TYK2 PSEUDOKINASE LIGANDS

BACKGROUND OF THE INVENTION

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The four JAK family members are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2) and have been shown to be key components of cytokine-mediated effects. Unlike JAK1 deficient mice, TYK2 deficient mice are viable and the TYK2 deficiency has been shown to be protective in various models of autoimmunity.

SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds of Formula (I) or Formula (II):

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wherein:

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- is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally substituted with 1, 2, 3, or 4 R₇;
- X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;
- L₁is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or —O—C(R₉)(R₁₀)—;
- L₂is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁and R₂are combined to form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkyl ring;
- each R₃is independently hydrogen or C₁-C₆alkyl; or R₂and R₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- each R₇is independently selected from deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- each R₉and each R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₇is hydrogen or C₁-C₆alkyl;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4;
- or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

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In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

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In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from:

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In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl selected from:

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In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —C(O)N(R₃)—. In some embodiments is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(R₆)—.

In another aspect, provided herein are compounds of Formula (III) or Formula (IV):

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- Y is =N— or ═C(R₁₅)—;
- Z is =N— or ═C(R₁₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅and R₁₆are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4;
- or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

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In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

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In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is =N— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is selected from hydrogen, halogen, or C₁-C₆alkyl. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is =N—. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is selected from hydrogen, halogen, or C₁-C₆alkyl. In some embodiments is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is =N— and Z is ═N—.

In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₉and R₁₀are hydrogen. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆haloalkyl, C₁-C₆alkoxy, C₂-C₉heteroaryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₂-C₉heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆haloalkyl, C₂-C₉heteroaryl, —OR₁₁, —CN, —C(═O)N(R₁₁)₂, —NR₁₁S(═O)₂R₁₂, wherein C₂-C₉heteroaryl is optionally substituted with 1 or 2 groups selected from halogen or C₁-C₆alkyl. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, and C₁-C₆alkyl. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁is hydrogen. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₂is hydrogen. In some embodiments is a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is hydrogen.

In another aspect described herein is a pharmaceutical composition comprising a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

In another aspect described herein is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, intestinal bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION
Definitions

In the context of this disclosure, a number of terms shall be utilized.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4^thEd.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

As used herein, C₁-C_xincludes C₁-C₂, C₁-C₃. . . C₁-C_x. C₁-C_xrefers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carbon-carbon triple bond). The alkyl group may also be an “unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “C₁-C₆alkyl” or similar designations. By way of example only, “C₁-C₆alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as defined herein.

The term “alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms —C(R)═CR₂, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. Non-limiting examples of an alkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂and —C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a “cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms —C≡C—R, wherein R refers to the remaining portions of the alkynyl group. Non-limiting examples of an alkynyl group include —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃and —C≡CCH₂CH₂CH₃. The “R” portion of the alkynyl moiety may be branched, straight chain, or cyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_xH_ygroup, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂group, where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

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and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, 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 term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include —CH₂C₁, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limiting examples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “deuteroalkyl” refers to an alkyl group that is substituted with one or more deuteriums.

The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

“Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne, C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivatives thereof. By way of example, an optional substituents may be L^sR^s, wherein each L^sis independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and each R^sis independently selected from among H, (C₁-C₆alkyl), (C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C₁-C₆heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

The term a “therapeutically effective amount” as used herein refers to the amount of a TYK2 pseudokinase ligand that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent conditions related to skin aging.

As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

The term “modulate” encompasses either a decrease or an increase in activity or expression depending on the target molecule.

The term “activator” is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

The term “patient” or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

The term “soft-drug” as used herein, refers to drug substance and/or a chemical compound that is biologically active in the desired target tissue and that is metabolized, after exerting its effect in the target tissue, to a compound that is inactive against the biological target. In some embodiments, the soft-drug has no target biological activity in systemic circulation.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

As used herein, “treatment” or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

TYK2 Pseudokinase Ligands

As a member of the JAK family of tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines and therefore represents a target for treating various inflammatory and autoimmune diseases. The hallmark structural feature of the JAK family is the pseudokinase (JH2) domain immediately N-terminal to the catalytic domain (JH1). Although the JH2 domain shares the overall fold of a typical catalytic domain, a series of individual residue and conformational differences between the TYK2 JH1 and JH2 domains points to the lack of catalytic activity of the JH2 domain. The JH2 domains of the JAK family have been shown to regulate the function of the JH1 domains. The overall body of evidence is consistent with the TYK2 pseudokinase domain being auto-inhibitory, stabilizing the inactivated state of the kinase domain and that small molecule ligands can stabilize this auto-inhibitory conformation thereby preventing protein function in an allosteric manner (Moslin et al., Med. Chem. Commun., 2017, 700-712).

The compounds of Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or (IVd) described herein are TYK2 pseudokinase ligands. The compounds of Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or (IVd) described herein, and compositions comprising these compounds, are useful for the treatment of an inflammatory or autoimmune disease.

In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

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- is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally substituted with 1, 2, 3, or 4 R₇;
- X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;
- L₁is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or —O—C(R₉)(R₁₀)—;
- L₂is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁and R₂are combined to form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkyl ring;
- each R₃is independently hydrogen or C₁-C₆alkyl; or R₂and R₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- each R₇is independently selected from deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- each R₉and each R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₇is hydrogen or C₁-C₆alkyl;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein

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is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from:

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In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl selected from:

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In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —C(O)N(R₃)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —N(R₃)C(O)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —C(R₉)(R₁₀)—O—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —O—C(R₉)(R₁₀)—.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(R₆)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(H)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(R₆)CH₂—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(H)CH₂—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —CH₂N(R₆)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —CH₂N(H)—.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(R₁₇)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—O—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is C₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is C₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₃is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R₃is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R₃is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₂and R₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH.

In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is deuterium. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

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- is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally substituted with 1, 2, 3, or 4 R₇;
- X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;
- L₁is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or —O—C(R₉)(R₁₀)—;
- L₂is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁and R₂are combined to form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkyl ring;
- each R₃is independently hydrogen or C₁-C₆alkyl; or R₂and R₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- each R₇is independently selected from deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- each R₉and each R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₇is hydrogen or C₁-C₆alkyl;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heteroaryl selected from:

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In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

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is C₂-C₉heterocycloalkyl selected from:

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In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —C(O)N(R₃)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —N(R₃)C(O)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —C(R₉)(R₁₀)—O—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₁is —O—C(R₉)(R₁₀)—.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(R₆)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(H)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(R₆)CH₂—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —N(H)CH₂—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —CH₂N(R₆)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L₂is —CH₂N(H)—.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(R₁₇)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)— and n is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—O—. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O— and n is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂O—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is C₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is C₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₃is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R₃is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R₃is C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₂and R₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH.

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is deuterium. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

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wherein.

- X is —O— or —C(R₉)(R₁₀)—;
- Y is ═N— or ═C(R₁₅)—;
- Z is ═N— or ═C(R₁₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅and R₁₆are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is halogen, and R₁₆is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═N—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═N—.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₃is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is deuterium. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅and R₁₆are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen and R₁₆is halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen and R₁₆is hydrogen.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₆is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is halogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- Y is ═N— or ═C(R₁₅)—;
- Z is ═N— or ═C(R₁₆)—;
- each R₁is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₂is independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₅is selected from hydrogen, deuterium, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₁₃is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;
- each R₁₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅and R₁₆are independently selected from hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;
- R₁₈is hydrogen, deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is halogen, and R₁₆is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅is hydrogen, and R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═N—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═N—.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₃is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₅and R₁₃together with the atoms to which they are attached are combined to form a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is hydrogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is deuterium. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₈is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅and R₁₆are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen and R₁₆is halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen and R₁₆is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen and R₁₆is hydrogen.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₆is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is halogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₆is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each Rn is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R₁₅is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is halogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₅is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof:

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wherein:

- X is —O— or —C(R₉)(R₁₀)—;
- each R₁is independently selected from hydrogen and C₁-C₆alkyl;
- each R₂is independently selected from hydrogen and C₁-C₆alkyl;
- R₃is hydrogen or C₁-C₆alkyl;
- R₄and R₅are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;
- R₆is hydrogen or C₁-C₆alkyl;
- R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;
- R₉and R₁₀are independently selected from hydrogen and C₁-C₆alkyl;
- each R₁is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;
- each R₁₂is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl;
- each R₁₄is independently selected from hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl; and
- n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each halogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is halogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆haloalkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is C₁-C₆alkoxy. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is hydrogen and R₈is —CN. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is halogen and R₈is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is C₁-C₆alkoxy and R₈is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₇is —CN and R₈is hydrogen.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 2. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 2, each R₁is hydrogen, and one R₂is hydrogen and one R₂is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— and n is 3. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—, n is 3, one R₁is C₁-C₆alkyl and one R₂is C₁-C₆alkyl and the remaining R₁and R₂are each hydrogen.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂are hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 2. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 2, and each R₁and each R₂are hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and each R₁and each R₂are hydrogen.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are independently selected from hydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄is hydrogen and R₅is C₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₄and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₃is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is hydrogen. In some embodiments is a compound of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof, wherein R₆is C₁-C₆alkyl.