WO2024131939A1 - Cbl-b inhibitors and methods of uses thereof - Google Patents

Cbl-b inhibitors and methods of uses thereof Download PDF

Info

Publication number
WO2024131939A1
WO2024131939A1 PCT/CN2023/141007 CN2023141007W WO2024131939A1 WO 2024131939 A1 WO2024131939 A1 WO 2024131939A1 CN 2023141007 W CN2023141007 W CN 2023141007W WO 2024131939 A1 WO2024131939 A1 WO 2024131939A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
heterocycloalkyl
compound
optionally substituted
Prior art date
Application number
PCT/CN2023/141007
Other languages
French (fr)
Inventor
Xiao DING
Xiaosong Liu
Fanye MENG
Feng Ren
Yazhou WANG
Original Assignee
Insilico Medicine Ip Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Insilico Medicine Ip Limited filed Critical Insilico Medicine Ip Limited
Publication of WO2024131939A1 publication Critical patent/WO2024131939A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Dysregulated signaling is a prominent feature in cellular transformation and tumorigenesis.
  • the proto-oncogene Casitas B-lineage lymphoma (Cbl or c-Cbl) , encodes an E3 ubiquitin ligase that downregulates PTK-directed cell signaling through ubiquitination, thereby targeting these kinases for lysosomal or proteasomal degradation.
  • Cbl is a member of the Cbl family of proteins, so characterized based on a highly conserved N-terminal region that contains the structural components required for ubiquitin ligase activity.
  • Cbl protein In simpler eukaryotic organisms, such as Caenorhabditis elegans and Dictyostelium discoideum, only one Cbl protein is present, but in mammals there are three, including Cbl, Cbl-b and Cbl-c.
  • the conserved N-terminus of Cbl family proteins contains a substrate tyrosine kinase-binding domain (TKBD) , a linker helix region (LHR) and a RING domain.
  • TKBD substrate tyrosine kinase-binding domain
  • LHR linker helix region
  • RING domain confers specificity to Cbl’s ligase activity based on the selective recruitment of phosphorylated substrates containing an (N/D) XpY (S/T) XXP, DpYR or RA (V/I) XNQpY (S/T) motif.
  • the RING domain mediates the transfer of ubiquitin (Ub) from an E2 Ub-conjugating enzyme to the substrate.
  • Cbl and Cbl-b also have extensive C-termini that confer adaptor-like functions to these proteins based on the ability to mediate multiple protein-protein interactions. These include a proline rich region that mediates interactions with SH3 domain-containing proteins and a tyrosine rich region that, upon phosphorylation, becomes a binding motif for other SH2 domain-containing proteins. Cbl and Cbl-b terminate with an ubiquitin-associated domain, which is crucial for homo-and heterodimerization of these two Cbl proteins.
  • Cbl-b is an important T cell immune response braker.
  • Cbl-b mainly regulates peripheral T-cell activation through negative regulation of TCR (T-cell receptor) signal transduction pathways.
  • TCR T-cell receptor
  • Cbl-b inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production in T cells.
  • Cbl-b also ubiquitylates PIK3R1/p85, which inhibits its recruitment to CD28 and TCR ⁇ , therefore suppressing the activation of PI3K, an important kinase involved in T cell activation and differentiation.
  • Cbl-b inhibits PLCG1 activation and calcium mobilization upon restimulation and thus promotes T cell anergy. Therefore, Cbl-b restricts unnecessary T cell overactivation under physiological condition. Indeed, Cbl-b KO mice had increased T cell proliferation, spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs. On the other hand, in tumor microenvironment, T cells anergy, exhaustion and exclusion are widely present. Thus, to unleash T cell’s full power through release of the Cbl-b brake as an immune-oncological anti-cancer therapy holds great promise.
  • the compound is of Formula (Ia) , (IIa) , or (IIIa) :
  • the compound is of Formula (Ia) , or a pharmaceutically acceptable salt or stereoisomer thereof:
  • the compound is of Formula (IIa) , or a pharmaceutically acceptable salt or stereoisomer thereof:
  • the compound is of Formula (IIIa) , or a pharmaceutically acceptable salt or stereoisomer thereof:
  • Also disclosed herein is a compound of Formula (IV) , Formula (IVa) , Formula (IVb) , Formula (IVc) , or a pharmaceutically acceptable salt or stereoisomer thereof, as described herein.
  • Also disclosed herein is a compound of Formula (V) , Formula (Va) , Formula (Vb) , Formula (Vc) , or a pharmaceutically acceptable salt or stereoisomer thereof, as further described herein. Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating a cancer, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • the cancer is a hematologic cancer. In some embodiments, the cancer is a lymphoma, a leukemia, or a myeloma. In some embodiments, the cancer is a non-hematologic cancer. In some embodiments, the cancer is a sarcoma, a carcinoma, or a melanoma. In some embodiments, the cancer is solid tumor cancer.
  • Also disclosed herein is a method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of modulating the immune response, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method for treating a disease or condition associated with Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six 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, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 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 present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1- 6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 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 covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 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 present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • 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 may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the 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.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, 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.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • Haloalkoxy refers to a radical of the formula -Ohaloalkyl where haloalkyl is as defined above. In some embodiments, the haloalkoxy comprises 1 to 3 halogens. In some embodiments, the haloalkoxy comprises 1 to 3 fluoros. In some embodiments, the haloalkoxy is -OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCH 2 CHF 2 , or -OCH 2 CH 2 F.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by 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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by 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. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • 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-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may 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, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, 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, di
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with cbl-b” or, alternatively, “acbl-b-mediated disease or disorder” means any disease or other deleterious condition in which cbl-b, or a mutant thereof, is known or suspected to play a role.
  • Described herein are compounds, or a pharmaceutically acceptable salt or stereoisomer thereof, useful in the treatment of a disease or disorder associated with cbl-b.
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 20 is independently 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • s 0, 1, 2, 3, or 4;
  • L 1 is absent or -CR 3 R 4 -;
  • R 3 and R 4 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form an oxo
  • R 5 and R 6 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ;
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • t 0, 1, 2, 3, or 4;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 10 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) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ;
  • R 22 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 optionally substituted with one or more halogens, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl optionally substituted with one or more halogens) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a ;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • the compound of Formula (A) is of Formula (Aa)
  • Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • p 0, 1, 2, 3, or 4.
  • Ring A is C 6-12 aryl, or 5-12 membered heteroaryl, provided that is not wherein *represents the attachment point to the ring B and **represents the attachment point to -CR 8 R 9 -.
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CR 7’ ;
  • R 7’ is hydrogen or R 7 ;
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 20 is independently 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • s 0, 1, 2, 3, or 4;
  • L 1 is absent or -CR 3 R 4 -;
  • R 3 and R 4 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form an oxo
  • R 5 and R 6 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ;
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • t 0, 1, 2, 3, or 4;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 10 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) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ;
  • R 22 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 optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl optionally substituted with one or more halogens) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R 21 is independently 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 optionally substituted with one or more halogen, or heterocycloalkyl.
  • X 1 , X 2 , and X 6 are independently N or CR 7’ ;
  • Y 1 is O, S, or NR 7” ;
  • R 7’ is hydrogen or R 7 ;
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 20 is independently 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • s 0, 1, 2, 3, or 4;
  • L 1 is absent or -CR 3 R 4 -;
  • R 3 and R 4 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form an oxo
  • R 5 and R 6 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ;
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • t 0, 1, 2, 3, or 4;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 10 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) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ;
  • R 22 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 optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl optionally substituted with one or more halogens) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R 21 is independently 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 optionally substituted with one or more halogen, or heterocycloalkyl.
  • X 10 , X 11 , and X 12 are independently N or CR 7’ ;
  • X 7 is N or C
  • X 8 is O, S, N, or NR 7” and X 14 is N or CR 7 ; or X 14 is O, S, N, or NR 7” and X 8 is N or CR 7’ ;
  • X 9 and X 13 are independently N or C, provided that X 9 and X 13 are not both N;
  • R 7’ is hydrogen or R 7 ;
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 20 is independently 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • s 0, 1, 2, 3, or 4;
  • L 1 is absent or -CR 3 R 4 -;
  • R 3 and R 4 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form an oxo
  • R 5 and R 6 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ;
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • t 0, 1, 2, 3, or 4;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 10 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) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ;
  • R 22 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 optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl optionally substituted with one or more halogens) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R 21 is independently 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 optionally substituted with one or more halogen, or heterocycloalkyl.
  • the compound is of Formula (Ia) , (IIa) , or (IIIa) :
  • Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • p 0, 1, 2, 3, or 4.
  • Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is phenyl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is 6-membered heteroaryl.
  • p is 0, 1, or 2. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 1 or 2. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 0 or 1. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 0.
  • p is 1. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 2.
  • Ring C is heteroaryl.
  • Ring C is 5-membered heteroaryl.
  • Ring C is imidazolyl or triazolyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring C is triazolyl.
  • each R 20 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R 20 is independently C 1 -C 6 alkyl.
  • each s is 0, 1, or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 1 or 2.
  • each s is 0 or 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 0. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 2.
  • Ring B is aryl or heteroaryl.
  • Ring B is phenyl.
  • Ring B is 6-membered heteroaryl.
  • Ring B is pyridinyl.
  • Ring B is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is
  • each R 21 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
  • each R 21 is independently cycloalkyl optionally substituted with one or more halogens.
  • each R 21 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 21 is independently cycloalkyl.
  • t is 0, 1, or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 1 or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 0 or 1.
  • t is 0. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 0. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 2.
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is
  • R 22 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , R 22 is hydrogen.
  • each U is independently -N-or -CR 1 -;
  • each R 1 is 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 optionally substituted with one or more halogen, or heterocycloalkyl;
  • 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 optionally substituted with one or more halogen, or heterocycloalkyl;
  • L 1 is absent or -CR 3 R 4 -;
  • R 3 and R 4 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 3 and R 4 are taken together to form an oxo
  • R 5 and R 6 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ;
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a ;
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a ;
  • X is -N-or -CR X -;
  • R X is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • Y is -N-or -CR Y -;
  • Z is -N-or -CR Z -;
  • R Z is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • W is -N-or -CR W -;
  • R W is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • R X and R Y are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • R Y and R Z are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 10 is 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 the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R Y is 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 optionally substituted with one or more halogen, or heterocycloalkyl.
  • Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is a 6-6 fused ring. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is a 6-5 or 5-6 fused ring containing 3 or more heteroatoms selected from N, O, and S.
  • Ring A is a 6-6 fused ring containing 1-4 ring nitrogen atoms. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , wherein Ring A is a 6-6 fused ring containing 2 ring nitrogen atoms. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , wherein Ring A is a 6-6 fused ring containing 3 ring nitrogen atoms.
  • n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1, 2, or 3. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1 or 2. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 2. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 3.
  • the compound of Formula (IV) is of Formula (IVa) :
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CR 7’ ;
  • R 7’ is hydrogen or R 7 .
  • the compound of Formula (IV) is of Formula (IVb) :
  • X 1 , X 2 , and X 6 are independently N or CR 7’ ;
  • Y 1 is O, S, or NR 7” ;
  • R 7’ is hydrogen or R 7 ;
  • the compound of Formula (IV) is of Formula (IVc) :
  • X 7 is N or C
  • X 8 is O, S, N, or NR 7” and X 14 is N or CR 7’ ; or X 14 is O, S, N, or NR 7” and X 8 is N or CR 7’ ;
  • X 9 and X 13 are independently N or C, provided that X 9 and X 13 are not both N;
  • X 10 , X 11 , and X 12 are independently N or CR 7’ ;
  • R 7’ is hydrogen or R 7 ;
  • X 1 is CR 7’ . In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X 1 is N.
  • X 2 is CR 7’ . In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X 2 is N.
  • X 3 is CR 7’ . In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X 3 is N.
  • X 4 is CR 7’ . In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X 4 is N.
  • X 5 is CR 7’ . In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X 5 is N.
  • X 6 is CR 7’ . In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , X 6 is N.
  • Y 1 is O. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y 1 is S. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y 1 is NR 7” .
  • X 7 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 7 is C.
  • X 9 is N and X 13 is C. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 9 is C and X 13 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 9 is C and X 13 is C.
  • X 10 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 10 is CR 7’ .
  • X 11 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 11 is CR 7’ .
  • X 12 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 12 is CR 7’ .
  • X 8 is O, S, N, or NR 7” and X 14 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 8 is O, S, N, or NR 7” and X 14 is CR 7 . In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 14 is O, S, N, or NR 7” and X 8 is N.
  • X 14 is O, S, N, or NR 7” and X 8 is CR 7 . In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X 14 is N and X 8 is CR 7 .
  • a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , is
  • a compound of Formula (A) , (Aa) , (II) , (IIa) , (IV) , or (IVb) is In some embodiments of a compound of Formula (A) , (Aa) , (II) , (IIa) , (IV) , or (IVb) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) ,
  • R 7 is 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 heteroalkyl.
  • R 7 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 7 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R 7” is hydrogen. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R 7” is C 1 -C 6 alkyl.
  • each R 7 is independently 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, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 7 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • each R 7 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 7 is independently halogen or C 1 -C 6 haloalkyl.
  • each R 7 is independently C 1 -C 6 haloalkyl.
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , or (IVa) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II)
  • each U is independently -CR 1 -.
  • one U is -N-and the other U is -CR 1 -.
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R 1 is independently hydrogen or halogen.
  • each R 1 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R 1 is independently hydrogen.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R 2 is hydrogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R 2 is C 1 -C 6 alkyl.
  • a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is
  • a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , X is -CR X -. In some embodiments of
  • R X is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R X is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R X is hydrogen or halogen.
  • R X is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R X is hydrogen.
  • Y is -CR Y -. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Y is -N-.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkoxy.
  • R Y is -OR a .
  • R Y is C 1 -C 6 haloalkoxy.
  • R Y is C 1 -C 3 haloalkoxy.
  • R Y is -OCH 2 F.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, C 1 -C 6 alkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Y is hydrogen or cycloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Y is hydrogen.
  • R Y is cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Y is cycloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Z is -CR Z -. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Z is -N-.
  • R Z is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Z is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Z is hydrogen or halogen.
  • R Z is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R Z is hydrogen.
  • W is -CR W -. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , W is -N-.
  • R W is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R W is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R W is hydrogen or halogen.
  • R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R W is hydrogen.
  • a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is
  • L 1 is -CR 3 R 4 -. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , L 1 is absent.
  • R 3 and R 4 are each independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R 3 and R 4 are each independently hydrogen.
  • R 5 and R 6 are each independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 5 and R 6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a .
  • R 5 and R 6 are taken together to form a cycloalkyl optionally substituted with one or more R 5a .
  • R 5 and R 6 are taken together to form a heterocycloalkyl optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form a phenyl optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form a heteroaryl optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form a 5-or 6-membered heteroaryl optionally substituted with one or more R 5a .
  • L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form a 6-membered heteroaryl optionally substituted with one or more R 5a .
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  • each R 5a is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  • each R 5a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  • each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or cycloalkyl optionally substituted with one or more halogens.
  • each R 5a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 2 -C 6 alkynyl.
  • each R 5a is independently halogen or C 2 -C 6 alkynyl.
  • each R 5a is independently C 2 -C 6 alkynyl.
  • each R 5a is independently halogen.
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is
  • each R 8 and R 9 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , each R 8 and R 9 are each hydrogen.
  • R 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl optionally substituted with one or more halogens, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) ; wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 10a .
  • R 10 is C 1 -C 6 hydroxyalkyl or C 1 -C 6 alkylene (cycloalkyl) ; wherein the alkyl, alkylene, and cycloalkyl is independently optionally substituted with one or more R 10a .
  • R 10 is C 1 -C 6 hydroxyalkyl.
  • R 10 is C 1 -C 6 alkylene (cycloalkyl) ; wherein the alkylene and cycloalkyl optionally substituted with one or more R 10a .
  • each R 10a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 10a is -OH.
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are taken together to form a bond, and R 5 and R 3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R 5a .
  • R 10 and R 22 are taken together to form a heterocycloalkyl optionally substituted with one or more R 10a , provided that L 1 is -CR 3 R 4 -, R 4 and R 6 are defined as above, and R 5 and R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 5a .
  • a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III)
  • each U is independently -N-or -CR 1 -;
  • each R 1 is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • p 0, 1, 2, 3, or 4;
  • X is -N-or -CR X -;
  • R X is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • Y is -N-or -CR Y -;
  • Z is -N-or -CR Z -;
  • R Z is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • W is -N-or -CR W -;
  • R W is 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 optionally substituted with one or more halogens, or heterocycloalkyl;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 8 and R 9 are each 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 8 and R 9 are taken together to form an oxo
  • Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • each R a is independently 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;
  • each R b is 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;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R Y is 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 optionally substituted with one or more halogen, or heterocycloalkyl.
  • Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (V) , Ring A is heteroaryl. In some embodiments of a compound of Formula (V) , Ring A is a 6-6 fused ring. In some embodiments of a compound of Formula (V) , Ring A is a 6-5 or 5-6 fused ring containing 3 or more heteroatoms selected from N, O, and S.
  • n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (V) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (V) , n is 1, 2, or 3. In some embodiments of a compound of Formula (V) , n is 1 or 2. In some embodiments of a compound of Formula (V) , n is 1. In some embodiments of a compound of Formula (V) , n is 2. In some embodiments of a compound of Formula (V) , n is 3.
  • the compound of Formula (V) is of Formula (Va) :
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CR 7’ ;
  • R 7’ is hydrogen or R 7 .
  • the compound of Formula (V) is of Formula (Vb) :
  • X 1 , X 2 , and X 6 are independently N or CR 7’ ;
  • Y 1 is O, S, or NR 7” ;
  • R 7’ is hydrogen or R 7 ;
  • the compound of Formula (V) is of Formula (Vc) :
  • X 7 is N or C
  • X 8 is O, S, N, or NR 7” and X 14 is N or CR 7’ ; or X 14 is O, S, N, or NR 7” and X 8 is N or CR 7’ ;
  • X 9 and X 13 are independently N or C, provided that X 9 and X 13 are not both N;
  • X 10 , X 11 , and X 12 are independently N or CR 7’ ;
  • R 7’ is hydrogen or R 7 ;
  • X 1 is CR 7’ . In some embodiments of a compound of Formula (Va) or (Vb) , X 1 is N.
  • X 2 is CR 7’ . In some embodiments of a compound of Formula (Va) or (Vb) , X 2 is N.
  • X 3 is CR 7’ . In some embodiments of a compound of Formula (Va) , X 3 is N.
  • X 4 is CR 7’ . In some embodiments of a compound of Formula (Va) , X 4 is N.
  • X 5 is CR 7’ . In some embodiments of a compound of Formula (Va) , X 5 is N.
  • X 6 is CR 7’ . In some embodiments of a compound of Formula (Vb) , X 6 is N.
  • Y 1 is O. In some embodiments of a compound of Formula (Vb) , Y 1 is S. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y 1 is NR 7” .
  • X 7 is N. In some embodiments of a compound of Formula (Vc) , X 7 is C.
  • X 9 is N and X 13 is C. In some embodiments of a compound of Formula (Vc) , X 9 is C and X 13 is N. In some embodiments of a compound of Formula (Vc) , X 9 is C and X 13 is C.
  • X 10 is N. In some embodiments of a compound of Formula (Vc) , X 10 is CR 7’ .
  • X 11 is N. In some embodiments of a compound of Formula (Vc) , X 11 is CR 7’ .
  • X 12 is N. In some embodiments of a compound of Formula (Vc) , X 12 is CR 7’ .
  • X 8 is O, S, N, or NR 7” and X 14 is N. In some embodiments of a compound of Formula (Vc) , X 8 is O, S, N, or NR 7” and X 14 is CR 7 . In some embodiments of a compound of Formula (Vc) , X 14 is O, S, N, or NR 7” and X 8 is N. In some embodiments of a compound of Formula (Vc) , X 14 is O, S, N, or NR 7” and X 8 is CR 7 . In some embodiments of a compound of Formula (Vc) , X 14 is N and X 8 is CR 7 .
  • a compound of Formula (V) or (Va) is In some embodiments of a compound of Formula (V) or (Va) , is In some embodiments of a compound of Formula (V) or (Va) , is In some embodiments of a compound of Formula (V) or (Va) , is In some embodiments of a compound of Formula (V) or (Va) , is
  • a compound of Formula (V) or (Vc) is In some embodiments of a compound of Formula (V) or (Vc) , is In some embodiments of a compound of Formula (V) or (Vc) , is
  • each R 7 is independently 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, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 7 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 7 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 7 is independently halogen or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 7 is independently C 1 -C 6 haloalkyl.
  • R 7 is 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 heteroalkyl.
  • R 7 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 7 is hydrogen or C 1 -C 6 alkyl.
  • R 7 is hydrogen.
  • R 7 is C 1 -C 6 alkyl.
  • a compound of Formula (V) , (Va) , (Vb) , or (Vc) is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is
  • each U is independently -CR 1 -.
  • one U is -N-and the other U is -CR 1 -.
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 1 is independently hydrogen or halogen.
  • each R 1 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 1 is independently hydrogen.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R 2 is hydrogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R 2 is C 1 -C 6 alkyl.
  • a compound of Formula (V) , (Va) , (Vb) , or (Vc) is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (
  • X is -CR X -. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , X is -N-.
  • R X is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R X is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R X is hydrogen or halogen.
  • R X is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R X is hydrogen.
  • Y is -CR Y -. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Y is -N-.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  • R Y is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkoxy.
  • R Y is -OR a .
  • R Y is C 1 -C 6 haloalkoxy.
  • R Y is C 1 -C 3 haloalkoxy.
  • R Y is -OCH 2 F.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen, C 1 -C 6 alkyl, or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen or cycloalkyl optionally substituted with one or more halogens.
  • R Y is hydrogen or cycloalkyl.
  • R Y is hydrogen
  • R Y is cycloalkyl optionally substituted with one or more halogens.
  • R Y is cycloalkyl
  • Z is -CR Z -. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Z is -N-.
  • R Z is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R Z is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R Z is hydrogen or halogen.
  • R Z is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R Z is hydrogen.
  • W is -CR W -. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , W is -N-.
  • R W is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R W is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R W is hydrogen or halogen.
  • R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R W is hydrogen.
  • Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is phenyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is 6-membered heteroaryl.
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 5a is independently halogen or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 5a is independently halogen.
  • p is 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 2.
  • each R 8 and R 9 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 8 and R 9 are each hydrogen.
  • Ring E is 3-or 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 3-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 4-membered heterocycloalkyl.
  • Ring E is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 6-membered heterocycloalkyl.
  • each R 11 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) .
  • each R 11 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 11 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 11 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R 11 is independently C 1 -C 6 alkyl.
  • m is 0, 1, or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 1 or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 0 or 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 0.
  • m is 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 2.
  • each R a is independently 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) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently 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, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently 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, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is 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) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is 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, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is 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, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • 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, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl 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, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl 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, cycloalkyl, or heterocycloalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHC 1 -C 3 alkyl, -N (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 cycloalkyl optionally substituted with one or more halogens.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, or C 3 -C 6 cycloalkyl optionally substituted with one or more halogens.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • each R is independently halogen, -CN, -OH, -NH 2 , or C 1 -C 3 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 3 alkyl.
  • one or more of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R 11 , R 21 , R 22 , R X , R Y , R Z , R W , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R 11 , R 21 , R 22 , R X , R Y , R Z , R W , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R 11 , R 21 , R 22 , R X , R Y , R Z , R W , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more 1 H of Ring A, Ring B, Ring C, Ring D, or Ring E are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof is one of the compounds in Table 1.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof is one of the compounds in Table 2 or Table 3.
  • 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,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • 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.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number 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.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium) , 2 H (deuterium) , and 3 H (tritium) .
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in 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 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such 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, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be 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.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • an immune cell e.g., a T-cell, a B-cell, or a NK-cell
  • methods of modulating the activity of an immune cell such as by contacting the immune cell with an effective amount of a Cbl-b inhibitor described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition thereof.
  • a method of modulating activity of an immune cell comprising contacting the immune cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of treating a cancer, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of modulating the immune response, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • Also disclosed herein is a method for treating a disease or condition associated with Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  • the disease or condition associated with Cbl-b activity is cancer.
  • the cancer is a hematologic cancer. In some embodiments, the cancer is a lymphoma, a leukemia, or a myeloma. In some embodiments, the cancer is a non-hematologic cancer. In some embodiments, the cancer is a sarcoma, a carcinoma, or a melanoma. In some embodiments, the cancer is solid tumor cancer.
  • Hematologic cancers include, but are not limited to, one or more leukemias such as B-cell acute lymphoid leukemia ( “BALL” ) , T-cell acute lymphoid leukemia ( “TALL” ) , acute lymphoid leukemia (ALL) ; one or more chronic leukemias including, but not limited to, chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) ; additional hematologic cancers or hematologic conditions including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm (BPDCN) , Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell-or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma,
  • Non-hematologic cancers include but are not limited to, a neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer (e.g., NSCLC) , pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.
  • a neuroblastoma renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer (e.g., NSCLC) , pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • 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 of the symptoms of the disease or condition. Amounts effective for this use 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 amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • the dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be 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 practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions 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 compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • Example 1 Preparation of (S) -3- (6-cyclopropyl-4- (4-fluoro-2- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) pyridin-2-yl) -6- ( (3-methylpiperidin-1-yl) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Step 3 Preparation of (S) -3- (6-cyclopropyl-4- (4-fluoro-2- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) pyridin-2-yl) -6- ( (3-methylpiperidin-1-yl) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 2 Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Step 10 Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Step 7 Preparation of 1- ( ( ( (2- (3- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclobutan-1-ol
  • Example 5 Preparation of 6- ( ( ( (1-fluorocyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Step 3 Preparation of N- ( (3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -4-oxo-8- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) methyl) cyclobutanecarboxamide
  • Example 7 Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) (methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 8 Preparation of 6- ( ( ( (1-methoxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 9 Preparation of 6- ( ( ( (3, 3-difluoro-1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 10 Preparation of 1- ( ( ( (2- (3- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclopentan-1-ol
  • Example 11 Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -7- (trifluoromethyl) -3, 5-dihydro-4H-pyrrolo [3, 2-d] pyrimidin-4-one
  • Step 2 Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -7- (trifluoromethyl) -3, 5-dihydro-4H-pyrrolo [3, 2-d] pyrimidin-4-one
  • Example 12 Preparation of 3- (4- ( (1s, 3s) -1- (4- (difluoromethyl) -4H-1, 2, 4-triazol-3-yl) -3-methylcyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 13 Preparation of 3- (6-cyclopropyl-4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • Example 14 Preparation of 3- (6- (fluoromethoxy) -4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) quinazolin-4 (3H) -one
  • Example 19 Preparation of 3- (4- ( (1s, 3s) -1- (4- (difluoromethyl) -4H-1, 2, 4-triazol-3-yl) -3-methylcyclobutyl) pyridin-2-yl) -6- (1- ( (1-methylcyclobutyl) amino) ethyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
  • CBL-B GST-Tag
  • BPS BPS
  • a fluorescence labeled Cbl-b binding probe was made in-house.
  • Anti GST-Tb cryptate monoclonal antibody was from Cisbio (61GSTTLB) .
  • compounds were diluted and transferred to opti-384F black plate (PE, 6007279) by echo.
  • 1x Assay Buffer HPES pH 7.5 50 mM, NaCl 50 mM, MgCl 2 5 mM, TCEP 1 mM, Tween-20 0.01%
  • 2x Protein mix 10 nM
  • 2x Probe mix 120 nM
  • 10 ⁇ L 2x Protein mix or 1x Assay buffer, as no protein control
  • 10 ⁇ l 2x Probe mix was added for another 2 h incubation at 25°C.
  • Data were collected by Envision reading using Ex340/Em495/520.
  • CYP isoform and substrate specific probe reactions were employed as per reported methods. The methods were standardized and validated. phenacetin O-deethylation for CYP1A2, diclofenac 4-hydroxylation for CYP2C9, S-mephenytoin 4-hydroxylation for CYP2C19, dextromethorphan Odemethylation for CYP2D6, midazolam 1′-hydroxylation for CYP3A4.
  • the typical incubation systems consisted of 100 mM potassium phosphate buffer (pH 7.4) , 33 mM MgCl2, 10 mM NADPH, HLM (0.253 mg/mL) . Substrates, compounds/positive controls, HLM, and NADPH solutions were added to corresponding wells, mixed, and incubated for 10 minutes for all CYPs at 37 water bath. Reaction was terminated by adding 400 ⁇ l cold stop solution (200 ng/ml Tolbutamide and Labetalol in CAN) . Samples were centrifuged at 4000 rpm for 20 minutes to precipitate protein. 200 ⁇ l supernatant was transferred to 100 ⁇ l HPLC water and shaken for 10 minutes.
  • Microsomes (final concentration 0.5 mg/mL) , 100 mM phosphate buffer pH 7.4, and compound (final concentration 1 ⁇ M) were added to the assay plate and allowed to preincubate for 10 min at 37 °C.
  • the reaction was initiated by the addition of NADPH (final concentration 1 mM) , and the plate was constantly shaken at 37 °C. After 0, 5-, 15-, 30-, 45-, and 60-min aliquots were taken, and the reaction was quenched using cold acetonitrile. The samples were shaken for 10 min, then centrifuged at 4000 rpm for 20 min at 4 °C and analyzed by LC-MS/MS. The in vitro intrinsic clearance was calculated from the rate of compound disappearance.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The disclosure provides for compounds and methods for modulating or inhibiting CBL-B.

Description

CBL-B INHIBITORS AND METHODS OF USES THEREOF
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2022/141595, filed December 23, 2022; International Application No. PCT/CN2023/073188, filed January 19, 2023; and International Application No. PCT/CN2023/095484, filed May 22, 2023; and which are incorporated herein by reference in their entirety.
BACKGROUND
Dysregulated signaling is a prominent feature in cellular transformation and tumorigenesis. The proto-oncogene Casitas B-lineage lymphoma (Cbl or c-Cbl) , encodes an E3 ubiquitin ligase that downregulates PTK-directed cell signaling through ubiquitination, thereby targeting these kinases for lysosomal or proteasomal degradation. Cbl is a member of the Cbl family of proteins, so characterized based on a highly conserved N-terminal region that contains the structural components required for ubiquitin ligase activity. In simpler eukaryotic organisms, such as Caenorhabditis elegans and Dictyostelium discoideum, only one Cbl protein is present, but in mammals there are three, including Cbl, Cbl-b and Cbl-c.
The conserved N-terminus of Cbl family proteins contains a substrate tyrosine kinase-binding domain (TKBD) , a linker helix region (LHR) and a RING domain. The TKBD confers specificity to Cbl’s ligase activity based on the selective recruitment of phosphorylated substrates containing an (N/D) XpY (S/T) XXP, DpYR or RA (V/I) XNQpY (S/T) motif. The RING domain mediates the transfer of ubiquitin (Ub) from an E2 Ub-conjugating enzyme to the substrate. Within the LHR is a conserved tyrosine (Tyr371 in Cbl) that is crucial for regulating ligase activity. Phosphorylation of this tyrosine enhances ligase activity and is essential for ubiquitination of receptor PTKs. In addition to the highly conserved N-terminus, Cbl and Cbl-b also have extensive C-termini that confer adaptor-like functions to these proteins based on the ability to mediate multiple protein-protein interactions. These include a proline rich region that mediates interactions with SH3 domain-containing proteins and a tyrosine rich region that, upon phosphorylation, becomes a binding motif for other SH2 domain-containing proteins. Cbl and Cbl-b terminate with an ubiquitin-associated domain, which is crucial for homo-and heterodimerization of these two Cbl proteins.
Cbl-b is an important T cell immune response braker. In contrast to Cbl, which mainly regulates thymocyte development, Cbl-b mainly regulates peripheral T-cell activation through negative regulation of TCR (T-cell receptor) signal transduction pathways. Specifically, Cbl-b inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production in T cells. Cbl-b also ubiquitylates PIK3R1/p85, which inhibits its recruitment to CD28 and TCRζ , therefore suppressing the activation of PI3K, an important kinase involved in T cell activation and differentiation. Moreover, in activated T-cells, Cbl-b inhibits PLCG1 activation and calcium mobilization upon restimulation and thus promotes T cell anergy. Therefore, Cbl-b restricts unnecessary T cell overactivation under physiological condition. Indeed, Cbl-b KO mice had increased T  cell proliferation, spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs. On the other hand, in tumor microenvironment, T cells anergy, exhaustion and exclusion are widely present. Thus, to unleash T cell’s full power through release of the Cbl-b brake as an immune-oncological anti-cancer therapy holds great promise.
There is a need for new cancer therapies, specifically using Cbl-b inhibitors.
SUMMARY
Disclosed herein are compounds, or a pharmaceutically acceptable salt or stereoisomer thereof, that are Cbl-b inhibitors.
Disclosed herein is a compound of Formula (A) , or a pharmaceutically acceptable salt or stereoisomer thereof:
Also disclosed herein is a compound of Formula (I) , Formula (II) , or Formula (III) , or a pharmaceutically acceptable salt or stereoisomer thereof:
as described herein.
In some embodiments, the compound is of Formula (Ia) , (IIa) , or (IIIa) :
as described herein.
In some embodiments the compound is of Formula (Ia) , or a pharmaceutically acceptable salt or stereoisomer thereof:
as described herein.
In some embodiments the compound is of Formula (IIa) , or a pharmaceutically acceptable salt or stereoisomer thereof:
as described herein.
In some embodiments the compound is of Formula (IIIa) , or a pharmaceutically acceptable salt or stereoisomer thereof:
as described herein.
Also disclosed herein is a compound of Formula (IV) , Formula (IVa) , Formula (IVb) , Formula (IVc) , or a pharmaceutically acceptable salt or stereoisomer thereof, as described herein.
Also disclosed herein is a compound of Formula (V) , Formula (Va) , Formula (Vb) , Formula (Vc) , or a pharmaceutically acceptable salt or stereoisomer thereof, as further described herein. Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating a cancer, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
In some embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is a lymphoma, a leukemia, or a myeloma. In some embodiments, the cancer is a non-hematologic cancer. In some embodiments, the cancer is a sarcoma, a carcinoma, or a melanoma. In some embodiments, the cancer is solid tumor cancer.
Also disclosed herein is a method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of modulating the immune response, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method for treating a disease or condition associated with Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference 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
Definitions
In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the 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 descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the 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 employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“oxo” refers to =O.
“Carboxyl” refers to -COOH.
“Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six 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, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , 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 present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1- 6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. 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.
“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl” , 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 covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl” , 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 present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
“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 may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the 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 stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
“Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl) , from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl) , from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl) , from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl) , from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl) , or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, 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. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
“Haloalkoxy” refers to a radical of the formula -Ohaloalkyl where haloalkyl is as defined above. In some embodiments, the haloalkoxy comprises 1 to 3 halogens. In some embodiments, the haloalkoxy comprises 1 to 3 fluoros. In some embodiments, the haloalkoxy is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, or -OCH2CH2F.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by 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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by 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. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised 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 rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some  embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl) , from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl) , or two to four 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-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 the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the  heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may 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, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may 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, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, 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, 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, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
As used herein, a “disease or disorder associated with cbl-b” or, alternatively, “acbl-b-mediated disease or disorder” means any disease or other deleterious condition in which cbl-b, or a mutant thereof, is known or suspected to play a role.
Compounds
Described herein are compounds, or a pharmaceutically acceptable salt or stereoisomer thereof, useful in the treatment of a disease or disorder associated with cbl-b.
Disclosed herein is a compound of Formula (A) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R20 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
s is 0, 1, 2, 3, or 4;
L1 is absent or -CR3R4-;
R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R3 and R4 are taken together to form an oxo;
R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
t is 0, 1, 2, 3, or 4;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
R10 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
R22 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl optionally substituted with one or more halogens) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a;
each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo.
In some embodiments of a compound of Formula (A) , the compound of Formula (A) is of Formula (Aa)
wherein:
is a single bond or a double bond;
Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
and
p is 0, 1, 2, 3, or 4.
In some embodiments of a compound of Formula (A) or (Aa) , Ring A is C6-12 aryl, or 5-12 membered heteroaryl, provided thatis notwherein *represents the attachment point to the ring B and **represents the attachment point to -CR8R9-.
Also disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein
X1, X2, X3, X4, and X5 are independently N or CR7’;
R7’ is hydrogen or R7;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R20 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
s is 0, 1, 2, 3, or 4;
L1 is absent or -CR3R4-;
R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R3 and R4 are taken together to form an oxo;
R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
t is 0, 1, 2, 3, or 4;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
R10 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
R22 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl optionally substituted with one or more halogens) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo.
In some embodiments of a compound of Formula (I) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl.
In some embodiments of a compound of Formula (I) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
Also disclosed herein is a compound of Formula (II) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein
X1, X2, and X6 are independently N or CR7’;
Y1 is O, S, or NR7” ;
R7’ is hydrogen or R7;
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R20 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
s is 0, 1, 2, 3, or 4;
L1 is absent or -CR3R4-;
R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R3 and R4 are taken together to form an oxo;
R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
t is 0, 1, 2, 3, or 4;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
R10 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
R22 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl optionally substituted with one or more halogens) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo.
In some embodiments of a compound of Formula (II) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl.
In some embodiments of a compound of Formula (II) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
Also disclosed herein is a compound of Formula (III) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein
X10, X11, and X12 are independently N or CR7’;
X7 is N or C;
X8 is O, S, N, or NR7” and X14 is N or CR7; or X14 is O, S, N, or NR7” and X8 is N or CR7’;
X9 and X13 are independently N or C, provided that X9 and X13 are not both N;
R7’ is hydrogen or R7;
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R20 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
s is 0, 1, 2, 3, or 4;
L1 is absent or -CR3R4-;
R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R3 and R4 are taken together to form an oxo;
R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
t is 0, 1, 2, 3, or 4;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
R10 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
R22 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl optionally substituted with one or more halogens) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo.
In some embodiments of a compound of Formula (III) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl.
In some embodiments of a compound of Formula (III) , each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
In some embodiments, the compound is of Formula (Ia) , (IIa) , or (IIIa) :

wherein:
is a single bond or a double bond;
Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
and
p is 0, 1, 2, 3, or 4.
In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is phenyl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , Ring D is 6-membered heteroaryl.
In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 0, 1, or 2. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 1 or 2. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 0 or 1. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 0. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 1. In some embodiments of a compound of Formula (Aa) , (Ia) , (IIa) , or (IIIa) , p is 2.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring C is heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring C is 5-membered heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring C is imidazolyl or triazolyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring C is triazolyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R20 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R20 is independently C1-C6alkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 0, 1, or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 1 or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 0 or 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 0. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each s is 2.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is phenyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is pyridinyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , Ring B is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R21 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R21 is independently cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R21 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , each R21 is independently cycloalkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 0, 1, or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 1 or 2. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 0 or 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 0. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 1. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , t is 2.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , R22 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , or (IIIa) , R22 is hydrogen.
Also disclosed herein is a compound of Formula (IV) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
each U is independently -N-or -CR1-;
each R1 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl;
R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl;
L1 is absent or -CR3R4-;
R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R3 and R4 are taken together to form an oxo;
R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
X is -N-or -CRX-;
RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
Y is -N-or -CRY-;
RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl  optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
Z is -N-or -CRZ-;
RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
W is -N-or -CRW-;
RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
or RX and RY are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
or RY and RZ are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
R10 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, - C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo;
provided thatis not wherein *represents the attachment point to the ring containing X, Y, Z and W and **represents the attachment point to -CR8R9-.
In some embodiments of a compound of Formula (IV) , RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl.
In some embodiments of a compound of Formula (IV) , RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is heteroaryl. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is a 6-6 fused ring. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , Ring A is a 6-5 or 5-6 fused ring containing 3 or more heteroatoms selected from N, O, and S.
In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , wherein Ring A is a 6-6 fused ring containing 1-4 ring nitrogen atoms. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , wherein Ring A is a 6-6 fused ring containing 2 ring nitrogen atoms. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , wherein Ring A is a 6-6 fused ring containing 3 ring nitrogen atoms.
In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1, 2, or 3. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1 or 2. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 1. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 2. In some embodiments of a compound of Formula (A) , (Aa) , or (IV) , n is 3.
In some embodiments of a compound of Formula (IV) , the compound of Formula (IV) is of Formula (IVa) :
wherein
X1, X2, X3, X4, and X5 are independently N or CR7’; and
R7’ is hydrogen or R7.
In some embodiments of a compound of Formula (IV) , the compound of Formula (IV) is of Formula (IVb) :
wherein:
X1, X2, and X6 are independently N or CR7’;
Y1 is O, S, or NR7” ;
R7’ is hydrogen or R7; and
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (IV) , the compound of Formula (IV) is of Formula (IVc) :
X7 is N or C;
X8 is O, S, N, or NR7” and X14 is N or CR7’; or X14 is O, S, N, or NR7” and X8 is N or CR7’;
X9 and X13 are independently N or C, provided that X9 and X13 are not both N;
X10, X11, and X12 are independently N or CR7’;
R7’ is hydrogen or R7; and
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X1 is CR7’. In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X1 is N.
In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X2 is CR7’. In some embodiments of a compound of Formula (I) , (Ia) , (II) , (IIa) , (IVa) , or (IVb) , X2 is N.
In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X3 is CR7’. In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X3 is N.
In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X4 is CR7’. In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X4 is N.
In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X5 is CR7’. In some embodiments of a compound of Formula (I) , (Ia) , or (IVa) , X5 is N.
In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , X6 is CR7’. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , X6 is N.
In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y1 is O. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y1 is S. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y1 is NR7”.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X7 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X7 is C.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X9 is N and X13 is C. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X9 is C and X13 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X9 is C and X13 is C.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X10 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X10 is CR7’.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X11 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X11 is CR7’.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X12 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X12 is CR7’.
In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X8 is O, S, N, or NR7” and X14 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X8 is O, S, N, or NR7” and X14 is CR7. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X14 is O, S, N, or NR7” and X8 is N. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X14 is O, S, N, or NR7” and X8 is CR7. In some embodiments of a compound of Formula (III) , (IIIa) , or (IVc) , X14 is N and X8 is CR7.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) ,  is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) ,  is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) ,  isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (Ia) , (IV) , or (IVa) , is
In some embodiments of a compound of Formula (A) , (Aa) , (II) , (IIa) , (IV) , or (IVb) ,  is In some embodiments of a compound of Formula (A) , (Aa) , (II) , (IIa) , (IV) , or (IVb) , isIn some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (III) , (IIIa) , (IV) , or (IVc) ,  is
In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R7” is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R7” is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R7” is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R7”is hydrogen. In some embodiments of a compound of Formula (IIa) , (IIIa) , (IVb) , or (IVc) , R7” is C1-C6alkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently halogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R7 is independently C1-C6haloalkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , or (IVa) , is
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each U is independently -CR1-. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , one U is -N-and the other U is -CR1-.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R1 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R1 is independently hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R1 is independently hydrogen or halogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R1 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , each R1 is independently hydrogen.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R2 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R2 is hydrogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , R2 is C1-C6alkyl.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , X is -CRX-. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , X is -N-.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RX is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RX is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RX is hydrogen or halogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RX is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RX is hydrogen.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Y is -CRY-. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Y is -N-.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6haloalkoxy.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is -ORa. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is C1-C6haloalkoxy. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is C1-C3haloalkoxy. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is -OCH2F.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl optionally substituted with one or more halogens, or  heterocycloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, halogen, C1-C6alkyl, or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen, C1-C6alkyl, or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen or cycloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is hydrogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RY is cycloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Z is -CRZ-. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , Z is -N-.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RZ is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RZ is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RZ is hydrogen or halogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RZ is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RZ is hydrogen.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , W is -CRW-. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , W is -N-.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RW is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RW is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RW is hydrogen or halogen. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RW is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , RW is hydrogen.
In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is In some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) ,  isIn some embodiments of a compound of Formula (IV) , (IVa) , (IVb) , or (IVc) , is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , L1 is -CR3R4-. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , L1 is absent.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R3 and R4 are each independently hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R3 and R4 are each independently hydrogen.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R5 and R6 are each independently hydrogen, halogen, or C1-C6alkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R5 and R6 are taken together to form a cycloalkyl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , or (IVb) , or (IVc) , R5 and R6 are taken together to form a heterocycloalkyl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form a phenyl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form a heteroaryl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form a 5-or 6-membered heteroaryl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form a 6-membered heteroaryl optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen, -CN, -OH, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen, C1-C6alkyl, C2-C6alkynyl, or cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen or C2-C6alkynyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently C2-C6alkynyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , (IVb) , or (IVc) , each R5a is independently halogen.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (IV) , (IVa) , (IVb) , or (IVc) , is
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , each R8 and R9 are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , each R8 and R9 are each hydrogen.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , R10 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl optionally substituted with one or more halogens, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) ; wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , R10 is C1-C6hydroxyalkyl or C1-C6alkylene (cycloalkyl) ; wherein the alkyl, alkylene, and cycloalkyl is independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , R10 is C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , R10 is C1-C6alkylene (cycloalkyl) ; wherein the alkylene and cycloalkyl optionally substituted with one or more R10a. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , each R10a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , each R10a is -OH.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a. In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) ,  R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a.
In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , is In some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , isIn some embodiments of a compound of Formula (A) , (Aa) , (I) , (II) , (III) , (Ia) , (IIa) , (IIIa) , (IV) , (IVa) , or (IVb) , is
Also disclosed herein is a compound of Formula (V) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
each U is independently -N-or -CR1-;
each R1 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
is a single bond or a double bond;
Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
p is 0, 1, 2, 3, or 4;
X is -N-or -CRX-;
RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
Y is -N-or -CRY-;
RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
Z is -N-or -CRZ-;
RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
W is -N-or -CRW-;
RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or R8 and R9 are taken together to form an oxo;
Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R11 on the same atom are taken together to form an oxo;
m is 0, 1, 2, 3, 4, 5, or 6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
or two R on the same atom form an oxo;
provided thatis notwherein * represents the attachment point to the ring containing X, Y, Z and W and **represents the attachment point to -CR8R9-.
In some embodiments of a compound of Formula (V) , RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl.
In some embodiments of a compound of Formula (V) , RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (V) , Ring A is heteroaryl. In some embodiments of a compound of Formula (V) , Ring A is a 6-6 fused ring. In some embodiments of a compound of Formula (V) , Ring A is a 6-5 or 5-6 fused ring containing 3 or more heteroatoms selected from N, O, and S.
In some embodiments of a compound of Formula (V) , n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (V) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (V) , n is 1, 2, or 3. In some embodiments of a compound of Formula (V) , n is 1 or 2. In some embodiments of a compound of Formula (V) , n is 1. In some embodiments of a compound of Formula (V) , n is 2. In some embodiments of a compound of Formula (V) , n is 3.
In some embodiments of a compound of Formula (V) , the compound of Formula (V) is of Formula (Va) :
wherein
X1, X2, X3, X4, and X5 are independently N or CR7’; and
R7’ is hydrogen or R7.
In some embodiments of a compound of Formula (V) , the compound of Formula (V) is of Formula (Vb) :
wherein:
X1, X2, and X6 are independently N or CR7’;
Y1 is O, S, or NR7” ;
R7’ is hydrogen or R7; and
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (V) , the compound of Formula (V) is of Formula (Vc) :
X7 is N or C;
X8 is O, S, N, or NR7” and X14 is N or CR7’; or X14 is O, S, N, or NR7” and X8 is N or CR7’;
X9 and X13 are independently N or C, provided that X9 and X13 are not both N;
X10, X11, and X12 are independently N or CR7’;
R7’ is hydrogen or R7; and
R7” is hydrogen, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (Va) or (Vb) , X1 is CR7’. In some embodiments of a compound of Formula (Va) or (Vb) , X1 is N.
In some embodiments of a compound of Formula (Va) or (Vb) , X2 is CR7’. In some embodiments of a compound of Formula (Va) or (Vb) , X2 is N.
In some embodiments of a compound of Formula (Va) , X3 is CR7’. In some embodiments of a compound of Formula (Va) , X3 is N.
In some embodiments of a compound of Formula (Va) , X4 is CR7’. In some embodiments of a compound of Formula (Va) , X4 is N.
In some embodiments of a compound of Formula (Va) , X5 is CR7’. In some embodiments of a compound of Formula (Va) , X5 is N.
In some embodiments of a compound of Formula (Vb) , X6 is CR7’. In some embodiments of a compound of Formula (Vb) , X6 is N.
In some embodiments of a compound of Formula (Vb) , Y1 is O. In some embodiments of a compound of Formula (Vb) , Y1 is S. In some embodiments of a compound of Formula (II) , (IIa) , or (IVb) , Y1 is NR7”.
In some embodiments of a compound of Formula (Vc) , X7 is N. In some embodiments of a compound of Formula (Vc) , X7 is C.
In some embodiments of a compound of Formula (Vc) , X9 is N and X13 is C. In some embodiments of a compound of Formula (Vc) , X9 is C and X13 is N. In some embodiments of a compound of Formula (Vc) , X9 is C and X13 is C.
In some embodiments of a compound of Formula (Vc) , X10 is N. In some embodiments of a compound of Formula (Vc) , X10 is CR7’.
In some embodiments of a compound of Formula (Vc) , X11 is N. In some embodiments of a compound of Formula (Vc) , X11 is CR7’.
In some embodiments of a compound of Formula (Vc) , X12 is N. In some embodiments of a compound of Formula (Vc) , X12 is CR7’.
In some embodiments of a compound of Formula (Vc) , X8 is O, S, N, or NR7” and X14 is N. In some embodiments of a compound of Formula (Vc) , X8 is O, S, N, or NR7” and X14 is CR7. In some embodiments of a compound of Formula (Vc) , X14 is O, S, N, or NR7” and X8 is N. In some embodiments of a compound of Formula (Vc) , X14 is O, S, N, or NR7” and X8 is CR7. In some embodiments of a compound of Formula (Vc) , X14 is N and X8 is CR7.
In some embodiments of a compound of Formula (V) or (Va) , is In some embodiments of a compound of Formula (V) or (Va) ,  isIn some embodiments of a compound of Formula (V) or (Va) , isIn some embodiments of a compound of Formula (V) or (Va) , is
In some embodiments of a compound of Formula (V) or (Vb) , is In some embodiments of a compound of Formula (V) or (Vb) , is
In some embodiments of a compound of Formula (V) or (Vc) , is In some embodiments of a compound of Formula (V) or (Vc) , is In some embodiments of a compound of Formula (V) or (Vc) , is
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently halogen or C1-C6haloalkyl. In some  embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R7 is independently C1-C6haloalkyl.
In some embodiments of a compound of Formula (Vb) or (Vc) , R7” is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (Vb) or (Vc) , R7” is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Vb) or (Vc) , R7” is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (Vb) or (Vc) , R7” is hydrogen. In some embodiments of a compound of Formula (Vb) or (Vc) , R7” is C1-C6alkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each U is independently -CR1-. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , one U is -N-and the other U is -CR1-.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R1 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R1 is independently hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R1 is independently hydrogen or halogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R1 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R1 is independently hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R2 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R2 is hydrogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , R2 is C1-C6alkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , isIn some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , isIn some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , isIn some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , isIn some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , isIn some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , is
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , X is -CRX-. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , X is -N-.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RX is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RX is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RX is hydrogen or halogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RX is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RX is hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Y is -CRY-. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Y is -N-.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6haloalkoxy.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is -ORa. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is C1-C6haloalkoxy. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is C1-C3haloalkoxy. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is -OCH2F.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, halogen, C1-C6alkyl, or cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen, C1-C6alkyl, or cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen or cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen or cycloalkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is cycloalkyl optionally substituted with one or more halogens.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RY is cycloalkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Z is -CRZ-. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Z is -N-.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RZ is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RZ is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RZ is hydrogen or halogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RZ is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RZ is hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , W is -CRW-. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , W is -N-.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RW is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) ,  (Vb) , or (Vc) , RW is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RW is hydrogen or halogen. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RW is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , RW is hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is phenyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring D is 6-membered heteroaryl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R5a is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R5a is independently halogen or C2-C6alkynyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R5a is independently halogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 0, 1, or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 1 or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 0 or 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 0. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , p is 2.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R8 and R9 are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R8 and R9 are each hydrogen.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 3-or 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 3-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 4-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , Ring E is 6-membered heterocycloalkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R11 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) . In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R11 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R11 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R11 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , each R11 is independently C1-C6alkyl.
In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 0, 1, or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 1 or 2. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 0 or 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 0. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 1. In some embodiments of a compound of Formula (V) , (Va) , (Vb) , or (Vc) , m is 2.
In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each hydrogen. In some embodiments of a compound disclosed herein, Rc and Rd are each independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, or C3-C6cycloalkyl optionally substituted with one or more halogens. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, or C1-C3alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C1-C3alkyl.
In some embodiments of a compound disclosed herein, one or more of R, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R10a, R11, R21, R22, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
In some embodiments of a compound disclosed herein, one or more 1H are replaced with one or more deuteriums in one or more of the following groups R, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R10a, R11, R21, R22, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd.
In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R10a, R11, R21, R22, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments of a compound disclosed herein, one or more 1H of Ring A, Ring B, Ring C, Ring D, or Ring E are replaced with one or more deuteriums.
Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 1.
TABLE 1



*trans and cis isomers were not separated.
**trans and cis isomers were separated and the absolute stereochemistry of cyclobutyl group was determined.
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 2 or Table 3.
TABLE 2

TABLE 3a

TABLE 3b

Further Forms of 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 as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting 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, the 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, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Isotopically enriched compounds
Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number 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, denoted 1H (protium) , 2H (deuterium) , and 3H (tritium) . Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H) , tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms.
The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to  form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, 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-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, 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.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such 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, 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, tertiary 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, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, and their pharmaceutically acceptable acid addition salts.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative  examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be 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.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Method of Treatment
Disclosed herein are methods of modulating the activity of an immune cell (e.g., a T-cell, a B-cell, or a NK-cell) such as by contacting the immune cell with an effective amount of a Cbl-b inhibitor described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition thereof. Also disclosed herein is a method of modulating activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of treating a cancer, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of modulating the immune response, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
Also disclosed herein is a method for treating a disease or condition associated with Cbl-b activity, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
In some embodiments, the disease or condition associated with Cbl-b activity is cancer.
In some embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is a lymphoma, a leukemia, or a myeloma. In some embodiments, the cancer is a non-hematologic cancer. In some embodiments, the cancer is a sarcoma, a carcinoma, or a melanoma. In some embodiments, the cancer is solid tumor cancer.
Hematologic cancers include, but are not limited to, one or more leukemias such as B-cell acute lymphoid leukemia ( “BALL” ) , T-cell acute lymphoid leukemia ( “TALL” ) , acute lymphoid leukemia (ALL) ; one or more chronic leukemias including, but not limited to, chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) ; additional hematologic cancers or hematologic conditions including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm (BPDCN) , Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell-or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, macroglobulinemia, and “preleukemia, ” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells.
Non-hematologic cancers include but are not limited to, a neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer (e.g., NSCLC) , pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.
Dosing
In certain embodiments, the compositions containing the compound (s) described herein are administered for therapeutic treatments. 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 of the symptoms of the disease or condition. Amounts effective for this use 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 amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
In various embodiments, the dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be 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 practitioner.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
Pharmaceutical Compositions/Formulations
The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
In another aspect, provided herein are pharmaceutical compositions 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 compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (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, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999) , herein incorporated by reference for such disclosure.
EXAMPLES
The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art  would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.
Example 1: Preparation of (S) -3- (6-cyclopropyl-4- (4-fluoro-2- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) pyridin-2-yl) -6- ( (3-methylpiperidin-1-yl) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
Step 1: Preparation of Compound 1-1
A mixture of 2-amino-5-bromo-3- (trifluoromethyl) benzoic acid (1 g, 3.521 mmol) in formamide (10 mL) was stirred at 110 ℃overnight in sealed tube. Upon completion, the mixture was partitioned between EtOAc (30 mL) and H2O (30 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to afford Compound 1-1 (250 mg) . LCMS: 292.9 [M+H] +.
Step 2: Preparation of Compound 1-2
To a solution of Compound 1-1 (250 mg, 0.853 mmol) in dioxane (5 mL) and H2O (1.5 mL) was added Ruphos Pd G4 (145.10 mg, 0.171 mmol) , Cs2CO3 (555.93 mg, 1.706 mmol) and potassium (S) -trifluoro ( (3-methylpiperidin-1-yl) methyl) borate (560.76 mg, 2.559 mmol) . The resulting mixture was stirred at 90 ℃ for 16 hrs under N2. Upon completion, the mixture was diluted with H2O (20 mL) and then extracted with EtOAc (40 mL × 3) . The combined organic layers was washed with brine (50 mL) , dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford Compound 1-2 (100 mg) . LCMS: 326.0 [M+H] +.
Step 3: Preparation of (S) -3- (6-cyclopropyl-4- (4-fluoro-2- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) pyridin-2-yl) -6- ( (3-methylpiperidin-1-yl) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
To a solution of Compound 1-3 (40 mg, 0.122 mmol, synthesized according to the standard procedure in WO2022217276) and Compound 1-2 (43.5 mg, 0.134 mmol) in dioxane (1.5 mL) were added CuI (7.0 mg, 0.036 mmol) , DMEDA (8.6 mg, 0.097 mmol) and K2CO3 (45.4 mg, 0.328 mmol) at room temperature. The mixture was stirred at 110 ℃ for 5 hrs under N2. Upon completion, the reaction  mixture was cooled to room temperature and then partitioned between water (3 mL) and EtOAc (6 mL) . The organic phase was separated, washed with water (2 mL × 3) , and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford the title compound. LCMS: 618.1 [M+H] +; 1H NMR (400 MHz, Methanol-d4) δ 8.59 -8.43 (m, 3H) , 8.20 (s, 1H) , 7.83 -7.76 (m, 1H) , 7.56 -7.45 (m, 2H) , 7.37 (s, 1H) , 7.16 (s, 1H) , 3.70 (s, 2H) , 3.35 (s, 3H) , 2.87 -2.78 (m, 2H) , 2.15 -1.97 (m, 3H) , 1.74 -1.64 (m, 4H) , 1.06 -0.99 (m, 4H) , 0.91 -0.84 (m, 4H) .
Example 2: Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
Step 1: Preparation of Compound 2-7
To a solution of Compound 1-1 (300 mg, 1.024 mmol) in dioxane (5 mL) was added (Tributylstannyl) methanol (986.3 mg, 3.072 mmol) and XPhos Pd G2 (80.6 mg, 0.102 mmol) . The mixture was stirred at 80 ℃ for 12 hrs under N2. The solvent was concentrated to give a residue, which was purified by flash silica gel chromatography to afford Compound 2-7 (182 mg) as a white solid. LCMS: 245.1 [M+H] +;
Step 2: Preparation of Compound 2-1
A solution of 2-bromo-4-methylpyridine (20 g, 116 mmol) in 1-tert-butoxy-N, N, N', N'-tetramethylmethanediamine (40.5 g, 232 mmol) was stirred at 110 ℃ for 15 hours. After being cooled to room temperature, the reaction mixture was concentrated to afford a residue, to which was added water (20 mL) and aminomethanesulfonic acid (2.5 g, 22.106 mmol) . The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was filtered, suspended in water, and extracted with DCM (100 mL × 2) . The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford Compound 2-1 (18.0 g) . LCMS: 198.0 [M+H] +;
Step 3: Preparation of Compound 2-2
To a solution of Compound 2-1 (9.00 g, 45.7 mmol) and 1, 3-dibromo-2-methylpropane (9.90 g, 45.7 mmol) in N, N-Dimethylformamide (6 mL) was added sodium hydride (2.20 g, 91.4 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched by addition of the saturated aqueous NH4Cl. The mixture was extracted with EtOAc (300mL ×2) . The combined organic layers was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel chromatography to give Compound 2-2 (7.40 g) . LCMS: 252.0 [M+H] +;
Step 4: Preparation of Compound 2-3
A solution of Compound 2-2 (7.40 g, 29.5 mmol) and sodium hydroxide (3.5 g, 88.4 mmol) in ethanol (68 mL) and H2O (13 mL) was stirred at 80 ℃ for 16 hours. The pH was adjusted to 5 by addition of 1 M HCl at 0 ℃. The aqueous layer was extracted with EtOAc (400 mL × 3) . The combined organic layer was washed with brine (100 mL) , dried over anhydrous Na2SO4, filtered, and concentrated to afford Compound 2-3 (6 g) . LCMS: 271.9 [M+H] +;
Step 5: Preparation of Compound 2-4
To a solution of Compound 2-3 (5.8 g, 21.5 mmol) , DIPEA (14.2 mL, 85.9 mmol) and N-methylhydrazinecarbothioamide (2.50 g, 23.6 mmol) in DMF (50 mL) was added T3P (10.2 g, 32.2 mmol) at 0 ℃. The mixture was stirred at room temperature for 16 hrs. Upon completion, the mixture was concentrated under reduced pressure to afford a residue, which was purified by silica gel chromatography to afford Compound 2-4 (3.80 g) . LCMS: 358.6 [M+H] +;
Step 6: Preparation of Compound 2-5
A mixture of Compound 2-4 (3.00 g, 53.2 mmol) and KOH (3.80 g, 10.6 mmol) in H2O (20 mL) was stirred at 25 ℃ for 16 hrs. The pH was adjusted to 5 by addition of 1 M HCl at 0 ℃. The aqueous layer was extracted with EtOAc (150 mL × 3) . The combined organic layer was washed with brine (100 mL) , dried over anhydrous Na2SO4, filtered, and concentrated to afford Compound 2-5 (1.40 g) . LCMS: 339.0 [M+H] +;
Step 7: Preparation of Compound 2-6
To a solution of Compound 2-5 (3.50 g, 10.3 mmol) in dichloromethane (20 mL) and acetic acid (2.06 mL, 36.104 mmol) was added hydrogen peroxide (1.80 g, 51.6 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 1 hrs. The reaction was quenched with 20%Na2S2O3 aqueous solution (10 mL) and the mixture was adjusted to pH = 7 with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with  DCM (200 mL × 3) , the combined organic layer was washed with brine (200 mL) , dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to afford Compound 2-6 (1.20 g) . LCMS: 308.9 [M+H] +;
Step 8: Preparation of Compound 2-8
To a solution of Compound 2-7 (182 mg, 0.745 mmol) and Compound 2-6 (343.4 mg, 1.118 mmol) in dioxane (3 mL) was added CuI (71.0 mg, 0.373 mmol) , K2CO3 (206.0 mg, 1.491 mmol) and DMEDA (65.7 mg, 0.745 mmol) . The mixture was stirred at 100 ℃ for 12 hrs under N2. After concentrated, the residue was purified by prep-HPLC to afford Compound 2-8 (301 mg) . LCMS: 471.5 [M+H] +;
Step 9: Preparation of Compound 2-9
To a solution of Compound 2-8 (100 mg, 0.213 mmol) in DCM (3 mL) was added DMP (135.2 mg, 0.319 mmol) at 0 ℃. The mixture was stirred at room temperature for 1 h under N2. The mixture was filtered and the cake was washed with DCM (5 mL × 2) , the filtrate was concentrated to afford the crude Compound 2-9 (90 mg) . The crude product was used directly to the next step without further purification. LCMS: 469.1 [M+H] +;
Step 10: Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
To a solution of Compound 2-9 (100 mg, 0.213 mmol) and 1- (aminomethyl) cyclobutan-1-ol (32.2 mg, 0.319 mmol) in DCE (3 mL) was added AcOH (1 drop) , the mixture was stirred at 25 ℃ for 30 min, then NaBH (OAc) 3 (225.2 mg, 1.063 mmol) was added. The mixture was stirred at 25 ℃ for 12 hrs. The reaction mixture was partitioned between DCM (10 mL) and NaHCO3 (aq. sat. 10 mL) . The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford the title compound (29.85 mg) . LCMS: 554.8 [M+H] +; 1H NMR: (400 MHz, Chloroform-d) δ 8.75 (s, 1H) , 8.66 -8.53 (m, 3H) , 8.18 (s, 1H) , 7.65 -7.60 (m, 1H) , 7.56 -7.51 (m, 1H) , 4.45 (s, 2H) , 3.44 (s, 3H) , 3.31 (s, 2H) , 2.96 -2.89 (m, 2H) , 2.76 -2.70 (m, 3H) , 2.18 -2.06 (m, 4H) , 1.81 -1.72 (m, 1H) , 1.61 -1.51 (m, 1H) , 1.21 -1.13 (m, 3H) .
Example 3: Preparation of 1- ( ( ( (2- (3- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclobutan-1-ol
Step 1: Preparation of Compound 3-1
To a solution of 2-methyl-1-nitro-3- (trifluoromethyl) benzene (15 g, 73.121 mmol) in concentrated H2SO4 (150 mL) was added 1, 3-dibromo-4, 4-dimethyl-2-oxotetrahydro-1H-imidazol-5-one (12.54 g, 43.872 mmol) at 0 ℃. Then the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water (200 mL) . After 10 min, the mixture was extracted with ethyl acetate (300 mL × 3) . The combined organic layers were washed with saturated NaHCO3 (aq. ) , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 3-1 (12 g) . 1H NMR: (400 MHz, CDCl3) δ 8.04 (d, J = 1.8 Hz, 1H) , 7.99 (d, J = 1.8 Hz, 1H) , 2.51 (d, J = 1.4 Hz, 3H) .
Step 2: Preparation of Compound 3-2
To a solution of Compound 3-1 (1.00 g, 3.521 mmol) and benzoic peroxyanhydride (0.09 g, 0.352 mmol) in tetrachloromethane (30 mL) was added NBS (0.66 g, 3.697 mmol) . The mixture was stirred at 80 ℃ for 18 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography to afford Compound 3-2 (789 mg) . LCMS: 383.9 [M+Na] +.
Step 3: Preparation of Compound 3-3
To a mixture of Compound 3-2 (1 g, 2.755 mmol) and molecular sieves (200 mg) in MeCN (10 mL) was added 4-methyl-1, 4-oxazinane 4-oxide (0.68 g, 5.841 mmol) at room temperature and the resulting mixture was stirred for 1.5 h under N2. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with H2O, 1N HCl. The organic layer was washed with brine 70 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 3-3 (1.4 g) .
Step 4: Preparation of Compound 3-4
To a solution of Compound 3-3 (30.0 mg, 0.101 mmol) in propan-2-ol (6 mL) was added 3- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) aniline (26.83 mg, 0.111 mmol) , and the mixture was stirred at 80 ℃ for 4 h. Then tributylphosphane (93.95 mg, 0.464 mmol) was added and the resulting mixture was stirred at 80 ℃ for 16 h. The mixture was cooled to room temperature and diluted with EtOAc (10 mL) . The organics was washed with brine (5 mL) , dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford Compound 3-4. LCMS: 490.0 [M+1] +.
Step 5: Preparation of Compound 3-5
To a solution of Compound 3-4 (288 mg, 0.587 mmol) in dioxane (5 mL) was added (tributylstannyl) methanol (565.79 mg, 1.762 mmol) and XPhos Pd G2 (3.21 mg, 0.004 mmol) . The mixture was stirred at 80 ℃ for 5 hrs. Then the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to afford Compound 3-5 (145 mg) . LCMS: 442.2 [M+H] +;
Step 6: Preparation of Compound 3-6
To a solution of Compound 3-5 (50 mg, 0.113 mmol) in DCM (2 mL) was added 1, 1-diacetoxy-3-oxo-1, 3-dihydrobenzo [d] [1, 2] iodoxole-1-yl acetate (72.06 mg, 0.170 mmol) . The mixture was stirred at 20 ℃ for 1 hrs. The reaction was diluted with DCM (20 mL) , washed with saturated Na2SO3 (10 M) , saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , and then concentrated to give Compound 3-6 (50 mg) , which was used to next step without further purification. LCMS: 440.2 [M+H] +
Step 7: Preparation of 1- ( ( ( (2- (3- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclobutan-1-ol
According to the procedure of Step 10 in Example 2, the title compound (8.71 mg) was synthesized with Compound 3-6 (100 mg, 0.228 mmol) as the substrate. LCMS: 525.3 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.55 -8.42 (m, 1H) , 8.11 -7.80 (m, 3H) , 7.79 -7.68 (m, 1H) , 7.58 -7.44 (m, 2H) , 7.43 -7.31 (m, 1H) , 4.18 (s, 2H) , 3.30 -3.19 (m, 4H) , 3.03 -2.88 (m, 4H) , 2.78 -2.66 (m, 2H) , 2.17 -2.03 (m, 4H) , 1.81 -1.70 (m, 1H) , 1.58 -1.43 (m, 1H) , 1.21 -1.11 (m, 3H) .
Example 4: Preparation of 1- ( ( ( (2- (3- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclobutan-1-ol
According to the procedure of Example 3, the title compound (formate form) was synthesized with 3- (3- ( (4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) oxetan-3-yl) aniline as the starting material. LCMS: 527.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H) , 8.23 -8.19 (m, 2H) , 8.04 (d, J = 8.7 Hz, 1H) , 7.93 (s, 1H) , 7.90 -7.84 (m, 1H) , 7.62 (s, 1H) , 7.48 (t, J = 7.9 Hz, 1H) , 7.01 (d, J = 7.5 Hz, 1H) , 4.98 (s, 4H) , 3.93 (s, 2H) , 3.59 (s, 2H) , 3.00 (s, 3H) , 2.56 (s, 2H) , 2.08 -1.55 (m, 6H) .
Example 5: Preparation of 6- ( ( ( (1-fluorocyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
The title compound was synthesized according to Example 2. LCMS: 556.3 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.50 (s, 1H) , 8.20 (s, 1H) , 8.04 (s, 1H) , 7.93 (s, 1H) , 7.32 (s, 1H) , 4.05 (s, 2H) , 3.33 (s, 3H) , 2.99 –2.62 (m, 7H) , 2.44 –2.10 (m, 4H) , 1.96 –1.75 (m, 1H) , 1.51 –1.39 (m, 2H) , 1.17 (d, J = 6.1 Hz, 3H) .
Example 6: Preparation of N- ( (3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -4-oxo-8- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) methyl) cyclobutanecarboxamide
Step 1: Preparation of Compound 6-1
To a solution of Compound 2-9 (62 mg, 0.132 mmol) and NH2Boc (46.5 mg, 0.397 mmol) in ACN (2 mL) was added Et3SiH (153.9 mg, 1.324 mmol) and TFA (45.3 mg, 0.397 mmol) . The mixture was stirred at 25 ℃ for overnight. The reaction mixture was concentrated under reduced pressure to give a crude Compound 6-1, which was used directly for the next step without purification. LCMS: 570.2 [M+H] +;
Step 2: Preparation of Compound 6-2
To a solution of Compound 6-1 (80 mg, 0.140 mmol) in DCM (1 mL) was added TFA (160.1 mg, 1.404 mmol) . The mixture was stirred at 25 ℃ for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a crude Compound 6-2, which was used directly for the next step without purification. LCMS: 470.3 [M+H] +;
Step 3: Preparation of N- ( (3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -4-oxo-8- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) methyl) cyclobutanecarboxamide
To a solution of cyclobutanecarboxylic acid (29.8 mg, 0.298 mmol) and DIEA (0.06 mL, 0.373 mmol) in DMF (2 mL) were added HATU (85.0 mg, 0.224 mmol) and Compound 6-2 (70 mg, 0.149 mmol) , the mixture was stirred at 25 ℃ overnight. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (5 mL) . The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford the title compound. LCMS: 552.4 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H) , 8.64 (d, J = 5.3 Hz, 1H) , 8.43 –8.38 (m, 2H) , 8.33 (s, 1H) , 8.13 (s, 1H) , 7.82 (s, 1H) , 7.47 (d, J = 5.3 Hz, 1H) , 4.46 (d, J = 6.0 Hz, 2H) , 3.26 (s, 3H) , 3.10 (p, J = 8.5 Hz, 1H) , 2.93 –2.83 (m, 2H) , 2.69 –2.54 (m, 3H) , 2.19 –2.02 (m, 4H) , 1.91 (h, J = 8.8 Hz, 1H) , 1.82 –1.73 (m, 1H) , 1.09 (d, J = 5.3 Hz, 3H) .
Example 7: Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) (methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
The title compound was synthesized according to Step 10 in Example 2. LCMS: 568.0 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H) , 8.63 (d, J = 5.3 Hz, 1H) , 8.41 (s, 1H) , 8.36 (s, 1H) , 8.25 (s, 1H) , 7.84 (s, 1H) , 7.46 (dd, J = 5.3, 1.6 Hz, 1H) , 4.93 (s, 1H) , 3.82 (s, 2H) , 3.25 (s, 3H) , 2.90 –2.85 (m, 2H) , 2.72 –2.31 (m, 5H) , 2.27 (s, 3H) , 2.05 –1.99 (m, 2H) , 1.95 –1.87 (m, 2H) , 1.61 (d, J = 10.6 Hz, 1H) , 1.39 –1.26 (m, 1H) , 1.09 (d, J = 5.4 Hz, 3H) .
Example 8: Preparation of 6- ( ( ( (1-methoxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
The title compound was synthesized according to Example 2. LCMS: 568.3 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.52 (s, 1H) , 8.26 (s, 1H) , 8.07 (s, 1H) , 7.91 (s, 1H) , 7.37 –7.30 (m, 1H) , 4.25 –4.17 (m, 1H) , 4.12 (s, 2H) , 3.34 (s, 3H) , 3.17 (s, 3H) , 2.96  –2.88 (m, 2H) , 2.86 (s, 2H) , 2.81 –2.65 (m, 3H) , 2.27 –2.15 (m, 2H) , 1.98 –1.89 (m, 2H) , 1.80 –1.69 (m, 1H) , 1.61 –1.48 (m, 1H) , 1.17 (d, J = 6.0 Hz, 3H) .
Example 9: Preparation of 6- ( ( ( (3, 3-difluoro-1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
The title compound was synthesized according to Example 2. LCMS: 590.3 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H) , 8.57 (d, J = 5.2 Hz, 1H) , 8.50 (s, 1H) , 8.11 (s, 1H) , 8.05 (s, 1H) , 7.90 (s, 1H) , 7.38 –7.32 (m, 1H) , 4.09 (s, 2H) , 3.34 (s, 3H) , 2.99 –2.89 (m, 4H) , 2.82 –2.61 (m, 7H) , 2.18 –1.58 (m, 1H) , 1.17 (d, J = 6.1 Hz, 3H) .
Example 10: Preparation of 1- ( ( ( (2- (3- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) phenyl) -4- (trifluoromethyl) -2H-indazol-6-yl) methyl) amino) methyl) cyclopentan-1-ol
The title compound was synthesized according to Example 2. LCMS: 539.4 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H) , 8.05 –7.98 (m, 2H) , 7.96 (s, 1H) , 7.83 –7.67 (m, 1H) , 7.62 –7.47 (m, 2H) , 7.47 –7.32 (m, 1H) , 4.12 (s, 2H) , 3.25 (s, 3H) , 3.02 –2.91 (m, 2H) , 2.88 (s, 2H) , 2.79 –2.71 (m, 2H) , 1.86 –1.72 (m, 4H) , 1.69 –1.48 (m, 5H) , 1.18 (d, J = 5.3 Hz, 3H) .
Example 11: Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -7- (trifluoromethyl) -3, 5-dihydro-4H-pyrrolo [3, 2-d] pyrimidin-4-one
Step 1: Preparation of Compound 11-1
The title compound was synthesized according to Step 10 in Example 2 with 3- (4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -4-oxo-7- (trifluoromethyl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -4, 5-dihydro-3H-pyrrolo [3, 2-d] pyrimidine-6-carbaldehyde as the starting material. LCMS: 673.4 [M+H] +;
Step 2: Preparation of 6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -3- (4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -7- (trifluoromethyl) -3, 5-dihydro-4H-pyrrolo [3, 2-d] pyrimidin-4-one
To a solution of Compound 11-1 (158 mg, 0.235 mmol) in DCM (1.5 mL) was added TFA (6 mL, 0.705 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford the title compound. LCMS: 543.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.3 Hz, 1H) , 8.42 –8.32 (m, 2H) , 7.74 (s, 1H) , 7.45 (dd, J = 5.3, 1.6 Hz, 1H) , 5.04 (s, 1H) , 3.98 (s, 2H) , 3.26 (s, 3H) , 2.91 –2.85 (m, 2H) , 2.66 –2.56 (m, 4H) , 2.05 –1.82 (m, 5H) , 1.65 –1.55 (m, 1H) , 1.46 –1.35 (m, 1H) , 1.08 (d, J = 5.4 Hz, 3H) .
Example 12: Preparation of 3- (4- ( (1s, 3s) -1- (4- (difluoromethyl) -4H-1, 2, 4-triazol-3-yl) -3-methylcyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
Step 1: Preparation of Compound 12-1
A solution 2-3 (8.50 g, 31.5 mmol) in SOCl2 (35 mL) was stirred at 80 ℃ for 1 hr. Then the mixture was concentrated to give a residue. A solution of the above residue in DCM (35 mL) was added to NH3/MeOH (7 N, 35 mL) dropwise. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by flash silica gel column chromatography to afford Compound 12-1 (5.0 g, 70.7 %) . LCMS: 225.0 [M+H] +.
Step 2: Preparation of Compound 12-2
A solution of Compound 12-1 (5.0 g, 22.3 mmol) in DMF-DMA (20 mL) was stirred at 100 ℃for 12 hrs. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give the crude Compound 12-2 (5.0 g, crude) , which was used to the next step without further purification. LCMS: 280.2 [M+H] +.
Step 3: Preparation of Compound 12-3
To a solution of Compound 12-2 (5.0 g, crude) in HOAc (14 mL) was added hydrazine hydrate (14 mL) . The mixture was stirred at 80 ℃ for 4 hrs. After being cooled to room temperature, the reaction mixture was concentrated to give a residue, which was diluted with water (200 mL) and extracted with EtOAc (300 mL × 3) . The combined organic layers were washed with brine (100 mL) , dried over  anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reversed-phase HPLC to afford Compound 12-3 (4 g, 72.3%) . LCMS: 249.0 [M+H] +;
Step 4: Preparation of Compound 12-4
To a solution of Compound 12-3 (2.00 g, 8.07 mmol) in DMF (20 mL) was added sodium 2-chloro-2, 2-difluoroacetate (2.50 g, 16.1 mmol) and K2CO3 (2.20 g, 16.1 mmol) . The mixture was stirred at 140 ℃ for 5 hrs. After being cooled to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 3) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue, which was purified by reversed-phase HPLC to afford Compound 12-4 (0.15 g, 5.0 %) . LCMS: 299.0 [M+H] +.
Step 5: Preparation of Compound 12
The title compound was synthesized according to the previous steps with Compound 12-4 as the starting material. LCMS: 590.2 [M+H] +; 1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H) , 8.60 (d, J = 5.3 Hz, 1H) , 8.53 (s, 1H) , 8.42 (s, 1H) , 8.18 (s, 1H) , 7.95 (s, 1H) , 7.31 (d, J = 5.1 Hz, 1H) , 6.74 (t, J = 60.4 Hz, 1H) , 4.11 (s, 2H) , 2.97 –2.84 (m, 4H) , 2.80 (t, J = 10.1 Hz, 2H) , 2.74 –2.64 (m, 1H) , 2.15 –1.98 (m, 4H) , 1.82 –1.71 (m, 1H) , 1.58 –1.46 (m, 1H) , 1.18 (d, J = 6.2 Hz, 3H) .
Example 13: Preparation of 3- (6-cyclopropyl-4- (3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
Step 1: Preparation of 13-1
To a stirred solution of 2, 6-dichloro-4-methylpyridine (63 g, 388.889 mmol) in anhydrous THF (500 mL) was slowly added LDA (388.89 mL, 777.778 mmol) at -78 ℃ under N2. The mixture stirred at -78 ℃ for 0.5 h. A solution of methyl methoxymethanoate (81.94 mL, 972.222 mmol) in dry THF (130 mL) was added dropwise. The solution was stirred at 0 ℃ for 1 h. The reaction was quenched with aq. NH4Cl (500 mL) . The resulting mixture was extracted with EtOAc (200 mL × 3) . The combined organic phase was washed with aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to afford Int 13-1. LCMS: 220.1 [M+H] +.
Step 2: Preparation of 13-2
To a solution of 13-1 (50.0 g, 231.364 mmol) in DMF (510 mL) was added NaH (20.4 g, 509 mmol) in batches at 0 ℃. The mixture was stirred at 0 ℃ for 30 mins. Then the solution was stirred at 25 ℃ for 2 hrs. Upon completion, the mixture was poured into ammonium chloride aqueous solution (700 mL) . Then the mixture was extracted with Ethyl acetate (300 mL × 3) . The combined organic phase was  washed with brine (100 mL) , dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography to afford 13-2. LCMS: 274.1 [M+H] +.
Step 3: Preparation of 13-3
With 13-2 as the substrate, 13-3 was synthesized according to the previous steps. LCMS: 297.1 [M+H] +.
Step 4: Preparation of 13-4
To a solution of Compound 13-3 (200 mg, 0.673 mmol) and cyclopropylboronic acid (60.7 mg, 0.707 mmol) in toluene (2 mL) was added K3PO4 (428.6 mg, 2.02 mmol) , PCy3 (24.5 mg, 0.088 mmol) and Pd (OAc) 2 (19.6 mg, 0.088 mmol) at room temperature. After addition, the mixture was stirred at 110 ℃ for 4 hrs under N2. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 13-4 (crude) , which was used to next step without further purification. LCMS: 303.2 [M+H] +;
Step 5: Preparation of Compound 13
With 13-4 as the substrate, the title compound was synthesized according to the previous steps. LCMS: 594.3 [M+H] +.
Example 14: Preparation of 3- (6- (fluoromethoxy) -4- ( (1s, 3s) -3-methyl-1- (4-methyl-4H-1, 2, 4-triazol-3-yl) cyclobutyl) pyridin-2-yl) -6- ( ( ( (1-hydroxycyclobutyl) methyl) amino) methyl) quinazolin-4 (3H) -one
Step 1: Preparation of Compound 14-1
To a solution of 13-3 (400 mg, 1.346 mmol) in DMSO (6 mL) was added K2CO3 (558.0 mg, 4.038 mmol) and N-hydroxyacetamide (303.2 mg, 4.038 mmol) . The mixture was stirred at 80 ℃ for 18 hrs. The mixture was purified by reverse phase prep-HPLC to afford Compound 14-1. LCMS: 279.2 [M+H] +.
Step 2: Preparation of Compound 14-2
To a solution of Compound 14-1 (250 mg, 0.897 mmol) in DMF (3 mL) was added Cs2CO3 (292.2 mg, 0.897 mmol) . The mixture was stirred at 0 ℃ for 10 min and then fluoromethyl 4-methylbenzenesulfonate (366.3 mg, 1.794 mmol) was added. The resulting mixture was heated to 80 ℃for 2 hrs under N2. The mixture was purified by reverse phase prep-HPLC to afford Compound 14-2. LCMS: 311.2 [M+H] +.
Step 3: Preparation of Compound 14
With 14-2 as the substrate, the title compound was synthesized according to the previous steps. LCMS: 534.4 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H) , 8.24 (s, 1H) , 8.06 (s, 1H) , 7.90 (d, J = 7.5 Hz, 1H) , 7.76 –7.60 (m, 2H) , 6.91 (s, 1H) , 6.03 (d, J = 51.8 Hz, 2H) , 4.13 (s, 2H) , 3.38 (s,  3H) , 3.07 –2.87 (m, 4H) , 2.81 –2.66 (m, 3H) , 2.19 –2.07 (m, 4H) , 1.83 –1.74 (m, 1H) , 1.61 –1.48 (m, 1H) , 1.17 (d, J = 4.1 Hz, 3H) .
The following compounds were synthesized according to a similar procedure with the corresponding substrates.
Example 19: Preparation of 3- (4- ( (1s, 3s) -1- (4- (difluoromethyl) -4H-1, 2, 4-triazol-3-yl) -3-methylcyclobutyl) pyridin-2-yl) -6- (1- ( (1-methylcyclobutyl) amino) ethyl) -8- (trifluoromethyl) quinazolin-4 (3H) -one
Step 1: Preparation of Compound 19-1
To a solution of Compound 1-1 (1.00 g, 3.41 mmol) in 1, 4-dioxane (30 mL) were added 1-Ethoxyvinyltri-n-butyltin (2.50 g, 6.8 mmol) , Pd (PPh3) 4 (0.2 g, 0.17 mmol) at room temperature. The resulting mixture was stirred at 110℃ for 3 hrs under nitrogen atmosphere. The mixture was quenched by the addition of Potassium fluoride solution (5 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na2SO4, filtered and concentrated to afford Compound 19-1 (900 mg, 92.8%) . The crude product was used into the next step without further purification. LCMS: 285.0 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H) , 8.54 (s, 1H) , 8.31 (s, 1H) , 8.27 (d, J = 3.3 Hz, 1H) , 5.09 (d, J = 3.2 Hz, 1H) , 4.52 (d, J = 3.0 Hz, 1H) , 4.01 –3.94 (m, 2H) , 1.40 (t, J = 7.0 Hz, 3H) .
Step 2: Preparation of Compound 19-2
To a solution of Compound 19-1 (900 mg, 3.16 mmol) in THF (10 mL) was added 3M HCl (28.46 mL, 56.92 mmol) . The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Isolera-Biotage Column: Agela C18 80 g; Mobile Phase A: 0.1%TFA, Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 0%B to 50%B in 60 min; Detector: UV 254 nm) to afford Compound 19-2 (650 mg, 80.1%) . LCMS: 257.0 [M+H] +; 1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H) , 8.87 (s, 1H) , 8.53 (s, 1H) , 8.39 (d, J = 3.7 Hz, 1H) , 2.73 (s, 3H) .
Step 3: Preparation of Compound 19-3
To a solution of Compound 19-2 (500 mg, 1.95 mmol) in DMF (5 mL) was added Cs2CO3 (1.91 g, 5.85 mmol) and SEMCl (488 mg, 2.92 mmol) at 0℃. The resulting mixture was stirred at room temperature for 3 hrs. The mixture was quenched with H2O (20 mL) , extracted with EtOAc (30 mL × 3) . The combined organic layers were washed brine (20 mL × 2) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue purified by flash silica gel chromatography (ISCO@; 25 g SepaFlash@Silica Flash Column, Eluent of 0-20%EtOAc/PE @30 mL/min) . (Plate1: PE/EtOAc =5/1) to afford Compound 19-3 (200 mg, 26.5%) . LCMS: 387.1 [M+H] +;
Step 4: Preparation of Compound 19-4
To a solution of Compound 19-3 (110 mg, 0.28 mmol) in Titanium tetraisopropanolate (1 mL) was added 1-methylcyclobutan-1-amine (36.4 mg, 0.43 mmol) at room temperature. The reaction solution was stirred at 100℃ for overnight. Then THF (1 mL) and NaBH4 (64.6 mg, 1.71 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with EtOAc (8 mL) , quenched by addition of water (1 mL) and MeOH (2 mL) at 10℃. The suspension was filtered, a filter cake was washed with EtOAc (8 mL × 3) , the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue purified by flash silica gel chromatography to afford Compound 19-4 (80 mg, 61.7%) . LCMS: 456.2 [M+H] +;
Step 5: Preparation of Compound 19-5
To a solution of Compound 19-4 (80 mg, 0.17 mmol) in 1, 4-dioxane (1 mL) was added HCl (in 1,4-dioxane, 4M, 1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was quenched by the addition of NaHCO3 (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography to afford Compound 19-5. LCMS: 326.3 [M+H] +;
Step 6: Preparation of Compound 19
With 19-5 as the substrate, the title compound was synthesized according to the previous step. LCMS: 629.4 [M+H+MeCN] +; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.67 –8.60 (m, 2H) , 8.51 (s, 1H) , 8.34 (s, 1H) , 7.86 (s, 1H) , 7.60 –7.28 (m, 2H) , 4.21 –4.06 (m, 1H) , 2.94 –2.78 (m, 3H) , 2.65 –2.59 (m, 3H) , 1.83 –1.71 (m, 2H) , 1.62 –1.50 (m, 2H) , 1.46 –1.39 (m, 1H) , 1.35 –1.20 (m, 4H) , 1.14 –1.03 (m, 6H) .
Example A: assay
An HTRF based binding assay was applied to assess the affinity of candidate compounds to Cbl-b protein. CBL-B (GST-Tag) was purchased from BPS (Cat# 80415) . A fluorescence labeled Cbl-b binding probe was made in-house. Anti GST-Tb cryptate monoclonal antibody was from Cisbio (61GSTTLB) . In brief, compounds were diluted and transferred to opti-384F black plate (PE, 6007279) by echo. 1x Assay Buffer (HEPES pH 7.5 50 mM, NaCl 50 mM, MgCl2 5 mM, TCEP 1 mM, Tween-20 0.01%) , 2x Protein mix (10 nM) , and 2x Probe mix (120 nM) were prepared. 10 μL 2x Protein mix (or 1x Assay buffer, as no protein control) was added to assay plate. After 30 min incubation 25℃, 10 μl 2x Probe mix was added for another 2 h incubation at 25℃. Data were collected by Envision reading using Ex340/Em495/520.
The results are found in Table 4.
TABLE 4


0 < A ≤ 20 nM; 20 nM < B ≤ 50 nM; 50 nM < C ≤ 500 nM; 500 nM < D ≤ 1000 nM ; E > 1000 nM
NT: not tested
Example B: CYP inhibition Assay
Pooled human liver microsomes supplied by Corning (Cat No. 452117) were used. CYP isoform and substrate specific probe reactions were employed as per reported methods. The methods were standardized and validated. phenacetin O-deethylation for CYP1A2, diclofenac 4-hydroxylation for CYP2C9, S-mephenytoin 4-hydroxylation for CYP2C19, dextromethorphan Odemethylation for CYP2D6, midazolam 1′-hydroxylation for CYP3A4. In general, the typical incubation systems consisted of 100 mM potassium phosphate buffer (pH 7.4) , 33 mM MgCl2, 10 mM NADPH, HLM (0.253 mg/mL) . Substrates, compounds/positive controls, HLM, and NADPH solutions were added to corresponding wells, mixed, and incubated for 10 minutes for all CYPs at 37 water bath. Reaction was terminated by adding 400 μl cold stop solution (200 ng/ml Tolbutamide and Labetalol in CAN) . Samples were centrifuged at 4000 rpm for 20 minutes to precipitate protein. 200 μl supernatant was transferred to 100 μl HPLC water and shaken for 10 minutes. Samples were analyzed by LC/MS/MS. XL fit was used to plot the percent of vehicle control versus the test compound concentrations, and for non-linear regression analysis of the data. IC50 values were reported as “>50 μM” when %inhibition at the highest concentration (50 μM) was less than 50%.
The results are found in Table 5.
Example C: Human and Mouse CL Determination
Microsomes (final concentration 0.5 mg/mL) , 100 mM phosphate buffer pH 7.4, and compound (final concentration 1 μM) were added to the assay plate and allowed to preincubate for 10 min at 37 ℃. The reaction was initiated by the addition of NADPH (final concentration 1 mM) , and the plate was constantly shaken at 37 ℃. After 0, 5-, 15-, 30-, 45-, and 60-min aliquots were taken, and the reaction was quenched using cold acetonitrile. The samples were shaken for 10 min, then centrifuged at 4000 rpm for 20 min at 4 ℃ and analyzed by LC-MS/MS. The in vitro intrinsic clearance was calculated from the rate of compound disappearance.
The results are found in Table 5.
TABLE 5
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and 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 (44)

  1. A compound of Formula (I) , or a pharmaceutically acceptable salt or stereoisomer thereof: 
    wherein
    X1, X2, X3, X4, and X5 are independently N or CR7’;
    R7’ is hydrogen or R7; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each R20 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
    s is 0, 1, 2, 3, or 4;
    L1 is absent or -CR3R4-;
    R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
    or R3 and R4 are taken together to form an oxo;
    R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
    or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
    or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
    or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
    each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, - NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
    Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each R21 is independently halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
    t is 0, 1, 2, 3, or 4;
    each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
    n is 0, 1, 2, 3, 4, 5, or 6;
    R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
    R10 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
    R22 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl optionally substituted with one or more halogens) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ;
    or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
    or R10 and R22 are taken together to form a heterocycloalkyl optionally substituted with one or more R10a, provided that L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
    each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
    each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
    or two R on the same atom form an oxo.
  2. A compound of Formula (IV) , or a pharmaceutically acceptable salt or stereoisomer thereof:
    wherein:
    each U is independently -N-or -CR1-;
    each R1 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl;
    R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl;
    L1 is absent or -CR3R4-;
    R3 and R4 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R3 and R4 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
    or R3 and R4 are taken together to form an oxo;
    R5 and R6 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
    or R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
    or L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a;
    or L1 is -CR3R4-, R4 and R6 are defined as above, and R5 and R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a;
    each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R5a on the same atom are taken together to form an oxo;
    X is -N-or -CRX-;
    RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
    Y is -N-or -CRY-;
    RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens;
    Z is -N-or -CRZ-;
    RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
    W is -N-or -CRW-;
    RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl;
    or RX and RY are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
    or RY and RZ are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
    Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 R7 on the same atom are taken together to form an oxo;
    n is 0, 1, 2, 3, 4, 5, or 6;
    R8 and R9 are each independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl,  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 R8 and R9 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
    R10 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a;
    each R10a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
    each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2,  C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl optionally substituted with one or more halogens;
    or two R on the same atom form an oxo;
    provided thatis not wherein *represents the attachment point to the ring containing X, Y, Z and W and **represents the attachment point to -CR8R9-.
  3. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.
  4. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 6-6 fused ring.
  5. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 6-5 or 5-6 fused ring containing 3 or more heteroatoms selected from N, O, and S.
  6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or cycloalkyl optionally substituted with one or more halogens; or two R7 on the same atom are taken together to form an oxo.
  7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R7 is independently halogen, -ORa, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; or two R7 on the same atom are taken together to form an oxo.
  8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R7 is independently C1-C6haloalkyl; or two R7 on the same atom are taken together to form an oxo.
  9. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (IV) is of Formula (IVa) :
    wherein
    X1, X2, X3, X4, and X5 are independently N or CR7’; and
    R7’ is hydrogen or R7.
  10. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, whereinis
  11. The compound of any one of claims 2-9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one U is -N-and the other U is -CR1-.
  12. The compound of any one of claims 2-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R1 is independently hydrogen.
  13. The compound of any one of claims 2-12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is C1-C6alkyl.
  14. The compound of any one of claims 2-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RX is hydrogen.
  15. The compound of any one of claims 2-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RY is hydrogen or cycloalkyl optionally substituted with one or more halogens.
  16. The compound of any one of claims 2-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RZ is hydrogen.
  17. The compound of any one of claims 2-16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RW is hydrogen.
  18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1 is -CR3R4-.
  19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R4 are each independently hydrogen, halogen, or C1-C6alkyl.
  20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R4 are each independently hydrogen.
  21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1 is absent.
  22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 and R6 are each independently hydrogen, halogen, or C1-C6alkyl.
  23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 and R6 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R5a.
  24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 and R6 are taken together to form a cycloalkyl optionally substituted with one or more R5a.
  25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 and R6 are taken together to form a heterocycloalkyl optionally substituted with one or more R5a.
  26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R5a.
  27. The compound of any one of claims 26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1 is -CR3R4-, R4 and R6 are taken together to form a bond, and R5 and R3 are taken together to form a phenyl optionally substituted with one or more R5a.
  28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl.
  29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R5a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl.
  30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R5a is independently halogen or C2-C6alkynyl.
  31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R8 and R9 are each independently hydrogen or C1-C6alkyl.
  32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R10 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl optionally substituted with one or more halogens, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) ; wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R10a.
  33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R10 is C1-C6hydroxyalkyl or C1-C6alkylene (cycloalkyl) ; wherein the alkyl, alkylene, and cycloalkyl is independently optionally substituted with one or more R10a.
  34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R10 is C1-C6hydroxyalkyl.
  35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R10 is C1-C6alkylene (cycloalkyl) ; wherein the alkylene and cycloalkyl optionally substituted with one or more R10a.
  36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R10a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R10a is -OH.
  38. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound in table 1 or table 2.
  39. A pharmaceutical composition comprising a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  40. A method of treating a cancer, the method comprising administering an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  41. A method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  42. A method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  43. A method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
  44. A method for treating a disease or condition associated with Cbl-b activity, the method comprising administering an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject in need thereof.
PCT/CN2023/141007 2022-12-23 2023-12-22 Cbl-b inhibitors and methods of uses thereof WO2024131939A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN2022141595 2022-12-23
CNPCT/CN2022/141595 2022-12-23
CNPCT/CN2023/073188 2023-01-19
CN2023073188 2023-01-19
CN2023095484 2023-05-22
CNPCT/CN2023/095484 2023-05-22

Publications (1)

Publication Number Publication Date
WO2024131939A1 true WO2024131939A1 (en) 2024-06-27

Family

ID=91587699

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/141007 WO2024131939A1 (en) 2022-12-23 2023-12-22 Cbl-b inhibitors and methods of uses thereof

Country Status (1)

Country Link
WO (1) WO2024131939A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020236654A1 (en) * 2019-05-17 2020-11-26 Nurix Therapeutics, Inc. Cyano cyclobutyl compounds for cbl-b inhibition and uses thereof
WO2020264398A1 (en) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof
WO2021021761A1 (en) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Urea, amide, and substituted heteroaryl compounds for cbl-b inhibition
WO2022169997A1 (en) * 2021-02-03 2022-08-11 Genentech, Inc. Lactams as cbl-b inhibitors
WO2022221704A1 (en) * 2021-04-16 2022-10-20 Hotspot Therapeutics, Inc. Compounds, compositions and methods of treating cancer
WO2023072273A1 (en) * 2021-10-29 2023-05-04 先声再明医药有限公司 Polycyclic compound as cbl-b inhibitor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020236654A1 (en) * 2019-05-17 2020-11-26 Nurix Therapeutics, Inc. Cyano cyclobutyl compounds for cbl-b inhibition and uses thereof
WO2020264398A1 (en) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof
WO2021021761A1 (en) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Urea, amide, and substituted heteroaryl compounds for cbl-b inhibition
WO2022169997A1 (en) * 2021-02-03 2022-08-11 Genentech, Inc. Lactams as cbl-b inhibitors
WO2022221704A1 (en) * 2021-04-16 2022-10-20 Hotspot Therapeutics, Inc. Compounds, compositions and methods of treating cancer
WO2023072273A1 (en) * 2021-10-29 2023-05-04 先声再明医药有限公司 Polycyclic compound as cbl-b inhibitor

Similar Documents

Publication Publication Date Title
US11964989B2 (en) KRas G12D inhibitors
WO2021127429A1 (en) Sos1 inhibitors
US20230339976A1 (en) Kras g12d inhibitors
CA3069829A1 (en) Aryl-phosphorus-oxygen compound as egfr kinase inhibitor
CN110092787B (en) Preparation and application of compound or medicinal salt or composition thereof
CA2683624A1 (en) Pharmaceutical compounds
WO2019148161A1 (en) 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof
CN118556053A (en) Lysine acetyl transferase 6A (KAT 6A) inhibitor and application thereof
CA3226158A1 (en) Pyridinone mk2 inhibitors and uses thereof
US12077538B2 (en) Diacylglycerol kinase (DGK) alpha inhibitors and uses thereof
AU2022373595A1 (en) Methionine adenosyltransferase 2a (mat2a) inhibitors and uses thereof
WO2023155892A1 (en) Membrane-associated tyrosine-and threonine-specific cdc2-inhibitory kinase (pkmyt1) inhibitors and uses thereof
WO2023165525A1 (en) Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof
WO2023165509A1 (en) Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof
WO2023241627A1 (en) Cdk8/19 dual inhibitors and methods of use thereof
WO2024131939A1 (en) Cbl-b inhibitors and methods of uses thereof
WO2023165528A1 (en) Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof
WO2024002157A1 (en) Inhibitors of fgfr2 and fgfr3 and uses thereof
WO2023174397A1 (en) Pyrazole membrane-associated tyrosine-and threonine-specific cdc2-inhibitory kinase (pkmyt1) inhibitors and uses thereof
WO2024017201A1 (en) Cbl-b inhibitors and methods of uses thereof
WO2024193542A1 (en) Inhibitors of fgfr2 and fgfr3 and uses thereof
WO2024183726A1 (en) Cdk8/19 dual inhibitors and methods of use thereof
WO2024141015A1 (en) Protein tyrosine phosphatase inhibitors and uses thereof
WO2024061300A1 (en) Inhibitors of trex1 and uses thereof
WO2024140799A1 (en) Inhibitors of kif18a and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23906094

Country of ref document: EP

Kind code of ref document: A1