Combo therapies using GLP-1 and CD38 modulators

Abstract

The disclosure provides a method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a GLP-1 agonist and a CD38 modulator. The disease or disorder may be obesity, MASLD, or MASH.

Description

Attorney Docket No. 53210-738601COMBO THERAPIES USING GLP-1 AND CD38 MODULATORS CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 723,440 filed on November 21, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control, lower A1C and weight, and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Several case reports have linked the use of these drugs with the occurrence of acute kidney injury, primarily through emodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis.SUMMARY OF THE INVENTION

[0003] There is a need for improved therapies that use GLP-1 receptor agonists. In some cases, the improved therapies can reduce the side effects of receiving a GLP-1 receptor agonist by, for example, reducing the amount of GLP-1 receptor agonist administered to the subject or alleviating the side effects directly. In some cases, the improved therapies can induce a stronger therapeutic effect. As shown herein, a new therapy that combines the use of a GLP-1 receptor agonist and a CD38 modulator leads to a significant decrease in body weight loss than compared to the monotherapy of using the GLP-1 receptor agonist or CD38 modulator.

[0004] In an aspect, the present disclosure provides a method of treating a disease or disorder by administering to a subject in need thereof a therapeutically effective amount of a GLP-1 agonist and a CD38 modulator. In some cases, the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD) and obesity. In some cases, the disease or disorder is selected from metabolic dysfunction associated steatohepatitis (MASH) and obesity.Attorney Docket No. 53210-738601

[0005] In some embodiments, the CD38 modulator is represented by the structure of Formula I:Formula (I),or a pharmaceutically acceptable salt or solvate thereof; whereintXT ’Z is selected fromR andY N, wherein t represents the point of connection between Z and the imidazole ring;X is selected from O and S;Y is selected from -N(R10)2, -OR10, and -SR10;A is selected from N and CR18;D is selected from N and CR19;R4is selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-6 alkoxyalkyl, Ci-6 alkyl-N(R20)2, C3-5 cycloalkyl, and 3- to 6-membered heterocycle;R5is selected from hydrogen and C1-6 alkyl;R6is selected from hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, C1-6 alkyl-N(R20)2, C4-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl;R7is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2,Attorney Docket No. 53210-738601-NH2, oxo, Ci-io alkyl, -Ci-iohaloalkyl, -O-Ci-io alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;each R10is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, and Ci-Ce alkyl- N(R20)2;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, - C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -N02, -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2- 10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0006] In some embodiments, the CD38 modulator is represented by the structure of Formula (II):Formula (II),Attorney Docket No. 53210-738601or a pharmaceutically acceptable salt or solvate thereof; whereinR5^R51’R50-Z is selected from R50, wherein t represents the point of connection between Z andY is selected from -0-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, Ci-Ce alkyl; or come together toform ™IL_;each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl;k is selected from 1 and 2;A is selected from N and CR18;is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and Ci-6 alkyl;R7is selected from hydrogen; and Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C 14 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, wherein the C1-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected fromAttorney Docket No. 53210-738601halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;each R14is independently selected from halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci- ioalkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -S(O)2(Ci-6 alkyl), C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.INCORPORATION BY REFERENCE

[0007] 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.Attorney Docket No. 53210-738601BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0009] FIG. 1 shows a graph of body weight in grams (g) by number of days of mice using compound 3 A and semaglutide under various treatment schedules.

[0010] FIG. 2 shows a graph of change in body weight in percentage (%) by number of days of mice using compound 3 A and semaglutide under various treatment schedules.DETAILED DESCRIPTION OF THE INVENTION

[0011] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Definitions

[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0013] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0014] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx.yalkylene-refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0015] " Alkyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferablyAttorney Docket No. 53210-738601having from one to fifteen carbon atoms (z.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (z.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (z.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (z.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (z.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (z.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (z.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (z.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (z.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (z.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl (z.w-butyl),1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0016] " Alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0017] " Alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0018] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx.yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -Attorney Docket No. 53210-738601C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene-refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0019] " Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. An alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0020] " Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. An alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0021] " Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. An alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0022] " Halo" or "halogen" as used herein refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0023] " Haloalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl,Attorney Docket No. 53210-738601bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluorom ethane, iodomethane), di-and trihalom ethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens. When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected, for example l-chloro,2-bromoethane.

[0024] " Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane- 1,2-diamine, pentane- 1, 2, 4-triamine and the like.

[0025] " Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1,4-diol, pentane- 1, 2, 4-triol, and the like.

[0026] " Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3 -dimethoxybutane, 1 -methoxypropane, 2-ethoxypentane, and the like.

[0027] " Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0028] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. A carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.Attorney Docket No. 53210-738601

[0030] The term “cycloalkyl” as used herein refers to a saturated carbocycle. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbomane. Carbocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] The term “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in the cycle. For example, the term “C3-6 carbocycle” refers to a saturated, unsaturated, or aromatic ring comprising from 3 to 6 carbons. For example -C3-6 carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted.

[0032] " Aryl" as used herein refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0033] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiro heterocycle” or “spiroheterocycle” or “spiro-ring heterocycle”. In some cases, spiro heterocycle, spiro-ring heterocycles or spiroheterocycles have at least two molecular rings with only one common atom. The spiro heterocycle, spiro-ring heterocycle or spiroheterocycle comprises one or more heteroatoms.

[0034] “Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, theAttorney Docket No. 53210-738601heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine.

[0035] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0036] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0037] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0038] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl,Attorney Docket No. 53210-738601aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0039] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0040] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0041] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animalsAttorney Docket No. 53210-738601without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0042] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0043] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0044] As used herein, the phrase "a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0045] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound shouldAttorney Docket No. 53210-738601be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0046] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0047] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0048] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays theAttorney Docket No. 53210-738601onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0049] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0050] The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0051] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0052] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Compounds (CD38 Modulators)

[0053] Nicotinamide Adenine Dinucleotide (NAD+) is a biochemical found in all cells that was first characterized over 100 years ago due to its role in oxidoreductase reactions. Since then, NAD+and its related pyridine nucleotides NADH, NADP+, and NADPH are recognized as the major redox carriers in all organisms. These pyridine dinucleotides regulate the cytosolic and mitochondrial redox state and are key participants monitoring the metabolic status of the cell. This is because NAD+and NADH act as hydride accepting and donating cofactors for metabolic enzymes involved in glycolysis, the TCA cycle, and the respiratory chain and thereby redistribute reducing equivalents generated from these catabolic processes into the de novo synthesis of new biomolecules. (Houtkooper et al Endo Reviews (2010) 31: 194-223; Koch-Nolte et al Science Signaling (2009) 2:mrl; Houtkooper and Auwerx J. Cell Biol (2012) 199:205-209; Berger et al Trends in Bioch Sci (2004) 29:111-18).

[0054] In addition to its long recognized role as a cofactor for oxidoreductases, more recent research demonstrates that NAD+is also a substrate for various enzymes, where it is consumed in the process of donating its ADP ribose to acceptor molecules. The enzymes that are the majorAttorney Docket No. 53210-738601consumers of NAD+are the ADP ribosyl transferases (i.e., PARP and ART family of enzymes), the sirtuins (Sirtl -7), and the DP ribosyl cyclases / hydrolases (CD38 / CD 157). These enzymes are involved in pathways that regulate Ca++signaling, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. Thus, NAD+and its phosphorylated relatives NADP and NAADP, both of which are derived from NAD+, also act as signaling molecules. NAD+is also a key component of the circadian cycle with daily oscillations that tie cellular metabolism to chromatin remodeling and gene transcription.

[0055] It is known that exercise and caloric restriction elevate NAD+levels, while aging and obesity decrease cellular NAD+levels. Restoring NAD+levels in disease states that consume significant amounts of NAD+will likely have medical benefits as the cell strives to maintain its energy status during stress. (Tevy et al Trends in Endo and Metab (2013) 24:229-237; Pugh et al Aging Cell (2013) 12:672-681; Massudi et al PLoS ONE (2012) 7:e42357; Xu and Sauve (2010) Meeh of Ageing and Development 131:287-298). Cellular NAD+is produced by either the de novo synthesis pathway from tryptophan or by a salvage synthesis pathway from precursors such as nicotinic acid (niacin) and nicotinamide, both of which are obtained from dietary sources.

[0056] A third way to modulate cellular NAD+levels is to block consumption of NAD+by inhibiting enzymes that consume NAD+. CD38 is one such consumer of NAD+. Also known as ADP ribosyl cyclase, CD38 is a type II membrane-anchored enzyme. It efficiently catalyzes the breakdown of NAD+ to nicotinamide and ADPR and hydrolyzes NAADP to ADPRP. CD38 can also act as a cyclase converting NAD+to cADPR, although it is 100-fold less efficient as a cyclase than as a hydrolase.

[0057] CD38 was first characterized as a surface antigen on immune cells and is broadly distributed throughout most tissues in the body. It exists on the plasma membrane and on the membranes of intracellular organelles such as the nucleus and mitochondria. As predicted from its function as a NAD+glycohydrolase, CD38 KO mice have elevated NAD+levels relative to wild-type controls. Likewise, inhibitors of CD38 enzyme activity also modulate NAD+tissue levels and would be useful in treating various diseases where CD38 is over expressed or where cellular NAD+levels are depressed or desynchronized. Compounds which inhibit CD38 and thereby raise NAD+ levels are useful in treating diseases or conditions indicated to benefit from NAD+ including mitochondrial-related diseases or disorders.

[0058] The following compounds may be used in the methods of the disclosures.

[0059] In some embodiments, the CD38 modulator is an antibody.

[0060] In some embodiments, the CD38 modulator is a small molecule.

[0061] In some embodiments, the CD38 modulator is a peptide.Attorney Docket No. 53210-738601

[0062] In some embodiments, the CD38 modulator is selected from daratumumab, isatuximab, TAK-079, N1 -Inosine 5'-monophosphate (Nl-IMP), MK-0159, and CD38-IN-78c. In some embodiments, the CD38 modulator is MK-0159.

[0063] In some embodiments, the CD38 modulator is a CD38 inhibitor. In some embodiments, the CD38 modulator is a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG).

[0064] In some embodiments, the CD38 modulator is a compound represented by the structure of Formula (I):Formula (I),or a pharmaceutically acceptable salt or solvate thereof; whereinN '1Z is selected fromR9andY, wherein t represents the point of connection between Z and the imidazole ring;X is selected from O and S;Y is selected from -N(R10)2, -OR10, and -SR10;A is selected from N and CR18;D is selected from N and CR19;R4is selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-6 alkoxyalkyl, Ci-6 alkyl-N(R20)2, C3-5 cycloalkyl, and 3- to 6-membered heterocycle;R5is selected from hydrogen and C1-6 alkyl;R6is selected from hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, C1-6 alkyl-N(R20)2, C4-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl;R7is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;Attorney Docket No. 53210-738601each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;each R10is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, and Ci-Ce alkyl- N(R20)2;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, - C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -N02, -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2- 10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.Attorney Docket No. 53210-738601

[0065] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), A is N. In some cases, A is CR18. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 haloalkyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, and trifluoroethyl. In some cases, R18is selected from hydrogen, halogen, -OH, -CN, methyl, and trifluorom ethyl. In some cases, R18is selected from hydrogen, fluorine, -OH, -CN, methyl, and trifluorom ethyl. In some cases, R18is selected from hydrogen, fluorine, -OH, and methyl. In some cases, R18is selected from hydrogen, fluorine, and methyl. In some cases, R18is methyl. In some cases, R18is fluorine.

[0066] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), D is N. In some cases, D is CR19. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 haloalkyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, and trifluoroethyl. In some cases, R19is selected from hydrogen, halogen, -OH, -CN, methyl, and trifluorom ethyl. In some cases, R19is selected from hydrogen, fluorine, -OH, -CN, methyl, and trifluorom ethyl. In some cases, R19is selected from hydrogen, fluorine, -OH, and methyl. In some cases, R19is selected from hydrogen, fluorine, and methyl. In some cases, R19is methyl. In some cases, R19is fluorine.

[0067] In some embodiments, Formula (I) is represented by Formula (IA):N:1R9Formula (I A),Attorney Docket No. 53210-738601or a pharmaceutically acceptable salt or solvate thereof.

[0068] In some embodiments, Formula (I) is represented by Formula (IB):Formula (IB),or a pharmaceutically acceptable salt or solvate thereof.

[0069] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), R4is selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-6 alkoxyalkyl, and Ci-6 alkyl-N(R20)2. In some cases, R4is selected from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl. In some cases, R4is hydrogen.

[0070] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), R6is selected from hydrogen, Ci-6 alkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-6 alkoxyalkyl, and Ci-6 alkyl-N(R20)2. In some cases, R6is hydrogen.

[0071] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), R5is selected from hydrogen and methyl. In some cases, R5is hydrogen.

[0072] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IC), or Formula (II), R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle. In some cases, R9is selected hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2. In some cases, R9is selected from hydrogen and C1-6 alkyl. In some cases, R9is selected from hydrogen and methyl. In some cases, R9is hydrogen. In some cases, R9is selected from C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl. In some cases, R9is hydrogen. In some cases, R9is selected from C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl.Attorney Docket No. 53210-738601

[0073] In some embodiments, for a compound or salt of Formula (I), Formula (IB), or Formula (ID), each R10is selected from hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some cases, each R10is selected from hydrogen and Ci-6 alkyl. In some cases, at least one occurrence of R10is hydrogen. In some cases, each R10is independently selected from hydrogen, Ci-6 alkyl, and Ci-Ce alkoxyalkyl. In some cases, each R10is independently selected from Ci-Ce alkoxyalkyl. In some cases, each R10is independently selected from C1-C2 alkoxyalkyl. In somecases, each R10is independently selected from>

[0074] In some embodiments, Formula (I) is represented by Formula (IC):1R9Formula (IC),or a pharmaceutically acceptable salt or solvate thereof.

[0075] In some embodiments, Formula (I) is represented by Formula (ID):Formula (ID),or a pharmaceutically acceptable salt or solvate thereof.

[0076] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IC), R9is selected from hydrogen and methyl.

[0077] In some embodiments, for a compound or salt of Formula (I), Formula (IB), or Formula (ID), R10is selected from hydrogen and methyl. In some cases, R10is hydrogen. In some cases, R10is methyl.

[0078] In an aspect, the present disclosure provides a compound represented by the structure of Formula (II):Formula (II),or a pharmaceutically acceptable salt or solvate thereof; whereinAttorney Docket No. 53210-738601R5^R51’R50-Z is selected from R50, wherein t represents the point of connection between Z andY is selected from -O-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, Ci-Ce alkyl; or come together toform ™LI—;each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl;k is selected from 1 and 2;A is selected from N and CR18;is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and Ci-6 alkyl;R7is selected from hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C14 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8; each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, wherein the C1-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected fromAttorney Docket No. 53210-738601halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -S(O)2(Ci-6 alkyl), C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0079] In some embodiments, for a compound or salt of Formula (II) Z is R50. InR50 V^— Ysome cases, K is 1. In some cases, K is 2. In some cases,Z is R50Attorney Docket No. 53210-738601

[0080] In some embodiments, for a compound or salt of Formula (II), each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl. In some cases, each R51is independently selected from hydrogen, halogen, methyl, ethyl, and isopropyl. In some cases, each R51is independently selected from hydrogen, F, Cl, methyl, ethyl, and isopropyl. In some cases, each R51is independently selected from hydrogen, F, and methyl. In some cases, each R51is independently selected from hydrogen and methyl. In some cases, each R51is independently selected from hydrogen and F. In some cases, each R51is hydrogen.

[0081] In some embodiments, for a compound or salt of Formula (II):R503^Y X Z is selected from R50, wherein t represents the point of connection between Z andY is selected from -O-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, Ci-Ce alkyl; or come together to oformA is selected from N and CR18;( C )' is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and C1-6 alkyl;R7is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C14 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8; each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2,Attorney Docket No. 53210-738601-NH2, oxo, Ci-io alkyl, -Ci-iohaloalkyl, -O-Ci-io alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, - C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -N02, -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0082] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R5is selected from hydrogen and Ci-Ce alkyl. In some cases, R5is selected from hydrogen and C1-C4 alkyl. In some cases, R5is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In some cases, R5is selected from hydrogen, methyl, and ethyl. In some cases, R5is selected from hydrogen and methyl. In some cases, R5is hydrogen. In some cases, R5is methyl.Attorney Docket No. 53210-738601

[0083] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Ce-Cs carbocycle and 5- to 6-membered heterocycle, each of which are optionally substituted with one or more R8. In some cases, R7is selected from Ce-Cs carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Ce carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Ce cycloalkyl, which is optionally substituted with one or more R8. In some cases, R7is selected from C7 carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Cscarbocycle, which is optionally substituted with one or more R8. In some cases,R7is ', which is optionally substituted with one or more R8. In some cases, the Ce carbocycle is substituted at the para position. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-ealkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =0, -CN, C1-6 alkyl-N(R20)2, C1-6 haloalkyl, C1-6 alkyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from fluoro, chloro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =0, -CN, C1-6 alkyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, =0, and C1-6 alkyl. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, =0, and C1-4 alkyl. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, methyl, ethyl, propyl, and isopropyl. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), methyl, and ethyl. In some cases, R8is -S(O)2(R20). In some cases, each R8is -OR20. In some cases, each R8is fluoro.Attorney Docket No. 53210-738601In some cases, each R8is methyl. In some cases, each R8is -S(O)2(R20). In some cases, R7is

[0084] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-Cn carbocycle, and 4- to 12-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, OXO, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, Cs-Cn carbocycle, and 4- to 12-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the Cs-Cn carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -N02, -NH2, OXO, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)OR20, -OC(O)N(R20)2, -CN, Ci-6 haloalkyl, Ci-6hydroxyalkyl, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-Ci2carbocycle and 4-to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -N02, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, Ci-6 haloalkyl, Ci-ehydroxyalkyl, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-Ci2Attorney Docket No. 53210-738601carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -Ci-iohaloalkyl, -O-C1-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkyl, C3-C8 carbocycle, and 4- to 8-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C8 carbocycle and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, C1-6 haloalkyl, Ci-6hydroxyalkyl, Ci-6alkyl, C3-Cs cycloalkyl, and 4- to 8-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C8 cycloalkyl and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, R8is independently selected from halogen, -N(R20)2, -OR20, -NR20S(O)2R20, -C(O)N(R20)2, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6 alkyl, C3-C8 cycloalkyl, and 4- to 8-membered heteroaryl, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C8 cycloalkyl and 4- to 8-membered heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl.

[0085] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, each R8* is independently selected from 4-to 10-membered heterocycle, wherein the 4- to 10-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, each R8* is independently selected from 4- to 10-membered heterocycle, wherein the 4- to 10-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, -CN, -NH2, Ci-6 alkyl, -Ci-6 haloalkyl, -Attomey Docket No. 53210-738601O-Ci-6 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, each R8* is independently selected from 4- to 10-membered heterocycle, wherein the 4- to 10-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, -CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CHF3, -CH2CF3, -CF2CF3, -OCH3, -OCH2CH3, and -OCH(CH3)2. In some cases, each R8* is independently selected from 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, -CN, -NH2, C1-6 alkyl, -C1-6 haloalkyl, -O-C1-6 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl. In some cases, each R8* is independently selected from 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, -CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CHF3, -CH2CF3, -CF2CF3, -OCH3, -OCH2CH3, and -OCH(CH3)2.

[0086] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Ce-Cs carbocycle and 5- to 6-membered heterocycle, each of which are optionally substituted with one or more R8. In some cases, R7is selected from Ce-Cs carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Ce carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Ce cycloalkyl, which is optionally substituted with one or more R8. In some cases, R7is selected from C7 carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from Cs carbocycle, which is optionally substituted with one or more R8. In some cases R7is selected from C4-C6 carbocycle, which is optionally substituted with one or more R8. In some cases R7is selected from C5 carbocycle, which is optionally substituted with one or more R8. In some cases R7is selected from C5 cycloalkyl, which is optionally substituted with one or more R8. In some cases R7is selected from C4 carbocycle, which is optionally substituted with one or more R8. In some cases R7is selected from C4 cycloalkyl, which is optionally substituted with one or moreR8. In some cases, R7is selected fromand which isoptionally substituted with one or more R8. In some cases, R7is selected fromandand, which is optionally substituted with one or more R8. In some cases, R7is selectedAttorney Docket No. 53210-738601fromand, which is optionally substituted with one or more R8. In somecases, R7is selected fromand, which is optionally substituted with one ormore R8. In some cases, R7is selected from, which is optionally substituted with oneor more R8. In some cases, R7is selected from, which is optionally substituted withone or more R8. In some cases, R7is selected from, which is optionally substituted with one or more R8. In some cases, the C4 carbocycle is substituted at the para position. In some cases, the C5 carbocycle is substituted at the 3 position. In some cases, the C5 carbocycle is substituted at the 2 position. In some cases, the Ce carbocycle is substituted at the para position.

[0087] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), each R8is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4-to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R8is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, Ci-6hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2,, C3-C12 carbocycle and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2,Attorney Docket No. 53210-738601oxo, Ci-io alkyl, -Ci-iohaloalkyl, and -O-Ci-io alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-io alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-6 alkyl, -Ci-6 haloalkyl, and -O-Ci-6 alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-ehydroxyalkyl, -OR20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-6 alkyl, -Ci-6 haloalkyl, and -O-Ci-6 alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-ehydroxyalkyl, -OR20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, Ci-6 alkyl, -Ci-6 haloalkyl, and -O-Ci-6 alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl. In somecases, each R8is independently, selected from from F,Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601

[0088] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC),Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is which isoptionally substituted with one or more R8. In some casesR7is which is optionally substituted with one or two R8. In some cases, each R8is independently selected from halogen, Ci-6haloalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, Ci-6alkyl-N(R20)2, -C(O)N(R20)2, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-io alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl. In some cases, each R8is independently selected from -N(R20)2, and Ci-6 alkyl-N(R20)2. In some cases, each R8is independently selected from -N(R20)2. In somevo^ozcases, each R is independently selected from fluorine, -CH3, -CF3, -OH, -OCH3, 'Attorney Docket No. 53210-738601from halogen and Ci-ehaloalkyl. In some cases, each R8is independently selected from fluorineand -CF3. In some cases, R7is selected fromsome cases, R7Fis selected from'. In some cases, each R8is independently selected from -OR20. In some cases, R20is independently selected at each occurrence from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, and -O-Ci-10 alkyl. In some cases, each R8is independently selected from -OCH3,VO^^CF3 N,. In some cases, In some cases, R7is selected from '3. In some cases, each R8is independently selected from -N(R20)2. In some cases, R20is independently selected at each occurrence from hydrogen and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R20is different. In some F H I■SZHN^C„F3 N^Fcases, each R8is independently selected fromN. In some cases, R7isAttorney Docket No. 53210-738601. In some cases, each R8is independently selected from -NR20S(O)2R20. In some cases, each R8is independently selected from -NHS(O)2R20. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from -O-Ci-io alkyl. In some cases, each R8is independently selected fromIn some cases, R7is selected fromIn some cases, each R8is independently selected from -C(O)N(R20)2. In some cases, R20is independently selected at each occurrence Ofrom hydrogen and Ci-6 alkyl. In some cases, each R8is independently selected fromH O1 ]HIn some cases,R7is. In some cases, each R8is independently selected from 5-to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, Ci-io alkyl, -Ci-iohaloalkyl, and -O-Ci-io alkyl. In some cases, each R8is independently selected from 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituentsselected from halogen. In some cases, each R8is independently selected fromsome cases,R7is

[0089] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC),Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from,Attomey Docket No. 53210-738601and which is optionally substituted with one or more R8. In some cases,R7is selected from and and, which is optionally substituted with one ormore R8. In some cases, R7is selected fromand which is optionallysubstituted with one or more R8. In some cases, R7is selected from X^^^ and which is optionally substituted with one or more R8. In some cases, R7is selected from, which is optionally substituted with one or more R8. In some cases, R7is selectedfromwhich is optionally substituted with one or more R8. In some cases R7iswhich is optionally substituted with one or two R8. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-io alkyl, -Ci-iohaloalkyl, and -O-Ci-io alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-ehydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, Ci-6 alkyl, -Ci-6 haloalkyl, and -O-Ci-6 alkyl; and wherein the Ci-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl. In some cases, each R8is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, -OR20, -C(O)N(R20)2, and 4- to 6-Attorney Docket No. 53210-738601membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-6 alkyl, -C1-6 haloalkyl, and -O-C1-6 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl. In some cases, each R8is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -OR20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from F, Cl, -OH, C1-6 alkyl, -C1-6 haloalkyl, and -O-C1-6 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituentsAttorney Docket No. 53210-738601some cases, each R8is independently selected from halogen and Ci-ehaloalkyl. In some cases, each R8is independently selected from fluorine and -CF3. In some cases, R7is selected from / \. CF3I ^rFI I', and '. In some cases, each R8is independently selected from -OR20. In some cases, R20is independently selected at each occurrence from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, and -O-Ci-10 alkyl. In some cases, each R8is independently selected from -OCH3,Attomey Docket No. 53210-738601. In some cases, In some cases, R7is selected from. In some cases, each R8is independently selected from -N(R20)2. In some cases, R20is independently selected at each occurrence from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R20is different. In somecases, each R8is independently selected fromIn some cases, R7isindependently selected from -NR20S(O)2R20. In some cases, each R8is independently selected from -NHS(O)2R20. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from -O-Ci-io alkyl. In some cases, each R8is independently selected fromIn some cases, R7is selected fromIn some cases, each R8is independently selected from -C(O)N(R20)2. In some cases, R20is independently selected at each occurrence from hydrogen and Ci-6 alkyl. In Osome cases, each R8is independently selected fromxH. in some cases, R7isOr j H. In some cases, each R8is independently selected from 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, Ci-io alkyl, -Ci-iohaloalkyl, and -O-Ci-io alkyl. In some cases, each R8is independently selected from 5- to 6-membered heterocycle, wherein the 5- to 6-Attorney Docket No. 53210-738601membered heterocycle is optionally substituted with one or more substituents selected fromVFNLFhalogen. In some cases, each R8is independently selected from. In some cases, R7F^.NrJ^Fis '

[0090] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from 5- to 6-membered heterocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from 5-membered heterocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from 6-membered heterocycle, which is optionally substituted with one or more R8. In some cases, the heterocycle of R7has at least one nitrogen atom. In some cases, the heterocycle of R7has at least one oxygen atom. In some cases, the heterocycle of R7has at least one sulfur atom. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, Ci-6alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-ealkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =0, -CN, Ci-6 alkyl-N(R20)2, Ci-6 haloalkyl, Ci-6 alkyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from fluoro, chloro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =0, -CN, Ci-6 alkyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(0)R20(=NR20), =0, and Ci-6 alkyl. In some cases, each R8is independently selected from fluoro, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), =0, and Ci-4 alkyl. In some cases, each R8is independently selected from fluoro, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(0)R20(=NR20), methyl, ethyl, propyl, isopropyl, and =0. In some cases, each R8is independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), and =0. In some cases, each R8is independently selected from -S(O)2(R20) andAttorney Docket No. 53210-738601=0. In some cases, each R8is independently selected from fluoro, methyl, -S(O)2(R20) and =0. In some cases, each R8is -S(O)2(R20). In some cases, each R8is =0. In some cases, each R8ismethyl. In some cases, each R8is fluoro. In some cases, R7is selected from

[0091] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is unsubstituted. In some caes, R7is substituted.

[0092] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is substituted with at least one R8group. In some cases, R7is substituted with at least two R8groups. In some cases, R7is substituted with at least three R8groups. In some embodiments, for a compound or salt of Formula (I), R7is substituted with no more than three R8groups. In some cases, R7is substituted with no more than two R8groups. In some cases, R7is substituted with no more than one R8group. In some embodiments, for a compound or salt of Formula (I), R7is substituted with three R8groups. In some cases, R7is substituted with two R8groups. In some cases, R7is substituted with one R8group.

[0093] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 8-membered heterocycle. In some cases, the saturated 4- to 8-membered heterocycle is optionally substituted with one or more R8. In some cases, R7is selected from an optionally substituted saturated 5-membered heterocycle. In some cases, the 5-membered heterocycle is optionally substituted with one or more R8. In some cases, R7is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is optionally substituted with one or more R8. In some cases, R7isAttomey Docket No. 53210-738601selected from an optionally substituted saturated 4- to 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 5- to 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 4-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 5-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the saturated 4- to 6-membered heterocycle has at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some cases, the saturated 4- to 6-membered heterocycle has atmost one heteroatom. In some cases, R7is selected from, wherein each is optionally substituted with one or more substituents independently selected from R8. In somecases, R7is selected fromand, wherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7is selected fromS.zs\o'xo, and O wherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7is selected froms.zs\o'xo, and

[0094] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 8-membered heterocycle. In some cases, the saturated 4- to 8-membered heterocycle is optionally substituted with one or more R8. In some cases, R7is selected from an optionally substituted saturated 5-membered heterocycle. In some cases, the 5-Attorney Docket No. 53210-738601membered heterocycle is optionally substituted with one or more R8. In some cases, R7is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is optionally substituted with one or more R8. In some cases, R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 5- to 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 4-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 5-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the saturated 4- to 6-membered heterocycle has at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some cases, the saturated 4- to 6-membered heterocycle has atmost one heteroatom. In some cases, R7is selected fromoptionally substituted with one or more substituents independently selected from R8. In someone or more substituents independently selected from R8. In some cases, R7is selected fromwherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7is selected from

[0095] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionallyAttorney Docket No. 53210-738601substituted saturated 4- to 6-membered heterocycle, wherein the optionally substituted saturated 4- to 6-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted saturated 4- to 6-membered heterocycle contains only 1 nitrogen atom. In some cases, the optionally substituted saturated 4- to 6-membered heterocycle contains at most 1 nitrogenatom. In some cases, R7is selected fromwherein each is optionally substituted with one or more substituents independently selected fromR8. In some cases, R7is selected fromwherein each is optionally substituted with one or more susbsituents selected from halogen, -C(O)R20and -S(O)2(R20). In some cases, R7is selected fromwherein each is substituted with -S(O)2(R20). In some cases, R7isselected fromwherein each is substituted with - S(O)2(R20). In some cases, each R20is independently selected at each occurrence from hydrogen; C1-6 alkyl and C3-12 carbocycle, wherein the C1-6 alkyl is optionally substituted with one or more -O-Ci-10 alkyl. In some cases, each R20is independently selected at each occurrence from hydrogen; C1-6 alkyl and C3-6 carbocycle. In some cases, each R20is independently selected at each occurrence from C1-6 alkyl and C3-6 carbocycle. In some cases, each R20is independently selected at each occurrence from C1-6 alkyl. In some cases, each R20is independently selected ateach occurrence from C3-6 carbocycle. In some cases, R7is selected fromAttorney Docket No. 53210-738601

[0096] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the optionally substituted saturated 4- to 6-membered heterocycle contains at least one nitrogen atom. In some cases, R7is selected, wherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7is a beta lactam 4- to 8-membered saturated heterocyle, wherein each is optionally substituted withAttorney Docket No. 53210-738601one or more substituents independently selected from R8. In some cases, R7is selected fromNand H, wherein each is optionally substituted with one or moresubstituents independently selected from R8. In some cases, R7is H, which is optionally substituted with one or more substituents independently selected from R8. In some cases, R7iseach of which is optionally substituted with one orNmore substituents independently selected from R8. In some cases,R7is H which is optionally substituted with one or more substituents independently selected from R8. In some cases, each R8is selected from Ci-6 alkyl, =0, and saturated 4- to 8-membered heterocycle. In some cases, each R8is selected from Ci-6 alkyl and =0. In some cases, each R8is selected fromAttorney Docket No. 53210-738601

[0097] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an saturated 4- to 6-membered heterocycle, wherein the saturated 4- to 6-membered heterocycle contains at least one nitrogen atom and is substituted with at least one oxo, and is further optionallysubstituted with one or more R8. In some cases, R7is selected from,JH, and H, wherein each is substituted with at least one oxo and one or moresubstituents independently selected from R8. In some cases, R7is selected from, andNH, wherein each is subsituted with at least one oxo and further optionally substitutedwith one or more substituents independently selected from R8. In some cases, R7is H which is substituted with at least one oxo and further optionally substituted with one or more substituents independently selected from R8. In some cases, each R8is selected from Ci-6 alkyl, =0, and saturated 4- to 8-membered heterocycle. In some cases, each R8is selected from Ci-6 alkyl and =0. In some cases, each R8is selected from Ci-6 alkyl. In some cases, each R8isN ^0 selected from =0. In some cases, R7is selected fromAttorney Docket No. 53210-738601

[0098] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 7- to 8-membered spiro heterocycle. In some cases, the spiro heterocycle has at least one nitrogen atom. In some cases, the spiro heterocycle has at least one oxygenatom. In some cases, R7is selected from, each of which is optionally substituted with one or more substituents independently selected from R8. In somecases, R7is selected from, which is optionally substituted with one or more substituents independently selected from R8. In some cases, each R8is independently selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, -CN, C 1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, Ci-ehaloalkyl, C1-6 alkoxyalkyl, C1-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from C1-6 alkyl, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected fromCi-6 alkyl and -S(O)2(R20). In some cases,R7is

[0099] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the optionally substituted saturatedAttorney Docket No. 53210-7386014- to 6-membered heterocycle contains at least one nitrogen atom and is subsittued with at leastone halogen, and least one -S(O)2(R20). In some cases,R7is

[0100] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 6-membered heterocycle, and Ce cycloalkyl substituted with one or more R8. In some cases, the saturated 6-membered heterocycle contains 1 nitrogen atom. In some cases, the saturated 6-membered heterocycle contains only 1 nitrogen atom and no furtherheteroatoms. In some cases, R7is selected from'X / 1'1"and H, each of which is optionally substituted with one or more substituents independently selected from R8; and Cecycloalkyl substituted with one or more R8. In some cases, R7is selected fromwhich is optionally substituted with -C(O)R20and -S(O)2(R20); and Ce cycloalkyl substitutedwith one or more halogen. In some cases, R7is selected from, which is optionally substituted with -S(O)2(R20); and Ce cycloalkyl substituted with one or more halogen. In some

[0101] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionallyAttorney Docket No. 53210-738601substituted saturated 6-membered heterocycle, and optionally substituted C4 cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halogen, Ci-ehaloalkyl, C1-6 alkoxyalkyl, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R7is selected from an optionally substituted saturated 6-membered heterocycle, and unsubstituted C4 cycloalkyl, wherein the saturated 6-membered heterocycle is optionally substituted with one or more substituents independently selected from -S(O)2(R20). In some cases, R7is selected from unsubstituted C4JH blcycloalkyl,, and H, each of which is optionally substituted with -S(O)2(R20)and halogen. In some cases, R7is selected from unsubstituted C4 cycloalkyl,, each of which is optionally substituted with -S(O)2(R20). In some cases, R7is selected from

[0102] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 8-membered heterocycle, wherein the optionally substituted saturated 4- to 8-membered heterocycle contains at least one oxygen atom. In some cases, the optionally substituted saturated 4- to 8-membered heterocycle contains only 1 oxygen atom. In some cases, the optionally substituted saturated 4- to 6-membered heterocycle contains at most 1 oxygenAttorney Docket No. 53210-738601atom. In some cases, R7is selected from0,, 0, and wherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the optionally substituted saturated 4- to 6-membered heterocycle containsat least one oxygen atom. In some cases,, R7is selected from, andeach is optionally substituted with one or more substituents independently selectedfrom R8. In some cases, R7is, which is optionally substituted with one or moresubstituents independently selected from R8. In some cases, R7is, which is optionally substituted with one or more substituents independently selected from R8.

[0103] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is an optionally substituted 6-membered saturated heterocycle containing one oxygen atom and no further heteroatoms. In some cases, the heterocycle is tetrahydropyran. In some cases, each R8is independently selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, =0, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, Ci-ehaloalkyl, C1-6 alkoxyalkyl, C1-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from halogen, -OR20, =0, -CN, C 1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C 1 -6 haloalky 1, C1-6 alkoxyalkyl, and C1-6 alkyl. In some cases, each R8is independently selected from halogen and C1-6 alkyl. In some cases, the heterocycle is unsubstituted. In some cases, the heterocycle isAttomey Docket No. 53210-738601substituted. In some cases, R7is selected from

[0104] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 8-membered heterocycle, wherein the optionally substituted saturated 8-membered heterocycle contains at least one oxygen atom. In some cases, the saturated 8-membered heterocycle is a bridged heterocycle. In some cases, R7is

[0105] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted saturated 4- to 6-membered heterocycle, wherein the optionally substituted saturated 4- to 6-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted saturated 4- to 6-membered heterocycle contains only 1 sulfur atom. In some cases, the optionally substituted saturated 4- to 6-membered heterocycle contains at most 1 sulfur atom.In some cases, R7is selected fromsubstituted with one or more substituents independently selected from R8. In some cases, R7isselected from, wherein each is optionally substituted with one or more substituents independently selected from R8. In some cases, R7isAttorney Docket No. 53210-738601O. In some cases, R7is selected from

[0106] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), each R8is independently selected from halogen, -OR20, =0, Ci-ehydroxyalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, -S(O)2(NR202), and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from halogen, -OR20, =0, Ci-6hydroxyalkyl, Ci-6alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from -C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and -S(O)(NR20)R20. In some cases, each R8is independently selected from halogen, -OR20, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, each R8is independently selected from halogen, -OR20, =0, Ci-6 hydroxyalkyl, Cihaloalkyl, C3-6 haloalkyl, Ci-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is selected from halogen, =0, Ci-6 hydroxyalkyl, Ci haloalkyl, Ci-6alkyl, -C(O)R20, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is selected from =0, -C(O)R20, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(N R20)N(R20)2. In some cases, R8is selected from -S(O)2(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is selected from -S(O)2(R20). In some cases, R8is selected from -C(O)N(R20)2, -S(O)2(R20), -S(O)(NR20)R20, and -C(O)R20. In some cases, R8is selected from -C(O)N(R20)2, -S(O)2(R20), and -S(O)(NR20)R20. In some cases, R8is -S(O)2(NR202). In some cases, R8is selected from -S(O)2(R20) and -C(O)R20. In some cases, R8is -C(O)N(R20)2. In some cases, R8is -S(O)2(R20). In some cases, R8is is -S(O)(NR20)R20. In some cases, R8is selected from halogen, -OR20, and =0. In some cases, R8is selected from Ci-6 hydroxyalkyl, C 1-6 haloalkyl, and Ci-6 alkyl. In some cases, R8is selected fromAttorney Docket No. 53210-738601halogen. In some cases, each R20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected at each occurrence from hydrogen; C1-6 alkyl and C3-12 carbocycle, wherein the C1-6 alkyl is optionally substituted with one or more -O-Ci-10 alkyl. In some cases, R20is 3- to 6-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl. In some cases, each R20is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected at each occurrence from hydrogen, C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected at each occurrence from hydrogen and C1-6Attorney Docket No. 53210-738601R7is selected from,and O O. in some cases, R7is selected fromand O. In some cases, R7is selected fromIn some cases, R7is selected from O In some cases,In some cases, R7is selected from. In some cases, R7is selected from

[0107] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from 5- to 10-membered heterocycle, each of which are optionally substituted with one or more R8. In someAttorney Docket No. 53210-738601it O >, and c x sx>, each of which are optionally substituted with one or more R8. In some cases, the heterocycle has one oxygen atom. In some cases, the heterocycle has one nitrogen atom. In some cases, the heterocycle has only one heteroatom. In some cases, the heterocycle has only two heteroatoms. In some cases, the heterocycle has only three heteroatoms. In some cases, the heterocycle has one sulfur atom. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -C(O)OR20, =0, Ci-6 alkyl, and Ci-6 haloalkyl. In some cases, each R8is independently selected from =0, -S(O)2(Ci-6 alkyl), -CF3, -j / \ > CH3, -C(0)0Ci-6 alkyl, -OMe, and »0 0. In some cases, R7is selected fromI l[ / / ^O o-

[0108] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from 5- to 10-membered heterocycle, each of which are optionally substituted with one or more R8. In someAttorney Docket No. 53210-738601R8. In some cases, R7is selected fromO >, and CX s>, each of which are optionally substituted with one or more R8. In someNS. N NNO N H O, and S, each of which are optionally Osubstituted with one or more R8. In some cases, R7is selected fromO L JL >, and L JL / °, each of which are optionally substituted with one or more R8. In some cases, the heterocycle has one oxygen atom. In some cases, the heterocycle has one nitrogen atom. In some cases, the heterocycle has only one heteroatom. In some cases, the heterocycle has only two heteroatoms. In some cases, the heterocycle has only three heteroatoms. In some cases, the heterocycle has one sulfur atom. In some cases, each R8is independently selected from halogen, -OR20, -N(R20)2, -S(O)2(R20), -C(O)OR20, =0, Ci-6 alkyl,Attomey Docket No. 53210-738601Ci-6 haloalkyl, and and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases,

[0109] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from a 6-Attorney Docket No. 53210-738601membered heterocycle, each of which is optionally substituted with one or more R8. In some cases, the heterocycle has one oxygen atom. In some cases, the heterocycle has one nitrogen atom. In some cases, the heterocycle has one sulfur atom. In some cases, the heterocycle has only one heteroatom. In some cases, the heterocycle has only two heteroatoms. In some cases, the heterocycle has only three heteroatoms. In some cases, R7is selected from an 6-membered heteroaryl, which is optionally substituted with one or more R8. In some cases, the heteroaryl has one oxygen atom. In some cases, the heteroaryl has one nitrogen atom. In some cases, the heteroaryl has one sulfur atom. In some cases, the heteroaryl has only one heteroatom. In some cases, the heteroaryl has only two heteroatoms. In some cases, the heteroaryl has only three heteroatoms. In some cases, the heteroaryl has one sulfur atom. In some cases, the 6-memberedr ]]NIHheteroaryl has one nitrogen atom. In some cases, R7is selected fromand, each of which is optionally substituted with one or more R8. In some cases, R7is selected from, each of which is optionally substituted with one or more R8. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -CN, =0, Ci-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R8is independently selected from halogen, -S(O)2(R20), =0, Ci-6 alkyl, and Ci-6 haloalkyl. In some cases, R20is Ci-6 alkyl. In some cases, each R8is independently selected from CF3, Me, =0, or -S(O)2(Ci-6 alkyl). In somecases, R7is selected from

[0110] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from 9- to 10-membered heterocycle, each of which are optionally substituted with one or more R8. In some cases, R7is selected from 9-membered heterocycle, which optionally substituted with one or more R8. In some cases, R7is selected from 10-membered heterocycle, which optionally substituted with one or more R8. In some cases, the 9- to 10-membered heterocycle is bicyclic. In some cases, the 9- to 10-membered heterocycle is a fused heterocycle. In some cases, the 9- to 10-membered heterocycle is aromatic. In some cases, the 9- to 10-membered heterocycle is nonaromatic. In some cases, the 9- to 10-membered heterocycle is fully saturated. In some cases, the 9- to 10-membered heterocycle is partially saturated. In some cases, the 9- to 10-memberedAttorney Docket No. 53210-738601heterocycle is non- saturated. In some cases, the heterocycle has one oxygen atom. In some cases, the heterocycle has one nitrogen atom. In some cases, the heterocycle has one sulfur atom. In some cases, the heterocycle has only one heteroatom. In some cases, the heterocycle has only two heteroatoms. In some cases, the heterocycle has only three heteroatoms. In some cases, the heterocycle has only four heteroatoms. In some cases, the heterocyle has a combination of different heteroatoms. In some cases, the 9- to 10-membered heterocycle is not fully saturated. Insome cases, R7is selected fromoptionally substituted with one or more R8. In some cases, R7is, which is optionallysubstituted with one or more R8. In some cases, R7is selected fromwhich are optionally substituted with one or more R8. In some cases, R7is selected fromf l. JN O, and L^^£^N / >, each of which are optionally substituted with one or more R8. InAttorney Docket No. 53210-738601selected fromeach of which are optionally substituted with one or more R8. In some cases, R7is substituted with one to six R8. In some cases, R7is substituted with one to three R8. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -C(O)OR20, =0, -N(R20)2, C1-6 alkyl, and C1-6 haloalkyl. In some cases, each R8is independently selected from halogen, -OR20, -S(O)2(R20), -N(R20)2, -C(O)OR20, =0, C1-6 alkyl, and C1-6 haloalkyl. In some cases, each R8is independently selected from =0, -S(O)2(Ci-6alkyl), -CF3, -NHCH3, -N(CH3)2, -CH3, -C(O)OCi-6alkyl, -OMe,NH O,an(| O O jn some cases, R20 jsQ_6 aikyi,wherein each is optionallysubstituted with one, two, three substituents independently selected from halogen, -OH, -O-C1-6 alkyl. In some cases, each R20is methyl, ethyl, tert-butyl, and. In some cases, R7is

[0111] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC),Attorney Docket No. 53210-738601Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), R8is selected from -S(O)2(NR202) and -S(O)2(R20). In some cases, R8is selected from -S(O)2(NR202). In some cases, R20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-io alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, C2-io alkenyl, C2-10 alkynyl, Cs-i2carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from hydrogen and Ci-6 alkyl. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl. In some cases, R8isA / / / SxN^ OZ N\ N selected fromuH and \. In some cases, R7is H. In some

[0112] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R8is selected from -S(O)2(R20). In some cases, R20is 3- to 6-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-io alkyl, -Ci-10 haloalkyl, -O-C i-io alkyl, C2-io alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is 3- to 6-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-io alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl. In some cases, R20is 3- to 6-membered heterocycle. In some cases, R20is 6-membered heterocycle. In some cases, R20is saturated 6-membered heterocycle. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains at leastOz NLI one oxygen atom and at least one nitrogen atom. In some cases, R8is. in some°cases, R7is selectedZ" OofromAttorney Docket No. 53210-738601

[0113] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R8is selected from -C(O)R20. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl which is optionally substituted with one or more substituents independently selected from -O-Ci-10 alkyl, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -C1-10 haloalkyl, -O-C 1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl which is optionally substituted with 3- to 6-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl which is optionally substituted with 6- membered heterocycle. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains at least one oxygen atom and at least one nitrogen atom. In some cases, the 6-membered heterocycle is selected from morpholine. In some cases, R8is. insome cases, R8is selected from O. in some cases, R8is selected from

[0114] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is represented byAttorney Docket No. 53210-738601 / / ^S(O)2R20\BJS wherein B is selected from an unsubstituted 5- to 6-membered heterocycle.Z ^^XOR2°\cJIn some cases, R7is represented by- ', wherein C is selected from a C5-6 saturated carbocycle and R20is selected from C1-6 alkyl substituted by one -O-Ci-10 alkyl. In some cases, R7\B7is represented by- ', wherein B is selected from an unsubstituted 5- to 6-memberedT B )heterocycle. In some cases, R7is represented by, wherein B is selected from a 4- to 6-membered heterocycle having at least one sulfur atom, wherein the 4- to 6-memberedkB7 heterocycle is substituted with two =0. In some cases, R7is represented by, wherein B is selected from an unsubstituted 4- to 6-membered heterocycle having at least one oxygen atom.

[0115] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R8is selected from -S(O)2(R20). In some cases, R20is independently selected at each occurrence from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from C1-6 alkyl and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl. In some cases, R20is independently selected at each occurrence from C1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -C1-10 haloalkyl, and -O-Ci-10 alkyl. In some cases, R20is independently selected at each occurrence from C1-6 alkyl, which is optionally substituted withAttorney Docket No. 53210-738601one or more -O-Ci-io alkyl. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl. In some cases, R20is independently selected at each occurrence from methyl, ethyl and propyl. In some cases, R20is independently selected at each occurrence from C3-6 carbocycle, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -Ci-iohaloalkyl, and -O-Ci-10 alkyl. In some cases, R20is independently selected at each occurrence from C3-6 carbocycle, which is optionally substituted with one or more substituents independently selected from halogen, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl. In some cases, R20is independently selected at each occurrence

[0116] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from substituted Ce cycloalkyl and optionally substituted saturated 6-membered heterocycle. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle is unsubstituted. In some cases, the heterocycle is substituted. In some cases, the heterocycle is selected from tetrahydropyran and piperidine. In some cases, each R8is independently selected from halogen, -C(O)N(R20)2, -S(O)2(R20), and -Attorney Docket No. 53210-738601N" StA N S(O)2(NR202). In some cases, R7is selected from0 I, andO NH

[0117] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), each R8is independently selected from -C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and -S(O)(NR20)R20. In some cases, each R8is independently selected from -C(O)N(R20)2and -S(O)2(R20), and -S(O)(NR20)R20. In some cases, each R8is independently selected from -S(O)2(R20), and -S(O)(NR20)R20. In some cases, each R8is -C(O)N(R20)2. In some cases, each R8is -S(O)(NR20)R20. In some cases, R20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, Ci-io alkyl, -Ci-iohaloalkyl, -O-Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -Ci-iohaloalkyl, -O-Ci-io alkyl, C2. io alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -O-Ci-io alkyl. In some cases, R20is independently selected at each occurrence from Ci-6 alkyl. In somecases, R20is methyl. In some cases, R8is selected from,O. In some cases, R8isN NHselected from, O. in some cases, R8is selected from, O

[0118] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Ce cycloalkylAttorney Docket No. 53210-738601optionally substituted with one or more R8. In some cases, R8is independently selected at each occurrence from halogen, Ci-6 haloalkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), and -S(O)2(NR202). In some cases, R8is selected at each occurrence from halogen, Ci-6 haloalkyl, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), and -S(O)2(NR202). In some cases, R8is selected at each occurrence from halogen, Ci-6 haloalkyl, -N(R20)C(O)R20, and -N(R20)C(O)N(R20)2. In some cases, R8is selected at each occurrence from halogen and Ci -6 haloalkyl. In some cases, R8is selected at each occurrence from -N(R20)C(O)R20and -N(R20)C(O)N(R20)2. In some cases, R8is selected at each occurrence from halogen. In some cases, R8is independently selected at each occurrence from halogen, Ci-6haloalkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is independently selected at each occurrence from halogen, Ci-6 haloalkyl, -C(O)R20, -S(O)2(R20), -S(O)(R20), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is independently selected at each occurrence from halogen, -C(O)R20, and -S(O)2(R20). In some cases, R20is independently selected at each occurrence from hydrogen, and Ci-6 alkyl. In some cases, R20is independently selected at each occurrence from hydrogen, and Ci-6 alkyl. In some cases, R8is independently selected each occurrence from -OR20, -SR20, -N(R20)2, -NO2, =0, =S, =N(R20), -CN, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci -6 haloalkyl, and Ci-6 alkyl. In some cases, R8is selected each occurrence from -OR20, -SR20, -N(R20)2, -N02, =0, =S, =N(R20), and -CN. In some cases, R8is selected each occurrence from -OR20, -SR20, and -N(R20)2. In some cases, R8is selected each occurrence from -OR20. In some cases, R20is independently selected at each occurrence from hydrogen, and Ci-6 alkyl. In some cases, R20is independently selected at each occurrence from hydrogen, and Ci-6 alkyl.

[0119] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Ce cycloalkylsubstituted with one or more R8. In some cases, R7iswhich is substituted with one ormore R8. In some cases, R7iswhich is substituted with two R8. In some cases, R8isAttorney Docket No. 53210-738601independently selected at each occurrence from halogen, and Ci-6 haloalkyl. In some cases, R7isselected fromF

[0120] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Cs-io cycloalkyl, each of which is optionally substituted with one or more R8. In some cases, R7isselected fromwhich is optionally substituted with one or more R8. In some cases, R7is selected from Cs cycloalkyl, which is optionally substituted with one or more R8. In somecases, the Cs cycloalkyl is selected fromwhich is optionally substituted with one ormore R8. In some cases, R7iswhich is optionally substituted with one or more R8. Insome cases,R7is jnsome cases, R7is selected from Cio cycloalkyl, which isoptionally substituted with one or more R8. In some cases, R7iswhich is optionallysubstituted with one or more R8. In some cases, R7is selected fromandwhich is optionally substituted with one or more R8. In some cases, each R8is independently selected at each occurrence from halogen, -OR20, -N(R20)2, =0, -CN, Ci-6 aminoalkyl, Ci-ehydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkoxyalkyl, Ci-6 alkyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, -S(O)(NR20)N(R20)2, and 4- to 8-membered heterocycle. In some cases, each R8is independently selected at each occurrence from -OR20, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkoxyalkyl, and Ci-6 alkyl. In some cases, each R8is independently selected at each occurrence from -OR20, and Ci-6 alkyl.Attorney Docket No. 53210-738601In some cases, each R8is independently selected at each occurrence from -OH, and -O-Ci-6 alkyl.OH OHIn some cases, R7is. in some cases, R7is

[0121] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from C3-5 cycloalkyl, C7-8 cycloalkyl, and C9-10 cycloalkyl, each of which is optionally substituted with one or more R8. In some cases, R7is selected from C3 cycloalkyl, C5 cycloalkyl, C7-8 cycloalkyl, and C9-10 cycloalkyl, each of which is optionally substituted with one or more R8. In some cases, R7is selected from, and each of which is optionally substituted with one or more R8. In some cases, R8is independently selected at each occurrence from each halogen, -OR20, -SR20, -N(R20)2, -NO2, =0, =S, =N(R20), -CN, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6cyanoalkyl, Ci-ehaloalkyl, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(N R20)R20, and -S(O)(NR20)N(R20)2. In some cases, R8is independently selected at each occurrence from each halogen, -SR20, -N(R20)2, -NO2, =0, =S, =N(R20), -CN, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-ehaloalkyl, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(N R20)N(R20)2. In some cases, R8is selected from -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2. In some cases, R20is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, Ci-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, C1-10 alkyl, and -Ci-iohaloalkyl. In some cases, when R1is N, R3is imidazole, R7is C4 cycloalkyl, and R8is -OR20, R20is selected from Ci alkyl, C3-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, C1-10 alkyl, -Ci-10 haloalkyl, -0-C 1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, when R1is N, R3is imidazole, R7is C4 cycloalkyl, and R8is -OR20,Attorney Docket No. 53210-738601R20is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -Ci-10 haloalkyl, -O-C2-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- / \ / -^°\membered heterocycle. In some cases, R7is, V ', and

[0122] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted C5 cycloalkyl. In some cases, the C5 cycloalkyl is substituted. In some cases, R7is C5 cycloalkyl substituted with one or more fluorine atoms. In some cases, R7is selected / — \F< z ~F

[0123] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (IIE), Formula (IIF), or Formula (IIG), each R8is independently selected at each occurrence from halogen, -OR20, -SR20, -N(R20)2, -NO2, =0, =S, =N(R20), -CN, C1-6 aminoalkyl, Ci-ehydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -S(O)2(R20), -S(O)(R20), -S(O)2(NR202), -S(O)(NR20)R20, and -S(O)(NR20)N(R20)2.

[0124] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, R7is selected from an optionally substituted 6-membered heteroaryl. In some cases, R7is selected from an optionally substituted pyridine. In some cases, each R8is selected from halogen, -N(R20)2, OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, and Ci-6 alkyl. In some cases, eachR8is selected from halogen, -OR20, -CN, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, and Ci-6 alkyl. Insome cases, R7is selected fromAttorney Docket No. 53210-738601(IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionally substituted phenyl. In some cases, each R8is selected halogen, -N(R20)2, -OR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - C(O)R20, -C(O)OR20, -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl. In some cases, each R8is selected halogen, Ci-6 alkyl- N(R20)2, CI-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci -6 haloalkyl, Ci-6 alkyl. In some cases, each R20is selected form hydrogen and Ci-6 alkyl. In some cases, R7is selected from phenyl optionally substituted with one or more substituents selected from halogen and Ci-6hydroxyalkyl. In some cases, R7is selected from

[0126] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from an optionallysubstituted phenyl. In some cases, R7iswhich is optionally substituted with one or more R8. In some cases, each R8is independently selected from halogen, and -S(O)2(R20). InAttorney Docket No. 53210-738601some cases, each R8is independently selected from halogen and -S(O)2(CH3). In some cases, R7. Fifis selected

[0127] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (HD), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from Cs-Cn carbocycle, which is optionally substituted with one or more R8. In some cases, the carbocycle is bicyclic. In some cases, the carboyclce is non-aromatic. In some cases, R7is selected from C9carbocycle, which is optionally substituted with one or more R8. In some cases, R7isIn some cases,R7is

[0128] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected from C5-C10 carbocycle and 5- to 10-membered heterocycle, each of which are optionally substituted with one or more R8. In some cases, the carbocycle is bicyclic. In some cases, the carbocycle is monocyclic. In some cases, the heterocycle is monocyclic. In some cases, R7is selected fromS.NH, each of which is optionally substituted with one or more R8. In some cases, R7isselected fromS.NH, and, each of which is optionally substituted withNHAttorney Docket No. 53210-738601s.N, each of which is optionally substituted with one or more R8. In some cases, R7isselected fromC, each of which is optionally substituted with one or more v-NoR8. In some cases, R7is s, each of which is optionally substituted with one or more R8. In some cases, the heterocycle is bicyclic. In some cases, each R8is independently selected from halogen, -N(R20)2, -OR20, -S(O)2(R20), -NR20S(O)2R20, -C(O)N(R20)2, Ci-6haloalkyl, Ci-6alkyl and =0. In some cases, each R8is independently selected from fluorine, -S(O)2(Ci-6 alkyl),, -C(0)NHCH3, -NHS(O)2CI-6alkyl, -NHCI-6 alkyl, -NHS(O)2CI-6alkyl-O-Ci-6Attorney Docket No. 53210-738601o—

[0129] In an aspect, the present disclosure provides a compound represented by the structure of Formula (II):Formula (II),or a pharmaceutically acceptable salt or solvate thereof; whereinR5J / Or51\ XR50^— YZ is selected fromR50, wherein t represents the point of connection between Z andCDY is selected from -O-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, Ci-Ce alkyl; or come together to Oform — JL;each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl;k is selected from 1 and 2;A is selected from N and CR18;is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and C1-6 alkyl;Attorney Docket No. 53210-738601R7is selected from hydrogen; and Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C 14 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, wherein the Ci-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;Attorney Docket No. 53210-738601R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -S(O)2(Ci-6 alkyl), C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0130] In some embodiments, for a compound or salt of Formula (II):NR503^YZ is selected fromR50, wherein t represents the point of connection between Z andY is selected from -O-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, Ci-Ce alkyl; or come together to Oform =O;A is selected from N and CR18;( C )is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and C1-6 alkyl;R7is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C14 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8; each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are eachAttorney Docket No. 53210-738601optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, C2-10 alkynyl;R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, - C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0131] In some embodiments, for a compound or salt of Formula (II),is selected from an optionally substituted imidazole, wherein the imidazole is optionaly substituted with oneAttorney Docket No. 53210-738601, wherein q represents the point of connection to Z, and wherein each is optionalysubstituted with one or more R14. In some cases,

[0132] In some embodiments, for a compound or salt of Formula (II), R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, - O-Ci-10 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R14is selected from halogen, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, and C3-6 carbocycle. In some cases, R14is selected from halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci-ioalkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R14is selected from halogen, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci- 10 alkyl, and C3-6 carbocycle. In some cases, R14is selected from halogen, C1-10 alkyl, and C3-6 carbocycle. In some cases, R14is selected from halogen and C1-10 alkyl.

[0133] In some embodiments, for a compound or salt of Formula (II), Y is selected from -O-, -NR9-, -S-, and -SO2. In some cases, Y is -O-. In some cases, Y is -NR9-. In some cases, Y is -S-. In some cases, Y is -SO2. In some cases, Y is selected from -O- and -NR9-.

[0134] In some embodiments, for a compound or salt of Formula (II), R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and C3-6 carbocycle. In some cases, R9is selected from hydrogen and Ci-Ce alkyl. In some cases, R9is hydrogen. In some cases, R9is Ci-Ce alkyl.

[0135] In some embodiments, for a compound or salt of Formula (II), each R50is independently selected from hydrogen, halogen, and Ci-Ce alkyl. In some cases, each R50comes Otogether to form -1L~. In some cases, each R50is hydrogen.

[0136] In some embodiments, for a compound or salt of Formula (II), Z issome cases, Z is selected fromIn some cases, Z is selected fromR9. InAttorney Docket No. 53210-738601some cases, Z is selected from® R9. In some cases, Z is selected fromO. insome cases, Z is selected from

[0137] In some embodiments, for a compound or salt of Formula (II), Z is selected fromR50'R50, wherein t represents the point of connection between Z and. In somecases, Z is selected fromR50, wherein t represents the point of connection between Zand. In some cases, Z is selected from, wherein t represents the point ofconnection between Zand

[0138] In some embodiments, for a compound or salt of Formula (II), Z is selected fromR50, wherein t represents the point of connection between Z and

[0139] In some embodiments, for a compound or salt of Formula (II), R9is selected from hydrogen, Ci-Ce alkyl, and C3-6 carbocycle.

[0140] In some embodiments, Formula (II) is represented by Formula (IIA):NRR17Formula (IIA),or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No. 53210-738601

[0141] In some embodiments, Formula (II) is represented by Formula (IIB):Formula (IIB),or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, Formula (II) is represented by Formula (IIC):Formula (IIC),or a pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), A is selected from N and CH. In some cases, A is CH. In some cases, A is N.

[0144] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), A is selected from N, CF, and CH. In some cases, A is selected from N and CF. In some cases, A is selected from CF and CH. In some cases, A is CH. In some cases, A is N. In some cases A is CF.

[0145] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), D is selected from N and CH. In some cases, D is CH. In some cases, D is N.

[0146] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), D is selected from N, CF, and CH. In some cases, D is selected from N and CF. In some cases, D is selected from CF and CH. In some cases, D is CH. In some cases, D is N. In some cases, D is CF.

[0147] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), or Formula (IIC), R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -NO2, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocycle, and 5- to 6-membered heterocycle. In some cases, R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -CN, C1-6 haloalkyl, C1-6 alkyl, C3-6Attorney Docket No. 53210-738601carbocycle, and 5- to 6-membered heterocycle. In some cases, R17is selected from hydrogen, halogen, -O-Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkyl, and C3-6 carbocycle. In some cases, R17is selected from hydrogen, -Br, -OCH3, -CF3, methyl, and cyclopropyl. In some cases, R17is hydrogen. In some cases, R17is halogen. In some cases, R17is C1-6 haloalkyl. In some cases, R17is selected from halogen and C1-6 haloalkyl. In some cases, R17is -O-C1-6 alkyl. In some cases, R17is C3-6 carbocycle. In some cases, R17is C1-6 alkyl. In some cases, R17is selected from hydrogen and C1-6 alkyl. In some cases, R17is selected from hydrogen, C1-6 alkyl, and saturated C3-6 carbocycle.

[0148] In some embodiments, Formula (II) or Formula (IIA) is represented by Formula (IID):Formula (IID),or a pharmaceutically acceptable salt or solvate thereof.

[0149] In some embodiments, Formula (II) or Formula (IIB) is represented by Formula (HE):Formula (HE),or a pharmaceutically acceptable salt or solvate thereof.

[0150] In some embodiments, Formula (II) or Formula (IIC) is represented by Formula (HF):Formula (HF),or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No. 53210-738601

[0151] In some embodiments, Formula (II) is represented by Formula (IIF):Formula (IIG),or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, for a compound or salt of Formula (II), Formula (IID), Formula (IIE), Formula (IIF) or Formula (IIG), R17is selected from hydrogen, halogen, -OR20, Ci-6 alkyl, Ci-ehaloalkyl, saturated C3-6 carbocycle. In some cases, R17is selected from hydrogen, F, Cl, Br, -OCH3, -CF3, methyl, and cyclopropyl. In some cases, R17is hydrogen. In some cases, R17is halogen. In some cases, R17is C1-6 haloalkyl. In some cases, R17is selected from halogen and Ci-6 haloalkyl. In some cases, R17is -O-C1-6 alkyl. In some cases, R17is saturated C3-6 carbocycle. In some cases, R17is C1-6 alkyl. In some cases, R17is selected from hydrogen and C1-6 alkyl. In some cases, R17is selected from hydrogen, C1-6 alkyl, and saturated C3-6 carbocycle.

[0153] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (IIF), or Formula (IIG), each R8is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-6 alkyl, -C1-6 haloalkyl, and -O-C1-6 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R20is independently selected at each occurrence from hydrogen; C1-6 alkyl, C3-6 carbocycle, and 4- to 5-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -S(O)2(CI-6 alkyl), C1-6 alkyl, -C1-6 haloalkyl, -O-C1-6 alkyl, C3-6 carbocycle, and 4- to 5-membered heterocycle. In some cases, each R8is independently selected from F, methyl, ethyl,Attorney Docket No. 53210-738601

[0154] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), R7is selected from C4-C6 carbocycle, which is optionally substituted with one or more R8. In someor more R8. In some cases, R7iswhich is substituted with one R8. In some cases, each R8is independently selected from halogen, C1-6 alkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each R8isAttorney Docket No. 53210-738601R8is independently selected from -OR20, wherein R20is selected Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with one or more substituents independently selected from halogen, -OH, -CN, -Ci-10 haloalkyl, -S(O)2(Ci-6 alkyl), -O-Ci-io alkyl, C3-5 carbocycle, and 4- to 5-memberedheterocycle. In some cases, each R8is independently selected fromeach R8is independently selected from -OR20, wherein R20is selected C1-6 alkyl, wherein the C1-6 alkyl is substituted with one or more substituents independently selected from -O-C1-6 alkyl. Insome cases, each R8is independently selected from' and. In somecases, each R8is independently selected from. In some cases, each R8is independently selected from -OR20, wherein R20is selected C1-6 alkyl, wherein the C1-6 alkyl is substituted with one or more substituents independently selected from halogen. In some cases,VOJ^CF3each R8is independently selected from, F, \, andAttorney Docket No. 53210-738601. In some cases, each R8is independently selected from -OR20, wherein R20is selected Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with one or more substituentsC\independently selected from -S(O)2(Ci-6 alkyl). In some cases, each R8is'. In some cases, each R8is independently selected from -OR20, wherein R20is selected Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with one or more substituents independently selected from a 5-membered heterocycle. In some cases, the heterocycle has one oxygen atom. In some cases,each R8is'. In some embodiments, for a compound or salt of Formula (II), Formula (IID), Formula (HE), Formula (HF) or Formula (IIG), R7is selected from C4-C7 carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selected from C4-C6 carbocycle, which is optionally substituted with one or more R8. In some cases, R7is selectedsubstituted with one or more R8. In some cases, R7is selected from', \and, which is optionally substituted with one or more R8. In some cases,R7is selected from and, which is optionally substituted withone or more R8. In some cases, R7is selected fromwhich is optionally substitutedwith one or more R8. In some cases, R7is selected fromwhich is optionally substituted with one or more R8. In some cases, each R8is independently selected from halogen, C1-6 alkyl, Ci-6haloalky 1, Ci-6hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -Attorney Docket No. 53210-738601CN, -NH2, oxo, Ci-10 alkyl, -Ci-iohaloalkyl, and -O-Ci-10 alkyl; and wherein the C1-6 alkyl ofR8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen. Insome cases, each R8is independently selected from F, methyl, ethyl,alkyl. In some cases, R7is selected fromAttorney Docket No. 53210-738601

[0155] In some embodiments, for a compound or salt of Formula (II), Formula (IID), FormulaAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601

[0157] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), R7isAttorney Docket No. 53210-738601In some cases, R7is which is substituted with at least one R8selected from Ci-6 alkyl, Ci-6 hydroxyalkyl and Ci-6 haloalkyl. In some cases, R7is selected fromsubstituted with at least one R8selected from -S(O)2(R20). In some cases,R7is. In some cases, R7iswhich is substituted with at least one R8selected from -N(R20)2. In

[0158] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (HE), Formula (HF), or Formula (IIG), R7is selected fromAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601

[0159] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), each R8is independently selectedAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601yCH3independently selected from fluoro,F \ / FF Y°V°^ <3MeFO O O X, and. In some cases, each R8is independently selected from H H y, CH, CF3N^ / CF3 VN^ / CF3fluoro, OH 5 H H HN \ F / / \\ o / / \ 0 0 o, and \.

[0160] In some embodiments, for a compound or salt of Formula (II), (IIA), (IIB), (IIC), A is selected from N and CR18. In some cases, D is selected from N and CR19. In some cases, A is N and D is N. In some cases, A is N and D is CR19. In some cases, A is CR18and D is selected from N. In some cases, A is CR18and D is selected from CR19. In some cases, R17is selected from hydrogen, halogen, -OMe, Ci-6 haloalkyl, Ci-6 alkyl, and C3 carbocycle. In some cases, R18is selected from hydrogen and halogen. In some cases, R19is selected from hydrogen, and halogen.

[0161] In some embodiments, for a compound or salt of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIF), or Formula (IIG), substituents are selected from compounds of the example section.

[0162] In some embodiments, a compound of Formula (II), Formula (IIA), or Formula (IID)Attorney Docket No. 53210-738601oII, or a pharmaceutically acceptable salt of any one thereof.

[0163] In some embodiments, CD38 modulators disclosed in PCT / US2023 / 067887;PCT / US2021 / 025953; PCT / US2020 / 057921; PCT / US2022 / 073596; PCT / CN2022 / 089735; PCT / US2024 / 026107; and PCT / GB2022 / 052833 are all incorporated herein by reference. The CD38 modulators can be used with in the methods described herein. The CD38 modulators can be used with a GLP-1 agonist as described herein.

[0164] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0165] “Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.Attorney Docket No. 53210-738601

[0166] When stereochemistry is not specified, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0167] In certain embodiments, compositions of the disclosure may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0168] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:Attorney Docket No. 53210-738601H H H H

[0169] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0170] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0171] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0172] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.Attorney Docket No. 53210-738601

[0173] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0174] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0175] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0176] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0177] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0178] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desiredAttorney Docket No. 53210-738601molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0179] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0180] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0181] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).GLP-1 Agonists

[0182] Glucagon-like peptide-1 (GLP-1) agonists are a class of medications utilized to treat type 2 diabetes mellitus (T2DM) and obesity. As a class of medications, they are among several pharmacological options for these endocrine diseases. The function of GLP-1 agonists is toAttorney Docket No. 53210-738601lower serum glucose levels and thereby manage metabolism in affected patients. Glucagon-like peptide-1 (GLP-1) is derived from the proglucagon gene. The name reflect its genetic origin and similarity to glucagon. The proglucagon gene is expressed in the alpha cells of the pancreas, L-cells in the intestine, and certain neurons in the brain. In the pancreas, the proglucagon gene is processed to produce glucagon. However, the same proglucagon gene is processed differently in the intestinal L-cells and neurons, producing GLP-1, GLP-2, and another peptide called glicentin.

[0183] In some embodiments, the GLP-1 agonist is a peptide. In some embodiments, the GLP-1 agonist comprises a peptide. In some embodiments, the GLP-1 agonist is a non-peptide.

[0184] In some embodiments, the GLP-1 agonist is selected from semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide. In some cases, the GLP-1 agonist is semaglutide. In some cases, the GLP-1 agonist is dulaglutide. In some cases, the GLP-1 agonist is exenatide. In some cases, the GLP-1 agonist is liraglutide. In some cases, the GLP-1 agonist is lixisenatide. In some cases, the GLP-1 agonist is tirzepatide. In some cases, the GLP-1 agonist is orforglipron.Pharmaceutical Formulations

[0185] A compound or salt of any one of the Formulas or sub Formulas described herein (e.g., Formula (Formula (I), Formula (IA), Formula (IB), Formula (IC), or Formula (ID), Formula (II), etc.,) may be formulated in any suitable pharmaceutical formulation. Any CD38 modulator described herein may be formulated in any suitable pharmaceutical formulation. A GLP-1 agonist (e.g., semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of the Formulas, GLP-1 agonist, etc. described herein) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0186] In certain embodiments, a compound or salt of any one of the Formulas or sub Formulas described herein is formulated with an agent that inhibits degradation of the compound or salt. In certain embodiments, the compound or salt is formulated with one or more antioxidants. In certain embodiments, a GLP-1 agonist described herein is formulated with an agent that inhibits degradation of the compound or salt. In certain embodiments, a CD38 modulator described herein is formulated with an agent that inhibits degradation of the compound or salt. In certain embodiments, a GLP-1 agonist is formulated with one or moreAttorney Docket No. 53210-738601antioxidants. Acceptable antioxidants include, but are not limited to, citric acid, d, I-a-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propyl gallate. In certain embodiments, the formulation contains from 0.1 to 30%, from 0.5 to 25%, from 1 to 20%, from 5 to 15%, or from 7 to 12% (wt / wt) CCI-779, from 0.5 to 50%, from 1 to 40%, from 5 to 35%, from 10 to 25%, or from 15 to 20% (wt / wt) water soluble polymer, from 0.5 to 10%, 1 to 8%, or 3 to 5% (wt / wt) surfactant, and from 0.001% to 1%, 0.01% to 1%, or 0.1% to 0.5% (wt / wt) antioxidant. In certain embodiments, the antioxidants of the formulations of this invention will be used in concentrations ranging from 0.001% to 3% wt / wt.

[0187] In certain embodiments, a compound or salt of any one of the Formulas or sub Formulas described herein is formulated with a pH modifying agent to maintain a pH of about 4 to about 6. In certain embodiments, a GLP-1 agonist described herein is formulated with a pH modifying agent to maintain a pH of about 4 to about 6. In certain embodiments, a CD38 modulator described herein is formulated with a pH modifying agent to maintain a pH of about 4 to about 6. Acceptable pH modifying agents include, but are not limited to citric acid, sodium citrate, dilute HC1, and other mild acids or bases capable of buffering a solution containing a compound or a salt of the discloure to a pH in the range of about 4 to about 6.

[0188] In certain embodiments, a compound or salt of any one of the Formulas or sub Formulas described herein is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of any one of the Formulas described herein.

[0189] In certain embodiments a GLP-1 agonist described herein is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of any one of the Formulas described herein.

[0190] In certain embodiments a CD38 modulator described herein is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of any one of the Formulas described herein.

[0191] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, theAttorney Docket No. 53210-738601pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semisolid, or solid form.

[0192] The amount of a compound or salt of any one of the Formulas or sub Formulas described herein will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any one of the Formulas or sub Formulas described herein and the discretion of the prescribing physician.

[0193] The amount of a GLP-1 agonist described herein will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any one of the Formulas or sub Formulas described herein and the discretion of the prescribing physician.

[0194] The amount of a CD38 modulator described herein will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any one of the Formulas or sub Formulas described herein and the discretion of the prescribing physician.

[0195] In some embodiments, pharmaceutically acceptable carriers of a compound or salt of any one of the Formulas or sub Formulas described herein can include a physiologically acceptable compound that is an antioxidant.

[0196] In some embodiments, pharmaceutically acceptable carriers of a GLP-1 agonist described can include a physiologically acceptable compound that is an antioxidant.

[0197] In some embodiments, pharmaceutically acceptable carriers of a CD38 modulator described can include a physiologically acceptable compound that is an antioxidant.

[0198] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of any one of the Formulas or sub Formulas described herein and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.

[0199] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one GLP-1 agonist and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.

[0200] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one CD38 modulator described herein and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid,Attorney Docket No. 53210-738601gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.

[0201] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of the Formulas or sub Formulas described herein moistened with an inert liquid diluent.

[0202] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound or salt of any one of the Formulas described herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.

[0203] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a GLP-1 agonist described herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.

[0204] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a CD38 modulator described herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.

[0205] In certain embodiments, the compound or salt of any one of the Formulas or sub Formulas described herein may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0206] In certain embodiments, a GLP-1 agonist described herein may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, orAttorney Docket No. 53210-738601peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0207] In certain embodiments, a CD38 modulator described herein may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0208] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0209] Pharmaceutical compositions may also be prepared from a compound or salt of any one of the Formulas or sub Formulas described herein and / or a GLP-1 agonist and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0210] The disclosure also provides kits. The kits may include a compound or salt of any one of the Formulas or sub Formulas described herein, a GLP-1 agonist, and one or more additional agents in suitable packaging with written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. The kits may include a CD38 modulator described herein, a GLP-1 agonist, and one or more additional agents in suitable packaging with written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. In some cases, the compound and GLP-1 agonist are in separate kits. In some cases, the compound and GLP-1 agonist are in separate kits. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish theAttorney Docket No. 53210-738601activities and / or advantages of the composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, a compound or salt of any one of the Formulas or sub Formulas described herein and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, a compound or salt of any one of the Formulas or sub Formulas described herein and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.Therapeutic Applications

[0211] In an aspect, the present disclosure provides a method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a GLP-1 agonist and a CD38 modulator.

[0212] In some embodiments, the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD) and obesity.

[0213] In some embodiments, the disease or disorder is selected from metabolic dysfunction associated steatohepatitis (MASH) and obesity.

[0214] In some embodiments, the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD).

[0215] In some embodiments, the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASH).

[0216] In some embodiments, the disease or disorder is obesity.

[0217] In some embodiments, the disease or disorder is selected from: neurodegenerative disease, type I diabetes, insulin resistance, Leber's hereditary amaurosis, Parkinson's disease, amyelotrophic lateral sclerosis, chronic lymphocytic leukemia, periodontal disease, psoriasis, UV skin damage, radiation protection, diabetic neuropathy, skin hyperpigmentation, Pellagra, Hartnup disease, Diabetes, Huntington's disease, Bipolar disorder, Schizophrenia, postmenopausal osteoporosis, optic neuropathy, neurocognitive disorders, multiple sclerosis, Alzheimer’s disease, steatosis, NASH, hearing loss, dyslipidemia, end stage renal disease,Attorney Docket No. 53210-738601Metabolic Syndrome, obesity, sarcopenic obesity, gout, Irritable Bowel Syndrome, Colitis, COPD, Asthma, cystic fibrosis, pancreatitis, idiopathic pulmonary fibrosis, organ reperfusion injury, stroke, muscular dystrophy, cardiac hypertrophy, CHF, leishmaniasis, tuberculosis, hansen's disease, hypoxic pulmonary vasoconstriction, hypertension, renal clear cell carcinoma, small lung cell carcinoma, exercise intolerance, epilepsy, sleep disorders, ataxia - telangiectasia, rheumatoid arthritis, lupus, alcohol intolerance, hyperphosphatemia, acute lung injury, and ARDS.

[0218] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0219] In some embodiments, the disease or disorder is muscular dystrophy.

[0220] In some embodiments, the disease or disorder is a metabolic disorder.

[0221] In some embodiments, the disease or disorder is fibrosis.

[0222] In some embodiments, the disease or disorder is Duchenne muscular dystrophy.

[0223] In some embodiments, the disease or disorder is systemic sclerosis.

[0224] In some embodiments, the disease or disorder is selected from a brain disease, vascular disease, liver disease, muscle disease, pancreas disease, adipose tissue disease, and inflammation associated disease.

[0225] In some embodiments, the method further comprising treating the subject for a disease or disorder selected from: neurodegenerative disease, type I diabetes, insulin resistance, Leber's hereditary amaurosis, Parkinson's disease, amyelotrophic lateral sclerosis, chronic lymphocytic leukemia, periodontal disease, psoriasis, UV skin damage, radiation protection, diabetic neuropathy, skin hyperpigmentation, Pellagra, Hartnup disease, Diabetes, Huntington's disease, Bipolar disorder, Schizophrenia, postmenopausal osteoporosis, optic neuropathy, neurocognitive disorders, multiple sclerosis, Alzheimer’s disease, steatosis, NASH, hearing loss, dyslipidemia, end stage renal disease, Metabolic Syndrome, obesity, sarcopenic obesity, gout, Irritable Bowel Syndrome, Colitis, COPD, Asthma, cystic fibrosis, pancreatitis, idiopathic pulmonary fibrosis, organ reperfusion injury, stroke, muscular dystrophy, cardiac hypertrophy, CHF, leishmaniasis, tuberculosis, hansen's disease, hypoxic pulmonary vasoconstriction, hypertension, renal clear cell carcinoma, small lung cell carcinoma, exercise intolerance, epilepsy, sleep disorders, ataxia -telangiectasia, rheumatoid arthritis, lupus, alcohol intolerance, hyperphosphatemia, acute lung injury, and ARDS.

[0226] In some embodiments of the presently disclosed methods for treating a disease or disorder, the body weight of the subject is reduced as an outcome.

[0227] In some embodiments, a body weight of the subject is reduced by at least about 3%.

[0228] In some embodiments, a body weight of the subject is reduced by at least about 10%.

[0229] In some embodiments, a body weight of the subject is reduced by at least about 20%.Attorney Docket No. 53210-738601

[0230] In some embodiments, a body weight of the subject is reduced by at most about 50%.

[0231] In some embodiments, a body weight of the subject is reduced by at most about 40%.

[0232] In some embodiments, a body weight of the subject is reduced by about 3% to about 50%.

[0233] In some embodiments, a body weight of the subject is reduced by about 3 % to about 40 %. In some embodiments, a body weight of the subject is reduced by about 3 % to about 5 %, about 3 % to about 10 %, about 3 % to about 15 %, about 3 % to about 20 %, about 3 % to about 25 %, about 3 % to about 30 %, about 3 % to about 35 %, about 3 % to about 40 %, about 5 % to about 10 %, about 5 % to about 15 %, about 5 % to about 20 %, about 5 % to about 25 %, about 5 % to about 30 %, about 5 % to about 35 %, about 5 % to about 40 %, about 10 % to about 15 %, about 10 % to about 20 %, about 10 % to about 25 %, about 10 % to about 30 %, about 10 % to about 35 %, about 10 % to about 40 %, about 15 % to about 20 %, about 15 % to about 25 %, about 15 % to about 30 %, about 15 % to about 35 %, about 15 % to about 40 %, about 20 % to about 25 %, about 20 % to about 30 %, about 20 % to about 35 %, about 20 % to about 40 %, about 25 % to about 30 %, about 25 % to about 35 %, about 25 % to about 40 %, about 30 % to about 35 %, about 30 % to about 40 %, or about 35 % to about 40 %. In some embodiments, a body weight of the subject is reduced by about 3 %, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, or about 40 %. In some embodiments, a body weight of the subject is reduced by at least about 3 %, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, or about 35 %. In some embodiments, a body weight of the subject is reduced by at most about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, or about 40 %.

[0234] In some embodiments, a body weight of the subject is reduced by at least about 5 pounds (lbs).

[0235] In some embodiments, a body weight of the subject is reduced by at least about 10 pounds (lbs).

[0236] In some embodiments, a body weight of the subject is reduced by at least about 20 pounds (lbs).

[0237] In some embodiments, a body weight of the subject is reduced by at most about 250 pounds (lbs).

[0238] In some embodiments, a body weight of the subject is reduced by about 5 lbs to about 100 lbs. In some embodiments, a body weight of the subject is reduced by about 5 lbs to about 10 lbs, about 5 lbs to about 20 lbs, about 5 lbs to about 30 lbs, about 5 lbs to about 40 lbs, about 5 lbs to about 50 lbs, about 5 lbs to about 60 lbs, about 5 lbs to about 70 lbs, about 5 lbs to about 80 lbs, about 5 lbs to about 100 lbs, about 10 lbs to about 20 lbs, about 10 lbs to about 30 lbs,Attorney Docket No. 53210-738601about 10 lbs to about 40 lbs, about 10 lbs to about 50 lbs, about 10 lbs to about 60 lbs, about 10 lbs to about 70 lbs, about 10 lbs to about 80 lbs, about 10 lbs to about 100 lbs, about 20 lbs to about 30 lbs, about 20 lbs to about 40 lbs, about 20 lbs to about 50 lbs, about 20 lbs to about 60 lbs, about 20 lbs to about 70 lbs, about 20 lbs to about 80 lbs, about 20 lbs to about 100 lbs, about 30 lbs to about 40 lbs, about 30 lbs to about 50 lbs, about 30 lbs to about 60 lbs, about 30 lbs to about 70 lbs, about 30 lbs to about 80 lbs, about 30 lbs to about 100 lbs, about 40 lbs to about 50 lbs, about 40 lbs to about 60 lbs, about 40 lbs to about 70 lbs, about 40 lbs to about 80 lbs, about 40 lbs to about 100 lbs, about 50 lbs to about 60 lbs, about 50 lbs to about 70 lbs, about 50 lbs to about 80 lbs, about 50 lbs to about 100 lbs, about 60 lbs to about 70 lbs, about 60 lbs to about 80 lbs, about 60 lbs to about 100 lbs, about 70 lbs to about 80 lbs, about 70 lbs to about 100 lbs, or about 80 lbs to about 100 lbs. In some embodiments, a body weight of the subject is reduced by about 5 lbs, about 10 lbs, about 20 lbs, about 30 lbs, about 40 lbs, about 50 lbs, about 60 lbs, about 70 lbs, about 80 lbs, or about 100 lbs. In some embodiments, a body weight of the subject is reduced by at least about 5 lbs, about 10 lbs, about 20 lbs, about 30 lbs, about 40 lbs, about 50 lbs, about 60 lbs, about 70 lbs, or about 80 lbs. In some embodiments, a body weight of the subject is reduced by at most about 10 lbs, about 20 lbs, about 30 lbs, about 40 lbs, about 50 lbs, about 60 lbs, about 70 lbs, about 80 lbs, or about 100 lbs.

[0239] In some embodiments, the subject would benefit from inhibition of CD38.

[0240] In some embodiments, the method leads to inhibition of CD38 in the subject. In some embodiments, the method inhibits CD38 in the subject.

[0241] In some embodiments, the activity of the CD38 modulators can be measured as described in PCT / US2023 / 067887; PCT / US2021 / 025953; PCT / US2020 / 057921;PCT / US2022 / 073596; PCT / CN2022 / 089735; PCT / US2024 / 026107; and PCT / GB2022 / 052833, each of which is incorporated herein by reference.

[0242] In some embodiments, the CD38 modulator can be measured in a NAD+ Cyclase Activity Assay with Human or Mouse Recombinant CD38 Protein.Preparation of Compounds (CD38 modulators)

[0243] The compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.

[0244] In some embodiments, CD38 modulators can be prepared as described in PCT / US2023 / 067887; PCT / US2021 / 025953; PCT / US2020 / 057921; PCT / US2022 / 073596;Attorney Docket No. 53210-738601PCT / CN2022 / 089735; PCT / US2024 / 026107; and PCT / GB2022 / 052833, each of which is incorporated herein by reference.

[0245] The compounds described herein can be prepared as described in PCT / US2024 / 026107.

[0246] In some embodiments, the CD38 modulators are selected from:

[0247] / ‘cr / '-Butyl ((lr,4r)-4-(5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamido)cyclohexyl)carbamate (Compound 22)

[0248] \-(( 1 r,4r)-4-Aminocyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ l,4]oxazepine- 10-carboxamide hydrochloride (Compound 23)

[0249] ( / ?)-\-(Tetrahydro-2 / / -pyran-3-yl)-5.6-dihydrobenzo|f|imidazo| 1,5-d][l,4]oxazepine-10-carboxamide (Compound 1A)Attorney Docket No. 53210-738601

[0250] ( / )- X -( 1.1 - Diox idot et ra hy d rot IiiopIien-3-y 1 )-5.6-dihy d robenzo | f | im idazo | 1,5-d][l,4]oxazepine-10-carboxamide (Compound 2A)

[0251] 7V-((lr,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 3A)

[0252] 7V-(l-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 4A)

[0253] 7V-(4,4-Difluorocyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ 1,4]oxazepine-l 0-carboxamide (Compound 5A)Attorney Docket No. 53210-738601

[0254] (. S)-\-(2.3-l)iliydi()-l / / -inden-l-yl)-5.6-diliydi()benzo|f|iinidazo| 1.5-d][l,4]oxazepine-10-carboxamide (Compound 6A)

[0255] 7V-(Benzo[d]thiazol-5-yl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 7A)

[0256] 7V-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 8A)

[0257] 7V-(2,3-Dihydrobenzofuran-5-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 9A)

[0258] \-(6-(T rifluoromethyl)pyridin-3-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 10A)Attorney Docket No. 53210-738601

[0259] A-((lr,4r)-4-(2-Methoxyethoxy)cyclohexyl)-4-oxo-4,5-dihydroimidazo[l,5-a]quinoxaline-8-carboxamide (Compound 11 A)

[0260] (7?)-A-(l,l-Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[ 1,5-a]quinoxaline-8-carboxamide (Compound 12A)

[0261] ( / ?)-4-Oxo-\-(tetrahydro-2 / / -pyr:in-3-yl)-4.5-dihydroimidazo| 1,5-a]quinoxaline- 8-carboxamide (Compound 13A)

[0262] ( / ?)-\-(Tetrahydro-2 / / -pyran-3-yl)-4.5-dihydrobenzo|b|imidazo|1.2-d][l,4]oxazepine-9-carboxamide (Compound 14A)Attorney Docket No. 53210-738601

[0263] ( / ?)-\-(Tetrahydro-2 / / -pyran-3-yl)-4.5-dihydrobenzo|b|imidazo| 1,5-d][l,4]oxazepine-9-carboxamide (Compound 15A)

[0264] ( / ?)-5-Methyl-4-oxo-\-(tetrahydro-2 / / -pyran-3-yl)-4.5-dihydroiinidazo| 1.5-a]quinoxaline-8-carboxamide (Compound 16A)

[0265] 7V-((lr,4r)-4-(Methylcarbamoyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 17A)

[0266] 7V-(3-(Methylsulfonyl)phenyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ 1,4]oxazepine- 10-carboxamide (Compound 18A)Attorney Docket No. 53210-738601

[0267] \-(l.l-l)i()xid()-2.3-dihydr()benzo|b|thiophen-5-yl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 19A)

[0268] 7V-((lr,4r)-4-Methoxycyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 20A)

[0269] 7V-(4-Fluoro-3-(methylsulfonyl)phenyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 21A)

[0270] 7V-(5-(Methylsulfonyl)pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 22A)

[0271] terf-Butyl 5-(5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamido)isoindoline-2-carboxylate (Compound 23A)Attorney Docket No. 53210-738601

[0272] \-(Is()ind()liii-5-yl)-5.6-dihydr()benz()|f|iinidazo| 1,5-d] [ l,4]oxazepine-10-carboxamide hydrochloride (Compound 24A)

[0273] 7V-(2-(Methylsulfonyl)isoindolin-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 25A)

[0274] ( / ?)-\-(Tetrahydro-2 / / -pyran-3-yl)-6.7-dihydro-5 / / -benzo|b|imidazo|5.1-d][l,5]oxazocine-ll-carboxamide (Compound 26A)

[0275] (l?)-4-((2-Methoxyethyl)amino)-7V-(tetrahydro-2H-pyran-3-yl)imidazo[l,5-a]quinoxaline-8-carboxamide (Compound 27A)

[0276] ( / ?)-4-( Iethylaniino)-\-(tetrahydro-2 / / -pyran-3-yl)imidazo| 1,5-a]quinoxaline-8-carboxamide (Compound 28A)Attorney Docket No. 53210-738601

[0277] A-((lr,4r)-4-((2-Methoxyethyl)sulfonamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 29A)

[0278] 7V-(2,3-Dihydro- [1,4] dioxino [2,3-b] pyridin-6-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 30A)

[0279] 7V-(2,3-Dihydro- [1,4] dioxino [2,3-b] pyridin-7-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 31A)

[0280] 7V-(2,3-Dihydrobenzofuran-6-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 32A)

[0281] 7V-(l,3-Dihydroisobenzofuran-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 33A)Attorney Docket No. 53210-738601

[0282] \-( 1 / / - Benzo [d] imidazol-6-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d] [l,4]oxazepine- 10-carboxamide (Compound 34A)

[0283] Methyl 4-(dimethylamino)imidazo[l,5-a]quinoxaline-8-carboxylate

[0284] Lithium 4-(dimethylamino)imidazo[l,5-a]quinoxaline-8-carboxylate

[0285] ( / ?)-4-(l)iniethylaniino)-\-(tetrahydro-2 / / -pyran-3-yl)imidazo| l,5-a]quinoxaline- 8-carboxamide (Compound 35A)

[0286] N-( l-Methyl-2-oxo-l,2-dihydropyridin-4-yl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 36A)Attorney Docket No. 53210-738601

[0287] A-((lr,4r)-4-(Propylsulfonamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 37A)

[0288] ( / ?)-6 >-Dimet hyl-\-(tet rahydro-2 / / -pyran-3-yl)-5.6-dihydrobenzo|f| imidazo] 1.5-d][l,4]oxazepine-10-carboxamide (Compound 38A)

[0289] 7V-(Benzo[d]oxazol-6-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 39A)

[0290] \-( Ih iazolo [5,4-b] pyridin-6-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d] [1,4] oxazepine- 10-carboxamide (Compound 40A)Attorney Docket No. 53210-738601

[0291] A-(Benzo[d]thiazol-6-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 41A)

[0292] (R)-N-(tetrahydro-2H-pyran-3-yl)-6,7-dihydroimidazo[l,5-d]pyrido[3,2-b][l,4]oxazepine-2-carboxamide (Compound 42A)

[0293] (Z)-7V-((l?)-Tetrahydro-2H-pyran-3-yl)-5,6-dihydro-l,4-(metheno)pyrido[3,2-b][l,4,6]oxadiazonine-10-carboxamide (Compound 43A)

[0294] 7V-(2-Methoxybenzo[d]thiazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 44A)Attorney Docket No. 53210-738601

[0295] \-( 2-(2-M et hoxy et hoxy )benzo [d] thiazol-5-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 45A)

[0296] 8-Broino-\-(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 46A)

[0297] 7V-(2-(Methylamino)benzo[d]thiazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 47A)

[0298] 7V-(2-((2-Methoxyethyl)amino)benzo[d]thiazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 48A)Attorney Docket No. 53210-738601

[0299] \-(2-( Dimet hylain ino)benzo [d] thiazol-5-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 49A)

[0300] 8-Cyclopropyl-7V-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 50A)

[0301] (l?)-5,5-Dimethyl-7V-(tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 51A)

[0302] A-((lr,4r)-4-(Trifluoromethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 52A)Attorney Docket No. 53210-738601

[0303] \-((l r.4r)-4-(2- Iethoxyethoxy)cyclohexyl)-8-methyl-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 53A)

[0304] 8-Methoxy-\-((lr.4r)-4-(2-methoxyethoxy)cyclohexyl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 54A)

[0305] 7V-((lr,4r)-4-(2-Methoxyethoxy)cyclohexyl)-8-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 55A)

[0306] 7V-((lr,4r)-4-(2-Hydroxyethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 56A)Attorney Docket No. 53210-738601

[0307] 8-I luoro-\-(( 1 r.4r)-4-(2-methoxyethoxy)cyclohexyl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 57A)

[0308] \-(( 1 r,4r)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 58A)

[0309] 7V-((lr,4r)-4-((2-Methoxyethyl)carbamoyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 59A)

[0310] 7V-((lr,4r)-4-Acetamidocyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 60A)Attorney Docket No. 53210-738601

[0311] A-((lr,4r)-4-((2,2,2-Trifluoroethyl)carbamoyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 61A)

[0312] 7V-((lr,4r)-4-((2,2,2-Trifluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 62A)

[0313] 7V-((lr,4r)-4-((2,2-Difluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 63A)

[0314] 7V-((ls,4s)-4-(3,3-Difluoroazetidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 64A)Attorney Docket No. 53210-738601

[0315] \-((lr.4r)-4-(Hydroxymethyl)cyclohexyl)-5.6-dihydrobenzo|f|imidazo| 1.5-d][l,4]oxazepine-10-carboxamide (Compound 65A)

[0316] 7V-(3,3-Difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ l,4]oxazepine-10-carboxamide (Compound 66A)

[0317] \-((l r.4r)-4-(3-M ethoxy propanamido)cyclohexyl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 67A)

[0318] 5-Methyl-\-(( / ?)-tetr:ihydro-2 / / -pyran-3-yl)-5.6-dihydrobenzo|f|iinidazo| 1,5-d][l,4]oxazepine-10-carboxamide (Compound 68A)Attorney Docket No. 53210-738601

[0319] 7V-((ls,4s)-4-(3,3-Difluoropyrrolidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 69A)

[0320] \-( ( 1 r.4r )-4-( 2-M et hoxy et hoxy )cy clohexy I )-6.7 -dihydroimidazo [1,5-d] pyrido [3,2-b][l,4]oxazepine-2-carboxamide (Compound 70A)

[0321] V-((lr,4r)-4-(3,3-Difluoropyrrolidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 71A)

[0322] V-((lr,4r)-4-(3,3-Difluoroazetidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 72A)Attorney Docket No. 53210-738601

[0323] 7V-(4,4-Difluorocyclohexyl)-8-fluoro-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 73A)

[0324] 7V-((lr,4r)-4-(((l?)-l,l,l-Trifluoropropan-2-yl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 74A)H N CF3

[0325] A-((ls,4s)-4-((Tetrahydrofuran-2-yl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 75A)

[0326] 7V-((lr,4r)-4-((Tetrahydrofuran-2-yl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 76A)Attorney Docket No. 53210-738601

[0327] A-((ls,4s)-4-(3,3-Difluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 77A)

[0328] 7V-((lr,4r)-4-(3,3-Difluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 78A)

[0329] 7V-((ls,4s)-4-(3-Fluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 79A)

[0330] 7V-((lr,4r)-4-(3-Fluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 80A)

[0331] 7V-(2-(2-Methoxyethoxy)pyrimidin-5-yl)-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 81A)Attorney Docket No. 53210-738601

[0332] A-((lr,4r)-4-((2,2-Difluorocyclobutyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]i w / azo[l,5-d] [l,4]oxazepine-10-carboxamide (Compound 82A)

[0333] 7V-((lr,4r)-4-((2-Fluoro-2-methylpropyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 83A)

[0334] 7V-(3,3-Difluorocyclobutyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ 1,4]oxazepine-l 0-carboxamide (Compound 84A)

[0335] 7V-((lr,4r)-4-(3-(Methylsulfonyl)propoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 85A)Attorney Docket No. 53210-738601

[0336] \-(( 1 s.4s )-4-(3-(Met hylsulfonyl (propoxy )cyclohexyl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 86A)

[0337] 7V-((lr,4r)-4-(((5)-l,l,l-Trifluoropropan-2-yl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 87A)

[0338] 7V-((lr,4r)-4-((l,l,l-Trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 88A)

[0339] 7V-((ls,4s)-4-(3,3,3-Trifluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 89A)Attorney Docket No. 53210-738601

[0340] A-((lr,4r)-4-(3,3,3-Trifluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 90A)

[0341] 8,ll-Difluoro-V-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-car / >o.xaw«7 / e (Compound 91A)

[0342] (l?)-A-(3,3-Difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 92A)

[0343] (5)-7V-(3,3-Difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine- 10-carboxamide (Compound 93A)Attorney Docket No. 53210-738601

[0344] 8-Chloro-7V-((Ir,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 94A)

[0345] 8,9-Difluoro-7V-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 95A)

[0346] 7V-(3,3-Difluorocyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 96A)

[0347] \-(2.3- Dihydro- 11.41 dioxino [2,3-b] pyridin-7-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 97A)Attorney Docket No. 53210-738601

[0348] \-(4-Methyl-3.4-dihydro-2 / / -pyrido|3.2-b|| 1.4|ox:izin-7-yl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 98A)

[0349] V-(2-(3,3-Difluoroazetidin-l-yl)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 99A)

[0350] 7V-(2-((2,2,2-Trifluoroethyl)amino)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 100A)

[0351] \-( l-Methyl-2.3-dihydro-l / / -pyrido|2.3-b|| l,4]oxazin-7-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 101A)Attorney Docket No. 53210-738601

[0352] \-(2-(3-I'luoropropoxy)pyrimidin-5-yl)-5.6-dihydrobenzo|f|imidazo| 1.5-d][l,4]oxazepine-10-carboxamide (Compound 102A)

[0353] 7V-(2-(3,3-Difluoropropoxy)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 103A)

[0354] 7V-(2-(3,3,3-Trifluoropropoxy)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 104A)

[0355] 7V-((lr,4r)-4-((3,3-Difluoroazetidin-l-yl)methyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 105A)

[0356] V-((lr,4r)-4-((2-(Methylsulfonyl)ethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 106A)Attorney Docket No. 53210-738601

[0357] A-((lr,4r)-4-(3-(Trifluoromethyl)azetidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 107A)

[0358] (l?)-A-(3,3-Difluorocyclopentyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 108A)

[0359] 7V-(2-(2,2,2-Trifluoroethoxy)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 109A)CF3

[0360] 7V-((lr,4r)-4-((3,3,3-Trifluoropropyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 110A)H CF3Attorney Docket No. 53210-738601

[0361] A-((ls,4s)-4-((3,3,3-Trifluoropropyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 111A)

[0362] (l?)-8-Chloro-7V-(3,3-difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 112A)

[0363] A-((lr,4r)-4-(3-(Difluoromethyl)azetidin-l-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 113A)

[0364] 8-Fluoro-7V-((lr,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 114A)Attorney Docket No. 53210-738601

[0365] 8-Fluoro-A-((lr,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 115A)

[0366] ( / ?)- 7V-(3,3-Difluorocyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d] [ l,4]oxazepine- 10-carboxamide (Compound 116A)

[0367] (5)- \-(3.3- Difliioiocycloliexyl )-5.6-diliydiobenzo | f| imidazo [1,5-d] [1,4] oxazepine- 10-carboxamide (Compound 117A)

[0368] 7V-(( 1 s, 4s )-4-(( 1 -(Trifluoromet hyl)cyclopropyl )methoxy )cyclohexyl)-5, 6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 118A)Attorney Docket No. 53210-738601

[0369] A-(4-(2,2,2-Trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 119A)

[0370] 7V-((lr,4r)-4-(3,3,3-Trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 120A)

[0371] 7V-(( 1 s,4s)-4-(3,3,3-Trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 121A)

[0372] \-(( 1 r,4r)-4-(2,2,2-Trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 122A)Attorney Docket No. 53210-738601

[0373] A-((ls,4s)-4-(2,2,2-Trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 123A)

[0374] A-(2-(3-(Difluoromethyl)azetidin-l-yl)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 124A)

[0375] 7V-(4-Ethylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 125A)

[0376] \-(4-( 1 -Hydroxyethyl )cyclohexyl)-5.6-dihydrobenzo | f|iinidazo 11.5-d][l,4]oxazepine-10-carboxamide (Compound 126A)OHAttorney Docket No. 53210-738601

[0377] A-((lr,4r)-4-(2-Methoxy-2-methylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 127A)

[0378] 7V-((ls,4s)-4-(2-Methoxy-2-methylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 128A)

[0379] 8-Chloro-\-(2.3-dihydro-|1.4|dioxino|2.3-b|pyridin-7-yl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 129A)

[0380] ( / ?)-8-I'luoro-\-(tetr:ihydro-2 / / -pyran-3-yl)-5.6-dihydrobenzo|f|iinidazo| 1.5-d][l,4]oxazepine-10-carboxamide (Compound 130A)Attorney Docket No. 53210-738601

[0381] A-((lr,4r)-4-((2-Hydroxy-2-(trifluoromethyl)butyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 131A)CF3H I / OH

[0382] (l?)-V-(l,l-Dioxidotetrahydrothiophen-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 132A)

[0383] 7V-(4-(l,l,l-Trifluoropropan-2-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 133A)

[0384] 8-Chloro-A-(3,3-difluorocyclobutyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 134A)ClAttorney Docket No. 53210-738601

[0385] \-(3.3- Dill uorocy clobu t y I )-8-fl uoro-5.6-d ihy d robenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 135A)

[0386] \-(3-I luoro-3-inet hylcyclobutyl )-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 136A)

[0387] 8-Chloro-A-(4,4-difluorocyclohexyl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 137A)

[0388] 8-Fluoro-7V-(3-fluoro-3-methylcyclobutyl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 138A)Attorney Docket No. 53210-738601

[0389] \-( 2.2- Dili iioi-oc clobii t 1 )-5.6-d ih^d I'obenzo | f] im idazo [ 1.5-d ] [ 1.41 oxazepine- 10-carboxamide (Compound 139A)

[0390] \-( 2.2- Dill uorocy clobu t y I )-8-fl uoro-5.6-d ihy d robenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 140A)

[0391] \-(3.3-Diinethylcyclobutyl)-5.6-dihydrobenzo|f|imidazo| 1,5-d] [ 1,4]oxazepine-l 0-carboxamide (Compound 141A)

[0392] \-(( 1 r,4r)-4-(( 1 -(Trifluoromet hyl)cyclopropyl )methoxy )cyclohexyl)-5, 6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 142A)Attorney Docket No. 53210-738601

[0393] N-(3,3- Dimet hylcyclobutyl )-8-fluoro-5,6-dihydrobenzo [f] imidazo [1,5-d][l,4]oxazepine-10-carboxamide (Compound 143A)

[0394] \-(3-(Methoxymethyl)-2.3-dihydro-| 1.4|dioxino|2.3-b|pyridin-7-yl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 144A)

[0395] \-(2-(Methoxymethyl)-2.3-dihydro-| 1.4|dioxino|2.3-b|pyridin-7-yl)-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 145A)

[0396] 7V-(4-(Methylsulfonyl)cyclohexyl)-5,6-dihydrobenzo[f|imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 146A)Attorney Docket No. 53210-738601

[0397] \-( ( 1 r.4r )-4-( ( 1 s.3s )-3- Fl uorocy clobu t oxy )cy clohexy 1 )-5.6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 147A)

[0398] Az-((lr,4r)-4-((lr,3i')-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 148A)

[0399] 7V-((ls,4s)-4-((ls,3s)-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 149A)

[0400] A-((ls,4s)-4-((lr,3i')-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 150A)

[0401] 7V-(3-(Trifluoromethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 151A)Attorney Docket No. 53210-738601

[0402] N-((1r,4r)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 152A)

[0403] A-((ls,4s)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 153A)

[0404] 7V-(4,4-Difluorocyclohexyl)-8,9-difluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 154A)

[0405] 8-Fluoro-A-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 155A)AO CF3FAttorney Docket No. 53210-738601

[0406] 8-Fluoro-7V-((ls,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 156A)

[0407] 8-Chloro-A-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 157A)<\O CF3

[0408] 8-Chloro-7V-((ls,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 158A)

[0409] 8-Fluoro-N-(spiro[3.3]heptan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 159A)Attorney Docket No. 53210-738601

[0410] 8-Fluoro-A-(2-oxaspiro[3.3]heptan-6-yl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 160A)

[0411] 8-Fluoro-7V-(3-(trifluoromethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 161A)

[0412] 8-Fluoro-7V-(l-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 162A)

[0413] 8-Chloro-7V-(l-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 163A)ClAttorney Docket No. 53210-738601

[0414] 8-Fluoro-7V-(4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 164A)

[0415] 8-Chloro-7V-(4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 165A)

[0416] V-((lr,4r)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 166A)

[0417] 7V-((ls,4s)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 167A)Attorney Docket No. 53210-738601

[0418] 8-Fluoro-N-((1s,4s)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 168A)

[0419] 8-Fluoro-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 169A)

[0420] 8-Chloro-A-((lr,4r)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 170A)

[0421] 8-Chloro-7V-((ls,4s)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 171A)Attorney Docket No. 53210-738601

[0422] A-((lr,4r)-4-(3,3-difluorocyclobutoxy)cyclohexyl)-8-chloro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 172A)

[0423] 7V-((ls,4s)-4-(3,3-difluorocyclobutoxy)cyclohexyl)-8-chloro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]156xazepane-10-carboxamide (Compound 173A)

[0424] 8-Fluoro-V-(frans-2-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 174A)

[0425] 8-Fluoro-7V-(cis-2-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 175A)Attorney Docket No. 53210-738601

[0426] A-(#rans-2-#rans-6-Dimethylcyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 176A)

[0427] V-(frans-2-cis-6-Dimethylcyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 177A)

[0428] 7V-(c / s-2-cis-6-Dimethylcyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 178A)

[0429] 7V-((lr,4r)-4-(2-Methoxyethoxy)cyclohexyl)-8,9-dimethyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 179A)Attorney Docket No. 53210-738601

[0430] 7V-(4,4-Difluorocyclohexyl)-8,9-dimethyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 180A)

[0431] 8-Chloro-A-(3-(trifluoromethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 181A)

[0432] 8-Chloro-A-(2-methyl-4-(2,2,2-trifluoroethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 182A)CF3

[0433] 8-Chloro-A-(2-methyl-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 183A)CF3Attorney Docket No. 53210-738601

[0434] 8-Chloro-V-(c / s-2-methyl-c / s-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 184A)

[0435] 8-Fluoro-7V-(2-methyl-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 185A)CF3

[0436] 8-Fluoro-A-(c / s-2-methyl-c / s-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 186A)

[0437] 8,9-Difluoro-7V-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 187A) / CF3Attorney Docket No. 53210-738601

[0438] 8,9-Difluoro-7V-((ls,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 188A)F

[0439] 8,9-Dimethyl-A-(4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 189A)

[0440] 8-Chloro-A-(4,4-difluorocyclohexyl)-9-methyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 190A)

[0441] 8-Chloro-7V-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-9-methyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 191A)Attorney Docket No. 53210-738601

[0442]

[0443] Compound 1AMe

[0444]

[0445] Compound 2AMe

[0446] Compound 3AFAttorney Docket No. 53210-738601

[0447] Compound 3AMe

[0448] Compound 4AFO II

[0449] Compound 4AMe

[0450] Compound 5AFAttorney Docket No. 53210-738601

[0451] Compound 5AMe

[0452] Compound 6AF

[0453] Compound 6AMe

[0454] Compound 7AF

[0455] Compound 7AMeAttorney Docket No. 53210-738601

[0456] Compound 8AF

[0459] Compound 9AFMe

[0460] Compound 10AFAttorney Docket No. 53210-738601

[0462] Compound 14AF

[0463] Compound 14AMe

[0464] Compound 15AF

[0465] Compound 15AMe

[0466] Compound 17AFAttorney Docket No. 53210-738601

[0467] Compound 17AMeO

[0468] Compound 18AF

[0470] Compound 19AF

[0471] Compound 19AMeAttorney Docket No. 53210-738601

[0472] Compound 20AF

[0473] Compound 20AMe

[0474] Compound 21AF

[0475] Compound 21AMe

[0476] Compound 22AF

[0477] Compound 22AMeAttorney Docket No. 53210-738601

[0478] Compound 23 AF

[0479] Compound 23AMe

[0480] Compound 24AF

[0481] Compound 24AMe

[0482] Compound 25AFAttorney Docket No. 53210-738601

[0484]

[0485] Compound 29AMe

[0486] Compound 30AF

[0487] Compound 30AMe

[0488] Compound 31AFAttorney Docket No. 53210-738601

[0489] Compound 31AMe

[0490] Compound 32AF

[0491] Compound 32AMe

[0492] Compound 33AF

[0493] Compound 33AMe

[0494] Compound 34AFAttorney Docket No. 53210-738601

[0495] Compound 34AMe

[0496] Compound 36AF

[0497] Compound 36AMe

[0498] Compound 37AF

[0499] Compound 37AMeAttorney Docket No. 53210-738601

[0500] Compound 39AF

[0501] Compound 39AMe

[0502] Compound 40AF

[0503] Compound 40AMe

[0504] Compound 41AF

[0505] Compound 41AMeAttorney Docket No. 53210-738601

[0506] Compound 44AF

[0507] Compound 44AMe

[0508] Compound 45AF

[0510] Compound 46AFAttorney Docket No. 53210-738601

[0511] Compound 46AMe

[0512] Compound 47AF

[0514] Compound 48AF

[0516] Compound 49AFAttorney Docket No. 53210-738601

[0517] Compound 49AMe

[0518] Compound 52AF

[0520] Compound 56AF

[0521] Compound 56AMeAttorney Docket No. 53210-738601

[0522] Compound 58AF

[0523] Compound 58AMe

[0524] Compound 59AF

[0526] Compound 60AFAttorney Docket No. 53210-738601

[0527] Compound 60AMe

[0528] Compound 61AF

[0529]

[0530] Compound 62AF

[0531] Compound 62AMeAttorney Docket No. 53210-738601

[0532] Compound 63AF

[0533]

[0534] Compound 64AF

[0535] Compound 64AMe

[0536] Compound 65AFAttorney Docket No. 53210-738601

[0537] Compound 65AMe

[0538] Compound 66AF

[0539] Compound 66AMe

[0540] Compound 67AF

[0541] Compound 67AMeAttorney Docket No. 53210-738601

[0542] Compound 69AF

[0543]

[0544] Compound 71AF

[0545] Attorney Docket No. 53210-738601

[0546] Compound 72AF

[0548] Compound 74AF

[0549] Compound 74AMe

[0550] Compound 75AFAttorney Docket No. 53210-738601

[0551] Compound 75AMeO

[0552] Compound 76AF

[0553] Compound 76AMe

[0554] Compound 77AFAttorney Docket No. 53210-738601

[0556] Compound 78AF

[0558] Compound 79AF

[0560] Compound 80AF

[0561] Compound 80AMeAttorney Docket No. 53210-738601

[0562] Compound 81AF

[0563] Compound 81AMe

[0564] Compound 82AF

[0565] Compound 82AMe

[0566] Compound 83AFAttorney Docket No. 53210-738601

[0567] Compound 83AMe

[0568] Compound 84AF

[0569] Compound 84AMe

[0570] Compound 85AFAttorney Docket No. 53210-738601

[0572] Compound 86AF

[0576] Compound 88AFAttorney Docket No. 53210-738601

[0577] Compound 88AMe

[0578] Compound 89AF

[0579] Compound 89AMe

[0580] Compound 90AF

[0581] Compound 90AMeAttorney Docket No. 53210-738601

[0582] Compound 92AF

[0584] Compound 93AF

[0586] Compound 96AF

[0587] Compound 96AMeAttorney Docket No. 53210-738601

[0588] Compound 98AF

[0589] Compound 98AMe

[0590] Compound 99AF

[0591] Compound 99AMeAttorney Docket No. 53210-738601

[0592] Compound 100AF

[0593]

[0594] Compound 101AF

[0595] Compound 101AMe

[0596] Compound 102AFAttorney Docket No. 53210-738601

[0597] Compound 102AMe

[0598] Compound 103AF

[0599] Compound 103AMe

[0600] Compound 104AF

[0601] Compound 104AMe

[0602] Compound 105AFAttorney Docket No. 53210-738601

[0603] Compound 105AMe

[0604]

[0605] Compound 106AMe

[0606]

[0607] Attorney Docket No. 53210-738601

[0608] Compound 109AF

[0609] Compound 109AMe

[0610] Compound 110AF

[0611] Compound 110AMe

[0612] Compound 111AFAttorney Docket No. 53210-738601

[0613] Compound 111AMe

[0614] Compound 113AF

[0615] Compound 113AMe

[0616] Compound 116AF

[0617] Compound 116AMeAttorney Docket No. 53210-738601

[0618] Compound 117AF

[0619] Compound 117AMe

[0620] Compound 118AF

[0621] Compound 118AMe

[0622] Compound 119AFAttorney Docket No. 53210-738601

[0623] Compound 119AMe

[0624] Compound 120AF

[0627] Compound 121AMeAttorney Docket No. 53210-738601

[0628] Compound 122AF

[0629] Compound 122AMe

[0630] Compound 123AF

[0631] Compound 123AMe

[0632] Compound 124AFAttorney Docket No. 53210-738601

[0633] Compound 124AMe

[0634] Compound 125AF

[0635] Compound 125AMe

[0636] Compound 126AF

[0637] Compound 126AMeAttorney Docket No. 53210-738601

[0638] Compound 127AF

[0640] Compound 128AFAttorney Docket No. 53210-738601

[0643] Compound 131AMe

[0644] Compound 133AF

[0645] Compound 133AMeCF3

[0646] Compound 136AF

[0647] Compound 136AMeAttorney Docket No. 53210-738601

[0648] Compound 139AF

[0649] Compound 139AMe

[0650] Compound 141AF

[0651] Compound 141AMe

[0652] Compound 142AFAttorney Docket No. 53210-738601

[0653] Compound 142AMe

[0654] Compound 144AF

[0655]

[0656] Compound 145AF

[0657] Attorney Docket No. 53210-738601

[0658] Compound 146AF

[0659]

[0660] Compound 147AF

[0661]

[0662] Compound 148AFAttorney Docket No. 53210-738601

[0663] Compound 148AMe

[0664] Compound 149AF

[0665] Compound 149AMe

[0666] Compound 150AF

[0667] Compound 150AMe

[0668] Compound 151AFAttorney Docket No. 53210-738601

[0669] Compound 151AMe

[0670] Compound 152AF

[0672] Compound 153AFAttorney Docket No. 53210-738601

[0674] A-Cyclopentyl-8-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 200A)

[0675] 8-Fluoro-A-((lr,4r)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 201A)

[0676] 7V-(4,4-Difluorocyclohexyl)-9-fluoro-8-methyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 202A)Attorney Docket No. 53210-738601

[0677] 9-Fluoro-A-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-8-methyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 203A)

[0678] 7V-(4,4-Difluorocyclohexyl)-8-fluoro-9-methyl-5,6-dihydrobenzo[f]imidazo[ 1,5-d][l,4]oxazepine-10-carboxamide (Compound 204A)

[0679] 8-Fluoro-7V-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-9-methyl-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 205A)Attorney Docket No. 53210-738601

[0680] \-CycloIiexyl-8-nuoro-5.,6-diliydrobenzo| f|iniidazo| 1.5-d ] 11.4]oxazepine- 10-carboxamide (Compound 206A)

[0681] 8-Chloro-A-(4,4-difluorocyclohexyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 207A)

[0682] (l?)-8-Chloro-7V-(3,3-difluorocyclohexyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 208A)Attorney Docket No. 53210-738601

[0683] 8-Chloro-X-(cyclohexylnielIiyl)-5.,6-diliydrobenzo| f|iniidazo| 1.5-d ] 11.4]oxazepine- 10-carboxamide (Compound 209A)

[0684] 8-Chloro-7V-((4,4-difluorocyclohexyl)methyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 210A)

[0685] (l?)-7V-(3,3-Difluorocyclohexyl)-8,9-difluoro-5,6-dihydrobenzo[f]imidazo[l,5-d][l,4]oxazepine-10-carboxamide (Compound 211 A)Attorney Docket No. 53210-738601

[0686] 8-Chloro-\-(l-cyclohexylethyl)-5.6-dihydrobenzo|l'|imidazo| 1.5-d|| 1.4|oxazepine- 10-carboxamide (Compound 212A)

[0687] 8-Chloro-\-((tetrahydro-2 / / -pyr:in-4-yl)methyl)-5.6-dihydrobenzo|l'|imidazo| 1,5-d][l,4]oxazepine-10-carboxamide (Compound 213A)

[0688] 8-Chloro-\-(l-(tetrahydro-2 / / -pyran-4-yl)ethyl)-5.6-dihydrobenzo|f|imidazo| 1.5-d][l,4]oxazepine-10-carboxamide (Compound 214A)Attorney Docket No. 53210-738601

[0689] 8-Chloro-N-((tetrahydro-2H-pyran-3-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 215A)

[0690] 8-Chloro-7V-((3,3-difluorocyclohexyl)methyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][1,4]oxazepine-10-carboxamide (Compound 216A)

[0691] 8-Chloro-N-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 217A)ClAttorney Docket No. 53210-738601

[0692] 8-Chloro-A-((tetrahydrofuran-2-yl)methyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][1,4]oxazepine-10-carboxamide (Compound 218A)

[0693] 8-Chloro-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 219A)

[0694] 8-Chloro-7V-(oxetan-3-ylmethyl)-5,6-dihydrobenzo[f]imidazo[l,5-d][1,4]oxazepine-10-carboxamide (Compound 220A)ClAttorney Docket No. 53210-738601

[0695] 8-Chloro-N-((tetrahydrofuran-3-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide (Compound 221A)Numbered Embodiments

[0696] The following is a list of non-limiting embodiments provided by the present disclosure:Embodiment 1. A method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a GLP-1 agonist and a CD38 modulator.Embodiment 2. The method of Embodiment 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD) and obesity.Embodiment 3. The method of Embodiment 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatohepatitis (MASH) and obesity.Embodiment 4. The method of Embodiment 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD).Embodiment 5. The method of Embodiment 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASH).Embodiment 6. The method of Embodiment 1, wherein the disease or disorder is obesity. Embodiment 7. The method of any one of Embodiments 1 to 6, wherein a body weight of the subject is reduced by at least about 3%.Embodiment 8. The method of any one of Embodiments 1 to 7, wherein a body weight of the subject is reduced by at least about 10%.Embodiment 9. The method of any one of Embodiments 1 to 8, wherein a body weight of the subject is reduced by at least about 20%.Embodiment 10. The method of any one of Embodiments 1 to 9, wherein a body weight of the subject is reduced by at most about 50%.Embodiment 11. The method of any one of Embodiments 1 to 10, wherein a body weight of the subject is reduced by at most about 40%.Attorney Docket No. 53210-738601Embodiment 12. The method of any one of Embodiments 1 to 11, wherein a body weight of the subject is reduced by about 3% to about 50%.Embodiment 13. The method of any one of Embodiments 1 to 12, wherein a body weight of the subject is reduced by at least about 5 pounds (lbs).Embodiment 14. The method of any one of Embodiments 1 to 13, wherein a body weight of the subject is reduced by at least about 10 pounds (lbs).Embodiment 15. The method of any one of Embodiments 1 to 14, wherein a body weight of the subject is reduced by at most about 250 pounds (lbs).Embodiment 16. The method of any one of Embodiments 1 to 15, wherein the GLP-1 agonist is selected from semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide,Embodiment 17. The method of any one of Embodiments 1 to 15, wherein the GLP-1 agonist is semaglutide.Embodiment 18. The method of any one of Embodiments 1 to 17, wherein the CD38 modulator is a CD38 inhibitor.Embodiment 19. The method of any one of Embodiments 1 to 18, wherein the CD38 modulator is selected from daratumumab, isatuximab, TAK-079, N1 -Inosine 5'- monophosphate (Nl-IMP), and CD38-IN-78c.Embodiment 20. The method of any one of Embodiments 1 to 17, wherein the CD38 modulator is selected from a compound of Formula (II):NR17Formula (II),or a pharmaceutically acceptable salt or solvate thereof; whereintR50Z is selected from R50, wherein t represents the point of connection between Z andY is selected from -O-, -NR9-, -S-, and -SO2-;Attorney Docket No. 53210-738601each R50is independently selected from hydrogen, halogen, and Ci-Ce alkyl; or come together to Oform =O;each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl;k is selected from 1 and 2;A is selected from N and CR18;is selected from an optionally substituted imidazole, wherein the imidazole is optionally substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and Ci-6 alkyl;R7is selected from hydrogen; and Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C 14 carbocycle, and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, wherein the C1-6 alkyl is optionally substituted with one or more R8*, and wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle, and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10Attorney Docket No. 53210-738601alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, and C2-10 alkynyl;each R14is independently selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci- ioalkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -S(O)2(Ci-6 alkyl), C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.Embodiment 21. The method of Embodiment 20, whereinZ is Embodiment 22. The compound or salt of Embodiments 20 or 21, wherein Z isR50Embodiment 23. The method of Embodiment 20, wherein Formula (II) is represented by Formula (II A):Attorney Docket No. 53210-738601Formula (IIA),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 24. The method of Embodiment 20, wherein Formula (II) is represented by Formula (IIB):Formula (IIB),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 25. The method of Embodiment 20, wherein Formula (II) is represented by Formula (IIC):Formula (IIC),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 26. The method of any one of Embodiments 20 to 25, wherein A is selected from N, CF, and CH.Embodiment 27. The method of Embodiment 26, wherein A is CH.Embodiment 28. The method of Embodiment 26, wherein A is N.Embodiment 29. The method of any one of Embodiments 20 to 28, wherein D is selected from N, CF, and CH.Embodiment 30. The method of Embodiment 29, wherein D is CH.Embodiment 31. The method of Embodiment 29, wherein D is N.Embodiment 32. The method of any one of Embodiments 20 to 23, wherein Formula (II) is represented by Formula (IID):R7Attorney Docket No. 53210-738601Formula (IID),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 33. The method of any one of Embodiments 20 to 22 or 24, wherein Formula (II) is represented by Formula (HE):Formula (HE),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 34. The method of any one of Embodiments 20 to 22 or 25, wherein Formula (II) is represented by Formula (HF):Formula (HF),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 35. The method of Embodiment 20, wherein Formula (II) is represented by Formula (HF):Formula (IIG),or a pharmaceutically acceptable salt or solvate thereof.Embodiment 36. The method of any one of Embodiments 20 to 35, wherein R5 is selected from hydrogen and methyl.Embodiment 37. The method of any one of Embodiments 20 to 36, wherein R5 is hydrogen.Embodiment 38. The method of any one of Embodiments 20 to 37, wherein R7is selected from Ce-Cs carbocycle and 5- to 6-membered heterocycle, each of which are optionally substituted with one or more R8.Attorney Docket No. 53210-738601Embodiment 39. The method of any one of Embodiments 20 to 38, wherein R7is selected from Ce-Cs carbocycle, which is optionally substituted with one or more R8.Embodiment 40. The method of any one of Embodiments 20 to 37, wherein R7is selected from C4-C7 carbocycle, which is optionally substituted with one or more R8.Embodiment 41. The method of any one of Embodiments 20 to 40, wherein R7is selectedfrom, which is optionally substituted with one or more R8.Embodiment 42. The method of any one of Embodiments 20 to 41, wherein each R8is independently selected from halogen, C1-6 alkyl, Ci-ehaloalkyl, C1-6 hydroxyalkyl, -OR20, - N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and 4- to 6- membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-10 alkyl, - Ci-iohaloalkyl, and -O-Ci-10 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen.Embodiment 43. The method of any one of Embodiments 20 to 42, wherein each R8isAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Embodiment 45. The method of any one of Embodiments 20 to 40, wherein R7is selected from an optionally substituted phenyl, which is optionally substituted with one or more R8. Embodiment 46. The method of any one of Embodiments 20 to 40 or 45, wherein each R8 is independently selected from halogen, Cl -6 alkyl-N(R20)2, Cl -6 aminoalkyl, Cl -6 hydroxyalkyl, Cl -6 cyanoalkyl, Cl -6 haloalkyl, Cl -6 alkyl.Embodiment 47. The method of Embodiment 45 or 46, wherein R7is selected from phenyl optionally substituted with one or more substituents selected from halogen and Ci-6 hydroxy alkyl.Attorney Docket No. 53210-738601Embodiment 48. The method of Embodiment 47, wherein R7is selected fromEmbodiment 49. The method of any one of Embodiments 20 to 40, wherein R7is, which is optionally substituted with one or more R8.Embodiment 50. The method of any one of Embodiments 20 to 40 or 49, wherein each R8is independently selected from halogen and -S(O)2(R20).Embodiment 51. The method of Embodiments 49 or 50, wherein R7is selectedEmbodiment 52. The method of any one of Embodiments 20 to 37, wherein R7is selected from C9 carbocycle, which is optionally substituted with one or more R8.Embodiment 53. The method of Embodiment 52, wherein R7 is.Embodiment 54. The method of any one of Embodiments 20 to 37, wherein R7 is selected from 5- to 10-membered heterocycle, each of which are optionally substituted with one or more R8.Embodiment 55. The method of Embodiment 54, wherein R7is selected fromNS, each of which are optionally substituted with one or more R8.Embodiment 56. The method of any one of Embodiments 20 to 37, 54, or 55, wherein each R8is independently selected from halogen, -OR20, -N(R20)2, -S(O)2(R20), -C(O)OR20, =0,Attorney Docket No. 53210-738601Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen and -C1-3 haloalkyl.Embodiment 57. The method of any one of Embodiments 20 to 37, 54 to 56, wherein eachR8is independently selected fromAttorney Docket No. 53210-738601Embodiment 59. The method of any one of Embodiments 20 to 38, wherein R7is selected from 5- to 6-membered saturated heterocycle, each of which are optionally substituted with one or more R8.Embodiment 60. The method of any one of Embodiments 20 to 38 or 59, wherein each R8 is independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(0)R20(=NR20), and =0.Embodiment 61. The method of Embodiment 60, wherein each R8 is independently selected from -S(O)2(R20), and =0.Embodiment 62. The method of any one of Embodiments 20 to 38, or 59 to 61, wherein R7Embodiment 63. The method of any one of Embodiments 20 to 38, wherein R7 is selected from an optionally substituted 5- to 6-membered heteroaryl.Embodiment 64. The method of Embodiment 63, wherein R7 is selected from an optionally substituted 6-membered heteroaryl, which is optionally substituted with one or more R8.Embodiment 65. The method of Embodiment 64, wherein R7 is selected from an optionally substituted pyridine, which is optionally substituted with one or more R8.Embodiment 66. The method of any one of Embodiments 20 to 38 or 63 to 65, wherein each R8is independently selected from halogen, -N(R20)2, -OR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -CN, CI-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.Attorney Docket No. 53210-738601Embodiment 67. The method of Embodiment 66, wherein each R8is selected from halogen, -OR20, -CN, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. Embodiment 68. The method of any one of Embodiments 20 to 38 or 63 to 67, wherein R7Embodiment 69. The method of any one of Embodiments 20 to 38, wherein R7is selected from a 6-membered heterocycle, which is optionally substituted with one or more R8. Embodiment 70. The method of Embodiment 69, wherein the 6-membered heterocycle has one nitrogen atom.Embodiment 71. The method of any one of Embodiments 20 to 38, wherein R7 is selected from an 6-membered heteroaryl, which is optionally substituted with one or more R8. Embodiment 72. The method of Embodiment 71, wherein the 6-membered heteroaryl has one nitrogen atom.Embodiment 73. The method of any one of Embodiments 20 to 38 or 69 to 72, wherein each R8 is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(0)R20(=NR20), -CN, Cl -6 alkyl-N(R20)2, Cl -6 aminoalkyl, Cl -6 hydroxyalkyl, Cl -6 cyanoalkyl, Cl -6 haloalkyl, and Cl -6 alkyl.Embodiment 74. The method of any one of Embodiments 20 to 38 or 69 to 73, wherein wherein each R8is independently selected from halogen, -S(O)2(R20), =0, Ci-6 alkyl, and Ci-6 haloalkyl.Attorney Docket No. 53210-738601Embodiment 75. The method of any one of Embodiments 20 to 38 or 69 to 73, wherein R7Xis selected fromO OEmbodiment 76. The method of any one of Embodiments 20 to 37, wherein R7is selected from 9- to 10-membered heterocycle, each of which are optionally substituted with one or more R8;Embodiment 77. The method of Embodiment 76, wherein the 9- to 10-membered heterocycle is bicyclic.Embodiment 78. The method of Embodiments 76 or 77, wherein R7is selected from,with one or more R8. Embodiment 79. The method of any one of Embodiments 20 to 37 or 76 to 78, wherein each R8 is independently selected from halogen, -OR20, -S(O)2(R20), -C(O)OR20, =0, Cl -6 alkyl, and Cl -6 haloalkyl.Embodiment 80. The method of any one of Embodiments 20 to 37 or 76 to 79, wherein each R8 is independently selected from =0, -S(O)2(Cl-6 alkyl), -CF3, -CH3, -C(O)OCl-6alkyl, -OMe, and H ° °Embodiment 81. The method of any one of Embodiments 20 to 37 or 76 to 80, wherein R7Attorney Docket No. 53210-738601Embodiment 82. The method of any one of Embodiments 20 to 31 or 36 to 81, wherein R17is selected from hydrogen, halogen, -OR20, Ci-6 alkyl, Ci-6 haloalkyl, and saturated C3-6 carbocycle.Embodiment 83. The method of any one of Embodiments 20 to 41, wherein R7 isEmbodiment 84. The method of any one of Embodiments 20 to 41 or 83, wherein R7isEmbodiment 85. The method of any one of Embodiments 20 to 41 or 84, wherein R7 isEmbodiment 86. The method of any one of Embodiments 20 to 41 or 84, wherein R7isselected fromAttorney Docket No. 53210-738601Embodiment 87. The method of any one of Embodiments 20 to 41 or 84, wherein R7isEmbodiment 88. The method of any one of Embodiments 20 to 41, 83, or 84, wherein R7is 'Embodiment 89. The method of any one of Embodiments 20 to 41, wherein R7 ishydroxyalkyl, and Ci-6 haloalkyl.Embodiment 90. The method of any one of Embodiments 20 to 41 or 89, wherein R7isEmbodiment 91. The method of any one of Embodiments 20 to 41, wherein R7 is, which is substituted with at least one R8 selected from -S(O)2(R20).Embodiment 92. The method of any one of Embodiments 20 to 41 or 91, wherein R7 isEmbodiment 93. The method of any one of Embodiments 20 to 41, wherein R7is, which is substituted with at least one R8selected from -N(R20)2.Attorney Docket No. 53210-738601Embodiment 94. The method of any one of Embodiments 20 to 41 or 93, wherein R7 isEmbodiment 95. The method of any one of Embodiments 1 to 20, wherein the CD38Attorney Docket No. 53210-738601or a pharmaceutically acceptable salt or solvate thereof.Embodiment 96. The method of any one of Embodiments 1 to 20, wherein the CD38 modulator is selected from:Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601FAttorney Docket No. 53210-738601CF3Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601FAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601a pharmaceutically acceptable salt or solvate thereof.Embodiment 97. The method of any one of Embodiments 1 to 20, wherein the CD38or a pharmaceutically acceptable salt or solvate thereof.Embodiment 98. The method of any one of Embodiments 1 to 20, wherein the CD38 modulator is selected from compounds 22, 23, 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21 A, 22A, 23 A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31 A, 32A, 33 A, 34A, 35A, 36A, 37A, 38A, 39A, 40A, 41 A, 42A, 43 A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55 A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75 A, 76A, 77A, 78A, 79A, 80A, 81 A, 82A, 83 A, 84A, 85 A, 86A, 87A, 88A, 89A, 90A, 91A, 92A, 93 A, 94A, 95A, 96A, 97A, 98A, 99A, 100A, 101A, 102A, 103A, 104A, 105A, 106A, 107A, 108A, 109A, 110A, 111A, 112A, 113A, 114A, 115A, 116A, 117A, 118A, 119A, 120A, 121 A, 122A, 123 A, 124A, 125A, 126A, 127A, 128A, 129A, BOA, 131 A, 132A, 133A, 134A, 135A, 136A, 137A, 138A, 139A, 140A, 141A, 142A, 143A, 144A, 145 A, 146A, 147A, 148A, 149A, 150A, 151 A, 152A, 153 A, 154A, 155 A, 156A, 157A, 158A, 159A, 160A, 161A, 162A, 163A, 164A, 165A, 166A, 167A, 168A, 169A, 170A, 171A, 172A, 173A, 174A, 175A, 176A, 177A, 178A, 179A, 180A, 181A, 182A, 183A, 184A, 185A, 186A, 187A, 188A, 189A, 190A, 191A, 200A, 201A, 202A, 203A, 204A,Attorney Docket No. 53210-738601205A, 206A, 207A, 208A, 209A, 210A, 211 A, 212A, 213A, 214A, 215A, 216A, 217A, 218A, 219A, 220A, 221A, 1AF, 1AMe, 2AF, 2AMe, 3AF, 3 AMe, 4AF, 4AMe, 5AF, 5 AMe, 6AF, 6 AMe, 7AF, 7 AMe, 8AF, 8 AMe, 9AF, 9AFMe, 10AF, 10 AMe, 14AF, 14AMe, 15AF, 15AMe, 17AF, 17AMe, 18AF, 18AMe, 19AF, 19AMe, 20AF, 20AMe, 21AF, 21AMe, 22AF, 22AMe, 23 AF, 23 AMe, 24AF, 24AMe, 25AF, 25AMe, 29AF, 29AMe, 30AF, 30AMe, 31AF, 31 AMe, 32AF, 32AMe, 33AF, 33 AMe, 34AF, 34AMe, 36AF, 36 AMe, 37AF, 37 AMe, 39AF, 39 AMe, 40 AF, 40 AMe, 41AF, 41 AMe, 44 AF, 44AMe, 45AF, 45AMe, 46AF, 46AMe, 47AF, 47 AMe, 48AF, 48AMe, 49AF, 49AMe, 52AF, 52AMe, 56AF, 56AMe, 58AF, 58AMe, 59AF, 59AMe, 60AF, 60AMe, 61AF, 61AMe, 62AF, 62AMe, 63AF, 63AMe, 64AF, 64AMe, 65AF, 65AMe, 66AF, 66AMe, 67AMe, 69AF, 69AMe, 71AF, 71AMe, 72AF, 72AMe, 74AF, 74AMe, 75AF, 75AMe, 76AF, 76AMe, 77AF, 77AMe, 78AF, 78 AMe, 79AF, 79AMe, 80AF, 80AMe, 81AF, 81 AMe, 82AF, 82AMe, 83 AF, 83 AMe, 84AF, 84AMe, 85AF, 85 AMe, 86AF, 86AMe, 87AF, 87AMe, 88AF, 88AMe, 89AF, 89AMe, 90AF, 90AMe, 92AF, 92AMe, 93 AF, 93 AMe, 96AF, 96AMe, 98AF, 98AMe, 99AF, 99 AMe, 100AF, 100AMe, 101AF, lO1AMe, 102AF, 102AMe, 103AF, 103AMe, 104AF, 104AMe, 105AF, 105AMe, 106AF, 106AMe, 107AF, 107AMe, 109AF, 109AMe, 110AF, 110AMe, 111AF, ll1AMe, 113AF, 113AMe, 116AF, 116AME, 117AF, 117AMe, 118AF, 118AMe, 119AF, 119AMe, 120AF, 120AMe, 121AF, 121AMe, 122AF, 122AMe, 123AF, 123AMe, 124AF, 124AMe, 125AF, 125AMe, 126AF, 126AMe, 127AF, 127AMe, 128AF, 128AMe, 131AF, 131AMe, 133AF, 133AMe, 136AF, 136AMe, 139AF, 139AMe, 141AF, 141AMe, 142AF, 142AMe, 144AF, 144AMe, 145AF, 145AMe, 146AF, 146AMe, 147AF, 147AMe, 148AF, 148AMe, 149AF, 149AMe, 150AF, 150AMe, 151AF, 151 AMe, 152AF, 152AMe, 153AF, and 153 AMe. Embodiment 99. The method of any one of Embodiments 1 to 97, further comprising a pharmaceutical composition comprising: the CD38 modulator of any one of Embodiments 21 to 98 and at least one pharmaceutically acceptable excipient.Embodiment 100. The method of any one of Embodiments 1 to 97, further comprising a pharmaceutical composition comprising: the GLP-1 agonist of any one of Embodiments 16 to 17 and at least one pharmaceutically acceptable excipient.EXAMPLES

[0697] The following examples are offered to illustrate, but not to limit the claimed invention. It will be recognized that these preparation methods are illustrative and not limiting. Using the teaching provided herein, numerous other methods of producing the compounds described herein will be available to one of skill in the art.Attorney Docket No. 53210-738601

[0698] Example 1: Evaluating the Effect of Compound 3A Treatment on Metabolic Parameters in DIO Mouse Model

[0699] MATERIALS AND METHODS

[0700] Details of the methods mentioned in the subsequent section of the study plan arefollows.

[0701] TEST COMPOUNDName of TC / TC Code Compound 3ALotNo / Batch No. AJ-0730-013-S5sFormula Weight 385.8 g / molePurity >99% (Corrction factor will not be considered) Storage condition Need to be up-dateHandling Precautions Standard Laboratory Precautions

[0702] REFERENCE COMPOUNDStandard Drug SemaglutideLot No 351495Molecular Weight 4113.64 mole / gPurity 99.84%Storage condition At 4°CHandling Precautions Standard Laboratory Precautions

[0703] VEHICLE DETAILSFor Reference compound: lx PBS, pH 7.4

[0704] FORMULATION DETAILS

[0705] TEST COMPOUNDName Compound 3ADose 50 mg / kg, p.o. BIDDose volume 10 mL / kgType of formulation Suspension in 0.5 % methyl cellulose (4000cp)

[0706] REFERENCE COMPOUNDName SemaglutideDose 0.016 mg / kg, s.c. QDAttorney Docket No. 53210-738601Dose volume 10 mL / kgType of formulation Solution in PBS(Phosphate Buffer Saline

[0707] TEST SYSTEM DETAILSSpecies MiceStrain DIO / C57BL / 6JSex MaleAge / Body weight 18-20 weeks / < 40 gramSource The Jackson LaboratoryNo. of animals 96 (84 + 12 Extra)No. of animals / group 12 (Normal Diet Control: Gl) & 72 (HFD: G2-G7) Total no. of Groups 7

[0708] JUSTIFICATION FOR SELECTION OF TEST SYSTEM

[0709] High fat diet on lean mice were selected as the test system and it is commonly reported in literature for the evaluation of test item for obesity.

[0710] EXPERIMENTAL PROCEDURES

[0711] ANIMAL WELFARE

[0712] All procedures of the present study were be in accordance with the guidelines provided by the Committee of Control and Supervision of Experiments on Animals (CCSEA) as published in The Gazette of India, December 15, 1998. Prior approval of the Institutional Animal Ethics Committee (IAEC) has been obtained. The study procedures and husbandry care of the study animals were performed in compliance with AAALAC (Unit No. 001384) and CCSEA (Reg. No. 2121 / PO / Rc / S / 21 / CPCSEA) norms.

[0713] ANIMAL HUSBANDRYAnimal Room number Animal 3Location Laboratory Animal House, SAI Life Sciences Ltd.HyderabadTemperature 22 ± 3°CHumidity 30 to 70%Lighting (Artificial) The photoperiod was 12 h light and 12 h darkness. Light hours were controlled by an automated system.Housing Three mice per cage were housed together in Sterilized polycarbonate cages after randomization. Cage changing was done twice a week.Feed Standard sterilized Research Diets, Inc. DI 2492 (60kcal% fat) were provided ad libitum.Attorney Docket No. 53210-738601Water Sterilized reverse Osmosis water treated with UV light was provided ad libitum in polycarbonate bottles.Bedding Material Autoclaved com cob was used as a bedding material.Cage enrichment material was used (paper cutting, igloo house etc.) to reduce anxiety.Animal Identification During acclimatization and study period mice were identified by tail marking. The group of mice per cage were identified by cage card information.

[0714] QUARANTINE AND ACCLIMATIZATION

[0715] A total of 84 (12 regular and 72 male diet induce obese mice) were allowed to acclimatize for 1 to 7 days prior to study initiation. During this period, the mice were observed daily for clinical signs, mortality, and morbidity. Mice with any abnormalities or ill health or poor physical condition were excluded from the study.

[0716] ANIMAL RANDOMIZATION

[0717] Male lean mice and DIO mice were randomized based on body weight and fed blood glucose. After randomization, extra animals were used for blank sample preparation or returned to animal facility.

[0718] EXPERIMENTAL DESIGN

[0719] ALLOCATION OF GROUPSRoute of Animal Concentration for administration; Regimen, Numbers Group Treatment Test / ReferenceDosage volume forcompound Male test / Reference compoundNormal Chow +Age- 10 ml / kg p.o,G1 matched healthy 0 mg / ml 1-12 QDcontrols + vehicleG2 HFD + vehicle 0 mg / kg p.o., QD NA 13-24 0.016 mg / kg,G3 HFD + Semaglutide 0.0016 mg / mL 25-36 s.c., QDG4 HFD + Compound 3A 50 mg / kg, p.o. BID 5 mg / mL 37-48 HFD + Semaglutide + 0.016 mg / kg, s.c, QD + 50 0.0016 mg / ml and 5G5 49-60 Compound 3 A mg / kg, p.o. BID mg / mLAttorney Docket No. 53210-738601Route of Animal Concentration for administration; Regimen, Numbers Group Treatment Test / ReferenceDosage volume forcompound Male test / Reference compound0.016 mg / kg, s.c, QD, +Compound 3A for 14 daysHFD + Semaglutide + 0.0016 mg / mL and 5G6 (Semaglutide withdrawl) 61-72 Compound 3 A mg / mLFoil wed by Compound 3 A(50 mg / kg, p.o. BID)0.016 mg / kg, s.c, QD, for 14G7 HFD + Semaglutide 0.0016 mg / ml 73-84 days

[0720] Obesity is a chronic disease that results from an imbalance of endogenous and environmental exposures, such as basal metabolic rate, energy expenditure, and food intake. Excessive caloric intake and energy-dense meals are some of the leading causes of obesity.Surrogate animal models have been developed to study obesity-related complications. A high-fat diet-induced mouse model, which consists of 60 kcal %, to study pathophysiological changes associated with diabetes.

[0721] EXPERIMENTAL PROTOCOL

[0722] Male DIO mice (Diet induced obesity mice Age: 18-20 weeks) were procured from Jackson Laboratory. Mice were fed with normal and high fat diet (60 kcal%) for 14-16 weeks before initiating of experiment. All the animals were allowed to quarantine for 3-7 days and acclimatize for 1 to 7 day prior to experiment initiation. During this period, mice were observed daily once for clinical signs.

[0723] On Day 0, Animals were randomized based on body weight and blood glucose levels.

[0724] G1 was fed with normal control diet, while G2 to G7 were given with HFD ad libitum for the study duration of 28 days. Treatment schedule was followed for mice in the groups G1 to G7, as shown in the table above.

[0725] OBSERVATIONS

[0726] CLINICAL SIGNS & MORTALITY

[0727] Mice were observed daily for any clinical signs to treatment throughout the study. Cage-side observations were made to detect any changes and general activity of the animals. After dose application, all the mice were observed carefully for treatment related clinical signs, including morbidity and mortality.Attorney Docket No. 53210-738601

[0728] BODY WEIGHT

[0729] Body weight was measured weekly thrice during the study period. Body weight of mice under various treatment schedules are shown in FIG. 1 and Table 1. G1 for 28 days showed significant decrease in body weight compared to G2 from Day 1 onwards. G3 for 28 days showed significant decrease in body weight compared to G2 from day 9 onwards. G4 for 28 days showed significant decrease in body weight compared to G2 from day 9 onwards. G5 for 28 days showed a significant decrease in body weight compared to G2 from Day 5 onwards. G6 showed significant decrease in body weight compared to G2 from day 5 onwards. G7 showed significant decrease in body weight compared to G2 from day 9-16 and day 21-26. Change in body weight of mice under various treatment schedules are shown in FIG. 2 and Table 2. G1 for 28 days did not show significant change in % change body weight compared to G2. G3 for 28 days showed significant decrease in % change body weight compared to G2 from day 5 onwards. G4 for 28 days showed significant decrease in % change body weight compared to G2 from day 7 onwards. G5 for 28 days showed significant decrease in % change body weight compared to G2 from day 2 onwards. G6 showed significant decrease in % change body weight compared to G2 from day 2 onwards. G7 showed significant decrease in % change body weight compared to G2 from day 5 onwards. Data for FIGS. 1-2 and Tables 1-2 are shown as Mean ± S. E. M.(n= 12). * Significant difference as compared to G2, HFD + Vehicle (10 ml / kg,p.o.; BID) Control group. Two-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05,**P < 0.01,***P < o. OOl & ****p < 0.0001. As shown in FIG. 1, there is an increase in body weight loss when administering both semaglutide and compound 3 A.

[0730] Table 1. Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on Body Weight (g)Treatment Groups Body Weight (g) -Day 28G1 28.9 ± 0.4****G2 48.5 ± 1.4G3 39.2 ± 1.6****G4 40.2 ± 1.3***G5 31.5 ± 0.8****G6 38.3 ± 1.5****G7 44 8 ± 1 i****

[0731] Table 2. Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on % change in body weight (g).Treatment Groups % change in Body Weight (g) -Day 28G1 4.2 ± 1.1G2 4.3 ± 1.5Attorney Docket No. 53210-738601G3 -17.5 ± 1.9***G4 -13 3 ± 1 9****G5 -33 2± 1 4****G6 -18 i 24****G7.3 6 ± 1 7****

[0732] The effect of Compound 3 A in Diet Induced Obesity (DIO) Male Mouse Model on Dual Energy X-Ray Absorptiometry (DEXA) Scan measured by Fat mass (g), Lean +BMC (g), and % Lean Mass is shown in Table 3. DEXA scans were collected on day 27 of the study.

[0733] DEXA Scan Procedure: Rapid and accurate measures of fat and lean mass were carried out in isoflurane-anesthetized mice / rat, using a iNSiHT -OSTEOSYS dual energy X-ray absorptiometry (DEXA) device. Lean Mass, total bone mineral density (BMD, in gm / cm2) and bone mineral content (BMC, in mg) values were obtained automatically. (1.1) Switch on the instrument before 30 minutes of experiment initiation. (1.2) Calibrate the instrument with specimen provided by Osteosys. (1.3) Anesthetize animals using 2-4% isoflurane in O2 by inhalation. (1.4) Monitor animal - Anesthesia was assessed by response to toe and tail pinch, with lack of response indicative of adequate anesthesia. (1.5) Assuring that the animal’s spine is fully extended (gentle pull) and record measurement. (2.1) Place unconscious mouse on the specimen tray on the DEXA analyzer. Mice / Rat should be positioned with the legs slightly outstretched and the soles of the feet down as best possible.; the tail may be included by curling the tail around left side of mouse / rat toward the head or it can be left straight and excluded from the analysis. (2.2) Make sure the spine is in a straight line. Its nose should be positioned with head to the left (as looking at the machine). The mouse should be as flat as possible with the spine fully extended. (2.3) Enter subject ID i.e Animal i.d, gender, age and study number and start scan. When the first image of the mouse appears on the computer screen, ensure it is positioned correctly for the scan, with all limbs and body proper in the field. If not, stop the run, re-position the mouse, and re-start. (2.4) While the 1st measurement is being scanned, start to anesthetize the next mouse / rat. The DEXA scan will take about 2-3 minutes to run the full scan. Once scan is complete, return mouse to its home cage and monitor its recovery over 1 hr. (3.1) Later, the image files were processed to exclude the head region depending on requirement. Within the iNSiHT -OSTEOSYS software, this was accomplished by adjusting the placement of the green circle which removes the region from analysis. (3.2) The scanned data was then reprocessed and can be exported for further analysis. The standard data reported are shown below. Bone area measurement was generated by outlining or specifying the limits or dimensions of the entire skeletal bone regions of the body (limbs, neck, spine, and tail), excluding the head, as regions of interest (ROI) following a full body X-ray scan. (3.3) BoneAttorney Docket No. 53210-738601mineral content (BMC) is generated from iNSiHT -OSTEOSYS density scans which are assessed for accuracy using a set of 0.0 mg to 2,000 mg of hydroxyapatite standards. (3.4) BMD = BMC Bone area Lean body. (3.5) Lean Mass (non-fat) tissue weight = (Total body tissue weight - body fat weight) (3.6) Body fat tissue weight = (Total body tissue weight - lean body tissue weight). (3.7) Total body tissue weight = (BMC + Body fat tissue weight + Lean body tissue weight) Data collected units Body Composition (% fat) Lean and Fat tissue mass (g) Bone mineral density (BMD) (g / cm2 ) Bone mineral Content (BMC) (mg) Bone area (cm2)

[0734] For Fat Mass (g): Gl, G3, G4, G5, and G6 treatment groups showed significant decrease in Fat mass (g) whereas G7 did not show treatment effect on fat mass (g) on day 27 compared to G2.

[0735] For % Lean Mass: Gl, G4, G5, and G6 treatment groups showed significant decrease in % lean mass whereas G3 and G7 did not show treatment effect on % lean mass on day 27 compared to G2.

[0736] Data for Table 3 is shown as Mean ± S. E. M.(n= 12). * Significant difference as compared to G2, HFD + Vehicle (10 ml / kg,p.o.; BID) Control group. One-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05,**P < 0.01,***P < 0.001 & ****p < 0.0001.

[0737] Table 3. Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on DEXA Scan - Fat Mass(g)Treatment Groups Fat Mass(g) Lean± BMC (g) %Lean Mass Gl 5.28 ± 0.38**** 23.57 ± 0.51**** 78.51 ± 1.51* G2 11.93 ± 0.61 36.66 ± 0.83 74.51 ± 0.66 G3 8.24 ± 0.84**** 31.09 ± 0.84*** 78.13 ± 1.32 G4 8.19 ± 0.43**** 31.91 ± 0.96** 78.27 ± 0.63* G5 4.78 ± 0.29**** 26.12 ± 0.73**** 82.46 ± 0.85**** G6 7.20 ± 0.53**** 30.89 ± 0.93** 79.74 ± 0.75** G7 9.90 ± 0.53 34.54 ± 0.68 76.58 ± 0.76

[0738] The effect of Compound 3 A in DIO male mouse model on organ weight (brain, heart, liver, epididymal fat, and inguinal fat (g) were studied and is shown in Table 4. After overnight fasting, animals were sacrificed on day 36, at the end of the study period. Fat Pad such as Epididymal fat, Inguinal fat, Vital organs (Heart, Liver), Skeletal muscle was collected and weights were recorded. The tissue was split into 2 aliquots: one aliquot was fixed in 10% formalin for histopathology (e.g., H& E staining for NASH score determination, Oil O RedAttorney Docket No. 53210-738601Staining for Hepatic Lipid Accumulation score determination), the other aliquot was snap frozen for further analysis.

[0739] Brain weight (g) results: Gl, G3, G4, G5, G6, and G7 did not show treatment effect on brain weight on day 37 compared to G2.

[0740] Heart weight (g) results: Gl, G5 showed significant decrease in heart weight whereas G3, G4, G6, and G7 did not show treatment effect on heart weight (g) on day 37 compared to G2.

[0741] Liver weight (g): Gl, G3, G4, G5, and G6 treatment groups showed significant decrease in liver weight (g) whereas G7 did not show treatment effect on liver weight (g) on day 37 compared to G2.

[0742] Epididymal fat weight (g) results: Gl, G3, G4, G5, G6, and G7 treatment groups showed significant decrease in epididymal fat weight (g) effect on liver weight (g) on day 37 compared to G2.

[0743] Inguinal fat weight (g) results: Gl, G3, G4, G5, and G6 treatment groups showed significant decrease in inguinal fat weight (g) whereas G7 did not show treatment effect on liver weight (g) on day 37 compared to G2.

[0744] Data for Table 4 is shown as Mean ± S. E. M.(n= 12). * Significant difference as compared to G2, HFD + Vehicle (10 ml / kg,p.o.; BID) Control group. One-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05,**P < 0.01,***P < 0.001 & ****p < 0.0001.Table 4: Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on Brain, Heart, Liver, Epididymal Fat weight, Inguinal Fat Weight (g).Treatment Brain (g) Heart (g) Liver (g) Epididymal Inguinal Groups Fat (g) Fat (g)0.016± 0.005± 0.042± 0.012± 0.024± Gl0.000 0.000* 0.001**** 0.002**** 0.002**** 0.010± 0.004± 0.040± G2 0.037± 0.002 0.043± 0.0040.000 0.000 0.002 0.012± 0.004± 0.032± 0.034± 0.030± G30.000 0.000 o ooi**** 0.006**** 0.002** 0.012± 0.004± 0.032± 0.038± 0.035± G40.000 0.000 o ooi**** 0.006"* 0.002* 0.015± 0.004± 0.034± 0.018± 0.021± G50.000 0.000** 0.000**** 0.002**** 0.002**** 0.013± 0.004± 0.034± 0.029± 0.031± G60.001 0.000 0.002**** 0.004*** 0.002*Attorney Docket No. 53210-7386010.010± 0.003± 0.040± 0.031± G7 0.035± 0.0010.000 0.000 0.005" 0.002

[0745] The effect of Compound 3 A in Diet Induced Obesity (DIO) Male Mouse Model on Liver-NASH Score in shown in Table 5.

[0746] Hematoxylin and Eosin (H& E) Staining: Mouse liver tissues were collected immediately after euthanasia and rinsed in cold phosphate-buffered saline (PBS) to remove residual blood. For histological evaluation, a portion of the liver was fixed in 10% neutral buffered formalin for 24-48 hours, processed, and embedded in paraffin. Sections of 4-5 pm thickness were prepared for hematoxylin and eosin (H& E) staining. Paraffin-embedded liver sections were deparaffinized in xylene and rehydrated through graded ethanol series. Sections were stained with hematoxylin for nuclear visualization, followed by eosin for cytoplasmic and extracellular matrix contrast. Slides were dehydrated, cleared, and mounted using a resinous medium. H& E-stained sections were examined under light microscopy for general histopathology and NAS scoring.

[0747] Histological grading was performed according to the NASH Clinical Research Network criteria: Steatosis: Evaluated at 100x-200x magnification in 5-10 fields and scored as 0 (<5%), 1 (5-33%), 2 (34-66%), or 3 (>66%). Lobular Inflammation: Assessed at 200x magnification in 5-10 lobular fields (excluding portal areas) and scored as 0 (none), 1 (<2 foci per 200x field), 2 (2-4 foci), or 3 (>4 foci). Hepatocellular Ballooning: Evaluated at 400x magnification in 5-10 high-power fields and scored as 0 (none), 1 (few ballooned hepatocytes), or 2 (many ballooned hepatocytes with prominent cytoplasmic clearing and rounding). The total NAS score (0-8) was calculated by summing steatosis, inflammation, and ballooning scores: Feature Score Range DescriptionSteatosis 0 <5%1 5-33%2 34-66%3 >66%Lobular Inflammation 0 None1 <2 foci2 2-4 foci3 >4 fociHepatocellular Ballooning 0 None1 Few ballooned hepatocytes2 Many ballooned hepatocytesAttorney Docket No. 53210-738601Total NAS Score 0-8(Sum of steatosis, inflammation,and ballooning scores)

[0748] As compared to G2: G1 treatment group showed a significant difference in Liver-NASH score, G3, G4, G5, and G6 treatment groups also showed significant difference in Liver-NASH score, and G7 did not show significant change in Liver-NASH score on day 37. G6 showed that even after discontinuation of Semaglutide, per the treatment plan, a lower NASH score was found compared to G2, G3, and G7.Table 5: Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on Liver-NASH Score.Treatment Groups NASH ScoreG1 0.00 ± 0.00G2 5.42 ± 0.45G3 2.00 ± 0.37G4 2.67 ± 0.41G5 0.00 ± 0.00G6 0.75 ± 0.30G7 5.17 ± 0.34

[0749] The effect of Compound 3 A in Diet Induced Obesity (DIO) Male Mouse Model on Hepatic Lipid Accumulation Score is shown in Table 6.

[0750] Oil Red O Staining and Quantification: Mouse liver tissues were collected immediately after euthanasia and rinsed in cold phosphate-buff ered saline (PBS) to remove residual blood. For histological evaluation, a portion of the liver was fixed in 10% neutral buffered formalin for 24-48 hours, processed, and embedded in paraffin. For lipid visualization, fresh liver tissue was snap-frozen in optimal cutting temperature (OCT) compound and stored at -80°C. Cryosections of 8-10 pm thickness were obtained for Oil Red O staining. Frozen liver sections were air-dried, fixed in 10% formalin for 10 minutes, and rinsed with distilled water. Sections were incubated in freshly prepared Oil Red O working solution (0.5% Oil Red O in isopropanol diluted with water at 3:2 ratio) for 10-15 minutes at room temperature. Excess stain was removed by rinsing in 60% isopropanol, followed by counterstaining with hematoxylin. Slides were mounted using aqueous mounting medium. Image Analysis: Oil Red O-stained sections were imaged at 100* magnification using a bright-field microscope. Lipid dropletAttorney Docket No. 53210-738601accumulation was quantified using image analysis software (e.g., ImageJ). The percentage of hepatocytes containing lipid droplets was calculated across 5-10 randomly selected nonoverlapping fields. Steatosis was scored as follows:Score Droplets of Lipid in Hepatocytes0 <5%1 5-33%2 34-66%3 >67%

[0751] Gl, G3, G4, G5, and G6 treatment groups showed significant difference in hepatic lipid accumulation score whereas G7 did not show significant change in hepatic lipid accumulation score on day 37 compared to G2.

[0752] Data is shown as Mean ± S. E. M.(n= 12). * Significant difference as compared to G2, HFD + Vehicle (10 ml / kg,p.o.; BID) Control group. One-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05,**P < 0.01,***P < 0.001 & ****p < 0.0001.Table 6: Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on Hepatic Lipid Accumulation Score.Hepatic LipidTreatment GroupsAccumulation ScoreGl 0.00 ± 0.00****G2 2.67 ± 0.19G3 1.33 ± 0.33"G4 1.50 ± 0.26"G5 0.00 ± 0.00****G6 1.00 ± 0.39****G7 2.580.19

[0753] The effect of Compound 3 A in Diet Induced Obesity (DIO) Male Mouse Model on Fasted Plasma Liver Enzyme levels (mg / dL) is shown in Table 7.

[0754] Alanine Aminotransferase (ALT - U / L): Gl, G3, G4, G5, and G6 treatment groups showed significant decrease in Fasted Plasma Alanine Aminotransferase (ALT-U / L) whereas G7 did not show treatment effect on Fasted Plasma Alanine Aminotransferase (ALT-U / L) on day 37 compared to G2.Attorney Docket No. 53210-738601

[0755] Aspartate Transaminase (AST - U / L): Gl, G3, G4, G5, and G6 treatment groups showed significant decrease in Fasted Plasma Aspartate transaminase (AST-U / L) whereas G7 did not show treatment effect on Fasted Plasma Aspartate transaminase (AST-U / L)on day 37 compared to G2.

[0756] Data is shown as Mean ± S. E. M.(n= 12). * Significant difference as compared to G2, HFD + Vehicle (10 ml / kg,p.o.; BID) Control group. One-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05,**P < 0.01,***P < 0.001 & ****p < 0.0001.Table 7. Effect of Compound 3A in Diet Induced Obesity (DIO) Male Mouse Model on Fasted Plasma Liver Enzyme levels (mg / dL).TreatmentPlasma ALT (U / L) Plasma AST (U / L)GroupsGl 52.27± 14.72**** 127.98± 37.24****G2 191.65 ± 20.71 230.85 ± 16.29G3 60.64 ± 6.10**** 155.58 ± 20.73****G4 61.04 ± 8.16**** 131.25 ± 11.70****G5 33.13 ± 3.91**** 83.19 ± 5.07****G6 69.01 ± 12.90**** 133.51 ± 20.71****G7 193.55 ± 24.10 199.22 ± 23.89

[0757] EVALUATION AND INTERPRETATION OF RESULTS

[0758] All data was expressed as the mean ± SEM. Data on each parameter was summarized in tabular form. Appropriate graphical representation was done using suitable method.Statistical analysis was done with GraphPad Prism-9 using one way ANOVA followed by Dunnett’s test / Tukey’s post hoc test and / or two-way ANOVA followed by Bonferroni post hoc test. Data was considered statistically significant if P value is less than 0.05.

[0759] DATA ANALYSIS AND REPORT PREPARATION

[0760] All the observations were systematically recorded, with individual records being maintained for each mouse. Individual data was summarized in terms of the group. Deviations (if any) to the study plan were documented, acknowledged by the Study Director and maintained with the raw data.

[0761] Example 2: Chemical Synthesis - General analytical methods

[0762] General analytical methods

[0763] 1H,13C and19F NMR analyses were conducted on a JEOL ECZ400s 400 MHz NMR spectrometer using deuterated dimethyl sulfoxide or deuterated acetonitrile as solvent. The shiftAttorney Docket No. 53210-738601(5) of each signal was measured in parts per million (ppm) relative the residual solvent peak, and the multiplicity reported together with the associated coupling constant (J), where applicable.

[0764] Example 3: Waters Acquity UPLC-MS Analysis Methodology

[0765] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.

[0766] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v / v) MeCN in water. The resulting solutions were then filtered through a 0.2 pm syringe filter before submitting for analysis. All the solvents, including 36% ammonia solution, were purchased as the HPLC grade.

[0767] Specific differences between methods are as follows:

[0768] Basic 2 min

[0769] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50 °C; sample manager 20 °C; injection volume 2 pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH Cl 8 column (2.1 x 50 mm, 1.7 pm).Time (min) Eluent A (%) Eluent B (%)0.00 95 50.25 95 51.25 5 951.55 5 951.65 95 52.00 95 5

[0770] Basic 4 min

[0771] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50 °C; sample manager 20 °C; injection volume 2 pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH Cl 8 column (2.1 x 50 mm, 1.7 pm).Time (min) Eluent A (%) Eluent B (%)0.00 95 5Attorney Docket No. 53210-7386010.25 95 52.75 5 953.25 5 953.35 95 54.00 95 5

[0772] Basic 6 min

[0773] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50 °C; sample manager 20 °C; injection volume 2 pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH Cl 8 column (2.1 x 50 mm, 1.7 pm).Time (min) Eluent A (%) Eluent B (%)0.00 95 50.30 95 56.00 5 956.10 95 57.00 95 5Example 4: Synthesis of CD38 Modulator Compounds

[0774] General Schemes

[0775] Synthetic scheme I

[0776] The previously reported lithium carboxylate salts as described in PCT / US24 / 26107 can be coupled with corresponding amines using TCFH / NMI amide coupling conditions to generate the final synthetic compounds (e.g., compounds 200A-221A and 5AF, and also 1AF, 1AMe, 2AF, 2AMe, 3AF, 3 AMe, 4AF, 4AMe, 5 AMe, 6AF, 6AMe, 7AF, 7 AMe, 8AF, 8AMe, 9AF, 9AFMe, 10AF, lOAMe, 14AF, 14AMe, 15AF, 15AMe, 17AF, 17AMe, 18AF, 18AMe, 19AF, 19AMe, 20AF, 20AMe, 21AF, 21AMe, 22AF, 22AMe, 23 AF, 23 AMe, 24AF, 24AMe, 25AF, 25AMe, 29AF, 29AMe, 30AF, 30AMe, 31AF, 31 AMe, 32AF, 32AMe, 33AF, 33AMe, 34AF, 34AMe, 36AF, 36AMe, 37AF, 37AMe, 39AF, 39AMe, 40AF, 40AMe, 41AF, 41AMe, 44AF, 44AMe, 45AF, 45AMe, 46AF, 46AMe, 47AF, 47AMe, 48AF, 48AMe, 49AF, 49AMe,Attorney Docket No. 53210-73860152AF, 52AMe, 56AF, 56AMe, 58AF, 58AMe, 59AF, 59AMe, 60AF, 60AMe, 61AF, 61AMe, 62AF, 62AMe, 63AF, 63AMe, 64AF, 64AMe, 65AF, 65AMe, 66AF, 66AMe, 67AMe, 69AF, 69AMe, 71AF, 71AMe, 72AF, 72AMe, 74AF, 74AMe, 75AF, 75AMe, 76AF, 76AMe, 77AF, 77AMe, 78AF, 78AMe, 79AF, 79AMe, 80AF, 80AMe, 81AF, 81AMe, 82AF, 82AMe, 83 AF, 83AMe, 84AF, 84AMe, 85AF, 85AMe, 86AF, 86AMe, 87AF, 87AMe, 88AF, 88AMe, 89AF, 89AMe, 90AF, 90AMe, 92AF, 92AMe, 93 AF, 93AMe, 96AF, 96AMe, 98AF, 98AMe, 99AF, 99AMe, 100AF, 100AMe, 101AF, lO1AMe, 102AF, 102AMe, 103 AF, 103AMe, 104AF, 104AMe, 105AF, 105AMe, 106AF, 106AMe, 107AF, 107AMe, 109AF, 109AMe, 11 OAF, 110AMe, 111AF, ll1AMe, 113AF, 120AMe, 121AF, 121AMe, 122AF, 122AMe, 123 AF, 123AMe, 124AF, 124AMe, 125AF, 125AMe, 126AF, 126AMe, 127AF, 127AMe, 128AF, 128AMe, 131AF, 131AMe, 133AF, 133AMe, 136AF, 136AMe, 139AF, 139AMe, 141AF, 141AMe, 142AF, 142AMe, 144AF, 144AMe, 145AF, 145AMe, 146AF, 146AMe, 147AF, 147AMe, 148AF, 148AMe, 149AF, 149AMe, 150AF, 150AMe, 151AF, 151AMe, 152AF, 152AMe, 153AF, and 153AMe). Exemplary CD38 modulators (e.g., compounds 22, 23, and 1A-191 A) have been prepared and tested as described in PCT / US24 / 26107.113AMe, 116AF, 116AME, 117AF, 117AMe, 118AF, 118AMe, 119AF, 119AMe, 120AF,

[0777] Synthetic scheme IIB2pin2O Pd(dppf) O O [PY ^OMe1^0^ OMe H2O2r HMTABr^^y R Dioxane Bpin^T R Dioxane HO^T RTFA*R R RR R R

[0778] First the corresponding aromatic bromide is converted into the pinacol boron ester using Pd(dppf) and KO Ac. This crude compound is immediately converted to the phenol using hydrogen peroxide as the oxidant. The phenol is formylated using HMTA and TFA, hydrolysing with water. The resulting aldehyde is condensed with ethanolamine to generate the required imine. This is then reacted with Tosmic to produce the substituted imidazole compound.Mitsunobu of the phenol and alcohol tether using triphenylphosphine generates the oxazepine.Attorney Docket No. 53210-738601This is saponified with lithium hydroxide to generate the corresponding lithium carboxylate salt. This can then be coupled with desired amines using amide coupling conditions to generate the final synthetic compounds.

[0779] General Procedures

[0780] General Procedure A

[0781] 1 -Methylimidazole (3.5 - 4.5 eq.) was added to a suspension of lithium carboxylate salt (1 eq.), corresponding amine or amine hydrochloride (1.1 - 1.4 eq) and chloro- N, N', N'-tetramethylformamidinium hexafluorophosphate (2.2 eq) in MeCN (2 ml) and stirred at 25 °C for 16 h. The crude mixture was diluted with water (10 vol.) and if precipitation occurred the solid was filtered and washed with water to yield the desired product. If precipitation did not occur the solution was extracted with ethyl acetate (2 x 10 vol.). The combined organic layers were washed with brine (15 vol.), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude product. This was purified by reverse phase column chromatography over C18 eluting with a gradient of MeCN (0.1% NH3) (5% to 95%; v / v) in water (0.1% NH3), with further purification by preparative HPLC if necessary, to afford the desired product.

[0782] General Procedure B

[0783] Dichloro[l, T-bis(diphenylphosphino)ferrocene]palladium(II) (10 mol%) was added to a sparged suspension of corresponding bromide (1.0 eq.), bis(pinacolato)diboron (1.5 eq.) and potassium acetate (3.0 eq.) in 1,4-dioxane (0.2 mmol) and heated at 80 °C for 18 h. This was filtered through celite and diluted with water (25 mL). This was extracted with EtOAc (25 mL x 2). The combined organic layers were dried (Na2SC>4), filtered and concentrated under reduced pressure to give crude borate ester as a brown oil which was directly in the next step without charactisation assuming 100% conversion. The ester was re-dissolved in 1,4-dioxane (0.2 mmol) and hydrogen peroxide (35 wt.% in water, 4.0 eq.) was added dropwise and stirred for 1 - 3 h at rt. This was quenched with sat. aq. sodium metabisulfite (0.5 - 1 mL) and stirred for 30 minutes. This was concentrated under reduced pressure to give crude product. This was purified by column chromatography over C18 eluting with a gradient of MeCN (0.1% formic acid) (5% to 95%; v / v) in water (0.1% formic acid) to afford the desired product.

[0784] General Procedure C

[0785] Hexamethylenetetramine (2.0 - 4.6 eq.) was added to a suspension of corresponding phenol (1.0 eq.) and trifluoroacetic acid (5.0 - 12.0 mL) and the mixture heated at 73 °C for 1 -48 h. This was cooled to rt and water (minimum of 6x volume of TFA) was slowly added before stirring at rt for 1 h. This was cooled and the resulting precipitate filtered and dried, with further purification by normal phase chromatography over silica where necessary, to afford the desired product.Attorney Docket No. 53210-738601

[0786] General Procedure D

[0787] Ethanolamine (1.0 eq.) and aldehyde (1.0 eq.) were dissolved in methanol (0.1 - 0.2 mmol) and stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the desired product which was used directly in the next step.

[0788] General Procedure E

[0789] To a suspension of corresponding imine (1.0 eq.) and potassium carbonate (2.2 eq.) in DME and methanol (~5:3 ratio, 0.1- 1.0 mmol) was added 4-toluenesulfonylmethylisocyanide (1.2 eq.) portionwise and stirred for 18 h. The reaction was directly loaded onto an appropriately sized SCX-2 cartridge. The cartridge was washed with methanol (2 CV), then the compound was eluted with 2 M ammonia in methanol (2 CV). The eluent was concentrated to dryness under reduced pressure, with further purification by normal phase chromatography over silica or reverse phase column chromatography over Cl 8 where necessary (in some cases trituration from DMSO / water was also possible) to afford the desired product.

[0790] General Procedure F

[0791] To a solution of corresponding phenol (1.0 eq.) and triphenylphosphine (1.2 eq.) in THF (0.05 - 0.2 mmol) was added diisopropyl azodicarboxylate (1.5 eq.) and stirred for 18 - 80 h. Additional reagents, (0.5 eq.) and (0.6 eq.) respectively, were added if reaction was observed to have stalled after 18 h. The reaction was directly loaded onto an appropriately sized SCX-2 cartridge. The cartridge was washed with methanol (2 CV), then the compound was eluted with 2 M ammonia in methanol (2 CV). The eluent was concentrated to dryness under reduced pressure, with further purification by trituration from DMSO / water or diethyl ether or purification by normal / reverse chromatography to afford the desired product.

[0792] General Procedure G

[0793] A solution of lithium hydroxide monohydrate (1.0 - 1.05 eq.) in water (0.5 - 2 mL) was added to a suspension of corresponding ester (1.0 eq.) in tetrahydrofuran (2 - 6 mL) and stirred at rt for 18 h. If reaction had stalled further lithium hydroxide monohydrate (0.1 eq.) was added and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to afford the desired product which was used directly in further transformations with no further purification.Attorney Docket No. 53210-738601

[0794] Example 5: Synthesis of intermediates

[0795] Methyl 2-fluoro-4-hydroxy-3-methylbenzoate

[0796] Prepared from methyl 4-bromo-2-fluoro-3 -methylbenzoate according to General Procedure B to afford the des...

Claims

Attorney Docket No. 53210-738601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a GLP-1 agonist and a CD38 modulator.

2. The method of claim 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD) and obesity.

3. The method of claim 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatohepatitis (MASH) and obesity.

4. The method of claim 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASLD).

5. The method of claim 1, wherein the disease or disorder is selected from metabolic dysfunction associated steatotic liver disease (MASH).

6. The method of claim 1, wherein the disease or disorder is obesity.

7. The method of any one of claims 1 to 6, wherein a body weight of the subject is reduced by about 3% to about 50%.

8. The method of any one of claims 1 to 7, wherein a body weight of the subject is reduced by at least about 5 pounds (lbs).

9. The method of any one of claims 1 to 8, wherein a body weight of the subject is reduced by at most about 250 pounds (lbs).

10. The method of any one of claims 1 to 9, wherein the GLP-1 agonist is selected from semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide,11. The method of any one of claims 1 to 10, wherein the GLP-1 agonist is semaglutide.

12. The method of any one of claims 1 to 9, wherein the GLP-1 agonist is orforglipron.

13. The method of any one of claims 1 to 12, wherein the CD38 modulator is a CD38 inhibitor.

14. The method of any one of claims 1 to 13, wherein the CD38 modulator is a small molecule.

15. The method of any one of claims 1 to 13, wherein the CD38 modulator is selected from daratumumab, isatuximab, TAK-079, N1 -Inosine 5'-monophosphate (Nl-IMP), and CD38- IN-78c.

16. The method of any one of claims 1 to 14, wherein the CD38 modulator is MK-0159.

17. The method of any one of claims 1 to 14, wherein the CD38 modulator is selected from a compound of Formula (II):Attorney Docket No. 53210-738601Formula (II),or a pharmaceutically acceptable salt or solvate thereof; whereint vp51 / VR50^— YZ is selected fromR50, wherein t represents the point of connection between Z andY is selected from -O-, -NR9-, -S-, and -SO2-;each R50is independently selected from hydrogen, halogen, and Ci-Ce alkyl; or come together to Oform =O;each R51is independently selected from hydrogen, halogen, and Ci-Ce alkyl;k is selected from 1 and 2;A is selected from N and CR18;is selected from an optionally substituted imidazole, wherein the imidazole is optionally substituted with one or more R14;D is selected from N and CR19;R5is selected from hydrogen and C1-6 alkyl;R7is selected from hydrogen; and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-C 14 carbocycle, and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8;each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, wherein the C1-6 alkyl is optionally substituted with one or more R8*, andAttorney Docket No. 53210-738601wherein the C3-C12 carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, Ci-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, and Ci-Ce alkoxyalkyl;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C3-6 carbocycle, and 4- to 6-membered heterocycle, wherein the C3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl, Ci-Ce alkoxyalkyl, Ci-Ce alkyl-N(R20)2, C2-10 alkenyl, and C2-10 alkynyl;each R14is independently selected from halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci- ioalkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6hydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHCi-10 alkyl, -N(Ci-io alkyl)2, -O-Ci-10 alkyl, Ci-Ce alkyl, and Ci-Ce haloalkyl; andR20is independently selected at each occurrence from hydrogen; Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -S(O)2(Ci-6 alkyl), C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.Attorney Docket No. 53210-73860118. The compound or salt of claim 17, whereinZ is R5019. The method of claim 17 or 18, wherein Formula (II) is represented by Formula (IIA):Formula (IIA),or a pharmaceutically acceptable salt or solvate thereof.

20. The method of claim 17 or 18, wherein Formula (II) is represented by Formula (IIB):Formula (IIB),or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 17 or 18, wherein Formula (II) is represented by Formula (IIC):Formula (IIC),or a pharmaceutically acceptable salt or solvate thereof.

22. The method of any one of claims 17 to 21, wherein A is selected from N, CF, and CH.

23. The method of any one of claims 17 to 22, wherein D is selected from N, CF, and CH.

24. The method of any one of claims 17 to 19, wherein Formula (II) is represented by Formula (IID):Attorney Docket No. 53210-738601Formula (IID),or a pharmaceutically acceptable salt or solvate thereof.

25. The method of any one of claims 17 to 24, wherein R5is selected from hydrogen and methyl.

26. The method of claim 25, wherein R5is hydrogen.

27. The method of any one of claims 17 to 26, wherein R7is selected from Ce-Cs carbocycle and 5- to 6-membered heterocycle, each of which are optionally substituted with one or more R8.

28. The method of any one of claims 17 to 26, wherein R7is selected from C4-C7 carbocycle, which is optionally substituted with one or more R8.

29. The method of claim 27 or 28, wherein R7is selected from, which is optionally substituted with one or more R8.

30. The method of any one of claims 17 to 29, wherein each R8is independently selected from halogen, Ci-6 alkyl, Ci-ehaloalkyl, Ci-6 hydroxyalkyl, -OR20, -N(R20)2, -NR20S(O)2R20, - N(R20)C(O)R20, -C(O)N(R20)2, -S(O)2(R20), and 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2, oxo, C1-10 alkyl, -Ci-iohaloalkyl, and -O-Ci-10 alkyl; and wherein the C1-6 alkyl of R8is optionally substituted with one 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with one or more substituents selected from halogen.The method of any one of claims 17 to 26, wherein R7is selected fromAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-73860132. The method of any one of claims 17 to 26, wherein R7is selected from an optionally substituted phenyl, which is optionally substituted with one or more R8.

33. The method of any one of claims 27 to 29 or 32, wherein each R8is independently selected from halogen, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl.

34. The method of any one of claims 17 to 26, wherein R7is selected from C9 carbocycle, which is optionally substituted with one or more R8.

35. The method of any one of claims 17 to 26, wherein R7is selected from 5- to 10-membered heterocycle, each of which are optionally substituted with one or more R8.

36. The method of any one of claims 27 to 29 or 34 to 35, wherein each R8is independently selected from halogen, -OR20, -N(R20)2, -S(O)2(R20), -C(O)OR20, =0, Ci-6alkyl, Ci-6Attorney Docket No. 53210-738601haloalkyl, Ci-6 hydroxyalkyl, and 4- to 6-membered heterocycle, wherein the 4- to 6- membered heterocycle is optionally substituted with one or more substituents selected from halogen and -C1-3 haloalkyl.

37. The method of any one of claims 17 to 26, wherein R7is selected from 5- to 6-membered saturated heterocycle, each of which are optionally substituted with one or more R8.

38. The method of any one of claims 27 to 29 or 37, wherein each R8is independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), and =0.

39. The method of any one of claims 17 to 26, wherein R7is selected from an optionally substituted 5- to 6-membered heteroaryl.

40. The method of any one of claims 27 to 29 or 39, wherein each R8is independently selected from halogen, -N(R20)2, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl.

41. The method of any one of claims 17 to 26, wherein R7is selected from a 6-membered heterocycle, which is optionally substituted with one or more R8.

42. The method of any one of claims 27 to 29 or 41, wherein each R8is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl.

43. The method of any one of claims 17 to 26, wherein R7is selected from 9- to 10-membered heterocycle, each of which are optionally substituted with one or more R8;44. The method of any one of claims 27 to 29 or 43, wherein each R8is independently selected from halogen, -OR20, -S(O)2(R20), -C(O)OR20, =0, C1-6 alkyl, and C1-6 haloalkyl.

45. The method of any one of claims 17 to 30, wherein each R8is independently selected from halogen.

46. The method of any one of claims 17 to 23 or 25 to 45, wherein R17is selected from hydrogen, halogen, -OR20, C1-6 alkyl, C1-6 haloalkyl, and saturated C3-6 carbocycle.

47. The method of any one of claims 17 to 29, wherein R7isAttorney Docket No. 53210-73860150. The method of any one of claims 1 to 17, wherein the CD38 modulator is selected from:Attorney Docket No. 53210-738601H, andI; or a pharmaceutically acceptable salt or solvate thereof.

51. The method of any one of claims 1 to 17, wherein the CD38 modulator is selected from:Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601FAttorney Docket No. 53210-738601FAttorney Docket No. 53210-738601oAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601Cl F Cl FFFAttorney Docket No. 53210-738601Attorney Docket No. 53210-738601Attorney Docket No. 53210-738601a pharmaceutically acceptable salt or solvate thereof.

52. The method of any one of claims 1 to 17, wherein the CD38 modulator isor a pharmaceutically acceptable salt or solvate thereof.

53. The method of any one of claims 1 to 17, wherein the CD38 modulator is selected from compounds 22, 23, 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21 A, 22A, 23 A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31 A, 32A, 33A, 34A, 35A, 36A, 37A, 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A,Attorney Docket No. 53210-73860148A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63 A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A, 87A, 88A, 89A, 90A, 91A, 92A, 93 A, 94A, 95A, 96A, 97A, 98A, 99A, 100A, 101A, 102A, 103A, 104A, 105A, 106A, 107 A, 108A, 109A, 110A, 111A, 112A, 113A, 114A, 115A, 116A, 117A, 118A, 119A, 120A, 121 A, 122A, 123 A, 124A, 125A, 126A, 127A, 128A, 129A, 130A, 131 A, 132A, 133 A, 134A, 135A, 136A, 137A, 138A, 139A, 140A, 141A, 142A, 143A, 144A, 145A, 146A, 147A, 148A, 149A, 150A, 151A, 152A, 153A, 154A, 155A, 156A, 157A, 158A, 159A, 160A, 161A, 162A, 163A, 164A, 165A, 166A, 167A, 168A, 169A, 170A, 171A, 172A, 173A, 174A, 175A, 176A, 177A, 178A, 179A, 180A, 181A, 182A, 183A, 184A, 185A, 186A, 187A, 188A, 189A, 190A, 191A, 200A, 201A, 202A, 203A, 204A, 205A, 206A, 207A, 208A, 209A, 210A, 211 A, 212A, 213A, 214A, 215A, 216A, 217A, 218A, 219A, 220A, 221 A, 1AF, 1AMe, 2AF, 2AMe, 3AF, 3 AMe, 4AF, 4AMe, 5AF, 5 AMe, 6AF, 6AMe, 7AF, 7 AMe, 8AF, 8 AMe, 9AF, 9AFMe, 10AF, 10 AMe, 14AF, 14AMe, 15AF, 15 AMe, 17AF, 17AMe, 18AF, 18 AMe, 19AF, 19AMe, 20 AF, 20 AMe, 21AF, 21 AMe, 22AF, 22AMe, 23 AF, 23 AMe, 24AF, 24AMe, 25AF, 25AMe, 29AF, 29AMe, 30AF, 30AMe, 31AF, 31 AMe, 32AF, 32AMe, 33AF, 33AMe, 34AF, 34AMe, 36AF, 36AMe, 37AF, 37AMe, 39AF, 39AMe, 40AF, 40AMe, 41AF, 41AMe, 44AF, 44AMe, 45AF, 45AMe, 46AF, 46AMe, 47AF, 47AMe, 48AF, 48AMe, 49AF, 49AMe, 52AF, 52AMe, 56AF, 56AMe, 58AF, 58AMe, 59AF, 59AMe, 60AF, 60AMe, 61AF, 61AMe, 62AF, 62AMe, 63AF, 63AMe, 64AF, 64AMe, 65AF, 65AMe, 66AF, 66AMe, 67AMe, 69AF, 69AMe, 71AF, 71AMe, 72AF, 72AMe, 74AF, 74AMe, 75AF, 75AMe, 76AF, 76AMe, 77AF, 77AMe, 78AF, 78AMe, 79AF, 79AMe, 80AF, 80AMe, 81AF, 81AMe, 82AF, 82AMe, 83AF, 83AMe, 84AF, 84AMe, 85AF, 85AMe, 86AF, 86AMe, 87AF, 87AMe, 88AF, 88AMe, 89AF, 89AMe, 90AF, 90AMe, 92AF, 92AMe, 93 AF, 93 AMe, 96AF, 96AMe, 98AF, 98AMe, 99AF, 99AMe, 100AF, 100AMe, 101AF, lO1AMe, 102AF, 102AMe, 103AF, 103 AMe, 104AF, 104AMe, 105AF, 105 AMe, 106AF, 106AMe, 107AF, 107AMe, 109AF, 109AMe, 110AF, 110AMe, 111AF, ll1AMe, 113AF, 113AMe, 116AF, 116AME, 117AF, 117AMe, 118AF, 118AMe, 119AF, 119AMe, 120AF, 120AMe, 121 AF, 121AMe, 122AF, 122AMe, 123AF, 123AMe, 124AF, 124AMe, 125AF, 125AMe, 126AF, 126AMe, 127AF, 127AMe, 128AF, 128AMe, 131AF, 131AMe, 133AF, 133AMe, 136AF, 136AMe, 139AF, 139AMe, 141AF, 141AMe, 142AF, 142AMe, 144AF, 144AMe, 145AF, 145AMe, 146AF, 146AMe, 147AF, 147AMe, 148AF, 148AMe, 149AF, 149AMe, 150AF, 150AMe, 151AF, 151 AMe, 152AF, 152AMe, 153AF, and 153 AMe.