Bicyclic 1,4-diazepanones and their therapeutic uses

Abstract

Provided herein are compounds of formula (I): TIFF2023548342000347.tif48165 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined herein. Also provided herein are pharmaceutically acceptable compositions comprising a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein are methods of using a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to treat various diseases, disorders, and conditions responsive to modulation of skeletal muscle sarcomere contractility.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 110,776, filed November 6, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Provided herein are bicyclic 1,4-diazepanone compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and pharmaceutical compositions to treat various diseases, disorders, and conditions responsive to the modulation of skeletal muscle sarcomere contractility. [Background technology]

[0003] The cytoskeleton of skeletal muscle cells and cardiac muscle cells is unique compared to all other cells and consists of closely packed, crystalline arrays of cytoskeletal proteins called sarcomeres. Sarcomere structures are beautifully organized as interdigitated arrays of thin and thick filaments. Thick filaments are composed of myosin, a motor protein involved in converting the chemical energy of ATP hydrolysis into force and directional movement. Thin filaments are composed of actin monomers arranged in a helical array. Actin filaments are bound by four regulatory proteins, and contraction is regulated by calcium ions. Muscle contraction is initiated by calcium influx into the cell, driving repeated interactions between myosin motor domains and thin actin filaments, causing the thick and thin filaments to glide past each other.

[0004] Of the 13 distinct myosins in human cells, the myosin II class is involved in skeletal, cardiac, and smooth muscle contraction. This class of myosin differs significantly in amino acid composition and overall structure from the other 12 distinct classes of myosin. Myosin II forms homodimers, with two globular head domains linked together by a long α-helical coiled-coil tail, forming the core of the sarcomere's thick filament. The globular head contains the catalytic domain, where myosin's actin binding and ATPase activity occur. Upon binding to an actin filament, the release of phosphate (cf. ADP-Pi to ADP) signals a structural conformational change in the catalytic domain, which in turn reorients the light-chain-binding lever arm domain extending from the globular head. This movement is called the power stroke. This change in the orientation of the myosin head relative to actin causes the thick filament (of which the myosin head is a part) to move relative to the thin actin filament to which the myosin head is bound. The globular head is released from the actin filament (Ca 2+ The return of the catalytic domain and light chain to their original conformation / orientation completes the catalytic cycle involved in intracellular movement and muscle contraction.

[0005] Tropomyosin and troponin mediate the effect of calcium on the interaction between actin and myosin. The troponin complex consists of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds actin; and troponin T, which binds tropomyosin. The skeletal muscle troponin-tropomyosin complex simultaneously controls myosin-binding sites spread across multiple actin units.

[0006] Troponin, a complex of the three polypeptides mentioned above, is an accessory protein closely associated with actin filaments in vertebrate muscles. The troponin complex acts together with muscle-forming tropomyosin to transport Ca 2+Troponin mediates myosin ATPase activity, which is dependent on muscle contraction, thereby controlling muscle contraction. Troponin polypeptides T, I, and C are named for their tropomyosin-binding, tropomyosin-inhibitory, and calcium-binding activities, respectively. Troponin T binds to tropomyosin and is thought to position the troponin complex on the muscle thin filament. Troponin I binds to actin, and the complex formed by troponin I, troponin T, and tropomyosin inhibits the actin-myosin interaction. Skeletal muscle troponin C can bind up to four calcium molecules. Studies have shown that when calcium levels in muscle increase, troponin C exposes its binding site for troponin I and separates it from actin. This displaces the tropomyosin molecule, exposing the myosin-binding site on actin and stimulating myosin ATPase activity.

[0007] Human skeletal muscle is composed of different types of contractile fibers, classified by myosin type and referred to as either slow or fast fibers. Table 1 summarizes the various proteins that make up these types of muscle. [Table 1]

[0008] In healthy humans, most skeletal muscles consist of both fast-twitch and slow-twitch fibers, although the proportions of each vary depending on the muscle type. Slow-twitch skeletal fibers, often referred to as type I fibers, are structurally similar to cardiac muscle and tend to be used more for fine motor and postural control. They typically have greater oxidative capacity and are more resistant to fatigue with continued use. Fast-twitch skeletal fibers, often referred to as type II fibers, are classified as oxidative (type IIa) fast-twitch and glycolytic (type IIx / d) fast-twitch fibers. These muscle fibers have different myosin types but share many components, including troponin and tropomyosin regulatory proteins. Fast-twitch skeletal fibers can exert greater force than slow-twitch skeletal fibers but tend to fatigue more quickly, making them functionally useful for acute, large movements such as rising from a chair or recovering from a fall.

[0009] Muscle contraction and force generation are controlled through neural stimulation by stimulating motor neurons. Each motor neuron can stimulate a large number (approximately 100–380) of muscle fibers, called a motor unit, for overall contraction. When a muscle needs to contract, the motor neuron sends a nerve impulse (action potential) from the brainstem or spinal cord to each fiber in the motor unit. The contact area between the nerve and muscle fiber is a specialized synapse called the neuromuscular junction (NMJ). Here, an action potential resulting from membrane depolarization in the nerve is converted into an impulse within the muscle fiber through the release of the neurotransmitter acetylcholine (ACh). ACh triggers a second action potential within the muscle, which rapidly propagates along the fiber and into invaginations within the membrane called T-tubules. T-tubules then transport Ca2+ into the sarcoplasmic reticulum (SR) of the muscle via dihydropyridine receptors (DHPRs). 2+ Stimulation of the DHPR releases a second Ca2+ receptor within the SR. 2+ Activates the ryanodine receptor, a channel that allows Ca ions to enter the muscle cytoplasm from stores in the SR. 2+ When muscle stimulation ceases, calcium is released via the ATP-dependent Ca 2+Sarcoplasmic / endoplasmic reticulum Ca pump 2+ -ATPase (SERCA) and then rapidly transported back to the SR.

[0010] Currently, most neuromuscular diseases have limited or no treatments. Therefore, there is a need to develop new compounds that regulate skeletal muscle contractility. There remains a need for drugs that utilize new mechanisms of action, provide good results in both short- and long-term symptom relief, safety, and patient mortality, and have an improved therapeutic index. Summary of the Invention [Means for solving the problem]

[0011] The present invention provides novel compounds that are expected to be used as active ingredients in pharmaceutical compositions, particularly pharmaceutical compositions for preventing or treating diseases or conditions that respond to the regulation of skeletal muscle sarcomere contractility. The regulation of skeletal muscle sarcomeres can be, for example, regulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0012] In one aspect, provided herein is a compound of formula (I): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are each independently N or CR x and Each R x , R y , and R z are independently H, halo, and C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, or C 6-20 is aryl, R1 is C 3-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkenyl, or [ka] where R w is an optionally substituted C 1-12 is alkyl, R 2 teeth, a) C(O)-R h (In the formula, R h teeth, (i) optionally substituted amino, optionally substituted C 1-3 Alkoxy, optionally substituted —C(O)NH, optionally substituted —C 3-10 Cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted C 6-20 aryl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl, or (ii) C 1-12 Alkyl (where C 1-12 The alkyl may be unsubstituted or may contain one or more R n where R n is OH, oxo, halo, cyano, —C(O)NH2, optionally substituted amino, optionally substituted sulfonyl, optionally substituted C 1-12 Alkoxy, optionally substituted C 6-20 Aryloxy, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 cycloalkenyl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl), or b) C 1-12 Alkyl (where C 1-12The alkyl may be unsubstituted or may contain one or more R m where: R m OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3-15 membered heterocyclyl), NH2, -NH(C 1-12 alkyl), -N(C 1-12 alkyl)2, -NHC(O)-C 1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2-NH2, C 3-10 cycloalkyl, or 3- to 15-membered heterocyclyl, wherein R m C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH(C 1-12 C of alkyl) 1-12 Alkyl, -C(O)N(C 1-12 C of alkyl)2 1-12 Alkyl, -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3- to 15-membered heterocyclyl), NH, -NH(C 1-12 C of alkyl) 1-12 Alkyl, -N(C 1-12 C of alkyl)2 1-12 Alkyl, -NHC(O)-C 1-12 Alkyl C 1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl C 1-12 Alkyl, -S(O)-C 1-12 Alkyl C 1-12 Alkyl, -S(O)2-C1-12 Alkyl C 1-12 Alkyl, -S(O)2-NH2, C 3-10 Cycloalkyl or 3- to 15-membered heterocyclyl may be one or more of OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), C(O)OH, NH, -NH(C 1-12 alkyl), -N(C 1-12 Alkyl)2, C 3-10 Cycloalkyl, C 6-20 optionally further substituted by aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, or c) optionally replaced C 3-10 cycloalkenyl, or d) an optionally substituted 5- to 20-membered heteroaryl, or e) an optionally substituted 3- to 15-membered heterocyclyl, or f) optionally substituted amidinyl, or g) optionally substituted sulfonyl, or h) cyano; R 3 is H, optionally substituted C 1-12 alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 alkoxy, or R 2 and R 3 together with the atom to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted; R 4 is absent or H, optionally substituted C 1-12alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 alkoxy) or any variation or embodiment thereof.

[0013] In another aspect, provided herein is a compound of formula (II): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0014] In another aspect, provided herein is a compound of formula (III): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0015] In another aspect, provided herein is a compound of formula (IV): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y, R z , R 1 , R 2 , R 3 , and R 4 is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0016] In another aspect, provided herein is a compound of formula (V): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0017] In another aspect, provided herein is a compound of formula (IA): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 3 , R 4 , and R h is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0018] In a further aspect, provided herein is a compound of formula (IB): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1, X 2 , R y , R z , R 1 , R 3 , and R 4 is as defined for a compound of formula (I) or any variation or embodiment thereof.

[0019] In a further aspect, provided herein is a compound of formula (IC): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 3 , and R 4 is as defined for compounds of formula (I), and R q is an optionally substituted C 1-12 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 6-20 aryl, optionally substituted 3-15 membered heterocyclyl, or optionally substituted 5-20 membered heteroaryl, or any variation or embodiment thereof.

[0020] In another aspect, provided herein is a compound of formula (ID): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , and R 4is as defined for compounds of formula (I), and ring A is a 5-membered heterocyclyl or a 5-membered heteroaryl, where the 5-membered heterocyclyl or the 5-membered heteroaryl independently contain two or more ring heteroatoms, independently are optionally substituted, or any variation or embodiment thereof.

[0021] Unless otherwise specified, when a symbol in a formula is used in other formulas herein, the same symbol has the same meaning. When the same symbol is used more than once in a given formula, it is understood that each instance of that symbol in the formula represents an independently selected chemical moiety, and that not all instances of the symbol in the formula necessarily represent the same chemical moiety.

[0022] In a further aspect, the present invention relates to pharmaceutical compositions comprising one or more of the compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for the prevention or treatment of various diseases, disorders, and conditions responsive to the modulation of skeletal muscle sarcomere contractility.

[0023] In some aspects, the present invention provides the use of one or more of the compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, to treat frailty associated with aging (called sarcopenia); cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies, including somatic myositis myopathy, muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery ( for example, post-operative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, post-hip fracture recovery, ICU neuromuscular disorders, post-traumatic injury, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related frailty; recovery or reversal of neuromuscular blockade after anesthesia; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness; or demyelinating diseases including cerebrospinal ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0024] Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and practice of the disclosure.

[0025] For the sake of brevity, the disclosures of the publications cited herein, including patents, are hereby incorporated by reference. The present invention provides, for example, the following items. (Item 1) Compounds of formula (I):

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[0026] [Figure 1A] 1 shows the XRPD pattern of crystalline form I of compound 10. [Figure 1B] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of crystalline Form I of Compound 10. [Figure 2A] 1 shows the XRPD pattern of crystalline Form II of Compound 10. [Figure 2B] 1 shows DSC and TGA graphs of crystalline Form II of Compound 10. DETAILED DESCRIPTION OF THE INVENTION

[0027] definition As used herein, the following words and phrases are generally intended to have the following meanings, unless the context in which they are used indicates otherwise.

[0028] Throughout this application, unless otherwise stated, references to compounds of formula (I) include all subgroups of formula (I) defined herein, e.g., formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), and also include all substructures, subgenera, preferences, embodiments, examples, and specific compounds defined and / or described herein. A reference to a compound of formula (I) and sub-groups thereof, for example, formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) includes ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopically and / or protected forms thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof, e.g., Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof, e.g., (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) includes polymorphs, solvates, and / or co-crystals thereof.In some embodiments, references to compounds of Formula (I) and subgroups thereof, e.g., Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) include isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to a compound of Formula (I) and subgroups thereof, such as Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) includes solvates thereof. Similarly, a reference to a "salt" includes solvates of salts of the compound.

[0029] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6 Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbon atoms is specified, all branched and straight-chain versions having that number of carbon atoms are intended to be included. Thus, for example, "propyl" includes n-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0030] If a range of values ​​is specified (e.g., C 1~6 alkyl), each value within that range, and all ranges therebetween. For example, "C 1-6"Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 Contains alkyl.

[0031] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond, which may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0032] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0033] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, caged, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). Furthermore, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0034] "Cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as bridged, caged, and spirocyclic ring groups (e.g., norbornene, bicyclo[2.2.2]octene, spiro[3.3]heptene). In addition, one ring of a polycyclic cycloalkyl group can be aromatic, so long as the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, a 1,4-dihydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, but a 1,4-dihydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group.

[0035] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings in a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group can contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, but a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) would not be considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, an aryl is phenyl or naphthyl. In certain instances, an aryl is phenyl. Further examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0036] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise stated, a heteroaryl group can be attached to the parent structure by a carbon or nitrogen atom, valence permitting. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0037] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0038] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3- b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4 -b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[5,4-c]pyridine thiazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0039] In other cases, polycyclic heteroaryl groups can contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0040] "Heterocyclyl" includes heterocycloalkyl and heterocycloalkenyl moieties as defined below.

[0041] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., a 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Examples of spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane. Furthermore, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are set forth below.

[0042] "Heterocycloalkenyl" refers to a non-aromatic ring (e.g., a 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and at least one double bond derived by removing one hydrogen atom from the adjacent carbon atom, adjacent nitrogen atom, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are set forth below.

[0043] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo [d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As described herein, whether a ring is considered an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group depends on the atom through which the moiety is attached to the parent structure.

[0044] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0045] "Cyclic" refers to a moiety that is a ring member, including, but not limited to, a cycloalkyl ring, a cycloalkenyl ring, an aryl ring, a heteroaryl ring, or a heterocyclyl ring. For example, if a heteroaryl ring is described as "comprising two or more ring heteroatoms," then two or more of the ring members of the heteroaryl ring are heteroatoms.

[0046] Unless otherwise specified, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, it is intended that the compound include both the E and Z isomers. When a compound described herein contains a moiety capable of tautomerization, it is intended that the compound include all possible tautomers, unless otherwise specified.

[0047] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to be selectively carried out at an otherwise unprotected reactive site, and that allows the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" comprises at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0048] The term "pharmaceutically acceptable salt" refers to any salt of a compound herein that is known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compound described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0049] When the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0050] A "solvate" is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0051] The term "substituted" means that the specified group or moiety bears one or more substituents, including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term "unsubstituted" means that the specified group bears no substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any position in the system allowed by valence. When a group or moiety bears multiple substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety has 1 to 5 substituents. In some embodiments, a substituted group or moiety has one substituent. In some embodiments, a substituted group or moiety has two substituents. In some embodiments, a substituted group or moiety has three substituents. In some embodiments, a substituted group or moiety has four substituents. In some embodiments, a substituted group or moiety has five substituents.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description is intended to include instances in which the event or circumstance occurs and instances in which the event or circumstance occurs. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. As will be understood by those of skill in the art, with respect to any group that contains one or more substituents, it is not intended that such group introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable. It will also be understood that when a group or moiety is optionally substituted, the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0053] The compounds disclosed and / or described herein may be present in isotopically enriched form, e.g. 2 H, 3 H, 11 C. 13 C and / or 14The compound may be enriched in C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the means described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989,45(21),6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0054] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0055] The terms "patient," "individual," and "subject" refer to an animal, such as a mammal, bird, or fish. In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the object of treatment, observation, or experimentation. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0056] As used herein, the term "therapeutic" refers to the ability to treat a condition, disorder, or disease described herein, including, but not limited to, a condition, disorder, or disease responsive to modulation of skeletal muscle sarcomere contractility. As used herein, "modulation" refers to a change in activity relative to the activity in the absence of a chemical compound described herein, either directly or indirectly, in response to the chemical compound. This change may be an increase or a decrease in activity and may result from the direct interaction of the chemical compound with the target, or from the interaction of the chemical compound with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical compound may increase or decrease target activity, e.g., by directly binding to the target, by increasing or decreasing target activity (directly or indirectly) through another factor, or by increasing or decreasing the amount of target present in a cell or organism (directly or indirectly).

[0057] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of treatment as defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound can be an amount sufficient to treat a disease, disorder, or condition described herein, including, but not limited to, a condition, disorder, or disease responsive to modulation of skeletal muscle sarcomere contractility. A therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be ascertained experimentally, for example, by assessing blood levels of the chemical substance, or theoretically by calculating bioavailability.

[0058] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of preventing a disease or disorder (i.e., preventing clinical symptoms of a disease or disorder from occurring), inhibiting a disease or disorder, slowing or arresting the onset of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing a reduction or regression of clinical symptoms). The term encompasses situations in which a disease or disorder is already experienced by a patient, as well as situations in which a disease or disorder is not currently experienced but is expected to occur. The term encompasses both complete and partial reduction or prevention of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder. When used prophylactically, the compounds disclosed and / or described herein may prevent the onset of a disease or disorder or reduce the extent of a disease or disorder that may occur.

[0059] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0060] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or formulation, mean a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dose, amount, or weight percent.

[0061] As used herein, the term "polymorph" or "polymorphic form" refers to a crystalline form of a compound. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectra, as a result of the arrangement or conformation of molecules or ions within the crystal lattice. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (a key factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation, such as a dosage form consisting of one polymorph fading more rapidly than one consisting of another), mechanical changes (e.g., a tablet disintegrating during storage as a kinetically favorable polymorph converts to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are susceptible to disintegration at high humidity). As a result of differences in solubility / disintegration, some polymorphic transitions may be ineffective at one extreme or toxic at the other. In addition, the physical properties of the crystalline form may be important in processing; for example, some polymorphs may be more likely to form solvates or may be difficult to filter and wash to remove impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0062] As used herein, the term "substantially as shown," when referring to, for example, an XRPD pattern, a DSC graph, a TGA graph, or a GVS graph, includes patterns or graphs that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or variation recognized by one of ordinary skill in the art.

[0063] In some embodiments, the term "substantially pure" means that the crystalline form contains less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% by weight of impurities. In other embodiments, "substantially pure" refers to a material that is free of impurities. Impurities may include, for example, by-products or residual reagents from chemical reactions, contaminants, decomposition products, other crystalline forms, water, and solvents.

[0064] As used herein, the term "substantially free" means that a composition including a crystalline form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the specified substance(s).

[0065] compound Compounds and salts thereof (such as pharmaceutically acceptable salts) are described in detail herein, including the Summary and accompanying Claims. Also provided are all uses of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts, and solvates, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0066] In one aspect, provided is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X 1 and X 2 are each independently N or CR x and Each R x , R y , and R z are independently H, halo, and C3-10 Cycloalkyl, C 3-10 Cycloalkenyl, or C 6-20 is aryl, R 1 is C 3-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkenyl, or [ka] where R w is an optionally substituted C 1-12 is alkyl, R 2 teeth, a) C(O)-R h (In the formula, R h teeth, (i) optionally substituted amino, optionally substituted C 1-3 Alkoxy, optionally substituted —C(O)NH, optionally substituted —C 3-10 Cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted C 6-20 aryl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl, or (ii) C 1-12 Alkyl (where C 1-12 The alkyl may be unsubstituted or may contain one or more R n where R n is OH, oxo, halo, cyano, —C(O)NH2, optionally substituted amino, optionally substituted sulfonyl, optionally substituted C 1-12 Alkoxy, optionally substituted C 6-20 Aryloxy, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10cycloalkenyl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl), or b) C 1-12 Alkyl (where C 1-12 The alkyl may be unsubstituted or may contain one or more R m where: R m OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3-15 membered heterocyclyl), NH2, -NH(C 1-12 alkyl), -N(C 1-12 alkyl)2, -NHC(O)-C 1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2-NH2, C 3-10 cycloalkyl, or 3- to 15-membered heterocyclyl, wherein R m C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH(C 1-12 C of alkyl) 1-12 Alkyl, -C(O)N(C 1-12 C of alkyl)2 1-12 Alkyl, -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3- to 15-membered heterocyclyl), NH, -NH(C 1-12 C of alkyl) 1-12 Alkyl, -N(C 1-12 C of alkyl)2 1-12 Alkyl, -NHC(O)-C 1-12 Alkyl C1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl C 1-12 Alkyl, -S(O)-C 1-12 Alkyl C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl C 1-12 Alkyl, -S(O)2-NH2, C 3-10 Cycloalkyl or 3- to 15-membered heterocyclyl may be one or more of OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), C(O)OH, NH, -NH(C 1-12 alkyl), -N(C 1-12 Alkyl)2, C 3-10 Cycloalkyl, C 6-20 optionally further substituted by aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, or c) optionally replaced C 3-10 cycloalkenyl, or d) an optionally substituted 5- to 20-membered heteroaryl, or e) an optionally substituted 3- to 15-membered heterocyclyl, or f) optionally substituted amidinyl, or g) optionally substituted sulfonyl, or h) cyano; R 3 is H, optionally substituted C 1-12 alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 alkoxy, or R 2 and R 3together with the atom to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted; R 4 is absent or H, optionally substituted C 1-12 alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 It is an alkoxy.

[0067] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are each independently CR x and therefore the compound of formula (I) can be converted to a compound of formula (II): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined above for formula (I).

[0068] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N and X 2 is CR x and therefore the compound of formula (I) can be converted to a compound of formula (III): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined above for formula (I).

[0069] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR x and X 2 is N, and therefore the compound of formula (I) can be converted to a compound of formula (IV): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x , R y , R z , R 1 , R 2 , R 3 , and R 4 is as defined above for formula (I).

[0070] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N and X 2 is N, and therefore the compound of formula (I) can be converted to a compound of formula (V): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y , R z , R 1 , R 2 , R 3 , and R4 is as defined above for formula (I).

[0071] In some embodiments, provided are compounds of formula (I), e.g., compounds of formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C(O)-R h where R h is (i) optionally substituted amino, optionally substituted C 1-3 Alkoxy, optionally substituted —C(O)NH, optionally substituted —C 3-10 Cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted C 6-20 aryl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl, or (ii) C 1-12 Alkyl (where C 1-12 The alkyl may be unsubstituted or may contain one or more R n where R n is OH, oxo, halo, cyano, —C(O)NH2, optionally substituted amino, optionally substituted sulfonyl, optionally substituted C 1-12 Alkoxy, optionally substituted C 6-20 Aryloxy, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 cycloalkenyl, optionally substituted 3-15 membered heterocyclyl, or optionally substituted 5-20 membered heteroaryl).

[0072] In certain embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 3 , R 4 , and R h is as defined above for formula (I).

[0073] In some embodiments, provided herein are compounds of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N and X 2 is CR x where R x is as defined above for Formula (I). In other embodiments, provided herein are compounds of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR x and X 2 is N. In still other embodiments, provided herein are compounds of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are each independently x In some embodiments, provided herein are compounds of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2are each independently N. In certain embodiments, provided herein are compounds of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of Formula (I) or (IA) is a compound of Formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0074] In some embodiments of compounds of Formula (IA), (I-A1), (I-A2), (I-A3), or (I-A4), each R x are independently H, halo, or C 3-10 In other embodiments, each R x is independently H or halo. In some embodiments, halo is fluoro, chloro, or bromo. In certain embodiments, halo is fluoro. In some embodiments, each R x is independently H. In some embodiments, X is H, such as in compounds of formula (IA) or (I-A4). 1 and X 2 are each independently CR x If R x is independently H. In other embodiments, X is H, such as in compounds of formula (IA) or (I-A4): 1 and X 2 are each independently CR x If R x is independently halo. In certain embodiments, X is substituted or unsubstituted, such as in compounds of formula (IA) or (I-A4): 1 and X 2 are each independently CR x If R x is independently fluoro. In some embodiments, one R x is H, and the other R xis halo. In some embodiments, one R x is H, and the other R x is fluoro. In some embodiments, each R x are independently H.

[0075] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h In some embodiments, provided herein are compounds, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, is a compound of Formula (IB): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 3 , and R 4 is as defined above for formula (I).

[0076] In some embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N and X 2 is CR x where R xis as defined above for Formula (I). In other embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR x and X 2 is N. In still other embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are each independently x In some embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are each independently N. In certain embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of Formula (I) or (IB) is a compound of Formula (I-B1), (I-B2), (I-B3), (I-B4), or (I-B5): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0077] In some embodiments of compounds of Formula (IB), (I-B1), (I-B2), (I-B3), or (I-B4), each R x are independently H, halo, or C 3-10 In other embodiments, each R x is independently H or halo. In some embodiments, halo is fluoro, chloro, or bromo. In certain embodiments, halo is fluoro. In some embodiments, each R xis independently H. In some embodiments, X is H, such as in compounds of formula (IB) or (I-B4). 1 and X 2 are each independently CR x If R x is independently H. In other embodiments, X is H, such as in compounds of formula (IB) or (I-B4): 1 and X 2 are each independently CR x If R x is independently halo. In certain embodiments, X is substituted or unsubstituted, such as in compounds of formula (IB) or (I-B4): 1 and X 2 are each independently CR x If R x is independently fluoro. In some embodiments, one R x is H, and the other R x is halo. In some embodiments, one R x is H, and the other R x is fluoro. In some embodiments, each R x are independently H.

[0078] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is a substituted amino. In certain embodiments, R h The amino group of q where R q is an optionally substituted C 1-12 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 6-20 aryl, optionally substituted 3-15 membered heterocyclyl, or optionally substituted 5-20 membered heteroaryl. In some embodiments, R h The amino acid has two Rq In certain embodiments, R h The amino acid has one R q is replaced by

[0079] In some embodiments, R q is the unsubstituted C 1-12 Alkyl, unsubstituted C 3-10 Cycloalkyl, unsubstituted C 6-20 aryl, unsubstituted 3-15 membered heterocyclyl, or unsubstituted 5-20 membered heteroaryl. q is the unsubstituted C 1-12 In some embodiments, R q is the unsubstituted C 1-6 In some embodiments, R q is unsubstituted methyl.

[0080] In some embodiments, R q is C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, where R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl may independently be one or more R p where R p is OH, cyano, halo, oxo, optionally substituted —C(O)NH2, optionally substituted —C(O)NH(C 1-12 alkyl), optionally substituted —C(O)—(3- to 15-membered heterocyclyl), optionally substituted —S(O)—C 1-12 Alkyl, optionally substituted -S(O)2-C 1-12 Alkyl, optionally substituted -S(O)2-NH2, optionally substituted -N(C 1-12 alkyl), optionally substituted -NHC(O)-C 1-12Alkyl, optionally substituted -NHC(O)-NH, optionally substituted C 6-20 aryl, optionally substituted 3- to 15-membered heterocyclyl, or optionally substituted 5- to 20-membered heteroaryl.

[0081] In some embodiments, R q is C 1-12 alkyl, where R q C 1-12 Alkyl can independently be one or more R p where R p is OH, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)-(3- to 15-membered heterocyclyl), -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2-NH2, -N(C 1-12 alkyl)2, -NHC(O)-C 1-12 Alkyl, -NHC(O)-NH2, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, where R p C 6-20 The aryl, 3- to 15-membered heterocyclyl, 5- to 20-membered heteroaryl, or 3- to 15-membered heterocyclyl of C(O)—(3- to 15-membered heterocyclyl) may independently be one or more R v where R v is OH, oxo, -C(O)NH2, -C(O)OH, or C 1-12 alkyl, where R v C 1-12 The alkyl is optionally further substituted with one or more OH.

[0082] In some embodiments, R q is C 3-10 cycloalkyl, where R q C 3-10 Cycloalkyl can independently be one or more R p where R pis OH or cyano.

[0083] In some embodiments, R q is C 6-20 aryl, where R q C 6-20 Aryl can independently be one or more R p where R p is a halo.

[0084] In some embodiments, R q is a 3- to 15-membered heterocyclyl, where R q The 3- to 15-membered heterocyclyl may independently be one or more R p where R p is oxo, C 1-12 alkyl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, where R p C 1-12 Alkyl is one or more of OH, halo, C 1-12 Alkoxy, or C 3-10 The cycloalkyl is optionally substituted.

[0085] In some embodiments, R q is a 5- to 20-membered heteroaryl, where R q The 5- to 20-membered heteroaryl may independently be one or more R p where R p is C 1-12 Alkyl, C 1-12 Alkoxy, -NHC(O)-C 1-12 alkyl, —C(O)NH, or 5-20 membered heteroaryl, where R p C 1-12 Alkyl is one or more OH, halo, or C 1-12 Optionally substituted with alkoxy.

[0086] In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently selected from 1 to 6 R p In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently selected from 1 to 5 R p In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently selected from 1 to 4 R p In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently selected from 1 to 3 R p In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl may independently be one to two R p In some embodiments, R q C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-20 The aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl may independently be one R p is replaced by

[0087] In some embodiments, the compound of Formula (I) or (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of Formula (IC): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 3 , R 4 , and R q is as defined above.

[0088] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is C 1-12 alkyl, where C 1-12 The alkyl may be unsubstituted or may contain one or more R n where R n is OH, optionally substituted -SO2-C 1-12 Alkyl, optionally substituted -SO2-NH2, optionally substituted NH2, optionally substituted -NHC(O)-C 1-12 Alkyl, optionally substituted —C(O)NH, optionally substituted —C 1-12 Alkoxy, optionally substituted C 6-20 aryloxy, or optionally substituted 3- to 15-membered heterocyclyl.

[0089] In some embodiments, R h is the unsubstituted C 1-12 In some embodiments, R h is C 1-12 alkyl, where R h C 1-12 Alkyl is one or more R n where R n OH, -SO2-C 1-12 Alkyl, -SO2-NH2, NH2, -NHC(O)-C 1-12Alkyl, -C(O)NH2, C 1-12 Alkoxy, C 6-20 aryloxy, or 3- to 15-membered heterocyclyl, where R n C 1-12 Alkoxy, C 6-20 Aryloxy or 3- to 15-membered heterocyclyl may be one or more of OH, —C(O)NH2, or C 6-20 In certain embodiments, R h is C 1-12 alkyl, where R h C 1-12 Alkyl is one or more R n where R n is OH, NH2, or —C(O)NH2.

[0090] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is C 1-6 alkyl, where C 1-6 The alkyl may be unsubstituted or may contain one or more R n where R n is OH, optionally substituted -SO2-C 1-12 Alkyl, optionally substituted -SO2-NH2, optionally substituted NH2, optionally substituted -NHC(O)-C 1-12 Alkyl, optionally substituted —C(O)NH, optionally substituted —C 1-12 Alkoxy, optionally substituted C 6-20 aryloxy, or optionally substituted 3- to 15-membered heterocyclyl.

[0091] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is C 1-12 Alkyl or C 1-6 alkyl, and R h C 1-12 Alkyl or C 1-6 Alkyl is one to six R n In some of the foregoing embodiments, R h C 1-12 Alkyl or C 1-6 If it is alkyl, R h C 1-12 Alkyl or C 1-6 Alkyl is one to five R n In some of the foregoing embodiments, R h C 1-12 Alkyl or C 1-6 If it is alkyl, R h C 1-12 Alkyl or C 1-6 Alkyl is one to four R n In some of the foregoing embodiments, R h C 1-12 Alkyl or C 1-6 If it is alkyl, R h C 1-12 Alkyl or C 1-6 Alkyl is one to three R n In some of the foregoing embodiments, R h C 1-12 Alkyl or C 1-6 If it is alkyl, R h C 1-12 Alkyl or C 1-6 Alkyl is one or two R n In some of the foregoing embodiments, R h C 1-12 Alkyl or C 1-6 If it is alkyl, R h C1-12 Alkyl or C 1-6 Alkyl is one R n It is substituted with a substituent.

[0092] In some embodiments, R h is methyl, [ka] In certain embodiments, R h teeth, [ka] is.

[0093] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted C 1-3 In some embodiments, R h is the unsubstituted C 1-3 In certain embodiments, R h is unsubstituted methoxy.

[0094] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted 3-15 membered heterocyclyl. In some embodiments, R h The 3- to 15-membered heterocyclyl may be one or more R j where R j is OH, oxo, halo, NH2, -N(C 1-12 alkyl)2, -N(C 1-12 alkyl)-C(O)C 1-12Alkyl, -NH-SO2-C 1-12 Alkyl, -SO2-C 1-12 Alkyl, C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl)2, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, where R j C 1-12 Alkyl, C 1-12 The alkoxy, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl may independently be one or more R k where R k OH, C 1-12 Alkyl, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 Alkyl)2, C 6-20 aryl, or 5- to 20-membered heteroaryl, where R k C 1-12 The alkyl is optionally further substituted independently with one or more OH.

[0095] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted 5-20 membered heteroaryl. In some embodiments, R h is a 5- to 20-membered heteroaryl, wherein the 5- to 20-membered heteroaryl is independently selected from one or more R t where R t are OH, NH2, C 1-12 Alkyl, -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)NH2, -C(O)NH(C 1-12alkyl), -C(O)N(C 1-12 alkyl), or —C(O)—(3- to 15-membered heterocyclyl), where R t C 1-12 Alkyl, R t -C(O)-(3- to 15-membered heterocyclyl), R t -C(O)NH(C 1-12 C of alkyl) 1-12 Alkyl, or R t -C(O)N(C 1-12 C of alkyl)2 1-12 Alkyl can independently be one or more of OH, -C 1-12 In some embodiments, R h is a 5- to 20-membered heteroaryl, wherein the 5- to 20-membered heteroaryl is independently selected from one or more R t where R t is OH, NH2, or C 1-12 alkyl, where R t C 1-12 The alkyl is optionally further substituted with one or more OH.

[0096] In some embodiments, R h The optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-16 membered heteroaryl. h In yet another embodiment, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-11 membered heteroaryl. h The optionally substituted 5- to 20-membered heteroaryl is an optionally substituted 5- to 6-membered heteroaryl.

[0097] In some embodiments, R h is an optionally substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is independently one or more R t where Rt is OH, NH2, or C 1-12 alkyl, where R t C 1-12 The alkyl is optionally further substituted with one or more OH. In some embodiments, R h is an optionally substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is independently one or more R t where R t is C 1-12 alkyl, where R t C 1-12 The alkyl is optionally further substituted with one or more OH. In some embodiments, R h is an optionally substituted pyrazolyl, wherein the pyrazolyl is independently selected from one or more R t where R t is OH, NH2, or C 1-12 alkyl, where R t C 1-12 The alkyl is optionally further substituted with one or more OH. In some embodiments, R h is an unsubstituted 5-6 membered heteroaryl. In some embodiments, R h teeth, [ka] is.

[0098] In some embodiments, provided herein is a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted —C(O)NH. In certain embodiments, R h is unsubstituted —C(O)NH2.

[0099] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted C 6-20 In some embodiments, R h C 6-20 The aryl is optionally substituted with one or more OH, 5-20 membered heteroaryl, or -C(O)NH2.

[0100] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R h is an optionally substituted C 3-10 In some embodiments, R h C 3-10 The cycloalkenyl is optionally substituted with one or more oxo.

[0101] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-12 alkyl, where C 1-12 The alkyl may be unsubstituted or may contain one or more R m where R m OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3-15 membered heterocyclyl), NH2, -NH(C 1-12 alkyl), -N(C 1-12 alkyl)2, -NHC(O)-C1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2-NH2, C 3-10 cycloalkyl, or 3- to 15-membered heterocyclyl, where R m C 1-12 Alkyl, C 1-12 Alkoxy, C 6-20 Aryloxy, -C(O)NH(C 1-12 C of alkyl) 1-12 Alkyl, -C(O)N(C 1-12 C of alkyl)2 1-12 Alkyl, -C(O)OH, -C(O)-C 1-12 Alkoxy, -C(O)-(3- to 15-membered heterocyclyl), NH, -NH(C 1-12 C of alkyl) 1-12 Alkyl, -N(C 1-12 C of alkyl)2 1-12 Alkyl, -NHC(O)-C 1-12 Alkyl C 1-12 Alkyl, -NHC(O)-NH2, -NH-SO2-C 1-12 Alkyl C 1-12 Alkyl, -S(O)-C 1-12 Alkyl C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl C 1-12 Alkyl, -S(O)2-NH2, C 3-10 Cycloalkyl or 3- to 15-membered heterocyclyl may be one or more of OH, halo, cyano, oxo, C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 alkyl), C(O)OH, NH, -NH(C 1-12 alkyl), -N(C 1-12 Alkyl)2, C 3-10 Cycloalkyl, C 6-20Optionally further substituted aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl.

[0102] In certain embodiments, R 2 is C 1-12 alkyl, where C 1-12 The alkyl may be unsubstituted or may contain one or more R m where R m are OH, cyano, -C(O)NH2, -C(O)NH(C 1-12 alkyl), -C(O)N(C 1-12 Alkyl)2, C 3-10 Cycloalkyl, C 6-20 aryl, or 5- to 20-membered heteroaryl, where R m C 6-20 The aryl or 5- to 20-membered heteroaryl may independently be one or more halo or C 1-6 It is optionally further substituted with alkyl.

[0103] In certain embodiments, R 2 is C 1-6 alkyl, where C 1-6 The alkyl may be unsubstituted or may contain one or more R m In some embodiments, R 2 is the unsubstituted C 1-6 In another embodiment, R 2 is C 1-6 alkyl, where C 1-6 Alkyl is one or more R m In some embodiments, R m is OH or —C(O)NH. In certain embodiments, R 2 is —CH2—C(O)NH2.

[0104] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one to six R m In another embodiment, R 2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one to five R m In some embodiments, R 2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one to four R m In certain embodiments, R 2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one to three R m In yet another embodiment, R 2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one or two R m In a further embodiment, R 2 is C 1-12 Alkyl or C 1-6 alkyl, where C 1-12 Alkyl or C 1-6 Alkyl is one R m is replaced by

[0105] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2is an optionally substituted C 3-10 In some embodiments, R 2 C 3-10 Cycloalkenyl can be one or more R i where R i is oxo, NH2, -NH(C 1-12 alkyl), -N(C 1-12 alkyl)2, or 3- to 15-membered heterocyclyl, where R i 3-15 membered heterocyclyl, R i -NH(C 1-12 C of alkyl) 1-12 Alkyl, or R i -N(C 1-12 C of alkyl)2 1-12 Alkyl is independently one or more OH or C 1-12 In some embodiments, R 2 is C 3-10 cycloalkenyl, where R 2 C 3-10 Cycloalkenyl can be one or more R i where R i is oxo or 3- to 15-membered heterocyclyl, where R i The 3- to 15-membered heterocyclyl is optionally substituted with one or more OH. In certain embodiments, R 2 is one or more R i C optionally replaced with 3-10 cycloalkenyl, where R i is oxo. In other embodiments, R 2 is one or more R i C optionally replaced with 3-10 cycloalkenyl, where R i is a 3- to 15-membered heterocyclyl, where R i The 3- to 15-membered heterocyclyl is optionally substituted with one or more OH.

[0106] In some embodiments, optionally substituted C3-10 Cycloalkenyl is an optionally substituted C 3-8 In other embodiments, optionally substituted C 3-10 Cycloalkenyl is an optionally substituted C 3-6 In some embodiments, optionally substituted C 3-10 The cycloalkenyl is an optionally substituted cyclobutenyl. In certain embodiments, the cyclobutenyl is substituted with one or more oxo or 3-15 membered heterocyclyl, where the 3-15 membered heterocyclyl is optionally substituted with one or more OH. In one embodiment, R 2 teeth, [ka] where: [ka] is optionally further substituted with one or more 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl is optionally substituted with one or more OH. In some embodiments, R 2 teeth, [ka] is.

[0107] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is an optionally substituted 5-20 membered heteroaryl. In some embodiments, R 2 is an unsubstituted 5-20 membered heteroaryl. In other embodiments, R 2 is a 5- to 20-membered heteroaryl, wherein the 5- to 20-membered heteroaryl is selected from the group consisting of one or more of OH, NH, C 1-12 Alkyl, or C 1-12In some embodiments, R 2 is a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is selected from the group consisting of one or more OH, NH, or C 1-12 In some embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-16 membered heteroaryl. In other embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-12 membered heteroaryl. In still other embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-10 membered heteroaryl. In other embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-8 membered heteroaryl. In some embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5-6 membered heteroaryl. In other embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted 5 membered heteroaryl. In some embodiments, the optionally substituted 5-20 membered heteroaryl is an optionally substituted azolyl. In certain embodiments, the optionally substituted 5-20 membered heteroaryl is optionally substituted thiadiazolyl or optionally substituted thiazolyl. In some embodiments, the optionally substituted 5-20 membered heteroaryl is [ka] In some embodiments, the thiadiazolyl or thiazolyl is one or more of OH, NH, or C 1-12 In other embodiments, the optionally substituted 5-20 membered heteroaryl is optionally substituted tetrazolyl. In some embodiments, the optionally substituted 5-20 membered heteroaryl is [ka] is.

[0108] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is an optionally substituted 3-15 membered heterocyclyl. In certain embodiments, R 2 is unsubstituted 3-15 membered heterocyclyl. In other embodiments, R 2 is a 3- to 15-membered heterocyclyl, wherein the 3- to 15-membered heterocyclyl is selected from the group consisting of one or more OH, oxo, NH, or C 1-12 In certain embodiments, R 2 is a 3- to 15-membered heterocyclyl, wherein the 3- to 15-membered heterocyclyl is substituted with one or more OH, oxo, or NH. In some embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted 3- to 10-membered heterocyclyl. In still other embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted 3- to 8-membered heterocyclyl. In other embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted 3- to 6-membered heterocyclyl. In certain embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted 5- to 6-membered heterocyclyl. In some embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted 6-membered heterocyclyl. In some embodiments, the optionally substituted 3-15 membered heterocyclyl is an optionally substituted dihydropyrimidinyl. In some embodiments, the dihydropyrimidinyl is optionally substituted with one or more oxo, OH, or NH. In some embodiments, the optionally substituted 3-15 membered heterocyclyl is [ka] In some embodiments, the optionally substituted 3- to 15-membered heterocyclyl is [ka] In other embodiments, the optionally substituted 3- to 15-membered heterocyclyl is an optionally substituted dihydrooxadiazolyl. In certain embodiments, the dihydrooxadiazolyl is substituted with one or more oxo. In some embodiments, the optionally substituted 3- to 15-membered heterocyclyl is [ka] is.

[0109] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is an optionally substituted amidinyl. In some embodiments, R 2 is unsubstituted amidinyl. In other embodiments, R 2 is an amidinyl, where the amidinyl is one or more R s where R s OH, cyano, C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkoxy, C 6-20 Aryloxy, or -SO2-C 1-12 In certain embodiments, R 2 is an amidinyl, where the amidinyl is one or more R s where R s is cyano, C 1-12 Alkyl, or -C(O)-C 1-12 In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0110] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is an optionally substituted sulfonyl. In some embodiments, R 2 is unsubstituted sulfonyl. In other embodiments, R 2 is sulfonyl, where the sulfonyl is one or more R u where R u is C 1-12 Alkyl, NH2, -NH(C 1-12 alkyl), -N(C 1-12 alkyl)2, or C 6-20 aryl, where R u C 1-12 Alkyl or C 6-20 Aryl is independently one or more halo or C 1-12 In certain embodiments, R 2 is sulfonyl, where the sulfonyl is one or more R u where R u is C 1-12 Alkyl or -N(C 1-12 In some embodiments, R 2 is an optionally substituted sulfonyl, wherein the optionally substituted sulfonyl is [ka] is.

[0111] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is cyano.

[0112] In some embodiments, provided herein are compounds, e.g., compounds of Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are each independently H, optionally substituted C 1-12 alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 In certain embodiments, R 3 and R 4 One of the two is H and the other is R 3 and R 4 The other is optionally substituted C 1-12 alkyl, optionally substituted —C(O)NH2, or optionally substituted —C(O)—C 1-12 In certain embodiments, R 3 and R 4 One of the two is H and the other is R 3 and R 4 the other is C optionally substituted with OH 1-4 alkyl, optionally substituted -C(O)NH2, or CO2-C 1-6 In certain embodiments, R 3 and R 4 One of the two is H and the other is R 3 and R 4and the other is methyl, —CH—OH, —C(O)NHMe, or —C(O)Me. In certain embodiments, R 3 and R 4 In certain embodiments, provided herein are compounds, e.g., compounds of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are each independently H.

[0113] In certain embodiments, provided herein are compounds of formula (I) or (IB), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are each independently H, and therefore, a compound of formula (I) or (IB) can be prepared from a compound of formula (I-B6): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0114] In certain embodiments, provided herein are compounds, e.g., compounds of Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is C 3-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkenyl, or [ka] where R w is an optionally substituted C 1-12 In some embodiments, R 1 is C 3-12 Alkyl or C 3-10 In certain embodiments, R 1 is C 3-6 Alkyl or C 3-8 In some embodiments, C is cycloalkyl. 3-8 In some embodiments, R 1 is C 3-6 In certain embodiments, R 1 is sec-butyl or i-propyl. In some embodiments, R 1 is sec-butyl. In another embodiment, R 1 is i-propyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0115] In certain embodiments, provided herein are compounds of Formula (I), (IB), or (I-B6), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is sec-butyl, and therefore, compounds of formula (I), (IB), or (I-B6) can be converted to compounds of formula (I-B7): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0116] In certain embodiments, provided herein are compounds of Formula (I), (IB), (I-B6), or (I-B7), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is (S)-sec-butyl, and therefore, a compound of formula (I), (IB), (I-B6), or (I-B7) can be converted to a compound of formula (I-B7): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0117] In some embodiments, provided herein are compounds of formula (I-B8), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N and X 2 is CR x where R x is as defined above for Formula (I). In other embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR x and X 2 is N. In still other embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are each independently x In some embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2are each independently N. In certain embodiments, provided herein are compounds of Formula (I) or (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of Formula (I-B8) is a compound of Formula (I-B8-1), (I-B8-2), (I-B8-3), or (I-B8-4): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0118] In some embodiments of compounds of Formula (IB), (I-B8-1), (I-B8-2), (I-B8-3), or (I-B8-4), each R x are independently H, halo, or C 3-10 In other embodiments, each R x is independently H or halo. In some embodiments, halo is fluoro, chloro, or bromo. In certain embodiments, halo is fluoro. In some embodiments, each R x is independently H. In some embodiments, X is H, such as in compounds of formula (IB) or (I-B4). 1 and X 2 are each independently CR x If R x is independently H. In other embodiments, X is H, such as in compounds of formula (IB) or (I-B4): 1 and X 2 are each independently CR x If R x is independently halo. In certain embodiments, X is substituted or unsubstituted, such as in compounds of formula (IB) or (I-B4): 1 and X 2 are each independently CR x If R x is independently fluoro. In some embodiments, one R x is H, and the other R xis halo. In some embodiments, one R x is H, and the other R x is fluoro. In some embodiments, each R x are independently H.

[0119] In some embodiments, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), or (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 and R 3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, where the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached to form an unsubstituted 5- or 6-membered heterocyclyl or an unsubstituted 5- or 6-membered heteroaryl, where the unsubstituted 5- or 6-membered heterocyclyl or unsubstituted 5- or 6-membered heteroaryl independently contains two or more ring heteroatoms. 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, where the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently substituted with one or more oxo or OH.

[0120] In some embodiments, the 5- or 6-membered heterocyclyl is fully saturated. In other embodiments, the 5- or 6-membered heterocyclyl is partially unsaturated. In some embodiments, R 4 It is understood that may be absent in order to satisfy the valence requirements of the ring-forming atoms. For example, in certain embodiments, R2 and R 3 When the 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl formed by is partially or fully unsaturated, R 4 may be absent.

[0121] In certain embodiments, R 2 and R 3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl, where the 5- or 6-membered heterocyclyl independently contains two or more ring heteroatoms and is independently optionally substituted. In other embodiments, R 2 and R 3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heteroaryl, where the 5- or 6-membered heteroaryl independently contains two or more ring heteroatoms and is independently optionally substituted. In some embodiments, R 2 and R 3 together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, where the 5-membered heterocyclyl or the 5-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted.

[0122] In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached to form a 5-membered heterocyclyl, where the 5-membered heterocyclyl independently contains two or more ring heteroatoms and is independently optionally substituted. In some embodiments, the 5-membered heterocyclyl is unsubstituted. In other embodiments, the 5-membered heterocyclyl is substituted with one or more oxo or OH. In other embodiments, R 2 and R 3are taken together with the atoms to which they are attached to form a 5-membered heteroaryl, where the 5-membered heteroaryl independently contains two or more ring heteroatoms and is independently optionally substituted. In some embodiments, the 5-membered heteroaryl is unsubstituted. In other embodiments, the 5-membered heteroaryl is substituted with one or more OH.

[0123] In some embodiments, R 2 and R 3 together with the atom to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, where the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 2 to 4 ring heteroatoms and are independently optionally substituted. In other embodiments, the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 2 to 3 ring heteroatoms. In some embodiments, the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 4 ring heteroatoms. In other embodiments, the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 3 ring heteroatoms. In still other embodiments, the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 2 ring heteroatoms. In some embodiments, the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain 2 nitrogen atoms. In other embodiments, the 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl contains one nitrogen atom and one oxygen atom.

[0124] In some embodiments, provided herein are compounds of Formula (I) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are respectively, CR x and R 2 and R 3together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, where the 5- or 6-membered heterocyclyl or the 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted.

[0125] In some embodiments, provided herein are compounds of Formula (I) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are respectively, CR x and R 2 and R 3 together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, where the 5-membered heterocyclyl or the 5-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted, and thus a compound of formula (I) or (II) can be converted to a compound of formula (ID): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl independently contain two or more ring heteroatoms and are independently optionally substituted; and R x , R y , R z , R 1 , and R 4 is as defined above for compounds of formula (I).

[0126] In some embodiments of the compound of Formula (ID), ring A is [ka] where: [ka] is optionally substituted with one or more OH, and R 4 In some embodiments, ring A is [ka] In other embodiments, ring A is: [ka] where: [ka] is optionally substituted with one or more oxo or OH, and R 4 is H. In some embodiments, ring A is [ka] and R 4 is H.

[0127] In certain embodiments, provided herein are compounds, e.g., compounds of Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y and R z are independently H, halo, and C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, or C 6-20 In certain embodiments, R y and R z are independently H, halo, or C 3-10 In another embodiment, R y and R zis independently H or halo. In some embodiments, R y and R z One of them is H and the other is R y and R z and the other is halo. In some embodiments, R y and R z is independently H or fluoro. In some embodiments, R y and R z One of them is H and the other is R y and R z and the other is fluoro. In certain embodiments, R y and R z are both H.

[0128] In some embodiments, provided herein are compounds, e.g., compounds of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 and X 2 are respectively, CR x where each R x is H and R y is H and R z is H. In other embodiments, X 1 and X 2 are respectively, CR x where each R x is fluoro and R y is H and R z is H. In other embodiments, X 1 and X 2 are respectively, CR x where each R x is H and R y is fluoro and R z is H. In some embodiments, X 1 is N and X2 is CR x where R x is fluoro and R y is H and R z is H. In certain embodiments, X 1 is N and X 2 is N and R y is H and R z is H. In certain embodiments, X 1 is N and X 2 is CR x where R x is H and R y is H and R z is H. In some embodiments, X 1 is CR x where R x is fluoro and X 2 is N and R y is H and R z is H.

[0129] In some embodiments, provided herein is a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Table 2-55 Table 2-56 Table 2-57 Table 2-58 Table 2-59 Table 2-60 Table 2-61 Table 2-62 Table 2-63 Table 2-64 Table 2-65 Table 2-66 Table 2-67 Table 2-68 Table 2-69 Table 2-70 Table 2-71 Table 2-72 Table 2-73 Table 2-74 Table 2-75 Table 2-76 Table 2-77 Table 2-78 Table 2-79 Table 2-80 Table 2-81 Table 2-82 Table 2-83 Table 2-84 Table 2-85 Table 2-86 Table 2-87 Table 2-88 Table 2-89 Table 2-90 Table 2-91 Table 2-92 Table 2-93 Table 2-94 Table 2-95 Table 2-96 Table 2-97 Table 2-98 Table 2-99 Table 2-100 Table 2-101 Table 2-102

Table 2-103

[0130] In some variations, any of the compounds described herein, e.g., a compound of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or any variation thereof, or a compound in Table 2, may be deuterated (e.g., a hydrogen atom is replaced with a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding undeuterated compounds. Other methods known in the art may also be used to replace hydrogen atoms with deuterium atoms.

[0131]

[0014] In one aspect, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of Formula (I) is selected from the group consisting of: 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-3-oxopropanamide; 3-(sec-butyl)-N'-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-(sec-butyl)-4-(6-oxo-1,6-dihydropyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2H-tetrazol-5-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)acetamide; 3-Isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6,8-difluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 7-(sec-butyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrimido[5,4-e][1,4]diazepine-8-carboxamide; 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-carboxamide; 5-(sec-butyl)-3-hydroxy-5H-benzo[f]imidazo[1,5-d][1,4]diazepin-6(7H)-one; 4-acetyl-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-glycyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; Methyl 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxylate; 3-(sec-butyl)-N'-cyano-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; Methyl(amino(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)methylene)carbamate; 3-(sec-butyl)-4-(4-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one; 4-(5-amino-6-oxo-1,6-dihydropyrimidin-2-yl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(sec-butyl)-4-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-sulfonamide; 4-acetyl-3-cyclohexyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Cyclohexyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-4-(3-hydroxyazetidin-1-yl)cyclobut-3-ene-1,2-dione; 3-(sec-butyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-2-oxoacetamide; 3-(sec-butyl)-4-(3-methyl-1,2,4-thiadiazol-5-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(thiazol-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(sec-butyl)-7,11b-dihydro-1H,3H-benzo[f]oxazolo[3,4-d][1,4]diazepine-3,6(5H)-dione; 3-(sec-butyl)-5-(hydroxymethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-5-methyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N5-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4,5-dicarboxamide; 3-Isopropyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-8-fluoro-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-8-fluoro-4-(3-hydroxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-9-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(6-oxo-1,6-dihydropyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-oxo-1,2-dihydropyridine-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxy-1H-pyrazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-hydroxy-2-methylpropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(4-amino-6-oxo-1,6-dihydropyrimidin-2-yl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(6-oxo-1,6-dihydropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-amino-4-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)cyclobut-3-ene-1,2-dione; 3-(sec-butyl)-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-methoxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(5-amino-4-methoxypyrimidin-2-yl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1,3,5-triazin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-hydroxyethyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N'-cyano-3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-(sec-butyl)-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-chloro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 6-Bromo-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-cyclopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 4-acetyl-3-(sec-butyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(1H-pyrazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N'-cyano-7-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-(sec-butyl)-7-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-cyclopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-8-fluoro-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-9-fluoro-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-9-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-6-fluoro-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 3-(sec-butyl)-6-methyl-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N'-cyano-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboximidamide; 3-(sec-butyl)-4-(1H-pyrrolo[3,2-c]pyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-1H-pyrazole-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrole-2-carboxamide; 3-(sec-butyl)-4-(2-hydroxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N'-cyano-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-Isopropyl-4-(6-oxo-1,6-dihydropyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-((4-fluorophenyl)sulfonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-sulfonamide; 4-Acetyl-3-cycloheptyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Cyclohexyl-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(2-oxo-2,3-dihydro-1H-imidazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(dimethylamino)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxy-3-methylazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-2-oxo-N-(pyridin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(1H-pyrazol-4-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(hydroxymethyl)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)azetidine-2-carboxamide; 3-(sec-butyl)-4-(1H-imidazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-pyrazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(tetrahydrofuran-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(tetrahydrofuran-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(pyrazine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrazine-2-carboxamide; 2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-2-oxoethane-1-sulfonamide; 3-(sec-butyl)-4-(2-(methylsulfonyl)acetyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N'-(methylsulfonyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; N-(amino(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)methylene)acetamide; 3-(sec-butyl)-4-(pyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(4,6-dimethoxypyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-((2-methoxyethyl)sulfonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-sulfonamide; 3-Cyclobutyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-Cyclobutyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Cyclopentyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-Cyclohexyl-4-(3-hydroxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(3-cyclohexyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)benzamide; 4-(4-(1H-pyrazol-1-yl)benzoyl)-3-cyclohexyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Cyclohexyl-4-(3-methoxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Cyclohexyl-4-(furan-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-oxo-3-(pentan-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-4-(methylamino)cyclobut-3-ene-1,2-dione; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-4-(dimethylamino)cyclobut-3-ene-1,2-dione; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-4-((2-hydroxyethyl)amino)cyclobut-3-ene-1,2-dione; 3-(sec-butyl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(4-hydroxypiperidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(2-hydroxyethyl)-N-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3,4-dihydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-methylazetidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-(oxetan-3-yl)azetidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3,4-dihydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(piperidin-4-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-methylpyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-methylpyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carbonitrile; 3-(sec-butyl)-N-hydroxy-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-2,2-dimethyl-3-oxopropanamide; 3-(sec-butyl)-4-(1-methyl-5-oxopyrrolidine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxy-3-methylbutanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-1,2,4-triazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-1,2,3-triazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-6-oxo-1,6-dihydropyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-methyl-2H-1,2,3-triazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)picolinamide; 3-(sec-butyl)-4-(1-methyl-1H-1,2,3-triazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1H-imidazole-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(5-oxopyrrolidine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)nicotinamide; Ethyl 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrole-2-carboxylate; 3-(sec-butyl)-4-(1-(2-hydroxypropyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-oxoindoline-6-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrole-2-carboxylic acid; 3-(sec-butyl)-4-(2-oxoindoline-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxamide; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide; 3-(sec-butyl)-4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3H-imidazo[4,5-b]pyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-2-oxo-1,2-dihydropyridine-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(4-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrazol-1-yl)acetamide; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-N-(2-hydroxyethyl)-1H-pyrrole-2-carboxamide; 5-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-N-(2,3-dihydroxypropyl)-1H-pyrrole-2-carboxamide; 3-(sec-butyl)-4-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(Prolyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(D-prolyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(5-(3-hydroxyazetidine-1-carbonyl)-1H-pyrrole-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(5H-pyrrolo[2,3-b]pyrazine-6-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-hydroxy-3-methylbutanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(3-hydroxypyrrolidin-1-yl)propanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(3-hydroxypyrrolidin-1-yl)propanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 1-(3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-3-oxopropyl)pyrrolidine-2-carboxamide; 1-(3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-3-oxopropyl)pyrrolidine-2-carboxamide; 3-(2-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrrolidin-1-yl)propanamide; 3-(sec-butyl)-4-(1-methyl-1H-1,2,3-triazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(pyridazine-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(pyrimidine-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(pyridazine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-5-oxopyrrolidine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(1-methyl-5-oxopyrrolidine-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; N-(2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-2-oxoethyl)acetamide; N-(1-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-1-oxopropan-2-yl)acetamide; 4-(Acetyl-D-prolyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; N-(1-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-1-oxopropan-2-yl)acetamide; 3-(sec-butyl)-4-(3-hydroxybutanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(1-(benzyloxy)ethyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-2-oxoethoxy)benzamide; N-(6-acetamidopyridin-3-yl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-hydroxyethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(2-amino-2-oxoethyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(3-amino-3-oxopropyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(methylamino)-2-oxoethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2,3-dihydroxypropyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2,3-dihydroxypropyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-oxopyrrolidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-oxopyrrolidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(2-acetamidoethyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-ureidoethyl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(methylsulfinyl)ethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-((5-oxopyrrolidin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-oxopiperidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-oxopiperidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(6-oxopiperidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(6-oxopiperidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(methylsulfonyl)ethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-sulfamoylethyl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-hydroxyethyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(piperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; N-(2-amino-2-oxoethyl)-3-(sec-butyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-oxopiperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(4-methylpiperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-methylpiperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-(methylamino)-1-oxopropan-2-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-methyl-2-oxo-N-(pyrazin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; (3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-proline; 3-(sec-butyl)-N-methyl-N-((2-methyloxazol-4-yl)methyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperidine-3-carboxamide; 3-(sec-butyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-methyl-N-(2-(methylsulfonyl)ethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-8-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; N-(1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrrolidin-3-yl)-N-methylacetamide; Methyl 4-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperazine-1-carboxylate; 3-(sec-butyl)-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-oxo-2,8-diazaspiro[4.5]decane-8-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(4-(methylsulfonyl)piperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; N-(1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperidin-3-yl)methanesulfonamide; N-(1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperidin-3-yl)methanesulfonamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)azetidine-3-carboxylic acid; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)azetidine-3-carboxamide; 3-(sec-butyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(2-amino-2-oxo-1-phenylethyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(1-amino-1-oxopropan-2-yl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(6-oxo-1,6-dihydro-[3,4'-bipyridin]-5-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; (3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)glycyl-proline; 3-(sec-butyl)-2-oxo-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-((3-(hydroxymethyl)oxetan-3-yl)methyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(4-(4-carbamoylpiperidin-1-yl)butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(3-amino-2,2-dimethyl-3-oxopropyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-morpholinoazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(4-(pyridin-2-yl)piperazin-1-yl)azetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-((1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)azetidin-3-yl)oxy)-N,N-dimethylacetamide; 2-((1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)azetidin-3-yl)oxy)-N-methylacetamide; 4-(3-amino-3-methylazetidine-1-carbonyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(3-oxa-6-azabicyclo[3.1.1]heptane-6-carbonyl)-3-(sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-cyanocyclopropyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-benzyl-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(3-fluorophenyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; Methyl 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrrolidine-3-carboxylate; 3-(sec-butyl)-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(4-phenethylpiperazine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(2-(hydroxymethyl)pyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(2-carbamoylbenzyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; N-(2-amino-2-oxo-1-phenylethyl)-3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 4-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)benzamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrrolidine-3-carboxylic acid; 3-(sec-butyl)-N-(1-methylpiperidin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(5-methoxypyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-N-methylpyrrolidine-3-carboxamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-N,N-dimethylpyrrolidine-3-carboxamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)pyrrolidine-3-carboxamide; 3-(sec-butyl)-N-isopropyl-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(5-carbamoylpyridin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3,3-difluoroazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-4-(3-(hydroxymethyl)piperidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(3-(hydroxymethyl)piperidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperidine-3-carboxamide; 1-(3-(sec-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)piperidine-3-carboxamide; 3-(sec-butyl)-4-(3-fluoroazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-2-oxo-N-(pyrrolidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-2-oxo-N-(pyrrolidin-3-yl)-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-Cycloheptyl-4-(2-methoxyethyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-4-(2-methoxyethyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-N-methylacetamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)propanamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-N,N-dimethylpropanamide; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-N-methylpropanamide; 3-(sec-butyl)-4-(cyclopentylmethyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 2-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)acetonitrile; 3-(sec-butyl)-5-(hydroxymethyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 5-(sec-butyl)-7,11b-dihydro-1H,3H-benzo[f]oxazolo[3,4-d][1,4]diazepine-3,6(5H)-dione; 3-(sec-butyl)-5-methyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; Methyl 3-(sec-butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-5-carboxylate; 3-Isopropyl-4-(1-methyl-1H-pyrazole-3-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-4-(thiazol-2-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 4-acetyl-3-isopropyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-4-(2-oxo-1,2-dihydropyridine-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-3-isopropyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 5-(3-Isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepine-4-carbonyl)-1H-pyrrole-2-carboxamide; 3-Isopropyl-4-(1-(2-methoxyethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-4-(1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 4-(3-hydroxyazetidine-1-carbonyl)-3-isopropyl-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-Isopropyl-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-sulfonamide; 3-amino-4-(3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)cyclobut-3-ene-1,2-dione; 3-Isopropyl-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-N'-cyano-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboximidamide; 3-(sec-butyl)-6-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-6-fluoro-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-fluoro-4-(3-hydroxypropanoyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-6-fluoro-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(1H-1,2,4-triazole-5-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(6-oxo-1,6-dihydropyridine-2-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-sulfonamide; 3-(sec-butyl)-7-fluoro-4-(3-hydroxy-3-methylazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-7-fluoro-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(1-methylpyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(4-hydroxycyclohexyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(3-hydroxycyclopentyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(3-hydroxycyclobutyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-7-fluoro-N-(3-hydroxycyclobutyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 8-Fluoro-3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-N-(1-methylpyrrolidin-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 3-(sec-butyl)-8-fluoro-4-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[1,4]diazepin-2-one; 3-(sec-butyl)-8-fluoro-N-(1-(oxetan-3-yl)piperidin-4-yl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepine-4-carboxamide; 4-acetyl-3-(sec-butyl)-6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 3-(sec-butyl)-6-fluoro-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 3-(sec-butyl)-6-fluoro-4-(2-methoxyacetyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; Methyl 3-(sec-butyl)-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxylate; 3-(sec-butyl)-N'-cyano-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboximidamide; 3-amino-4-(3-(sec-butyl)-6-fluoro-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)cyclobut-3-ene-1,2-dione; 3-(sec-butyl)-6-fluoro-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-fluoro-2-oxo-N-(1H-pyrazol-3-yl)-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepine-4-carboxamide; 3-(sec-butyl)-6-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 4-(2-(benzyloxy)acetyl)-3-(sec-butyl)-6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[1,4]diazepin-4-yl)-4-morpholinocyclobut-3-ene-1,2-dione; 3-(sec-butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)-4-((2-hydroxyethyl)amino)cyclobut-3-ene-1,2-dione; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)-4-(3-hydroxyazetidin-1-yl)cyclobut-3-ene-1,2-dione; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)-4-(methylamino)cyclobut-3-ene-1,2-dione; 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)-4-(dimethylamino)cyclobut-3-ene-1,2-dione; 3-amino-4-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)cyclobut-3-ene-1,2-dione; 3-(sec-butyl)-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one; Phenyl 2-(sec-butyl)-N-cyano-3-oxo-3,4-dihydropyrido[3,4-b]pyrazine-1(2H)-carboimidate; and 3-(3-(sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-pyrido[3,4-e][1,4]diazepin-4-yl)-4-((2-methoxyethyl)amino)cyclobut-3-ene-1,2-dione, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided, where applicable, are any and all stereoisomers, including geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures, of the compounds described herein.

[0132] Any formula presented herein, such as Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), is intended to represent a compound having the structure depicted by the structural formula as well as specific variations or forms. In particular, compounds of any formula presented herein may have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of a general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of that formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. When a compound in Table 2 is depicted in a particular stereochemical configuration, any alternative stereochemical configuration of that compound, and mixtures of stereoisomers of that compound in any ratio, are also provided herein. For example, if a compound in Table 2 has a stereocenter in the "S" stereochemical configuration, then the enantiomer of that compound in which that stereocenter is in the "R" stereochemical configuration is also provided herein. Similarly, if a compound in Table 2 has a stereocenter in the "R" configuration, then the enantiomer of that compound in the "S" stereochemical configuration is also provided herein. Also provided are mixtures of compounds having both the "S" and "R" stereochemical configurations. Furthermore, when a compound in Table 2 has more than one stereocenter, then any enantiomer or diastereomer of that compound is also provided. For example, if a compound in Table 2 contains a first stereocenter and a second stereocenter with stereochemical configurations that are "R" and "R", respectively, then also provided are stereoisomers of that compound having first and second stereocenters with stereochemical configurations that are "S" and "S", respectively, stereochemical configurations that are "S" and "R", respectively, and stereoisomers of that compound having first and second stereocenters with stereochemical configurations that are "R" and "S", respectively.Also provided are stereoisomers of the compound having first and second stereocenters with "R" and "R" stereochemical configurations, respectively, when the compound of Table 2 contains a first stereocenter and a second stereocenter with "S" and "R" stereochemical configurations, respectively, and "R" and "S" stereochemical configurations, respectively. Also provided are stereoisomers of the compound having first and second stereocenters with "R" and "S" stereochemical configurations, respectively, when the compound of Table 2 contains a first stereocenter and a second stereocenter with "S" and "R" stereochemical configurations, respectively, and "S" and "S" stereochemical configurations, respectively. Similarly, if a compound in Table 2 contains a first stereocenter and a second stereocenter with stereochemical configurations that are "R" and "S," respectively, then stereoisomers of that compound having first and second stereocenters with stereochemical configurations that are "S" and "R," respectively, "R" and "R," and "S" and "S," respectively, are also provided. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Furthermore, any formula given herein is intended to refer to hydrates, solvates, and any one of the amorphous and crystalline forms of such compounds, as well as mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water and the solvate is a hydrate.

[0133] Representative examples of compounds detailed herein, including intermediate and final compounds, are shown in the Tables and elsewhere herein. In one aspect, it is understood that any compound may be used in the methods detailed herein, including intermediate compounds, which, where applicable, may be isolated and administered to an individual or subject.

[0134] The compounds provided herein may exist as salts even when the salt is not indicated, and as will be appreciated by one of ordinary skill in the art, the compositions and methods provided herein are understood to encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0135] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions are provided that include the compounds in substantially pure form. In another variation, pharmaceutical compositions are provided that include the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0136] X provided in this book 1 , X 2 , R x , R y , R z , R 1 , R 2 , R 3 , R 4 , R h , R i , R j , R k , R m , R n , R p , R q , R s , R t , R u , R v , and R w Any variation or embodiment of X 1 , X 2 , R x , R y , R z , R 1 , R 2 , R 3 , R 4 , R h , R i , Rj , R k , R m , R n , R p , R q , R s , R t , R u , R v , and R w and any other variations or embodiments of the present invention, each and every combination being equivalent as if individually and specifically described.

[0137] Other embodiments will become apparent to those skilled in the art from the following detailed description.

[0138] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0139] Formula (I) includes all subformulas thereof. For example, formula (I) includes compounds of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0140] The names of compounds 1-381 provided herein in Table 2 and Examples 1-57 are provided by ChemInnovation's Chem 4d software version 7.5.0.0. The names of intermediates 1.1-10.0 shown in Examples A-J are provided by ChemBioDraw Professional 15.0. Those skilled in the art will understand that compounds can be named or identified using a variety of commonly recognized nomenclature systems and symbols. For example, compounds can be named or identified by common name, systematic name, or non-systematic name. Nomenclature systems and symbols commonly recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).

[0141] Also provided herein is an amorphous form of Compound 10.

[0142] Crystalline morphology In one aspect, provided herein is a crystalline form of Compound 10, a compound having the structure shown below. [ka]

[0143] Crystalline forms may have properties such as bioavailability and stability under particular conditions that make them suitable for medical or pharmaceutical use.

[0144] Crystalline forms of compound 10 may offer bioavailability and stability advantages and may be suitable for use as an active agent in pharmaceutical compositions. Differences in the crystalline structure of a pharmaceutical drug substance may affect the drug's dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to prepare uniform doses of known strengths, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such differences may affect how pharmaceutical compositions are prepared or formulated in different dosage or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, crystalline forms may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, crystalline forms of compound 10 may offer advantages such as improving the manufacturing process of the active agent or the stability or storage of a pharmaceutical form of the active agent, or having suitable bioavailability and / or stability as an active agent.

[0145] It has been found that the use of certain conditions, such as the use of different solvents and / or temperatures, can result in different crystalline forms of Compound 10, including crystalline forms I and II described herein, which may exhibit one or more of the preferred characteristics described herein. The process for preparing the crystalline forms described herein and characterizing these crystalline forms is described in more detail below.

[0146] Form I In some embodiments, provided herein is crystalline Form I of Compound 10.

[0147] In some embodiments, Form I has an XRPD pattern substantially as shown in Figure 1 A. The 2θ angles and relative peak intensities that can be observed for Form I using XRPD are shown in Table 3. [Table 3]

[0148] In some embodiments, crystalline Form I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2θ angles with maximum intensity in the XRPD pattern substantially as shown in FIG. 1A or as shown in Table 3. It should be understood that relative intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, peak assignments listed herein, including crystalline Form I, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0149] In some embodiments, crystalline Form I has a viscosity of 8.26±0.2 degrees, 11.84±0.2 degrees, 12.49±0.2 degrees, 13.08±0.2 degrees, 14.11±0.2 degrees, 14.38±0.2 degrees, 15.71±0.2 degrees, 16.47±0.2 degrees, 16.96±0.2 degrees, 17.20±0.2 degrees, 18.05±0.2 degrees, 18.39±0.2 degrees, 18.92±0.2 degrees, 20.29±0.2 degrees, 20.68±0.2 degrees, 20.99±0.2 degrees, 22.13±0.2 degrees, 22.67±0.2 degrees, 23.65±0.2 degrees, 24.26±0.2 degrees, 25.26±0.2 degrees, 26.26±0.2 degrees, 27.26±0.2 degrees, 28.26±0.2 degrees, 29.26±0.2 degrees, 30.26±0.2 degrees, 31.26±0.2 degrees, 32.26±0.2 degrees, 33.26±0.2 degrees, 34.26±0.2 degrees, 35.26±0.2 degrees, 36.26±0.2 degrees, 37.26±0.2 degrees, 38.26±0.2 degrees, 39.26±0.2 degrees, 40.26±0.2 degrees, 41.26±0.2 degrees, 42.26±0.2 degrees, 43.26±0.2 degrees, 44.26±0.2 degrees, 45.26±0.2 degrees, 46.26±0 20.56±0.2 degrees, 24.36±0.2 degrees, 24.75±0.2 degrees, 25.30±0.2 degrees, 26.23±0.2 degrees, 26.57±0.2 degrees, 26.97±0.2 degrees, 27.30±0.2 degrees, 27.66±0.2 degrees, 28.07±0.2 degrees, 28.36±0.2 degrees, 29.06±0.2 degrees, 29.58±0.2 degrees, 29.98±0.2 degrees, 30.54±0.2 degrees, 31.04±0.2 degrees, 31.33±0.2 degrees, 31.67±0.2 degrees, and 32.70±0.2 degrees 2θ angles.

[0150] In some embodiments, provided is Compound 10: [ka] A crystalline form of is characterized by an XRPD pattern comprising peaks at 8.26±0.2 degrees, 16.47±0.2 degrees, 24.36±0.2 degrees, and 24.75±0.2 degrees 2θ. In some embodiments, the XRPD pattern is further characterized by additional peaks at 18.92±0.2 degrees, 26.57±0.2 degrees, and 31.67±0.2 degrees 2θ. In some embodiments, the XRPD patterns are 11.84±0.2 degrees, 12.49±0.2 degrees, 13.08±0.2 degrees, 14.11±0.2 degrees, 14.38±0.2 degrees, 15.71±0.2 degrees, 16.96±0.2 degrees, 17.20±0.2 degrees, 18.05±0.2 degrees, 18.39±0.2 degrees, 20.29±0.2 degrees, 20.68±0.2 degrees, 20.99±0.2 degrees, 22.13±0.2 degrees, 22.67±0.2 degrees, 23.65±0.2 degrees, The crystalline form is further characterized by having two or more additional peaks at 2θ angles selected from the group consisting of 25.30±0.2°, 26.23±0.2°, 26.97±0.2°, 27.30±0.2°, 27.66±0.2°, 28.07±0.2°, 28.36±0.2°, 29.06±0.2°, 29.58±0.2°, 29.98±0.2°, 30.54±0.2°, 31.04±0.2°, 31.33±0.2°, and 32.70±0.2°. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10°C per minute exhibiting an endothermic heat flow maximum at a temperature between 238°C and 250°C. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern with peak positions substantially in accordance with those of the pattern shown in Figure 1A. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in Figure 1B. In some embodiments, the crystalline form is characterized by a TGA graph substantially as shown in Figure 1B. In some embodiments, the crystalline form is characterized by exhibiting substantially no weight loss due to solvent loss prior to decomposition at 245°C, as determined by TGA.

[0151] Form II In some embodiments, provided herein is crystalline Form II of Compound 10.

[0152] In some embodiments, Form II has an XRPD pattern substantially as shown in Figure 2A. The 2θ angles and relative peak intensities that can be observed for Form II using XRPD are shown in Table 4. [Table 4]

[0153] In some embodiments, crystalline Form II has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2θ angles with maximum intensity of the XRPD pattern substantially as shown in FIG. 2A or as shown in Table 4. It should be understood that relative intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, peak assignments listed herein, including crystalline Form I, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0154] In some embodiments, crystalline Form II has a viscosity of 8.18±0.2 degrees, 10.16±0.2 degrees, 12.04±0.2 degrees, 13.86±0.2 degrees, 16.60±0.2 degrees, 17.42±0.2 degrees, 18.41±0.2 degrees, 19.54±0.2 degrees, 20.03±0.2 degrees, 20.44±0.2 degrees, 20.70±0.2 degrees, 21.72±0.2 degrees, 22.56±0.2 degrees, 24.25±0.2 degrees, 24.79±0.2 degrees, 25.06±0.2 degrees, 26.04±0.2 degrees, 27.06±0.2 degrees, 28.06±0.2 degrees, 29.06±0.2 degrees, 30.06±0.2 degrees, 31.06±0.2 degrees, 32.06±0.2 degrees, 33.06±0.2 degrees, 34.06±0.2 degrees, 35.06±0.2 degrees, 36.06±0.2 degrees, 37.06±0.2 degrees, 38.06±0.2 degrees, 39.06±0.2 degrees, 40.06±0.2 degrees, 41.06±0.2 degrees, 42.06±0.2 degrees, 43.06±0.2 degrees, 44.06±0.2 degrees, 45.06±0.2 degrees, 46.06±0.2 degrees, 47.06±0.2 degrees, 48.06±0.2 degrees, 49.06±0.2 degrees, 50.06±0.2 degrees, 51.06±0 20 degrees, 25.38±0.2 degrees, 25.73±0.2 degrees, 25.92±0.2 degrees, 26.51±0.2 degrees, 26.92±0.2 degrees, 28.38±0.2 degrees, 28.85±0.2 degrees, 29.33±0.2 degrees, 30.08±0.2 degrees, 30.33±0.2 degrees, 30.73±0.2 degrees, 31.63±0.2 degrees, 32.04±0.2 degrees, and 32.43±0.2 degrees 2θ angles.

[0155] In some embodiments, provided is Compound 10: [ka] A crystalline form of is characterized by an XRPD pattern comprising peaks at 2θ angles of 10.16±0.2 degrees, 13.86±0.2 degrees, 16.60±0.2 degrees, and 19.54±0.2 degrees. In some embodiments, the XRPD pattern is further characterized by additional peaks at 2θ angles of 20.70±0.2 degrees, 25.38±0.2 degrees, 26.51±0.2 degrees, and 26.92±0.2 degrees. In some embodiments, the XRPD patterns are 8.18±0.2 degrees, 12.04±0.2 degrees, 17.42±0.2 degrees, 18.41±0.2 degrees, 20.03±0.2 degrees, 20.44±0.2 degrees, 21.72±0.2 degrees, 22.56±0.2 degrees, 24.25±0.2 degrees, 24.79±0.2 degrees, 25.73±0.2 degrees, 25.92± The crystalline form is further characterized by having two or more additional peaks at 2θ angles selected from the group consisting of 28.0.2°, 28.38±0.2°, 28.85±0.2°, 29.33±0.2°, 30.08±0.2°, 30.33±0.2°, 30.73±0.2°, 31.63±0.2°, 32.04±0.2°, and 32.43±0.2°. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10°C per minute that does not exhibit any thermal events prior to thermal decomposition at 180°C. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10°C per minute that does not exhibit any thermal events prior to thermal decomposition at 220°C. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern with peak positions substantially in agreement with the peak positions of the pattern shown in FIG. 2A. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in Figure 2B. In some embodiments, the crystalline form is characterized by a TGA graph substantially as shown in Figure 2B. In some embodiments, the crystalline form is characterized by exhibiting substantially no weight loss due to solvent loss between 25°C and 150°C before decomposition at 245°C, as determined by TGA.

[0156] composition Compositions, such as pharmaceutical compositions, containing a compound disclosed and / or described herein and one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, etc. are also provided. Suitable agents and pharmaceuticals include those described herein. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, are provided.

[0157] In some embodiments, a pharmaceutically acceptable composition is provided comprising a compound of Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some aspects, the composition may contain a synthetic intermediate that can be used in the preparation of a compound described herein. The compositions described herein may contain any other suitable active or inactive agents.

[0158] Also provided herein are compositions containing a crystalline form of Compound 10 described herein, e.g., Form I of Compound 10, Form II of Compound 10, or a mixture thereof. In some embodiments, the composition contains Form I. In some embodiments, the composition contains Form II. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0159] In some embodiments, a composition is provided containing Form I of Compound 10. In some embodiments, the composition is substantially free of crystalline Form II of Compound 10. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of Compound 10. In some embodiments, the composition is substantially free of salts of Compound 10.

[0160] In some embodiments of a composition containing Form I of Compound 10, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of the total composition is Form I. In some embodiments of a composition containing Form I of Compound 10, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of Compound 10 is present in Form I.

[0161] In some embodiments, a composition is provided containing Form II of Compound 10. In some embodiments, the composition is substantially free of crystalline Form I of Compound 10. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of Compound 10. In some embodiments, the composition is substantially free of salts of Compound 10.

[0162] In some embodiments of a composition containing Form II of Compound 10, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of the total composition is Form II. In some embodiments of compositions containing Form II of Compound 10, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of Compound 10 is present in Form II.

[0163] In some embodiments, compositions are provided containing Form I and Form II of Compound 10. In some embodiments, Form I and Form II are present in a weight ratio of 99:1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 1:99. In some embodiments, the weight ratio of Form I to Form II is between 90:10 and 99:1. In some embodiments of a composition containing Form I and Form II, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of the total composition is Form I. In some embodiments of a composition containing Form I and Form II, at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least about 99.9 wt.% of Compound 10 is present in Form I.In some embodiments of a composition containing Form I and Form II, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of the total composition is Form II. In some embodiments of a composition containing Form I and Form II, at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least about 99.9 wt.% of Compound 10 is present in Form II.

[0164] In some embodiments, tablets or capsules are provided containing one or more of the crystalline forms described herein (e.g., Form I, II, or a mixture thereof) and one or more pharmaceutically acceptable carriers. In some embodiments, tablets or capsules are provided containing substantially pure crystalline Form I of Compound 10 and one or more pharmaceutically acceptable carriers. In some embodiments, tablets or capsules are provided containing substantially pure crystalline Form II of Compound 10 and one or more pharmaceutically acceptable carriers.

[0165] Any of the compositions described herein can be sterile or contain sterile components.Sterilization can be achieved by methods known in the art.Any of the compositions described herein can contain one or more substantially pure compounds or conjugates.

[0166] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0167] Method of preparation Form I In some embodiments, provided is Compound 10: [ka] 1. A method for preparing crystalline form I of (a) reacting (S)-3-((S)-sec-butyl)-6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one with potassium cyanate in the presence of a first acid to form compound 10; (b) isolating the crystalline form of Compound 10. In some embodiments, the step of isolating the crystalline form of compound 10 comprises: (b-1) dissolving compound 10 in acetic acid to form a homogeneous solution; (b-2) adding the homogeneous solution to water to form a heterogeneous solution; and (b-3) filtering the heterogeneous solution to obtain a solid. (b-4) drying the solid under reduced pressure to obtain crystalline Form I of Compound 10.

[0168] In some embodiments, step (a) is carried out in the presence of methyl tert-butyl ether. In some embodiments, the first acid is acetic acid. In some embodiments, the method further comprises reacting methyl ((3-amino-5-fluoropyridin-4-yl)methyl)-L-isoleucinate with a first base to form (S)-3-((S)-sec-butyl)-6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[3,4-e][1,4]diazepin-2-one. In some embodiments, the first base is sodium bis(trimethylsilyl)amide. In some embodiments, the method further comprises reacting 3-amino-5-fluoroisonicotinaldehyde or a salt thereof with methyl L-isoleucine in the presence of a reducing agent to form methyl ((3-amino-5-fluoropyridin-4-yl)methyl)-L-isoleucinate. In some embodiments, the reducing agent is sodium triacetoxyborohydride. In some embodiments, the 3-amino-5-fluoroisonicotinaldehyde or its salt is 3-amino-5-fluoroisonicotinaldehyde hydrochloride. In some embodiments, the method further comprises reacting tert-butyl (5-fluoro-4-formylpyridin-3-yl)carbamate with a second acid to form 3-amino-5-fluoroisonicotinaldehyde hydrochloride or its salt. In some embodiments, the second acid is hydrochloric acid. In some embodiments, the method further comprises reacting tert-butyl (5-fluoropyridin-3-yl)carbamate with dimethylformamide in the presence of a second base to form tert-butyl (5-fluoro-4-formylpyridin-3-yl)carbamate. In some embodiments, the second base is n-butyllithium. In some embodiments, the method further comprises reacting 5-fluoropyridin-3-amine with di-tert-butyl carbonate in the presence of a catalyst to form tert-butyl (5-fluoropyridin-3-yl)carbamate. In some embodiments, the catalyst is dimethylaminopyridine. It is also understood that Form I can be prepared using a suitable method, such as that described in Example 59 below. Form II

[0169] In some embodiments, provided are methods for preparing crystalline Form II of Compound 10, comprising: (1) forming a mixture of crystalline Form I of Compound 10 and a solvent; (2) removing the solvent to form an amorphous form of Compound 10; and (3) heating the amorphous form of Compound 10 to a first elevated temperature to form crystalline Form II of Compound 10. In some embodiments, the solvent comprises a mixture of tetrahydrofuran and water. In some embodiments, the mixture of tetrahydrofuran and water has a volume:volume ratio of 10:3 to 5:3. In some embodiments, the mixture of tetrahydrofuran and water has a volume:volume ratio of 7:3. In some embodiments, step (1) comprises heating the mixture to a second elevated temperature, such as about 80°C, about 75°C, about 70°C, about 65°C, about 60°C, about 55°C, about 50°C, about 45°C, about 40°C, or about 35°C. In some embodiments, step (1) comprises heating the mixture to 40 to 60°C. In some embodiments, step (1) comprises heating the mixture to about 50°C. In some embodiments, the mixture of step (1) is stirred before step (2) is performed. In some embodiments, the mixture of step (1) is stirred for 10 minutes to 6 hours. In some embodiments, the mixture of step (1) is stirred for about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours. In some embodiments, the mixture of step (1) is stirred for about 10 minutes. In some embodiments, step (1) comprises heating the amorphous form of compound 10 to about 120°C. In some embodiments, step (1) comprises heating the amorphous form of compound 10 to 100-140°C.

[0170] How to use Pharmaceutical compositions comprising the compounds, crystalline forms, and crude products detailed herein, such as a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein.

[0171] The present invention further relates to pharmaceutical compositions comprising a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II. Additionally, the present invention relates to a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a preceding compound. The present invention relates to a pharmaceutical composition for preventing or treating a disease or condition in a subject that responds to modulation of skeletal muscle sarcomere contractility, for example, modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising any of the pharmaceutically acceptable salts described above. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II.The present invention further relates to a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or The present invention relates to an agent for preventing or treating a disease or condition in a subject that responds to modulation of skeletal muscle sarcomere contractility, for example, modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising any of the foregoing pharmaceutically acceptable salts. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0172] The present invention further provides a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or or a pharmaceutically acceptable salt of any of the foregoing, for treating a disease or condition responsive to modulation of skeletal muscle sarcomere contractility in a subject, for example, modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II. The present invention further provides a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof. The present invention relates to an agent for treating a disease or condition responsive to modulation of skeletal muscle sarcomere contractility in a subject, for example, modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising:In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0173] The present invention further provides a compound of formula (I), e.g., The present invention relates to the use of a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0174] The present invention further provides a method for treating a disease or condition responsive to modulation of skeletal muscle sarcomere contractility in a subject, e.g., modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, using a compound of formula (I), e.g., a compound of formula (I

[0013] The present invention relates to the use of a compound of Formula I), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0175] In one aspect, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), for preventing or treating a disease or condition in a subject that is responsive to modulation of skeletal muscle sarcomere contractility, e.g., modulation of the troponin complex of skeletal fast muscle sarcomeres via one or more of skeletal fast muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. The present invention relates to the use of a compound of formula (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0176] In one aspect, provided herein is a compound of Formula (I), e.g., Formula (II), (II), for treating a disease or condition in a subject that is responsive to modulation of skeletal muscle sarcomere contractility, e.g., modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0023] The present invention relates to the use of a compound of Formula II), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0177] In one aspect, provided herein is a compound of Formula (I), e.g., a compound of Formula (I), for use in the prevention or treatment of a disease or condition responsive to modulation of skeletal muscle sarcomere contractility in a subject, e.g., modulation of the troponin complex of skeletal fast muscle sarcomeres via one or more of skeletal fast muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. I), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0178] In one aspect, provided herein is a compound of Formula (I), e.g., Formula (II), for use in treating a disease or condition responsive to modulation of skeletal muscle sarcomere contractility in a subject, e.g., modulation of the troponin complex of skeletal fast muscle sarcomeres via one or more of skeletal fast muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. , (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0179] In one aspect, provided herein is a method for preventing or treating a disease or condition in a subject that is responsive to modulation of skeletal muscle sarcomere contractility, e.g., modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of a compound of formula (I), e.g., For example, a method of treating a disease comprising administering a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II. Furthermore, a "subject" can be a human or non-human animal in need of prevention or treatment, and in one embodiment, a human in need of prevention or treatment.

[0180] In one aspect, provided herein is a method for treating a disease or condition in a subject that is responsive to modulation of skeletal muscle sarcomere contractility, e.g., modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of a compound of formula (I), e.g., (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II. Furthermore, a "subject" can be a human or non-human animal in need of prevention or treatment, and in one embodiment, a human in need of prevention or treatment.

[0181] In one aspect, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in pharmaceutical therapy. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II. Such pharmaceutical therapies may be relevant to diseases or conditions that respond to modulation of skeletal muscle sarcomere contractility, for example, modulation of the troponin complex of skeletal muscle fast sarcomeres via one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0182] In one aspect, a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, modulates skeletal muscle sarcomere contractility. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II. Specifically, the compounds modulate the troponin complex of fast skeletal muscle sarcomeres through one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "modulate" means either an increase or a decrease in activity. In some cases, a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, potentiates (i.e., increases the activity of) one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0183] In another aspect, provided herein are compounds of Formula (I), e.g., compounds of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, that inhibit (i.e., reduce the activity of) one or more of skeletal fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "activation of skeletal fast myofibrils, such as myofibrils," refers to activation of skeletal fast myofibrils by stimulation / Ca 2+ In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0184] In some aspects, provided herein are methods for treating age-related frailty (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies, including somatic myositis myopathy, muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; and rehabilitation-related disorders, including recovery from surgery. (e.g., post-operative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, post-hip fracture recovery, ICU neuromuscular disorders, post-traumatic injury, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related frailty; recovery or reversal of post-anesthesia neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, including stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness;or a demyelinating disease, including cerebrospinal ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing, comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof. or a pharmaceutically acceptable salt of any of the foregoing, or a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II.

[0185] In some aspects, provided herein are methods for treating age-related frailty (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies, including somatic myositis myopathy, muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; and rehabilitation-related disorders, including recovery from surgery. (e.g., post-operative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, post-hip fracture recovery, ICU neuromuscular disorders, post-traumatic injury, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related frailty; recovery or reversal of post-anesthesia neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, including stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness;or a demyelinating disease including cerebrospinal ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing, comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, if or a pharmaceutically acceptable salt of any of the foregoing, or a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II.

[0186] In some aspects, provided herein are methods for preventing or treating a disease or condition in a subject selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), or a compound of Formula (II). (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), e.g., Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0187] In some aspects, provided herein are methods for treating a disease or condition in a subject selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., Formulas (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (I-B9), (I-C10), (I-C11), (I-C12), (I-C13), (I-C14), (I-C15), (I-C16), (I-C17), (I-C18), (I-C19), (I-C20), (I-C21), (I-C22), (I-C23), (I-C24), (I-C25), (I-C26), (I-C27), (I-C28), (I-C29), (I-C30), (I-C31), (I-C32), (I-C33), (I-C34), (I-C35), (I-C36), (I-C37), (I-C38), (I-C39), (I-C40), (I-C41), (I-C42), (I-C43), (I-C44), (I-C45), (I-C46), (I-C47), (I-C48), (I-C49), (I-C49), (I-C49), (I-C4 (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0188] In some aspects, provided herein are methods for preventing or treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscle myopathy in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID). The present invention relates to a method for treating a rheumatoid arthritis, the method comprising administering a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0189] In some aspects, provided herein are methods for treating a disease or condition in a subject selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscle myopathy, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID). or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0190] In some aspects, provided herein are methods for preventing or treating a disease or condition in a subject selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting due to heart failure, cancer, or chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., Formulas (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (I-B9), (I-C10), (I-C11), (I-C12), (I-C13), (I-C14), (I-C15), (I-C16), (I-C17), (I-C18), (I-C19), (I-C20), (I-C21), (I-C22), (I-C23), (I-C24), (I-C25), (I-C26), (I-C27), (I-C28), (I-C29), (I-C30), (I-C31), (I-C32), (I-C33), (I-C34), (I-C35), (I-C36), (I-C37), (I-C38), (I-C39), (I-C40), (I-C41), (I-C42), (I-C43), (I-C44), (I-C45), (I-C46), (I-C47), ( In some embodiments, the method comprises administering a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0191] In some aspects, provided herein are methods for treating a disease or condition in a subject selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting due to heart failure, cancer, or chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, comprising administering to the subject an effective amount of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), e.g., Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0192] In some aspects, provided herein are methods for treating frailty associated with aging (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; myocardial infarction, myopathies, and cerebrovascular accidents. Muscle myopathies, including Qi, muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathies, and mitochondrial myopathies; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-trauma, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related frailty; paralysis Restoration or reversal of neuromuscular blockade after intoxication; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness; or to prevent or treat cerebrospinal ataxia or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing. and the use of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a pharmaceutical composition for the treatment of a disease or condition. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I.In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0193] In some aspects, provided herein are methods for treating frailty associated with aging (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; myositis; and other conditions. muscle myopathies, including muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathies, and mitochondrial myopathies; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-trauma, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related fatigue recovery or reversal of neuromuscular blockade after anesthesia; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness; or demyelinating diseases, including cerebrospinal ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing and the use of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a pharmaceutical composition for treating rheumatoid arthritis. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I.In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0194] In some aspects, provided herein is a method for the prevention or treatment of a disease or condition in a subject selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty. , a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0195] In some aspects, provided herein is the use of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a pharmaceutical composition for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty in a subject. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0196] In some aspects, provided herein is the use of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0197] In some aspects, provided herein is the use of a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a pharmaceutical composition for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0198] In some aspects, provided herein is a compound of formula (I) for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject. ), for example, a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0199] In some aspects, provided herein is a compound of Formula (I) for the manufacture of a pharmaceutical composition for treating a disease or condition in a subject selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke. In some embodiments, the compound is a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0200] In some aspects, provided herein are methods for treating frailty associated with aging (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; myositis; and other conditions. muscle myopathies, including muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathies, and mitochondrial myopathies; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-trauma, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related frailty recovery or reversal of neuromuscular blockade after anesthesia; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence, such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness; or pre-existing cerebrospinal ataxia or demyelinating disease, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0023] A compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in the prevention or treatment of rheumatoid arthritis. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I.In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0201] In some aspects, provided herein are methods for treating frailty associated with aging (called sarcopenia) in a subject; cachexia syndrome associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; myositis; and myocardial infarction. muscle myopathies, including muscular dystrophies (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathies, and mitochondrial myopathies; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), prolonged bed rest, akinetic / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-trauma, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and age-related fatigue recovery or reversal of neuromuscular blockade after anesthesia; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; dysfunction of the pelvic floor muscles and urethral / anal sphincter muscles (e.g., urinary incontinence, such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); ventilator-induced muscle weakness; or demyelinating diseases, including cerebrospinal ataxia or multiple sclerosis, post-polio syndrome, or any combination of the above.

[0023] In some embodiments, the compound is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in the treatment of atopic dermatitis. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I.In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0202] In some aspects, provided herein is a compound of Formula (I), e.g., Formula (II), (III), for use in the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty in a subject. III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0203] In some aspects, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy and muscle fatigue, and frailty in a subject. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0204] In some aspects, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0205] In some aspects, provided herein is a compound of Formula (I), e.g., a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0206] In some aspects, provided herein is a compound of formula (I), e.g., CI 1.002.004, for use in the prevention or treatment of a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, muscle wasting due to cancer, or chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, in a subject. For example, a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is Compound 10 in the form of crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in the form of crystalline Form I. In some embodiments, the compound is Compound 10 in the form of crystalline Form II.

[0207] In some aspects, provided herein is a compound of formula (I), e.g.,

[0023] In some embodiments, the compound is a compound of Formula (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is Compound 10 in crystalline Form I and / or crystalline Form II. In some embodiments, the compound is Compound 10 in crystalline Form I. In some embodiments, the compound is Compound 10 in crystalline Form II.

[0208] Dosage The compounds, crystalline forms, and compositions disclosed and / or described herein are administered at therapeutically effective dosages, e.g., dosages sufficient to effect treatment of a condition. Human dosage levels of the chemical entities described herein have not yet been optimized, but generally range from about 0.01 to 100 mg / kg body weight daily, in some embodiments from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg body weight. Thus, for a 70 kg human, the dosage range is, in some embodiments, from about 0.7 to 7000 mg per day, in some embodiments, from about 3.5 to 700.0 mg per day, and in some embodiments, from about 7 to 100.0 mg per day. The amount of chemical entity administered will depend, for example, on the subject and condition being treated, the severity of the condition, the mode and schedule of administration, and the judgment of the prescribing physician. For example, exemplary dosage ranges for oral administration are from about 5 mg to about 500 mg per day, and exemplary dosages for intravenous administration are from about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound.

[0209] The daily dose is the total amount administered in one day. The daily dose can be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, but is not limited thereto. In some embodiments, the daily dose is administered for a period ranging from one day to the subject's lifetime. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as two, three, or four divided doses. In some embodiments, the daily dose is administered in two divided doses.

[0210] Administration of the compounds, crystalline forms, and compositions disclosed and / or described herein can be via any acceptable mode of administration for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds, crystalline forms, or compositions are administered orally or intravenously. In some embodiments, the compounds, crystalline forms, or compositions disclosed and / or described herein are administered orally.

[0211] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained- or controlled-release dosage forms (e.g., controlled-release / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for extended timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0212] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, pharmaceutical compositions contain from about 0.005% to 95% by weight, or from about 0.5% to 50% by weight, of the compounds disclosed and / or described herein, depending on the intended mode of administration. Actual methods for preparing such dosage forms are known, or will become apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0213] In some embodiments, the composition takes the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) enclosed in gelatin capsules.

[0214] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and optional pharmaceutical excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms: as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient between 0.01% and 10% in solution are usable, and may be higher if the composition is solid and will later be diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of a compound disclosed and / or described herein in solution.

[0215] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0216] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein, as well as one or more additional drugs, pharmaceutical agents, adjuvants, etc. Suitable drugs and pharmaceutical agents include those described herein.

[0217] kit Also provided are articles of manufacture and kits containing any of the compounds, crystalline forms, or pharmaceutical compositions provided herein. The articles of manufacture may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit a condition described herein, and may indicate instructions for either in vivo or in vitro use.

[0218] In one aspect, provided herein is a kit comprising the compound or composition described herein and instructions for use. The kit may include instructions for use in treating cardiac disease in an individual or subject in need thereof. The kit may further include any material or device that can be used to administer the compound or composition, such as a vial, syringe, or IV bag. The kit may include a sterile package.

[0219] combination The compounds, crystalline forms, and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions. General synthesis method

[0220] Compounds of Formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID) will now be described by reference to the following exemplary synthetic schemes for the general preparation followed by specific examples. To obtain the various compounds herein, those skilled in the art will recognize that starting materials can be suitably selected such that the ultimately desired substituents, with or without appropriate protection, are retained throughout the reaction scheme to yield the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be replaced as appropriate with the desired substituent. In addition, one of skill in the art will recognize that protecting groups may be used to protect certain functional groups (e.g., amino, carboxy, or side chain groups) from the reaction conditions, and that such groups are appropriately removed under standard conditions. It is also understood that any of the steps shown in any of the following general schemes can be used in any combination and in any order that is chemically feasible to arrive at a desired intermediate or disclosed compound. Unless otherwise specified, variables are as defined above with respect to formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID).

[0221] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the mixture of corresponding enantiomers by using any suitable conventional procedure for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with a suitable chiral compound.The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the desired processes.

[0222] Chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0223] General methods for preparing the compounds described herein are illustrated in the following exemplary methods. The variables in the schemes provided herein are defined as with respect to formula (I), (II), (III), (IV), (V), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), (I-B8), (IC), or (ID), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0224] In some embodiments, compounds provided herein can be synthesized according to Scheme 1: Scheme 1 [ka] (In the formula, R 1 , R 2 , R 3 , and R 4is as described for a compound of formula (I), or any variation thereof).

[0225] In some embodiments, compounds provided herein can be synthesized according to Scheme 2: Scheme 2 [ka] (In the formula, R I and R II are each independently H or R q where R q is as defined herein for a compound of formula (I), or any variation thereof.

[0226] In some embodiments, compounds provided herein can be synthesized according to Scheme 3: Scheme 3 [ka] (In the formula, R h is as defined herein for a compound of formula (I), or any variation thereof.

[0227] In some embodiments, compounds provided herein can be synthesized according to Scheme 4: Scheme 4 [ka]

[0228] In some embodiments, compounds provided herein can be synthesized according to Scheme 5: Scheme 5 [ka]

[0229] In some embodiments, compounds provided herein can be synthesized according to Scheme 6: Scheme 6 [ka] (In the formula, R III and R IV are each independently H or R s where R s is as defined herein for a compound of formula (I), or any variation thereof.

[0230] In some embodiments, compounds provided herein can be synthesized according to Scheme 7: Scheme 7 [ka] wherein X is a leaving group and Ar is C 6-20 (aryl).

[0231] In some embodiments, compounds provided herein can be synthesized according to Scheme 8: Scheme 8 [ka]

[0232] In some embodiments, compounds provided herein can be synthesized according to Scheme 9: Scheme 9 [ka] (In the formula, R V and R VI are independently H, C 1-12 Alkyl, or R m where R m is as defined herein for a compound of formula (I), or any variation thereof.

[0233] In some embodiments, compounds provided herein can be synthesized according to Scheme 10: Scheme 10 [ka]

[0234] In some embodiments, compounds provided herein can be synthesized according to Scheme 11: Scheme 11 [ka]

[0235] In some embodiments, compounds provided herein can be synthesized according to Scheme 12: Scheme 12 [ka]

[0236] In some embodiments, compounds provided herein can be synthesized according to Scheme 13: Scheme 13 [ka]

[0237] In some embodiments, compounds provided herein can be synthesized according to Scheme 14: Scheme 14 [ka]

[0238] In some embodiments, compounds provided herein can be synthesized according to Scheme 15: Scheme 15 [ka]

[0239] In some embodiments, compounds provided herein can be synthesized according to Scheme 16: Scheme 16 [ka]

[0240] Also provided herein are intermediate compounds, or salts thereof, for making compounds of Formula (I). In some embodiments, the intermediate compounds are those shown in Schemes 1-16. In some embodiments, the intermediate compounds are those shown in the Examples section below. [Example]

[0241] The following examples are provided to illustrate, but not limit, the compounds, compositions, uses, and methods provided herein. In some examples, compounds and intermediates are prepared using the general methods described above.

[0242] The following abbreviations are used throughout the examples: HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), DIPEA (N,N-diisopropylethylamine), LRMS (low resolution mass spectrometry), Ac (acetyl), Et (ethyl), Me (methyl), tBu (tert-butyl), APCI (atmospheric pressure chemical ionization), THF (tetrahydrofuran), MTBE (methyl tert-butyl ether), DMAP (4-dimethylaminopyridine), TMEDA (N,N,N',N'-tetramethylethylenediamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), TFA (trifluoroacetic acid), HPLC (high performance liquid chromatography). lithography), DCM (dichloromethane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DavePhos (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), Boc (tert-butoxycarbonyl), LDA (lithium diisopropylamide), n-BuLi (n-butyllithium), NaHMDS (sodium bis(trimethylsilyl)amide), TEA (triethylamine), ES (electrospray), TBSCl (tert-butyldimethylsilyl chloride), TBAF (tetra-n-butylammonium fluoride), T3P (propanephosphonic anhydride), LAH (lithium aluminum hydride), Dess-Martin periodinane (3-oxo-1,3-dihydro-1λ 5 ,2-Benzoiodoxol-1,1,1-triyl triacetate), XRPD, (X-ray powder diffraction), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), DVS (dynamic vapor sorption), GVS (gravimetric vapor sorption), FaSSIF (fasting simulated intestinal fluid), and KF (Karl Fischer titration).

[0243] Example 1: Synthesis of Compound 5 [ka] Step 1: tert-Butyl ((2S,3S)-1-((2-(hydroxymethyl)phenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate. To an ice-cooled mixture of (tert-butoxycarbonyl)-L-isoleucine (50 g, 216 mmol) and (2-aminophenyl)methanol (40 g, 325 mmol) in CHCl (500 mL) was added HATU (86 g, 226 mmol) and DIPEA (56 mL, 327 mmol). The reaction mixture was stirred at room temperature under argon for 23 h and then quenched with water (275 mL). The organic layer was separated and added to 20 wt% citric acid (275 mL), followed by stirring at room temperature for 10 min. The precipitate was collected and washed with CHCl (110 mL), and the layers were shaken and separated. To the organic phase was added 20 wt% citric acid (275 mL), and the mixture was stirred at room temperature for 10 minutes. The precipitate was collected and washed with CHCl (55 mL), and the layers were shaken and separated. The organic layer was washed with brine (280 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified using silica gel chromatography (15-30% EtOAc / toluene) to give the product as an off-white solid, which was then recrystallized from ethyl acetate / hexane to give tert-butyl ((2S,3S)-1-((2-(hydroxymethyl)phenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (62.7 g, 186 mmol, 86%) as a colorless solid. [ka]

[0244] Step 2: tert-Butyl ((2S,3S)-1-((2-formylphenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate. To a 1 L round-bottom flask was added tert-butyl ((2S,3S)-1-((2-(hydroxymethyl)phenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (62.7 g, 186 mmol) and CHCl (500 mL). The flask was placed in a water bath, followed by the addition of MnO (286 g, 2.8 mol), and the reaction mixture was stirred at room temperature for 4 days. The mixture was then filtered through Celite, and the filter cake was washed twice with CHCl (800 mL). The filtrate was concentrated to give tert-butyl ((2S,3S)-1-((2-formylphenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (54.7 g, 164 mmol, 88%) as a pale yellow solid. [ka]

[0245] Step 3: (S)-3-((S)-sec-butyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one. To a 1 L round-bottom flask was added tert-butyl ((2S,3S)-1-((2-formylphenyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (54.6 g, 163 mmol) and EtOAc (270 mL). The flask was placed in a water bath, followed by the addition of 4 M HCl in EtOAc (200 mL, 800 mmol). The reaction mixture was stirred at room temperature for 16 hours, after which the resulting precipitate was collected and washed with EtOAc. The solid was mixed with CHCl and saturated sodium bicarbonate and then stirred for 30 minutes. The mixture was extracted three times with CHCl3, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give (S)-3-((S)-sec-butyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (27.6 g, 127 mmol, 78%) as a colorless solid. [ka]

[0246] Step 4: (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one. To a solution of (S)-3-((S)-sec-butyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (27.5 g, 127 mmol) in EtOH (150 mL) was added Pd / C-ethylenediamine complex (approximately 5 wt% Pd, 4 g, 1.5 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 30 h. The mixture was filtered through a Celite pad, and the cake was washed with EtOH and evaporated under vacuum. The residue was then mixed with EtOH (150 mL), Pd / C-ethylenediamine complex (approximately 5% Pd, 4 g, 1.5 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7.5 h. The mixture was filtered through a pad of Celite, the cake was washed with EtOH, and evaporated in vacuo. The residue was triturated with hexane, and the precipitate was collected to give (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (27 g, 124 mmol, 97%) as a colorless solid. [ka]

[0247] Step 5: (S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (Compound 5). To a 250 mL round-bottom flask was added (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (2.0 g, 9.2 mmol), AcOH (4.72 mL, 82.5 mmol), and EtOH (36 mL). The mixture was heated to 40° C., followed by the addition of sodium cyanate (20 mL of a 0.46 M solution in water, 9.3 mmol). After stirring at 40° C. for 1.5 hours, additional sodium cyanate (6 mL and 4 mL of a 0.46 M solution in water, 4.7 mmol) was added. The reaction mixture was stirred at 40 °C for 1 h, concentrated under reduced pressure, and recrystallized with 30 mL of water to give (S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (compound 5, 2.28 g, 8.72 mmol, 95%) as a colorless solid. LRMS (ES, m / z) 262.4 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1 H), 7.29 (d, J=7.7 Hz, 1 H), 7.21 - 7.27 (m, 1 H), 7.01 - 7.08 (m, 2 H), 6.13 (s, 2 H), 4.60 (d, J=9.7 Hz, 1 H), 4.38 - 4.50 (m, 2 H), 1.27 - 1.46 (m, 2 H), 0.90 - 1.03 (m, 1 H), 0.78 (d, J=6.8 Hz, 3 H), 0.69 (t, J=7.3 Hz, 3 H).

[0248] The following compounds were prepared by methods similar to those described for compound 5: [Table 5-1] [Table 5-2]

[0249] Example 2: Synthesis of Compound 29 [ka] (S)-3-Cyclohexyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (Compound 29). To a mixture of (S)-3-cyclohexyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (50 mg) and DIPEA (0.1 mL) in DMF (1 mL) was added isocyanato(trimethyl)silane (0.033 mL). After stirring overnight at room temperature, the resulting mixture was cooled in an ice bath, followed by the addition of isocyanato(trimethyl)silane (0.050 mL) and DIPEA (0.1 mL). The reaction was stirred at 0°C for 1 hour and then at room temperature overnight. The reaction mixture was diluted with water and saturated aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with HO, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give a solid, which was stirred in ethyl acetate (1 mL) for 1 h, followed by filtration and drying under vacuum to give (S)-3-cyclohexyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (compound 29, 21 mg) as a colorless solid. LRMS (APCI) m / z 288.2 (M+H). 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1 H), 7.30 (d, J=7.5 Hz, 1 H), 7.24 (td, J = 1.5 Hz, 7.7 Hz, 1 H), 7.07 - 7.01 (m, 2 H), 6.10 (s, 2 H), 4.62 (d, J=9.0 Hz,1 H), 4.50 - 4.34 (m, 2 H), 1.68 - 1.48 (m, 5 H), 1.39 - 1.26 (m, 1 H), 1.11 - 0.86 (m, 5 H).

[0250] Example 3: Synthesis of Compound 32 [ka] (S)-3-((S)-sec-butyl)-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (Compound 32). To a mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (300 mg) and DIPEA (1.2 mL) in THF (6 mL) was added triphosgene (140 mg). The mixture was stirred for 30 minutes, followed by the addition of azetidin-3-ol hydrochloride (300 mg). The reaction was stirred for 3 hours, concentrated, and partitioned between 10% aqueous citric acid and CHCl3. The organic layer was separated, concentrated, and purified using silica gel column chromatography (CHCl3 / MeOH) to give (S)-3-((S)-sec-butyl)-4-(3-hydroxyazetidine-1-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (compound 32, 379 mg) as a colorless solid. LRMS (ES) m / z 318.2 (M+H). 1 H NMR (399 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.20 - 7.32 (m, 2H), 7.01 - 7.09 (m, 2H), 5.58 (d, J=6.2 Hz, 1H), 4.46 - 4.52 (m, 1H), 4.31 - 4.44 (m, 3H), 4.13 - 4.19 (m, 1H), 4.03 - 4.10 (m, 1H), 3.63 - 3.75 (m, 2H), 1.33 - 1.49 (m, 2H), 0.91 - 1.06 (m, 1H), 0.80 (d, J=6.6 Hz, 3H), 0.72 (t, J=7.3 Hz, 3H).

[0251] The following compounds were prepared by methods similar to those described for compound 32 and related compounds. [Table 6-1] [Table 6-2] [Table 7-1] [Table 7-2]

[0252] Example 4: Synthesis of Compound 31 [ka] (S)-3-((S)-sec-butyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (Compound 31). To an ice-cooled mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (200 mg, 916 μmol) and DIPEA (470 μL, 2.75 mmol) in CHCl (4 mL) was added triphosgene (110 mg, 370 μmol). The reaction was stirred for 30 minutes and then cooled in an ice bath. Methylamine (2 M in THF, 1.3 mL, 2.6 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with water, the layers were separated, and the organic layer was concentrated. The residue was purified using silica gel chromatography (20-80% EtOAc / hexanes) to give a solid, which was triturated with diisopropyl ether and the precipitate was collected to give (S)-3-((S)-sec-butyl)-N-methyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide (compound 31, 161 mg, 584 μmol, 64%) as a colorless solid. LRMS (ES) m / z 276.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.22 - 7.31 (m, 2H), 7.02 - 7.07 (m, 2H), 6.52 - 6.58 (m, 1H), 4.59 (d, J=10.1 Hz, 1H), 4.38 - 4.48 (m, 2H), 2.58 (d, J=4.4 Hz, 3H), 1.32 - 1.43 (m, 1H), 1.17 - 1.32 (m, 1H), 0.86 - 1.00 (m, 1H), 0.76 (d, J=6.6 Hz, 3H), 0.67 (t, J=7.4 Hz, 3H).

[0253] Example 5: Synthesis of Compound 41 [ka] (S)-3-Isopropyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (Compound 41). 1-Methyl-1H-pyrazole-4-carbonyl chloride (62 mg, 0.431 mmol) was added to a stirred solution of (S)-3-isopropyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (80 mg, 0.392 mmol) and triethylamine (106 mL, 0.783 mmol) in CHCl (2 mL) at room temperature. After 4 h, the reaction was concentrated, and the resulting residue was suspended in MeOH (1.8 mL total), filtered through a 0.4 μm syringe filter, and subsequently purified using reverse-phase HPLC (0->30% MeCN / 0.1% formic acid in HO) to afford (S)-3-isopropyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one as a white solid (compound 41, 55 mg, 45%). LRMS (APCI) m / z 313.1 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.22 (dt, J = 7.3, 13.2 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.85 (s, 2H), 3.85 (s, 3H), 1.51 (s, 1H), 0.81 (d, J = 6.1 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H).

[0254] The following compounds were prepared by methods similar to those described for compound 41: [Table 8]

[0255] Example 6: Synthesis of Compound 15 [ka] (S)-4-Acetyl-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (Compound 15). To a mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (200 mg, 916 μmol), DMAP (12 mg, 98 μmol), and pyridine (2 mL) was added AcO (170 μL, 1.8 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-60% EtOAc / hexanes) to give (S)-4-acetyl-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (compound 15, 93 mg, 357 μmol, 39%) as a colorless solid. LRMS (ES) m / z 261.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1 H), 7.39 (d, J=7.5 Hz, 0.75 H), 7.32 - 7.26 (m, 1 H), 7.23 (d, J=7.5 Hz, 0.25 H), 7.12 - 7.03 (m, 2 H), 4.88 (d, J=10.1 Hz, 0.75 H), 4.81 (d, J=15.9 Hz, 0.25 H), 4.66 - 4.55 (m, 1.5 H), 4.49 - 4.37 (m, 0.25 H), 4.15 (d, J=10.1 Hz, 0.25 H), 2.14 (s, 2.25 H), 2.07 (s, 0.75 H), 1.49 - 1.37 (m, 0.5 H), 1.37 - 1.24 (m, 1.5 H), 1.09 - 0.97 (m, 0.25 H), 0.96 - 0.86 (m, 0.75 H), 0.84 (d, J=6.6 Hz, 0.75 H), 0.78 (d, J=6.6 Hz, 2.25 H), 0.73 (t, J=7.3 Hz, 0.75 H), 0.65 (t, J=7.3 Hz, 2.25 H)

[0256] The following compounds were prepared by methods similar to those described for compound 15: [Table 9]

[0257] Example 7: Synthesis of Compound 18 [ka] (S)-3-((S)-sec-butyl)-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one. To a mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (300 mg) and hydroxyacetic acid (157 mg) in DMF (6 mL) was added HATU (784 mg) and DIPEA (710 μL). The mixture was stirred for 3 days. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated ammonium chloride, brine, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / EtOAc) to give (S)-3-((S)-sec-butyl)-4-(2-hydroxyacetyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (compound 18, 152 mg) as a colorless solid. LRMS (ES), m / z 277.2 (M+H). 1 H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.29 - 7.34 (m, 1H), 7.04 - 7.13 (m, 2H), 4.83 (br d, J=10.3 Hz, 1H), 4.68 (t, J=5.7 Hz, 1H), 4.40 - 4.57 (m, 3H), 4.04 - 4.20 (m, 1H), 1.22 - 1.32 (m, 1H), 1.15 - 1.22 (m, 1H), 0.81 - 0.93 (m, 1H), 0.77 (d, J=6.6 Hz, 3H), 0.63 (t, J=7.3 Hz, 3H).

[0258] The following compounds were prepared by methods similar to those described for compound 18: [Table 10] [Table 11-1] [Table 11-2]

[0259] Example 8: Synthesis of Compound 16 [ka] (S)-3-((S)-sec-butyl)-4-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (Compound 16). To a mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (160 mg) and 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-4-carboxylic acid (210 mg) in DMF (3 mL) was added HATU (310 mg) and DIPEA (320 μL). The reaction mixture was stirred for 3.5 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with 50% brine solution, brine, then dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3 / EtOAc) to give 265 mg of (S)-3-((S)-sec-butyl)-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one. Methanol (1.5 mL) was then added to (S)-3-((S)-sec-butyl)-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one, followed by HCl / EtOAc (4 M, 1.5 mL). The reaction mixture was stirred for 2 hours and then concentrated in vacuo. The residue was purified by column chromatography on amino-functionalized silica gel (CHCl3 / MeOH) to give (S)-3-((S)-sec-butyl)-4-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (compound 16, 107 mg) as a colorless solid. LRMS (ES), m / z 357.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (1H, br s), 8.16 (1H, br s), 7.79 (1H, s), 7.23 - 7.35 (2H, m), 7.04 - 7.12 (2H, m), 4.69 - 4.99 (4H, m), 4.17 (2H, t, J=5.5 Hz), 3.71 - 3.79 (2H, m), 1.21 - 1.48 (2H, m), 0.88 - 1.04 (1H, m), 0.79 (3H, d, J=6.8 Hz), 0.65 (3H, t, J=7.4 Hz).

[0260] Example 9: Synthesis of Compound 1 [ka] 3-((S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-3-oxopropanamide (Compound 1). To a suspension of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (1.02 g, 4.67 mmol), malonamic acid (578 mg, 5.61 mmol), and HATU (2.13 g, 5.61 mmol) in DMF (10 mL) was added triethylamine (1.95 mL, 14.0 mmol), followed by stirring at room temperature overnight. The reaction was diluted with EtOAc (30 mL), washed with HO (10 mL) and brine (10 mL), dried over NaSO, filtered, purified by reverse-phase HPLC (5-70% MeCN / HO, 0.1% formic acid buffer), and repurified by silica gel (0-10% MeOH / DCM) to give 3-((S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-3-oxopropanamide (717 mg, 51%) as a white solid. LRMS (APCI) m / z 304.1 (M+H). 1H NMR (400 MHz, 343 K, DMSO-d6) δ 9.87 (s, 1H), 7.40 - 7.25 (m, 3H), 7.12 - 7.07 (m, 2H), 6.84 (s, 1H), 4.89 (d, J = 9.8 Hz, 1H), 4.73 (d, J = 14.6 Hz, 1H), 4.62 (d, J = 14.7 Hz, 1H), 3.52 (d, J = 15.2 Hz, 1H), 3.32 (d, J = 14.6 Hz, 1H), 1.45 - 1.26 (m, 2H), 1.00 - 0.90 (m, 1H), 0.88 - 0.76 (m, 3H), 0.73 - 0.63 (m, 3H).

[0261] Example 10: Synthesis of Compound 17

change

[0262] Example 11: Synthesis of Compound 33 [ka] 2-((S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-oxoacetamide (Compound 33). To a solution of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (60 mg, 0.28 mmol) and DIPEA (0.14 mL, 0.83 mmol) in DCM (1 mL) at 0 °C, methyl 2-chloro-2-oxoacetate (25 μL, 0.28 mmol) was added, and the mixture was stirred at 0 °C for 15 min. The reaction mixture was quenched by the addition of MeOH (2 mL). The reaction was concentrated, and DCM (1 mL) and ammonia (7 M in MeOH, 0.39 mL, 2.75 mmol) were added. The reaction mixture was then stirred at 50 °C overnight, concentrated, and purified using reverse-phase HPLC (5-70% MeCN / HO, 0.1% formic acid buffer) to give 2-((S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-oxoacetamide (compound 33, 37 mg, 47%) as a white solid. LRMS (APCI) m / z 290.1 ​​(M+H). 1H NMR (400 MHz, methanol-d4) δ 7.47–7.29 (m, 2H), 7.24–7.15 (m, 1H), 7.13–7.06 (m, 1H), 4.90–4.85 (m, 1H), 4.79–4.64 (m, 2H), 1.60–1.37 (m, 1H), 1.28–1.06 (m, 1H), 1.03–0.93 (m, 1H), 0.89–0.81 (m, 3H), 0.78–0.65 (m, 3H).

[0263] Example 12: Synthesis of Compound 51 [ka] (S)-3-((S)-sec-butyl)-4-(2-hydroxy-2-methylpropanoyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (Compound 51). To a mixture of (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (300 mg) and 2-hydroxy-2-methylpropanoic acid (310 mg) in DMF (6 mL) was added HATU (1.15 g) and DIPEA (710 μL). The mixture was stirred for 1 day, then diluted with water and extracted with EtOAc. The organic layer was washed with HO, brine, and then concentrated. The residue was purified by column chromatography on amino silica gel (hexane / EtOAc) to give (S)-3-((S)-sec-butyl)-4-(2-hydroxy-2-methylpropanoyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (compound 51, 78 mg) as a colorless solid. LRMS (ES) m / z 305.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br s, 1H), 7.26 (br d, J = 7.06 Hz, 2 H), 7.06 (br d, J = 7.94 Hz, 2 H), 5.70 - 5.20 (m, 2H), 5.02 - 4.66 (m, 2H), 1.48 - 1.09 (m, 8H), 0.98 - 0.56 (br s, 7H).

[0264] Example 13: Synthesis of Compound 64 [ka] (S,E)-N'-cyano-3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide (Compound 66). A mixture of phenyl(S,Z)-N-cyano-3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboimidate (77 mg, 0.22 mmol), ammonia (7 M in MeOH, 0.32 mL, 2.2 mmol), and THF (1 mL) was stirred at 100 °C in a microwave reactor for 30 minutes. The mixture was filtered and purified by reverse-phase HPLC (5-70% MeCN / HO, 0.1% formic acid buffer) to give (S,E)-N'-cyano-3-isopropyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide as a white solid (compound 66, 19 mg, 32%). LRMS (APCI) m / z 272.1 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.41 - 7.35 (m, 2H), 7.19 (dd, J = 7.4, 7.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.81 (d, J = 9.5 Hz, 1H), 4.71 (d, J = 14.6 Hz, 1H), 4.62 (d, J = 14.5 Hz, 1H), 1.68 - 1.54 (m, 1H), 0.91 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H).

[0265] The following compounds were prepared by methods similar to those described for compound 66: [Table 12]

[0266] Example 14: Synthesis of Compound 2 [ka] (S,E)-3-((S)-sec-butyl)-N'-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide (Compound 2). A mixture of phenyl(S,Z)-3-((S)-sec-butyl)-N-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboimidate (62 mg, 0.17 mmol), ammonia (7 M in MeOH, 0.24 mL, 1.7 mmol), and THF (1 mL) was stirred at 50°C for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (5-70% MeCN / HO, 0.1% formic acid buffer) to give (S,E)-3-((S)-sec-butyl)-N'-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide (compound 2, 19 mg, 39%) as a white solid. LRMS (APCI) m / z 286.1 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.42 - 7.35 (m, 2H), 7.20 (dd, J = 7.6, 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.87 (d, J = 10.4 Hz 1H), 4.73 - 4.60 (m, 2H), 1.51 - 1.41 (m, 1H), 1.37 - 1.24 (m, 1H), 1.14 - 1.01 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H).

[0267] Example 15: Synthesis of Compound 19 [ka] (S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide (Compound 19). A solution of tert-butyl ((Z)-((tert-butoxycarbonyl)imino)((S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)methyl)-12-azanecarboxylate (35 mg, 0.076 mmol) and TFA (0.12 mL, 1.52 mmol) in DCM (1 mL) was stirred at room temperature for 2 h. The crude material was filtered and purified by reverse-phase HPLC (0-50% MeCN / HO, 0.1% formic acid buffer) to give (S)-3-((S)-sec-butyl)-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide as a white solid (compound 19, 14 mg, 71%). LRMS (APCI) m / z 261.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.41 (s, 1H), 8.16 (s, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 7.7, 7.7 Hz, 1H), 7.16 - 7.10 (m, 2H), 4.64 - 4.52 (m, 2H), 4.40 (d, J = 9.4 Hz, 1H), 1.52 - 1.33 (m, 2H), 1.14 - 0.98 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H).

[0268] Example 16: Synthesis of Compound 21 [ka] (S,E)-3-((S)-sec-butyl)-N'-cyano-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide (Compound 21). To a suspension of diphenyl cyanocarbonimidate (40 mg, 0.17 mmol) in THF (1 mL) was added (S)-3-((S)-sec-butyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (37 mg, 0.17 mmol) and DIPEA (88 μL, 0.50 mmol), and the mixture was stirred at room temperature overnight. The reaction was filtered and purified by reverse-phase HPLC (2-60% MeCN / HO, 0.1% formic acid buffer) to give phenyl(S,Z)-3-((S)-sec-butyl)-N-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboimidate.

[0269] Phenyl (S,Z)-3-((S)-sec-butyl)-N-cyano-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carbomidate (from above) and dimethylamine (2 M in THF, 0.42 mL, 0.84 mmol) were stirred in THF (1 mL) at room temperature for 2 days. The reaction was filtered and purified using reverse-phase HPLC (5-35% MeCN / HO, 0.1% formic acid buffer) to give (S,E)-3-((S)-sec-butyl)-N'-cyano-N,N-dimethyl-2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboximidamide as a white solid (compound 21, 1 mg, 2%). LRMS (APCI) m / z 314.1 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.40 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 7.6, 7.6 Hz, 1H), 7.17 (dd, J = 7.5, 7.5 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.73 - 4.56 (m, 2H), 4.35 (d, J = 9.5 Hz, 1H), 3.11 (...

Claims

1. Compounds of formula (I): 【Chemistry 175】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X １ and X ２ are each independently N or C—R ｘ and Each R ｘ , R ｙ , and R ｚ are independently H, halo, C ３－１０ Cycloalkyl, C ３－１０ cycloalkenyl, or C ６－２０ is aryl, R １ is C ３－１２ Alkyl, C ２－１２ Alkenyl, C ２－１２ Alkynyl, C ３－１０ Cycloalkyl, C ３－１０ cycloalkenyl, or 【Chemistry 176】 where R ｗ is C １－１２ is alkyl, R ２ teeth, a) C(O)-R ｈ (In the formula, R ｈ teeth, (i) amino which is unsubstituted or substituted with one or more R q , wherein R q is C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, and wherein said C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl of R q is unsubstituted or substituted with one or more R p , wherein R p is OH, cyano, halo, oxo, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)—(3- to 15-membered heterocyclyl), —S(O)—C 1-12 alkyl, —S(O) 2 —C and R p is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v . The alkyl is unsubstituted or further substituted with one or more OH. C １－３ Alkoxy, -C(O)NH ２ 、 C ３－１０ cycloalkyl, C ３－１０ cycloalkenyl, wherein said C 3-10 cycloalkenyl is unsubstituted or substituted by one or more oxo; C ６－２０ aryl, wherein said C 6-20 aryl is unsubstituted or substituted with one or more OH, 5-20 membered heteroaryl, or —C(O)NH 2 ; 3- to 15-membered heterocyclyl (wherein said 3- to 15-membered heterocyclyl is unsubstituted or substituted with one or more R j , where R j is OH, oxo, halo, NH 2 , —N(C 1-12 alkyl) 2 , —N(C 1-12 alkyl)-C(O)C 1-12 alkyl, —NH—SO 2 —C 1-12 alkyl, —SO 2 —C 1-12 alkyl, C 1-12 alkyl, C 1-12 alkoxy, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 ). , a 3- to 15-membered heterocyclyl, or a 5- to 20-membered heteroaryl, wherein said R j C 1-12 alkyl, C 1-12 alkoxy, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently unsubstituted or further substituted with one or more R k , wherein R k is OH, C 1-12 alkyl, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , C 6-20 aryl, or a 5- to 20-membered heteroaryl, wherein said R k C 1-12 alkyl is independently unsubstituted or further substituted with one or more OH; 5-20 membered heteroaryl, wherein said 5-20 membered heteroaryl is unsubstituted or substituted with one or more R t , wherein R t is OH, NH 2 , C 1-12 alkyl, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl), wherein said R t C 1-12 alkyl, R t —C(O)-(3-15 membered heterocyclyl) C 1-12 alkyl, R t —C(O)NH(C 1-12 alkyl), or R t —C(O)N(C 1-12 alkyl) wherein the C 1-12 alkyl in 2 is independently unsubstituted or further substituted with one or more OH, —C 1-12 alkoxy, or —C(O)NH 2 ; or (ii) C １－１２ Alkyl (wherein the C １－１２ Alkyl is unsubstituted or has one or more R ｎ where R ｎ is OH, oxo, halo, cyano, -C(O)NH ２ , amino, sulfonyl, C １－１２ Alkoxy, C ６－２０ Aryloxy, C ３－１０ Cycloalkyl, C ３－１０ cycloalkenyl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl. is), or b) C １－１２ Alkyl (wherein the C １－１２ Alkyl is unsubstituted or has one or more R ｍ where: R ｍ is OH, halo, cyano, oxo, C １－１２ Alkyl, C １－３ Alkoxy, C ６－２０ Aryloxy, —C(O)NH ２ , -C(O)NH(C １－１２ alkyl), —C(O)N(C １－１２ alkyl) ２ , -C(O)OH, -C(O)-C １－１２ Alkoxy, —C(O)-(3- to 15-membered heterocyclyl), NH ２ , —NH(C １－１２ alkyl), -N(C １－１２ alkyl) ２ , -NHC(O)-C １－１２ Alkyl, —NHC(O)—NH ２ , —NH—SO ２ -C １－１２ Alkyl, —S(O)—C １－１２ Alkyl, —S(O) ２ -C １－１２ Alkyl, —S(O) ２ -NH ２ , C ３－１０ cycloalkyl, or 3- to 15-membered heterocyclyl, wherein The R ｍ C １－１２ Alkyl, C ６－２０ Aryloxy, —C(O)NH(C １－１２ C of alkyl) １－１２ Alkyl, —C(O)N(C １－１２ alkyl) ２ C １－１２ Alkyl, —C(O)OH, —C(O)—C １－１２ Alkoxy, 3- to 15-membered heterocyclyl of —C(O)-(3- to 15-membered heterocyclyl), NH ２ , —NH(C １－１２ C of alkyl) １－１２ Alkyl, —N(C １－１２ alkyl) ２ C １－１２ Alkyl, —NHC(O)—C １－１２ Alkyl C １－１２ Alkyl, —NHC(O)—NH ２ , —NH—SO ２ -C １－１２ Alkyl C １－１２ Alkyl, —S(O)—C １－１２ Alkyl C １－１２ Alkyl, —S(O) ２ -C １－１２ Alkyl C １－１２ Alkyl, —S(O) ２ -NH ２ , C ３－１０ The cycloalkyl or 3- to 15-membered heterocyclyl may be unsubstituted or may contain one or more of OH, halo, cyano, oxo, C １－１２ Alkyl, C １－１２ Alkoxy, —C(O)NH ２ , -C(O)NH(C １－１２ alkyl), —C(O)N(C １－１２ alkyl) ２ , C(O)OH, NH ２ , —NH(C １－１２ alkyl), -N(C １－１２ alkyl) ２ , C ３－１０ Cycloalkyl, C ６－２０ aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl), or c) C ３－１０ cycloalkenyl (wherein said C 3-10 cycloalkenyl is unsubstituted or substituted with one or more R i , where R i is oxo, NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , or 3- to 15-membered heterocyclyl, where said 3- to 15-membered heterocyclyl of R i , —NH(C 1-12 alkyl)C 1-12 alkyl of R i , or —N(C 1-12 alkyl) 2 C 1-12 alkyl of R i is independently unsubstituted or substituted with one or more OH or C 1-12 alkoxy), or d) a 5- to 20-membered heteroaryl, wherein said 5- to 20-membered heteroaryl is unsubstituted or substituted with one or more OH, NH 2 , C 1-12 alkyl, or C 1-12 alkoxy; or e) a 3- to 15-membered heterocyclyl, wherein said 3- to 15-membered heterocyclyl is unsubstituted or substituted with one or more OH, oxo, NH 2 , or C 1-12 alkyl; or f) amidinyl, wherein said amidinyl is unsubstituted or substituted with one or more R s , where R s is OH, cyano, C 1-12 alkyl, —C(O)—C 1-12 alkyl, —C(O)—C 1-12 alkoxy, C 6-20 aryloxy, or —SO 2 —C 1-12 alkyl, or g) sulfonyl, wherein said sulfonyl is unsubstituted or substituted with one or more R u , where R u is C 1-12 alkyl, NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , or C 6-20 aryl, wherein said C 1-12 alkyl or C 6-20 aryl of said R u is independently unsubstituted or further substituted with one or more halo or C 1-12 alkoxy, or h) cyano; R ３ is H, C １－１２ Alkyl, —C(O)NH ２ or —C(O)—C １－１２ alkoxy, or R ２ and R ３ together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently contain two or more ring heteroatoms and are independently unsubstituted or substituted with one or more oxo; R ４ is absent or H, C １－１２ Alkyl, —C(O)NH ２ , or -C(O)-C １－１２ alkoxy).

2. X １ is N and X ２ is C-R ｘ 2. The compound of claim 1, wherein:

3. X １ is C-R ｘ and X ２ 2. The compound of claim 1, wherein is N, or a pharmaceutically acceptable salt thereof.

4. X １ and X ２ However, each independently, C-R ｘ 2. The compound of claim 1, wherein:

5. Each R ｘ are independently H, halo, or C ３－１０ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

6. Each R ｘ The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is independently H or fluoro.

7. X １ and X ２ and R are each N, or a pharmaceutically acceptable salt thereof.

8. R ２ is C(O)-R ｈ where R ｈ but (i) amino which is unsubstituted or substituted with one or more R q , wherein R q is C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, and wherein said C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl of R q is unsubstituted or substituted with one or more R p , wherein R p is OH, cyano, halo, oxo, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)—(3- to 15-membered heterocyclyl), —S(O)—C 1-12 alkyl, —S(O) 2 —C and R p is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v . The alkyl is unsubstituted or further substituted with one or more OH. C 1-3 alkoxy, -C(O)NH2, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, wherein said C 3-10 cycloalkenyl is unsubstituted or substituted by one or more oxo; C 6-20 aryl, wherein said C 6-20 aryl is unsubstituted or substituted with one or more OH, 5-20 membered heteroaryl, or —C(O)NH 2 ; 3- to 15-membered heterocyclyl (wherein said 3- to 15-membered heterocyclyl is unsubstituted or substituted with one or more R j , where R j is OH, oxo, halo, NH 2 , —N(C 1-12 alkyl) 2 , —N(C 1-12 alkyl)-C(O)C 1-12 alkyl, —NH—SO 2 —C 1-12 alkyl, —SO 2 —C 1-12 alkyl, C 1-12 alkyl, C 1-12 alkoxy, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 ). , a 3- to 15-membered heterocyclyl, or a 5- to 20-membered heteroaryl, wherein said R j C 1-12 alkyl, C 1-12 alkoxy, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl is independently unsubstituted or further substituted with one or more R k , wherein R k is OH, C 1-12 alkyl, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , C 6-20 aryl, or a 5- to 20-membered heteroaryl, wherein said R k C 1-12 alkyl is independently unsubstituted or further substituted with one or more OH; 5-20 membered heteroaryl, wherein said 5-20 membered heteroaryl is unsubstituted or substituted with one or more R t , wherein R t is OH, NH 2 , C 1-12 alkyl, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl), wherein said R t C 1-12 alkyl, R t —C(O)-(3-15 membered heterocyclyl) C 1-12 alkyl, R t —C(O)NH(C 1-12 alkyl), or R t —C(O)N(C 1-12 alkyl) wherein the C 1-12 alkyl in 2 is independently unsubstituted or further substituted with one or more OH, —C 1-12 alkoxy, or —C(O)NH 2 ; or (ii) C 1-12 alkyl, wherein said C 1-12 alkyl is unsubstituted or substituted with one or more R n , and R n is OH, oxo, halo, cyano, —C(O)NH 2 , amino, sulfonyl, C 1-12 alkoxy, C 6-20 aryloxy, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl.

8. The compound according to any one of claims 1 to 7, wherein:

9. R ｈ is amino unsubstituted or substituted with one or more R q , wherein R q is C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl, and wherein said C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3- to 15-membered heterocyclyl, or 5- to 20-membered heteroaryl of R q is unsubstituted or substituted with one or more R p , wherein R p is OH, cyano, halo, oxo, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)—(3- to 15-membered heterocyclyl), —S(O)—C 1-12 alkyl, —S(O) 2 —C and R p is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, and wherein R v is independently unsubstituted or substituted with one or more R v .

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein alkyl is unsubstituted or further substituted with one or more OH.

10. R ｈ NH ２ 9. The compound of claim 8, wherein:

11. R １ But C ３－１２ Alkyl or C ３－１０ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

12. R １ But C ３－６ Alkyl or C ３－８ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

13. R １ The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is sec-butyl, i-propyl, or cyclohexyl.

14. R １ The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is sec-butyl.

15. R ３ and R ４ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each is independently H.

16. R ｙ and R ｚ are each independently H, halo, or C ３－１０ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

17. R ｙ and R ｚ The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each is independently H or fluoro.

18. A compound selected from the group consisting of: 【Chemistry 176-1】 【Chemistry 176-2】 【Chemistry 176-3】 【Chemistry 176-4】 【Chemistry 176-5】 【Chemistry 176-6】 【Chemistry 176-7】 【Chemistry 176-8】 【Chemistry 176-9】 【Chemistry 176-10】 【Chemistry 176-11】 【Chemistry 176-12】 【Chemistry 176-13】 【Chemistry 176-14】 【Chemistry 176-15】 【Chemistry 176-16】 【Chemistry 176-17】 [Chemistry 176-18] 【Chemistry 176-19】 【Chemistry 176-20】 【Chemistry 176-21】 【Chemistry 176-22】 [Chemistry 176-23] [Chemistry 176-24] 【Chemistry 176-25】 [Chemistry 176-26] [Chemistry 176-27] [Chemistry 176-28] [Chemistry 176-29] 【Chemistry 176-30】 【Chemistry 176-31】 [Chemistry 176-32] [Chemistry 176-33] [Chemistry 176-34] [Chemistry 176-35] [Chemistry 176-36] [Chemistry 176-37] [Chemistry 176-38] [Chemistry 176-39] [Chemistry 176-40] [Chemistry 176-41] [Chemistry 176-42] [Chemistry 176-43] [Chemistry 176-44] [Chemistry 176-45] [Chemistry 176-46] [Chemistry 176-47] [Chemistry 176-48] [Chemistry 176-49] 【Chemistry 176-50】 【Chemistry 176-51】 [Chemistry 176-52] [Chemistry 176-53] [Chemistry 176-54] 【Chemistry 176-55】 [Chemistry 176-56] [Chemistry 176-57] [Chemistry 176-58] [Chemistry 176-59] 【Chemistry 176-60】 【Chemistry 176-61】 [Chemistry 176-62] [Chemistry 176-63] [Chemistry 176-64] [Chemistry 176-65] 【Chemistry 176-66】 [Chemistry 176-67] [Chemistry 176-68] [Chemistry 176-69] 【Chemistry 176-70】 【Chemistry 176-71】 [Chemistry 176-72] [Chemistry 176-73] [Chemistry 176-74] [Chemistry 176-75] 【Chemistry 176-76】 [Chemistry 176-77] [Chemistry 176-78] [Chemistry 176-79] [Chemistry 176-80] [Chemistry 176-81] [Chemistry 176-82] [Chemistry 176-83] [Chemistry 176-84] 【Chemistry 176-85】 [Chemistry 176-86] [Chemistry 176-87] 【Chemistry 176-88】 [Chemistry 176-89] [Chemistry 176-90] 【Chemistry 176-91】 [Chemistry 176-92] [Chemistry 176-93] [Chemistry 176-94] 【Chemistry 176-95】 【Chemistry 176-96】 [Chemistry 176-97] 【Chemistry 176-98】 【Chemistry 176-99】 [Chemistry 176-100] 【Chemistry 176-101】 【Chemistry 176-102】 【Chemistry 176-103】 [Chemistry 176-104] 【Chemistry 176-105】 [Chemistry 176-106] [Chemistry 176-107] or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of: 【Chemistry 177】 or a pharmaceutically acceptable salt thereof.

20. The compound is Compound 9: 【Chemistry 178】 2. The compound of claim 1, wherein:

21. The compound is Compound 10: 【Chemistry 179】 2. The compound of claim 1, wherein:

22. The compound is Compound 12: 【Chemistry 180】 2. The compound of claim 1, wherein:

23. Compound 10: 【Chemistry 181】 2. A crystal of the formula (I), characterized in that the crystal has an XRPD pattern including peaks at 2θ angles of 8.26±0.2 degrees, 16.47±0.2 degrees, 24.36±0.2 degrees, and 24.75±0.2 degrees.

24. 24. The crystal of claim 23, wherein the XRPD pattern is further characterized by additional peaks at 2θ angles of 18.92±0.2 degrees, 26.57±0.2 degrees, and 31.67±0.2 degrees.

25. The XRPD pattern shows 11.84±0.2 degrees, 12.49±0.2 degrees, 13.08±0.2 degrees, 14.11±0.2 degrees, 14.38±0.2 degrees, 15.71±0.2 degrees, 16.96±0.2 degrees, 17.20±0.2 degrees, 18.05±0.2 degrees, 18.39±0.2 degrees, 20.29±0.2 degrees, 20.68±0.2 degrees, 20.99±0.2 degrees, 22.13±0.2 degrees, 22.67±0.2 degrees, 23.65±0.2 degrees, 25.30±0.2 degrees, 26 25. The crystal of claim 23 or 24, further characterized by having two or more additional peaks at 2θ angles selected from the group consisting of 23±0.2 degrees, 26.97±0.2 degrees, 27.30±0.2 degrees, 27.66±0.2 degrees, 28.07±0.2 degrees, 28.36±0.2 degrees, 29.06±0.2 degrees, 29.58±0.2 degrees, 29.98±0.2 degrees, 30.54±0.2 degrees, 31.04±0.2 degrees, 31.33±0.2 degrees, and 32.70±0.2 degrees.

26. 26. The crystal of any one of claims 23 to 25, characterized by a differential scanning calorimetry trace recorded at a heating rate of 10°C per minute, which exhibits an endothermic heat flow maximum at a temperature between 238°C and 250°C.

27. Compound 10: 【Chemistry 182】 1. A crystal of formula (I), characterized in that it has an XRPD pattern including peaks at 2θ angles of 10.16±0.2 degrees, 13.86±0.2 degrees, 16.60±0.2 degrees, and 19.54±0.2 degrees.

28. 30. The crystal of claim 27, wherein the XRPD pattern is further characterized by additional peaks at 2θ angles of 20.70±0.2 degrees, 25.38±0.2 degrees, 26.51±0.2 degrees, and 26.92±0.2 degrees.

29. The XRPD pattern showed the following peaks: 8.18±0.2 degrees, 12.04±0.2 degrees, 17.42±0.2 degrees, 18.41±0.2 degrees, 20.03±0.2 degrees, 20.44±0.2 degrees, 21.72±0.2 degrees, 22.56±0.2 degrees, 24.25±0.2 degrees, 24.79±0.2 degrees, 25.73±0.2 degrees, 25.92±0.2 degrees, 28.38±0.

29. The crystal of claim 27 or 28, further characterized by having two or more additional peaks at 2θ angles selected from the group consisting of 2θ angles of 28.2 degrees, 28.85±0.2 degrees, 29.33±0.2 degrees, 30.08±0.2 degrees, 30.33±0.2 degrees, 30.73±0.2 degrees, 31.63±0.2 degrees, 32.04±0.2 degrees, and 32.43±0.2 degrees.

30. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

31. 31. A composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting states, muscle myopathy, muscle atrophy and muscle fatigue, frailty, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, muscle myopathy, stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, muscle wasting due to cancer, or chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), muscle dysfunction after stroke, facioscapulohumeral muscular dystrophy, and Charcot-Marie-Tooth disease in a subject.

32. A composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the prevention or treatment of facioscapulohumeral muscular dystrophy.

33. A composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the prevention or treatment of Charcot-Marie-Tooth disease.

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