of the method of treating cancer, the cancer is epithelioid hemangioendothelioma.

[0014]

[0014] In some embodiments of the methods of treating cancer, the cancer is a solid tumor.

[0015] In some embodiments of the methods of treating cancer, the solid tumor has an NF2 mutation, a LATS1 mutation, a LATS2 mutation, or any combination thereof. In some embodiments of the methods of treating cancer, the solid tumor has an NF2 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a LATS1 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a LATS2 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a YAP1 / TAZ gene fusion. Incorporation by Reference

[0016]

[0016] All publications, patents, and patent applications mentioned in this specification are incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are intended to be interpreted in an open, inclusive sense, i.e., "including, but not limited to." Furthermore, headings provided herein are for convenience only and do not describe the scope or meaning of the claimed invention.

[0018]

[0018] Throughout this specification, references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally utilized in its sense, including "and / or," unless the content clearly dictates otherwise.

[0019]

[0019] As used herein, the following terms have the following meanings unless otherwise indicated:

[0020]

[0020] "Oxo" refers to =O.

[0021] "Carboxyl" refers to -COOH.

[0022] "Cyano" refers to -CN.

[0023] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range, e.g., "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the present invention also encompasses occurrences of the term "alkyl" without any numerical range specified. In some embodiments, alkyl is a C1- 10In some embodiments, the alkyl is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0024] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond(s) and should be considered to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, a numerical range, e.g., "C-C alkenyl" or "C- alkenyl," means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses occurrences of the term "alkenyl" without any numerical range specified. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0025] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. All occurrences herein are also intended to include numerical ranges, e.g., "C2-C6 alkynyl" or "C 2~6"Alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the present invention also encompasses occurrences of the term "alkynyl" without any numerical range specified. Unless otherwise specifically stated herein, alkynyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0026]

[0026] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0027] "Alkylidenyl" is an alkenyl as defined above attached through a terminal divalent carbon. For example, the compound: [ka] In the formula (I), the alkylidenyl group is enclosed in a box indicated by an arrow.

[0028]

[0028] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0029] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0030] "Cycloalkyl" refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spirocyclic, or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (e.g., C3 to C6). 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3 to C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl). In some embodiments, cycloalkyls are 3 to 10-membered fully saturated cycloalkyl or 3 to 10-membered cycloalkenyl. In some embodiments, cycloalkyls are 3 to 6-membered fully saturated cycloalkyl or 3 to 6-membered cycloalkenyl. In some embodiments, cycloalkyls are 5 to 6-membered fully saturated cycloalkyl or 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0032] "Haloalkyl" refers to an alkyl radical (as defined above) substituted with one or more halo radicals (as defined above), such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0033] "Hydroxyalkyl" refers to an alkyl radical (as defined above) substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] "Aminoalkyl" refers to an alkyl radical (as defined above) substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035]

[0035] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CH2CHOCH3, -CH2CHOCH2CHOCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0036] "Heterocycloalkyl" refers to the radical of a 3- to 24-membered partially or fully saturated ring containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spirocyclic, or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms of the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2 to C6). 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2 to C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-oxo-2-methyl-2-methyl-1 ... Examples of heterocycloalkyl include -piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) making up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0037] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms (selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur), and at least one aromatic ring. In some embodiments, a heteroaryl contains 1 to 13 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1 to 3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl Examples of heteroaryl include phenyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0038] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes cases where said event or circumstance occurs and cases where it does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art understand that with respect to any group containing one or more substituents, the introduction of any substitution or substitution pattern such that such group is sterically infeasible and / or synthetically infeasible is not intended. Thus, any described substituents should generally be understood to have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0039] The term "one or more," when referring to optional substituents, means that the group of interest is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group of interest is optionally substituted with one, two, three, or four substituents. In some embodiments, the group of interest is optionally substituted with one, two, or three substituents. In some embodiments, the group of interest is optionally substituted with one or two substituents. In some embodiments, the group of interest is optionally substituted with one substituent. In some embodiments, the group of interest is optionally substituted with two substituents.

[0040]

[0040] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0041]

[0041] The terms "treat," "treating," or "treating," as used herein, include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or interrupting a symptom of a disease or condition.

[0042]

[0042] As used herein, "TEAD-associated disease or disorder" or, alternatively, "TEAD-mediated disease or disorder" means any disease or other deleterious condition in which TEAD, or a variant thereof, is known or suspected to play a role.

[0043] compound

[0043] Described herein are compounds, or pharmaceutically acceptable salts, or stereoisomers thereof, that are useful for treating diseases or disorders associated with TEAD.

[0044] A compound of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] [In the formula, X is -N- or -CR X - and R X is hydrogen, halogen, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Y is -N-, -CR Y - or -C(=O)-, R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NRb C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a is optionally replaced by or two R on the same atom 1 together to form oxo, Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 1a together to form oxo, n is 0, 1, 2, 3, or 4; L is absent, -O-, -S-, -NR 2 -, -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, -C(R 3 )=C(R 3 )-, [ka] -C(R 3 )2O-, -OC(R 3 )2-, -C(R 3 )2S-, -SC(R 3 )2-, -C(R 3 )2NR 2 -, or -NR 2 C(R 3 )2- and R 2is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; Each R 3 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 3 together to form oxo, or two R on the same carbon 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different carbons 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, halogen, or C1-C6 alkyl, R 8 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , -C(=O)R 9 , -S(=O)2NR 10 R 11 , [ka] -S(=O)2R 9 , -S(=O)R 9 , -P(=O)(OR 10 )(OR 11 ), or -B(OR 10 )(OR 11 ) and R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be selected from one or more R 9a is optionally replaced by Each R 9a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR bS(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 9a together to form oxo, R 10 and R 11 are each independently hydrogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by or R 10 and R 11 together with the atoms to which they are attached form one or more R 10b forming a heterocycloalkyl optionally substituted with Each R 10a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a, -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10a together to form oxo, Each R 10b are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2Ra , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10b together to form oxo, U is -C- or -N-; T is -C- or -N-; provided that U and T cannot both be -N-, except that when ring B is phenyl or 6-membered heteroaryl, then U and T are both -C-; Ring B is phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, or C5-C7 cycloalkyl; Each R 12 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)ORb , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 12 together to form oxo, or two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different atoms 12together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, 4, 5, or 6; or one R 12 and R Y together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1 ~C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo] are disclosed herein.

[0045] In some embodiments of the compound of Formula (I), the compound is [ka] isn't it.

[0046] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (Ia): [ka] wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

[0047] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (Ib): [ka] wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

[0048] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (Ic): [ka] wherein ring B is phenyl, a 5- or 6-membered heteroaryl, or a 5-membered heterocycloalkyl.

[0049] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0050] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), X is -N-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), X is -CR X -It is.

[0051] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R X is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R X is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R X is hydrogen.

[0052] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Y is -N- or -CR Y In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Y is -N-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Y is -CR Y -It is.

[0053] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R Y is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R Y is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R Y is hydrogen.

[0054] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), X is -CR X - and Y is -CR Y In some embodiments, X is -CH- and Y is -CH-.

[0055] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), L is absent, —O—, —S—, —NR 2 -, -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, -C(R 3 )=C(R 3 )-, -C(R 3 )2O-, -OC(R 3 )2-, -C(R 3 )2S-, -SC(R 3 )2-, -C(R 3 )2NR 2 -, or -NR 2 C(R 3 )2-.

[0056] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), L is absent, —O—, —C(R 3 )2-, or -C(R 3 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), L is absent, —O—, or —C(R 3 )2-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is absent or -O-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O- or -C(R 3 )2O-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is absent. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -C(R 3 )2-.

[0057] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen.

[0058] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 is hydrogen.

[0059] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is fully saturated cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is fully saturated C5-C6 mono-cycloalkyl, fully saturated C7-C8 mono-cycloalkyl, fully saturated C9-C10 mono-cycloalkyl, fully saturated C11-C12 mono-cycloalkyl, fully saturated C12-C14 mono-cycloalkyl, fully saturated C13-C15 mono-cycloalkyl, fully saturated C14-C16 mono-cycloalkyl, fully saturated C15-C16 mono-cycloalkyl, fully saturated C16-C18 mono-cycloalkyl, fully saturated C17-C18 mono-cycloalkyl, fully saturated C18-C19 mono-cycloalkyl, fully saturated C19-C20 mono-cycloalkyl, fully saturated C19-C219 mono-cycloalkyl, fully saturated C19-C220 mono-cycloalkyl, fully saturated C19-C230 mono-cycloalkyl, fully saturated C19-C240 mono-cycloalkyl, fully saturated C19-C250 mono-cycloalkyl, fully saturated C20-C26 ... 10 Spiro-cycloalkyl, or fully saturated C 7~ C 10 and bridged cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is a partially saturated cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is a partially saturated C5-C6 cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is a mono-heterocycloalkyl, fused heterocycloalkyl, spiro-heterocycloalkyl, or bridged heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is a 5- or 6-membered mono-heterocycloalkyl, 7- to 10-membered spiro-heterocycloalkyl, or 7- to 10-membered bridged heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is aryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is phenyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is pyridyl or pyrimidyl.

[0060] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -CN, -OH, -SF5, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -OR a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 is independently C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently -OCF3, -CF3, -CHF2, -F, -Cl, -SF5, methyl, ethyl, isopropyl, or n-propyl.

[0061] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 1a together form oxo. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a, -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0062] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 3.

[0063] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] and each R1aa are independently hydrogen or R 1 is.

[0064] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0065] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0066] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen.

[0067] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 5 is hydrogen.

[0068] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 6 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 6 is hydrogen.

[0069] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is hydrogen.

[0070] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 , R 5 , R 6 , and R 7 Each of is hydrogen.

[0071] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , S(=O)2NR 10 R 11 , -P(=O)(OR 10 )(OR 11 ), or -B(OR 10 )(OR 11 )

[0072] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , or -S(=O)2NR 10 R 11 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is -C(=O)OR 9 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is -C(=O)NR 10 R 11 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is -S(=O)2NR 10 R 11 is.

[0073] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9is hydrogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be selected from one or more R 9a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently selected from one or more R 9a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 is hydrogen.

[0074] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 9a together form oxo. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 9a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0075] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0076] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by

[0077] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 are each independently hydrogen or one or more R 10ais heterocycloalkyl optionally substituted with

[0078] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by

[0079] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, heterocycloalkyl, C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by

[0080] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or heterocycloalkyl, and each alkyl and heterocycloalkyl is independently selected from one or more R 10a is optionally replaced by

[0081] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heterocycloalkyl, and each alkyl and heterocycloalkyl is independently selected from one or more R 10a is optionally replaced by

[0082] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is one or more R 10a is heterocycloalkyl optionally substituted with

[0083] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is one or more R 10a is a monocyclic heterocycloalkyl optionally substituted with

[0084] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 is one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R11 is one or more R 10a is a bicyclic spiroheterocycloalkyl optionally substituted with

[0085] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen and R 11 teeth, [ka] , each of which is one or more R 10a is optionally replaced by

[0086] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10a together form oxo. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently halogen, -OH, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a is independently halogen, —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a is independently —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10a are independently —OH.

[0087] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached form one or more R 10bIn some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10bIn some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are attached, form one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11together with the atom to which they are attached form a heterocycloalkyl, which contains 1 to 2 nitrogens and 0 to 1 oxygen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atom to which they are attached form a heterocycloalkyl, which heterocycloalkyl contains one nitrogen.

[0088] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are bonded, [ka] each of which is formed by one or more (e.g., one, two, or three) R 10b is optionally replaced by

[0089] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are bonded, [ka] which form one or more (e.g., one, two, or three) R 10b is optionally replaced by

[0090] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are bonded, [ka] each of which is formed by one or more (e.g., one, two, or three) R 10bIn some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are bonded, [ka] each of which is formed by one or more (e.g., one, two, or three) R 10b In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 and R 11 together with the atoms to which they are bonded, [ka] which form one or more (e.g., one, two, or three) R 10b is optionally replaced by

[0091] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10b together form oxo. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)Ra , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently -CN, -OH, -OR a , or -NR c R d In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b is independently —CN. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 10b are independently —OH.

[0092] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0093] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0094] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0095] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0096] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0097] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 teeth, [ka] is.

[0098] In some embodiments, Ring B is phenyl and U and T are both -C-. In some embodiments, Ring B is a 6-membered heteroaryl and U and T are both -C-.

[0099] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring B is phenyl, a 5- or 6-membered heteroaryl, or a 5-membered heterocycloalkyl.

[0100] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is a 5-membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, cyclopentyl, or cyclohexyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is phenyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is a 5-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring B is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is pyrazolyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is a 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is pyridinyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is a 5-membered heterocycloalkyl.

[0101] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently halogen, —CN, —OH, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently phenyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently a 5- or 6-membered heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 independently, C 3~ In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently a 5- or 6-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12is independently —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 12 is independently -CN, methyl, -CHF2, cyclopropyl, or pyridyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), methyl is -CD3.

[0102] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 0 or 1. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 0. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 1. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 2. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), m is 3.

[0103] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] and each R 12aa are independently hydrogen or R 12 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] and each R 12aa are independently hydrogen or R 12In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0104] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0105] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] teeth, [ka] is.

[0106] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), [ka] is.

[0107] A compound of formula (II), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] [In the formula, X is -N- or -C-; Y is -N- or -CR Y - and RY is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , methyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Z is -N- or -C-; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a is optionally replaced by or two R on the same atom 1 together to form oxo, Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 1a together to form oxo, n is 0, 1, 2, 3, or 4; L is absent, -O-, -S-, -NR 2 -, -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, -C(R 3 )=C(R 3 )-, [ka] -C(R 3 )2O-, -OC(R 3 )2-, -C(R 3 )2S-, -SC(R 3 )2-, -C(R 3 )2NR 2 -, or -NR 2 C(R 3 )2- and R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; Each R 3 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 3 together to form oxo, or two R on the same carbon 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different carbons 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, halogen, or C1-C6 alkyl, R 8 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , -S(=O)2NR 10 R 11 , -P(=O)(OR 10 )(OR 11 ), or -B(OR 10 )(OR 11 ) and R 9is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be selected from one or more R 9a is optionally replaced by Each R 9a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 9a together to form oxo, R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by or R 10 and R 11 together with the atoms to which they are attached form one or more R 10b forming a heterocycloalkyl optionally substituted with Each R 10a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c Rd , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10a together to form oxo, Each R 10b are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10b together to form oxo, Ring B is phenyl or 6-membered heteroaryl; Each R 12 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b, -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 12 together to form oxo, or two R on different atoms 12 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1 ~C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo] are also disclosed herein.

[0108] In some embodiments, the compound of formula (II) is [ka] is.

[0109] In some embodiments of the compound of Formula (II), the compound is a compound of Formula (IIa): [ka] is.

[0110] In some embodiments of the compound of Formula (II), the compound is a compound of Formula (IIb): [ka] is.

[0111] In some embodiments of the compound of Formula (II), (IIa), or (IIb), Y is -N-. In some embodiments of the compound of Formula (II), (IIa), or (IIb), Y is -CR Y -It is.

[0112] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R Y is hydrogen, halogen, methyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R Y is hydrogen.

[0113] In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is cycloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is heterocycloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is phenyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is heteroaryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring A is 5- or 6-membered heteroaryl.

[0114] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 are independently halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1 is independently C1-C6 haloalkyl.

[0115] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 1a together form oxo. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 1a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0116] In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 0, 1, or 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 0 or 1. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 1 or 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 0. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 1. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), n is 3.

[0117] In some embodiments of compounds of Formula (II), (IIa), or (IIb), [ka] teeth, [ka] is.

[0118] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 4 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 4 is hydrogen.

[0119] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 5 is hydrogen.

[0120] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 6 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 6 is hydrogen.

[0121] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 7 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 7 is hydrogen.

[0122] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 8 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , or -S(=O)2NR 10 R 11 In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 8 is -C(=O)OR 9 In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 8 is -C(=O)NR 10 R 11 In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 8 is -S(=O)2NR 10 R 11 is.

[0123] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently selected from one or more R 9a In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 9 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R9 is hydrogen.

[0124] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 9a together form oxo. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 9a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0125] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11are each independently hydrogen or C1-C6 alkyl.

[0126] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10a together form oxo. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10ais independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0127] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b to form an optionally substituted heterocycloalkyl.

[0128] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10b together form oxo. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10b are independently halogen, -CN, -OH, -ORa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), each R 10b is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 10b are independently -OH, -OR a , or -NR c R d is.

[0129] In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is phenyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is a 6-membered heteroaryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is pyridinyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is pyrimidinyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), ring B is pyrazinyl.

[0130] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 12are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 12 is independently halogen, —CN, —OH, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 12 is independently —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 12 is independently C1 to C6 alkyl.

[0131] In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 0 or 1. In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 1 or 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 0. In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 1. In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), m is 3.

[0132] In some embodiments of compounds of Formula (II), (IIa), or (IIb), [ka] teeth, [ka] is.

[0133] A compound of formula (III), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] [In the formula, X is -N- or -CR X - and R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Y is -N- or -CR Y - and R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a is optionally replaced by or two R on the same atom 1 together to form oxo, Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 1a together to form oxo, n is 0, 1, 2, 3, or 4; L is absent, -O-, -S-, -NR 2 -, -C(R 3 )2, -C(R 3 )2-C(R 3 )2-, -C(R 3 )=C(R 3 )-, -C(R 3 )2O-, -OC(R 3 )2-, -C(R 3 )2S-, -SC(R 3 )2-, -C(R 3 )2NR 2 -, or -NR 2 C(R 3 )2- and R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; Each R 3 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 3 together to form oxo, or two R on the same carbon 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different carbons 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; L 1 is -[C(R 13 )2] p - and Each R 13 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 13 together to form oxo, or two R on the same carbon 13 together form a C2-C6 alkylidenyl optionally substituted with one or more R; or two R on adjacent carbons 13together to form a double bond, or two R on the same carbon 13 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 2, 3, or 4; R 14 and R 15 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R 14 and R 15 together form a heterocycloalkyl optionally substituted with one or more R; U is -C- or -N-; T is -C- or -N-; However, U and T cannot both be -N-. Ring B is a 5-membered heteroaryl or 5-membered heterocycloalkyl; Each R 12 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NRc R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 12 together to form oxo, or two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different atoms 12 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, 4, 5, or 6; or one R 12 and R Y together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1 ~C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo] are also disclosed herein.

[0134] In some embodiments of the compound of Formula (III), the compound is a compound of Formula (IIIa): [ka] is.

[0135] In some embodiments of the compound of Formula (III), the compound is a compound of Formula (IIIb): [ka] is.

[0136] In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), X is -N-. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), X is -CR X -It is.

[0137] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R X is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R X is hydrogen or halogen. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R X is hydrogen.

[0138] In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), Y is -N-. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), Y is -CR Y -It is.

[0139] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R Yis hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R Y is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R Y is hydrogen or halogen. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R Y is hydrogen.

[0140] In some embodiments of the compounds of Formula (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt, or stereoisomer thereof, L is absent, —O—, —C(R 3 )2, or -C(R 3 In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), L is absent, —O—, or —C(R 3 )2. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), L is absent or -O-. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), L is -O- or -C(R 3 )O-. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), L is absent. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), L is -O-. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), L is -C(R 3 )2.

[0141] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 2is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 2 is hydrogen.

[0142] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 3 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 3 is hydrogen.

[0143] In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is cycloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is heterocycloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is phenyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is heteroaryl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring A is 5- or 6-membered heteroaryl.

[0144] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1 are independently halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1is independently C1-C6 haloalkyl.

[0145] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 1a together form oxo. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 1ais independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0146] In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0, 1, or 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1 or 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 3.

[0147] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), [ka] teeth, [ka] is.

[0148] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 13 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R13 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 13 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), two R 13 together form a C2-C6 alkylidenyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), two R on adjacent carbons 13 In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), two R on the same carbon 13 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), two R on the same carbon 13 together form a cycloalkyl optionally substituted with one or more R.

[0149] In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), p is 2 or 3. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), p is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), p is 3. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), p is 4.

[0150] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0151] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, and each alkyl is independently optionally substituted with one or more R.

[0152] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), R 14 and R 15 together form a heterocycloalkyl optionally substituted with one or more R.

[0153] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), [ka] teeth, [ka] is.

[0154] In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is a 5-membered heteroaryl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is pyrazolyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is a 6-membered heteroaryl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), Ring B is pyridinyl. In some embodiments of the compound of Formula (III), (IIIa), or (IIIb), Ring B is a 5-membered heterocycloalkyl.

[0155] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 12 is independently halogen, —CN, —OH, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 12 is independently —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), each R 12 is independently C1 to C6 alkyl.

[0156] In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 1 or 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), m is 3.

[0157] In some embodiments of compounds of Formula (III), (IIIa), or (IIIb), [ka] teeth, [ka] is.

[0158] A compound of formula (IV), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] [In the formula, X is -N- or -CR X - and R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Y is -N- or -CR Y - and R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; W is -C(R 17 )2-, -O-, or -NR 18 - and Each R 17 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 17 together to form oxo, or two R on the same carbon 17together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R 18 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; R 19 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , -S(=O)2NR 10 R 11 , -P(=O)(OR 10 )(OR 11 ), or -B(OR 10 )(OR 11 ) and R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be selected from one or more R 9a is optionally replaced by Each R 9a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 9a together to form oxo, R 10 and R 11are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a is optionally replaced by or R 10 and R 11 together with the atoms to which they are attached form one or more R 10b forming a heterocycloalkyl optionally substituted with Each R 10a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10a together to form oxo, Each R 10b are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10b together to form oxo, Each R 1 are independently halogen, -CN, -OH, -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; n is 0, 1, 2, 3, or 4; R 16 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring B is a 5-membered heteroaryl or 5-membered heterocycloalkyl; Each R 12 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )Rb , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 12 together to form oxo, or two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different atoms 12 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, 4, 5, or 6; or one R 12 and R Y together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each Ra are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1 ~C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo] are also disclosed herein.

[0159] In some embodiments of the compound of Formula (IV), X is -N-. In some embodiments of the compound of Formula (IV), X is -CR X -It is.

[0160] In some embodiments of the compound of Formula (IV), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), R X is hydrogen.

[0161] In some embodiments of the compound of Formula (IV), Y is -N-. In some embodiments of the compound of Formula (IV), Y is -CR Y -It is.

[0162] In some embodiments of the compound of Formula (IV), R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), R Y is hydrogen.

[0163] In some embodiments of the compound of Formula (IV), W is —C(R 17 )2-. In some embodiments of the compound of Formula (IV), W is -O-. In some embodiments of the compound of Formula (IV), W is -NR 18 -It is.

[0164] In some embodiments of the compound of Formula (IV), each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), each R 17 is hydrogen.

[0165] In some embodiments of the compound of Formula (IV), R 18 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), R 18 is hydrogen.

[0166] In some embodiments of the compound of Formula (IV), R 19 is -C(=O)OR 9 , -C(=O)NR 10 R 11 , or -S(=O)2NR 10 R 11 In some embodiments of the compound of Formula (IV), R 19 is -C(=O)OR 9 In some embodiments of the compound of Formula (IV), R 19 is -C(=O)NR 10 R 11 In some embodiments of the compound of Formula (IV), R 19 is -S(=O)2NR 10 R11 is.

[0167] In some embodiments of the compound of Formula (IV), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of the compound of Formula (IV), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 9a In some embodiments of the compound of Formula (IV), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently selected from one or more R 9a In some embodiments of the compound of Formula (IV), R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (IV), R 9 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), R 9 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R9 is hydrogen.

[0168] In some embodiments of the compound of Formula (IV), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 9a together form oxo. In some embodiments of the compound of Formula (IV), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 9a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 9a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0169] In some embodiments of the compound of Formula (IV), R10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of the compound of Formula (IV), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, aryl, and heteroaryl is independently selected from one or more R 10a In some embodiments of the compound of Formula (IV), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), R 10 and R 11 are each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), R 10 and R 11 are each independently hydrogen or C1-C6 alkyl.

[0170] In some embodiments of the compound of Formula (IV), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c Rd , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10a together form oxo. In some embodiments of the compound of Formula (IV), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 10a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0171] In some embodiments of the compound of Formula (IV), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b to form an optionally substituted heterocycloalkyl.

[0172] In some embodiments of the compound of Formula (IV), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10b together form oxo. In some embodiments of the compound of Formula (IV), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (IV), each R 10b is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a, -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl.

[0173] In some embodiments of the compound of formula (IV), [ka] teeth, [ka] is.

[0174] In some embodiments of the compound of Formula (IV), each R 10b are independently -OH, -OR a , or -NR c R d is.

[0175] In some embodiments of the compound of Formula (IV), R 16 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), R 16 is C1-C6 haloalkyl.

[0176] In some embodiments of the compound of Formula (IV), ring B is a 5-membered heteroaryl. In some embodiments of the compound of Formula (IV), ring B is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of the compound of Formula (IV), ring B is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl. In some embodiments of the compound of Formula (IV), ring B is pyrazolyl. In some embodiments of the compound of Formula (IV), ring B is a 5-membered heterocycloalkyl.

[0177] In some embodiments of the compound of Formula (IV), each R 12 are independently halogen, -CN, -OH, -OR a, -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (IV), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (IV), each R 12 is independently halogen, —CN, —OH, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (IV), each R 12 is independently —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IV), each R 12 is independently C1 to C6 alkyl.

[0178] In some embodiments of the compound of Formula (IV), m is 0 or 1. In some embodiments of the compound of Formula (IV), m is 1 or 2. In some embodiments of the compound of Formula (IV), m is 0. In some embodiments of the compound of Formula (IV), m is 1. In some embodiments of the compound of Formula (IV), m is 2. In some embodiments of the compound of Formula (IV), m is 3.

[0179] In some embodiments of the compound of formula (IV), [ka] teeth, [ka] is.

[0180] A compound of formula (V), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] [In the formula, X is -N- or -CR X - and R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Y is -N- or -CR Y - and R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a is optionally replaced by or two R on the same atom 1 together to form oxo, Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 1a together to form oxo, n is 0, 1, 2, 3, or 4; L is absent, -O-, -S-, -NR 2 -, -C(R 3 )2, -C(R 3 )2-C(R 3 )2-, -C(R 3 )=C(R 3 )-, -C(R 3 )2O-, -OC(R 3 )2-, -C(R 3 )2S-, -SC(R 3 )2-, -C(R 3 )2NR 2 -, or -NR 2 C(R 3 )2- and R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; Each R 3 are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon 3 together to form oxo, or two R on the same carbon 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different carbons 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, halogen, or C1-C6 alkyl, R 10 is hydrogen or C1-C6 alkyl, and R 11 is one or more R 10a is a bicyclic heterocycloalkyl optionally substituted with or R 10 and R 11 together with the atoms to which they are attached form one or more R 10b forming a bicyclic heterocycloalkyl optionally substituted with Each R 10a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)Ra , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10a together to form oxo, Each R 10b are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NRc R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 10b together to form oxo, U is -C- or -N-; T is -C- or -N-; provided that U and T cannot both be -N-, except that when ring B is phenyl or 6-membered heteroaryl, then U and T are both -C-; Ring B is phenyl, 5- or 6-membered heteroaryl, or 5-membered heterocycloalkyl; Each R 12 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a, -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom 12 together to form oxo, or two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different atoms 12 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, 4, 5, or 6; or one R 12 and R Ytogether form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1 ~C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo] are disclosed herein.

[0181] In some embodiments of the compound of Formula (V), the compound is a compound of Formula (Va): [ka] wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

[0182] In some embodiments of the compound of Formula (V), the compound is a compound of Formula (Vb): [ka] wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

[0183] In some embodiments of the compound of Formula (V), the compound is a compound of Formula (Vc): [ka] wherein ring B is phenyl, 5- or 6-membered heteroaryl, or 5-membered heterocycloalkyl.

[0184] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0185] In some embodiments of the compound of Formula (V) or (Va)-(Vc), X is -N-. In some embodiments of the compound of Formula (V) or (Va)-(Vc), X is -CR X -It is.

[0186] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R X is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R X is hydrogen or halogen. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R X is hydrogen.

[0187] In some embodiments of the compound of Formula (V) or (Va)-(Vc), Y is -N-. In some embodiments of the compound of Formula (V) or (Va)-(Vc), Y is -CR Y -It is.

[0188] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R Y is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R Yis hydrogen or halogen. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R Y is hydrogen.

[0189] In some embodiments of compounds of Formula (V) or (Va)-(Vc), L is absent, —O—, —C(R 3 )2, or -C(R 3 In some embodiments of compounds of Formula (V) or (Va)-(Vc), L is absent, —O—, or —C(R 3 )2. In some embodiments of the compound of Formula (V) or (Va)-(Vc), L is absent or -O-. In some embodiments of the compound of Formula (V) or (Va)-(Vc), L is -O- or -C(R 3 )2O-. In some embodiments of the compound of Formula (V) or (Va)-(Vc), L is absent. In some embodiments of the compound of Formula (V) or (Va)-(Vc), L is -O-. In some embodiments of the compound of Formula (V) or (Va)-(Vc), L is -C(R 3 )2.

[0190] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 2 is hydrogen.

[0191] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 3 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R3 is hydrogen.

[0192]

[0192] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is cycloalkyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is heterocycloalkyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is aryl or heteroaryl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is phenyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is heteroaryl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring A is 5- or 6-membered heteroaryl.

[0193] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently selected from one or more R 1a In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 are independently halogen, -CN, -OH, -OR a, -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 are independently halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 is independently halogen or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 is independently C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1 are independently halogen.

[0194] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 1a together form oxo. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 1a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0195] In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 0, 1, or 2. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 0 or 1. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 1 or 2. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 0. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 1. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 2. In some embodiments of a compound of Formula (V) or (Va)-(Vc), n is 3.

[0196] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0197] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 4 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 4 is hydrogen.

[0198] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 5 is hydrogen.

[0199] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 6 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 6 is hydrogen.

[0200] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 7 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 7 is hydrogen.

[0201] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 is hydrogen and R11 is one or more R 10a In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 is hydrogen and R 11 is one or more R 10a In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 is hydrogen and R 11 is one or more R 10a In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 is hydrogen and R 11 is one or more R 10a is a bicyclic spiroheterocycloalkyl optionally substituted with

[0202] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 is hydrogen and R 11 teeth, [ka] , each of which is one or more R 10a is optionally replaced by

[0203] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10a together form oxo. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently halogen, -OH, -OR a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a is independently halogen, —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a is independently —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10a are independently —OH.

[0204] In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are attached form one or more R 10b In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are bonded, [ka] each of which contains one or more R 10b In some embodiments of compounds of Formula (V) or (Va)-(Vc), R 10 and R 11 together with the atoms to which they are bonded, [ka] each of which contains one or more R 10b is optionally replaced by

[0205] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R, or two R on the same atom. 10b together form oxo. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b are independently -OH, -OR a , or -NR c R d In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b is independently —OH, C1-C6 alkoxyl, or amino. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 10b is independently —OH. In some embodiments of compounds of Formula (V) or (Va)-(Vc), at least one R 10b is -OH.

[0206] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0207] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0208] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0209] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0210]

[0210] In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is phenyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is a 5-membered heteroaryl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is pyrazolyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is a 6-membered heteroaryl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is pyridinyl. In some embodiments of the compounds of Formula (V) or (Va)-(Vc), ring B is a 5-membered heterocycloalkyl.

[0211] In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 12 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 12 is independently halogen, —CN, —OH, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 12 is independently —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V) or (Va)-(Vc), each R 12 is independently C1 to C6 alkyl.

[0212] In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 0 or 1. In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 1 or 2. In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 0. In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 1. In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 2. In some embodiments of the compound of Formula (V) or (Va)-(Vc), m is 3.

[0213] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] teeth, [ka] is.

[0214] In some embodiments of compounds of Formula (V) or (Va)-(Vc), [ka] is.

[0215] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1 to C6 alkyl.

[0216] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b is independently C1 to C6 alkyl.

[0217] In some embodiments of the compounds disclosed herein, R c and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), where each alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d and R are each hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1 to C6 alkyl.

[0218] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0219] In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —SF, —NH, —NHC-C alkyl, —N(C-C alkyl), —C(═O)C-C alkyl, —C(═O)OH, —C(═O)OC-C alkyl, —C(═O)NH, —C(═O)NHC-C alkyl, —C(═O)N(C-C alkyl), —P(═O)(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —SF, —NH, —NHC alkyl, —N(C-C alkyl), —P(═O)(C-C alkyl), C-C alkyl, C-C alkoxy, or C-C haloalkyl, or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom form oxo.

[0220] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9a , R 10 , R 10a , R 10b , R 11 , R12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R X , R Y , R a , R b , R c , and R d One or more of the groups contains a percentage of deuterium that is higher than the natural abundance of deuterium.

[0221] In some embodiments of the compounds disclosed herein, one or more 1 H is the following R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9a , R 10 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R X , R Y , R a , R b , R c , and R d One or more of the groups are replaced with one or more deuterium atoms.

[0222] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 9a , R 10 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R X , R Y , R a , R b , R c , and R d The abundance of deuterium in each of is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0223]

[0223] In some embodiments of the compounds disclosed herein, one or more of ring A or ring B may be 1 H is replaced by one or more deuterium atoms.

[0224]

[0224] All combinations of the groups described above for the various variables are contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0225]

[0225] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, is one of the compounds in Table 1.

[0226] [Table 1-1]

[0227]

Table 1-2

[0228]

Table 1-3

[0229]

Table 1-4

[0230]

Table 1-5

[0231]

Table 1-6

[0232]

Table 1-7

[0233]

Table 1-8

[0234]

Table 1-9

[0235]

Table 1-10

[0236]

Table 1-11

[0237]

Table 1-12

[0238] [Table 1-13]

[0239] [Table 1-14]

[0240] [Table 1-15]

[0241] [Table 1-16]

[0242] [Table 1-17]

[0243] [Table 1-18]

[0244] [Table 1-19]

[0245] [Table 1-20]

[0246]

[0226] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, is one of the compounds in Table 2.

[0247] [Table 2-1]

[0248] [Table 2-2]

[0249] [Table 2-3]

[0250] [Table 2-4]

[0251] [Table 2-5]

[0252] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers produced from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0253]

[0228] Unless otherwise stated, in this disclosure, solid wedge shapes ( [ka] ) and dashed wedge ( [ka] ) are used to indicate the absolute configuration of a chiral center, and solid lines ( [ka] ) and dashed lines ( [ka] ) are used to indicate the relative configuration of chiral centers, and wavy lines ( [ka] ) are bonds represented by (1) solid wedge ( [ka] ) or dashed wedge ( [ka] ) or (2) solid line ( [ka] ) or dashed line ( [ka] ) is used to indicate

[0254] Isotopically enriched compounds

[0229] Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, which are 1 H (protium), 2 H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium can provide several therapeutic advantages, such as increased half-life and / or exposure in vivo, or can provide compounds useful for investigating in vivo pathways of drug excretion and metabolism.

[0255] For example, the compounds described herein may be artificially enriched with one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes not primarily found in nature. In some embodiments, the compounds described herein may be artificially enriched with deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes selected from: 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125It may be artificially enriched with one or more isotopes selected from I. In some embodiments, the abundance of the enriched isotopes is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0256] In some embodiments, the compounds are deuterated at at least one position. In some embodiments, the compounds disclosed herein are deuterated at some or all of the positions. 1 H atoms 2 It is replaced by a H atom.

[0257]

[0232] Synthetic methods for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedures described in US Pat. Nos. 5,846,514 and 6,334,997, as well as the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, Dennis C. (ed.); Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; Vol. 6 (No. 10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, Vol. 45 (No. 21), pp. 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, Vol. 64 (No. 1-2), pp. 9-32.

[0258] Deuterated starting materials are readily available and, when subjected to the synthetic methods described herein, result in the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical vendors, such as Aldrich Chemical Co.

[0259] pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0260] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by separately reacting the purified free form of the compound with the appropriate acid or base and isolating the salt thus formed.

[0261] Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds described herein with an inorganic, organic acid, or inorganic base, including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ- hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0262] Additionally, the compounds described herein can be prepared by dissolving the free base form of the compounds in a pharmaceutically acceptable inorganic or organic acid, such as, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. The compounds can be prepared as pharmaceutically acceptable salts formed by reaction with inorganic or organic acids, including organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, are utilized in the preparation of salts useful as intermediates to obtain the compounds disclosed herein, or stereoisomers thereof and their pharmaceutically acceptable acid addition salts.

[0263]

[0238] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, etc. of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4alkyl)4.

[0264] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0265] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0266] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processing described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0267] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom with the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0268] Treatment methods

[0243] Disclosed herein is a method for treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a TEAD inhibitor described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition described herein.

[0269]

[0244] In some embodiments, the disease is mediated by TEAD activity.

[0270] In some embodiments, the disease is an advanced solid tumor. In some embodiments, the disease is a solid tumor. In some embodiments, the disease is cancer or a proliferative disorder. In some embodiments, the cancer is associated with increased TEAD expression. In some embodiments, the cancer is associated with increased TEAD activity.

[0271]

[0246] In some embodiments, the cancer is one in which YAP is localized in the nucleus of cancer cells.

[0272] In some embodiments, the increased TEAD expression or activity is increased TEAD1 expression or activity. In some embodiments, the increased TEAD expression or activity is increased TEAD2 expression or activity. In some embodiments, the increased TEAD expression or activity is increased TEAD3 expression or activity. In some embodiments, the increased TEAD expression or activity is increased TEAD4 expression or activity.

[0273] In some embodiments, the disease is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic lung carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, Intestinal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), germ cell carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hemangioendothelioma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle Sarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer (NMC), midline myeloma (MTM), thyroid carcinoma (NTM), and thyroid carcinoma (NTM). Lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, malignant synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular cancer, uterine cancer, or Wilms' tumor.

[0274]

[0249] Also disclosed herein is a method for treating cancer in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0275] In some embodiments of the methods of treating cancer, the cancer is mesothelioma. In some embodiments of the methods of treating cancer, the cancer is NF2-deficient mesothelioma.

[0276]

[0251] In some embodiments of the methods of treating cancer, the cancer is epithelioid hemangioendothelioma.

[0277] In some embodiments of the methods of treating cancer, the cancer is a liquid tumor. In some embodiments of the methods of treating cancer, the cancer is a solid tumor.

[0278]

[0253] The method of claim 222, wherein the solid tumor has an NF2 mutation, a LATS1 mutation, a LATS2 mutation, or any combination thereof. In some embodiments of the methods of treating cancer, the solid tumor has an NF2 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a LATS1 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a LATS2 mutation. In some embodiments of the methods of treating cancer, the solid tumor has a YAP1 / TAZ gene fusion.

[0279]

[0254] Also disclosed herein is a method for treating a disease in which Hippo pathway inhibition is beneficial in a subject in need of treatment, comprising administering to a subject in need of treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0280] dosage In certain embodiments, compositions containing a compound(s) described herein are administered for therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging studies.

[0281]

[0256] In certain embodiments in which the patient's condition does not improve, at the physician's discretion, the compound is administered chronically, i.e., for an extended period of time, including over the patient's lifetime, to improve or control or limit the symptoms of the patient's disease or condition.

[0282]

[0257] Once improvement of the patient's condition occurs, a maintenance dose is administered if necessary, followed in certain embodiments by a reduction in the dosage or frequency of administration, or both, as a function of symptoms.

[0283]

[0258] The amount of a given drug corresponding to such an amount will vary depending on factors such as the particular compound, the condition and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), and the like, but will be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0284] In some embodiments, dosages utilized for adult human treatment typically range from 0.01 mg to 5000 mg per day. In some embodiments, suitable daily dosages for the compounds described herein, or pharmaceutically acceptable salts thereof, are from about 0.01 to about 50 mg / kg of body weight. In various embodiments, the daily dosage and unit dosage will vary depending on several variables, including, but not limited to, the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0285] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0286] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is selectively absorbed by that organ. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation.

[0287] Pharmaceutical Compositions / Formulations

[0262] The compounds described herein are administered to a subject in need thereof, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, as a pharmaceutical composition according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0288]

[0263] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically usable preparation. The proper formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference for such disclosures.

[0289]

[0264] In some embodiments, the pharmaceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrating agent, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a wetting agent, a plasticizer, a stabilizer, a transdermal absorption enhancer, a humectant, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0290] Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsed release formulations, multiple granule formulations, and mixed immediate and controlled release formulations.

[0291] combination

[0266] Disclosed herein are methods for treating diseases or disorders associated with TEAD using the compounds disclosed herein, or pharmaceutically acceptable salts, or stereoisomers thereof, in combination with an additional therapeutic agent.

[0292] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0293]

[0268] In some embodiments, the additional therapeutic agent is an anti-cancer agent. [Example]

[0294]

[0269] The following examples are offered to illustrate, but not to limit, the claimed invention. The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope.

[0295] The following synthetic schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods for making the compounds described herein. Those skilled in the art will understand that these compounds can be produced by similar methods or by combining other methods known to those skilled in the art. Those skilled in the art will also understand that they can be produced in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial sources, synthesized according to literature known to those skilled in the art, or prepared as described herein.

[0296] Example 1 [ka] Step 1: Preparation of Compound 1-1 To a solution of 7-bromo-5-nitro-1H-indazole (9.80 g, 40.49 mmol) in THF (10.0 mL) was added NaH (1.94 g, 48.5 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for 30 minutes, then cooled to 0° C., and SEM-Cl (8.10 g, 48.5 mmol, 8.6 mL) was added. The mixture was then stirred at 25° C. for 3 hours and filtered. The reaction mixture was poured into HO (200 mL) and then extracted with EtOAc (40 mL × 5). The organic layer was washed with brine (60 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 1-1 (13.0 g, 34.9 mmol, 86.2% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 5.91 (s, 2H), 3.77 - 3.68 (m, 2H), 3.37 (s, 2H), 0.98 - 0.89 (m, 2H), 0.01 (s, 9H).

[0297] Step 2: Preparation of Compound 1-2 To a mixture of compound 1-1 (4.00 g, 10.7 mmol) and NH4Cl (4.02 g, 75.2 mmol) in EtOH (15 mL) and HO (15 mL) was added Fe (4.20 g, 75.2 mmol) in three portions. The mixture was stirred at 80 °C for 3 h, and the iron powder was removed by filtration. Ethanol was removed, and the residue was extracted with EtOAc (50 mL x 2) and HO (100 mL). The organic layer was dried over Na2SO4 and concentrated. Compound 1-2 (3.50 g, 10.2 mmol, 76.1% yield) was purified by column chromatography. LCMS: 342.0 [M+H] + .

[0298] Step 3: Preparation of Compounds 1-3 A mixture of compound 1-2 (3.00 g, 8.76 mmol) in HCl (12 M, 14.6 mL) and HO (15.0 mL) was cooled to 0 °C, and NaNO (1.81 g, 26.2 mmol) was added. The reaction was stirred at 0 °C for 30 min, and a mixture of NaI (9.20 g, 61.3 mmol) and CuI (834 mg, 4.38 mmol) in HO (5.0 mL) was added dropwise, and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with NaSO (aqueous, 30 mL), neutralized with NaCO (aqueous, 30 mL), and extracted with EtOAc (30 mL × 2). The organic layer was dried over NaSO and concentrated. The residue was purified by HPLC to give compound 1-3 (700 mg, 2.16 mmol, 24.5% yield). LCMS: 322.8 [M+H] + .

[0299] Step 4: Preparation of Compounds 1-4 To a solution of compound 1-3 (700 mg, 2.17 mmol) in THF (10.0 mL) was added NaH (173 mg, 4.34 mmol, purity 60.0%) portionwise at 0° C. After stirring at 25° C. for 0.5 h, SEM-Cl (542 mg, 3.25 mmol, 575 μL) was added dropwise, and the resulting mixture was stirred at 25° C. for 1 h. NH4Cl (aqueous, 30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 1-4 (600 mg, 1.32 mmol, yield 60.8%). LCMS: 455.0 [M+H] + .

[0300] Step 5: Preparation of Compounds 1-5 A mixture of compound 1-4 (600 mg, 1.32 mmol), (4-(trifluoromethyl)phenyl)boronic acid (226 mg, 1.19 mmol), Pd(dppf)Cl (96.8 mg, 1.32 mmol), and KCO (365 mg, 2.65 mmol) in dioxane (10 mL) and HO (3 mL) was stirred at 80 °C for 3 h under a N atmosphere. The reaction mixture was extracted with EtOAc (10 mL × 2) and HO (10 mL). The organic layer was dried over NaSO and concentrated, and the residue was purified by column chromatography to give compound 1-5 (500 mg, 1.06 mmol, 80.3% yield). LCMS: 473.0 [M+H] + .

[0301] Step 6: Preparation of Compounds 1-6 A mixture of compound 1-5 (700 mg, 1.48 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (356 mg, 1.48 mmol), Pd(dppf)Cl (108 mg, 1.48 mmol), and KCO (615 mg, 4.45 mmol) in dioxane (10 mL) and HO (2 mL) was stirred at 90 °C for 2 h under a N atmosphere. The reaction mixture was extracted with EtOAc (50 mL × 2) and HO (50 mL). The organic layer was dried over NaSO and concentrated, and the residue was purified by column chromatography to give compound 1-6 (250 mg, 0.49 mmol, 33.18% yield). LCMS: 505.3 [M+H] + .

[0302] Step 7: Preparation of Compounds 1-7 A solution of compound 1-6 (150 mg, 0.30 μmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 25° C. for 3 h. The mixture was concentrated, and to the residue was added EtOH (2.0 mL) and NH3·H2O (0.5 mL). The mixture was stirred at 25° C. for 0.5 h and concentrated to give compound 1-7 (100 mg, crude). LCMS: 375.2 [M+H] + .

[0303] Step 8: Preparation of Example 1 To a solution of compound 1-7 (40.0 mg, 106 μmol) in dioxane (3.0 mL) and HO (1.0 mL), LiOH·HO (13.4 mg, 320 μmol) was added, and the mixture was stirred at 25° C. for 1 h. The reaction was neutralized with HCl (1 M) to around pH 7, poured into HO (10 mL), and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated. The residue was purified by preparative HPLC to give Example 1 (12.5 mg, 36.1 μmol, 33.8% yield). LCMS: 347.2 [M+H] + . 1HNMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.86–7.83 (m, 2H), 7.75–7.72 (m, 2H), 7.36 (s, 1H), 2.92–2.87 (m, 1H), 2.12–2.08 (m, 1H), 1.72–1.68 (m, 1H), 1.58–1.53 (m, 1H).

[0304] Examples 2 and 3 [ka] Step 1: Preparation of Compound 2-1 and Compound 3-1 To a solution of compound 1-7 (100 mg, 267 μmol) in THF (2 mL) was added NaH (21.3 mg, 534 μmol, purity 60.0%) portionwise at 0° C. After stirring at 25° C. for 1 h, MeI (75.8 mg, 534 μmol, 33.2 μL) was added dropwise, and the resulting mixture was stirred at 25° C. for 1 h. Aqueous NH4Cl (10 mL) was added to the mixture, which was then extracted with EtOAc (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give a mixture of compound 2-1 (40.0 mg, 102 μmol, yield 38.1%) and compound 3-1 (50 mg, 126 μmol, yield 47.31%).

[0305]

[0280] Compound 2-1:LCMS:389.2[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.92 (s, 1H), 7.68 (s, 5H), 7.21 (s, 1H), 4.21–4.17 (m, 5H), 3.05–2.99 (m, 1H), 2.61–2.49 (m, 1H), 1.92–1.79 (m, 1H), 1.79–1.66 (m, 1H), 1.31–1.27 (m, 3H).

[0306]

[0281] Compound 3-1:LCMS:389.2[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.78 (s, 1H), 7.68 (s, 4H), 7.30 (s, 1H), 4.37 (s, 3H), 4.30–4.15 (m, 2H), 3.10–3.05 (m, 1H), 2.13–1.97 (m, 1H), 1.75–1.72 (m, 1H), 1.63–1.53 (m, 1H), 1.35–1.31 (m, 3H).

[0307] Step 2: Preparation of Example 2 To a solution of compound 2-1 (50.0 mg, 0.129 mmol) in dioxane (3 mL) and HO (1 mL) was added LiOH·HO (20.0 mg, 0.386 mmol), and the reaction was stirred at 25° C. for 2 h. The reaction was neutralized with HCl (1 M) to around pH 7, poured into HO (10 mL), and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over NaSO, concentrated, and the residue was purified by preparative HPLC to give Example 2 (20.0 mg, 0.055 mmol, 53.8% yield). LCMS: 361.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.25 (s, 1H), 7.84–7.80 (m, 3H), 7.73–7.71 (m, 2H), 7.28–7.27 (m, 1H), 4.24 (s, 3H), 3.01–2.96 (m, 1H), 2.30–2.25 (m, 1H), 1.82–1.78 (m, 1H), 1.66–1.61 (m, 1H).

[0308] Step 3: Preparation of Example 3 Example 3 (21.2 mg, 0.059 mmol, 45.6% yield) was prepared following a procedure similar to that of Example 2, starting from compound 3-1 (50.0 mg, 0.129 mmol). LCMS: 361.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.93–7.92 (m, 1H), 7.84–7.82 (m, 2H), 7.74–7.72 (m, 2H), 7.46–7.45 (m, 1H), 4.38 (s, 3H), 3.12–3.07 (m, 1H), 2.02–1.98 (m, 1H), 1.71–1.67 (m, 2H).

[0309] Example 4 [ka] Step 1: Preparation of compound 4-1 A mixture of compound 1-3 (1.20 g, 8.85 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.52 g, 7.21 mmol), K2CO3 (3.67 g, 26.5 mmol), and Pd(dppf)Cl2 (0.65 g, 0.885 mmol) in dioxane (20 mL) and HO (5 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 100 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 4-1 (2.70 g, 9.27 mmol, crude product). LCMS: 341.0 [M+H] + .

[0310] Step 2: Preparation of compound 4-2 A mixture of compound 4-1 (1.20 g, 3.51 mmol), 3-fluoropyridine (6.83 g, 70.3 mmol), and K2CO3 (0.97 g, 7.035 mmol) in DMF (20 mL) was degassed and purged with N2 three times, then stirred at 120 °C under microwave conditions for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 4-2 (400 mg, 9.27 mmol, crude product). LCMS: 419.2 [M+H] + .

[0311] Step 3: Preparation of compound 4-3 A mixture of compound 4-2 (400 mg, 9.27 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (0.90 g, 3.73 mmol), K2CO3 (1.03 g, 7.46 mmol), and Pd(dppf)Cl2 (0.18 g, 0.25 mmol) in dioxane (10.0 mL) and HO (2.00 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 100 °C for 3 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give compound 4-3 (150 mg, 0.33 mmol, crude product). LCMS: 452.1 [M+H] + .

[0312] Step 4: Preparation of Example 4 To a solution of compound 4-3 (150 mg, 0.64 mmol) in THF (5.0 mL) was added a solution of LiOH (54.0 mg, 1.29 mmol) in HO (5.0 mL). The mixture was stirred at 65° C. for 24 hours. The reaction mixture was diluted with water (5.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were washed with brine (20.0 mL), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC to give Example 9 (30.0 mg, 0.07 mmol, 21.2% yield). LCMS: 424.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 2.5 Hz, 1H), 9.30 (s, 1H), 8.70 - 8.68 (m, 1H), 8.54 - 8.51 (m, 1H), 8.02 - 8.00 (m, 3H), 7.83 - 7.81 (m, 2H), 7.69 - 7.66 (m, 1H), 7.48 - 7.47 (m, 1H), 2.99 - 2.94 (m, 1H), 2.48 - 2.44 (m, 1H), 1.97 - 1.92 (m, 1H), 1.58-1.53 (m, 1H).

[0313] Example 5 [ka] Step 1: Preparation of compound 5-1 To a solution of 6-bromo-4-nitro-1H-indazole (9.00 g, 37.2 mmol) in THF (90.0 mL), NaH (2.97 g, 74.4 mmol, purity 60.0%) was added portionwise at 0-10° C., and the mixture was stirred at 25° C. for 1 h. SEM-Cl (9.30 g, 55.8 mmol, 9.87 mL) was added dropwise, and the mixture was stirred at 25° C. for 1 h. The mixture was poured into aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 5-1 (9.69 g, 26.0 mmol, 70.0% yield). LCMS: 374.1 [M+H]+ .

[0314] Step 2: Preparation of compound 5-2 A mixture of compound 5-1 (9.00 g, 24.2 mmol), Pd(dppf)Cl (1.77 g, 2.42 mmol), (4-(trifluoromethyl)phenyl)boronic acid (4.59 g, 24.2 mmol), and NaCO (7.69 g, 72.5 mmol) in dioxane (50 mL) and HO (20 mL) was stirred at 80 °C for 2 h under a N atmosphere. The mixture was poured into HO (100 mL) and extracted with EtOAc (100 mL). The combined organic layers were dried over NaSO and concentrated. The residue was purified by column chromatography to give compound 5-2 (9.20 g, 21.0 mmol, 87.0% yield). LCMS: 438.3 [M+H] + .

[0315] Step 3: Preparation of Compound 5-3 To a solution of Pd / C (0.50 g, 10% purity) in MeOH (20.0 mL) was added compound 5-2 (2.00 g, 4.57 mmol), and the mixture was stirred under H2 (15.0 psi) at 25 °C for 2 h. The mixture was filtered through Celite, and the solvent was removed to give crude compound 5-3 (2.10 g, crude product). LCMS: 408.2 [M+H] + .

[0316] Step 4: Preparation of compound 5-4 To a solution of compound 5-3 in HCl (10 mL) and H2O (10 mL) was added NaNO2 (508 mg, 7.36 mmol) at 0 °C. After stirring for 0.5 h, a mixture of CuI (234 mg, 1.23 mmol) and NaI (1.84 g, 12.3 mmol) in H2O (1.00 mL) was added dropwise, and the mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with aqueous Na2S2O3 (20.0 mL), neutralized with aqueous Na2CO3 (20.0 mL), extracted with EtOAc (60.0 mL), and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give compound 5-4. LCMS: 518.8 [M+H] + .

[0317] Step 5: Preparation of compound 5-5 A mixture of compound 5-4 (550 mg, 1.06 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (382 mg, 1.59 mmol), Pd(dppf)Cl (77.6 mg, 106 μmol), and NaCO (337 mg, 3.18 mmol) in dioxane (10.0 mL) and HO (5.00 mL) was stirred at 85° C. for 10 hours under a N atmosphere. The mixture was poured into water (200 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 5-5. LCMS: 505.2 [M+H] + .

[0318] Step 6: Preparation of Compounds 5-6-1 and 5-6-2 To a solution of compound 5-5 (750 mg, 1.49 mmol) in DCM (4 mL) was added TFA (2.31 g, 20.3 mmol, 1.50 mL). The mixture was stirred at 25° C. for 10 hours and concentrated to give a residue, which was purified by preparative HPLC to give compound 5-6-1 (100 mg, 267 μmol, yield 17.97%) and compound 5-6-2 (40.0 mg, 0.11 mmol, yield 7.38%).

[0319]

[0294] Compound 5-6-1:LCMS:375.2[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 8.23 ​​(s, 1H), 7.75–7.70 (m, 4H), 7.51 (s, 1H), 7.31 (s, 1H), 3.86–3.76 (m, 2H), 2.91–2.87 (m, 1H), 2.34–2.30 (m, 1H), 1.90–1.88 (m, 1H), 0.90–0.87 (m, 3H).

[0320]

[0295] Compound 5-6-2:LCMS:375.2[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 8.15 (s, 1H), 7.68–7.60 (m, 4H), 7.44 (s, 1H), 7.23 (s, 1H), 3.83–3.64 (m, 2H), 2.80 (q, J = 8.4 Hz, 1H), 2.28–2.22 (m, 1H), 1.83–1.78 (m, 1H), 1.48–1.43 (m, 1H), 0.81 (t, J = 7.1 Hz, 3H).

[0321] Step 7: Preparation of Example 5 To a solution of compound 5-6-1 (20.0 mg, 53.4 μmol) in EtOH (2.00 mL) and HO (1 mL) was added LiOH.HO (2.24 mg, 53.4 μmol). The mixture was stirred at 25° C. for 2 hours and concentrated to give a residue, which was purified by preparative HPLC to give Example 5. LCMS: 347.2 [M+H] + . 1HNMR (400 MHz, methanol-d4) δ 8.19 (d, J = 1.0 Hz, 1H), 7.88–7.86 (m, 2H), 7.77–7.75 (m, 2H), 7.66 (s, 1H), 7.15 (s, 1H), 2.93–2.87 (m, 1H), 2.14–2.06 (m, 1H), 1.72–1.60 (m, 2H).

[0322] Examples 6 and 7 [ka] Step 1: Preparation of Compound 6-1 and Compound 7-1 A mixture of compound 6-1 and compound 7-1 (20.0 mg, 51.5 μmol, 32.1% yield) was prepared starting from compound 5-6-1 (60.0 mg, 155 μmol) following a procedure similar to that for compounds 2-1 and 3-1. LCMS: 389.2 [M+H] + .

[0323] Step 2: Preparation of Examples 6 and 7

[0298] Example 6 (15.0 mg, 41.5 μmol, 46.1%) and Example 7 (10.0 mg, 27.8 μmol, 30.8% yield) were prepared following procedures similar to those of Examples 2 and 3, starting from Compound 6-1 and Compound 7-1 (35.0 mg, 90 μmol).

[0324] Example 6 LCMS: 361.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 7.86–7.84 (m, 2H), 7.76–7.74 (m, 2H), 7.71 (s, 1H), 7.10 (s, 1H), 4.24 (s, 3H), 2.81–2.76 (m, 1H), 2.10–2.05 (m, 1H), 1.67–1.57 (m, 2H).

[0325] Example 7 LCMS: 361.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.41 (s, 1H), 8.13 (s, 1H), 7.90–7.88 (m, 2H), 7.77–7.75 (m, 2H), 7.67 (s, 1H), 7.13 (s, 1H), 4.11 (s, 3H), 2.89–2.80 (m, 1H), 2.09–2.02 (m, 1H), 1.69–1.63 (m, 1H), 1.59–1.50 (m, 1H).

[0326] Example 8 [ka] Example 8 (30.0 mg, 0.08 mmol, 80.8%) was prepared following procedures similar to those of Examples 6 and 7, starting from compound 5-6-2 (40.0 mg, 0.11 mmol). LCMS: 361.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 7.94–7.91 (m, 2H), 7.79–7.77 (m, 2H), 7.69 (s, 1H), 7.35 (s, 1H), 2.98–2.92 (m, 1H), 2.35–2.30 (m, 1H), 1.84–1.80 (m, 1H), 1.57–1.52 (m, 1H).

[0327] Example 9 [ka] Step 1: Preparation of compound 9-1 To a solution of 4-bromo-6-iodo-1H-indazole (600 mg, 1.86 mmol) and KF (432 mg, 7.43 mmol) in ACN (10.0 mL) was added diethyl (bromodifluoromethyl)phosphonate (992 mg, 3.72 mmol) under N at 25° C. for 2 hours. The mixture was stirred at 25° C. for 5 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×2). The organic layer was washed with brine (20 mL×2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 9-1 (200 mg, 0.54 mmol, 28.9%). LCMS: 374.8 [M+H] + .

[0328] Step 2: Preparation of compound 9-2 To a solution of compound 9-1 (200 mg, 0.54 mmol), (4-(trifluoromethyl)phenyl)boronic acid (91.7 mg, 0.48 mmol), and Pd(dppf)Cl (39.2 mg, 0.05 mmol) in dioxane (6 mL) and HO (2 mL) was added NaCO (114 mg, 1.07 mmol). The reaction was stirred at 80 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 9-2 (140 mg, 0.36 mmol, 66.7%). LCMS: 392.8 [M+H] + .

[0329] Step 3: Preparation of compound 9-3 To a solution of compound 9-2 (140 mg, 0.36 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (129 mg, 0.54 mmol), and Pd(dppf)Cl (26.2 mg, 0.04 mmol) in dioxane (3 mL) and HO (1 mL), KCO (98.9 mg, 0.72 mmol) was added, and the reaction was stirred at 80 °C under N for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC to give compound 9-3 (30.0 mg, 0.07 mmol, 19.8%). LCMS: 425.1 [M+H] + .

[0330] Step 4: Preparation of Example 9 To a solution of compound 9-3 (30.0 mg, 0.07 mmol) in EtOH (4 mL) and HO (2 mL) was added LiOH (5.93 mg, 0.14 mmol). The mixture was stirred at 60 °C for 30 min and concentrated. The residue was purified by preparative HPLC to give Example 9 (11.8 mg, 0.03 mmol, 42.5%). LCMS: 397.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.42–8.41 (m, 1H), 8.00–7.71 (m, 6H), 7.32 (s, 1H), 2.96–2.94 (m, 1H), 2.18–2.14 (m, 1H), 1.75–1.72 (m, 1H), 1.69–1.64 (m, 1H).

[0331] Example 10 [ka] Step 1: Preparation of compound 10-1 To a solution of 6-bromo-1-methyl-4-nitroindazole (10 g, 39.05 mmol) in EtOH (100 mL) was added a solution of NH4Cl (10.44 g, 195.27 mmol) in HO (50 mL) and Fe (10.90 g, 195.27 mmol). The mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 10-1 (4.2 g, 18.577 mmol, 47.57%). LCMS: 226.1 [M+H] + .

[0332] Step 2: Preparation of compound 10-2 To a solution of compound 10-1 (450 mg, 1.99 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (615 mg, 3.00 mmol), and Pd(dppf)Cl (146 mg, 0.20 mmol) in dioxane (3 mL) and HO (1 mL) was added KCO (825 mg, 5.97 mmol), and the reaction was stirred at 80 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 10-2 (600 mg, 1.95 mmol, 98.1%). LCMS: 308.3 [M+H] + .

[0333] Step 3: Preparation of compound 10-3 To a solution of compound 10-2 (400 mg, 1.30 mmol) in HCl (1 mL) and HO (1 mL) was added sodium nitrite (180 mg, 2.60 mmol) in HO (1 mL) slowly at 0 °C. The reaction was stirred at 0 °C for 30 min, and then CuI (18.6 mg, 0.10 mmol) and KI (648 mg, 3.91 mmol) were added slowly at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 10-3 (200 mg, 0.478 mmol, 36.74%). LCMS: 419.2 [M+H] + .

[0334] Step 4: Preparation of compound 10-4 To a solution of compound 10-3 (200 mg, 0.48 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (172 mg, 0.72 mmol), and Pd(dppf)Cl (70.0 mg, 0.10 mmol) in dioxane (4 mL) and HO (1 mL), KCO (198 mg, 1.44 mmol) was added, and the reaction was stirred at 80 °C under N for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 10-4 (30 mg, 0.074 mmol, 15.51%). LCMS: 405.2 [M+H] + .

[0335] Step 5: Preparation of Example 10 To a solution of compound 10-4 (50.0 mg, 0.12 mmol) in EtOH (4.0 mL) and HO (2.0 mL) was added LiOH (10.4 mg, 0.25 mmol), and the reaction was stirred at 25° C. for 2 h. The mixture was concentrated, and the residue was purified by preparative HPLC to give Example 10 (10.0 mg, 0.03 mmol). LCMS: 377.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.13 (s, 1H), 7.83–7.81 (m, 2H), 7.65 (s, 1H), 7.40–7.38 (m, 2H), 7.13 (s, 1H), 4.13 (s, 3H), 2.91–2.86 (m, 1H), 2.13–2.08 (m, 1H), 1.72–1.61 (m, 2H).

[0336] Example 11 Example 11 (10.0 mg, 0.03 mmol) was prepared following a procedure similar to that of Example 10 by replacing (4-(trifluoromethyl)phenyl)boronic acid with (4-isopropylphenyl)boronic acid. LCMS: 335.1 [M+H] + . 1 HNMR (400 MHz, methanol-d₄) δ 8.11 (s, 1H), 7.66–7.64 (m, 2H), 7.60 (s, 1H), 7.37–7.35 (m, 2H), 7.13 (s, 1H), 4.12 (s, 3H), 3.01–2.94 (m, 1H), 2.90–2.85 (m, 1H), 2.11–2.06 (m, 1H), 1.71–1.60 (m, 2H), 1.32 (d, J = 6.9 Hz, 6H).

[0337] Example 12 Example 12 (30 mg, 0.138 mmol) was prepared from 6-bromo-1-methyl-4-nitroindazole together with 5-bromo-2-methyl-7-nitro-2H-indazole following a procedure similar to that of Example 10. LCMS: 377.2 [M+H]+ . 1 HNMR (400 MHz, methanol-d4) δ 8.23 ​​(s, 1H), 7.77–7.71 (m, 3H), 7.34 (d, J = 8.1 Hz, 2H), 7.24–7.23 (m, 1H), 4.25 (s, 3H), 3.02–2.97 (m, 1H), 2.30–2.25 (m, 1H), 1.82–1.78 (m, 1H), 1.67–1.62 (m, 1H).

[0338] Example 13 Example 13 (10 mg, 0.028 mmol) was prepared following a procedure similar to that of Example 10 by replacing 6-bromo-1-methyl-4-nitroindazole with 8-bromo-6-nitroquinoline. LCMS: 358.4 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.96–8.95 (m, 1H), 8.43–8.40 (m, 1H), 8.11–8.10 (m, 1H), 7.99–7.97 (m, 2H), 7.82–7.80 (m, 2H), 7.69–7.68 (m, 1H), 7.60–7.57 (m, 1H), 3.68–3.63 (m, 1H), 2.16–2.14 (m, 1H), 1.79–1.75 (m, 1H), 1.71–1.66 (m, 1H).

[0339] Example 14 Example 14 (15 mg, 41.3 μmol) was prepared following a procedure similar to that of Example 10 by replacing 6-bromo-1-methyl-4-nitroindazole with 4-bromo-6-nitrobenzo[d]thiazole. LCMS: 364.3 [M+H] + . 1HNMR (400 MHz, methanol-d4) δ 9.28 (s, 1H), 8.25 (s, 1H), 7.92–7.90 (m, 2H), 7.79–7.77 (m, 2H), 7.70 (s, 1H), 3.27–3.21 (m, 1H), 2.40–2.38 (m, 1H), 1.92–1.87 (m, 1H), 1.64–1.59 (m, 1H).

[0340] Example 15 [ka] Step 1: Preparation of compound 15-1 To a solution of methyl 4-bromo-2-iodo-6-methylbenzoate (3.00 g, 8.45 mmol) in CCl4 (30.0 mL) was added NBS (3.31 g, 18.5 mmol) and benzoic acid peroxyanhydride (1.02 g, 4.22 mmol). The mixture was stirred at 80 °C for 7 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give methyl 4-bromo-2-(bromomethyl)-6-iodobenzoate (3.20 g, 7.38 mmol, 87.3%). LCMS: 433.9 [M+H] + . To a solution of 4-bromo-2-(bromomethyl)-6-iodobenzoate (3.20 g, 7.37 mmol) in THF (30 mL) was added methanamine (0.60 g, 18.43 mmol). The mixture was stirred and heated at 50 °C for 8 hours. The reaction mixture was diluted with H O (50 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography to give compound 15-1 (1.10 g, 3.12 mmol, 42.4%). LCMS: 351.8 [M+H] + .

[0341] Step 2: Preparation of Example 15 Example 15 (15.0 mg, 0.04 mmol) was prepared following a procedure similar to that of Example 10 by replacing compound 10-3 with compound 15-1. LCMS: 398.2 [M+Na] + . 1 HNMR: (400 MHz, methanol-d4) δ 7.87 - 7.85 (m, 2H), 7.79 - 7.77 (m, 2H), 7.68 (s, 1H), 7.26 (s, 1H), 4.52 (s, 2H), 3.90 - 3.85 (m, 1H), 3.20 (s, 3H), 2.03 - 1.99 (m, 1H), 1.71 - 1.66 (m, 1H), 1.61 - 1.56 (m, 1H).

[0342] Example 16, Examples 16a and 16b [ka] Step 1: Preparation of compound 16-1 To a solution of 4-(trifluoromethyl)phenol (15.7 g, 96.7 mmol) and 4-fluoro-2-methyl-1-nitrobenzene (10.0 g, 64.5 mmol) in DMF (20 mL) was added K2CO3 (8.90 g, 64.5 mmol), and the reaction was stirred at 80 °C for 5 h. The mixture was poured into water (200 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (100 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 16-1 (8.00 g, 26.9 mmol, 41.7%).

[0343] Step 2: Preparation of compound 16-2 To a solution of compound 16-1 (6000 mg, 20.2 mmol) and NH4Cl (3240 mg, 60.6 mmol) in EtOH (60 mL) and HO (30 mL), Fe (3380 mg, 60.6 mmol) was added, and the reaction was stirred at 60 °C for 2 h. The mixture was filtered and concentrated. The residue was poured into HO (50 mL) and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 16-2 (5.20 g, 19.5 mmol, 96.4%). LCMS: 268.1 [M+H] + .

[0344] Step 3: Preparation of compound 16-3 To a solution of compound 16-2 (5.20 g, 19.5 mmol) in ACN (60 mL) was added NBS (6.90 g, 38.9 mmol), and the reaction was stirred at 0° C. for 1 h. The mixture was concentrated, and the residue was purified by column chromatography to give compound 16-3 (4.60 g, 13.3 mmol, 68.3%). LCMS: 347.9 [M+H] + .

[0345] Step 4: Preparation of compound 16-4 To a solution of compound 16-3 (4.60 g, 13.3 mmol) in AcOH (38 mL) and H2O (10 mL) was added NaNO2 (0.90 g, 13.3 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated, diluted with H2O (200 mL), and extracted with EtOAc (40 mL × 3). The combined organic layer was washed with brine (120 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 16-4 (4.00 g, 11.2 mmol, 84.3%). LCMS: 358.9 [M+H] + .

[0346] Step 5: Preparation of compound 16-5 To a solution of compound 16-4 (3.00 g, 8.40 mmol) in EtOAc (30 mL) was added trimethyloxonium tetrafluoroborate (1.50 g, 10.1 mmol), and the reaction was stirred at 20° C. for 2 h. The reaction mixture was concentrated. The residue was purified by column chromatography to give compound 16-5 (2.50 g, 6.74 mmol, 80.2%). LCMS: 371.1 [M+H] + .

[0347] Step 6: Preparation of compound 16-6 To a solution of compound 16-5 (250 mg, 0.67 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (162 mg, 0.67 mmol), and Pd(dppf)Cl (493 mg, 0.67 mmol) in dioxane (6 mL) and HO (2 mL), KCO (93.1 mg, 0.67 mmol) was added, and the reaction was stirred at 80 °C under N for 2 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 16-6 (100 mg, 0.25 mmol, 36.7%). LCMS: 405.0 [M+H] + .

[0348] Step 7: Preparation of Example 16 To a solution of compound 16-6 (60.0 mg, 0.15 mmol) in EtOH (3 mL) and HO (1 mL) was added LiOH (12.5 mg, 0.30 mmol), and the reaction was stirred at 25° C. for 2 h. The mixture was concentrated. The residue was purified by preparative HPLC to give Example 16 (20.0 mg, 0.05 mmol, 35.8%). LCMS: 377.3 [M+H] + . 1HNMR (400 MHz, methanol-d4) δ 8.14 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 1.9 Hz, 1H), 4.22 (s, 3H), 2.94 - 2.91 (m, 1H), 2.24 - 2.13 (m, 1H), 1.69 - 1.67 (m, 1H), 1.62 - 1.58 (m, 1H)

[0349] Step 8: Chiral Separation of Examples 16a and 16b Racemic Example 16 (60 mg, 0.16 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD 250 mm x 30 mm, 10 μm; mobile phase: [CO₂-EtOH]; gradient: 20% to 20% B over 2.5 min) to give Example 16a (24 mg, 0.07 mmol, 43.8%). Retention time: 1.24 min. LCMS: 377.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.12 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 1.8 Hz, 1H), 4.22 (s, 3H), 2.98 - 2.88 (m, 1H), 2.23 - 2.15 (m, 1H), 1.68 - 1.58 (m, 2H)

[0350] Further Example 16b (19 mg, 0.05 mmol, 31.6%) was obtained. Retention time: 1.41 min. LCMS: 377.1 [M+H] + . 1HNMR (400 MHz, methanol-d₄) δ 8.11 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.15–7.03 (m, 3H), 6.77 (s, 1H), 4.22 (s, 3H), 2.89–2.82 (m, 1H), 2.14–2.05 (m, 1H), 1.54 (dt, J = 9.0, 4.5 Hz, 1H), 1.38 (dd, J = 16.7, 7.8 Hz, 1H).

[0351] Example 17 [ka] Step 1: Preparation of compound 17-1 To a solution of 6-methoxyquinolin-8-amine (4.00 g, 23.0 mmol) in ACN (50 mL) was added CuBr (0.10 g, 18.3 mmol). After stirring at room temperature for 30 minutes, 2-methyl-2-(nitrosooxy)propane (2.37 g, 23.0 mmol) was slowly added. The mixture was then stirred at 60 °C for 2 hours. The mixture was poured into H O (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography to give compound 17-1 (500 mg, 2.10 mmol, 9.10%). LCMS: 240.1 [M+H] + .

[0352] Step 2: Preparation of compound 17-2 To a solution of compound 17-1 (500 mg, 2.10 mmol) in DCM (15 mL) was added tribromoborane (526 mg, 2.10 mmol) at 0° C. The mixture was stirred at 25° C. for 3 hours, filtered, and concentrated to give compound 17-2 (400 mg, 1.78 mmol, 85.0%). LCMS: 224.1 [M+H] + .

[0353] Step 3: Preparation of compound 17-3 To a solution of compound 17-2 (400 mg, 1.78 mmol) and 1-fluoro-4-(trifluoromethyl)benzene (586 mg, 3.57 mmol) in DMF (5 mL) was added Cs2CO3 (1.75 g, 5.36 mmol). The reaction was stirred at 110 °C for 10 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 17-3 (250 mg, 0.68 mmol, 38.0%). LCMS: 370.1 [M+H] + .

[0354] Step 4: Preparation of compound 17-4 To a solution of compound 17-3 (200 mg, 0.54 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (130 mg, 0.54 mmol), and Pd(dppf)Cl (397 mg, 0.54 mmol) in dioxane (4 mL) and HO (1 mL) was added KCO (75.1 mg, 0.54 mmol), and the reaction was stirred at 80 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 17-4 (60.0 mg, 0.15 mmol, 27.5%).

[0355] Step 5: Preparation of Example 17 To a solution of compound 17-4 (100 mg, 0.25 mmol) in EtOH (4 mL) and HO (2 mL) was added LiOH (10.5 mg, 0.25 mmol), and the reaction was stirred at 25° C. for 2 h. The mixture was concentrated. The residue was purified by preparative HPLC to give Example 17 (20.0 mg, 0.05 mmol, 21.5%). LCMS: 374.2 [M+H] + . 1HNMR (400 MHz, chloroform-d): 9.03 (s, 1H), 8.16 - 8.14 (m, 1H), 7.68 - 7.66 (m, 2H), 7.54 - 7.53 (m, 1H), 7.24 - 7.20 (m, 2H), 7.16 - 7.14 (m, 2H), 3.74 - 3.69 (m, 1H), 1.98 - 1.94 (m, 1H), 1.90 - 1.86 (m, 1H), 1.64 - 1.59 (m, 1H).

[0356] Example 18 Example 18 (38.7 mg, 0.103 mmol) was prepared following a procedure similar to that of Example 17 by replacing 8-bromo-6-(4-(trifluoromethyl)phenoxy)quinoline with 4-bromo-1-methylindazol-6-ol. LCMS: 377.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.13 (s, 1H), 7.69–7.67 (m, 2H), 7.16–7.09 (m, 3H), 6.65 (s, 1H), 4.02–3.98 (m, 3H), 2.85 (s, 1H), 2.03 (brs, 1H), 1.66 (brs, 1H), 1.54 (brs, 1H).

[0357] Example 19 Example 19 (20.0 mg, 0.051 mmol) was prepared following a procedure similar to that of Example 17 by replacing 8-bromo-6-(4-(trifluoromethyl)phenoxy)quinoline with 4-bromo-1-methylindazol-6-ol and 1-fluoro-4-(trifluoromethyl)benzene with 1-(chloromethyl)-4-(trifluoromethyl)benzene. LCMS: 391.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.76 (dd, J = 26.2, 8.2 Hz, 4H), 7.09 (s, 1H), 6.57 - 6.56 (m, 1H), 5.30 (s, 2H), 3.99 (s, 3H), 2.70 - 2.66 (m, 1H), 2.02 - 1.92 (m, 1H), 1.53 - 1.49 (m, 2H).

[0358] Example 20 [ka] Step 1: Preparation of compound 20-1 To a solution of 1H-pyrrolo[3,2-b]pyridine (4.00 g, 33.8 mmol) in DMF (40.0 mL) was added 1-fluoro-4-(trifluoromethyl)benzene (6.11 g, 37.2 mmol) and CsCO (33.0 g, 101 mmol) under N. The reaction was stirred at 80 °C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (50 mL × 3), dried over NaSO, and filtered to give compound 20-1. LCMS: 263.1 [M+H] + .

[0359] Step 2: Preparation of compound 20-2 To a solution of compound 20-1 (1.00 g, 3.81 mmol) in DMF (15 mL) and ACN (15 mL) was added NIS (1.72 g, 7.62 mmol) under N2, and the reaction was stirred at 25 °C for 12 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 20-2. LCMS: 389.3 [M+H] + .

[0360] Step 3: Preparation of compound 20-3 To a solution of compound 20-2 (860 mg, 2.21 mmol) and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (798 mg, 3.32 mmol) in dioxane (10 mL) and HO (2 mL) was added KCO (918 mg, 6.64 mmol) and Pd(dppf)Cl (162 mg, 0.22 mmol). The mixture was degassed and purged with N three times and stirred at 100 °C for 12 h. The mixture was diluted with HO (5 mL) and extracted with EtOAc (10 mL × 4). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC to give compound 20-3. LCMS: 375.1 [M+H] + .

[0361] Step 4: Preparation of Example 20 To a solution of compound 20-3 (50.0 mg, 0.13 mmol) in THF (0.5 mL) and HO (0.5 mL) was added LiOH.HO (16.8 mg, 0.401 mmol) under N at 25 °C. The reaction was stirred at 40 °C for 3 h. 2 M HCl was added to adjust the pH to around 6, followed by the addition of EtOAc (10 mL). The organic phase was collected, and the aqueous layer was extracted with EtOAc (10.0 mL × 4). The combined organic layers were washed with HO (5 mL) and brine (5 mL), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC to give Example 20. LCMS: 347.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 4.6, 1.1 Hz, 1H), 8.06 (dd, J = 8.4, 1.1 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.27 (dd, J = 8.4, 4.6 Hz, 1H), 2.67 - 2.59 (m, 1H), 2.22 - 2.13 (m, 1H), 1.69 (td, J = 8.1, 3.6 Hz, 1H), 1.46 - 1.39 (m, 1H).

[0362] Example 21 Example 21 (20.0 mg, 0.051 mmol) was prepared following a procedure similar to that of Example 20 by replacing 1H-pyrrolo[3,2-b]pyridine with 5-methyl-1H-indole. LCMS: 358.1 [MH] - . 1 HNMR (400 MHz, methanol-d4) δ 7.85–7.83 (m, 2H), 7.74–7.72 (m, 2H), 7.54–7.49 (m, 2H), 7.34 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 2.60–2.55 (m, 1H), 2.48 (s, 3H), 1.89–1.84 (m, 1H), 1.60–1.55 (m, 1H), 1.48–1.43 (m, 1H).

[0363] Example 22 [ka] To a solution of Example 2 (20.0 mg, 55.5 μmol), HATU (158 mg, 0.42 mmol), and TEA (0.06 mL, 0.42 mmol) in DMF (1.0 mL) was added methanamine (17.2 mg, 0.56 mmol). The mixture was stirred under N at 25° C. for 2 h, then poured into H O (50 mL) and extracted with EtOAc (20 mL×2). The organic layer was washed with brine (20 mL×2), dried over Na SO , filtered, and concentrated. The residue was purified by preparative HPLC to give Example 22 (15.96 mg, 42.7 μmol, 76.9% yield). LCMS: 374.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.26 (s, 1H), 7.85–7.84 (m, 3H), 7.75–7.73 (m, 2H), 7.29–7.28 (m, 1H), 4.25 (s, 3H), 2.92–2.87 (m, 1H), 2.80 (s, 3H), 2.33–2.29 (m, 1H), 1.71–1.66 (m, 1H), 1.64–1.59 (m, 1H).

[0364] The following compounds in Table 3 were prepared according to the synthetic sequence in Example 22 using the corresponding starting materials.

[0365] [Table 3-1]

[0366] [Table 3-2]

[0367] [Table 3-3]

[0368] [Table 3-4]

[0369] [Table 3-5]

[0370] [Table 3-6]

[0371] [Table 3-7]

[0372] Example 40 [ka] Step 1: Preparation of compound 40-1 A mixture of compound 10-1 (2.00 g, 8.846 mmol), (2.52 g, 13.3 mmol), K2CO3 (3.67 g, 26.5 mmol), and Pd(dppf)Cl2 (0.65 g, 0.885 mmol) in dioxane (20 mL) and HO (5 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 100 °C for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 40-1 (2.70 g, 9.27 mmol, crude product). LCMS: 292.2 [M+H] + .

[0373] Step 2: Preparation of compound 40-2 To a solution of compound 40-1 (2.70 g, 9.27 mmol) in HO (10 mL) was added a solution of HCl (15.5 mL, 185 mmol) and sodium nitrite (1.92 g, 27.8 mmol) in HO (10 mL). The mixture was stirred at 0 °C for 0.5 h. Potassium iodide (7.69 g, 46.3 mmol) and copper(I) iodide (0.88 g, 4.64 mmol) in HO (10 mL) were added to the mixture, which was stirred at 25 °C for 2 h. The mixture was quenched with NaSO (30 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with NaHCO (100 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 40-2 (2.20 g, 5.47 mmol, 59.0%).

[0374] Step 3: Preparation of Example 40 To a solution of compound 40-2 (30.0 mg, 0.06 mmol) in DCM (1.0 mL) was added TFA (0.3 mL, 0.06 mmol), and the mixture was stirred at 25° C. under N atmosphere for 6 hours. The mixture was concentrated, and the residue was purified by reverse-phase HPLC to give Example 40 (6.14 mg, 0.02 mmol, 26.4%). LCMS: 410.0 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.98–7.96 (m, 2H), 7.83–7.79 (m, 3H), 7.63 (s, 1H), 5.93 (s, 1H), 7.85 (s, 1H), 4.45 (s, 2H), 4.16 (s, 3H), 3.51–3.43 (m, 5H), 2.65 (s, 3H).

[0375] Example 41 and Example 42 [ka] Step 1: Preparation of compound 41-1 To a solution of 1-(4-methoxyphenyl)-N-methylmethanamine (1.50 g, 9.92 mmol) in DCM (10 mL) was added TEA (4.83 mL, 34.7 mmol), followed by 2-chloroethane-1-sulfonyl chloride (1.78 g, 10.9 mmol) at 0° C. The mixture was stirred for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give N-(4-methoxybenzyl)-N-methylethenesulfonamide (2.00 g, 8.28 mmol, 83.5%). 1HNMR (400 MHz, methanol-d4) δ 7.36 - 7.22 (m, 2H), 6.97 - 6.90 (m, 2H), 6.73 - 6.58 (m, 1H), 6.20 (d, J = 16.5 Hz, 1H), 6.12 - 6.04 (m, 1H), 4.18 (s, 2H), 3.85 - 3.76 (m, 3H), 2.65 (s, 3H).

[0376] To a solution of compound 40-2 (150 mg, 0.37 mmol), N-(4-methoxybenzyl)-N-methylethenesulfonamide (135 mg, 0.56 mmol), and Pd(OAc) (8.37 mg, 0.04 mmol) in DMF (4 mL) was added TEA (0.16 mL, 1.12 mmol). The reaction was stirred at 80 °C for 2 h. The reaction mixture was poured into H O (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over Na SO , filtered, and concentrated. The residue was purified by preparative TLC to give compound 41-1 (80.0 mg, 0.16 mmol, 41.6%). LCMS: 516.1 [M+H] + .

[0377] Step 2: Preparation of Example 41 To a solution of compound 41-1 (100 mg, 0.194 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25° C. under N atmosphere for 2 hours. The mixture was concentrated. The crude product was purified by reverse-phase HPLC to give Example 41 (40.0 mg, 0.101 mmol, 52.1%). LCMS: 396.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.37 - 8.34 (m, 1H), 8.02 - 7.96 (m, 3H), 7.85 - 7.77 (m, 4H), 7.30 - 7.24 (m, 1H), 4.19 (s, 3H), 2.72 (s, 3H)

[0378] Step 3: Preparation of Example 42 To a solution of Example 41 (15.0 mg, 0.04 mmol) in MeOH (2 mL) was added Pd / C (20.0 mg, 10% purity) under an Ar atmosphere. The suspension was degassed and purged with H2 (0.01 g, 6.01 mmol) three times. The mixture was stirred under H2 (30 Psi) at 20 °C for 10 h. The mixture was filtered, the cake was washed with THF (5 mL x 3), and the filtrate was concentrated. The crude product was purified by reverse-phase HPLC to give Example 42 (8.63 mg, 0.02 mmol, 57.2%). LCMS: 398.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.80–7.72 (m, 3H), 7.40 (s, 1H), 4.13 (s, 3H), 3.51–3.43 (m, 5H), 2.74 (s, 3H).

[0379] Example 43 [ka] Step 1: Preparation of compound 43-1 To a solution of trimethylsulfoxide iodide (128 mg, 0.58 mmol) in DMSO (5 mL) was added NaH (23.2 mg, 0.58 mmol). After stirring at 25° C. for 0.5 h, a solution of compound 41-1 (100 mg, 0.19 mmol) in DMSO (5 mL) was added under N2. The reaction was stirred at 25° C. for 10 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (10 mL x 5). The organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to give compound 43-1 (30.0 mg, crude). LCMS: 530.1 [M+H] + .

[0380] Step 2: Preparation of Example 43 To a solution of compound 43-1 (50.0 mg, 0.12 mmol), 2-amino-N-methylacetamide (16.4 mg, 0.19 mmol), Pd(dba) (22.8 mg, 0.03 mmol), and Xantphos (36.0 mg, 0.06 mmol) in toluene (4 mL) was added CsCO (122 mg, 0.37 mmol), and the reaction was stirred at 100 °C under N for 6 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC to give Example 43 (8.19 mg, 0.03 mmol, 26.05%). LCMS: 263.4 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.94 - 7.88 (m, 3H), 7.85 - 7.79 (m, 2H), 7.14 (s, 1H), 6.22 (s, 1H), 4.00 (s, 4H), 3.88 (s, 3H), 2.61 (d, J = 4.6 Hz, 3H)

[0381] Example 44 [ka] Step 1: Preparation of compound 44-1 To a solution of 5-bromo-2-methyl-7-nitro-2H-indazole (1.00 g, 3.91 mmol), (4-(trifluoromethyl)phenyl)boronic acid (1.11 g, 5.86 mmol), and Pd(dppf)Cl (285 mg, 0.39 mmol) in dioxane (20 mL) and HO (5 mL) was added KCO (1.62 mg, 11.7 mmol). The reaction was stirred under N at 80 °C for 2 h. The mixture was poured into HO (100 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 44-1 (1.00 g, 3.11 mmol, 79.7%). LCMS: 322.3 [M+H]+ .

[0382] Step 2: Preparation of compound 44-2 To a solution of Pd / C (331 mg, 10%) in MeOH (10 mL) was added compound 44-1 (1.00 mg, 3.11 mmol), and the reaction was stirred at 25° C. for 3 h. The mixture was filtered and concentrated to give compound 44-2 (650 mg, 2.23 mmol, 71.7%). LCMS: 292.1 [M+H] + .

[0383] Step 3: Preparation of compound 44-3 To a solution of compound 44-2 (450 mg, 1.55 mmol) in HO (2 mL) and concentrated HCl (2.0 mL) was slowly added sodium nitrite (128 mg, 1.85 mmol) in HO (2.0 mL) at 0 °C, and the reaction was stirred at 0 °C for 30 min. Potassium iodide (769 mg, 4.63 mmol) in HO (2 mL) was slowly added, and the mixture was stirred at 25 °C for 1 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 44-3 (300 mg, 0.75 mmol, 48.29%). LCMS: 402.9 [M+H] + .

[0384] Step 4: Preparation of compound 44-4 To a solution of compound 44-3 (150 mg, 0.37 mmol), N-(4-methoxybenzyl)-N-methylethenesulfonamide (135 mg, 0.56 mmol), and Pd(OAc) (8.37 mg, 0.04 mmol) in DMF (4 mL), TEA (0.16 mL, 1.12 mmol) was added, and the reaction was stirred at 80 °C for 2 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 44-4 (80.0 mg, 0.16 mmol, 41.6%). LCMS: 516.1 [M+H] + .

[0385] Step 5: Preparation of compound 44-5 To a solution of compound 44-4 (60 mg, 0.12 mmol) in DCM (3 mL) was added TFA (0.20 mL, 0.04 mmol), and the reaction was stirred at 25° C. for 2 h. The mixture was poured into H2O (50 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to give compound 44-5 (50.0 mg, 0.13 mmol, crude). LCMS: 396.2 [M+H] +

[0386] Step 5: Preparation of Example 44 To a solution of Pd / C (13.5 mg, 10% purity) in MeOH (2 mL) was added compound 44-5 (50.0 mg, 0.13 mmol), and the reaction was stirred under H at 25° C. for 2 h. The mixture was filtered, and the liquid phase was concentrated. The residue was purified by preparative HPLC to give Example 44 (10.0 mg, 0.03 mmol, 19.9%). LCMS: 398.2 [M+H] + . 1HNMR (400 MHz, methanol-d4) δ 8.30 (s, 1H), 7.93 - 7.91 (m, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.52 (s, 1H), 4.60 (s, 1H), 4.27 (s, 3H), 3.65 - 3.58 (m, 2H), 3.53 - 3.44 (m, 2H), 2.77 (s, 3H).

[0387] Example 45 [ka] Step 1: Preparation of compound 45-1 To a solution of compound 16-5 (200 mg, 0.54 mmol), N-(4-methoxybenzyl)-N-methylethenesulfonamide (195 mg, 0.81 mmol), and palladium(0) bis[tris(2-methylprop-2-yl)phosphane] (27.5 mg, 0.05 mmol) in DMF (2 mL), TEA (0.22 mL, 1.62 mmol) was added, and the reaction was stirred at 100 °C for 2 h under microwave conditions. The mixture was poured into HO (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 45-1 (190 mg, 0.36 mmol, 66.3%). LCMS: 554.2 [M+Na] + .

[0388] Step 2: Preparation of compound 45-2 To a solution of compound 45-1 (200 mg, 0.38 mmol) in DCM (5 mL) was added TFA (0.50 mL, 0.38 mmol). The mixture was stirred for 2 hours and concentrated to give compound 45-2 (120 mg, 0.29 mmol, 77.5%). LCMS: 412.0 [M+H] + .

[0389] Step 3: Preparation of Example 45 A mixture of compound 45-2 (120 mg, 0.29 mmol) and Pd / C (310 mg, 10% purity) in MeOH (10 ml) was degassed and purged with H three times, and the mixture was stirred under H atmosphere at 25° C. for 3 hours. The mixture was filtered and concentrated. The residue was purified by reverse-phase HPLC to give Example 45 (35.3 mg, 0.08 mmol, 29.5%) as a white solid. LCMS: 414.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.17 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.99 - 6.98 (m, 1H), 4.24 (s, 3H), 3.59 - 3.53 (m, 2H), 3.43 - 3.39 (m, 2H), 2.75 (s, 3H).

[0390] Example 46 [ka] Step 1: Preparation of compound 46-1 A mixture of compound 44-2 (2 g, 6.87 mmol) and bromine (10 mL) in HO (10 mL) was cooled to 0 °C, and then sodium nitrite (0.5 g, 6.87 mmol) in HO (10 mL) was added. The mixture was stirred at 0 °C for 15 min, and then sodium nitrite (0.5 g, 6.87 mmol) and copper(I) bromide (1.1 g, 7.55 mmol) in HBr (10 mL) were slowly added. The mixture was stirred at 25 °C for 12 h, and saturated aqueous NaHCO was added to adjust the pH to around 7. The mixture was then extracted with EtOAc (5 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography to give compound 46-1 (1 g, 2.82 mmol, 41.0%). LCMS: 356.9 [M+H] + .

[0391] Step 2: Preparation of compound 46-2 A mixture of compound 46-1 (100 mg, 0.282 mmol), N-[(4-methoxyphenyl)methyl]ethenesulfonamide (83.2 mg, 0.366 mmol), palladium(0) bis[tris(2-methylprop-2-yl)phosphane] (14.4 mg, 0.028 mmol), and TEA (0.120 mL, 0.845 mmol) in DMF (1 mL) was stirred at 120 °C for 2 hours under microwave conditions. The reaction was quenched with HO (1 mL), extracted with EtOAc (1 mL × 3), washed with brine (1 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 46-2 (70 mg, 0.140 mmol, 49.6%). LCMS: 502.0 [M+H] + .

[0392] Step 3: Preparation of compound 46-3 To a solution of compound 46-2 (70 mg, 0.140 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added and stirred at 40° C. for 2 h. Saturated aqueous NaHCO was added to the mixture to adjust the pH to around 8, extracted with DCM (1 mL×3), dried over NaSO, filtered, and concentrated to give crude product compound 46-3 (60 mg, 0.157 mmol). LCMS: 763.3 [2M+H] + .

[0393] Step 3: Preparation of compound 46-4 To a solution of compound 46-3 (60 mg, 0.157 mmol) in 0.25 mL of DCM, acetyl chloride (38.5 mg, 0.472 mmol) in 1 mL of DCM and TEA (0.11 mL, 0.787 mmol) was added at 0° C. The mixture was stirred at 25° C. for 5 h, quenched by the addition of saturated aqueous NaHCO (1 mL), and then extracted with DCM (1 mL×3), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 46-4 (20.0 mg, 0.047 mmol, 30.0%). LCMS: 424.1 [M+H] + .

[0394] Step 4: Preparation of Example 46 A mixture of compound 46-4 (20.0 mg, 0.047 mmol) and Pd / C (2.00 mg, 10% purity) in MeOH (0.20 mL) was stirred under an H atmosphere at 25° C. The reaction was filtered, concentrated, and purified by preparative HPLC to give Example 46 (2.26 mg, 0.005 mmol, 28.2%). LCMS: 426.1 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.28 (s, 1H), 7.92–7.89 (m, 1H), 7.89–7.84 (m, 2H), 7.76–7.70 (m, 2H), 7.51–7.48 (m, 1H), 4.25 (s, 3H), 3.95–3.86 (m, 2H), 3.57–3.45 (m, 2H), 2.66 (s, 3H).

[0395] Example 47 [ka] Step 1: Preparation of compound 47-1 To a solution of 1-(4-methoxyphenyl)-N-methylmethanamine (1.00 g, 6.61 mmol) in DCM (10 mL) was added TEA (1.30 g, 13.2 mmol) and prop-2-ene-1-sulfonyl chloride (0.90 g, 6.61 mmol), and the reaction was stirred at room temperature for 18 hours. The reaction mixture was extracted with EtOAc (10 mL × 3), washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give the crude product N-(4-methoxybenzyl)-N-methylprop-2-ene-1-sulfonamide (71.9 mg, 0.28 mmol). This was further dissolved in DMF (1 mL), and compound 46-1 (100 mg, 0.282 mmol), TEA (0.12 mL, 0.85 mmol), and palladium(0) bis[tris(2-methylprop-2-yl)phosphane] (14.4 mg, 0.028 mmol) were added. The mixture was degassed, purged with N2 three times, and stirred at 130 °C under N2 atmosphere for 2 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc (2 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 47-1 (88.0 mg, 0.166 mmol, 59.0%). LCMS: 530.4 [M+H] + .

[0396] Step 2: Preparation of compound 47-2 A mixture of compound 47-1 (88.0 mg, 0.166 mmol) and TFA (1 mL, 0.161 mmol) in DCM (1 mL) was degassed and purged with N 3 times, and the mixture was stirred under N atmosphere at 25° C. for 2 h. Saturated aqueous NaHCO 3 was added to the mixture to adjust the pH to around 7. 10 mL water was added, extracted with EtOAc (2 mL×3), dried over Na 2 SO 4 , filtered, and concentrated to give compound 47-2 (63.0 mg, 0.15 mmol, 92.6%). LCMS: 410.3 [M+H] + ;

[0397] Step 3: Preparation of Example 47 To a solution of compound 47-2 (63.0 mg, 0.15 mmol) in MeOH (2 mL) was added Pd / C (30 mg, 10% purity) under N2 atmosphere. The suspension was degassed, purged with H2 three times, and stirred under H2 (15 Psi) at 25 °C for 12 h. The reaction was filtered, concentrated, and purified by preparative HPLC to give Example 47 (23.8 mg, 0.06 mmol, 37.6%). LCMS: 412.3 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.29 (s, 1H), 7.91 - 7.84 (m, 3H), 7.78 - 7.72 (m, 2H), 7.48 (s, 1H), 4.30 - 4.25 (m, 3H), 3.23 - 3.17 (m, 2H), 3.16 - 3.10 (m, 2H), 2.66 (s, 3H), 2.36 - 2.26 (m, 2H)

[0398] Example 48 [ka] Step 1: Preparation of compound 48-1 To a solution of 7-bromo-5-nitro-2H-indazole (5.00 g, 20.6 mmol) in EtOAc (50 mL) was added trimethyloxonium tetrafluoroborate (3.1 g, 20.6 mmol), and the reaction was stirred at 25° C. for 18 h. Concentration under reduced pressure removed EtOAc, and the residue was concentrated and the pH adjusted to around 8 with NaHCO solution. After filtration, the solid residue was washed with water (100 mL×3) and concentrated to give compound 48-1 (5.90 g, 19.5 mmol, crude product). 1 H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.81 (m, 1H), 8.15- 8.14 (m, 1H), 4.25 (s, 3H).

[0399] Step 2: Preparation of compound 48-2 To a solution of compound 48-1 (5.90 g, 19.5 mmol, crude product) in EtOH (60 mL) and HO (60 mL), Fe (5.10 g, 92.1 mmol) and NHCl (4.90 g, 92.1 mmol) were added under N, and the reaction was stirred at 80 °C for 2 h. The reaction was filtered, concentrated, and extracted with DCM (100 mL × 4). The combined organic layer was dried over anhydrous NaSO and concentrated to give compound 48-2 (3.8 g, 16.8 mmol, 73.0% yield). LCMS: 228.3 [M+H] + ;

[0400] Step 3: Preparation of compound 48-3 To a solution of compound 48-2 (300 mg, 1.17 mmol) and N-(4-methoxybenzyl)-N-methylethenesulfonamide (384 mg, 1.59 mmol) in DMF (3 mL), TEA (551 μL, 3.98 mmol) and Pd(P(t-Bu)) (67.8 mg, 0.133 mmol) were added under N at 25 °C, and the reaction was stirred at 120 °C for 2 h under microwave irradiation. The reaction was extracted with EtOAc (20 mL × 4) and HO (10 mL), washed with brine (1 mL × 3), dried over NaSO, filtered, concentrated, dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC to give compound 48-3 (265 mg, 0.686 mmol, 51.7% yield). LCMS: 387.4 [M+H] + ;

[0401] Step 4: Preparation of compound 48-4 To a solution of compound 48-3 (210 mg, 0.543 mmol) in HBr (2 mL) and HO (2 mL) was added NaNO (45.0 mg, 0.652 mmol) in HO (2 mL) solution under N at 0° C. The reaction was stirred at 0° C. for 0.5 h, CuBr (233 mg, 1.63 mmol) in HBr (2 mL) was added at 0° C. under N, and the reaction was stirred at 25° C. for 8 h. A solution of CuBr (77.9 mg, 0.543 mmol) in HBr (1 mL) was added at 0 °C under N2, and the reaction was stirred at 25 °C for 8 h. The pH was adjusted to around 6 with NaHCO3 solution, then filtered, extracted with 60 mL of EtOAc (20 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC to give compound 48-4 (101 mg, 0.224 mmol, 41.3% yield). LCMS: 452.3 [M+H] + ;

[0402] Step 5: Preparation of compound 48-5 To a solution of compound 48-4 (80 mg, 0.178 mmol) and 8-azaspiro[4.5]decane hydrochloride (46.8 mg, 0.266 mmol) in DMF (1 mL), t-BuONa (51.2 mg, 0.533 mmol), RuPhos (33.2 mg, 0.071 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one]bis[palladium(0)] (32.5 mg, 0.036 mmol) were added under N at 25 °C, and the reaction was stirred at 100 °C for 2 h. The reaction mixture was quenched with H2O (5 mL), extracted with EtOAC (10 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC to give compound 48-5 (51 mg, 0.100 mmol, 56.4%). LCMS: 509.5 [M+H] + ;

[0403] Step 6: Preparation of compound 48-6 A solution of compound 48-5 (51 mg, 0.100 mmol) in DCM (1 mL) and TFA (0.3 mL) was stirred under N2 atmosphere at 25 °C for 2 h, and the pH was adjusted to around 7 with NaHCO3 solution. The reaction mixture was extracted with EtOAc (5 mL x 4), dried over Na2SO4, filtered, and concentrated to give compound 48-6 (42.0 mg, 0.108 mmol, crude product). LCMS: 389.4 [M+H] + .

[0404] Step 7: Preparation of Example 48 To a solution of compound 48-6 (42.0 mg, 0.108 mmol) in MeOH (5 mL) was added Pd / C 10% (20 mg, 0.188 mmol) under Ar atmosphere. The suspension was degassed, purged with H 3 times, and stirred under H (15 Psi) at 25° C. for 8 h. The reaction was filtered, washed with MeOH (20 mL×3), concentrated, and purified by HPLC to give Example 48 (6.8 mg, 0.017 mmol, 16.1%). LCMS: 391.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.02 (s, 1H), 7.09-7.03 (m, 2H), 4.18 (s, 3H), 3.56 - 3.50 (m, 2H), 3.40 - 3.34 (m, 2H), 3.14 - 3.09 (m, 4H), 2.72 (s, 3H), 1.72 - 1.67 (m, 8H), 1.57 - 1.51 (m, 4H)

[0405] Example 49 [ka] Step 1: Preparation of compound 49-1 Compound 48-3 (720 mg, 1.86 mmol), [(4-(trifluoromethyl)phenyl)boronic acid (389.1 mg, 2.04 mmol), copper(II) acetate (507.4 mg, 2.79 mmol), TEA (1.29 mL, 9.31 mmol) in DCM (0.5 mL) was stirred at 25 °C for 2 h. The reaction was quenched with HO (5 mL), extracted with DCM (3 mL × 3), dried over NaSO, filtered, concentrated, and purified by preparative TLC to give compound 49-1 (70.0 mg, 0.13 mmol). LCMS: 531.1 [M+H] + ;

[0406] Step 2: Preparation of compound 49-2 Compound 49-1 (70.0 mg, 0.13 mmol) was added to NaH (15.8 mg, 0.39 mmol) in DMF (0.5 mL) at 0° C. and stirred for 30 min, followed by the addition of iodomethane (20.6 mg, 0.14 mmol). After stirring at 25° C. for 5 h, the reaction was quenched with HO (1 mL), extracted with EtOAc (1 mL×3), washed with NaCl (1 mL×3), dried over NaSO, filtered, and concentrated to give compound 49-2 (140 mg, 0.25 mmol, crude). LCMS: 545.4 [M+H] + ;

[0407] Step 3: Preparation of compound 49-3 Compound 49-2 (130 mg, 0.23 mmol) in DCM (0.10 mL) was added with TFA (1.50 mL, 0.03 mmol) and stirred at 45° C. for 12 h. Aqueous NaHCO was added to adjust the pH value to around 8, and the mixture was extracted with EtOAc (2 mL×3), dried over NaSO, filtered, concentrated, and purified by preparative TLC to give compound 49-3 (25.0 mg, 0.05 mmol). LCMS: 425.2 [M+H] + ;

[0408] Step 4: Preparation of Example 49 Compound 49-3 (30.0 mg, 0.07 mmol) and Pd / C (7.50 mg, 0.07 mmol) in MeOH (0.5 mL) were stirred under H atmosphere at 25° C. for 2 h. The mixture was filtered, concentrated, and purified by preparative HPLC to give Example 49 (5.9 mg, 0.01 mmol, 19.5%). LCMS: 427.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 7.54 - 7.44 (m, 1H), 7.43 - 7.38 (m, 2H), 7.19 (s, 1H), 6.89 - 6.81 (m, 2H), 4.29 (s, 3H), 3.57 - 3.47 (m, 2H), 3.43 - 3.33 (m, 5H), 2.74 (s, 3H).

[0409] Example 50 [ka] Step 1: Preparation of compound 50-1 To cyclopropanesulfonyl chloride (2.00 g, 14.2 mmol) in DCM (20 mL) was added TEA (3.94 mL, 28.4 mmol) and DMAP (0.30 g, 2.13 mmol), and the mixture was stirred at 25° C. for 3 h. The reaction was diluted with water (50 mL), extracted with EtOAc (50 mL×3), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 50-1 (1.20 g, 8.87 mmol). 1 HNMR (400 MHz, DMSO-d6) δ 8.86 - 8.85 (m, 1H), 2.62 - 2.60 (m, 3H), 2.53 - 2.50 (m, 1H), 0.95 - 0.91 (m, 2H), 0.89 - 0.87 (m, 2H)

[0410] Step 2: Preparation of compound 50-2 To a mixture of compound 50-1 (0.90 g, 6.65 mmol) and B2pin2 (2.50 g, 9.99 mmol) in THF (5 mL) was added 2,9-dimethylpyrido[3,2-H]quinoline (0.10 g, 0.660 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.20 g, 0.333 mmol). The mixture was stirred at 100 °C for 5 h under microwave conditions. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 3), washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give compound 50-2 (1.60 g, 6.12 mmol). 1 HNMR (400 MHz, DMSO-d6) δ 8.87 - 8.86 (m, 1H), 2.65 - 2.60 (m, 3H), 2.53 - 2.50 (m, 1H), 1.16 (s, 12H), 0.95 - 0.92 (m, 2H), 0.89 - 0.88 (m, 2H)

[0411] Step 3: Preparation of Example 50 To a solution of compound 50-2 (441 mg, 1.68 mmol) and compound 46-1 (150 mg, 0.422 mmol) in dioxane (5 mL) and HO (2 mL) was added Pd(dppf)Cl (46.3 mg, 0.063 mmol) and KCO (146 mg, 1.05 mmol). After stirring at 95 °C under N atmosphere for 3 h, the mixture was diluted with HO (50 mL), extracted with EtOAc (80 mL x 2), dried over NaSO, filtered, concentrated, and purified by HPLC to give Example 50 (26.3 mg, 0.064 mmol, 15.2%). LCMS: 410.2 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.28 (s, 1H), 7.89 - 7.85 (m, 3H), 7.75 (s, 2H), 7.40 (s, 1H), 4.26 (s, 3H), 3.44 - 3.36 (m, 1H), 3.13 - 3.04 (m, 1H), 2.81 (s, 3H), 2.00 - 1.93 (m, 1H), 1.81 - 1.70 (m, 1H).

[0412] Example 51 [ka] Example 51 (3 mg, 0.007 mmol, 6.4%) was prepared following a procedure similar to that of Example 50, starting from compound 16-5 (150 mg, 0.422 mmol). LCMS: 426.2 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 7.62 - 7.60 (m, 2H), 7.20 - 7.19 (m, 1H), 7.07 - 7.05 (m, 2H), 6.87-6.86 (m, 1H), 4.21 (s, 3H), 3.31 - 3.25 (m, 1H), 3.06 - 2.97 (m, 1H), 2.76 (s, 3H), 1.86 - 1.84 (m, 1H), 1.71 - 1.69 (m, 1H).

[0413] Examples 76a and 76b [ka] Step 1: Preparation of compound 76-1 A mixture of compound 16-4 (4.00 g, 11.2 mmol), trideuterio(iodo)methane (1.95 g, 13.4 mmol), and CsCO (7.30 g, 22.4 mmol) in DMF (40 mL) was degassed and purged with N three times, and the mixture was stirred under N atmosphere at 25 °C for 12 h. The mixture was quenched with water (10 mL) at 25 °C, extracted with EtOAc (40 mL × 3), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 76-1 (1.25 g, 3.34 mmol). LCMS: 376.2 [M+H] + Compounds 76-3a and 76-3b were prepared starting from compound 76-1 following procedures similar to those of Examples 16a and 16b. Examples 76a and 76 were prepared following procedures similar to those of Examples 34a and 34b.

[0414] Example 76a (20.5 mg, 0.052 mmol, 39.6%). LCMS:393.4[M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.14 (s, 1H), 7.67 - 7.60 (m, 2H), 7.20 - 7.16 (m, 1H), 7.10 - 7.04 (m, 2H), 6.77 - 6.72 (m, 1H), 2.89 - 2.83 (m, 1H), 2.78 (s, 3H), 2.26 - 2.18 (m, 1H), 1.60 - 1.51 (m, 2H). Example 76b (30.2 mg, 0.077 mmol, 58.4%). LCMS: 393.1 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.14 (s, 1H), 8.12 - 8.03 (m, 1H), 7.67 - 7.60 (m, 2H), 7.20 - 7.15 (m, 1H), 7.10 - 7.03 (m, 2H), 6.76 - 6.71 (m, 1H), 2.90 - 2.82 (m, 1H), 2.81 - 2.74 (m, 3H), 2.26 - 2.18 (m, 1H), 1.62 - 1.52 (m, 2H).

[0415] Example 78 [ka] Step 1: Preparation of compound 78-1 A mixture of compound 16-4 (1.00 g, 2.80 mmol), cyclopropylboranediol (433 mg, 5.04 mmol), Na2CO3 (742 mg, 7.00 mmol), copper(II) acetate (763 mg, 4.20 mmol), and 2-(pyridin-2-yl)pyridine (875 mg, 5.60 mmol) in 1,2-dichloroethane (10 mL) was degassed and purged with N2 three times, and the mixture was stirred under N2 atmosphere at 25 °C for 12 h. The mixture was quenched with water (10 mL) at 25 °C, diluted with brine (10 mL), extracted with EtOAc (20 mL × 3), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give compound 78-1 (128 mg, 0.322 mmol). LCMS: 399.2 [M+H] + ;

[0416] Example 78 (21.21 mg, 0.051 mmol, 51.4%) was prepared starting from compound 78-1 according to procedures similar to those of Example 16 and Example 34. LCMS: 416.4 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.66 - 7.59 (m, 2H), 7.16 - 7.12 (m, 1H), 7.09 - 7.00 (m, 2H), 6.74 - 6.72 (m, 1H), 4.13 - 3.97 (m, 1H), 2.88 - 2.82 (m, 1H), 2.78 (s, 3H), 2.28 - 2.21 (m, 1H), 1.61 - 1.55 (m, 2H), 1.41 - 1.33 (m, 2H), 1.21 - 1.17 (m, 2H)

[0417] Example 79 [ka] Step 1: Preparation of compound 79-1 To a solution of compound 16-4 (2.00 g, 5.60 mmol), sodium 2-chloro-2,2-difluoroacetate (1.71 mg, 11.2 mmol) in DMF (20 mL) was added NaH (448 mg, 11.2 mmol) at 0 °C. The mixture was stirred at 80 °C for 12 h. The mixture was quenched by adding aqueous NH4Cl (10 mL) at 0 °C, diluted, washed with water (50 mL × 3), extracted with EtOAc (20 mL × 3), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give compound 79-1 (460 mg, 1.13 mmol). LCMS: 416.4 [M+H] + ;

[0418] Example 79 (71.0 mg, 0.167 mmol, 55.1%) was prepared following procedures similar to those of Example 16 and Example 34, starting from compound 79-1. LCMS: 426.3 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 7.97 - 7.76 (m, 1H), 7.70 - 7.64 (m, 2H), 7.20 - 7.17 (m, 1H), 7.17 - 7.06 (m, 2H), 6.93 - 6.88 (m, 1H), 2.89 - 2.82 (m, 1H), 2.78 (s, 3H), 2.39 - 2.27 (m, 1H), 1.72 - 1.65 (m, 1H), 1.61 - 1.55 (m, 1H).

[0419] Example 81 [ka] Example 81 (108 mg, 0.256 mmol, 18.8%) was prepared following a procedure similar to that of Example 50, starting from compound 17-3 (500 mg, 1.35 mmol). LCMS: 423.1 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.89 - 8.85 (m, 1H), 8.26 - 8.21 (m, 1H), 7.74 - 7.65 (m, 2H), 7.56 - 7.45 (m, 1H), 7.37 - 7.31 (m, 1H), 7.30 - 7.25 (m, 1H), 7.22 - 7.16 (m, 2H), 3.71 - 3.61 (m, 1H), 3.11 - 3.00 (m, 1H), 2.77 (s, 3H), 1.85 - 1.76 (m, 1H), 1.73 - 1.64 (m, 1H).

[0420] Example 82 Example 82 (1.14 mg, 0.003 mmol, 61.3%) was prepared following a procedure similar to that of Example 7, starting from 6-bromo-4-nitro-1H-indazole and replacing (4-(trifluoromethyl)phenyl)boronic acid with 4-(trifluoromethyl)hexahydropyridine. LCMS: 368.0 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.46 (br s, 1H), 7.92 (s, 1H), 6.76 - 6.72 (m, 1H), 6.71 - 6.60 (m, 1H), 3.97 (s, 3H), 3.90 - 3.83 (m, 2H), 2.82 - 2.67 (m, 3H), 2.41 - 2.30 (m, 1H), 2.05 - 1.91 (m, 3H), 1.81 - 1.67 (m, 2H), 1.63 - 1.54 (m, 1H), 1.50 - 1.40 (m, 1H)

[0421] Example 83 [ka] Step 1: Preparation of compound 83-1 To a solution of 6-aminopyridin-3-ol (3.00 g, 27.2 mmol) in DMF (20 mL) was added 4-fluoro-1-(trifluoromethyl)benzene (4.90 g, 30.0 mmol), CsCO (26.6 g, 81.7 mmol), and the reaction was stirred at 100° C. for 2 hours. The reaction was diluted with water (50 mL), extracted with EtOAc (40 mL×3), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 83-1 (6.00 g, 23.6 mmol, 86.6%). LCMS: 255.1 [M+H] + ;

[0422] Step 2: Preparation of compound 83-2 To a solution of compound 83-1 (6.00 g, 23.6 mmol) in ACN (60 mL) was added NBS (4.20 g, 23.6 mmol), and the reaction was stirred at 25° C. for 1 h. The mixture was diluted with EtOAc and water, washed with saturated aqueous NaCl, concentrated, and purified by column chromatography to give compound 83-2 (5 g, 15.01 mmol, 63.6%). LCMS: 333.2 [M+H] + ;

[0423] Step 3: Preparation of compound 83-3 To a solution of compound 83-2 (2.00 g, 6.00 mmol) in EtOH (20 mL), HO (4 mL) was added 2-chloroacetaldehyde (2.40 g, 12.0 mmol), NaHCO (0.6 g, 7.20 mmol), and the reaction was stirred at 90 °C for 3 h. The reaction was diluted and extracted with EtOAc (40 mL × 3), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 83-3 (1.20 g, 3.36 mmol, 56.0%). LCMS: 359.1 [M+H] + ;

[0424] Example 83 (4.38 mg, 0.012 mmol, 6.70%) was prepared following a procedure similar to that of Example 16 by replacing compound 16-5 with compound 83-3. LCMS: 363.2 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.25 (s, 1H), 7.84 (s, 1H), 7.69 - 7.63 (m, 2H), 7.58 (s, 1H), 7.17 - 7.10 (m, 2H), 6.80 - 6.74 (m, 1H), 2.98 - 2.86 (m, 1H), 2.05 - 1.94 (m, 1H), 1.66 - 1.54 (m, 1H), 1.35 - 1.25 (m, 1H).

[0425] Examples 85a and 85b Example 85a (17.63 mg, 0.041 mmol, 51.3%) and Example 85b (9.76 mg, 0.023 mmol, 28.4%) were prepared following procedures similar to Example 83, and similar to procedures for Example 58a and Example 58b, by replacing 2-chloroacetaldehyde with 1-chloropropan-2-one.

[0426]

[0394] Example 85a. LCMS:432.4[M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.30 - 8.19 (m, 1H), 7.72 - 7.62 (m, 3H), 7.20 - 7.14 (m, 2H), 6.98 - 6.92 (m, 1H), 4.64 - 4.54 (m, 1H), 4.53 - 4.45 (m, 1H), 4.32 - 4.20 (m, 1H), 4.11 - 4.01 (m, 1H), 3.90 - 3.74 (m, 1H), 2.89 - 2.77 (m, 1H), 2.50 - 2.43 (m, 3H), 2.10 - 1.99 (m, 1H), 1.67 - 1.60 (m, 1H), 1.53 - 1.46 (m, 1H)

[0427] Example 85b. LCMS: 432.3 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.28 - 8.24 (m, 1H), 7.71 - 7.64 (m, 3H), 7.20 - 7.14 (m, 2H), 6.98 - 6.94 (m, 1H), 4.66 - 4.56 (m, 1H), 4.54 - 4.46 (m, 1H), 4.31 - 4.19 (m, 1H), 4.11 - 4.04 (m, 1H), 3.90 - 3.76 (m, 1H), 2.89 - 2.79 (m, 1H), 2.52 - 2.43 (m, 3H), 2.11 - 2.00 (m, 1H), 1.68 - 1.59 (m, 1H), 1.54 - 1.46 (m, 1H)

[0428] The compounds in Table 4 below were prepared by following the synthetic sequences of Examples 16 / 16a / 16b using the corresponding starting materials to obtain the carboxyl intermediate or final compound, which was further coupled with an amine to produce the corresponding amide following a procedure similar to that of Example 22.

[0429] [Table 4-1]

[0430] [Table 4-2]

[0431] [Table 4-3]

[0432] Examples 106 and 107 [ka] Step 1: Preparation of compound 106-1 To a solution of Example 16b (500 mg, 1.33 mmol) in DMF (10 mL) was added HATU (757 mg, 1.99 mmol) and DIEA (2.20 mL, 13.2 mmol), and the reaction was stirred at 25° C. for 10 min. 2-Azabicyclo[2.2.1]hepta-5-ensalic acid (446 mg, 1.59 mmol) was added at 25° C., and the reaction was stirred at 25° C. for 2 h. The mixture was extracted with EtOAc (10 mL×5), water (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative TLC to give compound 106-1 (200 mg, 0.44 mmol). LCMS: 454.1 [M+H] + ;

[0433] Preparation of Example 106 To a solution of compound 106-1 (80 mg, 0.18 mmol) in DCM (2 mL) was added M-CPBA (72.5 mg, 0.35 mmol) at 0° C. under N2, and the reaction was stirred at 25° C. for 2 h. A saturated aqueous solution of Na2SO3 was added to the mixture, which was extracted with DCM (3×5 mL), dried over Na2SO4, filtered, concentrated, and purified by HPLC to give Example 106 (11 mg, 0.02 mmol, 12.9% yield). LCMS: 488.2 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.12 (s, 1H), 7.64 - 7.56 (m, 2H), 7.17 - 7.14 (m, 1H), 7.08 - 7.02 (m, 2H), 6.74 - 6.71 (m, 1H), 4.21 (s, 3H), 3.89 - 3.85 (m, 1H), 3.44 - 3.39 (m, 2H), 3.39 - 3.33 (m, 1H), 2.88 - 2.78 (m, 1H), 2.26 - 2.15 (m, 2H), 1.80 - 1.68 (m, 1H), 1.60 - 1.51 (m, 2H), 1.51 - 1.43 (m, 1H)

[0434] Preparation of Example 107 To a solution of compound 106-1 (120 mg, 0.27 mmol) in acetone (2 mL) and HO (0.4 mL) was added a solution of 4-methyl-1,4-oxazinane 4-oxide (62 mg, 0.53 mmol) and dipotassium dioxide dioxo-λ-osmium(VI) dehydrate (19.5 mg, 0.053 mmol) in 1-propanol (0.4 mL) at 0° C. under N, and the reaction was stirred at 25° C. for 8 h. Saturated aqueous NaSO was added to the mixture, which was extracted with DCM (3×5 mL), dried over NaSO, filtered, concentrated, and purified by HPLC to give Example 107 (32.2 mg, 0.07 mmol, 25.0% yield). LCMS: 506.2 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.12 (s, 1H), 7.63 - 7.58 (m, 2H), 7.17 - 7.12 (m, 1H), 7.07 - 7.02 (m, 2H), 6.74 - 6.70 (m, 1H), 4.21 (s, 3H), 4.13 - 3.92 (m, 2H), 3.87 - 3.66 (m, 2H), 3.47 - 3.33 (m, 1H), 3.26 - 3.11 (m, 1H), 2.88 - 2.79 (m, 1H), 2.39 - 2.14 (m, 2H), 1.99 - 1.77 (m, 1H), 1.65 - 1.44 (m, 3H)

[0435] Examples 108a and 108b [ka] Step 1: Preparation of compound 108-1 To 6-chloro-2-methylpyridin-3-amine (10.0 g, 70.1 mmol) in MeOH (100 mL) and AcOH (8 mL) was added Br (6.9 mL, 126.2 mmol) at 0 °C and stirred at 25 °C for 2 h. Quenched by the addition of saturated aqueous NaHCO (100 mL), extracted with DCM (3 × 50 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 108-1 (6.00 g, 27.0 mmol). LCMS: 223.0 [M+H] + ;

[0436] Step 2: Preparation of compound 108-2 Compound 108-1 (5.00 g, 22.5 mmol), potassium (trans-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (7.4 g, 33.8 mmol), Pd(dppf)Cl (1.70 g, 2.25 mmol), and CsCO (22.1 g, 67.7 mmol) in toluene (50 mL) and HO (5 mL) were stirred at 80 °C for 12 h. Quenched with HO (100 mL), extracted with EtOAc (3 × 20 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 108-2 (4.48 g, 17.59 mmol). LCMS: 255.0 [M+H] + ;

[0437] Step 3: Preparation of compound 108-3 NaBO3 (7.2 g, 87.9 mmol) was added to a mixture of AcOH (50 mL) and compound 108-2 (4.48 g, 17.5 mmol) and stirred at 55 °C for 2 h. Additional NaBO3 (7.2 g, 87.9 mmol) was added and stirred at 55 °C for 1 h. The mixture was quenched by adding saturated aqueous NaHCO3 (100 mL), adjusted to a pH value around 8, extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give compound 108-3 (2.14 g, 7.51 mmol). TLC (PE:EA = 3:1, P1: Rf = 0.6, R1: Rf = 0.3);

[0438] Step 4: Preparation of compound 108-4 Compound 108-3 (1.60 g, 5.62 mmol), 4-(trifluoromethyl)phenol (1.80 g, 11.2 mmol), and K2CO3 (2.30 g, 16.8 mmol) in DMF (20 mL) were stirred at 80 °C for 3 h. The mixture was filtered, extracted with EtOAc (3 × 10 mL), dried over Na2SO4, filtered, and concentrated to give compound 108-4 (3.82 g, 9.31 mmol, crude product). LCMS: 411.1 [M+H] + ;

[0439] Step 5: Preparation of compound 108-5 Compound 108-4 (3.30 g, 8.04 mmol), Fe (1.30 g, 24.1 mmol), and NH4Cl (1.30 g, 24.1 mmol) in EtOH (15 mL) and HO (15 mL) were stirred at 100° C. for 2 h. The mixture was extracted with EtOAc (10 mL×3), dried over Na2SO4, concentrated, and purified by column chromatography to give compound 108-5 (2.26 g, 5.94 mmol). LCMS: 381.1 [M+H] + ;

[0440] Step 6: Preparation of compound 108-6 Compound 108-5 (2.06 g, 5.41 mmol) in toluene (20 mL) was added with AcOH (9.3 mL, 162.4 mmol), isoamyl nitrite (1.00 g, 8.12 mmol), and potassium acetate (1.10 g, 10.8 mmol) and stirred at 30 °C for 3 h. The mixture was quenched by adding saturated aqueous NaHCO (100 mL), the pH value was adjusted to around 8, extracted with EtOAc (3 × 20 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 108-6 (1.78 g, 4.55 mmol). LCMS: 392.0 [M+H] + ;

[0441] Step 7: Preparation of compound 108-7 Compound 108-6 (1.58 g, 4.03 mmol) in EtOAc (20 mL) was added with trimethyloxonium tetrafluoroborate (0.80 g, 5.24 mmol) and stirred at 25 °C for 3 h. It was quenched by adding saturated aqueous NaHCO (20 mL), the pH value was adjusted to around 8, extracted with EtOAc (3 × 10 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 108-7 (1.20 g, 2.96 mmol). LCMS: 406.1 [M+H] + ;

[0442] Step 8: Preparation of compounds 108-8a and 108-8b To compound 108-7 (1.10 g, 2.71 mmol) in HO (2 mL) and ACN (10 mL) was added lithium hydroxide hydrate (0.30 g, 8.14 mmol) and stirred at 50 °C for 2 h. The mixture was added with HCl to adjust the pH to around 3, extracted with EtOAc (10 mL × 3), dried over NaSO, filtered, concentrated, and purified by SFC to give compound 108-8a (335 mg, 0.88 mmol). SFC retention time: 1.197, LCMS: 378.1 [M+H] + and compound 108-8b (417 mg, 1.11 mmol). SFC retention time: 1.345, LCMS: 378.1 [M+H] +

[0443] Preparation of Examples 108a and 108b To compound 108-8a or 108-8b (50 mg, 0.13 mmol) in DMF (1 mL) was added azetidin-3-ol hydrochloride (21.8 mg, 0.19 mmol), DIEA (0.07 mL, 0.39 mmol), and HATU (100 mg, 0.26 mmol), and the mixture was stirred at 25° C. for 2 hours. The mixture was concentrated and purified by HPLC to give Example 108a (20.9 mg, 0.04 mmol, 36.6%). LCMS: 433.1 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.06 - 8.04 (m, 1H), 7.89 - 7.55 (m, 2H), 7.41 - 7.26 (m, 2H), 6.88 - 6.69 (m, 1H), 4.66 - 4.42 (m, 2H), 4.31 - 4.22 (m, 1H), 4.21 - 4.16 (m, 3H), 4.15 - 3.99 (m, 1H), 3.86 - 3.75 (m, 1H), 2.87 - 2.77 (m, 1H), 2.61 - 2.39 (m, 1H), 1.94 - 1.80 (m, 1H), 1.72 - 1.59 (m, 1H); and Example 108b (27.7 mg, 0.06 mmol, 48.3%). LCMS: 433.1 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.75 - 7.70 (m, 2H), 7.36 - 7.30 (m, 2H), 6.86 - 6.83 (m, 1H), 4.64 - 4.44 (m, 2H), 4.29 - 4.21 (m, 1H), 4.20 - 4.15 (m, 3H), 4.13 - 4.00 (m, 1H), 3.85 - 3.77 (m, 1H), 2.84 - 2.76 (m, 1H), 2.53 - 2.44 (m, 1H), 1.91 - 1.81 (m, 1H), 1.69 - 1.61 (m, 1H)

[0444] Examples 109a and 109b [ka] Step 1: Preparation of compound 109-1 To a solution of 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (380 mg, 1.87 mmol) in toluene (5 mL) and HO (0.5 mL) was added potassium (trans-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (677 mg, 3.74 mmol), Pd(dppf)Cl (68.5 mg, 0.094 mmol), and CsCO (1.83 g, 5.62 mmol). The mixture was stirred at 80 °C for 3 h. The mixture was quenched at 25 °C by the addition of water (10 mL), extracted with EtOAc (20 mL × 3), dried over NaSO, filtered, concentrated, and purified by column chromatography to give compound 109-1 (177 mg, 0.631 mmol). LCMS: 281.1 [M+H] + ;

[0445] Step 2: Preparation of compound 109-2 To a solution of compound 109-1 (177 mg, 0.63 mmol) in toluene (3 mL) was added 4-(trifluoromethyl)phenol (102 mg, 0.63 mmol), Cs2CO3 (616 mg, 1.89 mmol), Pd2(dba)3 (57.7 mg, 0.06 mmol), and t-BuXPhos (54 mg, 0.13 mmol). The mixture was stirred at 120 °C for 12 h, quenched at 25 °C by the addition of water (2 mL), diluted with brine (1 mL), extracted with EtOAc (5 mL × 3), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC to give compound 109-2 (90.0 mg, 0.221 mmol). LCMS: 407.1 [M+H] + ; Example 109a (10.3 mg, 0.024 mmol, 29.9%) and Example 109b (11.6 mg, 0.027 mmol, 33.7%) were prepared following procedures similar to Examples 108a and 108b by replacing compound 108-7 with compound 109-2.

[0446] Example 109a. LCMS: 434.1 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 7.80 - 7.75 (m, 2H), 7.42 - 7.36 (m, 2H), 4.66 - 4.45 (m, 2H), 4.30 - 4.28 (m, 3H), 4.27 - 4.20 (m, 1H), 4.13 - 4.00 (m, 1H), 3.86 - 3.77 (m, 1H), 3.22 - 3.14 (m, 1H), 2.55 - 2.47 (m, 1H), 1.88 - 1.79 (m, 1H), 1.78 - 1.69 (m, 1H).

[0447] Example 109b. LCMS: 434.1 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 7.80 - 7.73 (m, 2H), 7.44 - 7.35 (m, 2H), 4.63 - 4.45 (m, 2H), 4.31 - 4.28 (m, 3H), 4.27 - 4.21 (m, 1H), 4.12 - 3.99 (m, 1H), 3.85 - 3.78 (m, 1H), 3.22 - 3.15 (m, 1H), 2.54 - 2.48 (m, 1H), 1.85 - 1.79 (m, 1H), 1.78 - 1.72 (m, 1H).

[0448] Example 113 [ka] Step 1: Preparation of compound 113-1 To a mixture of compound 16b (100 mg, 0.27 mmol) in DCM (5 mL) was added oxalyl dichloride (0.15 g, 1.116 mmol, 0.4 mL), and the mixture was stirred under N at 0° C. for 1 h. The reaction was concentrated to give compound 113-1 (56 mg, 0.14 mmol, crude).

[0449] Step 2: Preparation of compound 113-2 To a mixture of compound 113-2 (56 mg, 0.14 mmol) and methyl azetidine-3-carboxylate (97 mg, 0.82 mmol) in DCM (5 mL) was added TEA (282 μL, 2.03 mmol) at 0° C. and stirred at 25° C. for 1 h. The reaction was concentrated to give compound 113-2 (45 mg, 0.10 mmol, crude product). LCMS: 474.1 [M+H] + ;

[0450] Preparation of Example 113 To a mixture of compound 113-2 (45.2 mg, 0.10 mmol) in EtOH (8 mL) and HO (3 mL) was added LiOH (121 mg, 5 mmol), and the mixture was stirred at 25° C. for 5 h. The reaction was concentrated and purified by HPLC to give Example 113 (18.9 mg, 0.04 mmol, 40%). LCMS: 460.1 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.18 - 8.14 (m, 1H), 7.66-7.61 (m, 2H), 7.19 (s, 1H), 7.10 - 7.06 (m, 2H), 6.82 (s, 1H), 4.50 - 4.43 (m, 2H), 4.29 - 4.09 (m, 4H), 3.55 - 3.43 (m, 1H), 2.87 - 2.78 (m, 1H), 2.68 (s, 1H), 2.18 - 2.08 (m, 1H), 1.67 - 1.56 (m, 2H).

[0451] Example 142 Example 142 (11.3 mg, 0.028 mmol, 22.6%) was prepared following a procedure similar to that of Example 45. LCMS: 411.2 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 8.90 - 8.85 (m, 1H), 8.25 - 8.20 (m, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.56 - 7.47 (m, 2H), 7.38 (d, J = 2.6 Hz, 1H), 7.26 - 7.18 (m, J = 8.5 Hz, 2H), 3.71 - 3.60 (m, 2H), 3.60 - 3.49 (m, 2H), 2.77 (s, 3H)

[0452] Example 142 was added to a 10% Pd / C solution and stirred at 25° C. for 2 hours. The reaction mixture was filtered, concentrated, and purified by HPLC to give Example 143 (13.0 mg, 0.03 mmol, 32.0%). Similar preparative procedures were used with the corresponding starting materials to produce Example 144, Example 145, and Example 146.

[0453]

[0418] Example 143. LCMS:415.2[M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 7.55 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.69 - 6.62 (m, 1H), 6.64 - 6.58 (m, 1H), 3.36 - 3.32 (m, 2H), 3.30 - 3.25 (m, 2H), 2.97 - 2.82 (m, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.69 (s, 3H), 1.97 - 1.84 (m, 2H) Example 144. Starting materials: Example 17 and PtO2. LCMS: 377.6 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 7.60 - 7.50 (m, 2H), 7.02 - 6.89 (m, 2H), 6.64 - 6.58 (m, 1H), 6.57 - 6.51 (m, 1H), 3.43 - 3.35 (m, 2H), 2.83 - 2.73 (m, 2H), 2.29 - 2.15 (m, 1H), 1.99 - 1.89 (m, 2H), 1.74 - 1.63 (m, 1H), 1.54 - 1.42 (m, 1H), 1.24 - 1.13 (m, 1H)

[0454] Example 145. Starting materials: Example 80 and PtO2. LCMS: 391.0 [M+H] + , 1HNMR (400 MHz, methanol-d4) δ 7.59 - 7.51 (m, 2H), 7.02 - 6.90 (m, 2H), 6.61 - 6.57 (m, 1H), 6.57 - 6.53 (m, 1H), 3.41 - 3.34 (m, 2H), 2.78 - 2.74 (m, 5H), 2.17 - 2.07 (m, 1H), 1.98 - 1.88 (m, 2H), 1.76 - 1.68 (m, 1H), 1.47 - 1.38 (m, 1H), 1.04 - 0.97 (m, 1H)

[0455] Example 146. Starting materials: Example 81 and PtO2. LCMS: 427.2 [M+H] + , 1 HNMR (400 MHz, methanol-d4) δ 7.55 (d, J = 8.6 Hz, 2H), 7.05 - 6.89 (m, 2H), 6.70 - 6.54 (m, 2H), 3.47 - 3.35 (m, 2H), 2.82 - 2.70 (m, 5H), 2.68 - 2.51 (m, 1H), 2.39 - 2.23 (m, 1H), 2.01 - 1.81 (m, 2H), 1.68 - 1.55 (m, 1H), 1.51 - 1.33 (m, 1H)

[0456] Example A: Cell Growth Assay cell culture

[0421] RPMI1640 medium (Gibco, 31800) + 10% FBS (Biosera, FB-1058 / 500) for NCI-H226 cells (supplier: ATCC).

[0457] reagent

[0422] CellTiter-Glo Reagent (CTG Reagent, Promega, G7573).

[0458] procedure Cells were plated in 384-well microplates (150 cells / well, 50 mL medium / well). Additional plates were also seeded as control measurements on day 0. Microplates were incubated overnight at 37°C, 5% CO2.

[0459] Compounds were serially diluted 3-fold in DMSO to a final top concentration of 30 mM for 10 points. 0.3% DMSO served as a vehicle control. Additionally, 25 mL / well of CTG reagent was added to additional plates, incubated at room temperature for 30 minutes, and luminescence signals were detected using EnVision (PerkinElmer, 2104 Multilabel Reader) as a day 0 control.

[0460]

[0425] Plates treated with other compounds were further incubated at 37°C for 7 days, 25 mL / well of CTG reagent was added to the plates, incubated at room temperature for 30 minutes, and luminescent signals were detected.

[0461] Data analysis

[0426] The luminescence signal on day 0 was used as a negative control or baseline. signal 0日目 = Average luminescence signal of control cells on day 0. signal ブランク対照 = average luminescence signal of blank control. signal DMSOビヒクル対照 = Mean luminescence signal of DMSO vehicle control cells at day 7. signal 化合物処理 = luminescence signal of compound-treated cells at day 7. Inhibition % = 1 - (Signal 化合物処理 -signal ブランク対照 ) / (signal DMSOビヒクル対照 -signal ブランク対照 )*100.

[0462] Dose-response curves were used to determine the 50% inhibitory concentration (IC 50 ) and % maximum inhibition were calculated.

[0463] [Table 5-1]

[0464] [Table 5-2]

[0465] [Table 5-3]

[0466] Example B: Thermal Shift Assay Experimental Protocol

[0428] 1) Prepare a fresh 8x dilution of Protein Thermal Shift™ Dye (Applied Biosystems, 1000x) by using:

[0467] 2) To ensure the same DMSO concentration, compounds were diluted as follows: Prepare 10 mM stock solutions of compounds;

[0468] Final DMSO concentration was 0.1%

[0469] 10 μM: Dilute the stock solution to 100 μM by using PBS.

[0470] 1 μM: Dilute the stock solution to 1 mM using DMSO, then dilute to 10 μM using PBS.

[0471] 3) Prepare TEAD protein:

[0472] TEAD1: Stock concentration was 2.9 mg / ml. Final concentration was 0.2 mg / ml. TEAD2: Stock concentration was 1.8 mg / ml. Final concentration was 0.08 mg / ml.

[0473] TEAD3: Stock concentration was 2.4 mg / ml. Final concentration was 0.1 mg / ml.

[0474] TEAD4: Stock concentration was 2.3 mg / ml. Final concentration was 0.1 mg / ml.

[0475] 4) Place the appropriate reaction plate or tubes on ice, then prepare the protein lysis reaction:

[0476] [Table A]

[0477] 5) Mix each reaction well by pipetting up and down 10 times.

[0478]

[0439] 6) Seal the plate with MicroAmp™ Optical Adhesive Film and spin at 1000 rpm for 1 minute.

[0479]

[0440] 7) Set up and run the qPCR instrument.

[0480] Data analysis

[0441] Analysis is performed using Thermal Shift™ Software v1.3.

[0481] The data are shown in Table 6.

[0482] [Table 6-1]

[0483] [Table 6-2]

[0484] [Table 6-3]

[0485] Example C: Evaluation of Pharmacokinetic Profile Three SPF (Sino-British SIPPR / BK Lab Animal Ltd, Shanghai) CD-1 mice were intravenously administered the given compound (formulation: 5% DMSO + 10% solutol + 85% saline) or orally gavaged with the given compound (formulation: 5% DMSO + 10% solutol + 85% saline). Blood samples were collected via the cephalic vein at 30 μL / time point at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous (iv) administration or 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral gavage. Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifugation. Within 1 hour of collection, blood samples were centrifuged at 6800g for 6 minutes at 2-8°C and stored frozen at approximately -80°C. A 20 μL aliquot of plasma sample was protein precipitated with 400 μL of MeOH containing 100 ng / mL verapamil (IS). The mixture was vortexed for 1 minute and centrifuged at 18000g for 10 minutes. 400 μL of the supernatant was transferred to a 96-well plate. A 5 μL aliquot of the supernatant was injected for LC-MS / MS analysis on an LC-MS / MS-27 (TQ6500+) instrument. Quality control samples for intra-experimental variability were used to confirm the analytical results. Precision should be within 80-120% of the known value(s) in >66.7% of the quality control samples. The area under the curve (AUC) was calculated. (0-t) ), maximum plasma concentration (C max ), elimination half-life (T 1 / 2 A standard set of parameters, including α, β ...

[0486] The data for Example C is shown in Table 7.

[0487] [Table 7]

[0488] Example D: In vivo Pharmacodynamic and Efficacy Studies

[0443] The purpose of this study is to evaluate the in vivo antitumor efficacy of Examples 58b, 64, and 75a in a human lung cancer NCI-H226 xenograft model in BALB / c nude mice (Jiangsu GemPharmatech Co., Ltd., female, 6-9 weeks old).

[0489] method: NCI-H226 cancer cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO atmosphere in air. Cells in the exponential growth phase were collected and quantified with a cell counter before tumor inoculation. Each mouse received 1 x 10 NCI-H226 tumor cells in 0.2 ml of PBS mixed with Matrigel (1:1) for tumor development. 7 The mice were inoculated subcutaneously into the right anterior flank area. The mean tumor volume was 150–200 mm. 3 Animals were randomized when they reached 100%. From the day of grouping, the mice were orally administered the test article once daily for a total of 21 days (QD x 21 days). Animal weight changes were monitored regularly as an indicator of drug safety. The primary endpoint was to see whether tumor growth could be delayed or whether the mice could be cured. Tumor size was measured in two dimensions twice a week using calipers, and volume was calculated using the formula: V = 0.5a x b 2 where a and b are the long and short diameters of the tumor, respectively, to calculate the tumor size in mm 3 It was expressed as:

[0490]

[0445] The tumor volume was then used to calculate the TGI. The TGI is calculated for each group using the following formula: TGI (%) = [1 - (Ti- T0) / (C i -C0)]×100;T i is the mean tumor volume of the treatment group on a given day, T0 is the mean tumor volume of the treatment group on day 1 of treatment, and C i is T i where C is the mean tumor volume of the vehicle control group on the same day as treatment, and C is the mean tumor volume of the vehicle group on treatment day 1. To compare tumor volumes in different groups on prespecified days, the assumption of homogeneity of variance across all groups was checked using Bartlett's test. The results are shown in Table 8.

[0491] [Table 8]

[0492]

[0446] After 21 days of treatment, selected examples of the present application resulted in significant anti-tumor activity in tumor volume compared to the vehicle group.

[0493] It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art in light thereof and are intended to be included within the spirit and purview of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof: 【Chemical 1】 [In the formula, X is —N— or —CR Ｘ - and R Ｘ represents hydrogen, halogen, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Y is -N-, -CR Ｙ - or -C(=O)-, R Ｙ represents hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R １ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R １ａ and optionally replaced by or two R on the same atom １ together to form oxo, Each R １ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom １ａ together to form oxo, n is 0, 1, 2, 3, or 4; L is absent, —O—, —S—, or —NR ２ -, -C(R ３ ) ２ -, -C(R ３ ) ２ -C(R ３ ) ２ -, -C(R ３ ) = C(R ３ ) -, 【Chemistry 2】 -C(R ３ ) ２ O-, -OC(R ３ ) ２ -, -C(R ３ ) ２ S-, -SC(R ３ ) ２ -, -C(R ３ ) ２ NR ２ - or -NR ２ C (R ３ ) ２ - and R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; Each R ３ are independently hydrogen, halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; or two R on the same carbon ３ together to form oxo, or two R on the same carbon ３ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different carbons ３ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; R ４ , R ５ , R ６ , and R ７ are each independently hydrogen, halogen, or C １ ~C ６ is alkyl, R ８ は、-C(=O)OR ９ 、-C(=O)NR １０ R １１ 、-C(=O)R ９ 、-S(=O) ２ NR １０ R １１ 、 【Chemistry 3】 -S(=O) ２ R ９ , -S(=O)R ９ , -P(=O)(OR １０ ) (OR １１ ), or -B(OR １０ ) (OR １１ ) and R ９ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently is selected from one or more R ９ａ is optionally replaced by Each R ９ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom ９ａ together to form oxo, R １０ and R １１ are each independently hydrogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R １０ａ is optionally replaced by or R １０ and R １１ together with the atoms to which they are attached, form one or more R １０ｂ forming a heterocycloalkyl optionally substituted with Each R １０ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom １０ａ together to form oxo, Each R １０ｂ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom １０ｂ together to form oxo, U is —C— or —N—; T is —C— or —N—; provided that U and T cannot both be -N-, with the proviso that when Ring B is phenyl or 6-membered heteroaryl, then U and T are both -C-; Ring B is phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, or C ５ ~C ７ is cycloalkyl, Each R １２ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom １２ together to form oxo, or two R on the same carbon １２ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R on different atoms １２ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0, 1, 2, 3, 4, 5, or 6; or one R １２ and R Ｙ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each R ａ are independently １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, or —SF ５ , -SH, -S(=O)C １ ~C ３ Alkyl, —S(═O) ２ C １ ~C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ ~C ３ Alkyl, —S(═O) ２ N (C １ ~C ３ alkyl) ２ , -S(=O)(=NC １ ~C ３ alkyl) (C １ ~C ３ alkyl), -NH ２ , -NHC １ ~C ３ Alkyl, —N(C １ ~C ３ alkyl) ２ , -N=S(=O)(C １ ~C ３ alkyl) ２ , -C(=O)C １ ~C ３ Alkyl, —C(═O)OH, —C(═O)OC １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ ~C ３ Alkyl, —C(═O)N(C １ ~C ３ alkyl) ２ , -P(=O)(C １ ~C ３ alkyl) ２ , C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Heteroalkyl, or C ３ ~C ６ is cycloalkyl, or two R on the same atom form an oxo; However, the compound is 【Chemistry 4】 [Not applicable.]

2. The compound has the formula (Ia): 【Chemistry 5】 2. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

3. The compound has the formula (Ib): 【Chemistry 6】 2. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein ring B is a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

4. The compound has the formula (Ic): 【Chemistry 7】 2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is phenyl, 5- or 6-membered heteroaryl, or 5-membered heterocycloalkyl.

5. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein X is -N-.

6. X is -CR Ｘ 5. The compound of claim 1, wherein R is -, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. R Ｘ But hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 10. The compound of any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

8. R Ｘ But hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 8. The compound of any one of claims 1 to 4, or 6, or 7, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

9. R Ｘ 9. The compound of any one of claims 1 to 4 or 6 to 8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

10. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Y is -N-.

11. Y is -CR Ｙ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

12. R Ｙ But hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 12. The compound of any one of claims 1 to 9 or 11, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

13. R Ｙ 13. The compound of any one of claims 1 to 9 or 11 or 12, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

14. L is absent, —O—, —C(R ３ ) ２ , or -C(R ３ ) ２ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: O-.

15. L is absent, —O—, or —C(R ３ ) ２ 14. The compound of any one of claims 1 to 13, wherein:

16. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein L is absent.

17. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein L is -O-.

18. L is -C(R ３ ) ２ 14. The compound of any one of claims 1 to 13, wherein:

19. Each R ３ are independently hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

20. Each R ３ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

21. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is cycloalkyl or heterocycloalkyl.

22. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is cycloalkyl.

23. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is heterocycloalkyl.

24. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.

25. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is phenyl.

26. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is heteroaryl.

27. Each R １ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene (heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently is selected from one or more R １ａ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, or stereoisomer thereof, optionally substituted with:

28. Each R １ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

29. Each R １ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, or C １ ~C ６ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

30. Each R １ But independently, C １ ~C ６ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

31. 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 0, 1, or 2.

32. 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 0 or 1.

33. 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 1 or 2.

34. R ４ 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

35. R ５ 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

36. R ６ 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

37. R ７ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein is hydrogen.

38. R ８ is -C(=O)OR ９ , —C(═O)NR １０ R １１ , or -S(=O) ２ NR １０ R １１ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

39. R ８ -C(=O)OR ９ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

40. R ９ But hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

41. R ９ is hydrogen or C １ ~C ６ 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

42. R ８ -C(=O)NR １０ R １１ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

43. R ８ is -S (=O) ２ NR １０ R １１ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

44. R １０ and R １１ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R １０ａ 44. The compound of any one of claims 1 to 38, or 42, or 43, or a pharmaceutically acceptable salt, or stereoisomer thereof, optionally substituted with:

45. R １０ and R １１ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene (heteroaryl), and each alkyl, alkylene, aryl, and heteroaryl independently is selected from one or more R １０ａ 45. The compound of any one of claims 1 to 38 or 42 to 44, or a pharmaceutically acceptable salt, or stereoisomer thereof, optionally substituted with:

46. R １０ and R １１ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ 46. ​​The compound of any one of claims 1 to 38 or 42 to 45, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is heteroalkyl.

47. R １０ and R １１ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, or C １ ~C ６ 47. The compound of any one of claims 1 to 38 or 42 to 46, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is heteroalkyl.

48. R １０ and R １１ are each independently hydrogen or C １ ~C ６ 48. The compound of any one of claims 1 to 38 or 42 to 47, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

49. R １０ and R １１ are each independently hydrogen, or one or more R １０ａ 44. The compound of any one of claims 1 to 38, or 42, or 43, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R is heterocycloalkyl optionally substituted with R.

50. R １０ and R １１ together with the atoms to which they are attached to form one or more R １０ｂ 44. The compound of any one of claims 1 to 38, or 42, or 43, or a pharmaceutically acceptable salt, or stereoisomer thereof, which forms a heterocycloalkyl, optionally substituted with:

51. R １０ and R １１ together with the atoms to which they are attached to form one or more R １０ｂ 44. The compound of any one of claims 1 to 38, or 42, or 43, or a pharmaceutically acceptable salt, or stereoisomer thereof, which forms a monocyclic heterocycloalkyl optionally substituted with:

52. R １０ and R １１ together with the atoms to which they are attached to form one or more R １０ｂ 44. The compound of any one of claims 1 to 38, or 42, or 43, or a pharmaceutically acceptable salt, or stereoisomer thereof, which forms a bicyclic heterocycloalkyl, optionally substituted with:

53. Each R １０ｂ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, or C １ ~C ６ 53. The compound of any one of claims 1 to 38, or 42, or 43, or 51, or 52, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: is haloalkyl.

54. Each R １０ｂ are independently —OH, —OR ａ , or -NR ｃ R ｄ 54. The compound of any one of claims 1 to 38, or 42, or 43, or 51 to 53, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:

55. Each R １０ｂ is independently -OH, or a pharmaceutically acceptable salt, or stereoisomer thereof.

56. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is phenyl.

57. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is a 5- or 6-membered heteroaryl.

58. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is a 5-membered heteroaryl.

59. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl.

60. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl.

61. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is pyrazolyl.

62. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is a 6-membered heteroaryl.

63. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is pyridinyl, pyrimidinyl, or pyrazinyl.

64. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is pyridinyl.

65. 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring B is a 5-membered heterocycloalkyl.

66. Each R １２ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 66. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

67. Each R １２ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ 67. The compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

68. Each R １２ are independently selected from halogen, —CN, —OH, C １ ~C ６ Alkyl, C １ ~C ６ 68. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl, cycloalkyl, or heterocycloalkyl.

69. Each R １２ However, independently, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ 69. The compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, or stereoisomer thereof, which is haloalkyl.

70. Each R １２ But independently, C １ ~C ６ 70. The compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: R is alkyl.

71. 71. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 0 or 1.

72. 72. The compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 1 or 2.

73. 73. The compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 0.

74. 74. The compound of any one of claims 1 to 73, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 1.

75. A compound selected from the compounds of Table 1 or Table 2, or a pharmaceutically acceptable salt, or stereoisomer thereof.

76. 76. A pharmaceutical composition comprising a compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

77. 80. A method of treating cancer in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 76, or a pharmaceutically acceptable salt or stereoisomer thereof.

78. 78. The method of claim 77, wherein the cancer is mesothelioma.

79. 79. The method of claim 78, wherein the cancer is NF2-deficient mesothelioma.

80. 78. The method of claim 77, wherein the cancer is epithelioid hemangioendothelioma.

81. 78. The method of claim 77, wherein the cancer is a solid tumor.

82. 82. The method of claim 81, wherein the solid tumor has an NF2 mutation, a LATS1 mutation, a LATS2 mutation, or any combination thereof.

83. 83. The method of claim 82, wherein the solid tumor has an NF2 mutation.

84. 83. The method of claim 82, wherein the solid tumor has a LATS1 mutation.

85. 83. The method of claim 82, wherein the solid tumor has a LATS2 mutation.

86. 82. The method of claim 81, wherein the solid tumor has a YAP1 / TAZ gene fusion.

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