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WO2024217563A1 - Inhibiteur de lysine acétyltransférase 6a (kat6a), associations et utilisations associées - Google Patents

Inhibiteur de lysine acétyltransférase 6a (kat6a), associations et utilisations associées Download PDF

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WO2024217563A1
WO2024217563A1 PCT/CN2024/088931 CN2024088931W WO2024217563A1 WO 2024217563 A1 WO2024217563 A1 WO 2024217563A1 CN 2024088931 W CN2024088931 W CN 2024088931W WO 2024217563 A1 WO2024217563 A1 WO 2024217563A1
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alkyl
compound
formula
pharmaceutically acceptable
acceptable salt
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Xin CAI
Man ZHANG
Xin Cheng
Luoheng QIN
Feng Ren
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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Priority to AU2024259385A priority Critical patent/AU2024259385A1/en
Publication of WO2024217563A1 publication Critical patent/WO2024217563A1/fr
Priority to IL323885A priority patent/IL323885A/en
Priority to MX2025012351A priority patent/MX2025012351A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Lysine acetyltransferase 6A belongs to the MYST family of acetyltransferases and was first discovered approximately 25 years ago. KAT6A controls fundamental cellular processes, including gene transcription, cellular senescence, cardiac septum development, memory T-cell diversity, and maintenance of normal hematopoietic stem cells. Dysregulation of KAT6A acetyltransferase activity or aberrant expression of KAT6A has been associated with oncogenic function in a number of cancers, including leukemia, glioma, endometrial serous carcinoma, and breast cancer. As such, compounds that inhibit KAT6A are potential agents for treating a variety of cancers.
  • CDK4/6i cyclin-dependent kinase 4 and 6 inhibitors
  • ET endocrine therapy
  • KAT6A Molecular dysregulation of KAT6A has been observed in several cancers, including amplifications in breast, lung, and ovarian cancer and oncogenic fusions in AML.
  • KAT6A was found to be amplified and/or overexpressed in 10-15%of the ER-positive breast cancer population.
  • KAT6A is a direct transcriptional regulator of ESR1 and amplification is associated with a worse clinical outcome.
  • First-and second-line treatment options for HR-positive/HER2-negative breast cancer include endocrine therapy, CDK4/6 inhibitors, and targeted therapies. Patients with refractory disease have few treatment options. Therefore, KAT6A is considered a clinically meaningful therapeutic target for ER-positive/HER2-negative breast cancer.
  • provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • Y 1 is CR 1a or N
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N
  • Y 4 is CR 4a or N
  • Y 5 is CR 5a or N
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N; wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N;
  • X is selected from -C (R 6 ) (R 6a ) -, -O-, and -N (R 7 ) -;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1a , R 2a , R 3a , R 4a , R 5a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R
  • R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.
  • FIG. 1 shows the change of tumor volume in PDX model treated with vehicle and the compounds disclosed herein.
  • FIG. 2 shows the relative changes of body weight in PDX model treated with vehicle and the compounds disclosed herein.
  • FIG. 3A shows the percentage of viable cells normalized to control treatment of the breast cancer ER+/KAT6a high ZR-75-1 cells upon treatment with IC 10 /IC 25 /IC 50 /IC 75 of Compound 57, elacestrant, or Compound 57 + elacestrant.
  • FIG. 3B shows the dose response curve of Compound 57 alone or in combination with elacestrant (IC 25 , 56nM) .
  • FIG. 4 shows the statistical analysis of cytotoxicity data obtained with the breast cancer ER+/KAT6a high ZR-75-1 cell line.
  • FIG. 5 shows the Combenefit Combination Index plot representing the relationship between CIs and fraction affected (Fa) by drug combination (fraction of dead cells) .
  • FIG. 6 shows the Compusyn table of the synergism between Compound 57 and Elacestrant in the ER+/KAT6a high breast cancer ZR-75-1 cell line using the Combenefit software evaluates the synergism through the Loewe algorithm.
  • 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 -OR a where R a is an alkyl radical as defined. 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 (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • 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.
  • “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 (C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 fully saturated heterocycloalkyl or C 2 -C 5
  • 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 fully saturated heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated 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, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • 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.
  • 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 term "synergy” or “synergistic effect” when used in connection with a combination of agents means any measured effect of the combination which is greater that the effect predicted from a sum of the effects of the individual agents.
  • Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • enhancement means to increase or prolong either in potency or duration a desired effect.
  • enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount, ” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • Described herein are compounds of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) or (VI) , or a pharmaceutically acceptable salt or solvate thereof, which are KAT6A inhibitors and useful in the treatment of a disease or disorder associated with KAT6A inhibition.
  • the compounds of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) or (VI) , or a pharmaceutically acceptable salt or solvate thereof are useful in the treatment of cancer.
  • Y 1 is CR 1a or N
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N
  • Y 4 is CR 4a or N
  • Y 5 is CR 5a or N
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N; wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N;
  • X is selected from -C (R 6 ) (R 6a ) -, -O-, and -N (R 7 ) -;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1a , R 2a , R 3a , R 4a , R 5a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R
  • R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • Y 1 is CR 1a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 1 is N.
  • Y 2 is CR 2a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 2 is N.
  • Y 3 is CR 3a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 3 is N.
  • Y 4 is CR 4a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 4 is N.
  • Y 5 is CR 5a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 5 is N.
  • Y 1 is CR 1a and Y 5 is CR 5a .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are independently selected from hydrogen and -OR 10 .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • R 10 is C 1-6 alkyl.
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • R 10 is -CH 3 .
  • Z 1 is CR 1b . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Z 1 is N.
  • Z 2 is CR 2b . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Z 2 is N.
  • Z 3 is CR 3b . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Z 3 is N.
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N.
  • R 1a and R 5a are -OR 10 .
  • R 1a and R 5a are independently selected from -O-C 1-6 alkyl and -O-C 1- 6 haloalkyl.
  • R 1a and R 5a are -OCH 3 .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Y 2 is CR 2a ; Y 3 is N; and Y 4 is CR 4a .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is N; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are hydrogen.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , R 10 is C 1-6 alkyl substituted with one, two, or three halogen.
  • R 1a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 1a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is hydrogen.
  • R 1a is C 1-6 alkyl.
  • R 1a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is C 1-6 alkoxyl.
  • In some 1a is -OCF 3 .
  • R 2a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 2a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 2a is hydrogen.
  • R 2a is C 1-6 alkyl.
  • R 2a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, are C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted.
  • R 3a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2- 6 alkynyl.
  • R 3a is hydrogen.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 haloalkyl.
  • R 3a is C 2-6 alkenyl.
  • R 3a is C 2-6 alkynyl.
  • R 4a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 4a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 4a is hydrogen.
  • R 4a is C 1-6 alkyl.
  • R 4a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or-OR 10 .
  • R 5a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen.
  • R 5a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is C 1-6 alkoxyl.
  • R 5a is C 1-3 alkoxyl.
  • R 5a is -OCH 3 .
  • R 1b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b is hydrogen.
  • R 1b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 2b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 2b is hydrogen.
  • R 2b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 3b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 3b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is hydrogen.
  • R 3b is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is C 1-6 alkoxyl.
  • R 3b is C 1-3 alkoxyl. In some embodiments, R 3b is C 1-3 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen. In some embodiments, R 3b is -OCH 3 . In some embodiments, R 3b is -OCH 2 F. In some embodiments, R 3b is -OCF 3 . In some embodiments, R 3b is -OCHF 2 . In some embodiments, R 3b is -OCH 2 CF 3 .
  • X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, and -OH. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are hydrogen.
  • X is -O-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is hydrogen. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is C 1-6 alkyl.
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are unsubstituted.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are unsubstituted.
  • R 1 is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted imidazolyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted oxazolyl.
  • R 1 is unsubstituted pyridinyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridazinyl.
  • R 1 is selected from In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is in some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is
  • a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, is selected from
  • R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen. hydrogen. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 10 is hydrogen. In some embodiments, R 10 is -CH 3 . In some embodiments, R 10 is -CH 2 F. In some embodiments, R 10 is -CHF 2 . In some embodiments, R 10 is -CH 2 CF 3 . In some embodiments, R 10 is -CF 3 .
  • R 11 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 11 is C 1-6 alkyl.
  • R 12 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 12 is hydrogen. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 alkyl.
  • R 13 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 alkyl or C 1-6 haloalkyl.
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6- 10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (I) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (I) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (I) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (I) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (I) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N
  • Y 4 is CR 4a or N
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N; wherein at least one of Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , and Z 3 is N;
  • X is selected from -C (R 6 ) (R 6a ) -, -O-, and -N (R 7 ) -;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1a , R 2a , R 3a , R 4a , R 5a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R
  • R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • R 1a and R 5a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1a and R 5a are independently selected from hydrogen and -OR 10 . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1a and R 5a are -OR 10 .
  • R 1a and R 5a are -OR 10
  • R 10 is C 1-6 alkyl.
  • R 1a and R 5a are -OR 10
  • R 10 is -CH 3 .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Y 2 is CR 2a ; Y 3 is N; and Y 4 is CR 4a .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Y 2 is CR 2a . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, Y 2 is N.
  • Y 3 is CR 3a . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, Y 3 is N.
  • Y 4 is CR 4a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, Y 4 is N.
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Y 2 is CR 2a ; Y 3 is N; and Y 4 is CR 4a .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is N; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • Z 1 is CR 1b . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, Z 1 is N.
  • Z 2 is CR 2b . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, Z 2 is N.
  • Z 3 is CR 3b . In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, Z 3 is N.
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N.
  • R 1a and R 5a are -OR 10 .
  • R 1a and R 5a are independently selected from -O-C 1-6 alkyl and -O-C 1- 6 haloalkyl.
  • R 1a and R 5a are -OCH 3 .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are hydrogen.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , R 10 is C 1-6 alkyl substituted with one, two, or three halogen.
  • R 1a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 1a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is hydrogen.
  • R 1a is C 1-6 alkyl.
  • R 1a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is C 1-6 alkoxyl.
  • In some 1a is -OCF 3 .
  • R 2a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 2a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 2a is hydrogen.
  • R 2a is C 1-6 alkyl.
  • R 2a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, are C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted.
  • R 3a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2- 6 alkynyl.
  • R 3a is hydrogen.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 haloalkyl.
  • R 3a is C 2-6 alkenyl.
  • R 3a is C 2-6 alkynyl.
  • R 4a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 4a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 4a is hydrogen.
  • R 4a is C 1-6 alkyl.
  • R 4a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or-OR 10 .
  • R 5a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen.
  • R 5a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is C 1-6 alkoxyl.
  • R 5a is C 1-3 alkoxyl.
  • R 5a is -OCH 3 .
  • R 1b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b is hydrogen.
  • R 1b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 2b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 2b is hydrogen.
  • R 2b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 3b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 3b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is hydrogen.
  • R 3b is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is C 1-6 alkoxyl.
  • R 3b is C 1-3 alkoxyl. In some embodiments, R 3b is C 1-3 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen. In some embodiments, R 3b is -OCH 3 . In some embodiments, R 3b is -OCH 2 F. In some embodiments, R 3b is -OCF 3 . In some embodiments, R 3b is -OCHF 2 . In some embodiments, R 3b is -OCH 2 CF 3 .
  • X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, and -OH. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are hydrogen.
  • X is -O-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is hydrogen. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is C 1-6 alkyl.
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are unsubstituted.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are unsubstituted.
  • R 1 is unsubstituted pyrazolyl.
  • R 1 is unsubstituted imidazolyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted oxazolyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridinyl.
  • R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridazinyl.
  • R 1 is selected from
  • R 1 is
  • R 1 is In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is in some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1
  • a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, is selected from
  • R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen. hydrogen. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 10 is hydrogen. In some embodiments, R 10 is -CH 3 . In some embodiments, R 10 is -CH 2 F. In some embodiments, R 10 is -CHF 2 . In some embodiments, R 10 is -CH 2 CF 3 . In some embodiments, R 10 is -CF 3 .
  • R 11 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 11 is C 1-6 alkyl.
  • R 12 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 12 is hydrogen. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 alkyl.
  • R 13 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments of a compound of Formula (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 alkyl or C 1-6 haloalkyl.
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6- 10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (Ia) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (Ia) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (Ia) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (Ia) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (Ia) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • Y 1 is CR 1a or N
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N
  • Y 4 is CR 4a or N
  • Y 5 is CR 5a or N
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N
  • X is -O-or -S-;
  • X is selected from -C (R 6 ) (R 6a ) -and -N (R 7 ) -, wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1a , R 2a , R 3a , R 4a , R 5a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R
  • R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • X is -O-. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -S-. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -O-or -S-.
  • X is -C (R 6 ) (R 6a ) -, wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N.
  • X is -N (R 7 ) -, wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N.
  • Y 1 is CR 1a or N
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N
  • Y 4 is CR 4a or N
  • Y 5 is CR 5a or N
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N
  • X is -O-
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1a , R 2a , R 3a , R 4a , R 5a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • a compound of Formula (I’) has a structure of Formula (Ia) .
  • X is -O-. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -S-. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -.
  • Y 1 is CR 1a . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Y 1 is N.
  • Y 2 is CR 2a . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Y 2 is N.
  • Y 3 is CR 3a . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Y 3 is N.
  • Y 4 is CR 4a . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Y 4 is N.
  • Y 5 is CR 5a . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Y 5 is N.
  • Y 1 is CR 1a and Y 5 is CR 5a .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are independently selected from hydrogen and -OR 10 .
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • R 10 is C 1-6 alkyl.
  • Y 1 is CR 1a
  • Y 5 is CR 5a
  • R 1a and R 5a are -OR 10
  • R 10 is -CH 3 .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Y 2 is CR 2a ; Y 3 is N; and Y 4 is CR 4a .
  • Y 2 is N; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is N.
  • Y 2 is CR 2a ; Y 3 is CR 3a ; and Y 4 is CR 4a .
  • Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is N; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • Z 1 is CR 1b ; Z 2 is N; and Z 3 is CR 3b .
  • Z 1 is CR 1b . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Z 1 is N.
  • Z 2 is CR 2b . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Z 2 is N.
  • Z 3 is CR 3b . In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, Z 3 is N.
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 is CR 1a ; Y 2 is N; Y 3 is CR 3a ; Y 4 is CR 4a ; Y 5 is CR 5a ; Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , and Z 3 is N.
  • R 1a and R 5a are -OR 10 .
  • R 1a and R 5a are independently selected from -O-C 1-6 alkyl and -O-C 1- 6 haloalkyl.
  • R 1a and R 5a are -OCH 3 .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 2a , R 3a , R 4a , R 1b , R 2b , and R 3b are hydrogen.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 1b and R 2b are hydrogen, R 3b is -OR 10 , R 10 is C 1-6 alkyl substituted with one, two, or three halogen.
  • R 1a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 1a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is hydrogen.
  • R 1a is C 1-6 alkyl.
  • R 1a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 1a is C 1-6 alkoxyl.
  • In some 1a is -OCF 3 .
  • R 2a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 2a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 2a is hydrogen.
  • R 2a is C 1-6 alkyl.
  • R 2a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, are C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 3a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted.
  • R 3a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2- 6 alkynyl.
  • R 3a is hydrogen.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 alkyl.
  • R 3a is C 1-6 haloalkyl.
  • R 3a is C 2-6 alkenyl.
  • R 3a is C 2-6 alkynyl.
  • R 4a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 4a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 4a is hydrogen.
  • R 4a is C 1-6 alkyl.
  • R 4a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or-OR 10 .
  • R 5a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is hydrogen.
  • R 5a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 5a is C 1-6 alkoxyl.
  • R 5a is C 1-3 alkoxyl.
  • R 5a is -OCH 3 .
  • R 1b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b is hydrogen.
  • R 1b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 2b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 2b is hydrogen.
  • R 2b is halogen.
  • R 1b is C 1-6 alkyl.
  • R 1b is C 1-6 haloalkyl.
  • R 3b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 3b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is hydrogen.
  • R 3b is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 3b is C 1-6 alkoxyl.
  • R 3b is C 1-3 alkoxyl. In some embodiments, R 3b is C 1-3 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen. In some embodiments, R 3b is -OCH 3 . In some embodiments, R 3b is -OCH 2 F. In some embodiments, R 3b is -OCF 3 . In some embodiments, R 3b is -OCHF 2 . In some embodiments, R 3b is -OCH 2 CF 3 .
  • X is -C (R 6 ) (R 6a ) -.
  • X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, and -OH.
  • X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are hydrogen.
  • X is -O-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is hydrogen. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is C 1-6 alkyl.
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are unsubstituted.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are unsubstituted.
  • R 1 is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted imidazolyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted oxazolyl.
  • R 1 is unsubstituted pyridinyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridazinyl.
  • R 1 is selected from In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is in some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is
  • a compound of Formula (I’) or a pharmaceutically acceptable salt or solvate thereof, is selected from
  • R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen. hydrogen. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 10 is hydrogen. In some embodiments, R 10 is -CH 3 . In some embodiments, R 10 is -CH 2 F. In some embodiments, R 10 is -CHF 2 . In some embodiments, R 10 is -CH 2 CF 3 . In some embodiments, R 10 is -CF 3 .
  • R 11 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 11 is C 1-6 alkyl.
  • R 12 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 12 is hydrogen. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 alkyl.
  • R 13 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments of a compound of Formula (I’) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 alkyl or C 1-6 haloalkyl.
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6- 10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (I’) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (I’) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (I’) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • Z 1 is CR 1b
  • Z 2 is CR 2b
  • Z 3 is CR 3b
  • each R 1a and each R 5a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10
  • each R 2a , each R 3a , each R 4a , each R 1b , each R 2b , and each R 3b are independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, and -OR 10 , wherein R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or C 2- 9 heterocycloalkyl.
  • R 1 is an optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (I) , (I’) , or (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is an optionally substituted 5 membered heteroaryl.
  • R 1 is pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, , wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is selected from In some embodiments of a compound of Formula (I) , (I’) , or (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from In some embodiments of a compound of Formula (I) , (I’) , or (Ia) , or a pharmaceutically acceptable salt or solvate thereof, R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • X is selected from -C (R 6 ) (R 6a ) -, -O-, and -N (R 7 ) -;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • R 8a , R 8b , R 8c , R 8d , R 8e , R 9b , and R 9c are each independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 ,
  • R 9a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 14 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C (O) N
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • R 14 is independently selected from hydrogen, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
  • each R 15a , each R 15b , each R 15c , each R 15d , and each R 15e are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1- 9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) ,-N (R 12 ) C (O) N (R 10 ) (R 11 ) ,
  • R 8a and R 8e are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 . In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are independently selected from hydrogen and -OR 10 . In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are -OR 10 .
  • R 8a and R 8e are -OR 10 and R 10 is C 1-6 alkyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are -OR 10 and R 10 is -CH 3 .
  • R 8a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8a is hydrogen.
  • R 8a is C 1-6 alkyl.
  • R 8a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8a is C 1-6 alkoxyl.
  • R 8a is -OCF 3 .
  • R 8e is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8e is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8e is hydrogen.
  • R 8e is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8e is C 1-6 alkoxyl.
  • R 8e is C 1-3 alkoxyl.
  • R 8e is -OCH 3 .
  • R 8b , R 8c , R 8d , and R 9c are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, and -OR 10 .
  • R 8b , R 8c , R 8d , and R 9c are independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 8b , R 8c , R 8d , and R 9c are hydrogen.
  • R 8b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8b is hydrogen.
  • R 8b is C 1-6 alkyl.
  • R 8b is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8c is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, are C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 8c is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted.
  • R 8c is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2- 6 alkynyl.
  • R 8c is hydrogen.
  • R 8c is C 1-6 alkyl.
  • R 8c is C 1-6 alkyl.
  • R 8c is C 1-6 haloalkyl.
  • R 8c is C 2-6 alkenyl.
  • R 8c is C 2-6 alkynyl.
  • R 8d is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8d is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8d is hydrogen.
  • R 8d is C 1-6 alkyl.
  • R 8d is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 9c is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 9c is hydrogen.
  • R 9c is halogen.
  • R 9c is C 1-6 alkyl.
  • R 9c is C 1-6 haloalkyl.
  • R 9b is selected from hydrogen, halogen, and C 1-6 alkyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is hydrogen. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is halogen. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is C 1-6 alkyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is -CH 3 .
  • R 9b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 9b is hydrogen.
  • R 9b is halogen.
  • R 9b is C 1-6 alkyl.
  • R 9b is C 1-6 haloalkyl.
  • R 9a is -OR 14 . In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is C 1-6 haloalkyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is -CF 3 . In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is -CHF 2 .
  • R 9a is C 3-6 cycloalkyl are substituted with one, two, or three groups selected from R 15c .
  • R 9a is C 3-6 cycloalkyl are substituted with one, two, or three groups selected from R 15c and each R 15c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 9a is C 3-6 cycloalkyl are substituted with one, two, or three groups selected from R 15c and each R 15c is halogen.
  • R 9a is C 1-6 alkyl, C 1-6 haloalkyl, or -OR 14 .
  • R 9a is C 1-6 alkyl, C 1- 6 haloalkyl, or -O-C 1-6 haloalkyl.
  • R 9a is -O-C 1-6 haloalkyl.
  • R 9a is -O-C 1-6 haloalkyl.
  • R 9a is -OCH 2 F.
  • R 9a and R 9b are combined to form a C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, or C 2- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, and C 2-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15e .
  • R 9a and R 9b are combined to form a C 2- 9 heterocycloalkyl optionally substituted with one, two, or three groups selected from R 15e .
  • R 9a and R 9b are combined to form a C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups selected from from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 10 is hydrogen, C 1-6 alkyl, C 1- 6 haloalkyl, or C 3-6 cycloalkyl.
  • R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3- 6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen. hydrogen.
  • R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 10 is hydrogen.
  • R 10 is -CH 3 .
  • R 10 is -CH 2 F.
  • R 10 is -CHF 2 .
  • R 10 is -CH 2 CF 3 .
  • R 10 is -CF 3 .
  • R 9a and R 9b are combined to form a 5 to 7-membered ring. In some embodiments, R 9a and R 9b are combined to form a 6-membered ring. In some embodiments, R 9a and R 9b are combined to form a cycloalkyl. In some embodiments, R 9a and R 9b are combined to form a heterocycloalkyl. In some embodiments, R 9a and R 9b are combined to form a ring containing 1 or 2 oxygen and 0-2 nitrogen. In some embodiments, R 9a and R 9b are combined to form a ring containing 1 oxygen.
  • R 11 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 11 is C 1-6 alkyl.
  • R 12 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 12 is hydrogen. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 alkyl.
  • R 13 is C 1-6 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 alkyl.
  • R 14 is hydrogen, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R 14 is hydrogen, or C 1-6 haloalkyl. In some embodiments, R 14 is C 1-6 haloalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is -CH 2 F. In some embodiments, R 14 is -CH 2 CF 3 . In some embodiments, R 14 is -CF 3 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6- 10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (II) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (II) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (II) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are independently selected from hydrogen, halogen, C 1-6 alkyl, and -OH. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, X is -C (R 6 ) (R 6a ) -and R 6 and R 6a are hydrogen.
  • X is -O-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is hydrogen. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is C 1-6 alkyl.
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are unsubstituted.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are unsubstituted.
  • R 1 is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted imidazolyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted oxazolyl.
  • R 1 is unsubstituted pyridinyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridazinyl.
  • R 1 is selected from In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is in some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is
  • X is selected from -O-and -N (R 7 ) -;
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a ;
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • R 8a , R 8b , R 8c , R 8d , R 8e , R 9b , and R 9c are each independently selected from hydrogen, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 ,
  • R 9a is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and -OR 14 ;
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • R 14 is selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • each R 15a and each R 15b are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (
  • R 8a and R 8e are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 . In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are independently selected from hydrogen and -OR 10 . In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are -OR 10 .
  • R 8a and R 8e are -OR 10 and R 10 is C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 8a and R 8e are -OR 10 and R 10 is -CH 3 .
  • R 8a is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8a is hydrogen.
  • R 8a is C 1-6 alkyl.
  • R 8a is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8a is C 1-6 alkoxyl.
  • R 8a is -OCF 3 .
  • R 8e is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8e is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8e is hydrogen.
  • R 8e is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8e is C 1-6 alkoxyl.
  • R 8e is C 1-3 alkoxyl.
  • R 8e is -OCH 3 .
  • R 8b , R 8c , R 8d , and R 9c are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, and -OR 10 .
  • R 8b , R 8c , R 8d , and R 9c are independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 8b , R 8c , R 8d , and R 9c are hydrogen.
  • R 8b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8b is hydrogen.
  • R 8b is C 1-6 alkyl.
  • R 8b is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8c is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, are C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 8c is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted.
  • R 8c is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2- 6 alkynyl.
  • R 8c is hydrogen.
  • R 8c is C 1-6 alkyl.
  • R 8c is C 1-6 alkyl.
  • R 8c is C 1-6 haloalkyl.
  • R 8c is C 2-6 alkenyl.
  • R 8c is C 2-6 alkynyl.
  • R 8d is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • R 8d is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 8d is hydrogen.
  • R 8d is C 1-6 alkyl.
  • R 8d is C 1-6 alkoxyl, wherein the alkoxyl is optionally substituted with 1, 2 or 3 halogen.
  • R 9c is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 9c is hydrogen.
  • R 9c is halogen.
  • R 9c is C 1-6 alkyl.
  • R 9c is C 1-6 haloalkyl.
  • R 9b is selected from hydrogen, halogen, and C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is hydrogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is halogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9b is -CH 3 .
  • R 9b is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 9b is hydrogen.
  • R 9b is halogen.
  • R 9b is C 1-6 alkyl.
  • R 9b is C 1-6 haloalkyl.
  • R 9a is -OR 14 . In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is -CH 3 . In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is -OR 14 and R 14 is C 3-6 cycloalkyl. In some embodiments, R 9a is -OCH 2 F.
  • R 9a is C 1-6 alkyl, C 3-6 cycloalkyl, or -OR 14 . In some embodiments, R 9a is C 1-6 alkyl, C 1- 6 cycloalkyl, or C 1-6 alkoxyl, In some embodiments, R 9a is C 1-6 alkoxyl. In some embodiments, R 9a is C 1- 3 alkoxyl.
  • R 9a is hydrogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 9a is C 3- 6 cycloalkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, X is -O-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is hydrogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, X is -N (R 7 ) -and R 7 is C 1-6 alkyl.
  • R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen. hydrogen. In some embodiments, R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 10 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 10 is hydrogen. In some embodiments, R 10 is -CH 3 . In some embodiments, R 10 is -CH 2 F. In some embodiments, R 10 is -CHF 2 . In some embodiments, R 10 is -CH 2 CF 3 . In some embodiments, R 10 is -CF 3 .
  • R 11 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 11 is C 1-6 alkyl.
  • R 12 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 12 is hydrogen. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 alkyl.
  • R 13 is C 1-6 halaoalkyl, C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 alkyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 halaoalkyl.
  • R 14 is C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, R 14 is C 1-6 alkyl. In some embodiments, R 14 is C 3-6 cycloalkyl. In some embodiments, R 14 is -CH 3 .
  • each R 15a and each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6- 10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a and each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a and each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a and each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10 cycloalkyl, or -OR 10 .
  • each R 15a and each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (III) , each R 15a and each R 15b are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (III) , each R 15a and each R 15b are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a and each R 15b are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (III) , each R 15a and each R 15b are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (III) , each R 15a and each R 15b are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (III) , each R 15a and each R 15b are independently -OR 10 .
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are unsubstituted.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyridinyl are unsubstituted.
  • R 1 is unsubstituted pyrazolyl.
  • R 1 is unsubstituted imidazolyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted oxazolyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridinyl.
  • R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted pyridazinyl.
  • R 1 is selected from In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is in some embodiments, R 1 is selected from wherein each is optionally substituted with 1, 2 or 3 R 15a . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is
  • described herein is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from a compound of Table 1A:
  • R 2 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; each optionally substituted with one, two, three, or four groups selected from R 15c ;
  • Z 1 is CR 1b or N
  • Z 2 is CR 2b or N
  • Z 3 is CR 3b or N
  • R 1 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1b , R 2b , and R 3b are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R
  • R 2b and R 3b are taken together to form a C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1- 9 heteroaryl; wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, three, or four groups selected from R 15e ;
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O)
  • each R 10 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 11 is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 12 is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 2 is C 6-10 aryl or C 1-9 heteroaryl; each optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is C 1-9 heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is 5-or 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is pyridinyl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is phenyl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is
  • Z 1 is CR 1b ; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • Z 1 is N; Z 2 is CR 2b ; and Z 3 is CR 3b .
  • R 1b , R 2b , and R 3b are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) , wherein C 1-6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b , R 2b , and R 3b are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 1-6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b , R 2b , and R 3b are independently hydrogen, halogen, C 3-6 cycloalkyl, -OR 10 , -SR 10 , or -SF 5 , wherein C 3-6 cycloalkyl is optionally substituted with one, two, or three groups selected from R 15b .
  • R 1b , R 2b , and R 3b are independently hydrogen, halogen, -OR 10 , -SR 10 , or -SF 5 .
  • R 1b , R 2b , and R 3b are independently hydrogen or -OR 10 .
  • R 1b , R 2b , and R 3b are hydrogen.
  • R 1b is hydrogen
  • R 2b and R 3b are taken together to form a C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, three, or four groups selected from R 15e .
  • R 2b and R 3b are taken together to form C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; wherein C 3-6 cycloalkyl and C 2-9 heterocycloalkyl are optionally substituted with one, two, three, or four groups selected from R 15e .
  • R 2b and R 3b are taken together to form C 2-9 heterocycloalkyl optionally substituted with one, two, three, or four groups selected from R 15e .
  • R 2b and R 3b are taken together to form C 2-6 heterocycloalkyl optionally substituted with one, two, three, or four groups selected from R 15e .
  • R 2b and R 3b are taken together to form C 6-9 heterocycloalkyl optionally substituted with one, two, three, or four groups selected from R 15e .
  • R 2b and R 3b are taken together to form a 5-to 7-membered heterocycloalkyl containing one or two heteroatoms selected from O and N. In some embodiments of a compound of Formula (IV) , R 2b and R 3b are taken together to form a 6-membered heterocycloalkyl containing one heteroatom that is O.
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, or C 1-6 haloalkyl.
  • each R 15e are independently halogen, oxo, C 1-6 alkyl, or C 1-6 haloalkyl.
  • two R 15e on the adjacent carbon are taken together to form a C 2 alkenylene.
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl.
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl.
  • R 2b and R 3b are taken together to form
  • R 1 is C 6-10 aryl or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-or 6-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl and thiazolyl, wherein pyrazolyl and thiazolyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is thiazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1- 9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently halogen, C 1-6 alkyl, C 1- 6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15a are independently -OR 10 .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15b are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15b are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15b are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15b are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15b are independently -OR 10 .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , - C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (IV) , each R 15c are independently -OR 10 .
  • R 2 is C 1-9 heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c ;
  • Z 1 is CR 1b or N
  • R 1 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • X is -C (R 6 ) (R 6a ) -, -S-, -O-, or -N (R 7 ) -;
  • R 6 and R 6a are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C (O
  • R 6 and R 6a are taken together to form an oxo
  • R 7 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • Ring A is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl;
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O)
  • n 0-6;
  • each R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-
  • each R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 12 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 13 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl.
  • R 2 is 5-or 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is pyridinyl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is
  • Ring A is C 3-6 cycloalkyl or C 2- 9 heterocycloalkyl.
  • Ring A is C 2-9 heterocycloalkyl.
  • Ring A is C 2-6 heterocycloalkyl.
  • Ring A is C 6-9 heterocycloalkyl. In some embodiments of a compound of Formula (V) , Ring A is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (V) , Ring A is 5-to 7-membered heterocycloalkyl containing one or two heteroatoms elected from O and N. In some embodiments of a compound of Formula (V) , Ring A is 6-membered heterocycloalkyl containing one heteroatom that is O.
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, or C 1-6 haloalkyl.
  • each R 15e are independently halogen, oxo, C 1-6 alkyl, or C 1-6 haloalkyl.
  • two R 15e on the adjacent carbon are taken together to form a C 2 alkenylene.
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl.
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl.
  • n is 0-4. In some embodiments of a compound of Formula (V) , n is 2-4. In some embodiments of a compound of Formula (V) , n is 2. 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 1-3.
  • Z 1 is N. In some embodiments of a compound of Formula (V) , Z 1 is CR 1b .
  • R 1b is hydrogen or halogen. In some embodiments of a compound of Formula (V) , R 1b is hydrogen.
  • X is -C (R 6 ) (R 6a ) -, -S-, or -O-. In some embodiments of a compound of Formula (V) , X is -C (R 6 ) (R 6a ) -or -O-. In some embodiments of a compound of Formula (V) , X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (V) , X is -O-. In some embodiments of a compound of Formula (V) , X is -S-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (V) , X is -S-, -O-, or -N (R 7 ) -.
  • R 6 and R 6a are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments of a compound of Formula (V) , R 6 and R 6a are independently hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (V) , R 6 and R 6a are hydrogen. In some embodiments of a compound of Formula (V) , R 6 and R 6a are taken together to form an oxo.
  • R 7 is hydrogen, C 1-6 alkyl, or C 1- 6 haloalkyl. In some embodiments of a compound of Formula (V) , R 7 is hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (V) , R 7 is hydrogen.
  • R 1 is C 6-10 aryl or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-or 6-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl and thiazolyl, wherein pyrazolyl and thiazolyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is thiazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is In some embodiments of a compound of Formula (V) , R 1 is
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1- 9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently halogen, C 1-6 alkyl, C 1- 6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15a are independently -OR 10 .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently halogen, C 1- 6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15b are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15b are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15b are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15b are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15b are independently -OR 10 .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently halogen, C 1- 6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (V) , each R 15c are independently -OR 10 .
  • R 2 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; each optionally substituted with one, two, three, or four groups selected from R 15c ;
  • Z 1 is CR 1b or N
  • R 1 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a ;
  • R 1b is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
  • X is -C (R 6 ) (R 6a ) -, -S-, -O-, or -N (R 7 ) -;
  • R 6 and R 6a are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C (O
  • R 6 and R 6a are taken together to form an oxo
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • Ring B is C 3-6 cycloalkyl, C 6-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl;
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O)
  • n 0-6;
  • each R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
  • each R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 12 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • each R 13 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl.
  • R 2 is C 6-10 aryl or C 1-9 heteroaryl; each optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is C 1-9 heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is 5-or 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is 6-membered heteroaryl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is pyridinyl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is phenyl optionally substituted with one, two, three, or four groups selected from R 15c .
  • R 2 is
  • Ring B is C 6-9 heterocycloalkyl.
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15e are independently halogen, oxo, -CN, C 1-6 alkyl, or C 1-6 haloalkyl.
  • each R 15e are independently halogen, oxo, C 1-6 alkyl, or C 1-6 haloalkyl.
  • two R 15e on the adjacent carbon are taken together to form a C 2 alkenylene.
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the same atom are taken together to form a C 3-6 cycloalkyl.
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl or C 2-9 heterocycloalkyl; each optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 10 , and -N (R 10 ) (R 11 ) .
  • two R 15e on the different atom are taken together to form a C 3-6 cycloalkyl.
  • n is 0-4. In some embodiments of a compound of Formula (VI) , n is 2-4. In some embodiments of a compound of Formula (VI) , n is 2. In some embodiments of a compound of Formula (VI) , n is 1 or 2. In some embodiments of a compound of Formula (VI) , n is 1. In some embodiments of a compound of Formula (VI) , n is 1-3.
  • Z 1 is N. In some embodiments of a compound of Formula (VI) , Z 1 is CR 1b .
  • R 1b is hydrogen or halogen. In some embodiments of a compound of Formula (VI) , R 1b is hydrogen.
  • X is -C (R 6 ) (R 6a ) -, -S-, or -O-. In some embodiments of a compound of Formula (VI) , X is -C (R 6 ) (R 6a ) -or -O-. In some embodiments of a compound of Formula (VI) , X is -C (R 6 ) (R 6a ) -. In some embodiments of a compound of Formula (VI) , X is -O-. In some embodiments of a compound of Formula (VI) , X is -S-.
  • X is -N (R 7 ) -. In some embodiments of a compound of Formula (VI) , X is -S-, -O-, or -N (R 7 ) -.
  • R 6 and R 6a are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments of a compound of Formula (VI) , R 6 and R 6a are independently hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (VI) , R 6 and R 6a are hydrogen. In some embodiments of a compound of Formula (VI) , R 6 and R 6a are taken together to form an oxo.
  • R 7 is hydrogen, C 1-6 alkyl, or C 1- 6 haloalkyl. In some embodiments of a compound of Formula (VI) , R 7 is hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (VI) , R 7 is hydrogen.
  • R 1 is C 6-10 aryl or C 1-9 heteroaryl; each optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-or 6-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is 5-membered heteroaryl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is optionally substituted C 1-9 heteroaryl. In some embodiments of a compound of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 or 6 membered heteroaryl. In some embodiments of a compound of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 5 membered heteroaryl. In some embodiments of a compound of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is optionally substituted 6 membered heteroaryl.
  • R 1 is monocyclic heteroaryl. In some embodiments of a compound of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof, R 1 is bicyclic heteroaryl. In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from R 15a . In some embodiments, R 1 is optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxyl.
  • R 1 is optionally substituted with one, two, or three groups selected from oxo, -CN, amino, OH, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxyl, and C 3-6 cycloalkyl.
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, wherein pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one, two, or three groups selected from R 15a and each R 15a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, and pyridinyl are substituted with one group selected from R 15a and R 15a is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is C 1-9 heteroaryl selected from pyrazolyl and thiazolyl, wherein pyrazolyl and thiazolyl are optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is thiazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15a .
  • R 1 is In some embodiments of a compound of Formula (VI) , R 1 is
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1- 9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 .
  • each R 15a , each R 15b , and each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a , each R 15b , and each R 15c are independently C 1- 6 alkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a , each R 15b , and each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a , each R 15b , and each R 15c are independently -OR 10 .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15a are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently halogen, C 1-6 alkyl, C 1- 6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15a are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15a are independently -OR 10 .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15b are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15b are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15b are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15b are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15b are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15b are independently -OR 10 .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) R 13 , or -C (O) N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , or -N (R 10 ) (R 11 ) .
  • each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15c are independently halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15c are independently halogen, C 1-6 alkyl, or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15c are independently C 1-6 alkyl, C 3-10 cycloalkyl, or -OR 10 .
  • each R 15c are independently C 1-6 alkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15c are independently C 3-10 cycloalkyl or -OR 10 . In some embodiments of a compound of Formula (VI) , each R 15c are independently -OR 10 .
  • each R 10 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 10 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 10 is independently hydrogen, C 1- 6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 10 is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 10 is independently C 1-6 alkyl or C 1-6 haloalkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 10 is independently C 1-6 alkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 10 is methyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 10 is independently C 1-6 haloalkyl.
  • each R 11 is independently hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 11 is independently hydrogen. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 11 is independently C 1-6 alkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 12 is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • each R 12 is independently hydrogen or C 1-6 alkyl. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 12 is independently hydrogen. In some embodiments of a compound of Formula (IV) , (V) , or (VI) , each R 12 is independently C 1-6 alkyl.
  • each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl.
  • each R 13 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 13 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 13 is independently hydrogen, C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • each R 13 is independently hydrogen or C 1-6 alkyl.
  • each R 13 is independently C 1-6 alkyl.
  • described herein is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from a compound of Table 1B:
  • described herein is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from a compound of Table 1C:
  • 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.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 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 abundance of deuterium in each of the substituents disclosed herein 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 of the substituents disclosed herein 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 substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • 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 a solvate, or stereoisomer thereof, 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
  • 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, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • 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.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering such solvates.
  • the disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided 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.
  • a method of treating a disease in which inhibition of KAT6A is beneficial comprising administering a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administering a pharmaceutical composition comprising a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administering a compound selected from compounds 1-70, and the compounds of Table 1B, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound selected from compounds 1-70, and the compounds of Table 1B, or a pharmaceutically acceptable salt or solvate thereof. In some embodiment, the method comprises administering a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein, or a pharmaceutically acceptable salt or solvate thereof and an additional agent.
  • the method comprises administering a pharmaceutical composition comprising a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) disclosed herein, or a pharmaceutically acceptable salt or solvate thereof and an additional agent.
  • the method comprises administering a compound selected from compounds 1-70, and the compounds of Table 1B, or a pharmaceutically acceptable salt or solvate thereof and an additional agent.
  • the method comprises administering a pharmaceutical composition comprising a compound selected from compounds 1-70, and the compounds of Table 1B, or a pharmaceutically acceptable salt or solvate thereof and an additional agent.
  • the method comprises administering a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, or a pharmaceutically acceptable salt or solvate thereof and an additional agent.
  • the term “additional agent” is not a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein.
  • the additional agent when used in combination with a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein, achieves a better therapeutic effect than the sum of the therapeutic effect achieved by the additional agent and the compounds disclosed herein when administered separately.
  • the additional agent when administered in combination with a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein, achieves a synergistic effect.
  • the synergistic effect is exhibited by increased response rate (RR) , prolonged non-progress disease, time to disease progression (TTP) , slower progress of disease, reduced tumor size, prolonged survival time, higher survival rate, better efficacy, higher safety, or any combination thereof.
  • a method of treating a disease or disorder associated with KAT6A comprising administering to the subject a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administering a pharmaceutical composition comprising a compound of Formula (I) , (Ia) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, hepatocellular carcinoma, colon cancer, breast cancer, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from ER-positive breast cancer, glioblastoma, non-small cell lung cancer (NSCLC) , small cell lung cancer (SCLC) , melanoma, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer (CRC) , hepatocellular carcinoma (HCC) , renal cell carcinoma (RCC) , leukemia, lymphoma or multiple myeloma, acute lymphocytic leukemia (ALL) , acute myeloid leukemia (AML) , chronic lymphocytic leukemia (CLL) , chronic myeloid leukemia (
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is ER-positive breast cancer.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is glioblastoma.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is non-small cell lung cancer (NSCLC) .
  • NSCLC non-small cell lung cancer
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is small cell lung cancer (SCLC) .
  • SCLC small cell lung cancer
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is melanoma.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is ovarian cancer.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is prostate cancer.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is pancreatic cancer.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is colorectal cancer (CRC) .
  • CRC colorectal cancer
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is hepatocellular carcinoma (HCC) .
  • HCC hepatocellular carcinoma
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is renal cell carcinoma (RCC) .
  • RRC renal cell carcinoma
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is leukemia.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is lymphoma.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is multiple myeloma.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is acute lymphocytic leukemia (ALL) .
  • ALL acute lymphocytic leukemia
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is acute myeloid leukemia (AML) .
  • AML acute myeloid leukemia
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is chronic lymphocytic leukemia (CLL) .
  • CLL chronic lymphocytic leukemia
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is chronic myeloid leukemia (CML) .
  • CML chronic myeloid leukemia
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is non-Hodgkin’s lymphoma.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor with KAT6A/6B amplification or overexpression, or leukemia or solid tumor with KAT6A/6B fusion protein resulting from chromosomal translocation.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor with KAT6A/6B amplification or overexpression.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a leukemia or solid tumor with KAT6A/6B fusion protein resulting from chromosomal translocation.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a MYST overexpressing cancer.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer overexpresses more than one KATs of the MYST family.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer overexpresses more than one KATs of the MYST family selected from TIP60, KAT6A, KAT6B, HBO1, and MOF.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a bromodomain overexpressing cancer.
  • a method of treating a bromodomain overexpressing cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer overexpresses one or more bromodomain proteins selected from BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, TAF1/TAF1L, TFIID, SMARC2, and SMARC4.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from acute leukemia, lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, multiple myeloma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, hepatocellular carcinoma, colorectal cancer (CRC) , breast cancer, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland,
  • the additional agent comprises an endocrine therapy, a CDK inhibitor, PI3K-AKT-mTOR pathway inhibitor, androgen synthesis inhibitor, androgen receptor blocker, radiopharmaceutical agent, immunotherapy, chemotherapy, Bcl-2 inhibitor, Bcl-xL inhibitor, or any combination thereof.
  • the additional agent comprises 2, 3, 4 or more of an endocrine therapy, a CDK inhibitor, PI3K-AKT-mTOR pathway inhibitor, androgen synthesis inhibitor, androgen receptor blocker, radiopharmaceutical agent, immunotherapy, chemotherapy, Bcl-2 inhibitor, and Bcl-xL inhibitor.
  • the additional agent comprises one or two of an endocrine therapy, CDK inhibitor, chemotherapy, immunotherapy, radiotherapy, Bcl-2/bcl-xl inhibitor, and a PI3K-AKT-mTOR pathway inhibitor.
  • the additional agent comprises endocrine therapy and chemotherapy.
  • the additional agent comprises chemotherapy and immunotherapy.
  • the additional agent comprises endocrine therapy and CDK inhibitor.
  • the additional agent comprises chemotherapy and radiotherapy.
  • the additional agent comprises immunotherapy and radiotherapy.
  • the additional agent comprises Bcl-2 and/or Bcl-xl inhibitor and radiotherapy.
  • the additional agent comprises Bcl-2 and/or Bcl-xl inhibitor and chemotherapy.
  • the additional agent comprises endocrine therapy. In some embodiments the additional agent comprises chemotherapy. In some embodiments the additional agent comprises radiotherapy. In some embodiments the additional agent comprises Bcl-2 inhibitor. In some embodiments the additional agent comprises Bcl-xL inhibitor. In some embodiments the additional agent comprises Bcl-2 inhibitor and Bcl-xL inhibitor. In some embodiments the additional agent comprises Bcl-2 inhibitor and chemotherapy. In some embodiments the additional agent comprises Bcl-xL inhibitor and chemotherapy. In some embodiments the additional agent comprises Bcl-2 inhibitor, Bcl-xL inhibitor, and chemotherapy. In some embodiments the additional agent comprises hormone therapy. In some embodiments the additional agent comprises PI3K-AKT-mTOR inhibitor.
  • the additional agent comprises endocrine therapy.
  • the endocrine therapy comprises estrogen receptor modulator (SERM) , selective estrogen receptor degrader (SERD) , a complete estrogen receptor degrader, an aromatase inhibitor, another form of partial or complete estrogen antagonist or agonist or any combination thereof.
  • anti-estrogen compounds include, but are not limited to, SERMS (e.g., anordrin, adoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant) , aromatase inhibitors (e.g., aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole) , and antigonadotropins (e.g., leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate
  • anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, as well as US 2015/0005286, WO 2014/205136, WO 2014/205138, US Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos.
  • the endocrine therapy comprises tamoxifen, raloxifene, fulvestrant, elacestrant, camizestrant, amcenestrant, goserelin, imlunestrant, giredestrant, ARV-471, anastrozole, letrozole, exemestane, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the endocrine therapy comprises elacestrant.
  • the additional agent comprises CDK inhibitor. In some embodiments the additional agent comprises CDK2 selective inhibitor, CDK4-selective inhibitor, CDK2/4/6 selective inhibitor, CDK4/6 selective inhibitor, or any combination thereof. In some embodiments the additional agent comprises PF-07220060, alvocidib, AT7519, JNJ-7706621, PHA-793887, BMS-265246, milciclib (PHA-848125) , R547, riviciclib (P276-00) , MC180295, G1T38, ON123300, purvalanol A, SU9516, ribociclib (LEE011) , or BSJ-03-123, palbociclib, abemaciclib, dalpicilib, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the additional agent comprises a kinase inhibitor.
  • the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • the additional agent comprises PI3K-AKT-mTOR inhibitor.
  • the additional agent comprises wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib , palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2- [4- [2- (2-Isopropyl-5-methyl-l, 2, 4-triazol-3-yl) -5, 6-dihydroimidazo [l, 2-d] [l, 4] benzoxazepin-9-yl] pyrazol-l-yl] -2-methylpropanamide) , MLN-1117 ( (2R) -1-Phenoxy -2 -butanyl hydrogen (S) -methylphosphonate; or Methyl (oxo) ⁇ [ (2R) -l-phenoxy-2-butanyl] oxy ⁇ phospho
  • the additional agent comprises an mTOR inhibitor. In some embodiments, the additional agent comprises rapamycin or its analog, everolimus, temsirolimus, ridaforolimus, sirolimus, deforolimus, or any combination thereof.
  • the additional agent comprises alpelisib, rapamycin or an derivative/analog thereof, sirolimus, everolimus, AZD8055, temsirolimus (CCI-779) , PI-103, KU-0063794, torkinib (PP242) , ridaforolimus (deforolimus, MK-8669) , sapanisertib (MLN0128) , voxtalisib (XL765) , torin 1, torin 2, omipalisib (GSK2126458) , OSI-027, PF-04691502, apitolisib (GDC-0980) , GSK1059615, gedatolisib (PKI-587) , WYE-354, vistusertib (AZD2014) , WYE-125132 (WYE-132) , PP121, WYE-687, WAY-600, ETP-46464, G
  • the additional agent comprises immunotherapy.
  • the immunotherapy comprises a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitor, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the inhibitor is a small molecule, peptide, nucleotide, or an antibody. In some embodiments, the inhibitor is an antibody.
  • the additional agent comprises immune checkpoint inhibitors (e.g., antibodies targeting CTLA-4, PD-1, and PD-L1) , ipilimumab, 90Y-Clivatuzumab tetraxetan, pembrolizumab, nivolumab, trastuzumab, cixutumumab, ganitumab, demcizumab, cetuximab, nimotuzumab, dalotuzumab, sipuleucel-T, CRS-207, GVAX, pidilizumab (CT-011) , MPDL3280A/RG7446, MEDI4736, MSB0010718C, BMS 936559, a PDL2/lg fusion protein, such as AMP 224 or an inhibitor of B7-H3 (e g., MGA271) , B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3,
  • the immune checkpoint inhibitors block the checkpoints that prevent T-cells from attacking cancer cells.
  • the additional gent comprises PD-1 or PD-L1 antibodies.
  • the additional gent comprises nivolumab, pembrolizumab, pidilizumab, AMP -224 (AstraZeneca and Medlmmune) , PF-06801591 (Pfizer) , MEDI0680 (AstraZeneca) , PDR001 (Novartis) , REGN2810 (Regeneron) , SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation) , TSR-042 (Tesaro) , the PD-L1/VISTA inhibitor CA-170 (Curis Inc.
  • Atezolizumab durvalumab (AstraZeneca and Medlmmune) , KN035 (Alphamab) , BMS-936559 (Bristol-Myers Squibb) or any combination thereof.
  • the additional agent comprises hormone therapy.
  • the additional agent comprises androgen synthesis inhibitor, androgen receptor blocker, or any combination thereof.
  • the androgen synthesis inhibitor comprises abiraterone, ketoconazole, aminoglutethimide, dutasteride, epristeride, alfatradiol, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the androgen receptor blocker comprises flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, darolutamide, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the additional agent comprises abiraterone, ketoconazole, aminoglutethimide, dutasteride, epristeride, alfatradiol, flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, darolutamide, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the additional agent comprises radiotherapy.
  • the additional agent comprises a radioactive agent used in non-targeted (conventional) radiation therapy.
  • the additional agent comprises targeted radionuclide therapy.
  • the radiotherapy comprises a radionuclide (aradioactive chemical) linked to a cell-targeting molecule, such as a monoclonal antibody, and injected into the body. The cell-targeting molecule binds to a specific target found on some cancer cells. Radioactive agents in both the non-targeted radiation therapy and targeted radionuclide therapy are referred here as radiopharmaceuticals.
  • the additional agent comprises Bcl-2 inhibitor or Bcl-xL inhibitor. In some embodiments the additional agent comprises Bcl-2 inhibitor. In some embodiments the additional agent comprises Bcl-xL inhibitor. In some embodiments, the additional agent comprise Bcl-2 inhibitor and Bcl-xL inhibitor. In some embodiments, the additional agent comprise a dual Bcl-2/Bcl-xL inhibitor.
  • the additional agent comprises venetoclax, ABT-199 (4- [4- [ [2- (4-Chlorophenyl) -4, 4-dimethylcyclohex-l-en-l-yl] methyl] piperazin-l-yl] -N- [ [3-nitro-4- [ [ (tetrahydro-2H-pyran-4-yl) methyl] amino] phenyl] sulfonyl] -2- [ (lH-pyrrolo [2, 3-b] pyridin-5-yl) oxy] benzamide) , ABT-737 (4- [4- [ [2- (4-chlorophenyl) phenyl] methyl] piperazin-l-yl] -N- [4- [ [ (2R) -4- (dimethylamino) -l-phenylsulfanylbutan-2-yl] amino] -3-nitrophenyl] sulfonylbenzamide) (navitoclax), ABT-
  • the additional agent comprises ABT-737, navitoclax (ABT-263) , obatoclax (GX15-070) , TW-37, venetoclax (ABT-199) , AT101, HA14-1, sabutoclax, S55746, APG-2575, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the additional agent comprises chemotherapy.
  • the additional agent comprises alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
  • 5-fluorouracil 5-FU
  • leucovorin LV
  • irenotecan oxaliplatin
  • capecitabine paclitaxel
  • doxetaxel chemotherapeutic agents
  • alkylating agents such as thiotepa and cyclosphosphamide
  • alkyl sulfonates such as busulfan, improsulfan and piposulfan
  • aziridines such as benzodopa, carboquone, meturedopa, and uredopa
  • ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine
  • acetogenins e.g., bullatacin and bullatacinone
  • a camptothecin including the synthetic ana
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores) , aclacinomysins, actinomycin, azithromycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esor
  • chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention.
  • the chemotherapy comprises mitotic inhibitors.
  • the mitotic inhibitors block cell division by stopping the formation of the spindle fibers that pull chromosomes apart. Examples of mitotic inhibitors include, but are not limited to, paclitaxel, docetaxel, and vinblastine.
  • the additional agent comprises azacitidine, decitabine, idarubicin, daunorubicin, cytarabine, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, etoposide, irinotecan, topotecan, lurbinectedin, epirubicin, doxorubicin, liposomal doxorubicin, melphalan, bendamustine, thaliodomide, lenalidomide, pomalidomide, bortezomib, selinexor, cyclophosphamide, docetaxel, lobaplatin, temozoloide, capecitabine, dacarbazine, 5-FU, cabazitaxel, mitoxantrone, or estramustine, or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is breast cancer.
  • the mammal is diagnosed or suspected of having a HR+/HER2-breast cancer.
  • the HR+/HER2-breast cancer is ER+/HER2-breast cancer.
  • the ER+/HER2-breast cancer is ER+/KAT6a high breast cancer namely an ER+/HER2-breast cancer that overexpresses KAT6a (at level protein or mRNA level) .
  • the HR+/HER2-breast cancer, the ER+/HER2-breast cancer or ER+/KAT6a high breast cancer is resistant to endocrine therapy or chemotherapy.
  • the mammal has been treated with endocrine therapy and/or chemotherapy.
  • the HR+/HER2-breast cancer, ER+/HER2-breast or ER+/KAT6a high breast cancer is resistant to endocrine therapy.
  • the HR+/HER2-breast cancer, ER+/HER-breast cancer or ER+/KAT6a high breast cancer is resistant to endocrine therapy and the mammal has been treated with endocrine therapy comprising SERM, SERD, aromatase inhibitor, or CDK inhibitor.
  • the breast cancer is characterized by TP53 mutation, ESR1 mutation, Rb loss-of-function, and/or CCNE amplification.
  • the ESR1 mutation comprises L536Q, Y537N, Y537S, D538G, and/or E380Q.
  • the method comprising administering to the mammal an additional agent.
  • the additional agent comprises an endocrine therapy, a CDK inhibitor, PI3K-AKT-mTOR pathway inhibitor, or any combination thereof.
  • the additional agent comprises CDK inhibitor.
  • the additional agent comprises endocrine therapy.
  • the additional agent comprises PI3K-AKT-mTOR pathway inhibitor.
  • the additional agent comprises two of an endocrine therapy, a CDK inhibitor, and PI3K-AKT-mTOR pathway inhibitor.
  • the additional agent comprises an endocrine therapy and a CDK inhibitor. In some embodiments, the additional agent comprises an endocrine therapy and PI3K-AKT-mTOR pathway inhibitor. In some embodiments, the additional agent comprises a PI3K-AKT-mTOR pathway inhibitor and a CDK inhibitor. In some embodiments, the endocrine therapy comprises tamoxifen, raloxifene, fulvestrant, elacestrant, camizestrant, amcenestrant, goserelin, imlunestrant, giredestrant, ARV-471, anastrozole, letrozole, exemestane, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the endocrine therapy comprises elacestrant.
  • the CDK inhibitor comprises PF-07220060, alvocidib, AT7519, JNJ-7706621, PHA-793887, BMS-265246, milciclib (PHA-848125) , R547, riviciclib (P276-00) , MC180295, G1T38, ON123300, purvalanol A, SU9516, ribociclib (LEE011) , or BSJ-03-123, palbociclib, abemaciclib, dalpicilib, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the PI3K-AKT-mTOR pathway inhibitor comprises alpelisib, rapamycin or an derivative/analog thereof, sirolimus, everolimus, AZD8055, temsirolimus (CCI-779) , PI-103, KU-0063794, torkinib (PP242) , ridaforolimus (deforolimus, MK-8669) , sapanisertib (MLN0128) , voxtalisib (XL765) , torin 1, torin 2, omipalisib (GSK2126458) , OSI-027, PF-04691502, apitolisib (GDC-0980) , GSK1059615, gedatolisib (PKI-587) , WYE-354, vistusertib (AZD2014) , WYE-125132 (WYE-132) , PP121, WYE-687,
  • the HR+/HER2-breast cancer, ER+/HER-breast cancer or ER+/KAT6a high breast cancer is resistant to chemotherapy.
  • the HR+/HER2-breast cancer, ER+/HER-breast cancer or ER+/KAT6a high breast cancer is resistant to chemotherapy and the mammal has been treated with chemotherapy.
  • the mammal has been treated with a chemotherapy comprising epirubicin, doxorubicin, cyclophosphamide, docetaxel, paclitaxel, carboplatin, gemcitabine, lobaplatin, nab-paclitaxel, cisplatin, capecitabine, or any combination thereof.
  • the method comprising administering to the mammal an additional agent.
  • the additional agent comprises an endocrine therapy.
  • the endocrine therapy comprises tamoxifen, raloxifene, fulvestrant, elacestrant, camizestrant, amcenestrant, goserelin, imlunestrant, giredestrant, ARV-471, anastrozole, letrozole, exemestane, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the endocrine therapy comprises elacestrant.
  • the cancer is NSCLC, small cell lung cancer (SCLC) , triple-negative breast cancer (TNBC) , melanoma, colorectal cancer (CRC) , hepatocellular carcinoma (HCC) , pancreatic cancer, or ovarian cancer.
  • the cancer is NSCLC with EGFR genetic aberration.
  • the cancer is NSCLC with EGFR genetic aberration.
  • the NSCLC is optionally resistant to treatment by EGFR inhibitor .
  • the cancer is NSCLC with EGFR genetic aberration and the NSCLC is optionally resistant to treatment by EGFR inhibitor.
  • the EGFR genetic aberration is exon 19 deletion (19del) or missense mutation comprising L858R, T790M, and/or C797S.
  • the method comprising administering to the mammal an additional agent.
  • the additional agent comprises immunotherapy, chemotherapy or any combination thereof.
  • the additional agent comprise immunotherapy.
  • the additional agent comprise chemotherapy.
  • the additional agent comprise immunotherapy and chemotherapy.
  • the additional agent comprise immunotherapy and the immunotherapy comprises nivolumab, pembrolizumab, pidilizumab, AMP-224 (AstraZeneca and Medlmmune) , PF-06801591 (Pfizer) , MEDI0680 (AstraZeneca) , PDR001 (Novartis) , REGN2810 (Regeneron) , SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation) , TSR-042 (Tesaro) , the PD-L1/VISTA inhibitor CA-170 (Curis Inc.
  • Atezolizumab durvalumab (AstraZeneca and Medlmmune) , KN035 (Alphamab) , BMS-936559 (Bristol-Myers Squibb) or any combination thereof.
  • the additional agent comprises chemotherapy and the chemotherapy comprises azacitidine, decitabine, idarubicin, daunorubicin, cytarabine, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, etoposide, irinotecan, topotecan, lurbinectedin, epirubicin, doxorubicin, liposomal doxorubicin, melphalan, bendamustine, thaliodomide, lenalidomide, pomalidomide, bortezomib, selinexor, cyclophosphamide, docetaxel, lobaplatin, temozoloide, capecitabine, dacarbazine, 5-FU, cabazitaxel, mitoxantrone, or estramustine, or a pharmaceutically acceptable salt thereof.
  • the cancer is Metastatic castration-resistant prostate cancer (mCRPC) or prostate cancer.
  • the Metastatic castration-resistant prostate cancer (mCRPC) or prostate cancer is resistant to hormone therapy.
  • the mammal has been diagnosed or suspected of having Metastatic castration-resistant prostate cancer (mCRPC) or prostate cancer resistant to hormone therapy.
  • the Metastatic castration-resistant prostate cancer (mCRPC) or prostate cancer is resistant to ADT, androgen synthesis inhibitors such as abiraterone, ketoconazole, and aminoglutethimide, or androgen receptor blockers such as first-generation drugs flutamide, bicalutamide, and nilutamide, and the second-generation drugs enzalutamide, apalutamide, or darolutamide.
  • the mammal has been treated by hormone therapy.
  • the mammal has been treated by ADT, androgen synthesis inhibitors such as abiraterone, ketoconazole, and aminoglutethimide, or androgen receptor blockers such as first-generation drugs flutamide, bicalutamide, and nilutamide, and the second-generation drugs enzalutamide, apalutamide, or darolutamide, a pharmaceutical composition thereof, or any combination thereof.
  • the method comprising administering to the mammal an additional agent.
  • the additional agent comprises hormone therapy.
  • the additional agent comprises chemotherapy.
  • the additional agent comprises chemotherapy and hormone therapy.
  • the hormone therapy comprises abiraterone, ketoconazole, aminoglutethimide, dutasteride, epristeride, alfatradiol, flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, darolutamide, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the chemotherapy comprises azacitidine, decitabine, idarubicin, daunorubicin, cytarabine, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, etoposide, irinotecan, topotecan, lurbinectedin, epirubicin, doxorubicin, liposomal doxorubicin, melphalan, bendamustine, thaliodomide, lenalidomide, pomalidomide, bortezomib, selinexor, cyclophosphamide, docetaxel, lobaplatin, temozoloide, capecitabine, dacarbazine, 5-FU, cabazitaxel, mitoxantrone, or estramustine, or a pharmaceutically acceptable salt thereof.
  • the cancer is multiple myeloma optionally with 1q21 amplification.
  • the method comprising administering to the mammal an additional agent.
  • the additional agent comprises chemotherapy.
  • the additional agent comprises azacitidine, decitabine, idarubicin, daunorubicin, cytarabine, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, etoposide, irinotecan, topotecan, lurbinectedin, epirubicin, doxorubicin, liposomal doxorubicin, melphalan, bendamustine, thaliodomide, lenalidomide, pomalidomide, bortezomib, selinexor, cyclophosphamide, docetaxel, lobaplatin, temozoloide, capecitabine,
  • the cancer is chronic or acute leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the method comprising administering to the mammal an additional agent.
  • the additional agent comprises Bcl-2 inhibitor and/or Bcl-xL inhibitor. In some embodiments the additional agent comprises Bcl-2 inhibitor. In some embodiments the additional agent comprises Bcl-xL inhibitor. In some embodiments, the additional agent comprise Bcl-2 inhibitor and Bcl-xL inhibitor. In some embodiments, the additional agent comprise a dual Bcl-2/Bcl-xL inhibitor. In some embodiments, the additional agent comprises chemotherapy. In some embodiments, the additional agent comprises Bcl-2 inhibitor and/or Bcl-xL inhibitor and chemotherapy.
  • the Bcl-2 inhibitor and/or Bcl-xL inhibitor comprises ABT-737, navitoclax (ABT-263) , obatoclax (GX15-070) , TW-37, venetoclax (ABT-199) , AT101, HA14-1, sabutoclax, S55746, APG-2575, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the chemotherapy comprises azacitidine, decitabine, idarubicin, daunorubicin, cytarabine, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, etoposide, irinotecan, topotecan, lurbinectedin, epirubicin, doxorubicin, liposomal doxorubicin, melphalan, bendamustine, thaliodomide, lenalidomide, pomalidomide, bortezomib, selinexor, cyclophosphamide, docetaxel, lobaplatin, temozoloide, capecitabine, dacarbazine, 5-FU, cabazitaxel, mitoxantrone, or estramustine, or a pharmaceutically acceptable salt thereof.
  • compositions containing the compound (s) described herein and, when applicable, the additional agent are administered for prophylactic and/or 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. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose. ”
  • the precise amounts also depend on the patient’s state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof and, when applicable, the additional agent is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • compositions comprising a compound of Formula (I) , (I’) , (Ia) , (II) , (III) , (IV) , (V) , or (VI) , described herein, or a pharmaceutically acceptable salt or solvate thereof and, when applicable, the additional agent, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • compositions comprising a compound of Formula (I’) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (Ia) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (II) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • compositions comprising a compound of Formula (III) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (V) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions comprising a compound of Formula (VI) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • 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.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • LiHMDS lithium bis (trimethylsilyl) amide
  • Step 1 To a solution of 1-1 (4.0 g, 28.3 mmol) in methanol (20 mL) was added thionyl chloride (3.1 mL, 42.5 mmol) . The mixture was stirred at 90 °C for 18 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) , brine (30 mL) , dried over sodium sulfate and concentrated under reduced pressure to afford 1-2 (3.2 g, 73%yield) as a pale brown solid.
  • Step 2 To a solution of 1-2 (3.2 g, 20.63 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (7.12 g, 41.26 mmol) at one portion under an ice bath. The mixture was stirred under room temperature for 10 h. A saturated sodium bicarbonate solution (30 mL) was then added to the solution. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and then purified by flash silica gel chromatography to provide the corresponding 1-3 (2.5 g, 71%yield) as a white solid.
  • Step 3 To a solution of 1-3 (2.5 g, 14.6 mmol) in dichloromethane (20 mL) was added triethylamine (6.9 mL, 51.2 mmol) and TMSCN (6.2 mL, 51.2 mmol) under an ice bath. The mixture was stirred at room temperature for 20 h and then concentrated under reduced pressure and purified by flash silica gel chromatography to provide 1-4 (2.0 g, 76%yield) as a yellow solid.
  • Step 4 To a solution of 1-4 (1.0 g, 5.55 mmol) in DMF (10 mL) was added t-BuOK (1.24 g, 11.10 mmol) and N-hydroxyacetamide (833 mg, 11.1 mmol) . This reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 1-5 (500 mg, 47%yield) as a yellow solid. LCMS: 194.0 [M+H] + .
  • Step 5 To a solution of 1-5 (500 mg, 2.59 mmol) in DMF (10 mL) was added t-BuOK (580 mg, 5.18 mmol) and then Compound A (918.92 mg, 3.88 mmol) in DMF (1 mL) at 0 °C. This reaction mixture was stirred at 25 °C for 1 hour. This reaction mixture was concentrated in vacuum to crude product which was further purified by Prep-HPLC to afford 1-6 (200 mg, 20%yield) as a white solid. LCMS: 394.0 [M+H] + .
  • Step 6 To a solution of 1-6 (200 mg, 0.51 mmol) in THF (5 mL) was added LiBH 4 (22.15 mg, 1.02 mmol) at 0 °C. This reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched with water (10 mL) . The aqueous phase was extracted with DCM (20 mL x 2) . The combined organic phase was washed with brine (20 mL) , dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford 1-7 (60 mg, 0.16 mmol, 32%yield) as a white solid. LCMS: 365.9 [M+H] + .
  • Step 7 To a solution of 1-7 (60 mg, 0.16 mmol) in acetonitrile (3 mL) were added Compound B (26.4 mg, 0.18 mmol) and Cs 2 CO 3 (104 mg, 0.32 mmol) . The reaction was stirred at 70 °C for 2 h. The reaction mixture was concentrated. The residue was purified by Prep-HPLC to afford Compound 1 (5 mg, 7%yield) as a white solid. LCMS: 416.1 [M+H] + .
  • Step 1 To a solution of 2-1 (50.0 g, 260 mmol) in MeOH (500 mL) was added NaOMe (42.2 g, 781 mmol) . The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated to remove MeOH. Then the residue was diluted with DCM (500 mL) and washed with H 2 O (500 mL) . The organic layer was washed with aqueous brine (200 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 2-2 (40.0 g, 83%yield) as a white solid.
  • Step 2 To a solution of 2-2 (10.0 g, 54.3 mmol) in EtOH (200 mL) was added N 2 H 4 . H 2 O solution (14.8 mL, 272 mmol) and Raney Ni (2.00 g, 9.15 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 20 min. The reaction mixture was filtered and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 2-3 (8.00 g, 95%yield) as a white solid. LCMS: 155.0 [M+H] + .
  • Step 3 To a solution of 2-3 (650 mg, 4.22 mmol) in acetonitrile (10 mL) was added 2-4 (1.25 g, 5.06 mmol) and isopentyl nitrite (1.39 mL, 9.28 mmol) at 80 °C. This reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 2-5 (300 mg, 27%yield) as a brown oil. LCMS: 262.3 [M+H] + .
  • Step 4 To a solution of 2-5 (300 mg, 1.15 mmol) in MeCN (6 mL) was added HCl (0.630 mL, 1.26 mmol, 2 M) and NCS (920 mg, 6.89 mmol) at 0 °C. This reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was purified by flash silica gel chromatography to afford 2-6 as a white solid. LCMS: 238.1 [M+H] + .
  • Step 5 To a solution of 2-7 (30 g, 138 mmol) in THF (250 mL) and MeOH (50 mL) was added NaOMe (8.92 g, 165 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (300 mL) . The aqueous phase was extracted with ethyl acetate (300 mL x 2) . The combined organic phase was washed by brine (300 mL) , dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford 2-8 (22 g, 70%yield) as a white solid.
  • Step 6 To a solution of 2-8 (11.55 g, 50.2 mmol) in MeOH (250 mL) was added TEA (21.0 mL, 151 mmol) and Pd (dppf) Cl 2 (3.67 g, 5.02 mmol) . This reaction mixture was stirred at 80 °C for 12 h under CO (3 Mpa) atmosphere. This reaction mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 2-9 (7.39 g, 70%yield) as a white solid.
  • Step 7 To a solution of 2-9 (4.20 g, 20.1 mmol) in THF (45 mL) was added LiBH 4 (0.870 g, 40.2 mmol) at 0 °C. This reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched with water (40 mL) . The aqueous phase was extracted with DCM (50 mL x 2) . The combined organic phase was washed by brine (50 mL) , dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford 2-10 (3.63 g) as a white solid. LCMS: 182.0 [M+H] + .
  • Step 8 To a solution of 2-10 (650 mg, 3.59 mmol) and Compound B (629 mg, 4.30 mmol) in ACN (12 mL) was added Cs 2 CO 3 (1.40 g, 4.30 mmol) . The mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford 2-11 (500 mg, 60%yield) as a yellow solid. LCMS: 232.0 [M+H] + .
  • Step 9 To a solution of 2-11 (500 mg, 2.16 mmol) in acetonitrile (9 mL) and H 2 O (1 mL) was added 1, 1, 3, 3-tetramethylguanidine (1.49 g, 13.0 mmol) and N-hydroxyacetamide (487 mg, 6.49 mmol) . This reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 2-12 (300 mg, 57%yield) as a yellow solid. LCMS: 245.1 [M+H] + .
  • Step 10 To a solution of 2-12 (100 mg, 0.410 mmol) in DMF (2 mL) was added t-BuOK (138 mg, 1.23 mmol) and 2-6 (107.03 mg, 0.45 mmol) in THF (1 mL) at 0 °C. This reaction mixture was stirred at 25 °C for 1 h. This reaction mixture was concentrated in vacuum to give a residue which was further purified by Prep-HPLC to afford Compound 2 (5.88 mg, 22%yield) as a white solid. LCMS: 446.1 [M+H] + .
  • Step 2 To a solution of 3-2 (2.0 g, 9.26 mmol) in acetonitrile (20 mL) and H 2 O (20 mL) was added NaOH (14.84 g, 370 mmol) at -20 °C. 3-3 (4.94 g, 18.52 mmol, 3.18 mL) was then added and the reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with water (50 mL) . The aqueous layer was back extracted with DCM (50 mL x 3) . The combined DCM layer was washed with saturated NaCl solution (25 mL x 2) , dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash silica gel chromatography to give 3-4 (1.02 g, 39%yield) as a colorless oil.
  • Step 3 To a solution of 3-4 (1.02 g, 3.59 mmol) in MeOH (20 mL) were added Pd (dppf) Cl 2 (526 mg, 0.72 mmol) and TEA (1.49 mL, 10.77 mmol) . The reaction mixture was stirred at 100 °C for 18 h under CO (3 MPa) atmosphere. Then the reaction mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by flash silica gel chromatography to give 3-5 (630 mg, 72%yield) as a colorless oil.
  • Step 4 To a solution of 3-5 (630 mg, 2.58 mmol) in THF (10 mL) were added LiBH 4 (170 mg, 7.74 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched by Na 2 SO 4 . 10H 2 O and filtered. The filtrate was concentrated. The residue was purified by flash silica gel chromatography to give 3-6 (380 mg, 68%yield) as a green oil.
  • Step 5 To a solution of 3-6 (380 mg, 1.76 mmol) in acetonitrile (5 mL) were added Compound B (308 mg, 2.11 mmol) and Cs 2 CO 3 (688 mg, 2.11 mmol) . The reaction mixture was stirred at 70 °C for 2 h. Then the reaction mixture was concentrated. The residue was purified by flash silica gel chromatography to give 3-7 (220 mg, 47%yield) as an orange oil. LCMS: 268.0 [M+H] + .
  • Step 6 To a solution of 3-7 (220 mg, 0.82 mmol) in acetonitrile (5 mL) and water (0.5 mL) were added N-hydroxyacetamide (185 mg, 2.46 mmol) and 1, 1, 3, 3-tetramethylguanidine (566 mg, 0.56 mL, 4.92 mmol) . The reaction was stirred at 60 °C for 3 h. Then the reaction mixture was concentrated. The residue was purified by flash silica gel chromatography to afford 3-8 (150 mg, 47%yield) as a green solid. LCMS: 281.0 [M+H] + .
  • Step 7 To a solution of 3-8 (150 mg, 0.54 mmol) in THF (3 mL) were added t-BuOK (182 mg, 1.62 mmol) at 0 °C and the mixture was stirred for 10 min. Then Compound A (255 mg, 1.08 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give Compound 3 (22 mg, 9%yield) as a white solid. LCMS: 481.1 [M+H] + .
  • Step 1 To a solution of 3-2 (3.00 g, 13.95 mmol) in anhydrous DMF (25 mL) were added K 2 CO 3 (5.78 g, 41.85 mmol) and 4-1 (3.017 mL, 20.93 mmol) . The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (60 mL) , diluted with ethyl acetate (20 mL ⁇ 3) , washed with saturated NaCl (20 mL ⁇ 3) , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 4-2 (3.8 g, 92%yield) as a white solid.
  • Step 2 To a solution of 4-2 (3.8 g, 12.79 mmol) in MeOH (40 mL) were added TEA (3.88 g, 38.38 mmol, 5.3 mL) and Pd (dppf) Cl2 (936.02 mg, 1.28 mmol) . The mixture was stirred at 100 °C for 16 h under CO (3 MPa) atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 4-3 (2.9 g, 83%yield) as a white solid.
  • Step 3 To a solution of 4-3 (2.9 g, 10.58 mmol) in THF (50 mL) was added LiBH 4 (691.03 mg, 31.73 mmol) at 0 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 4-4 (1.6 g, 61%yield) as a white solid.
  • Step 4 To a solution of 4-4 (1.6 g, 6.45 mmol) in ACN (20 mL) was added Compound B (1.13 g, 7.74 mmol) and Cs 2 CO 3 (2.52 g, 7.74 mmol) . The mixture was stirred at 70 °C for 1 h and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography as a yellow solid. LCMS: 300.2 [M+H] + .
  • Step 5 To a solution of 4-5 (1.2 g, 4.02 mmol) in ACN/H 2 O (18 mL/2 mL) were added N-hydroxyacetamide (0.739 mL, 12.07 mmol) and 1, 1, 3, 3-tetramethylguanidine (2.77 g, 24.12 mmol) was added. The mixture was stirred at 60 °C for 3 h and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 4-6 (600 mg, 48%yield) as a white solid. LCMS: 313.0 [M+H] + .
  • Step 6 To a solution of 4-6 (100 mg, 0.32 mmol) in THF (5 mL) were added potassium bis (trimethylsilyl) amide (1.28 mL, 1.28 mmol, 1 M) at -78 °C. The reaction was stirred at -78 °C for 1 h. Then Compound A (113 mg, 0.481 mmol) was added, and the reaction mixture was stirred at -78 °C for 0.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give Compound 4 (50 mg, 30%yield) as a white solid. LCMS: 513.2 [M+H] + .
  • Step 1 To a solution of 8-1 (25 g, 106 mmol) in MeCN (500 mL) was added selectfluor (75.3 g, 213 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with water (100 mL) . The aqueous phase was extracted with ethyl acetate (500 mL x 3) . The combined organic phase was washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give crude product which was purified by flash silica gel chromatography to afford 8-2 (4.20 g, 16%yield) as an orange solid.
  • Step 2 To a solution of 8-2 (1.50 g, 5.93 mmol) in acetonitrile (20 mL) were added CuBr 2 (1.59 g, 7.11 mmol) and isopentyl nitrite (1.04 mL, 7.70 mmol) . The mixture was stirred at room temperature for 2 h. A saturated sodium bicarbonate solution (30 mL) was then added to the solution. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine, and dried over anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide the corresponding 8-3 (800 mg, 46%yield) as a colorless oil.
  • Step 3 To a solution of 8-3 (2.40 g, 7.57 mmol) in tetrahydrofuran (24 mL) was added LiBH 4 (0.49 g, 22.71 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to give 8-4 (1.3 g, 59%yield) as a colorless oil.
  • Step 4 To a solution of 8-4 (1.3 g, 4.50 mmol) in acetonitrile (13 mL) were added Compound B (0.79 g, 5.40 mmol) and Cs 2 CO 3 (1.76 g, 5.40 mmol) . The mixture was stirred at 70 °C for 2 h. Then the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 8-5 (600 mg, 39%yield) as a white solid. LCMS: 339.1 [M+H] + .
  • Step 5 To a solution of 8-5 (300 mg, 0.95 mmol) in dioxane (20 mL) and H 2 O (3 mL) were added potassium vinyltrifluoroborate (380 mg, 2.84 mmol) , Cs 2 CO 3 (924 mg, 2.84 mmol) , and Pd (dppf) Cl 2 (70 mg, 0.10 mmol) . The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 8-6 (200 mg, 80%yield) as a yellow solid. LCMS: 287.0 [M+H] + .
  • Step 6 A solution of 8-6 (200 mg, 0.76 mmol) in dichloromethane (5 mL) and methanol (1 mL) at -78 °C under O 3 atmosphere for 10 min. Dimethyl sulfide (5 mL) was then added to the solution. The reaction mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 8-7 (150 mg, 74%yield) as a colorless oil. LCMS: 289.0 [M+H] + .
  • Step 7 To a solution of 8-7 (150 mg, 0.56 mmol) in acetonitrile (5 mL) and H 2 O (10 mL) was added hydroxylamine-O-sulfonic acid (191 mg, 1.68 mmol) . This reaction mixture was stirred at 80 °C for 24 h. The aqueous phase was extracted with dichloromethane (20 mL x 2) . The combined organic phase was washed by brine (20 mL) , dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then purified by flash silica gel chromatography to provide the corresponding 8-8 (30 mg, 20%yield) as a colorless oil. LCMS: 286.0 [M+H] + .
  • Step 8 To a solution of 8-8 (30 mg, 0.11 mmol) in acetonitrile (5 mL) and H 2 O (1 mL) were added N-hydroxyacetamide (24 mg, 0.32 mmol) and 1, 1, 3, 3-tetramethylguanidine (73 mg, 0.63 mmol) . The mixture was stirred at 70 °C for 2 h. Then the reaction mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to afford 8-9 (20 mg, 64%yield) as a colorless oil. LCMS: 299.0 [M+H] + .
  • Step 9 To a solution of 8-9 (20 mg, 0.07 mmol) in pyridine (5 mL) were added 2, 6-dimethoxybenzenesulfonyl chloride (32 mg, 0.13 mmol) . The reaction was stirred at 120 °C for 2 h. The reaction mixture was concentrated. The residue was purified by Prep-HPLC to afford Compound 8 (1.5 mg, 4%yield) as a white solid. LCMS: 499.1 [M+H] + .
  • Step 1 To a solution of 2-8 (2.00 g, 8.69 mmol) were added t-BuXPhos (1.11 g, 2.61 mmol) , KOH (1.46 g, 26.08 mmol) , and Pd 2 (dba) 3 (1.46 g, 26.08 mmol) in dioxane (15 mL) and H 2 O (15 mL) . The reaction mixture stirred at 100°C for 5 h under N 2 . Water (30 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3) .
  • Step 2 To a mixture of 9-1 (200 mg, 1.20 mmol) and 2-bromopyridine (0.344 mL, 3.59 mmol) in toluene (5 mL) were added Cs 2 CO 3 (390 mg, 1.20 mmol) and Josiphos SL-J009-1 Pd G3 (2 mg, 0.12 mmol) . The mixture was stirred at 100 °C for 24 h. Water (10 mL) was then added to the mixture. Following extraction with ethyl acetate (20 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to afford 9-2 (230 mg, 79%yield) as a white solid. LCMS: 245.0 [M+H] + .
  • Step 3 To a mixture of 9-2 (230 mg, 0.94 mmol) , N-hydroxyacetamide (141 mg, 1.88 mmol) , and water (0.5 mL) in MeCN (5 mL) was added 1, 1, 3, 3-tetramethylguanidine (0.24 mL, 1.88 mmol) . The mixture was stirred at 70 °C for 2 h. Water (10 mL) was added to the mixture. Following extraction with ethyl acetate (20 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure and then purified by flash silica gel chromatography to afford 9-3 (180 mg, 74%yield) as a brown solid. LCMS: 258.0 [M+H] + .
  • Step 4 To a mixture of 9-3 (30 mg, 0.12 mmol) in pyridine (2 mL) was added 2, 6-dimethoxybenzenesulfonyl chloride (27.60 mg, 0.12 mmol) . The mixture was stirred at 120 °C for 1.5 h. The mixture was concentrated to give the crude product which was further purified by Prep-HPLC to afford Compound 9 (14 mg, 26%yield) as a white solid. LCMS: 458.1 [M+H] + .
  • Step 1 To a mixture of 3-2 (2.0 g, 9.26 mmol) and 3-bromoprop-1-ene (1.21 mL, 13.89 mmol) in acetone (30 mL) was added potassium carbonate (3.8 g, 27.78 mmol) . The mixture was stirred at 25°C for 16 h. Water (30 mL) was then added. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine and dried over anhydrous Na 2 SO 4, and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to afford the 10-1 (1.2 g, 51%yield) as a white solid.
  • Step 2 A reaction mixture of 10-1 (1.2 g, 4.69 mmol) in 1, 2-dichlorobenzene (12 mL) was stirred at 180 °C for 16 h under N 2 . Water (30 mL) was then added. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine, and dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide the 10-2 (0.6 g, 50%) as a white solid.
  • Step 3 10-2 (3.1 g, 12.11 mmol) was dissolved in DCM (30 mL) and MeOH (30 mL) . The solution was cooled to -78 °C and treated with O 3 until a pale blue color persists. O 2 was bubbled through the mixture for 5 min, then NaBH 4 (920 mg, 24.22 mmol) was added slowly. The mixture was warmed to room temperature slowly over 15 min. The mixture was diluted with ethyl acetate (30 mL) , and washed with 1N HCl (50 mL) , sat. NaHCO 3 (50 mL) , and brine. The organic solution was dried over Na 2 SO 4 and filtered. The filtrate was concentrated to give 10-3 (1.78 g, 57%yield) as a brown oil. LCMS: 258.2 [M+H] + .
  • Step 4 To a mixture of 10-3 (1.78 g, 6.86 mmol) and PPh 3 (2.70 g, 10.28 mmol) in THF (20 mL) was added DIAD (2.04 mL, 10.28 mmol) . The mixture was stirred at 0 °C for 0.5 h. Water (30 mL) was then added. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure and then purified by flash silica gel chromatography to afford 10-4 (1.2 g, 72%yield) as a white solid.
  • Step 5 To a mixture of 10-4 (0.06 g, 0.25 mmol) and TEA (0.052 mL, 0.37 mmol) in MeOH (10 mL) was added Pd (dppf) Cl 2 (0.02 g, 0.02 mmol) . The mixture was stirred at 70 °C under CO (3 MPa) atmosphere for 16 h. Water (5 mL) was then added. Following extraction with ethyl acetate (10 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to afford 10-5 (30 mg, 54%yield) as a white solid.
  • Step 6 To a mixture of 10-5 (0.42 g, 1.90 mmol) in THF (8 mL) was added LiBH 4 (0.08 g, 3.80 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 2 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3) , washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to give 10-6 (360 mg, 98%yield) as a colorless oil. LCMS: 194.0 [M+H] + .
  • Step 7 To a mixture of 10-6 (0.18 g, 0.93 mmol) , Compound B (0.16 g, 1.12 mmol) in acetonitrile (4 mL) was added Cs 2 CO 3 (0.36 g, 1.12 mmol) . The reaction mixture was stirred at 70°C for 2 h. Water (30 mL) was then added. Following extraction with ethyl acetate (50 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide the 10-7 (110 mg, 36%yield) as a white solid. LCMS: 243.9 [M+H] + .
  • Step 8 To a mixture of 10-7 (55 mg, 0.23 mmol) , N-hydroxyacetamide (51 mg, 0.68 mmol) , and water (0.1 mL) in MeCN (0.9 mL) was added 1, 1, 3, 3-tetramethylguanidine (0.18 mL, 1.36 mmol) . The reaction mixture was stirred at 60°C for 16 h. Water (10 mL) was then added. Following extraction with ethyl acetate (20 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to afford 10-8 (20 mg, 33%yield) as a brown solid. LCMS: 257.1 [M+H] + .
  • Step 9 To a mixture of 10-8 (20 mg, 0.078 mmol) in pyridine (2 mL) was added Compound A (37 mg, 0.156 mmol) . The reaction mixture was stirred at 120 °C for 1.5 h and then concentrated. The residue obtained was purified by Prep-HPLC to afford Compound 10 (1.0 mg, 3%yield) as a white solid. LCMS: 457.1 [M+H] + .
  • Step 1 To a mixture of 11-1 (10.0 g, 59.5 mmol) in MeCN (100 mL) were added dibenzyl disulfide (29.3 g, 119 mmol) and L (+) -Ascorbic acid (5.24 g, 29.8 mmol) . Then isoamyl nitrite (25.8 g, 220 mmol) was added to this reaction mixture at 0 °C and the reaction mixture was stirred at 25 °C for 12 h. This reaction mixture was concentrated under reduced pressure and the obtained residue was purified by flash silica gel chromatography to afford 11-2 (4.4 g, 27%yield) as a yellow oil. LCMS: 276.1 [M+H] + .
  • Step 2 To a mixture of 11-2 (1.00 g, 3.63 mmol) in MeCN (20 mL) , AcOH (2.5 mL) and water (5 mL) was added 1, 3-Dichloro-5, 5-dimethylhydantoin (858 mg, 4.36 mmol) at -15 °C. This reaction mixture was warmed to 25 °C with stirring for 1 h. Water (10 mL) was added to the mixture. Following extraction with DCM (20 mL x 3) , the organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 11-3 (660 mg, 72%yield) as a white solid. LCMS: 251.9 [M+H] + .
  • Step 3 To a mixture of 2-12 (18 mg, 0.08 mmol) in THF (5 mL) was added KHMDS (0.15 mL, 0.15 mmol) at -78 °C. The mixture was stirred at -78 °C for 0.5 h. 11-3 (29 mg, 0.11 mmol) in THF (1 mL) was added to this mixture and this reaction mixture was stirred at -78 °C for 1.5 h. The mixture was concentrated to give the crude product which was further purified by Prep-HPLC to afford Compound 11 (5 mg, 15%yield) . LCMS: 460.3 [M+H] + .
  • Step 1 To a mixture of 8-9 (20 mg, 0.07 mmol) in THF (3 mL) was added t-BuOK (21 mg, 0.20 mmol) at 0 °C and the mixture was stirred at this temperature for 0.5 h. Then 2-methoxybenzenesulfonyl chloride (21 mg, 0.10 mmol) was added and this reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the crude product which was further purified by Prep-HPLC to afford Compound 12 (2 mg, 6 %yield) . LCMS: 469.1 [M+H] + .
  • Step 1 To a solution of 13-1 (10.0 g, 53.5 mmol) in MeOH (100 mL) was added NaOMe (5.78 g, 107 mmol) at 0 °C. The reaction mixture was stirred at 40 °C for 5 h under N 2 . Water (100 mL) was added and the mixture was extracted with DCM (200 mL x 3) . The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuum to afford 13-2 (5.0 g, 51%) as a white solid. LCMS: 183.1 [M+H] + .
  • Step 2 To a solution of 13-2 (2.1 g, 11.5 mmol) in TFA (25 mL) were added H 2 O 2 (3.91 g, 34.5 mmol, 30%) . The reaction mixture was stirred at 70 °C for 1 h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL x 3) . The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography to afford 13-3 (1.6 g, 70%) as a white solid. LCMS: 199.0 [M+H] + .
  • Step 3 To a solution of 13-3 (900 mg, 4.5 mmol) in DCM (10 mL) were added TFAA (2.86 g, 22.7 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. This reaction mixture was concentrated in vacuum to give a residue. To this residue were added MeOH (10 mL) and K 2 CO 3 (3.13 g, 22.7 mmol) . The reaction mixture was stirred at 25 °C for 1 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL x 3) . The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography to afford 13-4 (280 mg, 31%) as a white solid. LCMS: 199.3 [M+H] + .
  • Step 4 To a solution of 13-4 (280 mg, 1.41 mmol) in MeCN (4 mL) were added N-hydroxyacetamide (318 mg, 4.23 mmol) and Cs 2 CO 3 (1.38 g, 4.23 mmol) . The reaction mixture was stirred at 25 °C for 3 h. This reaction mixture was concentrated. The residue was purified by flash silica gel chromatography to afford 13-5 (150 mg, 54%) as a white solid. LCMS: 196.2 [M+H] + .

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Abstract

L'invention concerne des méthodes de traitement du cancer à l'aide d'un inhibiteur de la lysine acétyltransférase 6a (KAT6A) à petites molécules et d'un agent supplémentaire.
PCT/CN2024/088931 2023-04-19 2024-04-19 Inhibiteur de lysine acétyltransférase 6a (kat6a), associations et utilisations associées Pending WO2024217563A1 (fr)

Priority Applications (3)

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AU2024259385A AU2024259385A1 (en) 2023-04-19 2024-04-19 Lysine acetyltransferase 6a (kat6a) inhibitor, combinations and uses thereof
IL323885A IL323885A (en) 2023-04-19 2025-10-12 Lysine acetyltransferase A6 (kat6a) inhibitor, its combinations and uses
MX2025012351A MX2025012351A (es) 2023-04-19 2025-10-16 Inhibidor de lisina-acetiltransferasa 6a (kat6a), combinaciones y usos del mismo

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CNPCT/CN2023/089277 2023-04-19
CN2023089277 2023-04-19
CN2024086020 2024-04-03
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019243491A1 (fr) * 2018-06-20 2019-12-26 Ctxt Pty Limited Composés
WO2020254989A1 (fr) * 2019-06-19 2020-12-24 Pfizer Inc. Dérivés de cycloalkyl et hétérocycloalkyl benzisoxazole sulfonamide
WO2020254946A1 (fr) * 2019-06-18 2020-12-24 Pfizer Inc. Dérivés de benzisoxazole sulfonamide
WO2022013369A1 (fr) * 2020-07-15 2022-01-20 Pfizer Inc. Méthodes et combinaisons d'inhibiteurs de kat6 pour le traitement du cancer
WO2022243983A1 (fr) * 2021-05-21 2022-11-24 Aurigene Discovery Technologies Limited Composés isoxazolyles fusionnés utilisés en tant qu'inhibiteurs de kat6a
WO2023280182A1 (fr) * 2021-07-05 2023-01-12 杭州英创医药科技有限公司 Composé servant d'inhibiteur de kat6
WO2023088233A1 (fr) * 2021-11-16 2023-05-25 Insilico Medicine Ip Limited Inhibiteurs de la lysine acétyltransférase 6a (kat6a) et leurs utilisations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019243491A1 (fr) * 2018-06-20 2019-12-26 Ctxt Pty Limited Composés
WO2020254946A1 (fr) * 2019-06-18 2020-12-24 Pfizer Inc. Dérivés de benzisoxazole sulfonamide
WO2020254989A1 (fr) * 2019-06-19 2020-12-24 Pfizer Inc. Dérivés de cycloalkyl et hétérocycloalkyl benzisoxazole sulfonamide
WO2022013369A1 (fr) * 2020-07-15 2022-01-20 Pfizer Inc. Méthodes et combinaisons d'inhibiteurs de kat6 pour le traitement du cancer
WO2022243983A1 (fr) * 2021-05-21 2022-11-24 Aurigene Discovery Technologies Limited Composés isoxazolyles fusionnés utilisés en tant qu'inhibiteurs de kat6a
WO2023280182A1 (fr) * 2021-07-05 2023-01-12 杭州英创医药科技有限公司 Composé servant d'inhibiteur de kat6
WO2023088233A1 (fr) * 2021-11-16 2023-05-25 Insilico Medicine Ip Limited Inhibiteurs de la lysine acétyltransférase 6a (kat6a) et leurs utilisations

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