AMPK agonists and methods of use

Abstract

Compounds and methods of use for treating conditions alleviated by AMPK activation are provided. JPEG2025504963000273.jpg48165

Description

[Technical field]

[0001] The present disclosure relates broadly to compounds and methods of use for treating conditions alleviated by AMPK activation.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to U.S. Provisional Patent Application No. 63 / 302,942, filed January 25, 2022, the entirety of which is incorporated herein by reference. [Background technology]

[0003] The drug candidates investigated so far are conventional AMP-dependent AMPK activators whose mechanism of action requires the elevation of AMP, brought about either by inhibition of RC (e.g., metformin, resveratrol) or conversion to AMP mimetics (e.g., AICAR). Indirect mechanisms involving inhibition of RC are not suitable when mitochondrial dysfunction is the cause, and AMP-dependent activation of AMPK leads to activation of other AMP-regulating enzymes, thereby exacerbating the pleiotropic effects. Furthermore, previous studies have identified direct AMP-dependent AMPK agonists for the purpose of treating diabetes, obesity, and metabolic syndrome.

[0004] Primary mitochondrial diseases are a group of clinically heterogeneous disorders that are usually progressive, multisystemic, and associated with high mortality in children. Primary mitochondrial diseases are caused by congenital defects in the mitochondrial respiratory chain (RC), leading to increased production of reactive oxygen and nitrogen species (ROS and RNS) and overall insufficient energy production. This results in metabolic imbalance, leading to cellular injury and ultimately cell death.

[0005] Currently, there is no cure for primary mitochondrial diseases. Only supportive care is available, involving treatment of specific symptoms (e.g., diabetes, heart disease, and ptosis) and a "mitochondrial cocktail" consisting of vitamin cofactors and antioxidants. Unfortunately, meta-analyses have shown that available supportive interventions lack efficacy, pointing out the need for novel treatments.

[0006] Secondary mitochondrial diseases also show mitochondrial dysfunction, but unlike primary mitochondrial diseases, they are not caused by genes related to 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 mitochondria.Therefore, it is expected that any treatment identified for primary mitochondrial diseases will also benefit disorders and conditions related to secondary mitochondrial dysfunction, including neurodegenerative disorders, neuromuscular disorders, and muscle wasting disorders.

[0007] There is a need in the art for new treatments for primary and secondary mitochondrial diseases. The present disclosure addresses this need in the art. Summary of the Invention

[0008] In one aspect, the disclosure provides a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka] (In formula (I), X1 is a CR 4a or N, X2 is a CR 4b or N, R1 is, [ka] is selected from R2 is H, C 1-3 selected from alkyl, -CF3, and halo; R3 is, for each occurrence, halo, -CN, [ka] -N(R 10 )2, C1- 10 Alkyl, C2- 10 Alkynyl, C1- 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 heterocycloalkenyl is independently selected from alkyl, aryl, and heteroaryl, 10 Alkyl, C2- 10 Alkynyl, C1- 10 Alkoxy, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10 The heterocycloalkenyl alkyl, aryl, or heteroaryl may be unsubstituted or may include deuterium, halo, C 1-6 Alkyl, C 3-6 substituted by 1 to 3 substituents selected from cycloalkyl, -OR5 and -OCOR7; R 4a For each occurrence, H, halo, C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R 4b For each occurrence, H, C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R5, H, C for each occurrence 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R6, H, C for each occurrence 1-6 Alkyl, and C 3-6 cycloalkyl; R7, for each occurrence, 1-10 Alkyl, C 3-7 Cycloalkyl and C 4-12 alkylcycloalkyl, where C 1-10 Alkyl, C 3-7 Cycloalkyl, or C 4-12Alkylcycloalkyl is unsubstituted or can be selected from halo, C 1-10 Alkyl, and -NR 12 ,R 12 is substituted with 1 to 3 substituents selected from R8 is H, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylheterocyclyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10 heterocycloalkenyl alkyl, aryl, heteroaryl, [ka] where C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylheterocyclyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10 heterocycloalkenyl alkyl, aryl, or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from deuterium, halo, and -OR5; R 10 For each occurrence, H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-12 Alkylcycloalkyl, [ka] and C 3-10 heterocyclyl, where C 1-6 Alkyl, C3-6 Cycloalkyl, C 4-12 Alkylcycloalkyl, or C 3-10 Heterocyclyl is unsubstituted or substituted with deuterium, halo, C 1-6 Alkyl, and C 3-6 substituted with 1 to 3 substituents selected from cycloalkyl substituents; R 11 For each occurrence, -OR 12 and -N(R 12 )2 are independently selected from R 12 For each occurrence, H, C 1-6 Alkyl, C 1-10 Haloalkoxy and C 3-6 cycloalkyl; n is an integer from 0 to 3, p is an integer from 1 to 5; q is an integer from 0 to 5; r is an integer from 1 to 5; s is an integer from 1 to 5; A is phenyl, pyridyl, pyrimidyl, pyridazyl, or the following 5-membered heterocycles: [ka] is selected from However, the compound of formula (I) [ka] isn't it).

[0009] In some embodiments, X1 is CR 4a In some embodiments, R 4a is H, Cl, or F. In some embodiments, X2 is N or CR 4b where R 4b In some embodiments, R2 is H. In some embodiments, R2 is halo. In some embodiments, R2 is Cl or F. In some embodiments, R6 is H.

[0010] In some embodiments, A is [ka] In some embodiments, R6 is H.

[0011] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, R1 is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0012] In some embodiments, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In one embodiment, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, the compound is [ka] is selected from.

[0013] In some embodiments, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0014] In some embodiments, R is [ka] 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0015] In some embodiments, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0016] In some embodiments, R is [ka] 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0017] In some embodiments, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0018] In some embodiments, R is [ka] In some embodiments, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0019] In some embodiments, R 10 is H, methyl, ethyl, -CD3, n-butyl, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, p is 2 or 3. In some embodiments, R3 is -F, -CN, ethyl, [ka] In some embodiments, R3 is selected from: [ka] In some embodiments, q is 0 or 1. In some embodiments, r is 2 or 3. In some embodiments, s is 1. In some embodiments, R 12 is methyl, ethyl, -OCF3, and [ka] In some embodiments, R8 is selected from H, methyl, ethyl, isopropyl, n-butyl, t-butyl, [ka] In some embodiments, R8 is selected from H, methyl, ethyl, n-butyl, [ka] In some embodiments, R8 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 Formulas 1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0021] In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1003, 1007, 1024, 1044, 1077, 1078, 1081, 1084, 1088, 1112, 1113, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0022] In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1001, 1006, 1008, 1010, 1013, 1014, 1016, 1017, 1018, 1022, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0023] In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1003, 1009, 1011, 1015, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0024] In some embodiments, A is a 5-membered heterocycle and R is [ka] and R8 is not H.

[0025] In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1003, 1007, 1009, 1011, 1015, 1019, 1023, 1024, 1025, 1026, and 1078, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, the compound of formula (I) is selected from a compound having a formula selected from formulas 1001, 1006, 1008, 1010, 1013, 1014, 1016, 1024, 1017, 1018, and 1022, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, the compound of Formula (I) is selected from a compound having a formula selected from formulas 1003, 1009, 1011, and 1015, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0026] In some embodiments, in formula (I), when A is a 5-membered heterocycle, R1 is [ka] and R8 is not H.

[0027] In another aspect, the present disclosure provides a pharmaceutical formulation comprising a compound having any of the following formulas: Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), and Formulas 1001-1114.

[0028] In another aspect, the disclosure provides a method of treating a patient with mitochondrial dysfunction. In some embodiments, the method includes identifying mitochondrial dysfunction in an individual and administering to the patient a compound having any of the formulas of Formula (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), or (1001-1114.

[0029] In another aspect, the disclosure provides a method of treating a patient with mitochondrial dysfunction. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound having any of the formulas: Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114.

[0030] In some embodiments, the mitochondrial dysfunction is a primary mitochondrial dysfunction. In some embodiments, the primary mitochondrial dysfunction is a primary mitochondrial dysfunction associated with autosomal dominant optic atrophy (ADOA), Alpers-Huttenlocher syndrome (nDNA deficiency), ataxic neuropathy syndrome, (nDNA deficiency), Barth syndrome / fatal infantile cardiomyopathy (LIC), coenzyme Q deficiency, complex I, complex II, complex III, complex IV and complex V deficiency (either a single deficiency or any combination of deficiencies), chronic progressive external ophthalmoplegia (CPEO), diabetes mellitus and hearing loss, Kearns-Sayre syndrome (mtDNA deficiency), leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL-leukodystrophy), Leigh syndrome (mtDNA and nDNA deficiency), Leber's hereditary optic neuropathy (LHON), Luft's disease, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke. and / or mitochondrial recessive ataxia syndrome (MIRAS) (mtDNA deficiency), mitochondrial enoyl-CoA reductase protein-associated neurodegeneration (MEPAN), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mtDNA deletion syndrome, mtDNA depletion syndrome, mtDNA maintenance disorder, mtDNA / RNA translation deficiency, mitochondrial tRNA synthetase deficiency, mitochondrial myopathy, mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuromuscular weakness, ataxia, and retinitis pigmentosa (NARP), Pearson syndrome, pyruvate dehydrogenase complex deficiency (PDCD / PDH), DNA polymerase gamma deficiency (POLG), pyruvate carboxylase deficiency, and thymidine kinase 2 deficiency (TK2).

[0031] In some embodiments, the mitochondrial dysfunction is secondary mitochondrial dysfunction. In some embodiments, the secondary mitochondrial dysfunction is associated with 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 disease (MND), N-glycanase deficiency (NGLY1), organic acid metabolism disorders, Parkinson's disease (PD) and PD-related disorders, prion diseases, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), Becker muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral dystrophy, and the like. myotonic dystrophy, myotonic dystrophy, oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, congenital myopathy, peripheral myopathy, endocrine myopathy (hyperthyroidism-associated myopathy, hypothyroidism-associated myopathy), giant axonal neuropathy, hereditary spastic paraplegia, inflammatory myopathy (dermatomyositis, inclusion body myositis, polymyositis), metabolic myopathy, neuromuscular junction disease, autism, cancer, diabetes, metabolic syndrome, chronic fatigue syndrome, inflammatory disorders, arthritis, aging, and mitochondrial epilepsy (epilepsy associated with primary mitochondrial disease).

[0032] In some embodiments, the compound having any of the formulas of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), and formulas 1001-1114 is administered in a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises the compound and at least one selected from a binder, a lubricant, a buffer, and a coating agent. In some embodiments, the compound is administered orally. In some embodiments, the compound is administered daily for at least one week.

[0033] In some embodiments, the method further comprises evaluating the effectiveness of the compound in the individual.

[0034] In some embodiments, a compound having any of the formulas (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), or (1001-1114 is administered orally, subcutaneously, intravenously, intraperitoneally, intranasally, dermal, intravitreal injection, or by inhalation. [Brief description of the drawings]

[0035] [Figure 1] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Diagram 2] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Diagram 3] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Figure 4] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Diagram 5] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Figure 6] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Figure 7] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Figure 8] 1 shows structures of non-limiting examples of compounds of the present disclosure. [Figure 9] 1 shows structures of non-limiting examples of compounds of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications referenced herein are incorporated by reference in their entirety.

[0037] definition As used herein, the terms "administer," "administration," or "administering" refer to (1) providing, giving, dispensing, and / or prescribing, either by or under the direction of a medical professional or his / her authorized representative, in accordance with this disclosure; and / or (2) placing into, ingesting, or consuming by a mammal in accordance with this disclosure.

[0038] The terms "co-administration," "co-administering," "administered in combination," "administering in combination," "simultaneous," and "concomitant use," as used herein, encompass administration of two or more pharmacologic active ingredients to a subject such that both pharmacologic active 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 one composition in which two or more pharmacologic active ingredients are present. Simultaneous administration in separate compositions and administration in one composition in which both agents are present are preferred.

[0039] The terms "active pharmaceutical ingredient" and "drug" include, but are not limited to, the compounds described herein, more specifically, any of the compounds 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), and formulas 1001 to 1114, and their characteristics and limitations described herein.

[0040] As used herein, the terms "patient," "subject," and "individual" are used interchangeably.

[0041] The term "in vivo" refers to an event that takes place inside a subject's body.

[0042] The term "in vitro" refers to events that occur outside of a subject's body. In vitro assays include cell-based assays, which use live or dead cells, and can also include cell-free assays, which do not use intact cells.

[0043] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to accomplish the intended use, including, but not limited to, disease treatment. The therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, and the like, and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in a target cell (e.g., increased susceptibility to apoptosis). The specific dose may vary depending on the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0044] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit. A prophylactic benefit 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.

[0045] The terms "QD", "qd", or "qd" mean quaque die, once a day, or once per day. The terms "BID", "bid", or "bid" mean bis in die, twice a day, or twice per day. The terms "TID", "tid", or "tid" mean ter in die, three times a day, or three times per day. The terms "QID", "qid", or "qid" mean quater in die, four times a day, or four times per day.

[0046] The term "pharmaceutically acceptable salts" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic 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 such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma-ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike salts, cocrystals typically do not involve hydrogen transfer between the cocrystal and the drug, but instead involve intramolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal former and the drug in the crystal structure.

[0047] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for pharmaceutically active ingredients is well known in the art. Except where any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the pharmaceutically active ingredient, its use in the therapeutic composition of the present disclosure is contemplated. Additional pharmaceutically active ingredients, such as other drugs disclosed herein, can also be incorporated into the compositions and methods described.

[0048] As used herein, the terms "treat," "treatment," and / or "treating" can refer to the management of a disease, disorder, or condition, or a symptom thereof, with the intent of curing, ameliorating, stabilizing, and / or controlling the disease, disorder, condition, or a symptom thereof. More specifically, with respect to control of a disease, disorder, or condition, "control" can include the absence of progression of the condition as assessed by response to the methods recited herein, which response may be complete (e.g., remission of the disease) or partial (e.g., reduction or amelioration of any symptoms associated with the condition).

[0049] As used herein, the terms "modulate" and "modulation" refer to a change in the biological activity of a biological molecule (e.g., a protein, gene, peptide, antibody, etc.), where such a change may relate to an increase in the biological activity of the biological molecule (e.g., increased activity, agonism, activation, expression, upregulation, and / or increased expression) or a decrease in the biological activity (e.g., decreased activity, antagonism, inhibition, inactivation, downregulation, and / or decreased expression). In some embodiments, biological molecules modulated by the methods and compounds of the present disclosure to effect treatment may include Mcl-1 oncoprotein and Bcl-2 oncoprotein.

[0050] As used herein, the term "prodrug" refers to a derivative of a compound described herein whose pharmacological action results from being converted into an active compound by chemical or metabolic processes in vivo. Prodrugs include compounds in which a polypeptide chain of one amino acid residue or two or more (e.g., 2, 3 or 4) amino acid residues is covalently bonded via an amide bond or an ester bond to a free amino group, a free hydroxyl group or a free carboxylic acid group of any of the compounds of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), and formulas 1001-1114. Amino acid residues include the 20 naturally occurring amino acids, which are commonly designated by one-letter or three-letter symbols, including, but not limited to, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone.

[0051] Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxymethyl esters). Prodrug esters as used herein include esters and carbonates formed by reacting one or more hydroxyls of the compounds of the disclosed method with alkyl, alkoxy, or aryl substituted acylating agents using procedures known to those skilled in the art to produce acetates, pivalates, methyl carbonates, benzoates, and the like. As further examples, free hydroxyl groups can also be derivatized using groups including, but not limited to, hemisuccinates, phosphates, dimethylaminoacetates, and sulforyloxymethyloxycarbonyls, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as well as 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 described prodrug moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities. Additionally, any compound that can be converted in vivo to provide a bioactive agent (e.g., any compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114) is a prodrug within the scope of the present disclosure. Various forms of prodrugs are well known in the art.Comprehensive descriptions of prodrugs and prodrug derivatives can be found 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). In general, prodrugs may be designed to improve drug absorption, extend the duration of action of the drug (slow release of the parent drug from the prodrug, reduced first pass metabolism of the drug), target drug action (e.g., organ or tumor targeting, lymphocyte targeting), alter or improve the water solubility of the drug (e.g., intravenous formulations and eye drops), improve local drug delivery (e.g., drug delivery to the skin and eye), improve the chemical / enzymatic stability of the drug, or reduce off-target effects of the drug, and more generally, improve the permeability of the drug across biological membranes to improve the therapeutic efficacy of the compounds utilized in the present disclosure.

[0052] Unless otherwise indicated, chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced with deuterium or tritium, or in which one or more carbon atoms are replaced with 13 C or 14 Compounds replaced with C-enriched carbons are within the scope of this disclosure.

[0053] When a range is used herein to describe a physical or chemical property, such as, for example, a molecular weight or a chemical formula, it is intended that all combinations and subcombinations of the range and specific embodiments are included. The use of the term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus the numerical value or numerical range may vary. The variation is typically 0% to 15%, preferably 0% to 10%, and more preferably 0% to 5% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments, such as embodiments of any configuration of the subject matter, method, or process that "consists" or "consists essentially of" the described features.

[0054] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., (C1- 10 ) alkyl or C1- 10Numerical ranges such as "1-10" whenever they occur herein refer to each integer in the given range, for example, "1-10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but this definition is intended to encompass cases where no numerical range is specifically specified for the term "alkyl." Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butylisobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl moiety, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl, may be attached to the remainder of the molecule by a single bond. Unless otherwise stated in the specification, alkyl groups are independently selected from the group consisting of 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t Ra (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a 2) optionally substituted with one or more of the following substituents: a is independently hydrogen, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0055] "Alkylaryl" refers to an -(alkyl)aryl radical, where the aryl and alkyl are as disclosed herein, optionally substituted with one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.

[0056] "Alkylhetaryl" refers to a -(alkyl)hetaryl radical, where the hetaryl and alkyl are as disclosed herein and are optionally substituted with one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.

[0057] "Alkylheterocycloalkyl" or "alkylheterocyclyl" refers to an -(alkyl)heterocycloalkyl radical, where the alkyl and heterocycloalkyl are as disclosed herein, optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl, respectively.

[0058] An "alkene" moiety refers to a group that consists of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group that consists of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety may be saturated or unsaturated, branched, straight chain, or cyclic.

[0059] "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 2 to 10 carbon atoms (i.e., (C- 10 ) alkenyl or C2- 10 alkenyl). Numerical ranges such as "2 to 10" whenever they appear in this specification refer to each integer in the given range, for example, "2 to 10 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms. The alkenyl moiety, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl, can be attached to the remainder of the molecule by a single bond. Unless otherwise stated in this specification, the alkenyl group can be independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... 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)N(R a )2, N(R a )C(NRa )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0060] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical, where the alkenyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl, respectively.

[0061] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from 2 to 10 carbon atoms (i.e., (C- 10 ) alkynyl or C2- 10Numerical ranges such as "2 to 10" whenever they appear in this specification refer to each integer in the given range, for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms. Alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl, can be attached to the remainder of the molecule by a single bond. Unless otherwise stated in this specification, alkynyl groups can be independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R ais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0062] "Alkynyl-cycloalkyl" refers to an -(alkynyl)cycloalkyl radical, where the alkynyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl, respectively.

[0063] "Carboxaldehyde" refers to the --(C.dbd.O)H radical.

[0064] "Carboxyl" refers to the --(C.dbd.O)OH radical.

[0065] "Cyano" refers to the -CN radical.

[0066] "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 3 to 10 ring atoms (i.e., (C3- 10 ) Cycloalkyl or C3- 10Numerical ranges such as "3 to 10" whenever they occur herein refer to each integer in the given range, for example, "3 to 10 carbon atoms" means that the cycloalkyl group consists of 3 carbon atoms, etc., and can contain up to 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, etc. Unless otherwise stated herein, cycloalkyl groups are independently selected from the group consisting of 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a)2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0067] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical, in which the cycloalkyl and alkenyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0068] "Cycloalkyl-heterocycloalkyl" refers to a -(cycloalkyl)heterocycloalkyl radical, where cycloalkyl and heterocycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0069] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl radical, where cycloalkyl and heteroaryl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0070] The term "alkoxy" refers to an -O-alkyl group containing 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 an alkoxy group containing 1 to 6 carbons.

[0071] The term "substituted alkoxy" refers to an alkoxy in which the alkyl moiety is substituted (i.e., -O-(substituted alkyl)). Unless otherwise stated in the specification, the alkyl portions of the alkoxy group are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0072] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon, where the alkoxy group has the specified number of carbon atoms. Thus, a (C1-6)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 where the alkoxy group is a lower alkoxy group.

[0073] The term "substituted alkoxycarbonyl" refers to a (substituted alkyl)-OC(O)- group, which is attached to a parent structure via a carbonyl functionality. Unless otherwise stated in the specification, the alkyl portions of the alkoxycarbonyl group are independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(Ra )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0074] The term "cycloalkyloxy" represents a cycloalkyl group having the indicated number of carbon atoms attached through an oxygen atom (eg, cyclopropyloxy and cyclohexyloxy).

[0075] "Acyl" refers to the (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)- groups, which are attached to the parent structure via a carbonyl functionality. When the R radical is heteroaryl or heterocycloalkyl, the heterocycle or heterochain atoms contribute to the total number of chain or ring atoms. Unless otherwise stated in the specification, the alkyl, aryl, or heteroaryl portions of the acyl group 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 )C(O)N(Ra )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0076] "Acyloxy" refers to the R(C=O)O- radical, where R is alkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, as described herein. If the R radical is heteroaryl or heterocycloalkyl, the heterocycle or heterochain atoms contribute to the total number of chain or ring atoms. Unless otherwise stated in the specification, the R of the acyloxy group is 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 )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0077] "Acylsulfonamide" is -S(O)2-N(R a )-C(=O)- radical, where R a is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. Unless stated otherwise in the specification, acylsulfonamide groups 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)Ra , -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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0078] "Alkylcycloalkyl" refers to an optionally substituted ring system containing a cycloalkyl group having one or more alkyl substituents, where cycloalkyl and alkyl are each as defined above. Exemplary alkylcycloalkyl groups include, for example, 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.

[0079] "Alkylheterocycloalkenyl" refers to a heterocycloalkyl or heterocyclyl, as defined herein, further containing one or two double bonds and having one or more alkyl substituents.

[0080] Unless otherwise stated herein, "amino" or "amine" refers to -N(R a )2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. a ) Two groups are non-hydrogen R a When substituted, the group can be attached to the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -N(R a )2 is meant to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise stated in the specification, amino groups are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t Ra (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0081] The term "substituted amino" also refers to -NHR, each of which is defined above. a and N.R. a R a It also refers to the N-oxides of the group, which can be prepared by treating the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0082] "Amide" or "amido" refers to a chemical moiety having the 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 may itself be optionally substituted. The R2 of the -N(R)2 of an amide may optionally form a 4-, 5-, 6-, or 7-membered ring together with the nitrogen to which it is attached. Unless otherwise stated herein, an amide group is independently optionally substituted with one or more of the substituents described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. Procedures and specific groups for making such amides are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3. rd Ed., John Wiley & Sons, New York, NY, 1999, which are incorporated herein by reference in their entireties.

[0083] "Aromatic" or "aryl" or "Ar" refers to an aromatic radical having 6 to 10 ring atoms (e.g., C6-C 10 Aromatic or C6-C 10aryl) (e.g., phenyl, fluorenyl, and naphthyl). Divalent radicals formed from substituted benzene derivatives and having free valences at ring atoms are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals, whose names end in "-yl" by removing one hydrogen atom from the carbon atom having a free valence, are named by adding "-yden" to the name of the corresponding monovalent radical, e.g., a naphthyl group having two points of attachment is called naphthylidene. Numeric ranges such as "6-10" refer to each integer in the given range whenever they occur herein, e.g., "6-10 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., and can contain up to 10 ring atoms. The term includes monocyclic or polycyclic fused ring (i.e., rings sharing a pair of adjacent ring atoms) groups. Unless otherwise stated in the specification, aryl moieties are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a(wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0084] The term "aryloxy" refers to the group --O-aryl.

[0085] The term "substituted aryloxy" refers to an aryloxy in which the aryl substituent is substituted (i.e., -O-(substituted aryl)). Unless otherwise stated in the specification, the aryl portions of the aryloxy group are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t Ra (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0086] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical, where the aryl and alkyl are as disclosed herein and are optionally substituted with one or more of the substituents described as suitable substituents for the aryl and alkyl, respectively.

[0087] "Cycloalkylalkyl" refers to an alkyl group in which one of the hydrogen atoms is replaced with a cycloalkyl group. In some embodiments, the hydrogen atom on the terminal carbon atom of the alkyl group is replaced with a cycloalkyl group. In some embodiments, the cycloalkyl group is 3-6 is a cycloalkyl group, and in some embodiments, C 5-6 In some embodiments, the alkanediyl portion of the cycloalkylalkyl group is, for example, a cycloalkyl group, and in some embodiments, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. In some embodiments, the alkanediyl portion of the cycloalkylalkyl group is, for example, a C 1-10 Alkanediyl, C 1-6 Alkanediyl, C 1-4 Alkanediyl, C 1-3 In some embodiments, the cycloalkylalkyl group is selected from the group consisting of alkanediyl, propane-1,3-diyl, ethane-1,2-diyl, and methane-diyl.4-16 Cycloalkylalkyl, C 4-12 Cycloalkylalkyl, C 4-10 Cycloalkylalkyl, C 6-12 Cycloalkylalkyl, or C 6-9 Cycloalkylalkyl. For example, C 6-9 Cycloalkylalkyl includes a C3 alkyl group bonded to a cyclopentyl or cyclohexyl group.

[0088] "Ester" refers to a chemical radical of the 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). Procedures and specific groups for making esters are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which are incorporated herein by reference in their entirety. Unless otherwise specified herein, ester groups are independently selected from 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)N(R a )2, N(R a )C(NR a)N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0089] "Fluoroalkyl" refers to an alkyl radical, as defined above, substituted by one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical can be optionally substituted as defined above for an alkyl group.

[0090] The terms "halo", "halide", or alternatively "halogen" are intended to mean fluoro, chloro, bromo, or iodo. The terms "haloalkyl", "haloalkenyl", "haloalkynyl", and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.

[0091] "Heteroalkyl", "heteroalkenyl", and "heteroalkynyl" refer to optionally substituted alkyl, alkenyl, and alkynyl radicals having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given, for example, C1-C4 heteroalkyl refers to the total chain length, in this example, 4 atoms in length. Heteroalkyl groups are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R ais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0092] "Heteroalkylaryl" refers to a -(heteroalkyl)aryl radical, where the heteroalkyl and aryl are as disclosed herein, optionally substituted with one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0093] "Heteroalkylheteroaryl" refers to a -(heteroalkyl)heteroaryl radical, where the heteroalkyl and heteroaryl are as disclosed herein, optionally substituted with one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0094] "Heteroalkylheterocycloalkyl" refers to a -(heteroalkyl)heterocycloalkyl radical, where heteroalkyl and heterocycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0095] "Heteroalkylcycloalkyl" refers to a -(heteroalkyl)cycloalkyl radical, where heteroalkyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0096] "Heteroaryl" or "heteroaromatic" or "HetAr" or "Het" refers to a 5- to 18-membered aromatic radical (e.g., C5-C6) that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur, and may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. 13Heteroaryl). Numerical ranges such as "5 to 18" whenever they occur herein refer to each integer in the given range, for example, "5 to 18 ring atoms" means that the heteroaryl group can contain 5 ring atoms, 6 ring atoms, etc., up to 18 ring atoms. Divalent radicals derived from monovalent heteroaryl radicals, whose names end in "-yl" by removing one hydrogen atom from the atom with the free valence, are named by adding "-yden" to the name of the corresponding monovalent radical, for example, a pyridyl group with two points of attachment is called pyridylidene. N-containing "heteroaromatic" or "heteroaryl" moieties refer to aromatic groups in which at least one of the skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heteroaryl may be attached to the remainder of the molecule through any atom of the ring(s). Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, 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, benzofurazanyl, benzothiazolyl, benzothienyl, and the like. benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl , 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydroquinazolinyl, Examples of heteroaryl moieties include, but are not limited to, 5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated in the specification, heteroaryl moieties 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(Ra )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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0097] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.

[0098] "Heteroarylalkyl" refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, where the connection to the remainder of the molecule is through the alkylene group.

[0099] "Heterocycloalkyl" or "heterocyclyl" refers to a stable 3-18 membered non-aromatic ring radical containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Numeric ranges such as "3-18" refer to each integer in the given range whenever they occur in this specification, for example, "3-18 ring atoms" means that the heterocycloalkyl group can consist of 3 ring atoms, 4 ring atoms, etc., up to 18 ring atoms. Unless otherwise stated in this specification, the heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, including fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl can be attached to the remainder of the molecule through any atom of the ring(s). Examples of such 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, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise stated in the specification, heterocycloalkyl moieties are independently selected from 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)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0100] "Heterocycloalkyl" also includes bicyclic ring systems in which one non-aromatic ring, typically having 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations containing at least one of the foregoing heteroatoms, and the other ring, typically having 3 to 7 ring atoms, optionally contains 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and is not aromatic.

[0101] "Heterocycloalkenyl" refers to a heterocycloalkyl or heterocyclyl as defined above, further comprising one or two double bonds. Non-limiting examples of heterocycloalkenyl include -(C4-C9)heterocycloalkenyl.

[0102] "Heterocycloalkenylalkyl" refers to an alkyl group in which one of the hydrogen atoms is replaced by a heterocycloalkenyl group. In some embodiments, a hydrogen atom on a terminal carbon atom of an alkyl group is replaced with a heterocycloalkenyl group. Non-limiting examples include dihydrofurylmethyl groups (e.g., 2,5-dihydrofuran-3-ylmethyl groups), dihydropyranylmethyl groups (e.g., 5,6-dihydro-2H-pyran-ylmethyl groups), dihydropyrrolylmethyl groups (3-pyrrolin-3-ylmethyl groups), tetrahydropyridylmethyl groups (e.g., 1,2,3,6-tetrahydropyridin-4-ylmethyl groups), tetrahydropyridylethyl groups (e.g., 1,2,3,6-tetrahydropyridin-4-yl-2-ethyl groups), dihydrothienylmethyl groups (e.g., 2,5-dihydrothiophen-3-ylmethyl groups), dihydrothiopyranylmethyl groups (e.g., 5,6-dihydro-2H-thiopyran-4-ylmethyl groups), dehydrohomopiperidinylmethyl groups (e.g., 4,5-dehydrohomopiperidin-4-ylmethyl groups), and the like.

[0103] "Nitro" refers to the -NO2 radical.

[0104] "Oxa" refers to the --O- radical.

[0105] "Oxo" refers to the =O radical.

[0106] "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., they have different stereochemical configurations. "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 indicate a racemic mixture when appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon may be specified as either (R) or (S). Resolved compounds whose absolute configuration is unknown may be specified as (+) or (-), depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R) or (S). The chemical entities, pharmaceutical compositions, and methods of the present invention 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. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0107] As used herein, "enantiomeric purity" refers to the relative amount of a particular enantiomer expressed as a percentage relative to the abundance of the other enantiomer. For example, when a compound potentially having (R) or (S)-isomer configuration exists as a racemic mixture, the enantiomeric purity is about 50% for either the (R)-isomer or the (S)-isomer. For a compound in which one isomeric form predominates over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound for the (S)-isomer form is 80%. The enantiomeric purity of a compound can be determined by many methods known in the art, such as, but not limited to, chromatography using a chiral support, polarimetry of polarized light rotation, nuclear magnetic resonance spectroscopy using chiral shift reagents, including but not limited to lanthanide-containing chiral complexes or sparcle reagents, or derivatization of the compound using a chiral compound such as Mosher's acid, followed by chromatography or nuclear magnetic resonance spectroscopy.

[0108] In some embodiments, the enantiomer-enriched composition has a higher potency in terms of therapeutic utility per unit mass than the racemic mixture of the composition. Enantiomers can be isolated from the mixture by methods well known to those skilled in the art, such as chiral high performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or the preferred enantiomer can be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); EL Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and EL Eliel and SH Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

[0109] The terms "enantiomerically enriched" and "non-racemic" as used herein refer to a composition in which the weight percentage of one enantiomer is greater than the amount of that one enantiomer in a mixture of a reference racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer refers to a preparation of a compound in which the (S)-enantiomer is greater than 50% by weight, e.g., at least 75% by weight, or e.g., at least 80% by weight, relative to the (R)-enantiomer. In some embodiments, the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched" or "substantially non-racemic" preparation, which refers to a preparation of a composition in which one enantiomer is at least 85% by weight, e.g., at least 90% by weight, or e.g., at least 95% by weight, relative to the other enantiomer. The terms "enantiomerically pure" or "substantially enantiomerically pure" refer to a composition that contains at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0110] "Moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a well-recognized chemical entity embedded in or appended to a molecule.

[0111] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropy or proton shift tautomerization, which are considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton with a change in bond order, often with the exchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. One example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0112] A "leaving group or atom" is any group or atom that will cleave from a starting material under selected reaction conditions, thereby facilitating reaction at a particular site. Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p-nitrobenzenesulfonyloxy, and tosyloxy groups.

[0113] "Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a polyfunctional compound, thereby allowing a chemical reaction to be selectively carried out at an otherwise unprotected reactive site, and then allowing the group to be easily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).

[0114] "Solvate" refers to a compound that is physically associated with one or more molecules of a pharma- ceutically acceptable solvent.

[0115] "Substituted" means that one or more additional groups, radicals or moieties may be attached to the referenced group, 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, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substitution on one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified group, radical or moiety.

[0116] "Sulfanyl" refers to groups including: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl).

[0117] "Sulfinyl" refers to groups including, -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).

[0118] "Sulfonyl" refers to groups including, -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

[0119] "Sulfonamidyl" or "sulfonamide" refers to the -S(=O)2-NRR radical, where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical may be taken together with the nitrogen to which they are attached to form a 4-, 5-, 6-, or 7-membered ring. The sulfonamide group is optionally substituted with one or more of the substituents described for alkyl, cycloalkyl, aryl, and heteroaryl, respectively.

[0120] "Sulfoxyl" refers to the -S(=O)2OH radical.

[0121] "Sulfonate" refers to the -S(=O)2-OR radical, 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). The sulfonate group is optionally substituted on R with one or more of the substituents described for alkyl, cycloalkyl, aryl, and heteroaryl, respectively.

[0122] Compounds of the present disclosure also include crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystalline forms" and "polymorphs" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referred to.

[0123] For the avoidance of doubt, it is intended that a particular feature (e.g., integer, property, value, use, disease, formula, compound or group) described herein in connection with a particular aspect, embodiment or example of the disclosure is also applicable to any other aspect, embodiment or example described herein, unless incompatible. Thus, such features may be used in combination with any of the definitions, claims or embodiments defined herein, where appropriate. All of the features and / or all of the steps of any disclosed method or process disclosed herein (including any accompanying claims, abstract and drawings) may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The disclosure is not limited to any details of any of the disclosed embodiments. The disclosure extends to any novel or novel combination of features disclosed herein (including any accompanying claims, abstract and drawings) or any novel or novel combination of steps of any disclosed method or process.

[0124] Furthermore, as used herein, the term "about" means that dimensions, sizes, formulations, parameters, shapes, and other quantities and characteristics are not, and need not be, exact, but are approximate and / or may be larger or smaller, if desired, taking into account tolerances, conversion factors, rounding, measurement errors, and other factors known to those of skill in the art. In general, dimensions, sizes, formulations, parameters, shapes, or other quantities or characteristics are "about" or "approximate," whether or not expressly stated. It should be noted that embodiments of widely differing sizes, shapes, and dimensions may be employed in the configurations described.

[0125] Furthermore, the transitional phrases "comprising," "consisting essentially of," and "consisting of," when used in the appended claims, both in their original and amended form, define the scope of the claim with respect to whether additional unrecited claim elements or steps, if any, are excluded from the scope of the claim. The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional unrecited elements, methods, steps, or materials. The term "consisting of" excludes elements, steps, or materials other than those specified in the claim, and in the latter case, also excludes impurities normally associated with the specified material(s). The term "consisting essentially of" limits the scope of the claim to the specified element, step, or material(s) and those that do not materially affect the basic and novel characteristic(s) of the disclosure. All embodiments of the present disclosure may alternatively be more specifically defined by any of the transitional phrases "comprising," "consisting essentially of," and "consisting of."

[0126] AMPK Modulators In one aspect, the present disclosure provides novel compounds that modulate AMPK. In some embodiments, the compounds of the present disclosure are AMPK agonists. In some embodiments, the compounds of the present disclosure are AMPK inhibitors.

[0127] In one aspect, the disclosure provides a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka] (In formula (I), X1 is a CR 4a or N, X2 is a CR 4b or N, R1 is, [ka] is selected from R2 is H, -CF3 or halo; R3 is, for each occurrence, halo, -CN, [ka] -N(R 10 )2, C1- 10 Alkyl, C2- 10 Alkynyl, C1- 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 heterocycloalkenyl is independently selected from alkyl, aryl, and heteroaryl, 10 Alkyl, C2- 10 Alkynyl, C1- 10 Alkoxy, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10The heterocycloalkenyl alkyl, aryl, or heteroaryl may be unsubstituted or may include deuterium, halo, C 1-6 Alkyl, C 3-6 substituted by 1 to 3 substituents selected from cycloalkyl, -OR5 and -OCOR7; R 4a For each occurrence, H, halo, C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R 4b For each occurrence, H, C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10 Alkyl, C 3-7 Cycloalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R5, H, C for each occurrence 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, and C 4-10 cycloalkylalkyl, where C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12Alkylcycloalkyl, or C 4-10 cycloalkylalkyl is unsubstituted or substituted with 1 to 3 halogen substituents; R6, H, C for each occurrence 1-6 Alkyl, and C 3-6 cycloalkyl; R7, for each occurrence, 1-10 Alkyl, C 3-7 Cycloalkyl and C 4-12 alkylcycloalkyl, where C 1-10 Alkyl, C 3-7 Cycloalkyl, or C 4-12 Alkylcycloalkyl is unsubstituted or can be selected from halo, C 1-10 Alkyl, and -NR 12 ,R 12 is substituted with 1 to 3 substituents selected from R8 is H, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylheterocyclyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10 heterocycloalkenyl alkyl, aryl, heteroaryl, [ka] where C 1-10 Alkyl, C 1-10 Alkoxy, C 3-7 Cycloalkyl, C 4-12 Alkylcycloalkyl, C 4-10 Cycloalkylalkyl, C 3-10 Heterocyclyl, C 4-12 Alkylheterocyclyl, C 3-7 Heterocycloalkenyl, C 4-12 Alkylheterocycloalkenyl, C 4-10heterocycloalkenyl alkyl, aryl, or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from deuterium, halo, and -OR5; R 10 For each occurrence, H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-12 Alkylcycloalkyl, [ka] and C 3-10 heterocyclyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-12 Alkylcycloalkyl, or C 3-10 Heterocyclyl is unsubstituted or substituted with deuterium, halo, C 1-6 Alkyl, and C 3-6 substituted with 1 to 3 substituents selected from cycloalkyl substituents; R 11 For each occurrence, -OR 12 and -N(R 12 )2 are independently selected from R 12 For each occurrence, H, C 1-6 Alkyl, C 1-10 Haloalkoxy and C 3-6 cycloalkyl; n is an integer from 0 to 3, p is an integer from 1 to 5; q is an integer from 0 to 5; r is an integer from 1 to 5; s is an integer from 1 to 5; A is phenyl, pyridyl, pyrimidyl, pyridazyl, or the following 5-membered heterocycles: [ka] is selected from However, the compound of formula (I) [ka] isn't it).

[0128] In some embodiments, X1 is CR 4a In some embodiments, R 4a is H, Cl, or F. In some embodiments, X2 is CR 4b In some embodiments, X2 is N or CR 4b where R 4b is H. In some embodiments, R 4b is C1- 10 In one embodiment, R 4b is CH3.

[0129] In one embodiment, A is selected from phenyl, pyridyl, pyrimidyl, pyridazyl, and the following 5-membered heterocycles: [ka]

[0130] In some embodiments, A and / or the 5-membered heterocycle is [ka] [ka] is selected from.

[0131] In some embodiments, A is [ka] is selected from.

[0132] In one embodiment, R2 is halo. In one embodiment, R2 is Cl or F.

[0133] In one embodiment, R6 is H.

[0134] In one aspect, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0135] In some embodiments, R is [ka] It is.

[0136] In one aspect, the disclosure provides a compound of formula (100), (110), (120), (130), (140), (150), (160), or (170), or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0137] In some embodiments, R is [ka] It is.

[0138] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0139] In one embodiment, R is [ka] It is.

[0140] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0141] In one embodiment, the compound of any one of formulas (300) to (370) is selected from: [ka]

[0142] In one embodiment, R is [ka] It is.

[0143] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0144] In one embodiment, R is [ka] It is.

[0145] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0146] In one embodiment, R is [ka] It is.

[0147] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0148] In one embodiment, R is [ka] It is.

[0149] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0150] In one embodiment, R is [ka] It is.

[0151] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0152] In one embodiment, R is [ka] It is.

[0153] In one embodiment, 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka]

[0154] In some embodiments, R 10 is H, methyl, ethyl, -CD3, n-butyl, [ka] is selected from.

[0155] In some embodiments, R 11 teeth, [ka] is selected from.

[0156] In some embodiments, p is 2 or 3.

[0157] In some embodiments, R3 is -F, -CN, ethyl, [ka] In some embodiments, R3 is selected from: [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] It is.

[0158] In some embodiments, q is 0 or 1.

[0159] In some embodiments, r is 2 or 3.

[0160] In some embodiments, s is 1.

[0161] In some embodiments, R 12 is methyl, ethyl, -OCF3, and [ka] In some embodiments, R8 comprises one or more -OCF3 groups. In some embodiments, R8 is selected from H and methyl.

[0162] In some embodiments, R8 is H, methyl, ethyl, isopropyl, n-butyl, t-butyl, [ka] In one embodiment, R8 is selected from H, methyl, and ethyl.

[0163] In some embodiments, in formula (10), formula (100), formula (200), formula (300), formula (500), formula (600), formula (700), or formula (800), R3 is C1- 10 Alkyl, C1- 10 Alkoxy, -CF3, -OCF3, [ka] In one embodiment, in formula (100), R3 is selected from C1- 10 Alkyl, C1- 10 Alkoxy, -CF3, -OCF3, [ka] and -OH. In one embodiment, in formula (200), R3 is selected from C 1-10 In one embodiment, in formula (300), R3 is C 1-10 In one embodiment, in formula (500), R3 is C 1-10 In one embodiment, in formula (600), R3 is C 1-10 In one embodiment, in formula (700), R3 is C 1-10 In one embodiment, in formula (800), R3 is C 1-10 In one embodiment, in formula (900), R3 is C 1-10 It is an alkoxy.

[0164] In some embodiments, in formula (11), formula (110), formula (710), or formula (810), R3 is [ka] In one embodiment, in formula (110), R3 is selected from: [ka] In one embodiment, in formula (710), R3 is selected from: [ka] In one embodiment, in formula (810), R3 is selected from: [ka] It is.

[0165] In some embodiments, in formula (12), formula (130), formula (230), or formula (330), R3 is [ka] It is.

[0166] In some embodiments, in formula (13), formula (120), or formula (420), R3 is [ka] It is.

[0167] In some embodiments, in Formula (14) or Formula (140), each R is independently selected from -F and -OCH; and each R 10 are independently C1- 10 In one embodiment, in formula (140), one R is -F, one R is -OCH, and each R 10 is -CH3.

[0168] In some embodiments, in formula (15), formula (150), or formula (350), each R3 is independently selected from -OCH3, -CN, -N(CH3)2, -Cl, and ethyl. In one embodiment, in formula (150), one R3 is -N(CH3)2 and one R3 is selected from -OCH3, -Cl, and ethyl. In another embodiment, in formula (150), one R3 is -CN and one R3 is -OCH3. In one embodiment, in formula (350), one R3 is -N(CH3)2 and one R3 is -OCH3.

[0169] In some embodiments, in formula (16) or formula (160), R3 is [ka] is selected from.

[0170] In some embodiments, in formula (17) or formula (170), R3 is [ka] is selected from.

[0171] In one embodiment, X1 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 pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka] wherein R2 is selected from H and -Cl, and each R 4b H and C 1-10 alkyl).

[0172] In one embodiment, the present disclosure provides a compound comprising the formula [ka] and R 4bis H. In one embodiment, the present disclosure provides a compound of formula (20), [ka] and R8 is C 1-10 In one embodiment, the present disclosure provides a compound of formula (20), wherein R is alkyl. [ka] and R3 is C 1-10 alkoxy, and each R 10 C 1-10 In one embodiment, the present disclosure provides a compound of formula (20), wherein R is alkyl. [ka] and R 4b is H and R3 is C 1-10 Alkoxy, R8 is C 1-10 alkyl, and each R 10 C 1-10 In one embodiment, the present disclosure provides a compound of formula (20), wherein R is alkyl. [ka] and R 4b is H, R is -OCH, R is selected from methyl and ethyl, and each R 10 is independently methyl.

[0173] In one embodiment, the present disclosure provides a compound comprising the formula [ka] and R 4b is H. In one embodiment, the present disclosure provides a compound of formula (21), wherein R [ka] and R2 is H. In one embodiment, the present disclosure provides a compound of formula (21), wherein R1 is [ka] and R3 is [ka] In one embodiment, the present disclosure provides a compound of formula (21), wherein R is [ka] and R8 is C 1-10 In one embodiment, the present disclosure provides a compound of formula (21), wherein R is alkyl. [ka] R2 is H and R3 is [ka] and R 4b is H and R8 is methyl.

[0174] In one embodiment, A is [ka] and R1 is [ka] and the compound of formula (I) is a compound of formula (180): [ka]

[0175] In one embodiment, the compound of formula (I) is a compound of formula (180), wherein R8 is C 1-10 In one embodiment, the compound of formula (I) is a compound of formula (180), wherein R3 is C 1-10alkoxy, and each R 10 is independently 1-10 In one embodiment, the compound of formula (I) is a compound of formula (180), wherein R is -OCH, R is methyl, and each R 10 is methyl.

[0176] In one embodiment, A is [ka] and R1 is [ka] and the compound of formula (I) is a compound of formula (190): [ka]

[0177] In one embodiment, the compound of formula (I) is a compound of formula (190), wherein R8 is C 1-10 In one embodiment, the compound of formula (I) is a compound of formula (190), wherein R3 is C 1-10 alkoxy, and each R 10 is independently 1-10 In one embodiment, the compound of formula (I) is a compound of formula (190), wherein R is -OCH, R is methyl, and each R 10 is methyl.

[0178] In some embodiments, the compound of Formula (I) is selected from a compound having a formula selected from formulas 1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0179] In some embodiments, the compound of formula (I) is selected from: [ka]

[0180] In some embodiments, the compound of formula (I) is selected from: [ka] [ka]

[0181] In some embodiments, the compound of formula (I) is selected from: [ka] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof.

[0182] In some embodiments, the present disclosure provides: [ka] The present invention provides a compound having any one of formulas (I), (10), (11), (12), (13), (14), (15), (16), (17), (100), (110), (120), (130), (140), (150), (160), (170), and formulas 1001 to 1114, excluding the above.

[0183] In some embodiments, the present disclosure provides a compound of formula (I), wherein A is a 5-membered heterocycle and R is [ka] When R8 is not H.

[0184] Treatment method The compounds and compositions described herein can be used in methods for treating a disease, disorder, dysfunction, and / or condition, including but not limited to, treating a condition by activating AMPK activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(57 0), formula (600)-(670), formula (700)-(770), formula (800)-(870), formula (900)-(970), formula 1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; a method for treating a patient suffering from a mitochondrial disorder and / or dysfunction, comprising administering a therapeutically effective amount of a compound having the formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), or 1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; and a method of treating a patient with a mitochondrial disorder and / or dysfunction, comprising identifying a mitochondrial dysfunction in an individual, and administering a compound having any of the following formulas: 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), or formulas 1001 to 1114, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0185] The compounds and compositions described herein can be used in methods for treating diseases, disorders, conditions, and / or dysfunctions, including, but not limited to, a method of treating a disease or disorder associated with AMPK activity in a patient, comprising modulating AMPK activity in the patient; and a method of treating a mitochondrial disorder and / or dysfunction, comprising identifying a mitochondrial disorder and / or dysfunction in a patient and modulating AMPK activity in the patient. In some embodiments, modulating AMPK activity comprises administering to the patient a therapeutically effective amount of a compound having any of the formulas (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), and (1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. In some embodiments, the disease or disorder associated with AMPK activity is a mitochondrial disorder and / or dysfunction. In some embodiments, the modulating step comprises activating AMPK in the patient. In some embodiments, the activating step comprises phosphorylating AMPK or providing an agonist for AMPK. In some embodiments, the modulating step comprises inhibiting AMPK in the subject. In some embodiments, the mitochondrial disorder and / or dysfunction is a primary mitochondrial disorder and / or dysfunction. In some embodiments, the mitochondrial disorder and / or dysfunction is a secondary mitochondrial disorder and / or dysfunction. In some embodiments, the method further comprises evaluating the efficacy of the compound in the individual.

[0186] In some embodiments, the mitochondrial disorder and / or dysfunction is a primary mitochondrial disorder and / or dysfunction. Non-limiting examples of primary mitochondrial dysfunction include autosomal dominant optic atrophy (ADOA), Alpers-Huttenlocher syndrome (nDNA deficiency), ataxic neuropathy syndrome, (nDNA deficiency), Barth syndrome / fatal infantile cardiomyopathy (LIC), coenzyme Q deficiency, complex I, complex II, complex III, complex IV and complex V deficiency (either a single deficiency or any combination of deficiencies), chronic progressive external ophthalmoplegia (CPEO), diabetes mellitus and hearing loss, Kearns-Sayre syndrome (mtDNA deficiency), leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL-leukodystrophy), Leigh syndrome (mtDNA and nDNA deficiency), Leber's hereditary optic neuropathy (LHON), Luft's disease, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke. These include Middle Ataxia Syndrome (MELAS) (mtDNA deficiency), Mitochondrial Enoyl-CoA Reductase Protein-Associated Neurodegeneration (MEPAN), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial Recessive Ataxia Syndrome (MIRAS), mtDNA Deletion Syndrome, mtDNA Depletion Syndrome, mtDNA Maintenance Disorder, mtDNA / RNA Translation Defect, Mitochondrial tRNA Synthetase Deficiency, Mitochondrial Myopathy, Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE), Neuromuscular Weakness-Ataxia-Retinitis Pigmentosa (NARP), Pearson Syndrome, Pyruvate Dehydrogenase Complex Deficiency (PDCD / PDH), DNA Polymerase Gamma Deficiency (POLG), Pyruvate Carboxylase Deficiency, and Thymidine Kinase 2 Deficiency (TK2).

[0187] In some embodiments, the mitochondrial disorder and / or dysfunction is a secondary mitochondrial disorder and / or dysfunction. Non-limiting examples of 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 disease (MND), N-glycanase deficiency (NGLY1), organic acid metabolism disorders, Parkinson's disease (PD) and PD-related disorders, prion diseases, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), Becker muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral dystrophy, and others. These include muscular dystrophies, myotonic dystrophy, oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, congenital myopathies, peripheral myopathies, endocrine myopathies (hyperthyroidism-associated myopathy, hypothyroidism-associated myopathy), giant axonal neuropathy, hereditary spastic paraplegia, inflammatory myopathies (dermatomyositis, inclusion body myositis, polymyositis), metabolic myopathies, neuromuscular junction diseases, autism, cancer, diabetes, metabolic syndrome, chronic fatigue syndrome, inflammatory disorders, arthritis, aging, and mitochondrial epilepsy (epilepsy associated with primary mitochondrial disease).

[0188] In some embodiments, the compounds and compositions described herein can be used in a method 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's ataxia (FA), autoimmune disorders involving muscle pathology (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 disorders, and / or obesity. In other embodiments, mitochondrial dysfunction is identified based on a molecular signature of the disease or dysfunction, for example, protein blot (Western blot), polymerase chain reaction (PCR), genotyping using genetic markers (e.g., single nucleotide polymorphisms (SNPs), expressed sequence tags (ESTs), simple sequence repeats (SSRs), etc.) to identify the particular disease or dysfunction present in the individual. In some embodiments, AMPK activation in cardiac tissue can result in reversible cardiac hypertrophy, and thus, in some embodiments, the compounds and compositions described herein can be used in methods for treating diseases, disorders, conditions, and / or dysfunctions associated with dilated cardiomyopathy. (See, e.g., Arad et al, Circ Res. 2007 Mar 2; 100(4): 474-88; Myers et al, Science. 2017 Aug 4; 357(6350): 507-511; the disclosures of which are incorporated herein by reference in their entirety).

[0189] In some embodiments, the compounds and compositions described herein can be used in methods for treating diseases, disorders, conditions, and / or dysfunctions, including, but not limited to, ocular diseases associated with mitochondrial dysfunction.

[0190] In some embodiments, the compounds and compositions described herein provide neuroprotection in individuals with ischemic stroke, improve motor function in individuals with mitochondrial dysfunction and muscle wasting diseases such as muscular dystrophies and autoimmune myositis disorders, increase muscle strength, endurance, and overall motor function in muscle degenerative disorders associated with mitochondrial dysfunction, increase mitochondrial function and / or glycogen stores in skeletal muscle, normalize energy levels in skeletal muscle, thereby preventing degeneration and muscle loss in skeletal muscle, and / or activate AMPK.

[0191] In some embodiments, the compound having any of the formulas (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), and (1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, is administered in a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises the compound and at least one selected from a binder, a lubricant, a buffer, and a coating agent. In some embodiments, the compound and / or pharmaceutical formulation is administered orally. In some embodiments, the compound and / or pharmaceutical formulation is administered daily for at least one week. In some embodiments, the compound and / or pharmaceutical formulation is administered orally, subcutaneously, intravenously, intraperitoneally, intranasally, dermal, intravitreal injection, or by inhalation.

[0192] The efficacy of the methods, compounds, and combinations of compounds described herein in treating, preventing, and / or managing the indicated disease or disorder can be tested using various animal models known in the art. For example, methods for determining the efficacy of the compounds of the present disclosure include, but are not limited to, measuring pACC in a sample as an indicator of increased AMPK activity. In some embodiments, methods for evaluating symptoms of a disease or disorder include, but are not limited to, examining molecular profiles, such as genotyping, gene expression, and other methods that would be understood by those skilled in the art. In some embodiments, diseases and disorders are identified based on symptoms exhibited by an individual. In some embodiments, diseases and disorders are identified based on methods including, but not limited to, molecular signatures of disease or dysfunction, such as 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.).

[0193] Pharmaceutical Compositions In one embodiment, the present disclosure provides pharmaceutical compositions for use in the treatment of the diseases and conditions described herein.

[0194] The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of any of the compounds of formula (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), and (1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof, as an active ingredient. Typically, the pharmaceutical compositions also include one or more pharma- ceutically acceptable excipients, carriers, such as inert solid diluents and fillers, diluents, such as sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizing agents, and adjuvants.

[0195] The pharmaceutical composition as described above is for use in treating mitochondrial dysfunction, including, but not limited to, the pharmaceutical composition comprising one or more compounds having any one of formulas (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), and (1001-1114, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof, and a pharma- ceutically acceptable carrier. In some embodiments, the mitochondrial dysfunction is primary mitochondrial dysfunction.In some embodiments, the present invention relates to a genetic disorder characterized by ... ) (mtDNA deficiency), mitochondrial enoyl-CoA reductase protein-associated neurodegeneration (MEPAN), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mtDNA deletion syndrome, mtDNA depletion syndrome, mtDNA maintenance disorder, mtDNA / RNA translation deficiency, mitochondrial tRNA synthetase deficiency, mitochondrial myopathy, mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuromuscular ataxia-retinitis pigmentosa (NARP), Pearson syndrome, pyruvate dehydrogenase complex deficiency (PDCD / PDH), DNA polymerase gamma deficiency (POLG), pyruvate carboxylase deficiency, and thymidine kinase 2 deficiency (TK2). In some embodiments, the mitochondrial dysfunction is secondary mitochondrial dysfunction.In some embodiments, the secondary mitochondrial dysfunction is associated with 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 disease (MND), N-glycanase deficiency (NGLY1), organic acid metabolism disorders, Parkinson's disease (PD) and PD-related disorders, prion diseases, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), Becker muscular dystrophy, congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreafs muscular dystrophy, facioscapulohumeral dystrophy, and / or other conditions. myotonic dystrophy, myotonic dystrophy, oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, congenital myopathy, peripheral myopathy, endocrine myopathy (hyperthyroidism-associated myopathy, hypothyroidism-associated myopathy), giant axonal neuropathy, hereditary spastic paraplegia, inflammatory myopathy (dermatomyositis, inclusion body myositis, polymyositis), metabolic myopathy, neuromuscular junction disease, autism, cancer, diabetes, metabolic syndrome, chronic fatigue syndrome, inflammatory disorders, arthritis, aging, and mitochondrial epilepsy (epilepsy associated with primary mitochondrial disease).

[0196] In some embodiments, the concentration of a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof provided in a pharmaceutical composition of the present disclosure is, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14% or more of the pharmaceutical composition. ,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%,0.04%,0.03%,0.02%,0.01%,0.009%,0.008%,0. 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or less than 0.0001% w / w, w / v or v / v.

[0197] In some embodiments, the concentration of a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof provided in a pharmaceutical composition of the present disclosure is independently 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% of the pharmaceutical composition. 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% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0.05%,0.04%,0.03%,0.02%,0 greater than 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v, or v / v.

[0198] In some embodiments, the concentration of the compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof provided in the pharmaceutical composition of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40% of the pharmaceutical composition. , 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%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v or v / v.

[0199] In some embodiments, the amines of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas (1001-1114), formulas (1002-1116), formulas (1003-1118), formulas (1004-1119), formulas (1005-1119), formulas (1006-1119), formulas (1007-1119), formulas (1008-1119), formulas (1009-1120), formulas (1010-1110), formulas (1011-1120), formulas (1012-1121), formulas (1013-1122), formulas (1014-1123), formulas (1015-1124), formulas (1016-1125), formulas (1017-1126), formulas (1018-1127), formulas (1019-1136), formulas (1019-1138), formulas (1019-1141), formulas (1019-1142), formulas (1019-1143), formulas (1019-1144), formulas (1019-1145), formulas (1019-1146), formulas (1019-1147), formulas (1019- The concentration of the compound, or a pharma- ceutically acceptable salt thereof, is within the range of 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%, or about 0.1% to about 0.9% w / w, w / v, or v / v of the pharmaceutical composition.

[0200] In some embodiments, the agonist of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formula (800)-(850), formula (900)-(950), formula (1000)-(10 ... The amount of the compound of formula (900) to (970), formula (1001) to (1114), or a pharma- ceutically acceptable salt thereof is 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, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0201] In some embodiments, the agonist of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas (1001)-(1002) are provided in the pharmaceutical composition of the present disclosure. The amount of the compound of ~1114, or a pharma- ceutically acceptable salt thereof, may be 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0. 006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g , 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1 g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g , 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0202] Each of the compounds provided according to the present disclosure is effective over a wide dosage range. For example, in the treatment of adult humans, dosages ranging from 0.01 to 1000 mg per day, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day, independently, are examples of dosages that may be used. The exact dosage may depend on the route of administration, the form in which the compound is administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0203] Non-limiting pharmaceutical compositions and methods for their preparation are described below.

[0204] Pharmaceutical Compositions for Oral Administration In a preferred embodiment, the present disclosure provides a pharmaceutical composition for oral administration comprising a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, and a pharmaceutical excipient suitable for administration.

[0205] In a preferred embodiment, the present disclosure provides a solid pharmaceutical composition for oral administration, comprising (i) an effective amount of a compound of formula (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), or (1001-1114, or a pharma- ceutically acceptable salt thereof, and (ii) a pharmaceutical excipient suitable for administration. In some embodiments, the composition further comprises (iii) an effective amount of an additional pharma- ceutical active ingredient. For example, the additional pharma-ceutical active ingredient as used herein may include one or more compounds that modulate AMPK activity. In some embodiments, the one or more compounds activate AMPK activity. In some embodiments, the one or more compounds phosphorylate AMPK and / or are AMPK agonists. In some embodiments, the one or more compounds inhibit AMPK activity. In some embodiments, the one or more compounds are competitive inhibitors and / or allosteric inhibitors that prevent AMPK catalysis.

[0206] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion.

[0207] The pharmaceutical compositions of the present disclosure suitable for oral administration may be presented as separate dosage forms such as capsules, sachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or in the form of granules, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil liquid emulsions, powders for reconstitution, powders for oral ingestion, bottles (containing powders or liquids in bottles), orally dissolving films, lozenges, pastes, tubes, gums, and packs. 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. In general, 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 appearance. For example, tablets 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 a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0208] The present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms, since water can accelerate the degradation of some compounds. For example, in the pharmaceutical arts, water is sometimes added (e.g., 5%) as a means of simulating long-term storage to determine characteristics such as the shelf life or stability over time of a formulation. The anhydrous pharmaceutical compositions and dosage forms of the present disclosure can be prepared using ingredients containing anhydrous or low moisture and conditions of low moisture or low humidity. Pharmaceutical compositions and dosage forms of the present disclosure containing lactose can be anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, and the like, unit dose containers, blister packs, and strip packs.

[0209] The medicament active ingredient can be mixed in intimate mixture with the pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take various forms depending on the form of preparation desired for administration. For the preparation of compositions for oral dosage forms, any of the usual pharmaceutical media can be used as carriers, for example, for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used, or for oral solid preparations, carriers such as starch, sugar, crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used, in some embodiments, without using lactose. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If desired, tablets can be coated by standard wet or dry techniques.

[0210] 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, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0211] Examples of 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, pregelatinized starch, and mixtures thereof.

[0212] Disintegrants can be used in the compositions of the present disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can cause the tablet to disintegrate in the bottle. Too little can result in insufficient disintegration, thereby altering the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant can be used to form a dosage form of the compounds disclosed herein, but not too little or too much to adversely alter the release of the active ingredient(s). The amount of disintegrant used can vary based on the type of formulation and mode of administration, and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant can 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, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0213] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present 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 oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. Lubricants can be optionally added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.

[0214] When aqueous suspensions and / or elixirs are desired for oral administration, the active pharmaceutical ingredient(s) can be combined with various sweetening or flavoring agents, coloring agents or pigments, and optionally emulsifying and / or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0215] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a long period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be utilized.Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0216] Surfactants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., mixtures of hydrophilic surfactants may be employed, mixtures of lipophilic surfactants may be employed, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0217] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and more soluble in oil, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​above about 10, as well as anionic, cationic, or zwitterionic compounds to which the HLB scale does not generally apply. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​of about 10 or less. However, the HLB value of a surfactant is only a rough guide that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0218] Hydrophilic surfactants can be either ionic or nonionic.Suitable ionic surfactants include but are not limited to alkyl ammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0219] In the aforementioned group, the ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0220] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactylate, stearoyl lactate, The ionized forms may be succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0221] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid 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 polyols with at least one of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0222] Other hydrophilic non-ionic surfactants include, but are not limited to, 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-32 oleate ... PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PE G-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soy Sterol Examples of suitable glyceryl esters include sucrose monostearate, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0223] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid 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, monoglyceride and diglyceride lactic acid derivatives, hydrophobic transesterification products of polyols and at least one of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols and at least one of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0224] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the disclosed compound and minimize precipitation of the disclosed compound.This may be particularly important for compositions for parenteral use, such as injection compositions.Solubilizers may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0225] Examples of suitable solubilizers include: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropylmethylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactone, glycerol ... tam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as, but not limited to, dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0226] Mixtures of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0227] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a biotolerable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the biotolerable amount, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before providing the composition to the patient. Thus, when present, the solubilizer may be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the total weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1% or less, may be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0228] The composition may further comprise one or more pharma- ceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavors, colorants, odorants, opacifiers, suspending agents, binders, bulking agents, plasticizers, lubricants, and mixtures thereof.

[0229] In addition, acids or bases can be incorporated into the composition to facilitate processing, improve stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, 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), etc. Also suitable are bases that are salts of pharma- ceutically acceptable acids, 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, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen monohydrogen phosphate, and sodium dihydrogen phosphate, may also be used. When the base is a salt, the cation may be any convenient pharma-ceutically acceptable cation, such as ammonium, alkali metals, and alkaline earth metals. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0230] Suitable acids are pharma- ceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include 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, 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.

[0231] Pharmaceutical Compositions for Injection In a preferred embodiment, the present disclosure provides a pharmaceutical composition for injection comprising a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, and a pharmaceutical excipient suitable for injection. The components and amounts of the compounds in the composition are as described herein.

[0232] Forms into which the compositions of the present disclosure can be incorporated for administration by injection include aqueous or oily suspensions or emulsions (such as those using sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0233] Aqueous solutions of physiological 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 utilized. Proper fluidity can be maintained, for example, by the use of a coating agent, such as lecithin, to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0234] Sterile injectable solutions are prepared by incorporating a compound of formula (I), formula (10)-(17), formula (20)-(26), formula (100)-(190), formula (200)-(270), formula (300)-(370), formula (400)-(470), formula (500)-(570), formula (600)-(670), formula (700)-(770), formula (800)-(870), formula (900)-(970), formula (1001-1114) or a pharma-ceutically acceptable salt thereof, as described herein, in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions can be prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some 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.

[0235] Pharmaceutical Compositions for Local Delivery In a preferred embodiment, the present disclosure provides a pharmaceutical composition for transdermal delivery comprising a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, and a pharmaceutical excipient suitable for transdermal delivery.

[0236] The composition of the present disclosure can be formulated into solid, semi-solid or liquid form preparations suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, liquid, oil, paste, suppository, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, carriers with high density can provide areas with prolonged exposure to active ingredients. In contrast, solution formulations can provide selected areas with more rapid exposure to active ingredients.

[0237] The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients, which are compounds that can increase the penetration or aid in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin.Many such penetration enhancing molecules are known to those skilled in the art of topical formulations.Examples of such carriers and excipients include, but are not limited to, 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, 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 glycol.

[0238] Another exemplary formulation for use in the methods of the present disclosure utilizes a transdermal delivery device ("patch"). Such a transdermal patch can be used to continuously or intermittently infuse a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, in a controlled amount, with or without another pharma- ceutically active ingredient.

[0239] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252; 4,992,445 and 5,001,139. ​​Such patches can be constructed for continuous, pulsatile or on-demand delivery of pharmaceutical agents.

[0240] Pharmaceutical Compositions for Inhalation Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients, as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by using an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a tent-like face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhalation delivery of the composition.

[0241] Other Pharmaceutical Compositions Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharma- ceutical acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intrathecal administration.The preparation of such pharmaceutical compositions is well known in the art.See, for example, Anderson, et al., eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, NY, 1990, each of which is incorporated herein by reference in its entirety.

[0242] Administration of the compounds 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 pharma- ceutically acceptable salts thereof, or pharmaceutical compositions of these compounds, described herein, can be by any method capable of delivering the compound to the site of action. 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, local delivery by catheter or stent, or by inhalation. The compounds of formula (I), formulae (10) to (17), formulae (20) to (26), formulae (100) to (190), formulae (200) to (270), formulae (300) to (370), formulae (400) to (470), formulae (500) to (570), formulae (600) to (670), formulae (700) to (770), formulae (800) to (870), formulae (900) to (970), formulae 1001 to 1114, or pharma- ceutically acceptable salts thereof described herein may also be administered intraadipose tissue or intrathecally.

[0243] The disclosed compositions can also be delivered via impregnated or coated devices, such as stents or cylindrical polymers inserted into arteries. Such administration methods may be useful for preventing or improving restenosis after procedures such as balloon angioplasty. Without being bound by theory, the disclosed compounds may slow down or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The disclosed compounds may be administered by local delivery, for example, from stent struts, stent grafts, grafts, or stent covers or sheaths. In some embodiments, the disclosed compounds are mixed with a matrix. Such a matrix may be a polymer matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters, such as polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release one or more compounds. The compounds of formula (I), formula (10)-(17), formula (20)-(26), formula (100)-(190), formula (200)-(270), formula (300)-(370), formula (400)-(470), formula (500)-(570), formula (600)-(670), formula (700)-(770), formula (800)-(870), formula (900)-(970), formula (1001-1114), or pharma- ceutically acceptable salts thereof described herein can 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 compound in a solvent can be applied and the solvent can be evaporated to form a layer of the compound on the stent.Alternatively, the compound may be placed in the body of the stent or graft, for example in microchannels or micropores. Once implanted, the compound diffuses out of the stent body and contacts the arterial wall. Such a stent may be prepared by immersing a stent manufactured to contain such micropores or microchannels in a solution of the compound of the present disclosure in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be further removed by a brief solvent wash. In yet other embodiments, the compound of the present disclosure may be covalently attached to the stent or graft. Covalent linkers may be used that degrade in vivo, resulting in the release of the compound of the present disclosure. Any biolabile linkage may be used for such purposes, such as ester, amide or anhydride linkages. The compounds 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), and formulas 1001 to 1114 described herein, or pharma- ceutically acceptable salts thereof, may be administered intravascularly from a balloon used during angioplasty. Extravascular administration of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, as described herein, may be performed to reduce restenosis, via pericardial or epicardial application of the formulations of the present disclosure.

[0244] Exemplary parenteral dosage forms include solutions or suspensions of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, in sterile aqueous solution, e.g., aqueous propylene glycol or dextrose. Such dosage forms may be suitably buffered, if desired.

[0245] The present disclosure also provides a kit comprising a compound of formula (I), (10)-(17), (20)-(26), (100)-(190), (200)-(270), (300)-(370), (400)-(470), (500)-(570), (600)-(670), (700)-(770), (800)-(870), (900)-(970), or (1001-1114, or a pharma- ceutically acceptable salt thereof, as described herein in suitable packaging, and written material that may include instructions for use, a discussion of clinical trials, and a list of side effects. Such kits may also include information showing or demonstrating the activity and / or benefits of the composition, such as scientific references, package insert samples, clinical trial results, and / or summaries thereof, and / or describing dosage, administration, side effects, drug interactions, or other information useful to health care providers. Such information may be based on the results of various studies, for example, studies using laboratory animals including in vivo models and studies based on human clinical trials. The kit may further contain another medicament active ingredient. In some embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof and another pharma- ceutically active ingredient described herein are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, and the agent are provided as a single composition in a container of the kit.Suitable packaging and additional items for use (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kits. The kits described herein may be provided, marketed, and / or promoted to health care providers, including physicians, nurses, pharmacists, dispensing personnel, etc. The kits may also, in some embodiments, be marketed directly to consumers.

[0246] The kits described above are preferably for use in the treatment of diseases and conditions described herein. In some embodiments, the kits described herein are for use in the treatment of mitochondrial dysfunction. In some embodiments, the mitochondrial dysfunction is primary mitochondrial dysfunction. In some embodiments, the present invention relates to a genetic disorder characterized by ... ) (mtDNA deficiency), mitochondrial enoyl-CoA reductase protein-associated neurodegeneration (MEPAN), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mtDNA deletion syndrome, mtDNA depletion syndrome, mtDNA maintenance disorder, mtDNA / RNA translation deficiency, mitochondrial tRNA synthetase deficiency, mitochondrial myopathy, mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuromuscular ataxia-retinitis pigmentosa (NARP), Pearson syndrome, pyruvate dehydrogenase complex deficiency (PDCD / PDH), DNA polymerase gamma deficiency (POLG), pyruvate carboxylase deficiency, and thymidine kinase 2 deficiency (TK2). In some embodiments, the mitochondrial dysfunction is secondary mitochondrial dysfunction.In some embodiments, the secondary mitochondrial dysfunction is associated with 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 disease (MND), N-glycanase deficiency (NGLY1), organic acid metabolism disorders, Parkinson's disease (PD) and PD-related disorders, prion diseases, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), Becker muscular dystrophy, congenital muscular dystrophies, Duchenne muscular dystrophy, Emery-Dreafs muscular dystrophy, facioscapulohumeral dystrophy, and / or other conditions. myotonic dystrophy, myotonic dystrophy, oculopharyngeal muscular dystrophy, Charcot-Marie-Tooth disease, congenital myopathy, peripheral myopathy, endocrine myopathy (hyperthyroidism-associated myopathy, hypothyroidism-associated myopathy), giant axonal neuropathy, hereditary spastic paraplegia, inflammatory myopathy (dermatomyositis, inclusion body myositis, polymyositis), metabolic myopathy, neuromuscular junction disease, autism, cancer, diabetes, metabolic syndrome, chronic fatigue syndrome, inflammatory disorders, arthritis, aging, and mitochondrial epilepsy (epilepsy associated with primary mitochondrial disease).

[0247] Dosage and Administration Regimen The dosage of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein will depend on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, the effective dosage of each is within the range of about 0.001 to about 100 mg / kg body weight per day, for example, about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this corresponds to about 0.05 to 7 g / day, for example, about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, larger doses may be employed without causing any adverse side effects, for example, such larger doses may be divided into several smaller doses and administered throughout the day. The dosage of 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 a pharma- ceutically acceptable salt thereof described herein may be expressed in mg / kg body weight or mg / m 2 It may be provided in units of body surface area.

[0248] In some embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered in multiple doses. In a preferred embodiment, the compound of formula (I), formula (10)-(17), formula (20)-(26), formula (100)-(190), formula (200)-(270), formula (300)-(370), formula (400)-(470), formula (500)-(570), formula (600)-(670), formula (700)-(770), formula (800)-(870), formula (900)-(970), formula 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times, or more than six times daily. Administration may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered from about once per day to about six times per day.In some embodiments, the amines represented by formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas (100)-(10 ... In another embodiment, the compound of formula (I), formula (10) to (17), formula (20) to (26), formula (100) to (190), formula (200) to (270), formula (300) to (370), formula (400) to (470), formula (500) to (501), formula (502) to (503), formula (504) to (505), formula (506) to (507), formula (508) to (509), formula (600) to (609), formula (601) to (609), formula (601) to (609), formula (601) to (609), formula (701) to (709), formula (801) to (809), formula (900) to (970), formula 1001 to 1114, or a pharma- ceutically acceptable salt thereof, is administered once daily, and in another embodiment, the compound of formula (I), formula (10) to (17), formula (20) to (26), formula (100) to (190), formula (200) to (270), formula (300) to (370), formula (400) to (470), formula (502) to (503), formula (504) to (505), formula (701) to (709), formula (801) to (809), formula (901) to (970), formula (1001) to ( In another embodiment, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formula (100), Formula (110), Formula (120), Formula (130), Formula (140), Formula (150), Formula (160), Formula (170), Formula (180), Formula (190), Formula (210), Formula (220), Formula (230), Formula (240), Formula (250), Formula (260), Formula (270), Formula (280), Formula (290), Formula (300), Formula (310), Formula (320), Formula (330), Formula (340), Formula (350), Formula (360), Formula (370), Formula (380), Formula (390), Formula (400), Formula (410), Formula (420), Formula (430), Formula (440), Formula (500), Formula (510), Formula (520), Formula (530), Formula (600), Formula (670), Formula (700), Formula (770), Formula (800), Formula (870), Formula (900), Formula (970), Formula (1001)-(1114), or a pharma- ceutically acceptable salt thereof is administered twice daily. The compound of formula (1001-1114), or a pharma- ceutically acceptable salt thereof, is administered three times daily.

[0249] Administration of a compound of formula (I) described herein, formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, may be continued for as long as necessary. In some embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered in less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Formula (I), Formulas (10)-(17), Formulas (20)-(26), Formulas (100)-(190), Formulas (200)-(270), Formulas (300)-(370), Formulas (400)-(470), Formulas (500)-(570), Formulas (600)-(670), Formulas (700)-(770), Formulas (800)-(870), Formulas (900)-(970), Formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is administered chronically, e.g., for the treatment of a chronic effect.In another embodiment, administration of a compound of formula (I), formula (10)-(17), formula (20)-(26), formula (100)-(190), formula (200)-(270), formula (300)-(370), formula (400)-(470), formula (500)-(570), formula (600)-(670), formula (700)-(770), formula (800)-(870), formula (900)-(970), formula 1001-1114, or a pharma- ceutically acceptable salt thereof described herein continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is administered and maintained for as long as necessary.

[0250] In some embodiments, an effective dosage of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof described herein is from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 250 mg, from about 25 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 5 ... The range is 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 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 mg to about 202 mg.

[0251] In some embodiments, a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a compound thereof described herein. An effective dosage of a pharma- ceutically acceptable salt is from about 0.01 mg / kg to about 4.3 mg / kg, from about 0.15 mg / kg to about 3.6 mg / kg, from about 0.3 mg / kg to about 3.2 mg / kg, from about 0.35 mg / kg to about 2.85 mg / kg, from about 0.15 mg / kg to about 2.85 mg / kg, from about 0.3 mg / kg to about 2.15 mg / kg, from about 0.45 mg / kg to about 1.7 mg / kg, from about 0.15 mg / kg to about 1.3 mg / kg, from about 0.5 mg / kg to about 1.6 mg / kg, from about 0.6 mg / kg to about 1.8 mg / kg, from about 0.8 mg / kg to about 1.6 mg / kg, from about 0.8 ... .3mg / kg~about 1.15mg / kg, about 0.45mg / kg~about 1mg / kg, about 0.55mg / kg~about 0.85mg / kg, about 0.65mg / kg~about 0.8mg / kg, about 0.7mg / kg~about 0 .75mg / kg, about 0.7mg / kg to about 2.15mg / kg, about 0.85mg / kg to about 2mg / kg, about 1mg / kg to about 1.85mg / kg, about 1.15mg / kg to about 1.7mg / kg, about 1.3 The range is from about 2.6 mg / kg to about 3.15 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.8 mg / kg to about 3 mg / kg, from about 2.85 mg / kg to about 2.9 ... or from about 2.7 mg / kg to about 3 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, or from about 2.85 mg / kg to about 2.95 mg / kg.

[0252] In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, larger doses may be employed without causing any adverse side effects, for example, such larger doses may be divided into multiple smaller doses administered throughout the day.

[0253] An effective amount of a compound of formula (I), formulas (10)-(17), formulas (20)-(26), formulas (100)-(190), formulas (200)-(270), formulas (300)-(370), formulas (400)-(470), formulas (500)-(570), formulas (600)-(670), formulas (700)-(770), formulas (800)-(870), formulas (900)-(970), formulas 1001-1114, or a pharma- ceutically acceptable salt thereof, described herein may be administered in either a single dose or multiple doses by any of the modes of administration of acceptable agents having similar utilities, for example, by rectal, buccal, intranasal and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant. EXAMPLES

[0254] The embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather as encompassing any variations that become evident as a result of the teachings provided herein.

[0255] Example 1: Synthesis of compounds of the present disclosure

[0256] General synthetic route R-1 [ka]

[0257] Any amide coupling reagent known in the art can be used to effect the coupling of indole with hydroxylamine. In an exemplary embodiment, the reagent is selected from BOP-Cl, TBTU, BOP, PyBop, HATU, EDCI / HOBT, DIC / HOBT; and DCC / HOBT.

[0258] A. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (1003) [ka] [ka]

[0259] Compound 1003 was prepared according to general synthetic route R-1. DIPEA (0.4 mL, 1.734 mmol) and HATU (0.34 g, 0.867 mmol) were added to a solution of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxylic acid (0.20 g, 0.578 mmol) in DMF (10 mL) at room temperature. O-methylhydroxylamine (0.06 g, 0.693 mmol) was then added and the reaction mass was stirred for 48 hours. The reaction was diluted with ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide as an off-white solid (14 mg, 11%).

[0260] LCMS: 99.81% (M / Z 373.15, [MH] +)

[0261] 1 H NMR;400 MHz, DMSO-d6: δ 11.42 (br, 2H), 7.93 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.31 (d, J = 8.40 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.07 (s, 6H).

[0262] B. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-ethoxy-1H-indole-3-carboxamide (1009) [ka]

[0263] Compound 1009 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0264] LCMS: 99.12% (M / Z 387.26, [MH])

[0265] 1 H NMR 400 MHz, DMSO-d6: δ 11.65-11.15 (br s, 2H), 7.95 (s, 1H), 7.92 (s, 1H), 7.56 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.40 Hz, 1H), 3.93-3.88 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.07 (s, 6H), 1.20 (t, J = 7.2 Hz, 3H).

[0266] C. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-isopropoxy-1H-indole-3-carboxamide (1010) [ka]

[0267] Compound 1010 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0268] LCMS: 99.16% (M / Z 403.34, [M+H]+)

[0269] 1 H NMR: 400 MHz, DMSO-d6: δ 11.66 (s, 1H), 10.86 (s, 1H), 7.97 (d, J = 2.80 Hz, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 4.11-4.04 (m, 1H), 3.76 (s, 3H), 3.07 (s, 6H), 1.19 (d, J = 6.40 Hz, 6H).

[0270] D. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-(2-methoxyethoxy)-1H-indole-3-carboxamide (1011) [ka]

[0271] Compound 1011 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0272] LCMS: 99.61% (M / Z 419.39, [M+H]+)

[0273] 1H NMR: 400 MHz, DMSO-d6: δ 11.68 (s, 1H), 11.12 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.99 (t, J = 4.80 Hz, 2H), 3.76 (s, 3H), 3.57 (t, J = 4.40 Hz, 2H), 3.32 (s, 3H), 3.07 (s, 6H).

[0274] E. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-phenoxy-1H-indole-3-carboxamide (1012) [ka]

[0275] Compound 1012 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0276] LCMS: 97.14% (M / Z 437.36, [M+H]+)

[0277] 1 H NMR: 400 MHz, DMSO-d6: δ 11.83 (s, 2H), 8.10 (s, 1H), 7.92 (s, 1H), 7.59 (s, 1H), 7.35-7.30 (m, 3H), 7.09 (d, J = 8.00 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.21 (d, J = 8.40 Hz, 1H), 3.76 (s, 3H), 3.06 (s, 6H).

[0278] F. Synthesis of 6-chloro-N-(cyclohexyloxy)-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (1013) [ka]

[0279] Compound 1013 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0280] LCMS: 96.97% (443.29, M+H);

[0281] 1 H NMR 400 MHz, DMSO-d6: δ 11.68 (s, 1H), 10.89 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.79-3.76 (m, 4H), 3.07 (s, 6H), 1.91-1.89 (m, 2H), 1.73-1.71 (m, 2H), 1.39-1.21 (m, 6H).

[0282] Synthesis of GN-(tert-butoxy)-6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (1014) [ka]

[0283] Compound 1014 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0284] LCMS: 99.43% (M / Z 417.41, [M+H]+)

[0285] 1 H NMR 400 MHz, DMSO-d6: δ 11.66 (s, 1H), 10.40 (s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.31 (d, J = 8.40 Hz, 1H), 6.22 (d, J = 8.40 Hz, 1H), 3.76 (s, 3H), 3.07 (s, 6H), 1.22 (s, 9H).

[0286] H. Synthesis of 6-chloro-N-(cyclopropylmethoxy)-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (1015) [ka]

[0287] Compound 1015 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0288] LCMS: 98.86% (M+H = 415.69)

[0289] 1H NMR (400 MHz, DMSO-d6): δ 11.66 (d, J = 2.00 Hz, 1H), 11.05 (s, 1H), 7.94 (t, J = 2.40 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J = 7.20 Hz, 2H), 3.07 (s, 6H), 1.14-1.07 (m, 1H), 0.56-0.54 (m, 2H), 0.34-0.32 (m, 2H).

[0290] Synthesis of IN-(benzyloxy)-6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (1016) [ka]

[0291] Compound 1016 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0292] LCMS: 95.56% (451.43, M+H);

[0293] 1 H NMR (400 MHz, DMSO-d6): δ 11.41 (br s, 2H), 7.93 (d, J = 3.20 Hz, 2H), 7.55 (s, 1H), 7.45-7.73 (m, 2H), 7.38-7.30 (m, 4H), 6.23 (d, J = 8.40 Hz, 1H), 4.91 (s, 2H), 3.77 (s, 3H), 3.07 (s, 6H).

[0294] J. Synthesis of 4,6-difluoro-N-((tetrahydro-2H-pyran-2-yl)oxy)-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1026) [ka]

[0295] Compound 1026 was prepared following general synthetic route R-1 using experimental procedures similar to those used for the preparation of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (compound 1003).

[0296] LCMS: 98.78% (MH = 455.38)

[0297] 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (br, 1H), 7.85 (s, 1H), 7.43-7.37 (m, 4H), 7.23 (d, J = 10.40 Hz, 1H), 4.96 (s, 1H), 4.39 (d, J = 2.00 Hz, 1H), 4.01-3.98 (m, 2H), 3.59-3.48 (m, 2H), 1.87-1.85 (m, 2H), 1.69-1.60 (m, 4H), 1.57-1.50 (m, 6H).

[0298] General synthetic route R-2 [ka]

[0299] Any Suzuki coupling conditions known in the art can be used to carry out the coupling of boronic acids / esters with aryl / heteroaryl halides. In an exemplary embodiment, 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 catalysts described in Bedford, RB and Cazin, CSJ (2001) Chem. Commun., 1540-1541) and a base (e.g., a carbonate, such as potassium carbonate).

[0300] K. Synthesis of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017) [ka]

[0301] Step 1: Synthesis of 5-bromo-6-chloro-N-methoxy-1H-indole-3-carboxamide [ka]

[0302] To a 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. Methoxyamine hydrochloride (1.22 g, 14.57 mmol) was added to the reaction in portions over 15 min and stirred at room temperature for 5 h. The reaction was diluted with EtOAc (200 mL), washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give 5-bromo-6-chloro-N-methoxy-1H-indole-3-carboxamide as an off-white solid (1.5 g; 67% yield). LCMS: 84.63% ([M+H]=303.19). This was used directly in the next step.

[0303] Step 2: Synthesis of 6-chloro-N-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide

[0304] 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. After adding Pd(OAc)2 (56 mg, 0.248 mmol) and PCy3 (70 mg, 0.248 mmol) and purging with nitrogen again, the reaction mixture was stirred at 80° C. for 8 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc and filtered through a celite bed. The filtrate was concentrated under reduced pressure to give crude 6-chloro-N-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide, which was used directly in the next step.

[0305] Step 3: Synthesis of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017) [ka]

[0306] Compound 1017 was prepared according to general synthetic route R-2. To a stirred solution of 5-bromo-6-methoxy-N-methylpyridin-2-amine (0.25 g, 1.152 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added 6-chloro-N-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide (0.5 g, 1.382 mmol) and K2CO3 (0.33 g, 2.304 mmol). The reaction mixture was purged with N2 and PdCl2(dPPf)2 and DCM (0.049 g, 0.058 mmol) were added. After stirring at 90 °C for 5 h, the reaction mixture was filtered through a celite bed and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide as an off-white solid (21 mg, 5.06%).

[0307] LCMS: 95.87% (361.30, M+H);

[0308] 1 H NMR 400 MHz, DMSO-d6: δ 11.64 (br s, 1H), 11.17 (br s, 1H), 7.92 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.21 (d, J = 8.00 Hz, 1H), 6.49-6.45 (m, 1H), 6.06 (d, J = 8.00 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.82 (d, J = 4.80 Hz, 3H).

[0309] L. Synthesis of 6-chloro-5-(6-(cyclopropylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (1018) [ka]

[0310] Compound 1018 was prepared following general synthetic route R-2 using experimental procedures similar to those used for the preparation of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017).

[0311] LCMS: 93.26% (387.34, M+H);

[0312] 1 H NMR (400 MHz, DMSO-d6): δ 11.83 (br s, 1H), 11.13 (br s, 1H), 7.92 (m, 2H), 7.55 (s, 1H), 7.29 (d, J = 7.60 Hz, 1H), 6.74 (s, 1H), 6.26 (d, J = 8.00 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 2.55 (br s, 1H), 0.71-0.70 (m, 2H), 0.48 (br s, 2H).

[0313] M. Synthesis of 5-(6-(azetidin-1-yl)-2-methoxypyridin-3-yl)-6-chloro-N-methoxy-1H-indole-3-carboxamide (1019) [ka]

[0314] Compound 1019 was prepared following general synthetic route R-2 using experimental procedures similar to those used for the preparation of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017).

[0315] LCMS: 97.06% (387.34, M+H);

[0316] 1H NMR 400 MHz, DMSO-d6: δ 11.35 (br s, 2H), 7.93-7.90 (m, 2H), 7.57 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 5.96 (d, J = 7.60 Hz, 1H), 3.98 (t, J = 7.20 Hz, 4H), 3.73 (s, 3H), 3.68 (s, 3H), 2.36-2.32 (m, 2H).

[0317] Synthesis of N-6-chloro-5-(6-(dimethylamino)-2-ethoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (1020) [ka]

[0318] Compound 1020 was prepared following general synthetic route R-2 using experimental procedures similar to those used for the preparation of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017).

[0319] LCMS: 99.09% (389.36, M+H);

[0320] 1 H NMR 400 MHz, DMSO-d6: δ 11.29 (br s, 2H), 7.93 (s, 2H), 7.56 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.20 (d, J = 8.00 Hz, 1H), 4.28 (q, J = 6.80 Hz, 2H), 3.69 (s, 3H), 3.05 (s, 6H), 1.22 (t, J = 6.80 Hz, 3H).

[0321] O. Synthesis of 6-chloro-5-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-N-methoxy-1H-indole-3-carboxamide (1024) [ka]

[0322] Compound 1024 was prepared following general synthetic route R-2 using experimental procedures similar to those used for the preparation of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017). LCMS: 99.39% ([M+H]= 371.34).

[0323] 1 H NMR (400 MHz, DMSO): δ 11.46 (br s, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 4H), 4.71 (s, 1H), 3.69 (s, 3H), 3.59 (s, 2H), 0.89-086 (m, 2H), 0.81-0.78 (m, 2H).

[0324] P. Synthesis of 6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-N-methoxy-1H-indole-3-carboxamide (1025) [ka]

[0325] Compound 1025 was prepared following general synthetic route R-2 using experimental procedures similar to those used for the preparation of 6-chloro-N-methoxy-5-(2-methoxy-6-(methylamino)pyridin-3-yl)-1H-indole-3-carboxamide (1017).

[0326] LCMS: 97.62% ([MH]= 369.24)

[0327] 1H NMR (400 MHz, DMSO): δ 11.41 (br s, 2H), 8.04 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.56 (d, J = 8.40 Hz, 2H), 7.41 (d, J = 8.00 Hz, 2H), 5.53 (s, 1H), 3.69 (s, 3H), 2.51-2.42 (m, 2H), 2.34-2.27 (m, 2H), 2.00-1.92 (m, 1H), 1.70-1.60 (m, 1H).

[0328] Q. Synthesis of 6-chloro-5-(6-(dimethylamino)-5-fluoro-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (1022) [ka]

[0329] Compound 1022 was prepared according to general synthetic route R-2. [ka]

[0330] Step 1: 5-Bromo-3,6-difluoro-N,N-dimethylpyridin-2-amine

[0331] To a stirred solution of 3,6-difluoro-N,N-dimethylpyridin-2-amine (1 g, 6.323 mmol) in ACN (10 mL) was added NBS (1.125 g, 6.323 mmol) in portions at room temperature under nitrogen atmosphere at 0° C. and stirred for 30 min at 0° C. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (100 mL), and concentrated under reduced pressure to give 5-bromo-3,6-difluoro-N,N-dimethylpyridin-2-amine as a pale yellow liquid (1.2 g; 80% yield).

[0332] Step 2: 5-Bromo-3-fluoro-6-methoxy-N,N-dimethylpyridin-2-amine

[0333] 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 3 h. The reaction mixture was concentrated under reduced pressure, quenched with cold water, and the precipitated solid was filtered off and dried under vacuum to give crude 5-bromo-3-fluoro-6-methoxy-N,N-dimethylpyridin-2-amine (1 g; 79%).

[0334] Step 3: Analogously to Example K, the product of Step 2 was coupled with 6-chloro-N-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide to give 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).

[0335] LCMS: 97.14% (M+H = 393.35)

[0336] 1 H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 11.14 (s, 1H), 7.95 (s, 2H), 7.57 (s, 1H), 7.35 (d, J = 12.80 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.09 (d, J = 2.00 Hz, 6H).

[0337] General synthetic route R-3 [ka]

[0338] Any Suzuki coupling conditions known in the art can be used to carry out the coupling of boronic acids / esters with aryl / heteroaryl halides. In an exemplary embodiment, 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 catalysts described in Bedford, RB and Cazin, CSJ (2001) Chem. Commun., 1540-1541) and a base (e.g., a carbonate, such as potassium carbonate).

[0339] R. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-2-methyl-1H-indole-3-carboxamide (1023) [ka] [ka]

[0340] Compound 1023 was prepared according to general synthetic route R-3.

[0341] Step 1: 1-(5-bromo-6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trichloroethan-1-one

[0342] To a stirred solution of 5-bromo-6-chloro-2-methyl-1H-indole (0.5 g, 2.04 mmol) in THF (10 mL) was added DMAP (25 mg, 0.20 mmol) and pyridine (0.6 mL, 7.16 mmol) at room temperature under nitrogen atmosphere and stirred for 10 min. Trichloroacetyl chloride (1.2 mL, 10.22 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 1-(5-bromo-6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trichloroethan-1-one as a pale red solid (0.55 g; 69%).

[0343] Step 2: 5-Bromo-6-chloro-N-methoxy-2-methyl-1H-indole-3-carboxamide

[0344] To a stirred solution of the product of step 1 (0.55 g, 1.41 mmol) in ACN (10 mL) was added O-methylhydroxylamine hydrochloride (0.59 g, 7.05 mmol) and TEA under nitrogen atmosphere and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 5-bromo-6-chloro-N-methoxy-2-methyl-1H-indole-3-carboxamide as a brown solid (0.15 g; 33%).

[0345] Step 3: 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-2-methyl-1H-indole-3-carboxamide

[0346] 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 K2CO3 (131 mg, 0.96 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was purged with N2 for 10 min. PdCl2(dppf).DCM (20 mg, 0.024 mmol) was added and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through a celite bed, washed with EtOAc, and the combined organics were concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (10 mg, 5%).

[0347] LCMS: 99.06% ([M+H] = 389.36)

[0348] 1 H NMR (400 MHz, DMSO): δ 11.63 (s, 1H), 10.70 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.32 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.06 (s, 6H), 2.57 (s, 3H).

[0349] S. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide (1021) [ka] [ka]

[0350] Compound 1021 was prepared according to general synthetic route R-3.

[0351] Step 1: 5-Bromo-N,N-dimethyl-6-(trifluoromethyl)pyridin-2-amine

[0352] To a stirred solution of N,N-dimethyl-6-(trifluoromethyl)pyridin-2-amine (1.9 g, 10.0 mmol) in ACN (20 mL) was added NBS (1.7 g, 10.0 mmol) under nitrogen atmosphere at 0° C. and stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography using neutral alumina to give 5-bromo-N,N-dimethyl-6-(trifluoromethyl)pyridin-2-amine as a yellowish oil (2.3 g, 83%).

[0353] Step 2: N,N-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine

[0354] 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) and PCy3 (13 mg, 0.0466 mmol) were added and the reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was diluted with EtOAc, filtered through Celite and the filtrate was concentrated under reduced pressure to give crude N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine as a pale yellow gum (470 mg). This material was used in the next step without purification.

[0355] Step 3: 6-chloro-5-(6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide

[0356] 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 K2CO3 (0.275 g, 1.98 mmol) in dioxane (10 mL) and water (2 mL) was purged with nitrogen for 10 min. PdCl2(dppf).DCM (0.40 g, 0.05 mmol) was added and the reaction mixture was stirred at 90 °C for 5 h, then diluted with EtOAc, filtered through Celite and concentrated under reduced pressure to give the crude product. Purification by preparative HPLC afforded 6-chloro-5-(6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-yl)-N-methoxy-1H-indole-3-carboxamide as a white solid (11 mg, 12%).

[0357] LCMS: 98.09% (413.34 [M+H]+)

[0358] 1 H NMR 400 MHz, DMSO-d6: δ 11.74 (br s, 1H), 11.18 (br s, 1H), 7.96 (m, 2H), 7.61 (s, 1H), 7.48 (d, J = 8.80 Hz, 1H), 6.97 (d, J = 8.80 Hz, 1H), 3.69 (s, 3H), 3.12 (s, 6H).

[0359] T. Synthesis of 4,6-difluoro-N-methoxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1007) [ka] [ka]

[0360] Compound 1007 was prepared according to general synthetic route R-3.

[0361] Step 1: 5-Bromo-4,6-difluoro-N-methoxy-1H-indole-3-carboxamide

[0362] To a solution of 5-bromo-4,6-difluoro-1H-indole-3-carboxylic acid (100 mg, 0.36 mmol) in DMF (5 mL) was added HATU (207 mg, 0.54 mmol) and DIPEA (0.2 ml, 1.1 mmol). After stirring at room temperature for 5 min, NHOMe.HCl (45 mg, 0.55 mmol) was added and the whole was stirred at room temperature for 16 h. The reaction was diluted with water and the product was extracted into EtOAc. After drying, the organic layer was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 5-bromo-4,6-difluoro-N-methoxy-1H-indole-3-carboxamide as a white solid (70 mg).

[0363] Step 2: 4,6-Difluoro-N-methoxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide

[0364] 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 K2CO3 (80 mg, 0.5765 mmol) in dioxane (5 mL) and water (1 mL) was purged with nitrogen for 10 min. PdCl2(dppf).DCM (9.4 mg, 0.012 mmol) was added and stirred at 90 °C for 4 h. The reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 4,6-difluoro-N-methoxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide as a white solid (8 mg).

[0365] LCMS: 97.78% (MH = 385.44)

[0366] 1 H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 7.85 (s, 1H), 7.44-7.26 (m, 5H), 4.38 (d, J = 10.40 Hz, 1H), 4.05 (d, J = 10.40 Hz, 1H), 3.66.3.56 (m, 4H), 1.88-1.86 (m, 2H), 1.65-1.47 (m, 4H).

[0367] U. Synthesis of 5-([1,1'-biphenyl]-4-yl)-6-chloro-N-methoxy-1H-indole-3-carboxamide (1008) [ka] [ka]

[0368] Compound 1008 was prepared according to general synthetic route R-3.

[0369] To a stirred solution of 5-bromo-6-chloro-N-methoxy-1H-indole-3-carboxamide (200 mg, 0.65 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added [1,1'-biphenyl]-4-ylboronic acid (0.16 g, 0.79 mmol) and K2CO3 (0.27 g, 1.98 mmol). The reaction mixture was purged with N2, 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 give the 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 (15 mg, 6.1%).

[0370] LCMS: 97.20% (377.14, M+H);

[0371] 1 H NMR 400 MHz, DMSO-d6: δ 11.48 (br s, 2H), 8.10 (s, 1H), 7.99 (s, 1H), 7.78-7.74 (m, 4H), 7.66 (s, 1H), 7.55-7.48 (m, 4H), 7.42-7.37 (m, 1H), 3.71 (s, 3H).

[0372] V. Synthesis of 4,6-difluoro-N-hydroxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1078) [ka] [ka]

[0373] Compound 1078 was prepared according to general synthetic route R-3.

[0374] To a solution of 4,6-difluoro-N-((tetrahydro-2H-pyran-2-yl)oxy)-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (see Example J) (70 mg, 0.15 mmol) in MeOH (5 mL), pTSA (5.2 mg, 0.03 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 4,6-difluoro-N-hydroxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide as a white solid (8 mg, 13% yield).

[0375] LCMS: 98.53% (M+H = 373.31)

[0376] 1H NMR (400 MHz, DMSO-d6): δ 11.12 (br, 1H), 8.85 (br s, 1H), 7.76 (s, 1H), 7.44-7.38 (m, 4H), 7.23 (d, J = 10.00 Hz, 1H), 4.39 (d, J = 1.60 Hz, 1H), 4.05 (d, J = 10.80 Hz, 1H), 3.59-3.54 (m, 1H), 1.87-1.84 (m, 2H), 1.59-1.53 ​​(m, 4H).

[0377] W. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-hydroxy-1H-indole-3-carboxamide (1001) [ka]

[0378] Compound 1001 was prepared following general synthetic route R-3 using experimental procedures similar to those used for the preparation of 4,6-difluoro-N-hydroxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1078).

[0379] LCMS: 95.20% (361.22 [M+H]+)

[0380] 1 H NMR;400 MHz, DMSO-d6: δ 11.55-10.71 (br, 2H), 8.75 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.21 (d, J =8.00 Hz, 1H), 3.76 (s, 3H), 3.07 (s, 6H).

[0381] X. Synthesis of 5-([1,1'-biphenyl]-4-yl)-6-chloro-N-hydroxy-1H-indole-3-carboxamide (1006) [ka]

[0382] Compound 1006 was prepared following general synthetic route R-3 using experimental procedures similar to those used for the preparation of 4,6-difluoro-N-hydroxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1078).

[0383] LCMS: 99.04% (361.10 [MH]-)

[0384] 1 H NMR 400 MHz, DMSO-d6: δ 11.69 (br s, 1H), 10.69 (br s, 1H), 8.79 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.77-7.73 (m, 4H), 7.65 (s, 1H), 7.55-7.48 (m, 4H), 7.39 (t, J = 7.2 Hz, 1H).

[0385] Building Blocks

[0386] Example A1. Synthesis of 3-bromo-6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridine (for 1058) [ka] [ka]

[0387] A mixture of 2,6-difluoropyridine (1.0 g, 0.87 mmol), K2CO3 (3.59 g, 0.0260 mol) and 4,4-difluoropiperidine hydrochloride in acetonitrile (25 mL) was heated to 80° C. for 3 h. The reaction was cooled to room temperature, the solid material was filtered off and the filtrate was concentrated under reduced pressure to give 3 as a pale yellow thick gum (1 g, 53%). This material was dissolved in DMF (2.5 mL) and reacted with NaOMe (25% in MeOH) (10 mL) at 100° C. for 3 h. The product was isolated by a water / diethyl ether extraction procedure to give 4 as a pale yellow liquid (1 g). This material was dissolved in acetonitrile (50 mL) and reacted with NBS (313 mg, 0.0018 mol) at −10° C. for 30 min under nitrogen atmosphere. The reaction mixture was then concentrated under reduced pressure and the product was isolated by a water / diethyl ether extraction procedure followed by column chromatography to give 3-bromo-6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridine (5) as a pale yellow liquid (0.5 g). LCMS (M+H=307.18).

[0388] The following intermediates were prepared in a similar manner:

[0389] 5-Bromo-N-(cyclobutylmethyl)-6-methoxy-N-methylpyridin-2-amine for 1054 [ka]

[0390] 1059 for 4-(5-bromo-6-methoxypyridin-2-yl)-1,4-oxazepane, LCMS: (M+H = 287.24) [ka]

[0391] N1-(5-bromo-6-methoxypyridin-2-yl)-N1,N2,N2-trimethylethane-1,2-diamine for 1063 [ka]

[0392] N1-(5-bromo-6-methoxypyridin-2-yl)-N1,N3,N3-trimethylpropane-1,3-diamine for 1064; LCMS: 302.27 (M+H) [ka]

[0393] 1095 for tert-butyl 4-(5-bromo-6-methoxypyridin-2-yl)piperazine-1-carboxylate; LCMS: 88% (M+H = 372.15) [ka]

[0394] 5-Bromo-4-methoxy-N,N-dimethylpyrimidin-2-amine for 1046; LCMS: ([M+H] = 232.01) [ka]

[0395] 5-Bromo-6-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine for 1057; LCMS: ([M+H] = 301.17) [ka]

[0396] Example A2. Synthesis of 4-(5-bromo-6-methoxypyridin-2-yl)morpholine (for synthesis of 1034) [ka] [ka]

[0397] To a solution of 4-(6-fluoropyridin-2-yl)morpholine (2.0 gm, 10.98 mmol) in ACN, prepared as in Example A1 above using morpholine, was added NBS (1.95 gm, 10.98 mmol) under nitrogen at 0° C. After 1 hour at room temperature, the product was isolated by aqueous organic workup and purified by flash column chromatography to give 4-(5-bromo-6-fluoropyridin-2-yl)morpholine (1.7 g, 83% yield) as a yellow liquid. LCMS: (269.40 (M+H)). This material in DMF (5 mL) was reacted with NaOMe at 90° C. for 3 hours to give 4-(5-bromo-6-methoxypyridin-2-yl)morpholine (0.8 g) as a pale yellow gum. LCMS: (316.28) (M+H).

[0398] The following intermediates were prepared in a similar manner:

[0399] 1-(5-bromo-6-methoxypyridin-2-yl)-4-methylpiperazine for 1048; LCMS: (286.05 (M+H)) [ka]

[0400] 3-Bromo-2-methoxy-6-(4-methylpiperidin-1-yl)pyridine for 1049; LCMS: (285.13 (M+H)) [ka]

[0401] 2-(5-bromo-6-methoxypyridin-2-yl)-2-azaspiro[3.3]heptane for 1050; LCMS: (285.13, M+H) [ka]

[0402] 5-Bromo-6-methoxy-N-(2-methoxyethyl)-N-methylpyridin-2-amine for 1051; LCMS: (275.13 [M+H] +) [ka]

[0403] 5-Bromo-N-(2-isopropoxyethyl)-6-methoxy-N-methylpyridin-2-amine for 1052; LCMS: (301.13, M+H) [ka]

[0404] 5-Bromo-N-butyl-N-ethyl-6-methoxypyridin-2-amine for 1056 [ka]

[0405] 3-Bromo-2-methoxy-6-(4-methoxypiperidin-1-yl)pyridine for 1055; LCMS: (301.13, M+H) [ka]

[0406] Example B.1-(5-bromopyridin-2-yl)cyclopropyl)methanol for the synthesis of 1101 [ka] [ka]

[0407] A mixture of 2-(5-bromopyridin-2-yl)acetonitrile (2 g, 10.2 mmol), 1,2-dibromoethane (1.74 g, 20.3 mmol), benzyltriethylammonium chloride (BTEAC, 254 mg, 1.116 mmol) in 50% aqueous NaOH (20 mL) was heated at 75° C. for 3 h. After aqueous organic workup, purification by flash chromatography afforded 1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile (1.8 g, 79.6% yield) as a light brown solid. LCMS: (M+2= 225.12). This product was treated with NaOH (1.93 g, 48.415 mmol) in MeOH:H2O (18 mL:18 mL) at 90° C. for 16 h to give 1-(5-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (1.6 g, 82.05%) as an off-white solid; LCMS: 95.93% (M+2= 244.06). This product was reduced with BH3 (23 mL, 23.54 mmol, 1 M in DMS) in THF (16 mL) at −78° C. and then at room temperature for 16 h to give (1-(5-bromopyridin-2-yl)cyclopropyl)methanol (0.9 g; 60% yield) as a white solid.

[0408] LCMS: 79.97% (M+H= 228.15)

[0409] 1 H NMR 400 MHz, DMSO-d6: δ 8.52 (s, 1H), 7.92 (dd, J = 2.40, 8.40 Hz, 1H), 7.49 (d, J = 8.80 Hz, 1H), 4.80 (t, J = 5.60 Hz, 1H), 3.72 (d, J = 5.20 Hz, 2H), 1.08 (d, J = 2.40 Hz, 2H), 0.92 (t, J = 2.40 Hz, 2H).

[0410] Example C. Synthesis of 1-(5-bromopyridin-2-yl)cyclobutan-1-ol (for synthesis of 1099) [ka] [ka]

[0411] n-BuLi (4 mL, 0.0247) was added slowly to a stirred solution of 5-bromo-2-iodopyridine (3.0 g, 0.026 mmol) in DCM (30 mL) at −78° C. After 45 min, cyclobutanone (2.99 g, 0.052 mmol) was added and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with NH4Cl solution (50 mL) to give, after aqueous-organic workup and purification by flash chromatography, 1-(5-bromopyridin-2-yl)cyclobutan-1-ol (0.9 g) as a brown gum.

[0412] LCMS: 83% (228, M+H)

[0413] 1 H NMR 400 MHz, CDCl3: δ 8.66 (d, J = 2.40 Hz, 1H), 7.99 (dd, J = 2.40, 8.40 Hz, 1H), 7.52 (d, J = 8.40 Hz, 1H), 5.82 (s, 1H), 2.50-0.00 (m, 2H), 2.18-2.25 (m, 2H), 1.82-1.87 (m, 1H), 1.89-1.92 (m, 1H).

[0414] Example D. Synthesis of 3-bromo-2-methoxy-6-((trimethylsilyl)ethynyl)pyridine (for synthesis of 1093) [ka] [ka]

[0415] NBS (14.27 g, 80.64 mmol) in DMF (20 mL) was added dropwise to a solution of 2-methoxypyridin-3-amine (10.0 g, 80.64 mmol) in DMF (60 mL) at 0° C., then stirred at room temperature for 16 h. After aqueous organic work-up and purification by flash column chromatography, 2-methoxypyridin-3-amine (8.5 g, 52% yield) was obtained as a brown solid (LCMS: ([M+H] = 205). A solution of this product (8 g, 39.40 mmol) and TMS acetylene (11.5 g, 118.2 mmol) in TEA (70 mL) was purged with nitrogen. CuI (748 mg, 0.003 mmol) and PdCl2(PPh3) (1.3 g, 1.97 mmol) were added and the reaction mixture was stirred at room temperature for 48 h. After aqueous organic work-up and purification by flash column chromatography, 2-methoxy-6-((trimethylsilyl)ethynyl)pyridin-3-amine (7.5 g, 86% yield) was obtained as a brown solid. LCMS: ([M+H] =221). A solution of this product (2 g, 43.10 mmol) in acetonitrile (20 mL) at 0° C. was treated dropwise with tert-butyl nitrite (4 g) followed by CuBr2 (4 g). The reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure and the crude product purified by flash column chromatography to give 3-bromo-2-methoxy-6-((trimethylsilyl)ethynyl)pyridine (1.8 g, 70% yield) as an orange liquid.

[0416] LCMS: (M+H]=284).

[0417] Example E. Synthesis of 4-(5-bromo-6-methoxypyridin-2-yl)-2-methylbut-3-yn-2-ol (for synthesis of 1093) [ka] [ka]

[0418] A solution of 6-bromo-2-methoxypyridin-3-amine (2.5 g, 12.31 mmol), 2-methylbut-3-yn-2-ol (2.07 g, 24.62 mmol) and piperidine (3.71 g, 43.7 mmol) in THF (10 mL) was purged with nitrogen for 5 min. Pd(PPh3)4 (32 mg, 0.027 mmol) and PPh3 (12 mg, 0.046 mmol) were added. Purging was continued, followed by addition of CuBr (12 mg, 0.086 mmol) and LiI (66 mg, 0.492 mmol). After 16 h at 90 °C, the reaction mixture was dried under reduced pressure and the crude product was purified by flash column to give 4-(5-amino-6-methoxypyridin-2-yl)-2-methylbut-3-yn-2-ol (1.8 g, 72% yield) as an orange solid. LCMS: ([M+H] = 207.32). As described in Example D, this product was reacted with tert-butyl nitrite (3.6 g) and CuBr2 (3.6 g) in acetonitrile (18 mL) at room temperature for 18 hours to give 4-(5-bromo-6-methoxypyridin-2-yl)-2-methylbut-3-yn-2-ol (0.8 g, 34% yield) as an off-white solid.

[0419] LCMS: ([M+H] = 270.09).

[0420] Synthesis of Compounds of the Disclosure

[0421] Example 1. Synthesis of 2-(4,6-difluoro-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indol-3-yl)-2-oxoacetic acid (1096) [ka] [ka]

[0422] A solution of 5-bromo-4,6-difluoro-1H-indole (100 mg, 0.43 mmol), 4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1,3,2-dioxaborolane (148 mg, 0.51 mmol) and K2CO3 (118 mg, 0.86 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was purged with nitrogen for 10 min. PdCl2(dppf).DCM (17.5 mg, 0.021 mmol) was added and the reaction mixture was stirred at 90 °C. After 16 hours, the reaction mixture was filtered through a celite bed, concentrated under reduced pressure and purified by flash column chromatography to give 4,6-difluoro-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole (60 mg. 44% yield) as an off-white solid; LCMS: 67.50% ([MH] =312.24). The product was dissolved in diethyl ether (10 mL) at 0° C., oxalyl chloride (0.2 mL, 0.9 mmol) was added and the mixture was stirred at room temperature for 5 hours. Evaporation to dryness gave 2-(4,6-difluoro-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indol-3-yl)-2-oxoacetic acid (50 mg) as a yellow solid.

[0423] LCMS: ([M+H] = 386.29).

[0424] Example 2. Synthesis of N-(butylsulfonyl)-6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (1108) [ka] [ka]

[0425] Potassium tert-butoxide (268 mg, 2.4 mmol) was added slowly to a stirred solution of 1-(5-bromo-6-chloro-1H-indol-3-yl)-2,2,2-trichloroethan-1-one (300 mg, 0.6 mmol) in DMF (5 mL) at 0° C. N-butylsulfonamide (219 mg, 1.6 mmol) was added and the reaction was heated in a microwave reactor at 120° C. for 3 h. The reaction mixture was cooled, filtered through Celite, evaporated to dryness and purified by reverse phase chromatography to give 5-bromo-N-(butylsulfonyl)-6-chloro-1H-indole-3-carboxamide (100 mg, 32% yield) as a pale yellow liquid (LCMS: (M+H = 393.26)). 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% purity) and K2CO3 (247 mg, 1.7895 mmol) in dioxane (10 mL) and water (1 mL) and purged with nitrogen for 10 min. PdCl2(dppf).DCM (28 mg, 0.03479 mmol) was added and the reaction mixture was heated to 90 °C for 5 h. The reaction mixture was cooled, filtered through Celite, evaporated to dryness and purified by reverse phase chromatography to give N-(butylsulfonyl)-6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxamide (5 mg; 4% yield) as a white solid.

[0426] LCMS: (M+H = 465.34)

[0427] 1H NMR 400 MHz, CDCl3: δ 11.19 (s, 1H), 8.12 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 8.00 Hz, 1H), 6.20 (d, J = 8.40 Hz, 1H), 3.76 (s, 3H), 3.06-3.01 (m, 8H), 1.57-1.53 ​​(m, 2H), 1.33-1.24 (m, 3H), 0.83 (t, J = 7.6 Hz, 3H).

[0428] Example 3. Synthesis of 4,6-difluoro-N-(2-methoxyethoxy)-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (1042) [ka] [ka]

[0429] To a solution of 5-bromo-4,6-difluoro-1H-indole-3-carboxylic acid (250 mg, 0.90 mmol) in DMF (5 mL), HATU (516 mg, 1.35 mmol), DIPEA (0.5 ml, 2.1 mmol) were added and stirred for 5 min, and O-(2-methoxyethyl)hydroxylamine (124 mg, 1.35 mmol) was added and stirred at room temperature for 2 h. The product was isolated by aqueous organic workup followed by flash column chromatography to give 5-bromo-4,6-difluoro-N-(2-methoxyethoxy)-1H-indole-3-carboxamide (80 mg, 25% yield) as a white solid. LCMS: (349.26 [M+H] +A solution of this product and (4-(tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (66.2 mg, 0.2298 mmol) and K2CO3 (80 mg, 0.57 mmol) in dioxane:water (4 mL:1 mL) was purged with nitrogen for 10 min, PdCl2(dppf).DCM (9.38 mg, 0.0114 mmol) was added and the reaction was heated at 90 °C for 4 h. Filtration through Celite, evaporation and purification by preparative HPLC gave 4,6-difluoro-N-(2-methoxyethoxy)-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-carboxamide (12 mg) as an off-white solid.

[0430] 1 H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1H), 11.01 (s, 1H), 7.84 (s, 1H), 7.44-7.38 (m, 4H), 7.24 (d, J = 10.00 Hz, 1H), 4.39 (d, J = 1.60 Hz, 1H), 4.05 (d, J = 11.60 Hz, 1H), 3.99 (t, J = 4.40 Hz, 2H), 3.59-3.53 (m, 3H), 3.28 (s, 3H), 1.88-1.85 (m, 2H), 1.70-1.49 (m, 4H).

[0431] LCMS: 99.66% (429.53 [MH] + ).

[0432] Example 4. Synthesis of 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-sulfonamide (1070) [ka] [ka]

[0433] Step 1: 5-Bromo-6-chloro-1H-indole-3-sulfonyl chloride

[0434] Chlorosulfonic acid (4 mL) was added dropwise to a solution of 5-bromo-6-chloro-1H-indole (2.0 g, 8.68 mmol) in acetonitrile at 0° C. After 2 h at room temperature, the reaction mixture was diluted with ice-cold water, (the precipitated solid was filtered, washed with water, and dried under vacuum to give 5-bromo-6-chloro-1H-indole-3-sulfonyl chloride as an off-white solid (1.7 g, 59% yield. LCMS: ([MH] = 325.91).

[0435] Step 2: 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-sulfonamide

[0436] A solution of the product of step 1 (1.5 g, 4.56 mmol) in DMF (15 mL) was cooled to 0° C. K2CO3 (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 room temperature. After 2 h, it was diluted with ice-cold water (200 mL) and the precipitated solid was filtered, washed with water and dried under vacuum to give 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-sulfonamide (0.5 g, 32% yield) as an off-white solid.

[0437] 1 H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 10.24 (s, 1H), 8.10 (d, J = 4.00 Hz, 2H), 7.80 (s, 1H), 3.66 (s, 3H). LCMS: ([MH] = 336.99).

[0438] Step 3: 6-Chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-sulfonamide

[0439] 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 K2CO3 (83 mg, 0.6 mmol) in 1,4-dioxane (1.8 mL) and water (0.2 mL) was purged with nitrogen for 10 min. PdCl2(dppf).DCM (13 mg, 0.015 mmol) was added and the reaction mixture was stirred at 100 °C. After 16 h, it was cooled, filtered through Celite, concentrated under reduced pressure and purified by flash column chromatography to give 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-N-methoxy-1H-indole-3-sulfonamide (25 mg, 20% yield).

[0440] 1 H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 10.14 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.32 (d, J = 8.00 Hz, 1H), 6.23 (d, J = 8.40 Hz, 1H), 3.77 (s, 3H), 3.63 (s, 3H), 3.07 (s, 6H); LCMS: ([M+H] = 411.25).

[0441] The following compounds were prepared in a similar manner:

[0442] 5-([1,1'-biphenyl]-4-yl)-6-chloro-N-methoxy-1H-indole-3-sulfonamide (1110) [ka]

[0443] 1H NMR (400 MHz, DMSO-d6):δ 12.32 (s, 1H), 10.20 (s, 1H), 8.10 (s, 1H), 7.73-7.82 (m, 6H), 7.49-7.57 (m, 4H), 7.38-7.42 (m, 1H), 3.65 (s, 3H);LCMS:([MH]=411.18).

[0444] 6-Chloro-N-methoxy-5-(4-(tetrahydro-2H-pyran-2-yl)phenyl)-1H-indole-3-sulfonamide (1109) [ka]

[0445] 1 H NMR (400 MHz, DMSO-d6): δ 12.32 (s, 1H), 10.20 (s, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.38-7.42 (m, 4H), 4.37 (dd, J = LCMS: ([MH] = 419.20).

[0446] Example 5. Synthesis of 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indol-3-yl)-2-oxoacetic acid (1113) [ka] [ka]

[0447] 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. After stirring at room temperature for 0.5 h, the reaction mixture was filtered, dried under vacuum and the crude product was purified by preparative HPLC to give 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indol-3-yl)-2-oxoacetic acid (15 mg, 6% yield) as a pale yellow solid.

[0448] LCMS: 97.23% (374.20 [M+H] - ).

[0449] 1 H NMR (400 MHz, DMSO-d6): δ 13.30 (br s, 1H), 11.78 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 7.30 (d, J = 8.00 Hz, 1H), 6.22 (d, J = 8.00 Hz, 1H), 3.76 (s, 3H), 3.07 (s, 6H).

[0450] Example 6. Synthesis of 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indol-3-yl)-N-methoxy-2-oxoacetamide (1083) [ka]

[0451] To a solution of 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indol-3-yl)-2-oxoacetic acid (400 mg, 1.0701 mmol)) in DMF (5 mL) at room temperature, HATU (610 mg, 1.6 mmol) and DIPEA (0.6 mL, 3.2 mmol) were added and the reaction was stirred for 15 min. HCl.NH2OMe (134 mg, 1.6 mmol) was then added and the reaction was stirred at room temperature for 16 h. After aqueous organic workup, the crude product was purified by preparative HPLC to give 2-(6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indol-3-yl)-N-methoxy-2-oxoacetamide (20 mg, 5% yield) as a yellow solid.

[0452] LCMS: 92.53% (403.32 [M+H] - ).

[0453] HPLC: 91.95%

[0454] 1 H NMR (400 MHz, DMSO-d6): δ 12.33 (s, 1H), 12.03 (s, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.33 (d, J = 8.40 Hz, 1H), 6.23 (d, J = 8.40 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.07 (s, 6H).

[0455] Example 2: EC 50 data

[0456] EC of the compounds of the present disclosure 50 The data was measured and the values ​​are shown in Table A below. [Table 1-1] [Table 1-2]

[0457] Example 3: Blood-Brain Barrier Data

[0458] Blood-brain barrier (BBB) ​​data for compounds of the present disclosure were evaluated and the values ​​are shown in Table B. Brain / plasma ratios were calculated at 3 hours. [Table 2]

[0459] Example 4: Spectral data for compounds of the present disclosure

[0460] NMR and LCMS data for compounds of the present disclosure are shown in Table C below: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14]

[0461] A number of patent and non-patent publications are cited herein to describe the state of the art to which this disclosure pertains. The disclosures of each of these publications are incorporated herein by reference in their entirety.

[0462] Although certain embodiments of the present disclosure have been described and / or illustrated above, various other embodiments will be apparent to those skilled in the art in light of the foregoing disclosure. Accordingly, the present disclosure is not limited to the specific embodiments described and / or illustrated, but rather is capable of numerous variations and modifications without departing from the scope and spirit of the appended claims.

Claims

[Claim 1] The invention described in the specification or drawings of this application.

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