WO2023245137A1 - Slow skeletal troponin activators - Google Patents

Slow skeletal troponin activators Download PDF

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Publication number
WO2023245137A1
WO2023245137A1 PCT/US2023/068537 US2023068537W WO2023245137A1 WO 2023245137 A1 WO2023245137 A1 WO 2023245137A1 US 2023068537 W US2023068537 W US 2023068537W WO 2023245137 A1 WO2023245137 A1 WO 2023245137A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
group
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PCT/US2023/068537
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French (fr)
Inventor
Makoto Yamasaki
Pu-Ping Lu
Bradley P. Morgan
Marc GARARD
Scott Collibee
Yohei Koganemaru
Yuichi SAMI
Kenji Negoro
Sunao Imada
Takashi Kamikubo
Noriko Ishikawa
Yusuke INAGAKI
Kei Ohnuki
Shota SATO
Hiroaki Tanaka
Junya Ishida
Tomoaki Abe
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Cytokinetics, Incorporated
Astellas Pharma Inc.
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Publication of WO2023245137A1 publication Critical patent/WO2023245137A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • heterocyclic compounds comprising such compounds, and methods of using such compounds and pharmaceutical compositions for treating various diseases, disorders, and conditions responsive to the modulation of the contractility of the skeletal sarcomere.
  • the cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called the sarcomere.
  • the sarcomere is elegantly organized as an interdigitating array of thin and thick filaments.
  • the thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed movement.
  • the thin filaments are composed of actin monomers arranged in a helical array.
  • myosin-II is responsible for contraction of skeletal, cardiac, and smooth muscle.
  • This class of myosin is significantly different in amino acid composition and in overall structure from myosin in the other twelve distinct classes.
  • Myosin-II forms homo-dimers resulting in two globular head domains linked together by a long alpha-helical coiled-coiled tail to form the core of the sarcomere’s thick filament.
  • the globular heads have a catalytic domain where the actin binding and ATPase functions of myosin take place. Once bound to an actin filament, the release of phosphate (cf.
  • ADP-Pi to ADP signals a change in structural conformation of the catalytic domain that in turn alters the orientation of the light-chain binding lever arm domain that extends from the globular head; this movement is termed the power stroke.
  • This change in orientation of the myosin head in relation to actin causes the thick filament, of which it is a part, to move with respect to the thin actin filament, to which it is bound.
  • Un-binding of the globular head from the actin filament (Ca 2+ regulated), coupled with return of the catalytic domain and light chain to their starting conformation/orientation completes the catalytic cycle, is responsible for intracellular movement and muscle contraction.
  • troponin and troponin mediate the calcium effect on the interaction on actin and myosin.
  • the troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin.
  • the skeletal troponin-tropomyosin complex regulates the myosin-binding sites extending over several actin units at once.
  • Troponin a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscle.
  • the troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the Ca 2+ dependency of myosin ATPase activity and thereby regulate muscle contraction.
  • the troponin polypeptides T, I, and C are named for their tropomyosin binding, inhibitory, and calcium binding activities, respectively.
  • Troponin T binds to tropomyosin and is believed to be responsible for positioning 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 interaction of actin and myosin.
  • Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the level of calcium in the muscle is raised, troponin C exposes a binding site for troponin I, recruiting it away from actin. This causes the tropomyosin molecule to shift its position as well, thereby exposing the myosin binding sites on actin and stimulating myosin ATPase activity.
  • **TPM3 represents tropomyosin 3
  • Muscle contraction and force generation is controlled through nervous stimulation by innervating motor neurons.
  • Each motor neuron may innervate many (approximately 100 to 380) muscle fibers as a contractile whole, termed a motor unit.
  • motor neurons send stimuli as nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit.
  • the contact region between nerve and muscle fibers is a specialized synapse called the neuromuscular junction (NMJ).
  • NMJ neuromuscular junction
  • membrane depolarizing action potentials in the nerve are translated into an impulse in the muscle fiber through release of the neurotransmitter acetylcholine (ACh).
  • ACh neurotransmitter acetylcholine
  • ACh triggers a second action potential in the muscle that spreads rapidly along the fiber and into invaginations in the membrane, termed t-tubules.
  • T-tubules are physically connected to Ca 2+ stores within the sarcoplasmic reticulum (SR) of muscle via the dihydropyridine receptor (DHPR). Stimulation of the DHPR activates a second Ca 2+ channel in the SR, the ryanodine receptor, to trigger the release of Ca 2+ from stores in the SR to the muscle cytoplasm where it can interact with the troponin complex to initiate muscle contraction.
  • SR sarcoplasmic reticulum
  • DHPR dihydropyridine receptor
  • the invention provides novel compounds that are expected to be used as an active ingredient in a pharmaceutical composition, and in particular, in a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere.
  • Modulation of the skeletal sarcomere may be modulation, for example, by modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • X 1 , R 1 and are defined by either (i) or (ii):
  • R 1 is oxo; and is a single bond; or
  • R 1 is hydrogen or Ci-Ce alkyl; and is a double bond;
  • X 2 and X 3 are each independently N or CH;
  • R 2 is hydrogen or halogen
  • R 3 is Ci-C 6 haloalkyl
  • L is absent or -CH2-
  • each R A is independently selected from the group consisting of Ci-Ce alkyl, halogen, -NHS(O) 2 R 4 , -NHC(O)OR 4 , -CN, -C(O)N(R 4 )2, -S(O) 2 N(R 4 )2, -C(O)R 4 , -OH, -OR 4 , - S(O) 2 R 4 ,
  • each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five R B ;
  • each R B is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R 4 is independently selected from the group consisting of:
  • Ci-C 6 alkyl optionally substituted with one to five R 5 ; each R 5 is independently selected from the group consisting of:
  • each R 6 is independently selected from the group consisting of H and Ci-Ce alkyl.
  • composition comprising a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • kits for treating a disease, a disorder, or condition in a subject in need thereof including administering to the subject a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof.
  • the disease, the disorder, or the condition is frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromy
  • ALS
  • Also provided are methods of activating slow skeletal muscle troponin wherein the method involves contacting the slow skeletal muscle troponin with a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof.
  • references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • References to a compound of Formula (I) include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
  • references to a compound of Formula (I) include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) include polymorphs, solvates, and/or co-crystals thereof. In some embodiments, references to a compound of Formula (I) include isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) include solvates thereof. Similarly, the term “salts” includes solvates of salts of compounds.
  • Alkyl encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
  • Ci-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and isopropyl; and "butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • 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.
  • Aryl indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.
  • Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
  • a l,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
  • 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group.
  • 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).
  • aryl is phenyl or naphthyl.
  • aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
  • Ci-6 alkyl When a range of values is given (e.g., Ci-6 alkyl), each value within the range as well as all intervening ranges are included.
  • Ci-6 alkyl includes Ci, C2, C3, C4, C 5 , C 6 , C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C14, C2 , C3-4, Ci-3, C2-3, and C1-2 alkyl.
  • Halogen or “halo” refers to fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an alkyl moiety, as defined herein, wherein one or more of the hydrogen atoms in the alkyl moiety are replaced by one or more independently selected halo moieties.
  • haloalkyl moieties include, but are not limited to, -CH2F, -CHF2, -CF 3 , -CH2-CH2CI, -CH2-CHCI2, -CH2-CCI3, and -CHF-CH2CI.
  • Cycloalkyl indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbomane, bicyclo[2.2.2]octane).
  • one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon.
  • a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group
  • l,2,3,4-tetrahydronaphthalen-5- yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.
  • Heteroaryl indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and 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 the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
  • a 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.
  • pyrrole pyrazole
  • a heteroaryl group is polycyclic. In some instances, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyrrolo[2,3- b]pyridine, lH-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[l,2,3]triazolo[4,5- b]pyridine, lH-pyrrolo[3,2-b]pyridine, lH-pyrazolo[4,3-b]pyridine, lH-imidazo[4,5- b]pyridine, lH-[l,2,3]triazol
  • polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
  • 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.
  • polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non- aromatic ring are described below.
  • polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl)
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • indenyl 2,3-dihydro-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imid
  • each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
  • Heterocyclyl includes heterocycloalkyl moieties and heterocycloalkenyl moieites, as defined below.
  • Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocyclo alkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
  • Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S -oxide and thiomorpholine S,S-dioxide.
  • spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro [3.3 ]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane.
  • one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocyclo alkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group
  • 1, 2,3,4- tetrahydroquinolin-8-yl group is not considered a heterocycloalkyl group.
  • Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
  • Heterocycloalkenyl indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl.
  • Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • 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-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-lH-imidazolyl, 4,5-dihydro-lH-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1, 2,3,4- tetrahydropyridinyl (
  • one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1,2-dihydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group
  • l,2-dihydroquinolin-8-yl group is not considered a heterocycloalkenyl group.
  • polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.
  • the compounds of the invention and disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like.
  • Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated.
  • the depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
  • compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group.
  • amines and other reactive groups may similarly be protected.
  • pharmaceutically acceptable salt refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are 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 with inorganic acids 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 with 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 including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).
  • bases compounds see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • 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 hemi-hydrates.
  • 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, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
  • substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamin
  • unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
  • a substituted group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another.
  • a substituted group or moiety bears from one to five substituents.
  • a substituted group or moiety bears one substituent.
  • a substituted group or moiety bears two substituents.
  • a substituted group or moiety bears three substituents.
  • a substituted group or moiety bears four substituents.
  • a substituted group or moiety bears five substituents.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
  • the compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound contains at least one deuterium atom.
  • deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein.
  • Deuterium substituted compounds can be synthesized using various 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.
  • 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 pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • the terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish.
  • the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans.
  • the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
  • the compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
  • the term “therapeutic” refers to the ability to modulate the slow skeletal muscle myosin.
  • modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the chemical entity with the a target or due to the interaction of the chemical entity with one or more other factors that in turn affect the target's activity.
  • the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
  • therapeutically effective amount refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
  • a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of slow skeletal muscle myosin.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
  • Treatment includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
  • the term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • prevention includes causing the clinical symptoms of a disease or disorder not to develop.
  • the term encompasses situations where the disease or disorder is not currently being experienced but is expected to arise.
  • the compounds disclosed and/or described herein may prevent a disease or disorder from developing or lessen the extent of a disease or disorder that may develop.
  • ATPase refers to an enzyme that hydrolyzes ATP.
  • ATPases include proteins comprising molecular motors such as the myosins.
  • selective binding refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types.
  • a compound selectively binds to slow skeletal muscle troponin if the compound preferentially binds slow skeletal muscle troponin in comparison with slow skeletal muscle troponin.
  • X 1 , R 1 and are defined by either (i) or (ii):
  • R 1 is oxo; and is a single bond; or
  • R 1 is hydrogen or Ci-Ce alkyl; and is a double bond;
  • X 2 and X 3 are each independently N or CH;
  • R 2 is hydrogen or halogen
  • R 3 is Ci-C 6 haloalkyl
  • L is absent or -CH2-;
  • A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one to five R A ;
  • each R A is independently selected from the group consisting of Ci-Ce alkyl, halogen, -NHS(O) 2 R 4 , -NHC(0)0R 4 , -CN, -C(O)N(R 4 )2, -S(O) 2 N(R 4 )2, -C(O)R 4 , -OH, -OR 4 , - S(O) 2 R 4 ,
  • each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five R B ;
  • each R B is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R 4 is independently selected from the group consisting of:
  • Ci-Ce alkyl optionally substituted with one to five R 5 ; each R 5 is independently selected from the group consisting of:
  • each R 6 is independently selected from the group consisting of H and Ci-Ce alkyl.
  • X 1 is CH, R 1 is hydrogen or Ci-Ce alkyl, and is a double bond. In some embodiments, R 1 is Ci-Ce alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is hydrogen. In some embodiments, X 1 is NH, R 1 is oxo, and is a single bond.
  • the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is a compound of Formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 is Ci-Ce alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is hydrogen.
  • the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is a compound of Formula (III): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • X 2 is N and X 3 is CH. In some embodiments, X 2 and X 3 are each N. In some embodiments, X 2 and X 3 are each CH. In some embodiments, X 2 is CH and X 3 is N.
  • X 2 is N. In some embodiments, X 2 is CH.
  • the compound of Formula (I) or (II) is a compound of Formula (Il-a):
  • R 1 is Ci-Ce alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is hydrogen.
  • the compound of Formula (I) or (II) is a compound of Formula (Il-b) :
  • R 1 is Ci-Ce alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is hydrogen.
  • the compound of Formula (I) or (III) is a compound of Formula (Ill-a): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I) or (III) is a compound of Formula (III-b) :
  • X 3 is N. In some embodiments, X 3 is CH.
  • R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is hydrogen.
  • R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is Ci haloalkyl. In some embodiments, R 3 is -CF3.
  • L is absent. In some embodiments, L is -CH2-.
  • A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl.
  • A is C1-C12 alkyl optionally substituted with one to five R A .
  • A is C1-C12 alkyl substituted with one to five R A .
  • A is C1-C12 alkyl substituted with R A .
  • A is C1-C12 alkyl.
  • A is C6-C12 alkyl optionally substituted with one to five R A .
  • A is C6-C12 alkyl substituted with one to five R A . In some embodiments, A is C6-C12 alkyl substituted with R A . In some embodiments, A is C6-C12 alkyl. In some embodiments, A is Cs alkyl optionally substituted with one to five R A . In some embodiments, A is Cs alkyl substituted with one to five R A . In some embodiments, A is Cs alkyl substituted with R A . In some embodiments, A is Cs alkyl. In some embodiments, A is any other alkyl substituted with R A . In some embodiments, A is Cs alkyl. In some embodiments, A is
  • A is C3-C8 cycloalkyl optionally substituted with one to five R A .
  • A is C3-C8 cycloalkyl substituted with one to five R A .
  • A is C3-C8 cycloalkyl optionally substituted with one to three R A .
  • A is C3-C8 cycloalkyl substituted with one to three R A .
  • A is C3-C8 cycloalkyl substituted with R A .
  • A is C3-C8 cycloalkyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R 4 , and -OR 4 , wherein the Ci-Ce alkyl is optionally substituted with one to five R 5 .
  • A is C3-C8 cycloalkyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R 4 , and -OR 4 , wherein the Ci-Ce alkyl is optionally substituted with R B .
  • A is C3-C8 cycloalkyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R 4 , and -OR 4 , wherein the Ci- Ce alkyl is optionally substituted with -OH or -CN.
  • A is C3-C8 cycloalkyl.
  • A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to five R A .
  • A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to three R A .
  • A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to three R A , wherein R A is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R 4 , and -OR 4 , wherein the Ci-Ce alkyl is optionally substituted with -OH or -CN.
  • A is cyclobutyl substituted with one to five R A .
  • A is cyclobutyl substituted with one to three R A . In some embodiments, A is cyclobutyl substituted with R A . In some embodiments, A is cyclobutyl substituted with R A and R A is -OR 4 , wherein R 4 is Ci-Ce alkyl. In some embodiments, A is cyclobutyl substituted with R A and R A is -OR 4 , wherein R 4 is prop-2-yl. In some embodiments, A is cyclopentyl substituted with one to five R A . In some embodiments, A is cyclopentyl substituted with one to three R A . In some embodiments, A is cyclopentyl substituted with R A .
  • A is cyclopentyl substituted with R A and R A is Ci-Ce alkyl substituted with R B .
  • A is cyclopentyl substituted with R A , R A is Ci-Ce alkyl substituted with R B , and R B is -CN or -OH.
  • A is cyclopentyl substituted with R A and R A is Ci-Ce alkyl substituted with -CN.
  • A is cyclopentyl substituted with R A and R A is -CH2-CN.
  • A is cyclopentyl substituted with R A and R A is Ci-Ce alkyl substituted with -OH.
  • A is cyclopentyl substituted with R A and R A is C3 alkyl substituted with -OH. In some embodiments, A is cyclopentyl substituted with R A and R A is 2-hydroxyprop-2-yl. In some embodiments, A is cyclohexyl substituted with one to five R A . In some embodiments, A is cyclohexyl substituted with one to three R A . In some embodiments, A is cyclohexyl substituted with R A . In some embodiments, A is cyclohexyl substituted with R A and R A is -NHS(O)2R 4 .
  • A is cyclohexyl substituted with R A , R A is -NHS(O)2R 4 , and R 4 is Ci-Ce alkyl. In some embodiments, A is cyclohexyl substituted with R A , R A is -NHS(O)2R 4 , and R 4 is methyl.
  • A is 4- to 8-membered heterocyclyl optionally substituted with one to five R A .
  • A is 4- to 8-membered heterocyclyl substituted with one to five R A .
  • A is 4- to 8-membered heterocyclyl optionally substituted with one to three R A .
  • A is 4- to 8-membered heterocyclyl substituted with one to three R A .
  • A is 4- to 8-membered heterocyclyl.
  • A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one to five R A .
  • A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one to three R A .
  • A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one or two R A .
  • A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with R A .
  • A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with two R A .
  • A is azetidinyl optionally substituted with one to four R A .
  • A is azetidinyl substituted with one to four R A .
  • A is azetidinyl substituted with R A .
  • A is azetidinyl substituted with R A and R A is Ci-C 6 alkyl substituted with one to five R B .
  • A is azetidinyl substituted with R A and R A is Ci-Ce alkyl substituted with one to five R B . In some embodiments, A is azetidinyl substituted with R A and R A is Ci-Ce alkyl substituted with R B . In some embodiments, A is azetidinyl substituted with R A , R A is Ci-Ce alkyl substituted with R B , and R B is OH. In some embodiments, A is azetidinyl substituted with R A and R A is 2- hydroxyethyl. In some embodiments, A is azetidinyl substituted with R A and R A is 2- hydroxy-2-methylpropyl.
  • A is pyrrolidinyl optionally substituted with one to five R A .
  • A is pyrrolidinyl substituted with one to five R A .
  • A is pyrrolidinyl substituted with one to three R A .
  • A is pyrrolidinyl substituted with one or two R A .
  • A is pyrrolidinyl substituted with R A .
  • A is pyrrolidinyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl optionally substituted with one to five R B , -OR 4 , and - C(O)N(R 4 )2. In some embodiments, A is pyrrolidinyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl substituted with one to five R B , -OR 4 , and - C(O)N(R 4 )2.
  • A is pyrrolidinyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl substituted with one to three R B , -OR 4 , and - C(O)N(R 4 )2. In some embodiments, A is pyrrolidinyl substituted with R A and R A is selected from the group consisting of Ci-Ce alkyl optionally substituted with R B , -OR 4 , and - C(O)N(R 4 )2. In some embodiments, A is pyrrolidinyl substituted with R A and R A is Ci-Ce alkyl substituted with R B .
  • A is pyrrolidinyl substituted with R A , R A is Ci-C 6 alkyl substituted with R B , and R B is -OH or phenyl. In some embodiments, A is pyrrolidinyl substituted with R A , R A is Ci-Ce alkyl substituted with R B , and R B is -OH. In some embodiments, A is pyrrolidinyl substituted with R A and R A l-hydroxy-2-methylprop-2- yl. In some embodiments, A is pyrrolidinyl substituted with R A , R A is Ci-Ce alkyl substituted with R B , and R B is phenyl.
  • A is pyrrolidinyl substituted with R A and R A is -CHi-phenyl. In some embodiments, A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl optionally substituted with one to five R 5 . In some embodiments, A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl substituted with one to five R 5 . In some embodiments, A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-C 6 alkyl substituted with one to three R 5 .
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl substituted with one or two R 5 .
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl.
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is C1-C3 alkyl.
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is methyl or prop-2-yl.
  • A is pyrrolidinyl substituted with R A , R A is - OR 4 , and R 4 is methyl. In some embodiments, A is pyrrolidinyl substituted with R A , R A is - OR 4 , and R 4 is prop-2-yl. In some embodiments, A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl substituted with R 5 . In some embodiments, A is pyrrolidinyl substituted with R A , R A is -OR 4 , R 4 is Ci-Ce alkyl substituted with R 5 , and R 5 is -OH.
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is Ci-Ce alkyl substituted with two R 5 .
  • A is pyrrolidinyl substituted with R A , R A is - OR 4 , R 4 is Ci-Ce alkyl substituted with two R 5 , and each R 5 is independently halogen.
  • A is pyrrolidinyl substituted with R A , R A is -OR 4 , and R 4 is 2,2- difluoropropyl.
  • A is pyrrolidinyl substituted with R A and R A is - C(O)N(R 4 )2.
  • A is pyrrolidinyl substituted with R A , R A is - C(O)N(R 4 )2, and R 4 is Ci-Ce alkyl.
  • A is pyrrolidinyl substituted with R A and R A is -C(O)N(CH3)2.
  • A is pyrrolidinyl substituted with two R A .
  • A is pyrrolidinyl substituted with Ci-Ce alkyl and -C(O)R 4 .
  • A is pyrrolidinyl substituted with Ci-Ce alkyl and -C(O)R 4- , and R 4 is Ci-Ce alkyl.
  • A is pyrrolidinyl substituted with methyl and -C(O)R 4 , wherein R 4 is prop-2-yl.
  • A is pyrrolidinyl substituted with -OR 4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , -C(O)OR 4 , 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five R B .
  • A is pyrrolidinyl substituted with -OR 4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , - C(O)OR 4 , 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently substituted with one to five R B .
  • A is pyrrolidinyl substituted with -OR 4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , -C(O)OR 4 , 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five R B ; wherein each R B is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), - C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to
  • A is pyrrolidinyl substituted with - OR 4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , -C(O)OR 4 , 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five R B ; wherein each R B is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci- Ce alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8
  • A is pyrrolidinyl substituted with -OR 4 wherein R 4 is Ci-Ce alkyl optionally substituted with one to five R 5 ; and A is substituted with a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , -C(O)OR 4 , 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl is independently optionally substituted with one to five R B ; wherein each R B is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C 6 alkyl), -C(O)O(Ci-C 6 alkyl), -C(O)(C)(C)
  • A is pyrrolidinyl substituted with -OR 4 wherein R 4 is selected from the group consisting of methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-2-yl, 2,2-difluoroethyl, 2- hydroxyethyl, 2-methoxyethyl, 2-(2-hydroxy-2-methylpropoxy)-2-methylprop-l-yl, 2- hydroxy-2-methylprop-l-yl, 2-morpholinoethyl, and 2-(4-methylpiperazin-l-yl)ethyl; and A is substituted with a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R 4 , -S(O)2R 4 , -C(O)OR 4 , 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl, wherein each Ci-Ce alkyl, 4-
  • A is pyrrolidinyl substituted with a first substituent selected from the group [0072]
  • A is piperidine substituted with one to five R A .
  • A is piperidine substituted with one to three R A .
  • A is piperidine substituted with one or two R A .
  • A is piperidine substituted with R A .
  • A is piperidine substituted with R A , wherein R A is selected from the group consisting of Ci-Ce alkyl and 4- to 8-membered heterocyclyl, wherein each of the Ci-Ce alkyl and 4- to 8-membered heterocyclyl is independently optionally substituted with one to five R B .
  • A is piperidine substituted with R A , wherein R A is selected from the group consisting of Ci-Ce alkyl and 4- to 8-membered heterocyclyl, wherein each of the Ci-Ce alkyl and 4- to 8-membered heterocyclyl is independently optionally substituted with one to five R B , and wherein each R B is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8- membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH.
  • A is piperidine substituted with R A , wherein R A is Ci-Ce alkyl optionally substituted with one to five R B , and wherein each R B is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH.
  • A is piperidine substituted with R A , wherein R A is Ci-Ce alkyl optionally substituted with one to five R B , and wherein each R B is independently selected from the group consisting of -OH and 4- to 8 -membered heterocyclyl.
  • A is piperidine substituted with R A , wherein R A is selected from the group consisting some embodiments, A is piperidine substituted with R A , wherein R A is 4- to 8-membered heterocyclyl optionally substituted with one to five R B , and wherein each R B is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8- membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH.
  • A is piperidine substituted with R A , wherein R A is 4- to 8-membered heterocyclyl optionally substituted with one to five R B , and wherein each R B is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), - C(O)(Ci-C6 alkyl), and 4- to 8-membered heterocyclyl.
  • R A is piperidine substituted with R A , wherein R A is 4- to 8-membered heterocyclyl substituted with R B , and wherein R B is selected from the group consisting of -C(O)O(Ci-C6 alkyl), -C(O)(Ci-
  • A is piperidine substituted with R A , wherein R A is selected from the group consisting of In some embodiments, A is piperidine substituted with R A , wherein R A is selected from the group consisting of embodiments, A is piperidine substituted with two R A . In some embodiments, A is piperidine substituted with halogen and a second substituent which is Ci-Ce alkyl substituted with one to five substituents independently selected from the group consisting of -OH, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH.
  • A is piperidine substituted with fluoro and a second substituent which is Ci-Ce alkyl substituted with one to five substituents independently selected from the group consisting of -OH, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH.
  • A is piperidine substituted with fluoro and a second substituent selected from the group consisting of
  • A is piperazine optionally substituted with one to five R A .
  • A is piperazine optionally substituted with one to three R A .
  • A is piperazine optionally substituted with one or two 2 R A .
  • A is piperazine substituted with two R A .
  • A is piperazine substituted with Ci-Ce alkyl or -C(O)R 4 , wherein R 4 is Ci-Ce alkyl, and with Ci-Ce alkyl or Ci-Ce alkyl substituted with Ce-Cio aryl.
  • A is piperazine substituted with two substituents selected from the group consisting of methyl, acetyl, and benzyl.
  • A is piperazine substituted with methyl and benzyl, methyl and acetyl, or acetyl and benzyl.
  • A is morpholine optionally substituted with one to five R A .
  • A is morpholine optionally substituted with one to three R A .
  • A is morpholine optionally substituted with one or two 2 R A .
  • A is morpholine substituted with R A .
  • A is morpholine substituted with -C(O)R 4 and R 4 is 4- to 8-membered heterocyclyl optionally substituted with -C(O)OC(Ci-C6 alkyl).
  • A is morpholine substituted with -C(O)R 4 and R 4 is azetidine substituted with -C(O)O(C(CH3)3).
  • A is tetrahydrofuran optionally substituted with one to five R A .
  • A is tetrahydrofuran optionally substituted with one to three R A .
  • A is tetrahydrofuran optionally substituted with one or two 2 R A .
  • A is tetrahydrofuran optionally substituted with R A .
  • A is tetrahydrofuran optionally substituted with -OR 4 . In some embodiments, A is tetrahydrofuran optionally substituted with -OR 4 and R 4 is Ci-Ce alkyl optionally substituted with one to five R 5 . In some embodiments, A is tetrahydrofuran optionally with -OR 4 and R 4 is Ci-C 6 alkyl substituted with R 5 . In some embodiments, A is tetrahydrofuran substituted with -OR 4 and R 4 is Ci-Ce alkyl substituted with OH or 5- to 6-membered heterocyclyl.
  • A is tetrahydrofuran substituted with or [0076]
  • A is 5- to 10-membered heteroaryl optionally substituted with one to five R A .
  • A is pyridine or oxazole, each independently optionally substituted with one to five R A .
  • A is 5- to 10-membered heteroaryl substituted with one to five R A .
  • A is pyridine or oxazole, each independently substituted with one to five R A . In some embodiments, A is pyridine or oxazole, each independently substituted with R A . In some embodiments, A is pyridine or oxazole, each independently substituted with Ci-Ce alkyl or -CN. In some embodiments, A is pyridine substituted with Ci-Ce alkyl. In some embodiments, A is pyridine substituted with methyl. In some embodiments, A is oxazole substituted with -CN.
  • A is 5- to 10-membered heteroaryl or C1-C12 alkyl, wherein each of which is optionally substituted with one to five R A .
  • A is C1-C12 alkyl optionally substituted with one to five R A .
  • A is C1-C12 alkyl substituted with one to five R A .
  • A is C1-C12 alkyl substituted with R A .
  • A is C1-C12 alkyl. In some embodiments, A is C6-C12 alkyl optionally substituted with one to five R A . In some embodiments, A is C6-C12 alkyl substituted with one to five R A . In some embodiments, A is C6-C12 alkyl substituted with R A . In some embodiments, A is C6-C12 alkyl. In some embodiments, A is Cs alkyl optionally substituted with one to five R A . In some embodiments, A is Cs alkyl substituted with one to five R A . In some embodiments, A is Cs alkyl substituted with R A . In some embodiments, A is Cs alkyl.
  • A is 2-hydroxy-2,5-dimethylhexan-4-yl. In some embodiments, A is . In some embodiments, A is 5- to 10-membered heteroaryl optionally substituted with one to five R A . In some embodiments, A is 5- to 10-membered heteroaryl substituted with one to five R A . In some embodiments, A is pyridine or oxazole, each independently substituted with one to five R A . In some embodiments, A is pyridine or oxazole, each independently substituted with R A . In some embodiments, A is pyridine or oxazole, each independently substituted with Ci-Ce alkyl or -CN. In some embodiments, A is pyridine substituted with Ci-Ce alkyl. In some embodiments, A is pyridine substituted with methyl. In some embodiments, A is oxazole substituted with -CN.
  • any of the compounds described herein such as a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom).
  • the compound is deuterated at a single site.
  • 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 nondeuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.
  • Any formula given herein such as Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
  • any formula given 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.
  • a compound of Table 2 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio.
  • a compound of Table 2 has a stereocenter that is in an “S” stereochemical configuration
  • enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration.
  • a compound of Table 2 has a stereocenter that is in an “R” configuration
  • enantiomer of the compound in an “S” stereochemical configuration also provided herein is enantiomer of the compound in an “S” stereochemical configuration.
  • mixtures of the compound with both the “S” and the “R” stereochemical configuration also provided are any enantiomer or diastereomer of the compound.
  • a compound of Table 2 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively
  • a compound of Table 2 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively.
  • a compound of Table 2 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively.
  • a compound of Table 2 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “R” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the solvent is water and the solvates are hydrates.
  • any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual or subject.
  • the compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts.
  • the compounds herein are synthetic compounds prepared for administration to an individual or subject.
  • compositions are provided containing a compound in substantially pure form.
  • pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • Any variation or embodiment of X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , L, A, and R A provided herein can be combined with every other variation or embodiment of X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , L, A, and R A , as if each combination had been individually and specifically described.
  • compositions such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
  • the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.
  • compositions such as pharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a pharmaceutically acceptable composition comprising Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.
  • a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein.
  • the compositions described herein may contain any other suitable active or inactive agents.
  • compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.
  • packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.
  • Compounds and compositions detailed herein such as a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease, a disorder, or a condition in an individual or subject.
  • a method of treating a disease, a disorder, or a condition in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.
  • Also provided herein is the use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treatment of a disease, a disorder, or a condition in a subject.
  • a compound or composition as described herein for use in a method of treatment of the human or animal body by therapy.
  • provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in a method of treatment of the human or animal body by therapy.
  • provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating or preventing a disease, a disorder, or a condition .
  • provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating a disease, a disorder, or a condition .
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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.
  • the invention relates to a pharmaceutical composition for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, in a subject, comprising a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a disease or condition responsive to modulation of the contractility of the skeletal sarcomere for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin
  • the invention relates to an agent for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin
  • the invention relates to a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, in a subject, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a disease or condition responsive to modulation of the contractility of the skeletal sarcomere for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin,
  • the invention relates to an agent for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and iso
  • the invention relates to use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof in a subject.
  • a disease or condition responsive to modulation of the contractility of the skeletal sarcomere for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myo
  • the invention relates to use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • a method for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the “subject” is a human or a non-human animal in need of the prevention or treatment, and in one embodiment, a human in need of the prevention or treatment.
  • a method for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the “subject” is a human or a non-human animal in need of the prevention or treatment, and in one embodiment, a human in need of the prevention or treatment.
  • Such medical therapy may be relating to a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (III- b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing modulates the contractility of the skeletal sarcomere.
  • the compounds modulate the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • “modulate” means either increasing or decreasing activity.
  • a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing potentiates (i.e., increases activity) of one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • “activation of the slow skeletal muscle fiber such as myofibril” means to amplify the response of slow skeletal muscle fiber (such as myofibril) to stimulation/Ca 2+ .
  • a method of preventing or treating frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture
  • a method of treating frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, I
  • a method for preventing or treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator- induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty, in a subject comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a
  • a method for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty, in a subject comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt
  • a method 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 myopathies comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • a method for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathies comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • myasthenia gravis and muscular
  • a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation- related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
  • a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • myasthenia gravis myasthenia gravis
  • muscular myopathies in a subject.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • myasthenia gravis myasthenia gravis
  • muscular myopathies in a subject.
  • SUI stress urinary incontinence
  • MUI mixed urinary incontinence
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive
  • SUI stress urinary incontinence
  • MUI mixed urinary incontinence
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary
  • a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
  • a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • myasthenia gravis myasthenia gravis
  • muscular myopathies in a subject.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • myasthenia gravis myasthenia gravis
  • muscular myopathies in a subject.
  • a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, s
  • a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia
  • the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.
  • a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight.
  • the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day.
  • the amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day
  • an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetic s .
  • a daily dose is the total amount administered in a day.
  • a daily dose may be, but is not limited to be, administered each day, every other day, each week, every 2 weeks, every month, or at a varied interval.
  • the daily dose is administered for a period ranging from a single day to the life of the subject.
  • the daily dose is administered once a day.
  • the daily dose is administered in multiple divided doses, such as in 2, 3, or 4 divided doses.
  • the daily dose is administered in 2 divided doses.
  • Administration of the compounds and compositions disclosed and/or described herein can be via any accepted 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.
  • the compound or composition is administered orally or intravenously.
  • the compound or composition disclosed and/or described herein is administered orally.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms.
  • the compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate.
  • sustained or controlled release dosage forms e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the compounds disclosed and/or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate).
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate).
  • the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, 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 acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives).
  • a diluent e.g., lactose, sucrose, dicalcium phosphate
  • a lubricant e.g., magnesium stearate
  • a binder e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives.
  • Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides)
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject.
  • composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
  • compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
  • compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • additional medicinal agents include those described herein.
  • the article of manufacture may comprise a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers 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 for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
  • kits containing a compound or composition described herein and instructions for use.
  • the kits may contain instructions for use in the treatment of a neuromuscular disease in an individual or subject in need thereof.
  • a kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
  • a kit may also contain sterile packaging.
  • 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.
  • a particular enantiomer of a compound this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • the esterification coupling reagent comprises 1- [bis (dimethy lamino)methy lene] - 1 H- 1 ,2 , 3 -triazolo [4,5 -b] pyridinium 3 -oxide hexafluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- hydroxy-7-azabenzotriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), benzotriazol- 1- yloxytris
  • the esterification coupling reagent comprises HATU, HBTU, EDCI, HOAt, HOBt, BOP, PyBOP, PyAOP, DEPBT, or a mixture of any of the foregoing, and a base such as, for non-limiting example, triethylamine (TEA), diisopropylethylamine (DIPEA), or 4-dimethylaminopyridine (DMAP).
  • a base such as, for non-limiting example, triethylamine (TEA), diisopropylethylamine (DIPEA), or 4-dimethylaminopyridine (DMAP).
  • Intermediate A may be synthesized according to Scheme 3.
  • Intermediate A (a carboxylic acid) is obtained by reacting Intermediate D (an ester) with a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH), wherein X 1 , X 2 , X 3 , R 1 , R 2 , and R 3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
  • a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH)
  • LiOH lithium hydroxide
  • NaOH sodium hydroxide
  • Intermediate A is Intermediate A-l, which may be synthesized according to Scheme 4.
  • Intermediate D-l may be synthesized according to Scheme
  • Intermediate D-l is obtained by reacting Intermediate F-l with Intermediate G-l in the presence of a base such as sodium hydride (NaH), wherein X 2 , X 3 , R 2 , and R 3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
  • a base such as sodium hydride (NaH)
  • X 2 , X 3 , R 2 , and R 3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
  • Intermediate A is Intermediate A-2, which may be synthesized according to Scheme 6.
  • Intermediate A-2 (a carboxylic acid) is obtained by reacting Intermediate D-2 (an ester) with a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH), wherein X 2 , X 3 , R 2 , and R 3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
  • a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH)
  • LiOH lithium hydroxide
  • NaOH sodium hydroxide
  • Intermediate D-2 may be synthesized according to Scheme 7.
  • Intermediate D-2 is obtained by cyclization of Intermediate H-2 in the presence of copper iodide (Cui), wherein X 2 , X 3 , R 2 , and R 3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
  • Cui copper iodide
  • Step 1 Synthesis of methyl l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2- c ]pyridine-6-carboxylate.
  • reaction mixture was then cooled to 0 °C and quenched with saturated aqueous NH4CI (200 mL).
  • the mixture was warmed to rt and extracted with ethyl acetate (4 x 200 mL).
  • the combined organic extracts were washed with water (4 x 100 mL) and brine (100 mL), dried over sodium sulfate, filtered, concentrated, and chromatographed (0-100% ethyl acetate / hexane) to provide methyl l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l//-pyrrolo[3,2-c]pyridine-6-carboxylate (17.0 g) as a white solid.
  • Step 2 Synthesis of l-(3-Fluoro-5-( trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine- 6-carboxylic acid.
  • Step 3 Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-l- carboxylate.
  • Step 4 Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-(2-hydroxy-2- methylpropoxy )pyrrolidine-l -carboxylate.
  • Step 6 Synthesis of tert-Butyl (3R,4R)-3-(l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH- pyrrolo[3,2-c]pyridine-6-carboxamido)-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l- carboxylate.
  • Step 7 Synthesis of ! -(3-Fluoro-5-(lrifluoromelhyl)pyridin-2-yl)-N-((3R,4R)-4-(2-hydroxy-2- methylpropoxy)pyrrolidin-3-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide hydrochloride.
  • Step 8 Synthesis ofN-((3R,4R)-l-Acetyl-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l- (3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide.
  • the reaction was then concentrated and purified directly using reverse phase HPLC (20-100% acetonitrile in water with 0.1% formic acid).
  • the resultant solid was dissolved in methanol (3 X 10 mL) and concentrated. Ethyl acetate (5 mL) was added, and the mixture was concentrated.
  • reaction mixture was warmed to rt, stirred for Ih, concentrated, and purified using reverse phase chromatography (20-100% CH3CN/H2O with 0.1% formic acid over 40 min) to give 22 mg of l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)- l-(oxetan-3-ylsulfonyl)pyrrolidin-3-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide as an off- white solid.
  • reaction mixture was stirred overnight, concentrated, and purified using reverse phase chromatography (0-50% CH3CN/H2O with 0.1% formic acid) to give 27 mg of A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)-l-methylpyrrolidin-3-yl)-l-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide as a white solid.
  • Step 1 Synthesis of methyl 4-(3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)ureido)-3- iodobenzoate.
  • triphosgene 816 mg
  • dichloromethane 50 mL
  • a solution of 3-fluoro-5- (trifluoromethyl)pyridin-2-amine 1.5 g
  • triethylamine 2.4 mL
  • dichloromethane 20 mL
  • the reaction mixture was stirred for 2 min, followed by the addition of methyl 4- amino-3 -iodobenzoate (2.3 g) and triethylamine (1.2 mL).
  • Step 2 Synthesis of methyl 3-(3-fh oro-5-(trifh oromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro- lH-benzo[d]imidazole-5-carboxylate.
  • Step 3 Synthesis of 3-(3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-lH- benzo[d ]imidazole-5-carboxylic acid.
  • Step 4 Synthesis ofN-((3S,4R)-3-Fluoro-l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-(3- fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxamide.
  • reaction mixture was stirred at rt fori h, filtered, and purified using reverse phase chromatography (0-40% CH3CN/H2O with 0.1% formic acid) to give 32 mg of A-((3R,4S)-4-(2-morpholinoethoxy)tetrahydrofuran-3-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z-benzo[d]imidazole-5-carboxamide as a white solid.
  • Step 1 Synthesis of tert-Butyl 4-(2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH- benzo[d ]imidazole-5-carboxamido )piperidine-l -carboxylate.
  • Step 2 Synthesis of2-Oxo-N-(piperidin-4-yl)-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3- dihydro-lH-benzo[d]imidazole-5-carboxamide.
  • Step 4 Synthesis ofN-(l-(l,3-Dihydroxypropan-2-yl)piperidin-4-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide.
  • reaction mixture was stirred at rt for 2 h, cooled to 0 °C, quenched with water (1 mL), concentrated under reduced pressure, and purified by reverse phase chromatography (Column, XB ridge Prep OBD C18 Column, 30*150 mm, 5 pm; mobile phase, water (10 mM NH4HCO3+0.1% NH 3 H 2 O) and CH 3 CN (30% - 60% over 8 min)) to afford 20 mg of A-(l-(l,3- dihydroxypropan-2-yl)piperidin-4-yl)-2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro- l/Z-benzo[d]imidazole-5-carboxamide (10%) as a white solid.
  • Step 1 Synthesis of methyl (S)-4-methyl-3-(2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3- dihydro-lH-benzo[d]imidazole-5-carboxamido)pentanoate.
  • reaction mixture was stirred at rt for 1 h, filtered, and directly purified using reverse phase chromatography (Phenomenex Gemini 5 pm C18 150 x 21.2 mm column, 10-70% CH3CN/H2O with 0.1% formic acid over 38 min) to give 44 mg of methyl (S)-4-methyl-3-(2- oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z-benzo[d]imidazole-5- carboxamido)pentanoate as a white solid.
  • Step 1 Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-(2-methoxyethoxy)pyrrolidine-l- carboxylate.
  • Step 2 Synthesis of (3R,4R)-N,N-Dibenzyl-4-(2-methoxyethoxy)pyrrolidin-3-amine.
  • Step 3 Synthesis of ethyl 2-((3R,4R)-3-(dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)- 2-methylpropanoate.
  • Step 4 Synthesis of2-((3R,4R)-3-(Dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)-2- methylpropan-1 -ol.
  • the reaction was stirred at 0 °C for 10 min, then warmed to rt and stirred for 2h.
  • the reaction was diluted with EtOAc (20 mL) and washed with saturated ammonium chloride (10 mL) and saturated sodium bicarbonate (10 mL).
  • myofibrils were washed 3 times in wash buffer (50 mM Tris, 100 mM potassium acetate, 5 mM KC1, 2 mM magnesium acetate, 0.5 mM NaNs, 2 mM DTT, 0.2 mM PMSF, final pH 7.4 at 4 °C) and once in storage buffer (12 mM PIPES, 60 mM KC1, 2 mM MgCh, 1 mM DTT, 0.2 mM PMSF, 1 pg/mL leupeptin, 1 pg/mL pepstatin, final pH 6.8).
  • wash buffer 50 mM Tris, 100 mM potassium acetate, 5 mM KC1, 2 mM magnesium acetate, 0.5 mM NaNs, 2 mM DTT, 0.2 mM PMSF, final pH 7.4 at 4 °C
  • storage buffer 12 mM PIPES, 60 mM KC1, 2 mM MgCh, 1 mM
  • Myofibril preparations consisted of bovine masseter muscle (ca 90% slow fibers) that had been mechanically homogenized and washed with a detergent (Triton X-100) to remove cellular membranes. This preparation retained all of the sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. Compounds were tested using a myofibril suspension and a level of calcium sufficient to increase enzymatic activity of the myofibrils to 25% of their maximal rate (termed pCa25).
  • Enzymatic activity was tracked via a pyruvate kinase and lactate dehydrogenase-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm.
  • the buffering system was 12 mM PIPES, 4 mM MgCh, 60 mM KC1 at pH 6.8. Data were reported as AC1.4, which is the concentration at which the compound increased the enzymatic activity by 40%. Results for compounds tested are provided in Table A. Compounds tested were prepared in accordance with the synthetic procedures described herein or using similar synthetic procedures with the appropriate reagents.

Abstract

Provided herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof. Also provided herein is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided 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.

Description

SLOW SKELETAL TROPONIN ACTIVATORS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 63/352,988, filed June 16, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes.
FIELD
[0002] Provided herein are heterocyclic compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and pharmaceutical compositions for treating various diseases, disorders, and conditions responsive to the modulation of the contractility of the skeletal sarcomere.
BACKGROUND
[0003] The cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called the sarcomere. The sarcomere is elegantly organized as an interdigitating array of thin and thick filaments. The thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed movement. The thin filaments are composed of actin monomers arranged in a helical array. There are four regulatory proteins bound to the actin filaments, which allows the contraction to be modulated by calcium ions. An influx of intracellular calcium initiates muscle contraction; thick and thin filaments slide past each other driven by repetitive interactions of the myosin motor domains with the thin actin filaments.
[0004] Of the thirteen distinct classes of myosin in human cells, the myosin-II class is responsible for contraction of skeletal, cardiac, and smooth muscle. This class of myosin is significantly different in amino acid composition and in overall structure from myosin in the other twelve distinct classes. Myosin-II forms homo-dimers resulting in two globular head domains linked together by a long alpha-helical coiled-coiled tail to form the core of the sarcomere’s thick filament. The globular heads have a catalytic domain where the actin binding and ATPase functions of myosin take place. Once bound to an actin filament, the release of phosphate (cf. ADP-Pi to ADP) signals a change in structural conformation of the catalytic domain that in turn alters the orientation of the light-chain binding lever arm domain that extends from the globular head; this movement is termed the power stroke. This change in orientation of the myosin head in relation to actin causes the thick filament, of which it is a part, to move with respect to the thin actin filament, to which it is bound. Un-binding of the globular head from the actin filament (Ca2+ regulated), coupled with return of the catalytic domain and light chain to their starting conformation/orientation completes the catalytic cycle, is responsible for intracellular movement and muscle contraction.
[0005] Tropomyosin and troponin mediate the calcium effect on the interaction on actin and myosin. The troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin. The skeletal troponin-tropomyosin complex regulates the myosin-binding sites extending over several actin units at once.
[0006] Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscle. The troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the Ca2+ dependency of myosin ATPase activity and thereby regulate muscle contraction. The troponin polypeptides T, I, and C, are named for their tropomyosin binding, inhibitory, and calcium binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for positioning 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 interaction of actin and myosin. Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the level of calcium in the muscle is raised, troponin C exposes a binding site for troponin I, recruiting it away from actin. This causes the tropomyosin molecule to shift its position as well, thereby exposing the myosin binding sites on actin and stimulating myosin ATPase activity.
[0007] Human skeletal muscle is composed of different types of contractile fibers, classified by their myosin type and termed either slow or fast fibers. Table 1 summarizes the different proteins that make up these types of muscle. Table 1
Figure imgf000005_0001
*MHC lib is not expressed in human muscle but is present in rodents and other mammals. **TPM3 represents tropomyosin 3
[0008] In healthy humans, most skeletal muscles are composed of both fast and slow fibers, although the proportions of each vary with muscle type. Slow skeletal fibers, often called type I fibers, have more structural similarity with cardiac muscle and tend to be used more for fine and postural control. They usually have a greater oxidative capacity and are more resistant to fatigue with continued use. Fast skeletal muscle fibers, often called type II fibers, are classified into fast oxidative (Ila) and fast glycolytic (type Ilx/d) fibers. While these muscle fibers have different myosin types, they share many components, including the troponin and tropomyosin regulatory proteins. Fast skeletal muscle fibers tend to exert greater force but fatigue faster than slow skeletal muscle fibers and are functionally useful for acute, large scale movements such as rising from a chair or correcting falls.
[0009] Muscle contraction and force generation is controlled through nervous stimulation by innervating motor neurons. Each motor neuron may innervate many (approximately 100 to 380) muscle fibers as a contractile whole, termed a motor unit. When a muscle is required to contract, motor neurons send stimuli as nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit. The contact region between nerve and muscle fibers is a specialized synapse called the neuromuscular junction (NMJ). Here, membrane depolarizing action potentials in the nerve are translated into an impulse in the muscle fiber through release of the neurotransmitter acetylcholine (ACh). ACh triggers a second action potential in the muscle that spreads rapidly along the fiber and into invaginations in the membrane, termed t-tubules. T-tubules are physically connected to Ca2+ stores within the sarcoplasmic reticulum (SR) of muscle via the dihydropyridine receptor (DHPR). Stimulation of the DHPR activates a second Ca2+ channel in the SR, the ryanodine receptor, to trigger the release of Ca2+ from stores in the SR to the muscle cytoplasm where it can interact with the troponin complex to initiate muscle contraction. If muscle stimulation stops, calcium is rapidly taken back up into the SR through the ATP dependent Ca2+ pump, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).
[0010] Currently, there is limited treatment or no cure for most neuromuscular diseases. Thus, there is a need for the development of new compounds that modulate skeletal muscle contractility. There remains a need for agents that exploit new mechanisms of action and which may have better outcomes in terms of relief of symptoms, safety, and patient mortality, both short-term and long-term and an improved therapeutic index.
SUMMARY
[0011] The invention provides novel compounds that are expected to be used as an active ingredient in a pharmaceutical composition, and in particular, in a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere. Modulation of the skeletal sarcomere may be modulation, for example, by modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0012] In one aspect, provided is a compound of Formula (I):
Figure imgf000006_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X1, R1, and are defined by either (i) or (ii):
(i) X1 is NH;
R1 is oxo; and is a single bond; or
(ii) X1 is CH;
R1 is hydrogen or Ci-Ce alkyl; and is a double bond;
X2 and X3 are each independently N or CH;
R2 is hydrogen or halogen;
R3 is Ci-C6 haloalkyl;
L is absent or -CH2-;
A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one to five RA; each RA is independently selected from the group consisting of Ci-Ce alkyl, halogen, -NHS(O)2R4, -NHC(O)OR4, -CN, -C(O)N(R4)2, -S(O)2N(R4)2, -C(O)R4, -OH, -OR4, - S(O)2R4,
-C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB; each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of:
(a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl,
(b) 4- to 8-membered heterocyclyl optionally substituted with one to three - C(O)OC(Ci-C6 alkyl), and
(c) Ci-C6 alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of:
(a) -OH,
(b) halogen,
(c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH,
(d) N(R6)2, and
(e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and each R6 is independently selected from the group consisting of H and Ci-Ce alkyl.
[0013] Provided in some embodiments are compounds selected from the group consisting of compounds of Table 2, or a pharmaceutically acceptable salt thereof.
[0014] Provided in another aspect is a pharmaceutical composition comprising a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0015] Provided in some aspects are methods of treating a disease, a disorder, or condition in a subject in need thereof, the method including administering to the subject a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, the disorder, or the condition is frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post-spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing.
[0016] Also provided are methods of activating slow skeletal muscle troponin, wherein the method involves contacting the slow skeletal muscle troponin with a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
Definitions
[0017] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0018] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein. References to a compound of Formula (I) include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. In some embodiments, references to a compound of Formula (I) include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) include polymorphs, solvates, and/or co-crystals thereof. In some embodiments, references to a compound of Formula (I) include isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) include solvates thereof. Similarly, the term “salts” includes solvates of salts of compounds.
[0019] “Alkyl” encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, Ci-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; 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.
[0020] “Aryl” indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a l,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a l,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered an aryl group, while 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via 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, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
[0021] When a range of values is given (e.g., Ci-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “Ci-6 alkyl” includes Ci, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C14, C2 , C3-4, Ci-3, C2-3, and C1-2 alkyl.
[0022] “Halogen” or “halo” refers to fluoro, chloro, bromo, or iodo.
[0023] “Haloalkyl” refers to an alkyl moiety, as defined herein, wherein one or more of the hydrogen atoms in the alkyl moiety are replaced by one or more independently selected halo moieties. Examples of haloalkyl moieties include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2-CH2CI, -CH2-CHCI2, -CH2-CCI3, and -CHF-CH2CI.
[0024] “Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbomane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while l,2,3,4-tetrahydronaphthalen-5- yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.
[0025] “Heteroaryl” indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and 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 the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
[0026] In some instances, a 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.
[0027] In other instances, a heteroaryl group is polycyclic. In some instances, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyrrolo[2,3- b]pyridine, lH-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[l,2,3]triazolo[4,5- b]pyridine, lH-pyrrolo[3,2-b]pyridine, lH-pyrazolo[4,3-b]pyridine, lH-imidazo[4,5- b]pyridine, lH-[l,2,3]triazolo[4,5-b]pyridine, lH-pyrrolo[2,3-c]pyridine, lH-pyrazolo[3,4- c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[l,2,3]triazolo[4,5-c]pyridine, lH-pyrrolo[3,2- c]pyridine, lH-pyrazolo[4,3-c]pyridine, lH-imidazo[4,5-c]pyridine, lH-[l,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, [l,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [l,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5- c]pyridine, isoxazolo[4,5-c]pyridine, [l,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [l,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, [l,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[l,2-a]pyridine, lH-pyrazolo[3,4-d]thiazole, 1H- pyrazolo[4,3-d]thiazole and imidazo[2,l-b]thiazole. [0028] In other instances, polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via 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.
[0029] 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-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imidazolyl, 2,3- dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, l,3-dihydrobenzo[c]isoxazolyl, 2,3- dihydrobenzo [d] isoxazolyl, 2,3 -dihydrobenzo [d] oxazolyl, 2,3 -dihydrobenzo [b] thiophenyl, 1, 3 -dihydrobenzo [c] thiophenyl, l,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 [d] thiazolyl, 5 ,6-dihydro-4Hpyrrolo [3 ,4- d]thiazolyl , 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-l-one, l,2-dihydroindazol-3-one, lH-benzo[d]imidazol-2(3H)-one, benzofuran- 2(3H)-one, benzofuran-3(2H)-one, isobenzofuran- l(3H)-one, benzo[c]isoxazol-3(lH)-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 ( 1 H)-one, benzo [d] isothiazol-3 (2H)-one, benzo [d] thiazol-2(3 H)-one, 4,5 -dihydropyrrolo [3 ,4-d] thiazol- 6-one, l,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline-2,4(lH,3H)-dione, quinoxalin-2(lH)-one, quinoxaline-2,3(lH,4H)-dione, cinnolin-4(3H)-one, pyridin-2(lH)-one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, lH-pyrrolo[3,2-b]pyridin-2(3H)-one, lH-pyrrolo[3,2-c]pyridin-2(3H)- one, lH-pyrrolo[2,3-c]pyridin-2(3H)-one, lH-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 discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
[0030] “Heterocyclyl” includes heterocycloalkyl moieties and heterocycloalkenyl moieites, as defined below.
[0031] “Heterocycloalkyl” indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocyclo alkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heterocycloalkyl groups may 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. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocyclo alkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1, 2,3,4- tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via 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 described below.
[0032] “Heterocycloalkenyl” indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may 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-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-lH-imidazolyl, 4,5-dihydro-lH-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). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while l,2-dihydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via 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 described below.
[0033] Furthermore, some compounds may sometimes exist in tautomeric forms. It will be understood that although structures are shown, or named, in a particular form, the invention also includes the tautomer thereof. Also, some compounds may sometimes exist in atropoisomeric forms. It will be understood that although structures are shown in a particular form, the invention also includes the corresponding atropoisomeric forms thereof.
[0034] The compounds of the invention and disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like. Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated. The depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
[0035] Unless otherwise indicated, compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
[0036] “Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.
[0037] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are 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 with inorganic acids 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 with 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 including 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.
[0038] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.
[0039] 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 hemi-hydrates.
[0040] 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, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.
[0041] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
[0042] The compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2H, 3H, nC, 13C and/or 14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure 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 compounds disclosed and/or described herein. Deuterium substituted compounds can be synthesized using various 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.
[0043] 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 pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
[0044] The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
[0045] As used herein, the term “therapeutic” refers to the ability to modulate the slow skeletal muscle myosin. As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the chemical entity with the a target or due to the interaction of the chemical entity with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
[0046] The term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of slow skeletal muscle myosin. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
[0047] “Treatment” (and related terms, such as “treat”, “treated”, “treating”) includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
[0048] “Prevention” (and related terms, such as “prevent”, “prevented”, “preventing”) includes causing the clinical symptoms of a disease or disorder not to develop. The term encompasses situations where the disease or disorder is not currently being experienced but is expected to arise. When used in a prophylactic manner, the compounds disclosed and/or described herein may prevent a disease or disorder from developing or lessen the extent of a disease or disorder that may develop.
[0049] “ATPase” refers to an enzyme that hydrolyzes ATP. ATPases include proteins comprising molecular motors such as the myosins.
[0050] As used herein, “selective binding” or “selectively binding” refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types. For example, a compound selectively binds to slow skeletal muscle troponin if the compound preferentially binds slow skeletal muscle troponin in comparison with slow skeletal muscle troponin.
Compounds
[0051] Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all 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 of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.
[0052] In one aspect, provided is a compound of Formula (I):
Figure imgf000021_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
X1, R1, and are defined by either (i) or (ii):
(i) X1 is NH;
R1 is oxo; and is a single bond; or
(ii) X1 is CH;
R1 is hydrogen or Ci-Ce alkyl; and is a double bond;
X2 and X3 are each independently N or CH;
R2 is hydrogen or halogen;
R3 is Ci-C6 haloalkyl;
L is absent or -CH2-; A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one to five RA; each RA is independently selected from the group consisting of Ci-Ce alkyl, halogen, -NHS(O)2R4, -NHC(0)0R4, -CN, -C(O)N(R4)2, -S(O)2N(R4)2, -C(O)R4, -OH, -OR4, - S(O)2R4,
-C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB; each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of:
(a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl,
(b) 4- to 8-membered heterocyclyl optionally substituted with one to three - C(O)OC(Ci-C6 alkyl), and
(c) Ci-Ce alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of:
(a) -OH,
(b) halogen,
(c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH,
(d) N(R6)2, and
(e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and each R6 is independently selected from the group consisting of H and Ci-Ce alkyl.
[0053] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X1 is CH, R1 is hydrogen or Ci-Ce alkyl, and is a double bond. In some embodiments, R1 is Ci-Ce alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen. In some embodiments, X1 is NH, R1 is oxo, and is a single bond.
[0054] In some embodiments, the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) is a compound of Formula (II):
Figure imgf000023_0002
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, R1 is Ci-Ce alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen.
[0055] In some embodiments, the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) is a compound of Formula (III):
Figure imgf000023_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0056] In some embodiments of the compounds of Formula (I), (II), or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X2 is N and X3 is CH. In some embodiments, X2 and X3 are each N. In some embodiments, X2 and X3 are each CH. In some embodiments, X2 is CH and X3 is N.
[0057] In some embodiments of the compounds of Formula (I), (II), or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X2 is N. In some embodiments, X2 is CH.
[0058] In some embodiments of the compounds of Formula (I) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) or (II) is a compound of Formula (Il-a):
Figure imgf000024_0001
(Il-a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, R1 is Ci-Ce alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen.
[0059] In some embodiments of the compounds of Formula (I) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) or (II) is a compound of Formula (Il-b) :
Figure imgf000024_0002
(Il-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, R1 is Ci-Ce alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen.
[0060] In some embodiments of the compounds of Formula (I) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) or (III) is a compound of Formula (Ill-a):
Figure imgf000025_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0061] In some embodiments of the compounds of Formula (I) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound of Formula (I) or (III) is a compound of Formula (III-b) :
Figure imgf000025_0002
(III-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. [0062] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X3 is N. In some embodiments, X3 is CH.
[0063] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2 is halogen. In some embodiments, R2 is fluoro. In some embodiments, R2 is hydrogen.
[0064] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3 is C1-C3 haloalkyl. In some embodiments, R3 is Ci haloalkyl. In some embodiments, R3 is -CF3.
[0065] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent. In some embodiments, L is -CH2-.
[0066] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl.
[0067] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is C1-C12 alkyl optionally substituted with one to five RA. In some embodiments, A is C1-C12 alkyl substituted with one to five RA. In some embodiments, A is C1-C12 alkyl substituted with RA. In some embodiments, A is C1-C12 alkyl. In some embodiments, A is C6-C12 alkyl optionally substituted with one to five RA. In some embodiments, A is C6-C12 alkyl substituted with one to five RA. In some embodiments, A is C6-C12 alkyl substituted with RA. In some embodiments, A is C6-C12 alkyl. In some embodiments, A is Cs alkyl optionally substituted with one to five RA. In some embodiments, A is Cs alkyl substituted with one to five RA. In some embodiments, A is Cs alkyl substituted with RA. In some embodiments, A is Cs alkyl. In some embodiments, A is
2 -hydroxy-2, 5-dimethylhexan-4-yl. In some embodiments,
Figure imgf000027_0001
[0068] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is C3-C8 cycloalkyl optionally substituted with one to five RA. In some embodiments, A is C3-C8 cycloalkyl substituted with one to five RA. In some embodiments, A is C3-C8 cycloalkyl optionally substituted with one to three RA. In some embodiments, A is C3-C8 cycloalkyl substituted with one to three RA. In some embodiments, A is C3-C8 cycloalkyl substituted with RA. In some embodiments, A is C3-C8 cycloalkyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R4, and -OR4, wherein the Ci-Ce alkyl is optionally substituted with one to five R5. In some embodiments, A is C3-C8 cycloalkyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R4, and -OR4, wherein the Ci-Ce alkyl is optionally substituted with RB. In some embodiments, A is C3-C8 cycloalkyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R4, and -OR4, wherein the Ci- Ce alkyl is optionally substituted with -OH or -CN. In some embodiments, A is C3-C8 cycloalkyl. In some embodiments, A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to five RA. In some embodiments, A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to three RA. In some embodiments, A is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, and A is optionally substituted with one to three RA, wherein RA is selected from the group consisting of Ci-Ce alkyl, -NHS(O)2R4, and -OR4, wherein the Ci-Ce alkyl is optionally substituted with -OH or -CN. In some embodiments, A is cyclobutyl substituted with one to five RA. In some embodiments, A is cyclobutyl substituted with one to three RA. In some embodiments, A is cyclobutyl substituted with RA. In some embodiments, A is cyclobutyl substituted with RA and RA is -OR4, wherein R4 is Ci-Ce alkyl. In some embodiments, A is cyclobutyl substituted with RA and RA is -OR4, wherein R4 is prop-2-yl. In some embodiments, A is cyclopentyl substituted with one to five RA. In some embodiments, A is cyclopentyl substituted with one to three RA. In some embodiments, A is cyclopentyl substituted with RA. In some embodiments, A is cyclopentyl substituted with RA and RA is Ci-Ce alkyl substituted with RB. In some embodiments, A is cyclopentyl substituted with RA, RA is Ci-Ce alkyl substituted with RB, and RB is -CN or -OH. In some embodiments, A is cyclopentyl substituted with RA and RA is Ci-Ce alkyl substituted with -CN. In some embodiments, A is cyclopentyl substituted with RA and RA is -CH2-CN. In some embodiments, A is cyclopentyl substituted with RA and RA is Ci-Ce alkyl substituted with -OH. In some embodiments, A is cyclopentyl substituted with RA and RA is C3 alkyl substituted with -OH. In some embodiments, A is cyclopentyl substituted with RA and RA is 2-hydroxyprop-2-yl. In some embodiments, A is cyclohexyl substituted with one to five RA. In some embodiments, A is cyclohexyl substituted with one to three RA. In some embodiments, A is cyclohexyl substituted with RA. In some embodiments, A is cyclohexyl substituted with RA and RA is -NHS(O)2R4. In some embodiments, A is cyclohexyl substituted with RA, RA is -NHS(O)2R4, and R4 is Ci-Ce alkyl. In some embodiments, A is cyclohexyl substituted with RA, RA is -NHS(O)2R4, and R4 is methyl.
[0069] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is 4- to 8-membered heterocyclyl optionally substituted with one to five RA. In some embodiments, A is 4- to 8-membered heterocyclyl substituted with one to five RA. In some embodiments, A is 4- to 8-membered heterocyclyl optionally substituted with one to three RA. In some embodiments, A is 4- to 8-membered heterocyclyl substituted with one to three RA. In some embodiments, A is 4- to 8-membered heterocyclyl. In some embodiments, A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one to five RA. In some embodiments, A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one to three RA. In some embodiments, A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with one or two RA. In some embodiments, A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with RA. In some embodiments, A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein A is optionally substituted with two RA.
[0070] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is azetidinyl optionally substituted with one to four RA. In some embodiments, A is azetidinyl substituted with one to four RA. In some embodiments, A is azetidinyl substituted with RA. In some embodiments, A is azetidinyl substituted with RA and RA is Ci-C6 alkyl substituted with one to five RB. In some embodiments, A is azetidinyl substituted with RA and RA is Ci-Ce alkyl substituted with one to five RB. In some embodiments, A is azetidinyl substituted with RA and RA is Ci-Ce alkyl substituted with RB. In some embodiments, A is azetidinyl substituted with RA, RA is Ci-Ce alkyl substituted with RB, and RB is OH. In some embodiments, A is azetidinyl substituted with RA and RA is 2- hydroxyethyl. In some embodiments, A is azetidinyl substituted with RA and RA is 2- hydroxy-2-methylpropyl.
[0071] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is pyrrolidinyl optionally substituted with one to five RA. In some embodiments, A is pyrrolidinyl substituted with one to five RA. In some embodiments, A is pyrrolidinyl substituted with one to three RA. In some embodiments, A is pyrrolidinyl substituted with one or two RA. In some embodiments, A is pyrrolidinyl substituted with RA. In some embodiments, A is pyrrolidinyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl optionally substituted with one to five RB, -OR4, and - C(O)N(R4)2. In some embodiments, A is pyrrolidinyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl substituted with one to five RB, -OR4, and - C(O)N(R4)2. In some embodiments, A is pyrrolidinyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl substituted with one to three RB, -OR4, and - C(O)N(R4)2. In some embodiments, A is pyrrolidinyl substituted with RA and RA is selected from the group consisting of Ci-Ce alkyl optionally substituted with RB, -OR4, and - C(O)N(R4)2. In some embodiments, A is pyrrolidinyl substituted with RA and RA is Ci-Ce alkyl substituted with RB. In some embodiments, A is pyrrolidinyl substituted with RA, RA is Ci-C6 alkyl substituted with RB, and RB is -OH or phenyl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is Ci-Ce alkyl substituted with RB, and RB is -OH. In some embodiments, A is pyrrolidinyl substituted with RA and RA l-hydroxy-2-methylprop-2- yl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is Ci-Ce alkyl substituted with RB, and RB is phenyl. In some embodiments, A is pyrrolidinyl substituted with RA and RA is -CHi-phenyl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl optionally substituted with one to five R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl substituted with one to five R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-C6 alkyl substituted with one to three R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl substituted with one or two R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is C1-C3 alkyl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is methyl or prop-2-yl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is - OR4, and R4 is methyl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is - OR4, and R4 is prop-2-yl. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl substituted with R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, R4 is Ci-Ce alkyl substituted with R5, and R5 is -OH. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is Ci-Ce alkyl substituted with two R5. In some embodiments, A is pyrrolidinyl substituted with RA, RA is - OR4, R4 is Ci-Ce alkyl substituted with two R5, and each R5 is independently halogen. In some embodiments, A is pyrrolidinyl substituted with RA, RA is -OR4, and R4 is 2,2- difluoropropyl. In some embodiments, A is pyrrolidinyl substituted with RA and RA is - C(O)N(R4)2. In some embodiments, A is pyrrolidinyl substituted with RA, RA is - C(O)N(R4)2, and R4 is Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with RA and RA is -C(O)N(CH3)2. In some embodiments, A is pyrrolidinyl substituted with two RA. In some embodiments, A is pyrrolidinyl substituted with Ci-Ce alkyl and -C(O)R4. In some embodiments, A is pyrrolidinyl substituted with Ci-Ce alkyl and -C(O)R4-, and R4 is Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with methyl and -C(O)R4, wherein R4 is prop-2-yl. In some embodiments, A is pyrrolidinyl substituted with -OR4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, -C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB. In some embodiments, A is pyrrolidinyl substituted with -OR4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, - C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently substituted with one to five RB. In some embodiments, A is pyrrolidinyl substituted with -OR4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, -C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB; wherein each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), - C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8- membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of (a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl, (b) 4- to 8-membered heterocyclyl optionally substituted with one to three -C(O)OC(Ci-C6 alkyl), and (c) Ci-Ce alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of (a) -OH, (b) halogen, (c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH, (d) N(R6)2, and (e) 4- to 8-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and wherein each R6 is independently selected from the group consisting of H and Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with - OR4 and a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, -C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB; wherein each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci- Ce alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of (a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl, (b) 4- to 8- membered heterocyclyl optionally substituted with one to three -C(O)OC(Ci-C6 alkyl), and (c) Ci-C6 alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of (a) -OH, (b) halogen, (c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH, (d) N(R6)2, and (e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and wherein each R6 is independently selected from the group consisting of H and Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with -OR4 wherein R4 is Ci-Ce alkyl optionally substituted with one to five R5; and A is substituted with a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, -C(O)OR4, 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl is independently optionally substituted with one to five RB; wherein each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10- membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and Cs-Cs cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of (a) 5- to 10- membered heteroaryl optionally substituted with Ci-C6 alkyl, (b) 4- to 8-membered heterocyclyl optionally substituted with one to three - C(O)OC(Ci-C6 alkyl), and (c) Ci-Ce alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of (a) -OH, (b) halogen, (c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH, (d) N(R6)2, and (e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and wherein each R6 is independently selected from the group consisting of H and Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with -OR4 wherein R4 is selected from the group consisting of methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-2-yl, 2,2-difluoroethyl, 2- hydroxyethyl, 2-methoxyethyl, 2-(2-hydroxy-2-methylpropoxy)-2-methylprop-l-yl, 2- hydroxy-2-methylprop-l-yl, 2-morpholinoethyl, and 2-(4-methylpiperazin-l-yl)ethyl; and A is substituted with a second substituent selected from the group consisting of selected from the group consisting of Ci-Ce alkyl, -C(O)R4, -S(O)2R4, -C(O)OR4, 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and Cs-Cs cycloalkyl is independently optionally substituted with one to five RB; wherein each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -O(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 5- to 10- membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of (a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl, (b) 4- to 8-membered heterocyclyl optionally substituted with one to three - C(O)OC(Ci-C6 alkyl), and (c) Ci-Ce alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of (a) -OH, (b) halogen, (c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH, (d) N(R6)2, and (e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and wherein each R6 is independently selected from the group consisting of H and Ci-Ce alkyl. In some embodiments, A is pyrrolidinyl substituted with a first substituent selected from the group
Figure imgf000033_0001
[0072] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is piperidine substituted with one to five RA. In some embodiments, A is piperidine substituted with one to three RA. In some embodiments, A is piperidine substituted with one or two RA. In some embodiments, A is piperidine substituted with RA. In some embodiments, A is piperidine substituted with RA, wherein RA is selected from the group consisting of Ci-Ce alkyl and 4- to 8-membered heterocyclyl, wherein each of the Ci-Ce alkyl and 4- to 8-membered heterocyclyl is independently optionally substituted with one to five RB. In some embodiments, A is piperidine substituted with RA, wherein RA is selected from the group consisting of Ci-Ce alkyl and 4- to 8-membered heterocyclyl, wherein each of the Ci-Ce alkyl and 4- to 8-membered heterocyclyl is independently optionally substituted with one to five RB, and wherein each RB is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8- membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH. In some embodiments, A is piperidine substituted with RA, wherein RA is Ci-Ce alkyl optionally substituted with one to five RB, and wherein each RB is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH. In some embodiments, A is piperidine substituted with RA, wherein RA is Ci-Ce alkyl optionally substituted with one to five RB, and wherein each RB is independently selected from the group consisting of -OH and 4- to 8 -membered heterocyclyl. In some embodiments, A is piperidine substituted with RA, wherein RA is selected from the group consisting
Figure imgf000034_0001
some embodiments, A is piperidine substituted with RA, wherein RA is 4- to 8-membered heterocyclyl optionally substituted with one to five RB, and wherein each RB is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), -C(O)(Ci-C6 alkyl), 4- to 8- membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH. In some embodiments, A is piperidine substituted with RA, wherein RA is 4- to 8-membered heterocyclyl optionally substituted with one to five RB, and wherein each RB is independently selected from the group consisting of -OH, -C(O)O(Ci-C6 alkyl), - C(O)(Ci-C6 alkyl), and 4- to 8-membered heterocyclyl. In some embodiments, A is piperidine substituted with RA, wherein RA is 4- to 8-membered heterocyclyl substituted with RB, and wherein RB is selected from the group consisting of -C(O)O(Ci-C6 alkyl), -C(O)(Ci-
Ce alkyl), and 4- to 8-membered heterocyclyl. In some embodiments, A is piperidine substituted with RA, wherein RA is selected from the group consisting of
Figure imgf000035_0001
Figure imgf000035_0002
In some embodiments, A is piperidine substituted with RA, wherein RA is selected from the group consisting of
Figure imgf000035_0003
Figure imgf000035_0004
embodiments, A is piperidine substituted with two RA. In some embodiments, A is piperidine substituted with halogen and a second substituent which is Ci-Ce alkyl substituted with one to five substituents independently selected from the group consisting of -OH, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH. In some embodiments, A is piperidine substituted with fluoro and a second substituent which is Ci-Ce alkyl substituted with one to five substituents independently selected from the group consisting of -OH, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH. In some embodiments, A is piperidine substituted with fluoro and a second substituent selected from the group consisting of
Figure imgf000035_0005
[0073] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is piperazine optionally substituted with one to five RA. In some embodiments, A is piperazine optionally substituted with one to three RA. In some embodiments, A is piperazine optionally substituted with one or two 2 RA. In some embodiments, A is piperazine substituted with two RA. In some embodiments, A is piperazine substituted with Ci-Ce alkyl or -C(O)R4, wherein R4 is Ci-Ce alkyl, and with Ci-Ce alkyl or Ci-Ce alkyl substituted with Ce-Cio aryl. In some embodiments, A is piperazine substituted with two substituents selected from the group consisting of methyl, acetyl, and benzyl. In some embodiments, A is piperazine substituted with methyl and benzyl, methyl and acetyl, or acetyl and benzyl.
[0074] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is morpholine optionally substituted with one to five RA. In some embodiments, A is morpholine optionally substituted with one to three RA. In some embodiments, A is morpholine optionally substituted with one or two 2 RA. In some embodiments, A is morpholine substituted with RA. In some embodiments, A is morpholine substituted with -C(O)R4 and R4 is 4- to 8-membered heterocyclyl optionally substituted with -C(O)OC(Ci-C6 alkyl). In some embodiments, A is morpholine substituted with -C(O)R4 and R4 is azetidine substituted with -C(O)O(C(CH3)3).
[0075] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is tetrahydrofuran optionally substituted with one to five RA. In some embodiments, A is tetrahydrofuran optionally substituted with one to three RA. In some embodiments, A is tetrahydrofuran optionally substituted with one or two 2 RA. In some embodiments, A is tetrahydrofuran optionally substituted with RA. In some embodiments, A is tetrahydrofuran optionally substituted with -OR4. In some embodiments, A is tetrahydrofuran optionally substituted with -OR4 and R4 is Ci-Ce alkyl optionally substituted with one to five R5. In some embodiments, A is tetrahydrofuran optionally with -OR4 and R4 is Ci-C6 alkyl substituted with R5. In some embodiments, A is tetrahydrofuran substituted with -OR4 and R4 is Ci-Ce alkyl substituted with OH or 5- to 6-membered heterocyclyl. In some embodiments, A is tetrahydrofuran substituted with
Figure imgf000036_0001
or
Figure imgf000036_0002
[0076] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is 5- to 10-membered heteroaryl optionally substituted with one to five RA. In some embodiments, A is pyridine or oxazole, each independently optionally substituted with one to five RA. In some embodiments, A is 5- to 10-membered heteroaryl substituted with one to five RA. In some embodiments, A is pyridine or oxazole, each independently substituted with one to five RA. In some embodiments, A is pyridine or oxazole, each independently substituted with RA. In some embodiments, A is pyridine or oxazole, each independently substituted with Ci-Ce alkyl or -CN. In some embodiments, A is pyridine substituted with Ci-Ce alkyl. In some embodiments, A is pyridine substituted with methyl. In some embodiments, A is oxazole substituted with -CN.
[0077] In some embodiments of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, A is 5- to 10-membered heteroaryl or C1-C12 alkyl, wherein each of which is optionally substituted with one to five RA. In some embodiments, A is C1-C12 alkyl optionally substituted with one to five RA. In some embodiments, A is C1-C12 alkyl substituted with one to five RA. In some embodiments, A is C1-C12 alkyl substituted with RA. In some embodiments, A is C1-C12 alkyl. In some embodiments, A is C6-C12 alkyl optionally substituted with one to five RA. In some embodiments, A is C6-C12 alkyl substituted with one to five RA. In some embodiments, A is C6-C12 alkyl substituted with RA. In some embodiments, A is C6-C12 alkyl. In some embodiments, A is Cs alkyl optionally substituted with one to five RA. In some embodiments, A is Cs alkyl substituted with one to five RA. In some embodiments, A is Cs alkyl substituted with RA. In some embodiments, A is Cs alkyl. In some embodiments, A is 2-hydroxy-2,5-dimethylhexan-4-yl. In some embodiments, A is
Figure imgf000037_0001
. In some embodiments, A is 5- to 10-membered heteroaryl optionally substituted with one to five RA. In some embodiments, A is 5- to 10-membered heteroaryl substituted with one to five RA. In some embodiments, A is pyridine or oxazole, each independently substituted with one to five RA. In some embodiments, A is pyridine or oxazole, each independently substituted with RA. In some embodiments, A is pyridine or oxazole, each independently substituted with Ci-Ce alkyl or -CN. In some embodiments, A is pyridine substituted with Ci-Ce alkyl. In some embodiments, A is pyridine substituted with methyl. In some embodiments, A is oxazole substituted with -CN.
[0078] In some embodiments, provided herein are compounds described in Table 2 and pharmaceutically acceptable salts thereof.
Table 2
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
[0079] In some variations, any of the compounds described herein, such as a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, may be deuterated (e.g., a hydrogen atom is replaced by 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 nondeuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.
[0080] Any formula given herein, such as Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given 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. Where a compound of Table 2 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. For example, where a compound of Table 2 has a stereocenter that is in an “S” stereochemical configuration, also provided herein is enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration. Likewise, when a compound of Table 2 has a stereocenter that is in an “R” configuration, also provided herein is enantiomer of the compound in an “S” stereochemical configuration. Also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration. Additionally, if a compound of Table 2 has two or more stereocenters, also provided are any enantiomer or diastereomer of the compound. For example, if a compound of Table 2 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “S” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Table 2 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Table 2 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Similarly, if a compound of Table 2 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “R” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.
[0081] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual or subject. [0082] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.
[0083] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
[0084] Any variation or embodiment of X1, X2, X3, R1, R2, R3, R4, R5, L, A, and RA provided herein can be combined with every other variation or embodiment of X1, X2, X3, R1, R2, R3, R4, R5, L, A, and RA, as if each combination had been individually and specifically described.
[0085] Other embodiments will be apparent to those skilled in the art from the following detailed description.
[0086] 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.
[0087] The compound names provided herein, including in Table 2, are provided by ChemDraw Professional 18.2.0.48. One of skilled in the art would understand that the compounds may be named or identified using various commonly recognized nomenclature systems and symbols. By way of example, the compounds may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC). Compositions
[0088] Also provided are compositions, such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions, such as pharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
[0089] In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided is a pharmaceutically acceptable composition comprising Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. In some aspects, a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein. The compositions described herein may contain any other suitable active or inactive agents.
[0090] Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.
[0091] Also provided are packaged pharmaceutical compositions, comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein. Methods of Use
[0092] Compounds and compositions detailed herein, such as a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
[0093] The compounds and pharmaceutical compositions herein may be used to treat or prevent a disease, a disorder, or a condition in an individual or subject.
[0094] In some embodiments, provided are methods of treating or preventing a disease, a disorder, or a condition in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided is a method of treating a disease, a disorder, or a condition in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.
[0095] Also provided herein is the use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treatment of a disease, a disorder, or a condition in a subject. In some aspects, provided is a compound or composition as described herein for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating or preventing a disease, a disorder, or a condition . In some embodiments, provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating a disease, a disorder, or a condition .
[0096] In other embodiments, provided herein are compounds of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in modulating the slow skeletal muscle troponin, such as activating slow skeletal muscle troponin.
[0097] Further, the invention relates to a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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. Furthermore, the invention relates to a pharmaceutical composition for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, in a subject, comprising a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Furthermore, the invention relates to an agent for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0098] Furthermore, the invention relates to a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, in a subject, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Furthermore, the invention relates to an agent for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0099] Moreover, the invention relates to use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof in a subject.
[0100] Moreover, the invention relates to use of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0101] In one aspect, provided herein is the use of the compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0102] In one aspect, provided herein is the use of the compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0103] In one aspect, provided herein is the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0104] In one aspect, provided herein is the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0105] In one aspect, provided herein is a method for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Further, the “subject” is a human or a non-human animal in need of the prevention or treatment, and in one embodiment, a human in need of the prevention or treatment.
[0106] In one aspect, provided herein is a method for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in a subject, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to the subject an effective amount of the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.Further, the “subject” is a human or a non-human animal in need of the prevention or treatment, and in one embodiment, a human in need of the prevention or treatment.
[0107] In one aspect, provided herein is the compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in medical therapy. Such medical therapy may be relating to a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0108] In one aspect, a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (III- b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, modulates the contractility of the skeletal sarcomere.Specifically, the compounds modulate the troponin complex of the slow skeletal muscle sarcomere through one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, “modulate” means either increasing or decreasing activity. In some instances, a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, potentiates (i.e., increases activity) of one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
[0109] In another aspect, provided herein is a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, inhibits (i.e., decreases activity) of one or more of slow skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, “activation of the slow skeletal muscle fiber such as myofibril” means to amplify the response of slow skeletal muscle fiber (such as myofibril) to stimulation/Ca2+.
[0110] In some aspects, provided herein is a method of preventing or treating: frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post- spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or an effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0111] In some aspects, provided herein is a method of treating: frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post- spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or an effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0112] In some aspects, provided herein is a method for preventing or treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator- induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0113] In some aspects, provided herein is a method for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0114] In some aspects, provided herein is a method 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 myopathies, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (III- a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0115] In some aspects, provided herein is a method for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathies, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0116] In some aspects, provided herein is a method 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0117] In some aspects, provided herein is a method for 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and poststroke muscle dysfunction, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0118] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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: frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post-spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject.
[0119] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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: frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post-spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject.
[0120] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 peripheral vascular disease, peripheral arterial disease, rehabilitation- related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject. [0121] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
[0122] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 myopathies in a subject.
[0123] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 myopathies in a subject.
[0124] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
[0125] In some aspects, provided herein is the use of a compound of Formula (I), (II), (II- a), (Il-b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
[0126] In some aspects, provided herein is the compound of Formula (I), (II), (Il-a), (II- b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in preventing or treating : frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post-spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject. [0127] In some aspects, provided herein is the compound of Formula (I), (II), (Il-a), (II- b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in treating : frailty associated with old age (termed sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), renal 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 neuropathies, Charcot-Marie-Tooth disease, Parkinson’s disease, stroke, spinal cord injury, and motor units disorders; muscular myopathies, including body myositis myopathy, muscular dystrophies (limb girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathies; rehabilitation-related deficits: recovery from surgery (e.g., post-surgical muscle weakness), prolonged bed rest, immobilization/disuse atrophy, post-hip fracture recovery, ICU neuromyopathy, post trauma, stroke rehabilitation; Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; post-anesthesia recovery or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic/ischemic disorders, or claudication; obesity; dysfunctions of pelvic floor and urethral/anal sphincter muscles (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); post-spinal cord injury (SCI) muscle dysfunction; ventilator-induced muscle weakness; or spinocerebral ataxias or demyelinating diseases, including multiple sclerosis, post-polio syndrome, or any combination of the foregoing, in a subject.
[0128] In some aspects, provided herein is the compound of Formula (I), (II), (Il-a), (II- b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in preventing or treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject. [0129] In some aspects, provided herein is the compound of Formula (I), (II), (ILa), (II- b), (III), (Ill-a), or (Ill-b), or a compound of Table 2, 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 deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
[0130] In some aspects, provided herein is the compound of Formula (I), (II), (ILa), (II- b), (III), (IILa), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in 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 myopathies in a subject.
[0131] In some aspects, provided herein is the compound of Formula (I), (II), (ILa), (II- b), (III), (IILa), or (Ill-b), or a compound of Table 2, 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 myopathies in a subject.
[0132] In some aspects, provided herein is the compound of Formula (I), (II), (ILa), (II- b), (III), (IILa), or (Ill-b), or a compound of Table 2, or a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, for use in 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
[0133] In some aspects, provided herein is the compound of Formula (I), (II), (ILa), (II- b), (III), (IILa), or (IILb), or a compound of Table 2, 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 stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
[0134] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.
Dosages
[0135] The compounds and compositions disclosed and/or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetic s .
[0136] A daily dose is the total amount administered in a day. A daily dose may be, but is not limited to be, administered each day, every other day, each week, every 2 weeks, every month, or at a varied interval. In some embodiments, the daily dose is administered for a period ranging from a single day to the life of the subject. 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 in 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.
[0137] Administration of the compounds and compositions disclosed and/or described herein can be via any accepted 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 compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and/or described herein is administered orally.
[0138] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
[0139] The compounds disclosed and/or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. [0140] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, 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 acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.
[0141] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
[0142] Pharmaceutical compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
[0143] In addition, pharmaceutical compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
Kits
[0144] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers 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 for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
[0145] In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of a neuromuscular disease in an individual or subject in need thereof. A kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags. A kit may also contain sterile packaging.
Combinations
[0146] The compounds 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 Synthetic Methods
[0147] Compounds of Formula (I) will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and 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 (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as defined above in reference to Formula (I).
[0148] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[0149] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
[0150] General methods of preparing compounds described herein are depicted in exemplified methods below. Variable groups in the schemes provided herein are as defined for Formula (I), (II), (Il-a), (Il-b), (III), (Ill-a), or (Ill-b), or any variation thereof. Other compounds described herein may be prepared by similar methods using the appropriate starting materials and reagents.
[0151] In some embodiments, compounds provided herein may be synthesized according to Scheme 1.
Scheme 1
Figure imgf000082_0001
Intermediate A Intermediate B
Figure imgf000082_0002
[0152] In Scheme 1, Intermediate A (a carboxylic acid) is reacted with Intermediate B (an amine) in the presence of an esterification coupling reagent, wherein X1, X2, X3, R1, R2, R3,
L, and A are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the esterification coupling reagent comprises 1- [bis (dimethy lamino)methy lene] - 1 H- 1 ,2 , 3 -triazolo [4,5 -b] pyridinium 3 -oxide hexafluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- hydroxy-7-azabenzotriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), benzotriazol- 1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7 -Azabenzo triazol- 1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one (DEPBT), or a mixture of any of the foregoing. In some embodiments, the esterification coupling reagent comprises HATU, HBTU, EDCI, HOAt, HOBt, BOP, PyBOP, PyAOP, DEPBT, or a mixture of any of the foregoing, and a base such as, for non-limiting example, triethylamine (TEA), diisopropylethylamine (DIPEA), or 4-dimethylaminopyridine (DMAP).
[0153] In some embodiments, compounds provided herein may be synthesized according to Scheme 2.
Scheme
Figure imgf000083_0001
Intermediate C
[0154] In Scheme 2, Intermediate C (which can be obtained, for example, through a reaction similar to the one described in Scheme 1) is further derivatized to obtain a compound of Formula (I), wherein X1, X2, X3, R1, R2, R3, L, and A are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
[0155] In some embodiments, Intermediate A may be synthesized according to Scheme 3.
Scheme 3
Figure imgf000084_0001
Intermediate D Intermediate A
[0156] In Scheme 3, Intermediate A (a carboxylic acid) is obtained by reacting Intermediate D (an ester) with a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH), wherein X1, X2, X3, R1, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
[0157] In some embodiments, Intermediate A is Intermediate A-l, which may be synthesized according to Scheme 4.
Scheme 4
Figure imgf000084_0002
Intermediate D-1 Intermediate A-1
[0158] In Scheme 4, Intermediate A-l (a carboxylic acid) is obtained by reacting
Intermediate D-l (an ester) with a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH), wherein X2, X3, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
[0159] In some embodiments, Intermediate D-l may be synthesized according to Scheme
5.
Scheme 5
Figure imgf000085_0001
[0160] In Scheme 5, Intermediate D-l is obtained by reacting Intermediate F-l with Intermediate G-l in the presence of a base such as sodium hydride (NaH), wherein X2, X3, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
[0161] In some embodiments, Intermediate A is Intermediate A-2, which may be synthesized according to Scheme 6.
Scheme 6
Figure imgf000085_0002
Intermediate D-2 Intermediate A-2
[0162] In Scheme 6, Intermediate A-2 (a carboxylic acid) is obtained by reacting Intermediate D-2 (an ester) with a hydroxide base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH), wherein X2, X3, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
[0163] In some embodiments, Intermediate D-2 may be synthesized according to Scheme 7.
Scheme 7
Figure imgf000086_0001
Intermediate H-2 Intermediate D-2
[0164] In Scheme 7, Intermediate D-2 is obtained by cyclization of Intermediate H-2 in the presence of copper iodide (Cui), wherein X2, X3, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
[0165] In some embodiments, Intermediate H-2 may be synthesized according to Scheme
Scheme 8
Figure imgf000086_0002
Intermediate K-2 Intermediate J-2 Intermediate H-2
[0166] In Scheme 8, Intermediate H-2 is obtained by reacting Intermediate K-2 and
Intermediate J-2 in the presence of phosgene or a phosgene substitute such as diphosgene, triphosgene, carbonyl diimidazole, or disuccinimidyl carbonate, wherein X2, X3, R2, and R3 are as defined elsewhere herein for a compound of Formula (I), or any variation thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and R is Ci-Ce alkyl.
EXAMPLES
[0167] The following examples are offered to illustrate but not to limit the compositions, uses, and methods provided herein. The compounds are prepared using the general methods described above.
[0168] The following abbreviations may be used throughout the Examples: DBU (1,8- Diazabicyclo(5.4.0)undec-7-ene), DIBAL (diisobutylaluminum hydride), DIPEA (N.N- diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), equiv (equivalent), EtOAc (Ethyl acetate), EtOH (ethanol), HBTU (N,N,N',N'-Tetramethyl-O-(lH-benzotriazol-l-yl)uronium hexafluorophosphate), HOAt (l-Hydroxy-7-azabenzotriazole), HPLC (High-performance liquid chromatography), MeMgBr (methylmagnesium bromide), NMP (l-methylpyrrolidin-2- one), Pd/C (palladium on carbon), PyBOP (Benzotriazole- 1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate), rt (room temperature), TFA (trifluoro acetic acid), and THF (tetrahydro furan).
Example 1: Synthesis of N-((3R,4R)-l-Acetyl-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3- yl)-l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide ( Compound 1 )
Step 1: Synthesis of methyl l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2- c ]pyridine-6-carboxylate.
Figure imgf000087_0001
[0169] A mixture of methyl l//-pyrrolo[3,2-c]pyridine-6-carboxylate (10.0 g) and DMF (90 mL) was cooled to 0 °C using an ice bath and stirred under nitrogen. Sodium hydride (3.0 g of a 60% dispersion in mineral oil) was added, and the reaction mixture was warmed to rt and stirred for 30 min. The reaction was cooled back to 0 °C, and a solution of 2,3- difluoro-5-(trifluoromethyl)pyridine (11.4 g) in DMF (10 mL) was added dropwise. The resulting solution was allowed to warm to rt and stirred for 1 h. The reaction mixture was then cooled to 0 °C and quenched with saturated aqueous NH4CI (200 mL). The mixture was warmed to rt and extracted with ethyl acetate (4 x 200 mL). The combined organic extracts were washed with water (4 x 100 mL) and brine (100 mL), dried over sodium sulfate, filtered, concentrated, and chromatographed (0-100% ethyl acetate / hexane) to provide methyl l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l//-pyrrolo[3,2-c]pyridine-6-carboxylate (17.0 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 9.09 (d, J = 1.0 Hz, 1H), 9.04 - 8.97 (m, 1H), 8.74 (dd, J = 10.8, 2.1 Hz, 1H), 8.63 (q, J = 1.1 Hz, 1H), 8.16 (t, J = 3.4 Hz, 1H), 7.11 (dd, J = 3.5, 0.9 Hz, 1H), 3.89 (s, 3H). LRMS (APCI) m/z 340.1 [M + H]+.
Step 2: Synthesis of l-(3-Fluoro-5-( trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine- 6-carboxylic acid.
Figure imgf000088_0001
[0170] To a 500 mL round bottom flask was added methyl l-(3-fluoro-5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxylate (17.0 g) and THF (170 mL). The mixture was placed in a water bath, followed by the drop wise addition of a lithium hydroxide solution (2.4 g in 20 mL of water). After the addition was complete, the reaction mixture was removed from the water bath and stirred at rt for 6 h and at 4 °C for 14 h. The reaction mixture was warmed to rt and acidified with 1 M HC1 (100 mL), and the resultant white solid was filtered. The solid was washed with water and dried in vacuo to give 16.1 g of l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6- carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 9.08 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.73 (dd, J = 11.0, 2.0 Hz, 1H), 8.63 (s, 1H), 8.16 (t, J = 3.5 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H). LRMS (APCI) m/z 326.1 [M + H]+.
Step 3: Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-l- carboxylate.
Figure imgf000088_0002
[0171] To a mixture of tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-l -carboxylate (30.0 g), DIPEA (77.5 mL), and acetonitrile (150 mL) was added benzyl bromide (42.2 mL). The reaction mixture was stirred at 60 °C for 14 h. Additional benzyl bromide (10.6 mL) was added, and the reaction mixture was stirred at 60 °C for 3 h. The mixture was then warmed to rt, concentrated, diluted with H2O (250 mL), and extracted with EtOAc (500 mL). The organic layer was washed with brine (100 mL x 2), dried over MgSCL, and concentrated in vacuo. The crude product was recrystallized using hexanes (100 mL) to give 45.0 g of tertbutyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-l-carboxylate as a white solid. ’ H NMR (400 MHz, DMSO-t/6) 5 7.52 - 7.09 (m, 10H), 5.16 (t, J = 4.1 Hz, 1H), 4.35 (p, J = 5.5 Hz, 1H), 3.77 - 3.58 (m, 4H), 3.53 (dd, J = 11.1, 6.6 Hz, 1H), 3.39 (d, J = 9.9 Hz, 1H), 3.27 - 3.08 (m, 2H), 2.96 (d, J = 7.3 Hz, 1H), 1.36 (d, J = 6.3 Hz, 9H). LRMS (APCI) m/z 383.1 [M + H]+.
Step 4: Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-(2-hydroxy-2- methylpropoxy )pyrrolidine-l -carboxylate.
Figure imgf000089_0001
[0172] To a 1 L round bottom flask was added tert-butyl (3R,4R)-3-(dibenzylamino)-4- hydroxypyrrolidine- 1 -carboxylate (45.0 g) and NMP (540 mL) under a nitrogen atmosphere. Dimethyloxirane (20.9 mL) and NaH (8.5 g of a 60% dispersion in mineral oil) were then added, and the reaction mixture was stirred at 70 °C for 16 h under nitrogen. The reaction was quenched with water (30 mL), followed by the addition of aqueous ammonium chloride (300 mL). The mixture was extracted with ethyl acetate (250 mL x 3), washed with brine (150 mL x 3), dried over MgSCL, filtered, and concentrated. The crude product was washed again with water (5 x 200 mL) and brine (200 mL), dried with MgSCL, filtered, and concentrated to give 57.8 g tert-butyl (3R,4R)-3-(dibenzylamino)-4-(2-hydroxy-2- methylpropoxy)pyrrolidine-l -carboxylate as a brown oil that was used without further purification. ’ H NMR (400 MHz, DMSO-t 6) 5 7.46 - 7.06 (m, 10H), 4.31 (s, 1H), 4.20 (d, J = 6.0 Hz, 1H), 3.75 - 3.55 (m, 5H), 3.43 (s, 1H), 3.26 (m, 1H), 3.18 (s, 2H), 3.11 - 2.96 (m, 2H), 1.37 (s, 9H), 1.06 (d, J = 13.0 Hz, 6H). LRMS (APCI) m/z 455.3 [M + H]+. Step 5: Synthesis of tert-Butyl (3R,4R)-3-amino-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l- carboxylate.
Figure imgf000090_0001
[0173] A reaction mixture of tert-butyl (3R,4R)-3-(dibenzylamino)-4-(2-hydroxy-2- methylpropoxy)pyrrolidine-l -carboxylate (57.8 g), 5% Pd/C (22.0 g), and methanol (550 mL) was stirred under a 50-60 psi hydrogen atmosphere for 7 h. The mixture was filtered through Celite and concentrated. The crude product was then diluted with methanol (100 mL), filtered through a syringe filter (0.45 micrometer GMF, Whatman), and concentrated to give 30.1 g of tert-butyl (3R,4R)-3-amino-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l- carboxylate as an oil which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 5 3.60 (q, J = 3.3, 2.3 Hz, 1H), 3.47 (td, J = 11.6, 4.7 Hz, 1H), 3.35 (d, J = 5.5 Hz, 4H), 3.18 (qd, J = 8.5, 7.3, 3.5 Hz, 3H), 2.99 (d, J = 9.4 Hz, 1H), 1.39 (s, 9H), 1.04 (d, J = 4.0 Hz, 7H). LRMS (APCI) m/z 275.2 [M + H]+.
Step 6: Synthesis of tert-Butyl (3R,4R)-3-(l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH- pyrrolo[3,2-c]pyridine-6-carboxamido)-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l- carboxylate.
Figure imgf000090_0002
[0174] To a mixture of l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2- c]pyridine-6-carboxylic acid (12.5 g), tert-butyl (3R,4R)-3-amino-4-(2-hydroxy-2- methylpropoxy)pyrrolidine-l -carboxylate (11.6 g), DMF (30 mL), and DIPEA (20.1 mL) was added HBTU (18.9 g), and the reaction mixture was stirred at rt fori h. Water was added (50 mL), and the resultant mixture was extracted with ethyl acetate (2 x 200 mL), washed with water (3 x 100 mL), brine (2 x 100 mL), dried over NaiSCL, filtered, concentrated, and purified using silica gel chromatography (10-100% ethyl acetate in hexane) to give 20.5 g tert-butyl (3R,4R)-3-(l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine- 6-carboxamido)-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l -carboxylate as a white solid. ’ H NMR (400 MHz, DMSO-76) 5 9.02 (d, J = 16.4 Hz, 2H), 8.93 (d, J = 7.1 Hz, 1H), 8.74 (dd, J = 10.9, 2.0 Hz, 1H), 8.58 (s, 1H), 8.11 (t, 7 = 3.4 Hz, 1H), 7.10 (d, J = 3.5 Hz, 1H), 4.42 (s, 1H), 4.33 (s, 1H), 4.11 (q, 7 = 3.0 Hz, 1H), 3.60 (dt, 7 = 12.0, 5.8 Hz, 2H), 3.41 - 3.33 (m, 2H), 3.26 (t, 7 = 10.6 Hz, 2H), 1.42 (d, 7 = 2.5 Hz, 9H), 1.06 (d, 7 = 1.3 Hz, 6H). LRMS (APCI) m/z 582.3 [M + H]+.
Step 7: Synthesis of ! -(3-Fluoro-5-(lrifluoromelhyl)pyridin-2-yl)-N-((3R,4R)-4-(2-hydroxy-2- methylpropoxy)pyrrolidin-3-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide hydrochloride.
Figure imgf000091_0001
[0175] To a solution of tert-butyl (3R,4R)-3-(l-(3-fluoro-5-(trifluoromethyl)pyridin-2- yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamido)-4-(2-hydroxy-2-methylpropoxy)pyrrolidine-l- carboxylate (1.5 g) in methanol (12.0 mL) at 0 °C was added 4 M HC1 in dioxane (12.7 mL). After the addition, the reaction mixture was allowed to warm to rt and stirred for 1 h. The mixture was concentrated to dryness. The solid was dissolved in methanol (15 mL) and concentrated. This step was repeated twice, affording 1.4 g of l-(3-fluoro-5- (trifluoromethyl)pyridin-2-yl)-A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)- 1 /7-pyrrolo[3,2-c]pyridinc-6-carboxamidc hydrochloride as an off white solid. 1 H NMR (400 MHz, DMSO-76) 5 9.56 (s, 1H), 9.43 (d, 7 = 7.4 Hz, 1H), 9.29 (s, 1H), 9.14 (s, 1H), 9.01 (d, 7 = 1.9 Hz, 1H), 8.76 (dd, 7 = 10.7, 2.0 Hz, 2H), 8.20 (t, 7 = 3.4 Hz, 1H), 7.18 (d, 7 = 3.5 Hz, 1H), 4.62 (s, 1H), 4.17 (d, 7 = 4.7 Hz, 1H), 3.53 (dt, 7 = 14.6, 7.1 Hz, 2H), 3.42 (dd, 7 = 9.7, 5.6 Hz, 2H), 3.28 (d, 7 = 9.4 Hz, 2H), 1.10 (d, 7 = 2.5 Hz, 6H). LRMS (APCI) m/z 482.2 [M + H]+.
Step 8: Synthesis ofN-((3R,4R)-l-Acetyl-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l- (3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide.
Figure imgf000092_0001
[0176] To a suspension of l-(3-fhioro-5-(trifhioromethyl)pyridin-2-yl)-A-((3R,4R)-4-(2- hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide hydrochloride (1.22 g) and methylene chloride (30 mL) was added triethylamine (1.4 mL) at 0 °C. Acetyl chloride (3.0 mL) was added dropwise and the reaction mixture was allowed to warm to rt and stir for 15 min. The reaction was then concentrated and purified directly using reverse phase HPLC (20-100% acetonitrile in water with 0.1% formic acid). The resultant solid was dissolved in methanol (3 X 10 mL) and concentrated. Ethyl acetate (5 mL) was added, and the mixture was concentrated. Ethyl acetate (5 mL) was added, and the mixture was again concentrated to give 1.17 g of A-((3R,4R)-l-acetyl-4-(2-hydroxy-2- methylpropoxy)pyrrolidin-3-yl)-l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2- c]pyridine-6-carboxamide as a white solid. 1 H NMR (400 MHz, DMSO-de) 5 9.08 - 8.89 (m, 3H), 8.79 - 8.70 (m, 1H), 8.59 (s, 1H), 8.11 (t, J = 3.5 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 4.48 (s, 1H), 4.34 (d, 7 = 3.3 Hz, 1H), 4.12 (d, J = 28.5 Hz, 1H), 3.82 (ddd, J = 16.9, 11.1, 5.8 Hz, 1H), 3.68 - 3.35 (m, 4H), 3.28 (dd, J = 9.4, 4.6 Hz, 1H), 1.97 (d, J = 3.7 Hz, 3H), 1.07 (s, 6H). LRMS (APCI) m/z 524.2 [M + H]+.
Example 2: Synthesis of l-(3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)-N-((3R,4R)-4-(2- hydroxy-2-methylpropoxy)-l-(oxetan-3-ylsulfonyl)pyrrolidin-3-yl)-lH-pyrrolo[3,2- c]pyridine-6-carboxamide (Compound 8)
Figure imgf000093_0001
[0177] To a solution of l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-A-((3R,4R)-4-(2- hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l//-pyrrolo[3,2-c]pyridine-6-carboxamide (24 mg) in methylene chloride (2 mL) was added triethylamine (20 mg). The mixture was cooled to 0 °C, followed by the addition of oxetane-3 -sulfonyl chloride (10 mg). The reaction mixture was warmed to rt, stirred for Ih, concentrated, and purified using reverse phase chromatography (20-100% CH3CN/H2O with 0.1% formic acid over 40 min) to give 22 mg of l-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)- l-(oxetan-3-ylsulfonyl)pyrrolidin-3-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide as an off- white solid. IH NMR (400 MHz, Chloroform-d) 5 8.91 (s, IH), 8.83 (s, IH), 8.76 (s, IH), 8.41 (d, J = 7.2 Hz, IH), 7.96 (dd, J = 10.5, 2.0 Hz, IH), 7.89 (t, J = 3.2 Hz, IH), 6.96 (d, J = 3.5 Hz, IH), 5.05 (q, J = 6.4 Hz, 2H), 4.94 (t, J = 7.6 Hz, 2H), 4.72 - 4.54 (m, 2H), 4.22 (d, J = 4.4 Hz, IH), 3.86 - 3.77 (m, 2H), 3.69 - 3.44 (m, 5H), 1.26 (s, 6H). LRMS (APCI) m/z 602.1 [M + H]+.
Example 3: Synthesis of N-((3R,4R)-4-(2-Hydroxy-2-methylpropoxy)-l-methylpyrrolidin-3- yl)-l-(5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide (Compound 16)
Figure imgf000093_0002
[0178] To a mixture of N-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide hydrochloride (50 mg), formaldehyde (41 mg), DIPEA (52 |jL), and CH3CN (1 mL) was added sodium cyanoborohydride (19 mg). The reaction mixture was stirred overnight, concentrated, and purified using reverse phase chromatography (0-50% CH3CN/H2O with 0.1% formic acid) to give 27 mg of A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)-l-methylpyrrolidin-3-yl)-l-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide as a white solid. 1H NMR (400 MHz, Methanol-d4) 59.15 (s, 1H), 8.95 - 8.86 (m, 2H), 8.37 (s, 1H), 8.25 (dd, J = 8.7, 2.5 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 3.6 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.19 (dt, J = 5.0, 2.1 Hz, 1H), 3.71 - 3.61 (m, 1H), 3.57 - 3.45 (m, 2H), 3.36 - 3.27 (m, 2H), 3.26 - 3.18 (m, 1H), 2.82 (s, 3H), 1.17 (d, J = 4.7 Hz, 6H). LRMS (APCI) m/z 478.2 [M + H]+.
Example 4: Synthesis ofN-((3R,4R)-4-(2-Hydroxy-2-methylpropoxy)-l-(2- hydroxyethyl)pyrrolidin-3-yl)-l-(5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2- c]pyridine-6-carboxamide (Compound 18)
Figure imgf000094_0001
[0179] A mixture of N-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)- 1-(5- (trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamide hydrochloride (50 mg), 2-bromoethanol (91 |jL), potassium carbonate (267 mg), sodium iodide (288 mg), and DMF (5 mL) was stirred overnight, followed by concentration of the reaction mixture and purification using reverse phase chromatography (0-50% CH3CN/H2O with 0.1% formic acid) to give 40 mg of A-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)-l-(2- hydroxyethyl)pyrrolidin-3-yl)-l-(5-(trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine- 6-carboxamide as a white solid. 1H NMR (400 MHz, Methanol-d4) 59.22 (s, 1H), 9.01 - 8.93 (m, 2H), 8.41 (s, 1H), 8.33 (dd, J = 8.8, 2.5 Hz, 1H), 8.24 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 4.74 - 4.66 (m, 1H), 4.29 (dt, J = 5.3, 2.4 Hz, 1H), 3.87 (t, J = 5.3 Hz, 2H), 3.78 (dd, J = 11.8, 7.3 Hz, 1H), 3.71 (dd, J = 12.1, 5.5 Hz, 1H), 3.60 (d, J = 9.3 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.29 (q, J = 5.1 Hz, 2H), 1.25 (d, J = 5.0 Hz, 6H). LRMS (APCI) m/z 508.2 [M + H]+. Example 5: Synthesis ofN-((3R,4R)-l-(3,3-Difluorocyclobutyl)-4-(2-hydroxy-2- methylpropoxy)pyrrolidin-3-yl)-l-(5-(trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2- c]pyridine-6-carboxamide (Compound 22)
Figure imgf000095_0001
[0180] A mixture of N-((3R,4R)-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)- 1-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide (40 mg), methylene chloride (0.8 mL), 3, 3 -difluorocyclobutane (50 mg), DIPEA (0.046 mL), and acetic acid (2 drops) were stirred for 20 min, followed by the addition of sodium triacetoxyborohydride (27 mg). The reaction was stirred overnight, diluted with methanol, filtered, and purified using (0-70% CH3CN/H2O with 0.1% formic acid) to give 27 mg of A-((3/?,4/?)-l-(3,3- difluorocyclobutyl)-4-(2-hydroxy-2-methylpropoxy)pyrrolidin-3-yl)-l-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamide as a white solid. 1H NMR (400 MHz, Methanol-d4) 59.16 (s, 1H), 9.00 - 8.85 (m, 2H), 8.29 (dd, J = 8.7, 2.4 Hz, 1H), 8.19 (d, J = 3.6 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 3.5 Hz, 1H), 4.61 (ddd, J = 6.9, 4.6, 2.2 Hz, 1H), 4.14 (dt, J = 5.7, 2.7 Hz, 1H), 3.57 (d, J = 9.3 Hz, 1H), 3.35 (d, J = 9.3 Hz, 1H), 3.24 (qd, J = 9.8, 9.0, 4.1 Hz, 3H), 2.84 (dddd, J = 26.9, 12.9, 8.9, 4.5 Hz, 4H), 2.75 - 2.59 (m, 2H), 1.23 (d, J = 3.0 Hz, 6H). LRMS (APCI) m/z 555.3.
Example 6: Synthesis of N-((3S,4R)-3-Fluoro-l-(2-hydroxy-2-methylpropyl)piperidin-4- yl)-3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxamide (Compound 53)
Step 1: Synthesis of methyl 4-(3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)ureido)-3- iodobenzoate.
Figure imgf000095_0002
[0181] To a 250 mL round bottom flask was added triphosgene (816 mg) and dichloromethane (50 mL). To this mixture was added a solution of 3-fluoro-5- (trifluoromethyl)pyridin-2-amine (1.5 g), triethylamine (2.4 mL), and dichloromethane (20 mL). The reaction mixture was stirred for 2 min, followed by the addition of methyl 4- amino-3 -iodobenzoate (2.3 g) and triethylamine (1.2 mL). The reaction mixture was stirred for 20 min, diluted with 50 mL of 20% EtOAc/hexanes, sonicated, and then filtered. The solid was then washed with 20 mL of 20% EtOAc/hexanes and dried in vacuo to give 3.2 g of about a 50% mixture of methyl 4-(3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)ureido)-3- iodobenzoate and triethylamine hydrochloride as a white solid. LRMS (APCI) m/z 482.0 [M - H .
Step 2: Synthesis of methyl 3-(3-fh oro-5-(trifh oromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro- lH-benzo[d]imidazole-5-carboxylate.
Figure imgf000096_0001
[0182] To a 40 mL scintillation vial was added a 50% mixture of methyl 4-(3-(3-fluoro- 5-(trifluoromethyl)pyridin-2-yl)ureido)-3-iodobenzoate and triethylamine hydrochloride (3.22 g), copper iodide (1.27 g), DBU (3.0 mL) and DMSO (20 mL). The reaction mixture was heated to 100 °C for 20 min. The reaction mixture was then poured into a separatory funnel containing 150 mL of dichloromethane and 30 mL of 10% citric acid solution. The layers were separated and the organic layer was washed three times with 10% citric acid solution (30 mL). The aqueous layer was washed with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. Addition of dichloromethane (20 mL) and 20% EtOAc/hexane 20 mL) induced formation of a precipitate which was filtered to give 570 mg of methyl 3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2- oxo-2, 3-dihydro-l /7-bcnzo[d]imidazolc-5-carboxylatc as an off-white solid. The filtrate was concentrated and chromatographed though silica gel (20-40% EtOAc/hexanes) to give an additional 450 mg of methyl 3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro- l/Z-benzo[d]imidazole-5-carboxylate as a white solid. 1 H NMR (400 MHz, DMSO-d6) 5 11.84 (s, 1H), 9.01 (dd, J = 2.1, 1.0 Hz, 1H), 8.69 (dd, J = 9.6, 2.0 Hz, 1H), 7.83 (dd, J = 8.3, 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H). LRMS (APCI) m/z 354.0 [M - H]“.
Step 3: Synthesis of 3-(3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-lH- benzo[d ]imidazole-5-carboxylic acid.
Figure imgf000097_0001
[0183] To a 40 mL scintillation vial was added methyl 3-[3-fluoro-5- (trifluoromethyl)pyridin-2-yl]-2-oxo-l/Z-l,3-benzodiazole-5-carboxylate (1.06 g), ethanol (10 mL), and 1 N sodium hydroxide (14 mL). The reaction mixture was heated to 70 °C for 2 h. The reaction was then slowly acidified with 1 N HC1 to a pH of 3-5, and the resultant precipitate was filtered and dried to give 788 mg of 3-(3-fluoro-5-(trifluoromethyl)pyridin-2- yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carboxylic acid as a white powder. 1H NMR (400 MHz, DMSO-d6) 5 12.80 (s, 1H), 11.79 (s, 1H), 9.00 (dd, J = 2.0, 0.9 Hz, 1H), 8.69 (dd, J = 9.6, 2.0 Hz, 1H), 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H). LRMS (APCI) m/z 340.0 [M - H]“.
Step 4: Synthesis ofN-((3S,4R)-3-Fluoro-l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-(3- fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxamide.
Figure imgf000098_0001
[0184] To a 250 mL round bottom flask was added 3-[3-fluoro-5- (trifluoromethyl)pyridin-2-yl]-2-oxo-lH-l,3-benzodiazole-5-carboxylic acid (688 mg, 2.0 mmol), l-[(3S,47?)-4-amino-3-fluoropiperidin-l-yl]-2-methylpropan-2-ol (384 mg, 2.0 mmol), methylene chloride (50 mL), triethylamine (0.9 mL, 6.3 mmol), and PyBOP (1.15 g, 2.2 mmol). The reaction was stirred at rt overnight. The reaction was then poured into a separatory funnel containing ethyl acetate (200 mL) and brine (50 mL). The organic layer was separated and washed with brine (50 mL). The combined aqueous layers were extracted twice with ethyl acetate (150 mL total), and the combined organic layers were dried over sodium sulfate, concentrated, and purified using reverse phase chromatography (Phenomenex Gemini C18 column, 5 pm, 150 x 21.2; 10-90% CH3CN/H2O over 45 min, five separate runs) to give 328 mg (32%) of A-((3S,4R)-3-fhioro-l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)- 3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-oxo-2,3-dihydro-l//-benzo[d]imidazole-5- carboxamide as a white powder. 1 H NMR (400 MHz, Methanol-d4) 5 8.89 (dt, J = 2.0, 0.9 Hz, 1H), 8.39 (dd, J = 9.3, 2.1 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.25 (dd, J = 8.3, 0.6 Hz, 1H), 4.81 (s, 1H), 4.25 - 4.09 (m, 1H), 3.64 (t, J = 11.8 Hz, 1H), 3.25 (d, J = 13.0 Hz, 1H), 2.93 (d, J = 13.7 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.77 - 2.68 (m, 1H), 2.70 - 2.61 (m, 1H), 2.25 (qd, J = 12.8, 4.0 Hz, 1H), 1.86 - 1.78 (m, 1H), 1.26 (d, J = 2.5 Hz, 6H). LRMS (APCI): calculated for C23H24F5N5O3 513.5 Da, measured 514.2 m/z [M + H]+.
Example 7: Synthesis of N-((3R,4S)-4-(2-Morpholinoethoxy)tetrahydrofuran-3-yl)-2-oxo- 3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (Compound 63)
Figure imgf000099_0001
[0185] To a mixture of 2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z- benzo[d]imidazole-5-carboxylic acid (60 mg), (3R,45)-4-(2- morpholinoethoxy)tetrahydrofuran-3-amine (40 mg), DMF (1 mL), and DIPEA (0.1 mL) was added HBTU (84 mg). The reaction mixture was stirred at rt fori h, filtered, and purified using reverse phase chromatography (0-40% CH3CN/H2O with 0.1% formic acid) to give 32 mg of A-((3R,4S)-4-(2-morpholinoethoxy)tetrahydrofuran-3-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z-benzo[d]imidazole-5-carboxamide as a white solid. ’ H NMR (400 MHz, Methanol-^) 5 8.90 (s, 1H), 8.68 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.25 (dd, J = 8.8, 2.5 Hz, 1H), 7.73 (dd, 7 = 8.3, 1.6 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.20 - 4.11 (m, 2H), 4.07 (ddd, J = 10.0, 8.4, 4.9 Hz, 2H), 3.96 - 3.81 (m, 7H), 3.25 (t, J = 5.2 Hz, 2H), 3.20 (t, J = 4.8 Hz, 4H). LRMS (APCI) m/z 522.2 [M + H]+.
Example 8: Synthesis of N-((4-Acetyl-l-benzylpiperazin-2-yl)methyl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (Compound 68)
Figure imgf000099_0002
[0186] To A-((l-benzylpiperazin-2-yl)methyl)-2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)- 2,3-dihydro-l/Z-benzo[d]imidazole-5-carboxamide (13 mg) dissolved in methylene chloride (1 mL) was added triethylamine (8 mg) and acetic anhydride (5 mg). The reaction was stirred at rt for 1 h, followed by dilution with methylene chloride (10 mL). The mixture was then washed with saturated sodium bicarbonate (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse phase chromatography (10-100% acetonitrile in water with 0.1% formic acid) to give A-((4-acetyl- l-benzylpiperazin-2-yl)methyl)-2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z- benzo[d]imidazole-5-carboxamide (6 mg) as an off-white solid. LRMS (APCI) m/z 553.0 [M+H],
Example 9: Synthesis of N-((l-Benzyl-4-methylpiperazin-2-yl)methyl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (Compound 73)
Figure imgf000100_0001
[0187] A mixture of A-((l-benzylpiperazin-2-yl)methyl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro- 1 //-bcnzo[d] i midazolc-5-carboxamidc (18 mg), methylene chloride (2 mL), 37% formaldehyde (29 mg), and sodium borohydride (75 mg) was stirred at rt for 2 h. The mixture was then washed with saturated sodium bicarbonate (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse phase chromatography (20-100% acetonitrile in water with 0.1% formic acid) to give A-((l-benzyl-4-methylpiperazin-2-yl)methyl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z-benzo[d]imidazole-5-carboxamide (15 mg) as an off-white solid. LRMS (APCI) m/z 525.2 [M+H],
Example 10: Synthesis of N-(l-(l,3-Dihydroxypropan-2-yl)piperidin-4-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (Compound 78)
Step 1: Synthesis of tert-Butyl 4-(2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH- benzo[d ]imidazole-5-carboxamido )piperidine-l -carboxylate.
Figure imgf000101_0001
[0188] To a stirring solution of 2-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]-l//-l,3- benzodiazole-5-carboxylic acid (1.0 g, 3.1 mmol, 1.0 equiv) in DMF (10 mL) at rt was added EDCI (892 mg, 4.7 mmol, 1.5 equiv), HO At (632 mg, 4.6 mmol, 1.5 equiv), DIPEA (1.2 g, 9.3 mmol, 3.0 equiv) and tert-butyl 4-aminopiperidine-l -carboxylate (681 mg, 3.4 mmol, 1.1 equiv). The reaction mixture was stirred at rt overnight. Water (20 mL) was then added, and the precipitated solids were collected by filtration and concentrated under reduced pressure to afford 1.0 g of tert-butyl 4-[2-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]-l//-l,3-benzodiazole- 5-amido]piperidine-l-carboxylate (64%) as a white solid. LRMS (ES) m/z 450 [M+H-56].
Step 2: Synthesis of2-Oxo-N-(piperidin-4-yl)-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3- dihydro-lH-benzo[d]imidazole-5-carboxamide.
Figure imgf000101_0002
[0189] To a stirring solution of tert-butyl 4-[2-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]- 1/7-1, 3-benzodiazole-5-amido]piperidine-l-carboxylate (1.0 g, 2.0 mmol, 1.0 equiv) in methylene chloride (5 mL) at rt was added TFA (5 mL). The reaction mixture was stirred at rt for 2 h. The mixture was then adjusted to pH 8 with 1 N NaOH, diluted with water (20 mL), and the resultant solution was extracted twice with methylene chloride (20 mL). The combined organic layers were washed twice with brine (10 mL), dried over anhydrous NaiSCL, and concentrated under reduced pressure to give 800 mg of 2-oxo-A/-(pipcridin-4- yl)-3-[5-(trifluoromethyl)pyridin-2-yl]-l//-l,3-benzodiazole-5-carboxamide as a yellow solid. LRMS (ES) m/z 406 [M+H], Step 3: Synthesis of Diethyl 2-(4-(2-oxo-3-(5-(trifh oromethyl)pyridin-2-yl)-2,3-dihydro-lH- benzo[d]imidazole-5-carboxamido)piperidin-l-yl)malonate.
Figure imgf000102_0001
[0190] To a stirring solution of 2-oxo-A-(piperidin-4-yl)-3-[5-(trifhioromethyl)pyridin-2- yl]-l/Z-l,3-benzodiazole-5-carboxamide (100 mg, 0.25 mmol, 1.0 equiv) in EtOH (2 mL) at rt was added TEA (50 mg, 0.5 mmol, 2.0 equiv) and 1,3-diethyl 2-bromopropanedioate (76 mg, 0.3 mmol, 1.3 equiv). The reaction mixture was heated to 80 °C and stirred for 2 h. The resulting mixture was then cooled to rt and concentrated under reduced pressure to afford 250 mg of 1,3-diethyl 2-(4-{2-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]-lH-l,3-benzodiazole-5- amido}piperidin-l-yl) propanedioate as a white solid. LRMS (ES) m/z 564 [M+H].
Step 4: Synthesis ofN-(l-(l,3-Dihydroxypropan-2-yl)piperidin-4-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide.
Figure imgf000102_0002
[0191] To a solution of 1,3-diethyl 2-(4-{2-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]-l/Z- l,3-benzodiazole-5-amido]piperidin-l-yl)propanedioate (230 mg, 0.4 mmol, 1.0 equiv) in THF (3 mL) at rt was added LiBPL (1.0 mL, 2M in THF, 5.0 equiv) dropwise. The reaction mixture was stirred at rt for 2 h, cooled to 0 °C, quenched with water (1 mL), concentrated under reduced pressure, and purified by reverse phase chromatography (Column, XB ridge Prep OBD C18 Column, 30*150 mm, 5 pm; mobile phase, water (10 mM NH4HCO3+0.1% NH3 H2O) and CH3CN (30% - 60% over 8 min)) to afford 20 mg of A-(l-(l,3- dihydroxypropan-2-yl)piperidin-4-yl)-2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro- l/Z-benzo[d]imidazole-5-carboxamide (10%) as a white solid. 1H NMR (400 MHz, DMSO- d6) 5 11.71 (s, 1H), 9.05 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.47 - 8.35 (m, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.71 (dd, J = 8.2, 1.7 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 4.25 (s, 2H), 3.79 - 3.69 (m, 1H), 3.47 (qd, J = 10.9, 6.1 Hz, 4H), 2.86 (d, J = 11.3 Hz, 2H), 2.54 (d, J = 10.4 Hz, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.53 (tt, J = 12.6, 6.4 Hz, 2H). LRMS (ES) m/z 480 [M+H],
Example 11: Synthesis of(S)-N-(5-Hydroxy-2,5-dimethylhexan-3-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (Compound 80)
Step 1: Synthesis of methyl (S)-4-methyl-3-(2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3- dihydro-lH-benzo[d]imidazole-5-carboxamido)pentanoate.
Figure imgf000103_0001
[0192] To a 40 mL scintillation vial was added 2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)- 2,3-dihydro-l/Z-benzo[d]imidazole-5-carboxylic acid (60 mg), methyl (S)-3-amino-4- methylpentanoate (43 mg), PyBOP (116 mg), DMF (1 mL), and DIPEA (0.13 mL). The reaction mixture was stirred at rt for 1 h, filtered, and directly purified using reverse phase chromatography (Phenomenex Gemini 5 pm C18 150 x 21.2 mm column, 10-70% CH3CN/H2O with 0.1% formic acid over 38 min) to give 44 mg of methyl (S)-4-methyl-3-(2- oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-l/Z-benzo[d]imidazole-5- carboxamido)pentanoate as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 11.73 (s, 1H), 9.03 (dt, J = 2.2, 1.0 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.47 - 8.37 (m, 2H), 8.13 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.2, 1.8 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 4.25 - 4.17 (m, 1H), 3.55 (s, 3H), 2.67 - 2.51 (m, 2H), 1.83 (dt, J = 13.4, 6.7 Hz, 1H), 0.89 (dd, J = 6.8, 2.3 Hz, 6H). LRMS (APCI) m/z 449.1 [M - H]“. Step 2: Synthesis of(S)-N-(5-Hydroxy-2,5-dimethylhexan-3-yl)-2-oxo-3-(5- (trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide.
Figure imgf000104_0001
[0193] Methyl (S)-4-methyl-3-(2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro- l/Z-benzo[d]imidazole-5-carboxamido)pentanoate (39 mg) was dissolved in THF (10 mL), and MeMgBr (0.18 mL of a 3N solution in diethyl ether) was slowly added. The reaction was stirred for 10 min, diluted with 1% acetic acid in methanol, concentrated, and purified using reverse phase chromatography (Phenomenex Gemini 5 pm C18 150 x 21.2 mm column, 10-60% CH3CN/H2O with 0.1% formic acid over 38 min) to give 3 mg of (5)-A-(5- hydroxy-2,5-dimethylhexan-3-yl)-2-oxo-3-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-lH- benzo[d]imidazole-5-carboxamide as a white solid. LRMS (APCI) m/z 449.1 [M - H]“.
Example 12: Synthesis of 2-((3R,4R)-3-(Dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l- yl)-2-methylpropan-l-ol
Step 1: Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-(2-methoxyethoxy)pyrrolidine-l- carboxylate.
Figure imgf000104_0002
[0194] To a solution of tert-butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-l- carboxylate (9.0 g) and THF (50 mL) at 0 °C was added sodium hydride (3.1 g of a 60% dispersion in mineral oil) in portions. The reaction mixture was stirred for 30 min, followed by the addition of 1 -bro mo-2-methoxy ethane (17.7 mL). The reaction mixture was warmed to rt, stirred for 30 min, and then heated to 70 °C and stirred overnight. Saturated ammonium chloride solution (20 mL) and water (20 mL) were then added, and extraction of this mixture was performed three times using ethyl acetate (100 mL each extraction). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, concentrated, and purified using silica gel chromatography to give 10.8 g of tert-butyl (3R,4R)-3- (dibenzylamino)-4-(2-methoxyethoxy)pyrrolidine-l -carboxylate as a light yellow oil.
LRMS (APCI) m/z 441.3 [M + H]+.
Step 2: Synthesis of (3R,4R)-N,N-Dibenzyl-4-(2-methoxyethoxy)pyrrolidin-3-amine.
Figure imgf000105_0001
[0195] To a solution of tert-butyl (3R,4R)-3-(dibenzylamino)-4-(2- methoxy ethoxy )pyrrolidine- 1 -carboxylate (6.0 g) and methanol (57 mL) was added 4M HCI in dioxane (51 mL). The reaction mixture was stirred for 1 h and concentrated. The resultant solid was mixed with methylene chloride and concentrated to give 5.2 g of (3RAR)-NJ !- dibenzyl-4-(2-methoxyethoxy)pyrrolidin-3-amine as a yellow solid. LRMS (APCI) m/z 341.2 [M + H]+.
Step 3: Synthesis of ethyl 2-((3R,4R)-3-(dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)- 2-methylpropanoate.
Figure imgf000105_0002
[0196] (3R,4R)-A,A-Dibenzyl-4-(2-methoxyethoxy)pyrrolidin-3-amine (300 mg), ethyl 2- bromo-2-methylpropanoate (2.1 g), acetonitrile (3 mL), and potassium carbonate (505 mg) were combined, heated to 85 °C, and stirred overnight. The reaction mixture was then filtered, concentrated, and purified using reverse phase chromatography (0-70% CH3CN/H2O with 0.1% formic acid) to give 220 mg of ethyl 2-((3R,4R)-3-(dibenzylamino)-4-(2- methoxyethoxy)pyrrolidin-l-yl)-2-methylpropanoate as a clear oil. LRMS (APCI) m/z 455.3 [M + H]+.
Step 4: Synthesis of2-((3R,4R)-3-(Dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)-2- methylpropan-1 -ol.
Figure imgf000106_0001
[0197] To a solution of ethyl 2-((3R,4R)-3-(dibenzylamino)-4-(2- methoxyethoxy)pyrrolidin-l-yl)-2-methylpropanoate (220 mg) in THF (2 mL) at 0 °C was added DIBAL dropwise (1 mL of a 25% solution in toluene). The reaction mixture was stirred for 45 min, diluted with saturated potassium sodium tartrate solution (10 mL), and stirred again for 30 min. The mixture was then extracted three times with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give 210 mg of 2-((3R,4R)- 3-(dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)-2-methylpropan-l-ol as a clear oil. LRMS (APCI) m/z 413.3 [M + H]+.
Example 13: Synthesis of (3R,4R)-N,N-Dibenzyl-l-(l-methoxy-2-methylpropan-2-yl)-4-(2- methoxyethoxy)pyrrolidin-3-amine
Figure imgf000106_0002
[0198] 2-((3R,4R)-3-(Dibenzylamino)-4-(2-methoxyethoxy)pyrrolidin-l-yl)-2- methylpropan-l-ol (200 mg) was dissolved in THF (2 mL), and the solution was cooled to 0 °C. Sodium hydride (39 mg of a 60% dispersion in mineral oil) was then added, and the mixture for stirred for 30 min. Methyl iodide (0.06 mL) was then added, and the reaction mixture was warmed to rt and stirred for 1 h. Methanol (1 mL) was added, and the mixture was concentrated and purified using reverse phase chromatography (0-70% CH3CN/H2O with 0.1% formic acid) to give 144 mg of (3R,4R)-A,A-dibenzyl-l-(l-methoxy-2-methylpropan-2- yl)-4-(2-methoxyethoxy)pyrrolidin-3-amine as a clear oil. (APCI) m/z 427.3 [M + H]+.
Example 14: Synthesis of tert-Butyl (3R,4R)-3-(2,2-difluoroethoxy)-4-(l-(5- (trifluoromethyl)pyridin-2-yl)-lH-pyrrolo[3,2-c]pyridine-6-carboxamido)pyrrolidine-l- carboxylate
Figure imgf000107_0001
[0199] To a solution of tert-butyl (3R,4R)-3-hydroxy-4-(l-(5-(trifluoromethyl)pyridin-2- yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamido)pyrrolidine-l-carboxylate (98 mg) in DMF (1 mL) at 0 °C was added sodium hydride (10 mg of a 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 10 min, followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (47 mg) drop wise. The reaction was stirred at 0 °C for 10 min, then warmed to rt and stirred for 2h. The reaction was diluted with EtOAc (20 mL) and washed with saturated ammonium chloride (10 mL) and saturated sodium bicarbonate (10 mL). The aqueous layers were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, concentrated, and purified using reverse phase chromatography (Phenomenex Gemini 5 pm C18 150 x 21.2 mm column, 20 - 100% CH3CN/H2O over 40 min) to give 70 mg of tert-butyl (3R,4R)-3-(2,2-difluoroethoxy)-4-(l-(5- (trifluoromethyl)pyridin-2-yl)-l/Z-pyrrolo[3,2-c]pyridine-6-carboxamido)pyrrolidine-l- carboxylate as an off white solid. LRMS (APCI) m/z 556.3 [M + H]+.
Example 15: Synthesis of Benzyl ((3R,4R)-4-(tert-butoxy)pyrrolidin-3-yl)carbamate
Figure imgf000108_0001
[0200] A mixture of tert-butyl (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4- hydroxypyrrolidine- 1 -carboxylate (160 mg), methylene chloride (3 mL), and tert-butyl 2,2,2- trichloroacetate (313 mg) was cooled to 0 °C, followed by the addition of triflic acid (14 mg). The reaction mixture was warmed to rt and stirred overnight. The reaction was then diluted with methylene chloride (10 mL) and washed with saturated sodium bicarbonate solution (5 mL) and brine (5 mL). The resultant organic layer was dried over sodium sulfate, concentrated, and purified using reverse phase chromatography (Phenomenex Gemini 5 micron C18 150 x 21.2 mm column, 10 - 100% CH3CN/H2O over 40 min) to give 60 mg of benzyl ((37?,47?)-4-(tert-butoxy)pyrrolidin-3-yl)carbamate. LRMS (APCI) m/z 293.2 [M + H]+.
Example 16: Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-(2-(4-methylpiperazin-l- yl)ethoxy )pyrrolidine-l-carboxylate
Figure imgf000108_0002
[0201] tert-Butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine- 1-carboxylate (765 mg) was dissolved in DMF (10 mL), and the mixture was cooled to 0 °C. Sodium hydride (320 mg of a 60% dispersion in mineral oil) was then added, the reaction mixture stirred for 10 min, followed by the addition of l-(2-chloroethyl)-4-methylpiperazine (589 mg) and sodium iodide (899 mg). The resulting mixture was stirred at rt for 16 h. The reaction mixture was then extracted with EtOAc, and the organic layer was separated and washed with brine. The organic layer was concentrated and purified using silica gel chromatography (EtOAc) to give 400 mg of tert-butyl (3R,4R)-3-(dibenzylamino)-4-(2-(4-methylpiperazin-l- yl)ethoxy)pyrrolidine-l -carboxylate as a solid.
Example 17: Synthesis of tert-Butyl (3R,4R)-3-(dibenzylamino)-4-isopropoxypyrrolidine-l- carboxylate
Figure imgf000109_0001
[0202] To a mixture of tert-butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-l - carboxylate (2.76 g) and isopropyl iodide (11 mL) was added silver oxide (5.0 g). The reaction mixture was stirred at 45 °C for 60 h, followed by dilution with ethyl acetate (100 mL) and filtration through Celite. The filtrate was concentrated and purified using silica gel chromatography (30% EtOAc/hexanes) to give 520 mg of tert-butyl (37?,47?)-3- (dibenzylamino)-4-isopropoxypyrrolidine-l -carboxylate as a pale yellow oil.
[0203] The following compounds were prepared in accordance with the synthetic procedures described herein or using similar synthetic procedures with the appropriate reagents.
Table 3
Figure imgf000109_0002
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Biological Example B-l
Preparation of slow skeletal myofibrils
[0204] Slow skeletal myofibrils were prepared from flash-frozen bovine masseter muscle (Pel-Freez Biologicals, Arkansas) based upon the method of (Herrmann, et al. 1993). Minced muscle was homogenized in 10 volumes of ice-cold detergent buffer (50 mM Tris, 100 mM potassium acetate, 5 mM KC1, 5 mM EDTA, 0.5 mM NaNs, 2 mM DTT, 1 mM benzamidine- HC1, 0.2 mM PMSF, 1 pg/mL leupeptin, 1 pg/mL pepstatin, and 0.5% (v/v) Triton X-100, final pH 7.4 at 4 °C) using an Omni-Macro homogenizer. Myofibrils were recovered by low speed centrifugation in a swinging bucket rotor (3000 x g, 10 minutes, 4 °C) and washed 2 more times in the detergent-containing buffer to ensure removal of cellular membranes.
Following the detergent washes, myofibrils were washed 3 times in wash buffer (50 mM Tris, 100 mM potassium acetate, 5 mM KC1, 2 mM magnesium acetate, 0.5 mM NaNs, 2 mM DTT, 0.2 mM PMSF, final pH 7.4 at 4 °C) and once in storage buffer (12 mM PIPES, 60 mM KC1, 2 mM MgCh, 1 mM DTT, 0.2 mM PMSF, 1 pg/mL leupeptin, 1 pg/mL pepstatin, final pH 6.8). The final pellet was resuspended in storage buffer and solid sucrose was added (10% w/v) prior to flash freezing in liquid nitrogen and storage at -80 °C. See Herrmann, C.; Sleep, J.; Chaussepied, P.; Travers, F.; Barman, T. A structural and kinetic study on myofibrils prevented from shortening by chemical cross-linking." Biochemistry 1993, 32(28), 7255-7263.
Activation of Slow Skeletal Myofibrils
[0205] Slow fiber activators were identified by measuring the enzymatic activity of muscle myofibril preparations using the assay system described in U.S. Patent Nos.
6,410,254, 6,743,599, 7,202,051, and 7,378,254. Myofibril preparations consisted of bovine masseter muscle (ca 90% slow fibers) that had been mechanically homogenized and washed with a detergent (Triton X-100) to remove cellular membranes. This preparation retained all of the sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. Compounds were tested using a myofibril suspension and a level of calcium sufficient to increase enzymatic activity of the myofibrils to 25% of their maximal rate (termed pCa25). Enzymatic activity was tracked via a pyruvate kinase and lactate dehydrogenase-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm. The buffering system was 12 mM PIPES, 4 mM MgCh, 60 mM KC1 at pH 6.8. Data were reported as AC1.4, which is the concentration at which the compound increased the enzymatic activity by 40%. Results for compounds tested are provided in Table A. Compounds tested were prepared in accordance with the synthetic procedures described herein or using similar synthetic procedures with the appropriate reagents.
Table A
Figure imgf000113_0001
Figure imgf000114_0001
[0206] While the foregoing written description of the compounds, uses, and methods described herein enables one of ordinary skill to make and use the compounds, uses, and methods described herein, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The compounds, uses, and methods provided herein should therefore not be limited by the above-described embodiments, methods, or examples, but rather encompasses all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.
[0207] All references disclosed herein are incorporated by reference in their entirety.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound of formula (I):
Figure imgf000116_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
X1, R1, and are defined by either (i) or (ii):
(i) X1 is NH;
R1 is oxo; and is a single bond; or
(ii) X1 is CH;
R1 is hydrogen or Ci-Ce alkyl; and is a double bond;
X2 and X3 are each independently N or CH;
R2 is hydrogen or halogen;
R3 is Ci-C6 haloalkyl;
L is absent or -CH2-; A is C1-C12 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one to five RA; each RA is independently selected from the group consisting of Ci-Ce alkyl, halogen, -NHS(O)2R4, -NHC(O)OR4, -CN, -C(O)N(R4)2, -S(O)2N(R4)2, -C(O)R4, -OH, -OR4, - S(O)2R4,
-C(O)OR4, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl, wherein each Ci-Ce alkyl, 4- to 8-membered heterocyclyl, and C3-C8 cycloalkyl is independently optionally substituted with one to five RB; each RB is independently selected from the group consisting of -OH, -CN, Ci-Ce alkyl, halogen, -0(Ci-C6 alkyl), -C(0)0(Ci-C6 alkyl), -C(0)(Ci-C6 alkyl), 5- to 10-membered heteroaryl, Ce-Cio aryl, 4- to 8-membered heterocyclyl optionally substituted with -OH, and C3-C8 cycloalkyl optionally substituted with -OH; each R4 is independently selected from the group consisting of:
(a) 5- to 10- membered heteroaryl optionally substituted with Ci-Ce alkyl,
(b) 4- to 8-membered heterocyclyl optionally substituted with one to three - C(O)OC(Ci-C6 alkyl), and
(c) Ci-Ce alkyl optionally substituted with one to five R5; each R5 is independently selected from the group consisting of:
(a) -OH,
(b) halogen,
(c) -O(Ci-C6 alkyl) optionally substituted with one to three -OH,
(d) N(R6)2, and
(e) 5- to 6-membered heterocyclyl optionally substituted with one to five Ci-Ce alkyl; and each R6 is independently selected from the group consisting of H and Ci-Ce alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1 is CH;
R1 is hydrogen or Ci-Ce alkyl; and is a double bond.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is Ci-C6 alkyl.
4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
X1 is NH;
R1 is oxo; and is a single bond.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X2 is N and X3 is CH.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X2 and X3 are each N.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X2 and X3 are each CH.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.
11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R3 is -CF3.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein L is absent.
14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is 4- to 8-membered heterocyclyl optionally substituted with one to three RA.
16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, and wherein A is optionally substituted with one to three RA.
17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is C3-C8 cycloalkyl optionally substituted with one to five RA.
18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: cyclobutyl, cyclopentyl, and cyclohexyl, and wherein A is optionally substituted with one to three RA.
19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heteroaryl or C1-C12 alkyl, wherein each of which is optionally substituted with one to five RA.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein A is substituted with one to three RA groups and wherein at least one of the RA groups is selected from the group consisting of fluorine, -OR4, and Ci-Ce alkyl substituted with -OH.
21. A compound selected from the group consisting of compounds of Table 2, or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising the compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
24. A method for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty, in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22.
25. A method for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathies, in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22.
26. A method for 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction, in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22.
27. The use of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
28. The use of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathies in a subject.
29. The use of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for the manufacture of a medicament for 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
30. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for use in treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, and frailty in a subject.
31. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, 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 myopathies in a subject.
32. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for use in 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, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, and post-stroke muscle dysfunction in a subject.
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