WO2023147312A1 - Ampk agonists and methods of use thereof - Google Patents

Ampk agonists and methods of use thereof Download PDF

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WO2023147312A1
WO2023147312A1 PCT/US2023/061185 US2023061185W WO2023147312A1 WO 2023147312 A1 WO2023147312 A1 WO 2023147312A1 US 2023061185 W US2023061185 W US 2023061185W WO 2023147312 A1 WO2023147312 A1 WO 2023147312A1
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formula
compound
formulas
alkyl
cycloalkyl
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French (fr)
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Michael J. Green
Amna T. ADAM
Alam Jahangir
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Evvia Therapeutics Inc
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Evvia Therapeutics Inc
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Priority to JP2024545035A priority Critical patent/JP2025504963A/ja
Priority to US18/832,088 priority patent/US20250109119A1/en
Priority to CN202380030086.XA priority patent/CN119013256A/zh
Priority to EP23707598.1A priority patent/EP4469436A1/en
Publication of WO2023147312A1 publication Critical patent/WO2023147312A1/en
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    • 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
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D401/10—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 linked by a carbon chain containing aromatic rings
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Definitions

  • AMPK AGONISTS AND METHODS OF USE THEREOF FIELD [001] The disclosure relates generally to compounds and methods of using the same for treating conditions alleviated by AMPK activation.
  • CROSS REFERENCE TO RELATED APPLICATIONS [002] The present application is an International Application which claims priority to U.S. Provisional Application No.63/302,942, filed January 25, 2022, which is herein incorporated by reference in its entirety.
  • AMP-dependent AMPK activators Previously studied drug candidates were conventional AMP-dependent AMPK activators, with the mechanism of action requiring elevations of AMP caused either by RC inhibition (e.g., metformin, resveratrol) or conversion into AMP mimetics (e.g., AICAR).
  • RC inhibition e.g., metformin, resveratrol
  • AICAR conversion into AMP mimetics
  • the indirect mechanism involving RC inhibition is not suitable for cases with underlying mitochondrial dysfunction, and AMP-dependent activation of AMPK results in the activation of other AMP- regulated enzymes, thereby compounding pleiotropic effects.
  • previous studies have identified direct, AMP-independent AMPK agonists for the purpose of treating diabetes, obesity, and metabolic syndrome.
  • Primary mitochondrial diseases are a clinically heterogeneous group of disorders that are usually progressive, multi-systemic, and are associated with a high mortality rate in children. They are caused by inherited deficiencies in the mitochondrial respiratory chain (RC), leading to an increased production of reactive oxygen and nitrogen species (ROS and RNS) as well as a deficiency in overall energy production. These resulting metabolic imbalances lead to cellular damage and ultimately to cell death.
  • RC mitochondrial respiratory chain
  • ROS and RNS reactive oxygen and nitrogen species
  • Secondary mitochondrial diseases also demonstrate mitochondrial dysfunction but, unlike primary mitochondrial diseases, are not caused by genes related to the mitochondrial respiratory chain. Secondary mitochondrial diseases, such as Parkinson’s disease or Alzheimer’s disease, are due to acquired mitochondrial abnormalities caused by other diseases, conditions, or environmental factors that indirectly damage the mitochondria. Consequently, any treatment identified for primary mitochondrial disease, would be expected to also benefit disorders and conditions associated with secondary mitochondrial dysfunction, including neurodegenerative, neuromuscular, and muscle wasting disorders. [007] There is a need in the art for novel treatments for primary and secondary mitochondrial diseases. This disclosure addresses this need in the art.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: formula (I) wherein in formula (I): X 1 is CR 4a or N; X 2 is CR 4b or N; R 1 is selected from R 2 is selected from H, C 1-3 alkyl, -CF 3 , and halo; R 3 is at each occurrence independently selected from halo, -CN, , N(R 10 ) 2 , C 1-10 alkyl, C 2 - 10 alkynyl, C 1-10 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 3-10 heterocyclyl, C 4-12 alkylcycloalkyl, C 4-10 cycloalkylalkyl, C 3-7 heterocycloalkenyl, C 4-12 alkylheterocycloalkenyl, C 4-10 heterocycloal
  • R 4a is H, Cl, or F.
  • X 2 is N or CR 4b, wherein R 4b is H.
  • R 2 is halo.
  • R 2 is Cl or F.
  • R 6 is H.
  • A is selected from: and .
  • R 6 is H.
  • the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (14), formula (15), formula (16), or formula (17), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is .
  • the compound of formula (I) is a compound of formula (100), formula (110), formula (120), formula (130), formula (140), formula (150), formula (160), or formula (170), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is .
  • the compound of formula (I) is a compound of formula (200), formula (210), formula (220), formula (230), formula (240), formula (250), formula (260), or formula (270) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is .
  • the compound of formula (I) is a compound of formula (300), formula (310), formula (320), formula (330), formula (340), formula (350), formula (360), or formula (370) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound is selected from:
  • R 1 is .
  • the compound of formula (I) is a compound of formula (400), formula (410), formula (420), formula (430), formula (440), formula (450), formula (460), or formula (470) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is In some embodiments, the compound of formula (I) is a compound of formula (500), formula (510), formula (520), formula (530), formula (540), formula (550), formula (560), or formula (570), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is .
  • the compound of formula (I) is a compound of formula (600), formula (610), formula (620), formula (630), formula (640), formula (650), formula (660), or formula (670), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is In some embodiments, the compound of formula (I) is a compound of formula (700), formula (710), formula (720), formula (730), formula (740), formula (750), formula (760), or formula (770), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. [0017] In some embodiments, R 1 is .
  • the compound of formula (I) is a compound of formula (800), formula (810), formula (820), formula (830), formula (840), formula (850), formula (860), or formula (870), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 1 is .
  • the compound of formula (I) is a compound of formula (900), formula (910), formula (920), formula (930), formula (940), formula (950), formula (960), or formula (970), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • R 10 is selected from H, methyl, ethyl, -CD3, n-butyl, , .
  • R 11 is selected from In some embodiments, p is 2 or 3.
  • R 3 is selected from -F, -CN, ethyl, , , , In some embodiments, R 3 is selected from In some embodiments, q is 0 or 1.
  • r is 2 or 3.
  • s is 1.
  • R 12 is selected from methyl, ethyl, -OCF 3 , and .
  • R 8 is selected from H, methyl, ethyl, isopropyl, n-butyl, t-butyl, . In some embodiments, R 8 is selected from H, methyl, ethyl, n-butyl, . In some embodiments, R 8 is selected from H, methyl, and ethyl. [0020] In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formula 1001-1114, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1003, 1007, 1024, 1044, 1077, 1078, 1081, 1084, 1088, 1112, 1113, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1001, 1006, 1008, 1010, 1013, 1014, 1016, 1017, 1018, 1022, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1003, 1009, 1011, 1015, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • A is a 5-membered ring heterocycle and R 1 is , R 8 is not H.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1001-1114, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1003, 1007, 1009, 1011, 1015, 1019, 1023, 1024, 1025, 1026, and 1078, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1001, 1006, 1008, 1010, 1013, 1014, 1016, 1024, 1017, 1018, and 1022, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1003, 1009, 1011, and 1015, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • formula (I) when A is a 5-membered ring heterocycle and R 1 is R 8 is not H.
  • the disclosure provides a pharmaceutical formulation including a compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114.
  • the disclosure provides a method of treating a patient with a mitochondrial dysfunction.
  • the method includes identifying a mitochondrial dysfunction in an individual; and administering a compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114 to the patient.
  • the disclosure provides a method of treating a patient with a mitochondrial dysfunction.
  • the method includes administering a therapeutically effective amount of a compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114 to the patient.
  • the mitochondrial dysfunction is a primary mitochondrial dysfunction.
  • the primary mitochondrial dysfunction is selected from the group consisting of Autosomal Dominant Optic Atrophy (ADOA), Alpers- Huttenlocher syndrome (nDNA defect), Ataxia neuropathy syndrome, (nDNA defect), Barth syndrome/ Lethal Infantile Cardiomyopathy (LIC), Co-enzyme Q deficiency, Complex I, complex II, complex III, complex IV and complex V deficiencies (either single deficiencies or any combination of deficiency), Chronic progressive external ophthalmoplegia (CPEO), Diabetes mellitus and deafness, Kearns-Sayre syndrome (mtDNA defect), Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL- leukodystrophy), Leigh syndrome (mtDNA and nDNA defects), Leber's hereditary optic neuropathy (LHON), Heil Disease, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke syndrome (MELAS) (mtDNA defect), Mito
  • ADOA
  • the mitochondrial dysfunction is a secondary mitochondrial dysfunction.
  • the secondary mitochondrial dysfunction is selected from the group consisting of age-related macular degeneration (AMD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD) and other dementias, Friedreich's ataxia (FA), Huntington's disease (HD), Motor neuron diseases (MND), N-glycanase deficiency (NGLY1 ), Organic acidemias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA), Becker muscular dystrophy , Congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic dystrophy, Oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, Congenital myopathies, Distal myopathies, En
  • the compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114 is administered in a pharmaceutical formulation.
  • the pharmaceutical formulation comprises the compound and at least one selected from a binding agent, a lubricating agent, a buffer, and a coating.
  • the compound is administered orally.
  • the compound is administered daily for at least one week.
  • the method further includes assessing the efficacy of the compound in the individual.
  • the compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114 is administered by oral administration, subcutaneous administration, intravenous administration, intraperitoneal administration, intranasal administration, dermal administration, intravitreal injection, or inhalation.
  • Fig.1 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.2 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.3 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.4 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.5 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.6 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.7 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.8 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • Fig.9 illustrates the structures of non-limiting examples of compounds of the disclosure.
  • DETAILED DESCRIPTION [0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties.
  • administer refers to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and/or (2) putting into, taking or consuming by the mammal, according to the disclosure.
  • co-administration encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.
  • active pharmaceutical ingredient and “drug” include, but are not limited to, the compounds described herein and, more specifically, compounds of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, and their features and limitations as described herein.
  • the terms “patient,” “subject,” and “individual” are used interchangeably.
  • the term “in vivo” refers to an event that takes place in a subject’s body.
  • the term “in vitro” refers to an event that takes places outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment.
  • a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells (e.g., increased sensitivity to apoptosis).
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • QD means quaque die, once a day, or once daily.
  • the terms “TID,” “tid,” or “t.i.d.” mean ter in die, three times a day, or three times daily.
  • the terms “QID,” “qid,” or “q.i.d.” mean quater in die, four times a day, or four times daily.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid 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. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • cocrystal refers to a molecular complex derived from a number of cocrystal formers known in the art.
  • a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art.
  • the terms “treat,” “treatment,” and/or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and/or control the disease, disorder, pathological condition or symptom thereof.
  • control may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).
  • the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule.
  • the biological molecules modulated by the methods and compounds of the disclosure to effect treatment may include the Mcl-1 oncoprotein and Bcl-2 oncoprotein.
  • prodrug refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of a compound of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3- methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters).
  • Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the disclosure with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like.
  • free hydroxyl groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups.
  • Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • any compound that can be converted in vivo to provide the bioactive agent e.g., a compound of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114) is a prodrug within the scope of the disclosure.
  • Various forms of prodrugs are well known in the art.
  • pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991).
  • prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g. dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the disclosure.
  • target the drug action e.g. organ or tumor-targeting, lymphocyte targeting
  • aqueous solubility of a drug e.g., i.v. preparations and eyedrops
  • topical drug delivery e.g. dermal and ocular drug delivery
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13 C- or 14 C-enriched carbons are within the scope of this disclosure.
  • ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C 1-10 )alkyl orC 1-10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range - e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl.
  • an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR a ,
  • Alkylaryl refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylhetaryl refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylheterocycloalkyl or “alkylheterocyclyl” refers to an -(alkyl) heterocycloalkyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • alkyl moiety may be branched, straight chain, or cyclic.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C 2 - 10 )alkenyl or C 2 - 10 alkenyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.
  • an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )
  • Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C 2-10 )alkynyl or C 2-10 alkynyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)
  • Alkynyl-cycloalkyl refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
  • Cyano refers to a -CN radical.
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3 - 10 )cycloalkyl or C 3 - 10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range - e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(
  • Cycloalkyl-alkenyl refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
  • Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.
  • Cycloalkyl-heteroaryl refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
  • alkoxy refers to the group -O-alkyl, including from 1 to 10 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy.
  • “Lower alkoxy” refers to alkoxy groups containing one to six carbons. [0079] The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)).
  • alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )
  • a (C 1 - 6 )alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • Lower alkoxycarbonyl refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
  • the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O
  • cycloalkyloxy represents a cycloalkyl group having the indicated number of carbon atoms attached through an oxygen atom (e.g., cyclopropyloxy and cyclohexyloxy).
  • “Acyl” refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)- C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality.
  • the R radical is heteroaryl or heterocycloalkyl
  • the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O) 2 , -
  • R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(
  • an acylsulfonamide group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C
  • alkylcycloalkyl groups include, for example, 2-methylcyclohexyl, 3,3- dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.
  • Alkylheterocycloalkenyl refers to a heterocycloalkyl or heterocyclyl as defined hereinand further including 1 or 2 double bonds and having one or more alkyl substituents.
  • Amino refers to a -N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryl
  • -N(R a ) 2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a)
  • substituted amino also refers to N-oxides of the groups -NHR a , and NR a R a each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • Amide or “amido” refers to a chemical moiety with formula -C(O)N(R) 2 or -NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted.
  • R 2 of -N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug.
  • the procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • “Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )
  • aryloxy refers to the group -O-aryl.
  • substituted aryloxy refers to aryloxy wherein the aryl substituent is substituted (i.e., -O-(substituted aryl)).
  • the aryl moiety of an aryloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a
  • “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • “Cycloalkylalkyl” refers to an alkyl group in which one of the hydrogen atoms is replaced by a cycloalkyl group. In some embodiments, the hydrogen atom on the terminal carbon atom of the alkyl group is substituted with a cycloalkyl group.
  • the cycloalkyl group is a C 3-6 cycloalkyl group, in some embodiments a C5-6 cycloalkyl group, and in some embodiments, a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl group.
  • the alkanediyl portion of a cycloalkylalkyl group may be, for example, C 1- 10 alkanediyl, C 1-6 alkanediyl, C 1-4 alkanediyl, C 1-3 alkanediyl, propane-1,3-diyl, ethane-1,2-diyl, or methane-diyl.
  • the cycloalkylalkyl group is C 4-16 cycloalkylalkyl, C 4- 12 cycloalkylalkyl, C 4-10 cycloalkylalkyl, C 6-12 cycloalkylalkyl, or C 6-9 cycloalkylalkyl.
  • C 6-9 cycloalkylalkyl includes a C 3 alkyl group bonded to a cyclopentyl or a cyclohexyl group.
  • “Ester” refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR a
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Halo “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo.
  • haloalkyl examples include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given - e.g., C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )C(O)OR a
  • Heteroalkylaryl refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.
  • Heteroalkylheteroaryl refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.
  • Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.
  • Heteroalkylcycloalkyl refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.
  • Heteroaryl or “heteroaromatic” or “HetAr” or “Het” refers to a 5- to 18-membered aromatic radical (e.g., C 5 -C 13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as “5 to 18” refers to each integer in the given range - e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • a N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical are optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benz
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (- O-) substituents, such as, for example, pyridinyl N-oxides.
  • “Heteroarylalkyl” refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
  • “Heterocycloalkyl” or “heterocyclyl” refer to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • a numerical range such as “3 to 18” refers to each integer in the given range - e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms.
  • the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
  • a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • Heterocycloalkenyl refers to a heterocycloalkyl or heterocyclyl as defined above and further including 1 or 2 double bonds.
  • heterocycloalkenyls include — (C 4 -C 9 )heterocycloalkenyl.
  • “Heterocycloalkenylalkyl” refers to an alkyl group in which one of the hydrogen atoms is replaced by a heterocycloalkenyl group. In some embodiments, the hydrogen atom on the terminal carbon atom of the alkyl group is substituted with a heterocycloalkenyl group.
  • Non- limiting examples include a dihydrofurylmethyl group (e.g., 2,5-dihydrofuran-3-ylmethyl group), a dihydropyranylmethyl group (e.g., a 5,6-dihydro-2H-pyran-ylmethyl group), a dihydropyrrolylmethyl group (a 3-pyrrolin-3-ylmethyl group), a tetrahydropyridylmethyl group (e.g., a 1,2,3,6-tetrahydropyridin-4-ylmethyl group), a tetrahydropyridylethyl group (e.g., a 1,2,3,6-tetrahydropyridin-4-yl-2-ethyl group), a dihydrothienylmethyl group (e.g., a 2,5- dihydrothiophen-3-ylmethyl group), a dihydrothiopyranylmethyl group (e.g., a 5,6-dihydro-2H
  • “Nitro” refers to the -NO 2 radical.
  • “Oxa” refers to the -O- radical.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S).
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%.
  • the enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley- Interscience, New York (1994).
  • HPLC high pressure liquid chromatography
  • an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight.
  • the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • the terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
  • “Moiety” refers to a specific segment or functional group of a molecule.
  • Tautomers are structurally distinct isomers that interconvert by tautomerization.
  • Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached.
  • keto-enol tautomerization An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4- hydroxypent-3-en-2-one tautomers.
  • phenol-keto tautomerization Another example of tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • a “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.
  • Protecting group is intended to mean 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 the group can then be readily removed or deprotected 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).
  • Solvate refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxy
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).
  • “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).
  • “Sulfonyl” refers to groups that include -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O 2 )-(optionally substituted amino), -S(O 2 )-(optionally substituted aryl), -S(O 2 )- (optionally substituted heteroaryl), and -S(O 2 )-(optionally substituted heterocycloalkyl).
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • a sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • Compounds of the disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • Crystal form and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • particular features for example integers, characteristics, values, uses, diseases, formulae, compounds or groups described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
  • the term “about” means that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.
  • the disclosure provides novel compounds that modulate AMPK.
  • the compounds of the disclosure are AMPK agonists.
  • the compounds of the disclosure are AMPK inhibitors.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: formula (I) wherein in formula (I): X 1 is CR 4a or N; X 2 is CR 4b or N; R 1 is selected from R 2 is H, -CF 3 or halo; R 3 is at each occurrence independently selected from halo, -CN, , - N(R 10 ) 2 , C 1-10 alkyl, C 2 - 10 alkynyl, C 1-10 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 3-10 heterocyclyl, C 4-12 alkylcycloalkyl, C 4-10 cycloalkylalkyl, C 3-7 heterocycloalkenyl, C 4-12 alkylheterocycloalkenyl, C 4-10 heterocycloalkenylalkyl, aryl and heteroary
  • X 1 is CR 4a .
  • R 4a is H, Cl, or F.
  • X 2 is CR 4b .
  • X 2 is N or CR 4b , wherein R 4b is H.
  • R 4b is C 1-10 alkyl.
  • R 4b is CH 3 .
  • A is selected from phenyl, pyridyl, pyrimidyl, pyridazyl and the following 5-membered ring heterocycles: [00138] In some embodiments, A and/or the 5-membered ring heterocycle is selected from
  • A is selected from [00140]
  • R 2 is halo.
  • R 2 is Cl or F.
  • R 6 is H.
  • the disclosure provides a compound of formula (10), formula (11), formula (12), formula (13), formula (14), formula (15), formula (16), or formula (17) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is [00144]
  • the disclosure provides a compound of formula (100), formula (110), formula (120), formula (130), formula (140), formula (150), formula (160), or formula (170) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is [00146]
  • the compound of formula (I) is a compound of formula (200), formula (210), formula (220), formula (230), formula (240), formula (250), formula (260), or formula (270) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: [00147]
  • R 1 is [00148]
  • the compound of formula (I) is a compound of formula (300), formula (310), formula (320), formula (330), formula (340), formula (350), formula (360), or formula (370) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: [00149]
  • the compound of any one of formulas (300)-(370) is selected from: [00150]
  • R 1 is [00151]
  • the compound of formula (I) is a compound of formula (400), formula (410), formula (420), formula (430),
  • R 1 is .
  • the compound of formula (I) is a compound of formula (800), formula (810), formula (820), formula (830), formula (840), formula (850), formula (860), or formula (870) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is [00161]
  • the compound of formula (I) is a compound of formula (900), formula (910), formula (920), formula (930), formula (940), formula (950), formula (960), or formula (970) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: [00162]
  • R 10 is selected from H, methyl, ethyl, -CD3, n-butyl, , [00163]
  • R 11 is selected from [00164]
  • p is 2 or 3.
  • R 3 is selected from -F, -CN, ethyl,
  • R 3 is selected from optionally . In some embodiments, is . In some embodiments, is [00166] In some embodiments, q is 0 or 1. [00167] In some embodiments, r is 2 or 3. [00168] In some embodiments, s is 1. [00169] In some embodiments, R 12 is selected from methyl, ethyl, -OCF 3 , and .In some embodiments, R 8 comprises one or more -OCF 3 groups. In some embodiments, R 8 is selected from H and methyl.
  • R 8 is selected from H, methyl, ethyl, isopropyl, n-butyl t-butyl, . In one embodiment, R 8 is selected from H, methyl, and ethyl.
  • R 3 is selected from C 1-10 alkyl, C 1-10 alkoxy, -CF 3 , -OCF 3 , , and -OH.
  • R 3 is selected from C 1-10 alkyl, C 1-10 alkoxy, -CF 3 , -OCF 3 , , and -OH.
  • R 3 is C 1-10 alkoxy.
  • in formula (300) R 3 is C 1-10 alkoxy.
  • in formula (500) R 3 is C 1-10 alkoxy.
  • in formula (600) R 3 is C 1- 10 alkoxy.
  • in formula (700) R 3 is C 1-10 alkoxy.
  • R 3 is C 1-10 alkoxy.
  • R 3 is C 1-10 alkoxy.
  • R 3 is C 1-10 alkoxy.
  • R 3 is C 1-10 alkoxy.
  • in formula (900) R 3 is C 1-10 alkoxy.
  • R 3 is selected from , , , , , , and , optionally . In one embodiment, in formula (110), R 3 is selected from , and , optionally . In one embodiment, in formula (710), R 3 is selected from optionally . In one embodiment, in formula (810), R 3 is .
  • R 3 is , optionally [00174] In some embodiments, in formula (13), formula (120), or formula (420), R 3 is [00175] In some embodiments, in formula (14) or formula (140), each R 3 is independently selected from -F and -OCH 3 and each R 10 is independently C 1-10 alkyl. In one embodiment, in formula (140), one R 3 is -F, one R 3 is -OCH 3 , and each R 10 is -CH 3 .
  • each R 3 is independently selected from -OCH 3 , -CN, -N(CH 3 ) 2 , -Cl, and ethyl.
  • one R 3 is -N(CH 3 ) 2 and one R 3 is selected from -OCH 3 , -Cl, and ethyl.
  • one R 3 is -CN and one R 3 is -OCH 3 .
  • one R 3 is -N(CH 3 ) 2 and one R 3 is -OCH 3 .
  • R 3 is selected from and [00178] In some embodiments, in in formula (17) or formula (170), R 3 is selected from [00179] In one embodiment, X 1 is N and the compound of formula (I) is a compound of formula (20), formula (21), formula (22), formula (23), formula (24), formula (25), or formula (26), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof: wherein R 2 is selected from H and -Cl and each R 4b is independently selected from H and C 1-10 alkyl. [00180] In one embodiment, the present disclosure provides a compound of formula (20) wherein R 1 is and R 4b is H.
  • the present disclosure provides a compound of formula (20) wherein R 1 is and R 8 is C 1-10 alkyl. In one embodiment, the present disclosure provides a compound of formula (20) wherein R 1 is , R 3 is C 1- 10 alkoxy, and each R 10 is independently C 1-10 alkyl. In one embodiment, the present disclosure provides a compound of formula (20) wherein R 1 is , R 4b is H, R 3 is C 1-10 alkoxy, R 8 is C 1-10 alkyl, and each R 10 is independently C 1-10 alkyl.
  • the present disclosure provides a compound of formula (20) wherein R 1 is R 4b is H, R 3 is -OCH 3 , R 8 is selected from methyl and ethyl, and each R 10 is independently methyl.
  • the present disclosure provides a compound of formula (21) wherein R 1 is and R 4b is H.
  • the present disclosure provides a compound of formula (21) wherein R 1 is and R 2 is H.
  • the present disclosure provides a compound of formula (21) wherein R 1 is and R 3 is optionally .
  • the present disclosure provides a compound of formula (21) wherein R 1 is wherein R8 is C1-10 alkyl.
  • the present disclosure provides a compound of formula (21) wherein R 1 is , R 2 is H, R 3 is optionally , R 4b is H, and R8 is methyl.
  • A is R 1 is
  • the compound of formula (I) is a compound of formula (180): formula (180).
  • the compound of formula (I) is a compound of formula (180) wherein R 8 is C 1-10 alkyl.
  • the compound of formula (I) is a compound of formula (180) wherein R 3 is C 1-10 alkoxy and each R 10 is independently C 1-10 alkyl.
  • the compound of formula (I) is a compound of formula (180) wherein R 3 is -OCH 3 , R 8 is methyl, and each R 10 is methyl.
  • A is , R 1 is , and the compound of formula (I) is a compound of formula (190): formula (190).
  • the compound of formula (I) is a compound of formula (190) wherein R 8 is C 1-10 alkyl.
  • the compound of formula (I) is a compound of formula (190) wherein R 3 is C 1-10 alkoxy and each R 10 is independently C 1-10 alkyl.
  • the compound of formula (I) is a compound of formula (190) wherein R 3 is -OCH 3 , R 8 is methyl, and each R 10 is methyl.
  • the compound of formula (I) is selected from a compound having a formula selected from formula 1001-1114, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • the compound of formula (I) is selected from: [00124] In some embodiments, the compound of formula (I) is selected from:
  • the compound of formula (I) is selected from:
  • the disclosure provides a compound having any one of formula (I), formula (10), formula (11), formula (12), formula (13), formula (14), formula (15), formula (16), formula (17), formula (100), formula (110), formula (120), formula (130), formula (140), formula (150), formula (160), (formula 170), formulas 1001 to 1114, but excluding .
  • the disclosure provides a compound of formula (I), wherein when A is a 5-membered ring heterocycle and R 1 is , then R 8 is not H.
  • the compounds and compositions described herein can be used in methods for treating diseases, disorders, dysfunctions, and/or conditions, including but not limited to: a method of treating a condition by activating AMPK activity in a patient in need of said treatment, the method comprising administering to the patient a therapeutically effective amount of a compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof; a method of treating a patient with a mitochondrial disorder and/or dysfunction, the method comprising a therapeutically effective
  • the compounds and compositions described herein can be used in methods for treating a disease, disorder, condition, and/or dysfunction, including but not limited to: a method of treating a disease or disorder associated with AMPK activity in the patient, the method comprising modulating AMPK activity in the patient; and a method of treating a mitochondrial disorder and/or dysfunction, the method comprising identifying a mitochondrial disorder and/or dysfunction in an patient, and modulating AMPK activity in the patient.
  • modulating AMPK activity comprises comprising administering to the patient a therapeutically effective amount of a compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • the disease or disorder associated with AMPK activity is a mitochondrial disorder and/or dysfunction.
  • the modulating step comprises activating AMPK in the patient.
  • the activating step comprises phosphorylating AMPK or providing an agonist to AMPK.
  • the modulating step comprises inhibiting AMPK in the subject.
  • the mitochondrial disorder and/or dysfunction is a primary mitochondrial disorder and/or dysfunction.
  • the mitochondrial disorder and/or dysfunction is a secondary mitochondrial disorder and/or dysfunction.
  • the method further comprising assessing the efficacy of the compound in the individual.
  • the mitochondrial disorder and/or dysfunction is a primary mitochondrial disorder and/or dysfunction.
  • primary mitochondrial dysfunction include Autosomal Dominant Optic Atrophy (ADOA), Alpers- Huttenlocher syndrome (nDNA defect), Ataxia neuropathy syndrome, (nDNA defect), Barth syndrome/ Lethal Infantile Cardiomyopathy (LIC), Co-enzyme Q deficiency, Complex I, complex II, complex III, complex IV and complex V deficiencies (either single deficiencies or any combination of deficiency), Chronic progressive external ophthalmoplegia (CPEO), Diabetes mellitus and deafness, Kearns-Sayre syndrome (mtDNA defect), Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL- leukodystrophy), Leigh syndrome (mtDNA and nDNA defects), Leber's hereditary optic neuropathy (LHON), Heil Disease, Mitochondrial myopathy, encephalopathy,
  • ADOA Autosomal Dominant Optic
  • the mitochondrial disorder and/or dysfunction is a secondary mitochondrial disorder and/or dysfunction.
  • secondary mitochondrial dysfunction include age-related macular degeneration (AMD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD) and other dementias, Friedreich's ataxia (FA), Huntington's disease (HD), Motor neuron diseases (MND), N-glycanase deficiency (NGLY1 ), Organic acidemias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA), Becker muscular dystrophy , Congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic dystrophy, Oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, Congenital myopathies, Distal myopathies, En
  • the compounds and compositions described herein can be used in methods for treating a disease, disorder, condition, and/or dysfunction selected from the treatment of N-glycanase (NGLY1) deficiency, age-related macular degeneration (AMD), ischemic stroke, muscular dystrophies (e.g., Duchenne and Becker), Friedreich ataxia (FA), autoimmune disorders with muscle involvement (e.g., inclusion body myositis, Polymyositis, and Dermatomyositis), and/or neurodegenerative disorders (e.g., Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease, and Alzheimer’s Disease), diabetes, metabolic disorder, and/or obesity.
  • NGLY1 N-glycanase
  • AMD age-related macular degeneration
  • FA Friedreich ataxia
  • autoimmune disorders with muscle involvement e.g., inclusion body myositis, Polymyositis, and Dermatomyositis
  • neurodegenerative disorders e.g., Amy
  • mitochondrial dysfunction will be identified based on molecular signatures of disease or dysfunction, such that protein blots (western blots), polymerase chain reaction (PCR), genotyping using genetic markers (e.g., single nucleotide polymorphisms (SNPs), expressed sequence tags (ESTs), simple sequence repeats (SSRs), etc.) will identify a particular disease or dysfunction present in the individual.
  • genetic markers e.g., single nucleotide polymorphisms (SNPs), expressed sequence tags (ESTs), simple sequence repeats (SSRs), etc.
  • AMPK activation in cardiac tissue can result in reversible cardiac hypertrophy, thus in some embodiments, the compounds and compositions described herein can be used in methods for treating a disease, disorder, condition, and/or dysfunction associated with dilated cardiomyopathy.
  • the compounds and compositions described herein can be used in methods for treating a disease, disorder, condition, and/or dysfunction including, but not limited to ophthalmic diseases associated with mitochondrial dysfunction.
  • the compounds and compositions described herein provide neuroprotection in individuals with ischemic stroke, improve motor performance in individuals with mitochondrial dysfunction as well as muscle wasting diseases, such as muscular dystrophies and autoimmune myositis disorders, enhance strength, endurance, and overall locomotor function in muscle-degenerative disorders associated with mitochondrial dysfunction, increasing mitochondrial function and/or glycogen storage in skeletal muscle, normalizing energy levels within skeletal muscle, thereby preventing degeneration and weakness, and/or activating AMPK in skeletal muscle.
  • muscle wasting diseases such as muscular dystrophies and autoimmune myositis disorders
  • enhance strength, endurance, and overall locomotor function in muscle-degenerative disorders associated with mitochondrial dysfunction increasing mitochondrial function and/or glycogen storage in skeletal muscle, normalizing energy levels within skeletal muscle, thereby preventing degeneration and weakness, and/or activating AMPK in skeletal muscle.
  • the compound having a formula of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof is administered in a pharmaceutical formulation.
  • the pharmaceutical formulation comprises the compound and at least one selected from a binding agent, a lubricating agent, a buffer, and a coating.
  • the compound and/or pharmaceutical formulation is administered orally.
  • the compound and/or pharmaceutical formulation is administered daily for at least one week.
  • the compound and/or pharmaceutical formulation is administered by oral administration, subcutaneous administration, intravenous administration, intraperitoneal administration, intranasal administration, dermal administration, intravitreal injection, or inhalation.
  • methods for determining efficacy of compounds of the disclosure include, but are not limited to, measuring pACC in a sample, as in indicator of increasing AMPK activity.
  • methods for assessing the disease or disorder symptoms include, but are not limited to, looking at molecular profiles, such as genotyping, gene expression, and other methods as would be understood by one of ordinary skill in the art.
  • the diseases and disorders are identified based on symptoms exhibited by an individual.
  • diseases and disorders are identified based on non-limiting methods including molecular signatures of disease or dysfunction, such that protein blots (western blots), polymerase chain reaction (PCR), genotyping using genetic markers (e.g., single nucleotide polymorphisms (SNPs), expressed sequence tags (ESTs), simple sequence repeats (SSRs), etc.).
  • pharmaceutical compositions [00200] In an embodiment, the disclosure provides a pharmaceutical composition for use in the treatment of the diseases and conditions described herein.
  • compositions are typically formulated to provide a therapeutically effective amount of a compound of any of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, as described herein, as the active ingredient.
  • the pharmaceutical compositions also comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • carriers including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions described above are for use in the treatment of, without limitation, a mitochondrial dysfunction, the pharmaceutical composition comprising one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, having any one of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, and a pharmaceutically acceptable carrier.
  • formulas (10) to (17) formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700)
  • the mitochondrial dysfunction is a primary mitochondrial dysfunction.
  • the mitochondrial dysfunction is a secondary mitochondrial dysfunction.
  • the secondary mitochondrial dysfunction is selected from the group consisting of age-related macular degeneration (AMD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD) and other dementias, Friedreich's ataxia (FA), Huntington's disease (HD), Motor neuron diseases (MND), N-glycanase deficiency (NGLY1 ), Organic acidemias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA), Becker muscular dystrophy , Congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic dystrophy, Oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, Congenital myopathies, Distal myopathies, Endocrine myopathie
  • ASD age-related
  • the concentration of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%
  • the concentration of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%
  • the concentration of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%,
  • the concentration of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v/v
  • the amount of a compound formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g
  • the amount of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 0.00, 0.005 g,
  • Each of the compounds provided according to the disclosure is effective over a wide dosage range.
  • dosages independently ranging from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • Described below are non-limiting pharmaceutical compositions and methods for preparing the same.
  • compositions for Oral Administration containing: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for administration.
  • a pharmaceutical excipient suitable for administration containing: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas
  • the disclosure provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient suitable for administration.
  • the composition further contains (iii) an effective amount of an additional active pharmaceutical ingredient.
  • additional active pharmaceutical ingredients may include one or more compounds that modulate AMPK activity.
  • the one or more compounds activate AMPK activity.
  • the one or more compounds phosphorylate AMPK and/or are AMPK agonists.
  • the one or more compounds inhibit AMPK activity.
  • the one or more compounds are competitive inhibitors and/or an allosteric inhibitors, which prevent AMPK from catalyzing a reaction.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs.
  • discrete dosage forms such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [00215] The disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • Active pharmaceutical ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein.
  • the amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof.
  • a lubricant can optionally be added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.
  • the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di-g
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, capry
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene steas; poly
  • the polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glycerol
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil- soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for compositions for non-oral use - e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as te
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti- foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.
  • compositions for Injection containing: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for injection.
  • Components and amounts of compounds in the compositions are as described herein.
  • Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • Sterile injectable solutions are prepared by incorporating a compound formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum- drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compositions for Topical Delivery containing: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for transdermal delivery.
  • a pharmaceutical excipient suitable for transdermal delivery containing: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800)
  • compositions of the present disclosure can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • penetration-enhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, in controlled amounts, either with or without another active pharmaceutical ingredient.
  • formulas (I) formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formula
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhaled delivery of the compositions.
  • Other Pharmaceutical Compositions [00248] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.
  • These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • parenteral injection including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion
  • topical e.g., transdermal application
  • rectal administration via local delivery by catheter or stent or through inhalation.
  • compositions of the disclosure may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the disclosure may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the disclosure may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the disclosure is admixed with a matrix.
  • a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate- based polymers or copolymers (e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters.
  • lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester
  • Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating.
  • the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the disclosure in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash.
  • compounds of the disclosure may be covalently linked to a stent or graft.
  • a covalent linker may be used which degrades in vivo, leading to the release of the compound of the disclosure. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, may additionally be administered intravascularly from a balloon used during angioplasty.
  • Exemplary parenteral administration forms include solutions or suspensions of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. [00252] The disclosure also provides kits.
  • kits include a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • the kit may further contain another active pharmaceutical ingredient.
  • the compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, and another active pharmaceutical ingredient are provided as separate compositions in separate containers within the kit.
  • the compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, and the agent are provided as a single composition within a container in the kit.
  • Suitable packaging and additional articles for use e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like are known in the art and may be included in the kit.
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer. [00253]
  • the kits described above are preferably for use in the treatment of the diseases and conditions described herein.
  • the kits described herein are for use in the treatment of a mitochondrial dysfunction.
  • the mitochondrial dysfunction is a primary mitochondrial dysfunction.
  • ADOA Autosomal Dominant Optic Atrophy
  • nDNA defect Alpers- Huttenlocher syndrome
  • Ataxia neuropathy syndrome (nDNA defect)
  • LIC Barth syndrome/ Lethal Infantile Cardiomyopathy
  • Co-enzyme Q deficiency Complex I, complex II, complex III, complex IV and complex V deficiencies (either single deficiencies or any combination of deficiency)
  • Chronic progressive external ophthalmoplegia CPEO
  • Diabetes mellitus and deafness Chronic progressive external ophthalmoplegia
  • CPEO Chronic progressive external ophthalmoplegia
  • CPEO Chronic progressive external ophthalmoplegia
  • mtDNA defect Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation
  • LSL- leukodystrophy Leigh syndrome
  • Leber's hereditary optic neuropathy (mtDNA and nDNA defects)
  • LHON Leber's hereditary optic neuropathy
  • MELAS Mit
  • the mitochondrial dysfunction is a secondary mitochondrial dysfunction.
  • the secondary mitochondrial dysfunction is selected from the group consisting of age-related macular degeneration (AMD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD) and other dementias, Friedreich's ataxia (FA), Huntington's disease (HD), Motor neuron diseases (MND), N-glycanase deficiency (NGLY1 ), Organic acidemias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA), Becker muscular dystrophy , Congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic dystrophy, Oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, Congenital myopathies, Distal myopathies, Endocrine myopathie
  • ASD age-related
  • Dosages and Dosing Regimens [00254] The amounts of: a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, administered will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician.
  • an effective dosage of each is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the dosage of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, may be provided in units of mg/kg of body mass or in mg/m 2 of body surface area.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein is administered in multiple doses.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects.
  • an effective dosage of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about
  • dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • An effective amount of a compound of formula (I), formulas (10) to (17), formulas (20) to (26), formulas (100) to (190), formulas (200) to (270), formulas (300) to (370), formulas (400) to (470), formulas (500) to (570), formulas (600) to (670), formulas (700) to (770), formulas (800) to (870), formulas (900) to (970), formulas 1001 to 1114, or pharmaceutically acceptable salt thereof, described herein, may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • the reagent is selected from BOP- Cl, TBTU, BOP, PyBop, HATU, EDCI/HOBT, DIC/HOBT; and DCC/HOBT.
  • Suzuki coupling conditions known in the art is of use in effecting the coupling of the boronic acid/ester to the aryl/heteroaryl halide.
  • the Suzuki coupling can be carried out in the presence of a palladium catalyst such as bis(tri-t- butylphosphine)palladium, tetrakis(triphenyl-phosphine)-palladium or a palladacycle catalyst (e.g. the palladacycle catalyst described in Bedford, R. B. and Cazin, C. S. J. (2001) Chem. Commun., 1540-1541) and a base (e.g.
  • Step 1 Synthesis of 5-bromo-6-chloro-N-methoxy-1H-indole-3-carboxamide [00310] To solution of 5-bromo-6-chloro-1H-indole-3-carboxylic acid (2.0 g, 7.29 mmol) in DMF (20 mL) was added DIPEA (3.82 mL, 21.87 mmol), HATU (4.16 g, 10.94 mmol) and the reaction mixture was stirred for 15 min.
  • Step 2 Synthesis of 6-chloro-N-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indole-3-carboxamide
  • Step 2 A stirred solution of the product of Step 1 (1.5 g, 4.96 mmol), Bis-Pin (1.90 g, 7.45 mmol) and KOAc (0.97 g, 9.92 mmol) in dioxane (25 mL) was purged with nitrogen for 10 min.
  • Step 3 Synthesis of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)- 1H-indole-3-carboxamide (1017) [00314] Compound 1017 was prepared according to General Synthesis Route R-2.
  • Step 1 5-bromo-3,6-difluoro-N,N-dimethylpyridin-2-amine
  • NBS N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-dimethylpyridin-2-amine
  • Step 2 5-bromo-3-fluoro-6-methoxy-N,N-dimethylpyridin-2-amine [00341] To a stirred solution of the product of Step 1 (1.2 g, 0.0051 mol) in DMF (5 mL) was added NaOMe solution (25% in MeOH, 20 mL) and heated at 100 °C for 3h.
  • Step 3 Coupling of the product of Step 2 with 6-chloro-N-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide as in Example K gave 6-chloro- 5-(6-(dimethylamino)-5-fluoro-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide as a white solid (35 mg; 9 % yield).
  • the Suzuki coupling can be carried out in the presence of a palladium catalyst such as bis(tri-t- butylphosphine)palladium, tetrakis(triphenyl-phosphine)-palladium or a palladacycle catalyst (e.g. the palladacycle catalyst described in Bedford, R. B. and Cazin, C. S. J. (2001) Chem. Commun., 1540-1541) and a base (e.g. a carbonate such as potassium carbonate).
  • a palladium catalyst such as bis(tri-t- butylphosphine)palladium, tetrakis(triphenyl-phosphine)-palladium or a palladacycle catalyst (e.g. the palladacycle catalyst described in Bedford, R. B. and Cazin, C. S. J. (2001) Chem. Commun., 1540-1541) and a base (e.g. a carbonate such as potassium carbon
  • Step 2 5-bromo-6-chloro-N-methoxy-2-methyl-1H-indole-3-carboxamide
  • Step 3 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-2-methyl- 1H-indole-3-carboxamide
  • a stirred solution of the product of Step 2 (150 mg, 0.47 mmol), 6-methoxy-N,N- dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (263 mg, 0.96 mmol) and K 2 CO 3 (131 mg, 0.96 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was purged with N2 for 10 min.
  • Step 1 5-bromo-N,N-dimethyl-6-(trifluoromethyl)pyridin-2-amine
  • NBS 1.7 g, 10.0 mmol
  • Step 2 N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- (trifluoromethyl)pyridin-2-amine
  • a solution of the product of Step 1 250 mg, 268 mmol), Bis-Pin (290 mg, 1.219 mmol) and KOAc (184 mg, 1.9 mmol) in dioxane (10 mL) was purged with nitrogen for 10 min.
  • Pd(OAc) 2 13 mg, 0.0466 mmol
  • PCy 3 13 mg, 0.0466 mmol
  • Step 3 6-chloro-5-(6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-yl)-N-methoxy-1H- indole-3-carboxamide
  • Step 4 A solution of the product of Step 2 (0.300 g, 0.99 mmol), 5-bromo-6-chloro-N-methoxy- 1H-indole-3-carboxamide (0.470 g, 1.48 mmol) and K 2 CO 3 (0.275 g, 1.98 mmol) in dioxane (10 mL) and water (2 mL) was purged with nitrogen for 10 min.
  • Step 1 5-bromo-4,6-difluoro-N-methoxy-1H-indole-3-carboxamide
  • HATU 207 mg, 0.54 mmol
  • DIPEA 0.2 ml, 1.1 mmol
  • Step 2 4,6-difluoro-N-methoxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3- carboxamide
  • Step 2 To a solution of the product of Step 1 (70 mg, 0.23 mmol), 4,4,5,5-tetramethyl-2-(4- (tetrahydro-2H-pyran-2-yl)phenyl)-1,3,2-dioxaborolane (80 mg, 0.27 mmol) and K 2 CO 3 (80 mg, 0.5765 mmol) in dioxane (5 mL) and water (1 mL) was purged with nitrogen for 10 min.
  • reaction mixture was purged with N 2, then PdCl2(dPPf) 2 .DCM (0.4 g, 0.652 mmol) was added and the reaction mixture was heated at 90°C for 5 h.
  • the reaction mixture was cooled to 25 °C, filtered through a celite bed and concentrated under reduced pressure to obtain a crude product which was purified by preparative HPLC purification to give 5-([1,1'-biphenyl]-4-yl)-6-chloro-N-methoxy-1H- indole-3-carboxamide as a white solid (15mg, 6.1%).
  • NBS 14.27 g, 80.64 mmol
  • DMF 20 mL
  • 2-methoxypyridin-3-amine 10.0 g, 80.64 mmol
  • DMF 60 mL
  • 2-methoxypyridin-3-amine 8.5 g, 52% yield
  • This product was mixed with 6-methoxy-N,N-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (283 mg, 1 mmol; 30% pure) and K 2 CO 3 (247 mg, 1.7895 mmol) in dioxane (10 mL) and water (1 mL) and purged with nitrogen for 10 min. PdCl 2 (dppf).DCM (28 mg, 0.03479 mmol) was added and the reaction mixture was heated to 90°C for 5 h.
  • Step 2 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole- 3-sulfonamide
  • K 2 CO 3 (2.52 g, 18.24 mmol) and methoxyamine hydrochloride (0.762 g, 9.12 mmol) were added at 0°C and the reaction mixture was stirred at RT.
  • Step 3 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole- 3-sulfonamide
  • a stirred solution of the product of Step 2 (100 mg, 0.3 mmol), 6-methoxy-N,N- dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (126 mg, 0.45 mmol) and K 2 CO 3 (83 mg, 0.6 mmol) in 1, 4-dioxane (1.8 mL) and water (0.2 mL) was purged with nitrogen for 10 min.
  • Example 5 Synthesis of 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H- indol-3-yl)-2-oxoacetic acid
  • Oxalyl chloride (0.28 ml, 3.31 mmol) was added dropwise to a solution of 5-(6-chloro- 1H-indol-5-yl)-6-methoxy-N,N-dimethylpyridin-2-amine (200 mg, 0.66 mmol) in diethyl ether (2 mL) at 0° C.
  • Example 3 Blood-Brain Barrier data
  • BBB Blood Brain Barrier
  • Table B BBB Data (compound numbers are shown)
  • Example 4 Spectral data for compounds of the disclosure
  • NMR and LCMS data are shown below in Table C for compounds of the disclosure: Table C: Spectral data

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WO2024209363A1 (en) * 2023-04-06 2024-10-10 Pfizer Inc. Substituted indazole propionic acid derivative compounds and uses thereof as ampk activators
WO2025021039A1 (zh) * 2023-07-21 2025-01-30 深圳众格生物科技有限公司 Ampk激动剂及其用途
WO2026074467A1 (en) * 2024-10-04 2026-04-09 Pfizer Inc. Extended release formulations comprising substituted indazole propionic acid derivative compounds and uses thereof

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