TW202339735A - Deuterated rock inhibitors, pharmaceutical compositions, and therapeutic applications - Google Patents

Abstract

Provided herein are deuterated ROCK inhibitors, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a ROCK.

Description

Deuterated ROCK inhibitors, pharmaceutical compositions and therapeutic applications

Provided herein are deuterated ROCK inhibitors and pharmaceutical compositions thereof. Also provided herein are methods for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by ROCK.

Glaucoma, a neurodegenerative disease of the optic nerve, is the leading cause of irreversible blindness worldwide. Rahic et al., Pharmaceutics 2020 , 13 , 28; Stein et al., JAMA 2021 , 325 , 164-74. Glaucoma is known as the "silent thief of sight" because the disease is initially asymptomatic and its symptoms are usually only felt later in the disease, when visual field and vision are severely impaired. Rahic et al., Pharmaceutics 2020 , 13 , 28. The only known modifiable risk factor for glaucoma is increased intraocular pressure (IOP). Stein et al., JAMA 2021 , 325 , 164-74. When IOP is substantially reduced, disease progression can be halted. Am. J. Ophthalmol. 2000 , 130 , 429-40. A recent study showed that patients who never missed a dose of glaucoma medication (approximately 47% of the medical group) experienced no visual field progression over an 8-year span. Newman-Casey et al., Ophthalmol. 2020 , 127 , 477-83. The same study also showed that reduced compliance with medication resulted in a direct and significant increase in the rate of visual field deterioration. Same as above.

Rho kinase (ROCK) is a serine-threonine protein kinase that regulates actin cytoskeleton dynamics, actomyosin contraction, cell adhesion, cell rigidity, cell morphology, and extracellular matrix (ECM) reorganization. Rao et al., Exp. Eye Res. 2017 , 158 , 23-32. ROCK has two isoforms: ROCK1 and ROCK2, and both isoforms are widely expressed in eye tissue. Kaneko et al., Scientific Reports 2016 , 6 , 19640. ROCK is implicated in the pathogenesis of glaucoma, ocular hypertension, diabetic nephropathy, age-related muscle edema, cataracts, corneal dysfunction and retinal disorders. Same as above. ROCK inhibitors have been shown to reduce ECM synthesis and lower IOP. Honjo and Tanihara, Jpn. J. Ophthalmol. 2018 , 62 , 109-26. ROCK inhibitors have also been shown to provide neuroprotective effects by increasing blood flow to the optic nerve through vasodilation. Jayanetti et al., J. Exp. Pharmacol. 2020 , 12 , 539-48.

Nitric oxide is a cell signaling molecule that activates the second messenger cyclic guanidine monophosphate (cGMP), which is involved in several homeostatic processes of the eye. Jeong et al., Mol. Pharmaceutics 2020 , 17 , 656-65. Intravenous administration of nitroglycerin has been shown to reduce IOP in humans in a dose-dependent manner without altering systemic blood pressure. Wizemann and Wizemann, Am. J. Ophthalmol . 1980 , 90 , 106-9. Nipradilol (a beta blocker and NO donor) has been approved in Japan for glaucoma by lowering IOP. Inoue et al., Clin. Ophthalmol. 2011 , 5 , 1211-6.

Although blindness from glaucoma is preventable, a major barrier to managing glaucoma is patient compliance. Cvenkel and Kolko, J. Ophthalmol . 2020 , 6138132; Rahic et al., Pharmaceutics 2020 , 13 , 28. Poor compliance with treatment is often the reason behind treatment failure due to increased dosing frequency or number of drug treatments required. Same as above. Long-term compliance with glaucoma treatment is extremely low. Feehan et al., J. Clin. Med. 2016 , 5 , 79. One study demonstrated that compliance with glaucoma medication decreased dramatically over time, with only 50% of patients still taking their prescribed topical therapy 6 months into treatment. Nordstrom et al., Am. J. Ophthalmol. 2005 , 140 , 598-606. Even more alarming, only 37% persisted in taking therapy over the past three years. Same as above. Adding pharmacotherapy to existing glaucoma monotherapy further reduces compliance and compliance. Robin and Covert, Ophthalmol. 2005 , 112 , 863-8. Instilling eye drops multiple times a day can also introduce harmful eye symptoms such as tearing, burning, stinging, headache, fatigue, exercise intolerance, and photosensitivity. Inoue, Clin. Ophthalmol. 2014 , 8 , 903-13. Patients treated with multiple topical medications reported worsening ocular discomfort compared with patients treated with only a single topical medication. Fechtner et al., Cornea 2010 , 26 , 618-21. Ocular surface disease and discomfort worsen with increased frequency of glaucoma drop use throughout the day. Rossi et al., Eur. J. Ophthalmol. 2013 , 23 , 296-302. Therefore, there is a need for effective treatments for glaucoma that improve patient compliance and compliance.

Provided herein is a compound of formula (I): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: R ¹ , R ² and R ³ are each independently (i) hydrogen; (ii) C _{1 -6} alkyl, C _1-6 heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl _, Heteroaryl or heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , - S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁴ is C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; each R ⁵ is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl , C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or Heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , - OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S (O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁶ is (i) hydrogen or nitro; (ii) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; (iii) -C(O)R ^1a , -C (O)-A-ONO ₂ , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -S(O)R ^1a , -S(O ) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR 1b R ^1c ; each R ^1a , ^{R 1b ,} R ^1c and R ^1d are independently hydrogen, deuterium, C _1-6 alkane Base, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl Or heterocyclyl; A and L are each independently C _1-6 alkylene; and m is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl , alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q , where each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, nitrooxy and pendant oxy; (b) C _1-6 alkyl, C _1-6 Heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, which Each is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents ^Qa ; and (c) -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C (S)NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS(O) R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , - NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S )R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -P(O)R ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen or deuterium; (ii) C _1-6 alkyl, _{C 1-6} heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl , heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (iii) R ^b and ^Rc together with the N atom to which it is attached form a heterocyclyl group, which is optionally substituted by one or more, in one embodiment, one, two, three or four substituents ^Qa ; wherein each ^{Qa is} independently Ground is selected from: (a) deuterium, cyano, halo, nitro, nitrooxy and side oxy; (b) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkene base, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(O)SR ^e , -C(NR ^e )NR ^f R ^g , -C(S)R ^e , -C( S)OR ^e , -C(S)NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , -OC(O) SR ^e , -OC(NR ^e )NR ^f R ^g , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C (O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -P(O)R ^f R ^g , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g and -S(O) ₂ NR ^f R ^g ; where each R ^e , R ^f , R ^g and R ^h are independently (i) Hydrogen or deuterium; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl , heteroaryl or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are connected form a heterocyclyl.

Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or an enantiomer thereof, a mixture of enantiomers, a diastereomer, two or more diastereomers Mixtures, tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof; and pharmaceutically acceptable excipients agent.

Additionally, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a ROCK-mediated disorder, disease, or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more Mixtures of tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

In addition, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of an eye disease in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or an enantiomer thereof, or a mixture of enantiomers, diastereomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or Its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of neurodegenerative eye disease in an individual, which includes administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), or an enantiomer thereof, or an enantiomer thereof. A mixture of enantiomers, diastereomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a mixture thereof; Pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

Provided herein is a method of reducing intraocular pressure in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or an enantiomer thereof, a mixture of enantiomers, a diastereomer Isomers, mixtures of two or more diastereoisomers, tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts or solvates thereof , hydrates or prodrugs.

Provided herein is a method for inhibiting the activity of ROCK, which includes combining the ROCK with an effective amount of a compound of formula (I) or an enantiomer thereof, a mixture of enantiomers, two or more diastereomers Mixtures of isomers, tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

Cross-references to related applications

This application claims the priority rights of International Application No. PCT/CN2022/074170 filed on January 27, 2022 under 35 U.S.C. 119(a); the full text of its disclosure is incorporated herein by reference.

To facilitate understanding of the invention set forth herein, a number of terms are defined below.

In general, the nomenclature used herein and the experimental procedures described herein in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "individual" refers to an animal, including, but not limited to, primates (eg, humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. For example, when referring to a mammalian subject, such as a human subject, the terms "individual" and "patient" are used interchangeably herein. In one embodiment, the individual is a human.

The term "treat" is intended to include the alleviation or abolition of a condition, disease or condition, or one or more of the symptoms associated with the condition, disease or condition; or the alleviation or eradication of the condition, disease or condition, The cause(s) of the disease or condition itself.

The term "prevent/preventing/prevention" is intended to include delaying and/or preventing the onset of a disorder, disease or condition and/or its accompanying symptoms; preventing an individual from acquiring a disorder, disease or condition; or reducing an individual from acquiring a disorder, disease Or method of risk of disease.

The term alleviate/alleviating means alleviating or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also refer to reducing an adverse effect associated with the primary ingredient. Sometimes, The beneficial effects of an individual resulting from a prophylactic or therapeutic agent do not result in cure of the disorder, disease or condition.

The term "contacting/contact" is intended to mean bringing together a therapeutic agent and a biomolecule (eg, protein, enzyme, RNA or DNA), cell or tissue such that physiological and/or chemical effects occur as a result of this contact. Exposure can occur in vitro, ex vivo or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, the therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting a therapeutic agent with a biomolecule, cell, or tissue includes administering the therapeutic agent to an individual having the biomolecule, cell, or tissue to be contacted.

The terms "therapeutically effective amount" or "effective amount" are intended to include, when administered, sufficient to prevent the development of one or more of the symptoms of the disorder, disease, or condition being treated, or to alleviate to a certain extent the disorder, disease, or condition being treated. or the amount of a compound that is one or more of the symptoms of a condition. The term "therapeutically effective amount" or "effective amount" also refers to an amount sufficient to cause the reaction of a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human being as administered by a researcher, veterinarian, physician, or The amount of a compound that produces a biological or medical response that is sought by the clinician.

The term " _IC50 " or " _EC50 " refers to the amount, concentration or dose of a compound required to inhibit 50% of the maximum response in an assay measuring the response.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to pharmaceutically acceptable materials , compositions or vehicles such as liquid or solid fillers, diluents, solvents or encapsulating materials. In one embodiment, each component is compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with tissues or organs of an individual (e.g., a human) without excessive toxicity, irritation, allergic reactions, immunogenicity or other problems. or complications and is "medically acceptable" in the sense of being proportionate to a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy , 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients , 9th ed.; Sheskey et al., eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives , 3rd edition; edited by Ash and Ash; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation , 1st edition; edited by Gibson; CRC Press, 2015.

The term "about/approximately" means the acceptable error for a particular value as determined by one of ordinary skill, which depends in part on how the value is measured or determined. In certain embodiments, the term "about/approximately" means within 1, 2, or 3 standard deviations. In some embodiments, the term "about/approximately" means 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5% of a given value or range. %, 4%, 3%, 2%, 1%, 0.5% or 0.05%.

The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical, wherein the alkyl radical is optionally substituted with one or more substituents Q as described herein. For example, C _1-6 alkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkyl group has 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ), or 1 to 6 ( C _1-6 ) straight-chain saturated monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to A branched chain saturated monovalent hydrocarbon group of 6 (C _3-6 ) carbon atoms. As used herein, straight chain C _1-6 and branched chain C _3-6 alkyl groups are also referred to as "lower carbon number alkyl groups." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, such as n-propyl and isopropyl), butyl (including all isomeric forms, such as n-propyl) Butyl, isobutyl, second butyl and third butyl), pentyl (including all isomeric forms, such as n-pentyl, isopentyl, second pentyl, neopentyl and third pentyl) group) and hexyl (including all isomeric forms, such as n-hexyl, isohexyl and second hexyl).

The terms "alkylene" and "alkylenediyl" are used interchangeably herein when referring to a straight or branched chain saturated divalent hydrocarbon radical, wherein the alkylenediyl is optionally modified by one or more of the Substituent Q substitutes. For example, C _1-6 alkanediyl refers to a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl group has 1 to 30 (C _1-30 ), 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ) or a linear saturated divalent hydrocarbon group of 1 to 6 (C _1-6 ) carbon atoms, or 3 to 30 (C _3-30 ), 3 to 20 (C _3-20 ), A branched chain saturated divalent hydrocarbon group with 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ) or 3 to 6 (C _3-6 ) carbon atoms. As used herein, linear C _1-6 and branched chain C _3-6 alkanediyl groups are also referred to as "lower carbon alkanediyl groups." Examples of alkanediyl include, but are not limited to, methyldiyl, ethylenediyl (including all isomeric forms, such as ethyl-1,1-diyl and ethyl-1,2-diyl), propylenediyl (includes all isomeric forms, e.g., prop-1,1-diyl, prop-1,2-diyl and prop-1,3-diyl), butanediyl (includes all isomeric forms, e.g. , butyl-1,1-diyl, butyl-1,2-diyl, butyl-1,3-diyl and butyl-1,4-diyl), pentanediyl (including all isomeric forms, such as , pentyl-1,1-diyl, pentyl-1,2-diyl, pentyl-1,3-diyl and pentyl-1,5-diyl) and hexanediyl (including all isomeric forms, e.g. , hex-1,1-diyl, hex-1,2-diyl, hex-1,3-diyl and hex-1,6-diyl). Examples of substituted alkylenediyl include, but are not limited to, -C(O)CH ₂ -, -C(O)(CH ₂ ) ₂ -, -C(O)(CH ₂ ) ₃ -, -C( O)(CH ₂ ) ₄ -, -C(O)(CH ₂ ) ₅ -, -C(O)(CH ₂ ) ₆ -, -C(O)(CH ₂ ) ₇ -, -C(O) (CH ₂ ) ₈ -, -C(O)(CH ₂ ) ₉ -, -C(O)(CH ₂ ) ₁₀ -, -C(O)CH ₂ C(O)-, -C(O)( CH ₂ ) ₂ C(O)-, -C(O)(CH ₂ ) ₃ C(O)-, -C(O)(CH ₂ ) ₄ C(O)- or -C(O)(CH ₂ ) ₅ C(O)-.

The term "heteroalkyl" refers to a linear or branched chain saturated monovalent hydrocarbon radical containing one or more heteroatoms each independently selected from O, S and N in its main chain. The heteroalkyl group is optionally substituted with one or more substituents Q as described herein. For example, C _1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl group has 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ), or 1 to 6 (C _1-6 ) Straight-chain saturated monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ) or 3 A branched chain saturated monovalent hydrocarbon group with 6 (C _3-6 ) carbon atoms. As used herein, linear C _1-6 and branched chain C _3-6 heteroalkyl groups are also referred to as "lower carbon number heteroalkyl groups." Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ , -OCH ₂ CH ₃ , -CH ₂ OCH ₃ , -NHCH ₃ , -ONHCH ₃ , -NHOCH ₃ , -SCH ₃ , -CH ₂ NHCH ₂ CH ₃ and -NHCH ₂ CH ₂ CH ₃ . Examples of substituted heteroalkyl groups include, but are not limited to, _-CH2NHC (O) _CH3 and -NHC(O) _{CH2CH3 .}

The term "alkenyl" refers to a linear or branched chain monovalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3 or 4, in another embodiment, one carbon-carbon double bond. The alkenyl group is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" includes groups having the "cis" or "trans" configuration or mixtures thereof, or alternatively, the " Z " or " E " configuration or mixtures thereof, as understood by one of ordinary skill. For example, C _2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkenyl group is 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _2-6 ) Straight-chain monovalent hydrocarbon groups of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 6 (C _3-6 ) Branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl (including all isomeric forms, for example, propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms). isomeric forms, for example, buten-1-yl, buten-2-yl, buten-3-yl and 2-buten-1-yl).

The term "alkynyl" refers to a linear or branched chain monovalent hydrocarbon group containing one or more, in one embodiment, 1, 2, 3 or 4, in another embodiment, one carbon-carbon triple bond. Alkynyl groups do not contain carbon-carbon double bonds. The alkynyl group is optionally substituted with one or more substituents Q as described herein. For example, C _2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group of 4 to 6 carbon atoms. In certain embodiments, the alkynyl group is 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _2-6 ) Straight-chain monovalent hydrocarbon groups of carbon atoms, or 4 to 20 (C _4-20 ), 4 to 15 (C _4-15 ), 4 to 10 (C _4-10 ), or 4 to 6 (C _4-6 ) Branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, for example, 1-propynyl (-C≡CCH ₃ ) and propargyl (- CH ₂ C≡CH)), butynyl (including all isomeric forms, such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms , for example, 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl) and hexynyl (including all isomeric forms, for example, 1-hexyn-1-yl and 2-yl) -hexyn-1-yl).

The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl group is saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkyl group has 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 7 ( C _3-7 ) carbon atom. In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl , bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl and adamantyl.

The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and/or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbocyclic ring. In certain embodiments, the aryl group has 6 to 20 (C _6-20 ), 6 to 15 (C _6-15 ), or 6 to 10 (C _6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, benzyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. The aryl group also refers to a bicyclic or tricyclic carbocyclic ring, wherein one of the rings is aromatic and the other of the rings can be saturated, partially unsaturated or aromatic, for example, dihydronaphthyl, indene base, indenyl or tetrahydronaphthyl/tetralinyl. In one embodiment, the aryl group is monocyclic. In another embodiment, the aryl group is bicyclic. In yet another embodiment, the aryl group is tricyclic. In yet another embodiment, the aryl group is polycyclic. In certain embodiments, the aryl group is optionally substituted with one or more substituents Q as described herein.

The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C _7-30 ), 7 to 20 (C _7-20 ), or 7 to 16 (C _7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl (including all isomeric forms, such as 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms) , for example, 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl). In certain embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

The term "heteroaryl" refers to a monovalent monocyclic aryl group or a monovalent polycyclic aryl group containing at least one aromatic ring containing one or more heteroaryls each independently selected from O, S and N. atoms in the ring. For a heteroaryl group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of a heteroaryl group may contain one or two O atoms, one or two S atoms, and/or 1 to 4 N atoms; as long as the total number of heteroatoms in each ring is four or less and each ring Contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine base, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophene base, benzotriazolyl, benzoxazolyl, furopyridyl (including all isomeric forms, for example, furo[2,3- b ]pyridyl, furo[2,3- c ]pyridine base, furo[3,2- b ]pyridyl, furo[3,2- c ]pyridyl, furo[3,4- b ]pyridyl and furo[3,4- c ]pyridyl) , Imidazopyridyl (including all isomeric forms, such as imidazo[1,2- a ]pyridyl, imidazo[4,5- b ]pyridyl and imidazo[4,5- c ]pyridyl ), imidazolyl (including all isomeric forms, such as imidazo[2,1- b ]thiazolyl and imidazo[4,5- d ]thiazolyl), indazolyl, indolizinyl, indo Indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[ c ]thienyl), isoindolyl, isoquinolinyl, aridinyl (including all isomeric forms, e.g., 1 ,5-Didinyl, 1,6-Didinyl, 1,7-Didinyl and 1,8-Didinyl), oxazolopyridinyl (including all isomeric forms, such as oxazolo [4,5- b ]pyridyl, oxazolo[4,5- c ]pyridyl, oxazolo[5,4- b ]pyridyl and oxazolo[5,4- c ]pyridyl), Phthalazinyl, pteridyl, purinyl, pyrrolopyridyl (including all isomeric forms, for example, pyrro[2,3- b ]pyridyl, pyrro[2,3- c ]pyridyl, pyrrolo and [3,2- b ]pyridyl and pyrrolo[3,2-c]pyridyl), quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl (including all isomers forms, for example, [1,2,5]thiadiazolo[3,4- d ]pyrimidinyl and [1,2,3]thiadiazolo[4,5- d ]pyrimidinyl), and thieno Pyridyl (includes all isomeric forms, such as thieno[2,3- b ]pyridyl, thieno[2,3- c ]pyridyl, thieno[3,2- b ]pyridyl, and thieno [3,2- c ]pyridyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, phenanthridinyl, phenanthrolinyl, phenanthridinyl (including all isomers body forms, for example, 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl and 2,10-phenanthrolinyl) , Phenozolinyl, phenazinyl, phenothiazinyl, phenoxazinyl and 𠮿yl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

The term "heterocyclyl" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring in which one or more of the non-aromatic ring atoms are heteroatoms each independently selected from O, S and N; and the remaining ring atoms are carbon atoms. For a heterocyclic group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heterocyclic group is not bonded to the rest of the molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be fused or bridged, and the nitrogen or sulfur atom is optionally oxidized, and the nitrogen atom is optionally quaternary. ammonium, and some rings can be partially or fully saturated or aromatic. The heterocyclyl group can be attached to the main structure at any heteroatom or carbon atom, which results in the creation of stable compounds. Examples of heterocyclyl groups include, but are not limited to, azepanyl, benzodioxanyl, benzodioxolyl, phenofuranonyl, cycloalkyl, decahydroisoquinolinyl , dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, for example, 1,4-dihydrobenzo[ d ][1,3] oxazinyl, 3,4-diazinebenzo[ c ][1,2]-oxazinyl and 3,4-dihydrobenzo[ d ][1,2]oxazinyl), dihydrobenzo Thiophenyl, dihydroisobenzofuranyl, dihydrobenzo[ c ]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl , dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolane, 1,4-dithiopyranyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, iso-𠳭 Alkyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolidinyl, oxa Cyclopropyl, piperidinyl, piperidinyl, 4-piperidinonyl, pyrazolinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinoline base, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, thioalkyl, tetrahydroquinolinyl and 1,3,5-trithiylyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

The term "halogen", "halide" or "halogen" refers to fluorine, chlorine, bromine and/or iodine.

The term "optionally substituted" is intended to mean a group or substituent such as alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or hetero Cyclic group) may be substituted with one or more, in one embodiment, one, two, three or four substituents Q, each of which is independently selected from (for example) (a) deuterium (-D ), cyano group (-CN), halo group, imine group (=NH), nitro group (-NO ₂ ), nitrooxy group (-ONO ₂ ) and side oxy group (=O); (b) C _1-6 alkyl, C _1-6 heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-10} cycloalkyl, C _6-14 aryl, C _7-15 aralkyl , heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents ^Qa ; and (c) -C( O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C(S)NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC (O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , - NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S)R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S (O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -P(O)R ^b R ^c , -SR ^a , -S(O )R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , where each R ^a , R ^b , R ^c and R ^d are independently (i) Hydrogen or deuterium; (ii) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally modified by one or more, in one embodiment, one, two, three or four substituents Q ^a is substituted; or (iii) R ^b and R ^c together with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted by one or more, in one embodiment, one, two, three or four The base Qa ^is substituted. As used herein, all groups that may be substituted are "optionally substituted."

In one embodiment, each Q ^a is independently selected from: (a) deuterium, cyano, halo, nitro, nitrooxy and pendant oxy; (b) C _1-6 alkyl, C _{1- 6} heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(O)SR ^e , -C(NR ^e )NR ^f R ^g , - C(S)R ^e , -C(S)OR ^e , -C(S)NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O) NR ^f R ^g , -OC(O)SR ^e , -OC(NR ^e )NR ^f R ^g , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O) R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -P(O)R ^f R ^g , - SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g and -S(O) ₂ NR ^f R ^g ; where each of R ^e , R ^f , R ^g and R ^h are independently (i) hydrogen or deuterium; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 Aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are connected form a heterocyclyl group.

In certain embodiments, "optical activity" and "enantiomeric activity" refer to having no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93% %, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5% or no less than about 99.8% A collection of molecules in enantiomeric excess. In certain embodiments, optically active compounds comprise about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. conformation. In certain embodiments, optically active compounds comprise about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. conformation. In certain embodiments, optically active compounds comprise about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. conformation.

In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the compound about its chiral center. (+) and (-) are used to represent the optical rotation of the compound, ie, the direction in which the plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise direction. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise direction. However, the signs of optical rotation (+) and (-) are not related to the absolute configurations R and S of the compound.

The term "isotopic enrichment" refers to a compound that contains an unnatural ratio of isotopes at one or more of the atoms that make up the compound. In certain embodiments, the isotope-enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( ¹ H), deuterium ( ² H), tritium ( ³ H), carbon-11 ( ¹¹ C), Carbon-12 ( ¹² C), Carbon-13 ( ¹³ C), Carbon-14 ( ¹⁴ C), Nitrogen-13 ( ¹³ N), Nitrogen-14 ( ¹⁴ N), Nitrogen-15 ( ¹⁵ N) , Oxygen-14 ( ¹⁴ O), Oxygen-15 ( ¹⁵ O), Oxygen-16 ( ¹⁶ O), Oxygen-17 ( ¹⁷ O), Oxygen-18 ( ¹⁸ O), Fluorine-17 ( ¹⁷ F), Fluorine -18 ( ¹⁸ F), Phosphorus-31 ( ³¹ P), Phosphorus-32 ( ³² P), Phosphorus-33 ( ³³ P), Sulfur-32 ( ³² S), Sulfur-33 ( ³³ S), Sulfur-34 ( ³⁴ S), sulfur-35 ( ³⁵ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I) . In certain embodiments, the isotope enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, the isotope-enriched compound contains unnatural proportions of one or more isotopes, including but not limited to hydrogen ( ^1H ), deuterium ( ^2H ), carbon-12 ( ^12C ), carbon-13 ( ¹³ C), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-16 ( ¹⁶ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ¹⁷ F), phosphorus-31 ( ³¹ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), sulfur-34 ( ³⁴ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl) , chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br) and iodine-127 ( ¹²⁷ I). In certain embodiments, the isotope-enriched compound is in an unstable form, ie, radioactive. In certain embodiments, the isotope-enriched compound contains unnatural proportions of one or more isotopes, including but not limited to tritium ( ³ H), carbon-11 ( ¹¹ C), carbon-14 ( ¹⁴ C), nitrogen -13 ( ¹³ N), oxygen-14 ( ¹⁴ O), oxygen-15 ( ¹⁵ O), fluorine-18 ( ¹⁸ F), phosphorus-32 ( ³² P), phosphorus-33 ( ³³ P), sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I). It will be understood that in compounds as provided herein, where feasible according to the judgment of one of ordinary skill, as an example, any hydrogen can be ² H, or as an example, any carbon can be ¹³ C, or as an example, Any nitrogen can be ¹⁵ N, or as an example, any oxygen can be ¹⁸ O.

The term "isotopic enrichment" refers to the substitution of a less common isotope of an element (for example, for deuterium or hydrogen-2, D) at a given position in a molecule for a more common isotope of that element (for example, for protium or hydrogen-1 , ^1H ) incorporation percentage. As used herein, when an atom at a particular position of a molecule is designated as a particular less common isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

The term "isotope concentration factor" refers to the ratio between the isotope abundance of an isotope-concentrating compound and the natural abundance of a particular isotope.

The term "hydrogen" or the symbol "H" refers to a composition of naturally occurring hydrogen isotopes that includes protium ( ¹ H), deuterium ( ² H or D), and tritium ( ³ H) in their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance greater than 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

The term "deuterium enrichment" refers to the percentage incorporation of deuterium in place of hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given location means that 1% of the molecules in a given sample contain deuterium at the specified location. Because the naturally occurring deuterium distribution averages about 0.0156%, the deuterium concentration at any position in a compound synthesized using non-concentrated starting materials averages about 0.0156%. As used herein, when a specific position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes that includes carbon-12 ( ^12C ) and carbon-13 ( ^13C ) in their natural abundance. Carbon-12 is the most common carbon isotope, with a natural abundance greater than 98.89%. Carbon-13 is a less common carbon isotope, with a natural abundance of approximately 1.11%.

The term "carbon-13 enrichment" or " ^13C enrichment" refers to the percentage incorporation of carbon-13 in place of carbon at a given position in the molecule. For example, 10% carbon-13 enrichment at a given location means that 10% of the molecules in a given sample contain carbon-13 at the specified location. Because the distribution of naturally occurring carbon-13 averages about 1.11%, the concentration of carbon-13 at any position in a compound synthesized using non-concentrated starting materials averages about 1.11%. As used herein, when a specific position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%) .

When referring to a substance, the terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to appear to be free of readily detectable impurities, as determined by standard analytical methods used by one of ordinary skill in the art. Including (but not limited to) thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR) and mass spectrometry (MS); or sufficiently pure such that further purification will not detectably alter the physical, chemical, biological and/or pharmacological properties of the substance, such as enzymatic and biological activities. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99%, or at least about 99.5% by weight, of a molecule is a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a specific position of an isotope-enriched molecule is designated as a specific less common isotope, a molecule containing other than the specified isotope at the specified position is an impurity with respect to the isotope-enriched compound. Thus, for a deuterated compound having an atom designated deuterium at a specific position, a compound containing protium at the same position is an impurity.

The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute (e.g., a compound provided herein) and one or more molecules of a solvent, in a stoichiometric or non-chemical Measured quantities exist. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate system is in crystalline form. In another embodiment, the complex or aggregate system is in a non-crystalline form. In the case where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

For divalent groups described herein, direction is not implied by the direction in which the divalent group is presented. For example, unless a specific direction is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

The phrase "its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof" having the same enantiomers, enantiomers, or enantiomers of the compounds mentioned in the phrase "(i) A mixture of isomers, diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; (ii) Pharmaceutically acceptable salts, solvates, hydrates or prodrugs of the compounds mentioned therein; or (iii) enantiomers, mixtures of enantiomers, diastereomers of the compounds mentioned therein Isomers, mixtures of two or more diastereoisomers, tautomers, or pharmaceutically acceptable salts, solvates, hydrates of mixtures of two or more tautomers "drug or prodrug" has the same meaning. Deuterated compounds

In one embodiment, provided herein are compounds of formula (I): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: R ¹ , R ² and R ³ are each independently (i) hydrogen; (ii) C _{1 -6} alkyl, C _1-6 heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl _, Heteroaryl or heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , - S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁴ is C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; each R ⁵ is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl , C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or Heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , - OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S (O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁶ is (i) hydrogen or nitro; (ii) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; (iii) -C(O)R ^1a , -C (O)-A-ONO ₂ , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -S(O)R ^1a , -S(O ) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR 1b R ^1c ; each R ^1a , ^{R 1b ,} R ^1c and R ^1d are independently hydrogen, deuterium, C _1-6 alkane Base, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl Or heterocyclyl; A and L are each independently C _1-6 alkylene; and m is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl , alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q , where each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, nitrooxy and pendant oxy; (b) C _1-6 alkyl, C _1-6 Heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, which Each is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents ^Qa ; and (c) -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C (S)NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS(O) R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , - NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S )R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -P(O)R ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen or deuterium; (ii) C _1-6 alkyl, _{C 1-6} heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl , heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (iii) R ^b and ^Rc together with the N atom to which it is attached form a heterocyclyl group, which is optionally substituted by one or more, in one embodiment, one, two, three or four substituents ^Qa ; wherein each ^{Qa is} independently Ground is selected from: (a) deuterium, cyano, halo, nitro, nitrooxy and side oxy; (b) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkene base, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(O)SR ^e , -C(NR ^e )NR ^f R ^g , -C(S)R ^e , -C( S)OR ^e , -C(S)NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , -OC(O) SR ^e , -OC(NR ^e )NR ^f R ^g , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C (O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -P(O)R ^f R ^g , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g and -S(O) ₂ NR ^f R ^g ; where each R ^e , R ^f , R ^g and R ^h are independently (i) Hydrogen or deuterium; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl , heteroaryl or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are connected form a heterocyclyl.

In another embodiment, provided herein is a compound of formula (II): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L and m are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (III): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L and m are each as as defined herein.

In yet another embodiment, provided herein is a compound of formula (IV): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L and m are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (V): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, L and m are each as described herein defined in.

In yet another embodiment, provided herein is a compound of formula (VI): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, L and m are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (VII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, L and m are each as described herein defined in.

In yet another embodiment, provided herein is a compound of formula (VIII): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, L and m are each as defined herein.

In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, in any one of formulas (I) to (IV), R ⁶ is -C(O)R ^1a , wherein R ^1a is C _1-6 alkyl, C _6-14 aryl or heteroaryl, each optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R ^is -C(O)-C _1-6 alkyl, optionally substituted by one or more substituents Q replace. In certain embodiments, in any one of formulas (I) to (IV), R is ^5- (nitrooxy)pentyl, optionally substituted with one or more substituents Q . In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is 2,2-dimethyl-5-(nitrooxy)pentyl.

In certain embodiments, in any one of Formulas (I) to (IV), R ^is -C(O)-C _6-14 aryl, optionally substituted with one or more substituents Q replace. In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is benzyl, optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (IV), ^R6 is benzyl. In certain embodiments, in any one of Formulas (I) to (IV), R ⁶ is benzyl, which is substituted with one substituent Q. In certain embodiments, in any of formulas (I) to (IV), R ⁶ is benzyl, which is substituted with two substituents Q. In certain embodiments, in any of formulas (I) to (IV), R ⁶ is benzyl, which is substituted with three substituents Q. In certain embodiments, in any of formulas (I) to (IV), R ⁶ is benzyl, which is substituted with four substituents Q. In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is dimethylbenzoyl. In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is 2,4-dimethylbenzoyl. In certain embodiments, in any one of Formulas (I) to (IV), R ^is -C(O)-bicycloC _8-14 aryl, optionally substituted with one or more substituents Q replaced. In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is -C(O)-naphthyl, optionally substituted with one or more substituents Q.

In certain embodiments, in any of Formulas (I) to (IV), R ⁶ is -C(O)-heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (IV), R ^is -C(O)-monocyclic heteroaryl, optionally substituted with one or more substituents Q . In certain embodiments, in any of Formulas (I) to (IV), R is ^-C (O)-(5- or 6-membered heteroaryl), each of which is optionally Or multiple substituents Q substituted. In certain embodiments, in any one of Formulas (I) to (IV), R ^is -C(O)-thienyl or -C(O)-pyridyl, each optionally Or multiple substituents Q substituted. In certain embodiments, in any of Formulas (I) to (IV), R ^is -C(O)-(bicyclic heteroaryl), optionally substituted by one or more substituents Q replace. In certain embodiments, in any one of Formulas (I) to (IV), R ⁶ is -C(O)-(5,5-, 5,6- or 6,6-fused hetero aryl), each of which is optionally substituted by one or more substituents Q.

In yet another embodiment, provided herein is a compound of formula (IX): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: each R ^6a is independently (i) deuterium, cyano, halo, nitro or nitro Oxygen group; (ii) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, each optionally substituted by one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; n is 0, 1, 2, 3, 4 or an integer of 5; and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^1a , R ^1b , R ^1c , R ^1d , L and m are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (X): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , L, m and n are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XI): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , L, m and n Each is as defined herein.

In yet another embodiment, provided herein is a compound of formula (XII): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , L, m and n are each as defined herein.

In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is C _6-14 aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q . In certain embodiments, in any of formulas (I) to (XII), R ⁴ is C _6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is phenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is bicyclic C _8-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is naphthyl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is naphth-2-yl, which is optionally substituted with one or more substituents Q.

In certain embodiments, in any of Formulas (I) to (XII), R ⁴ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is monocyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is thienyl or pyridyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is bicyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is 5,5-, 5,6-, or 6,6-fused heteroaryl, each as appropriate. Substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is thieno[2,3- c ]pyridyl or thiazolo[5,4- c ]pyridyl, Each of them is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XII), R ⁴ is thieno[2,3- c ]pyridin-2-yl or thiazolo[5,4- c ] Pyridin-2-yl, each optionally substituted by one or more substituents Q. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is benzo[ d ]isothiazolyl or benzo[ d ][1,2,3]thiadiazole radicals, each of which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is benzo[ d ]isothiazol-6-yl or benzo[ d ][1,2,3] Thiadiazol-6-yl, each optionally substituted by one or more substituents Q. In certain embodiments, in any of formulas (I) to (XII), R ⁴ is 6,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is isoquinolinyl or 1,6-didinyl, each of which is optionally substituted by one or more substituents Q replaced. In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is isoquinolin-6-yl or 1,6-tridin-2-yl, each of which is optionally One or more substituents Q substitute.

In certain embodiments, in any one of formulas (I) to (XII), R ⁴ is thieno[2,3- c ]pyridin-2-yl, 4-fluorothio[2,3 - c ]pyridin-2-yl, 4-chlorothieno[2,3- c ]pyridin-2-yl, 4-methylthieno[2,3- c ]pyridin-2-yl, 4-chloro- 3-methylthieno[2,3- c ]pyridin-2 -yl, thiazolo[5,4-c]pyridin-2-yl, 4-fluorothiazolo[5,4-c ] pyridin-2-yl base, 4-chlorothiazolo[5,4- c ]pyridin-2-yl, 4-methylthiazolo[5,4- c ]pyridin-2-yl, benzo[ d ]isothiazol-6-yl , 3-cyanobenzo[ d ]isothiazol-6-yl, 3-methylbenzo[ d ]isothiazol-6-yl, 3-fluoromethylbenzo[ d ]isothiazol-6-yl, 3-Hydroxybenzo[ d ]isothiazol-6-yl, 3-methoxybenzo[ d ]isothiazol-6-yl, 3-ethoxybenzo[ d ]isothiazol-6-yl, benzene And [ d ][1,2,3]thiadiazol-6-yl, isoquinolin-6-yl, 1,6-tridin-2-yl, 8-fluoro-1,6-tridin-2 -yl, 8-chloro-1,6-tridin-2-yl, 8-methyl-1,6-tridin-2-yl, or 8-ethyl-1,6-tridin-2-yl .

In yet another embodiment, provided herein is a compound of formula (XIII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: X is a bond, CR ^4a or N; Y and Z are each independently CR ^4a , O, NR ^4c , N or S; each R ^4a is independently hydrogen or R ^4b ; each R ^4b is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl, C _{1- 6} heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, Each of them is optionally substituted with one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O )R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S( O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; each R ^4c is independently (i) hydrogen; (ii) C _1-6 alkyl, C _1-6 heteroalkyl base, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, each of which depends on substituted by one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; p is 0, 1, 2 or 3 integers; and R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ^1a , R ^1b , R ^1c , R ^1d , L and m are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XIV): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ^4b , L, X, Y, Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XV): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ^4b , L, X, Y , Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XVI): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ^4b , L, X, Y, Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XVII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , A, L, X, Y, Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XVIII): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , A, L, X, Y, Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XIX): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , A, L, X, Y, Z, m and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XX): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , A, L, X, Y, Z, m and p are each as defined herein.

In certain embodiments, in any of Formulas (XIII) to (XVI), R ⁶ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, in any one of formulas (XIII) to (XVI), R ⁶ is -C(O)R ^1a , wherein R ^1a is C _1-6 alkyl, C _6-14 aryl or heteroaryl, each optionally substituted by one or more substituents Q. In certain embodiments, in any one of formulas (XIII) to (XVI), R ^is -C(O)-C _1-6 alkyl, optionally substituted by one or more substituents Q replace. In certain embodiments, in any one of Formulas (XIII) to (XVI), R is ^5- (nitrooxy)pentyl, which is optionally substituted with one or more substituents Q. . In certain embodiments, in any one of Formulas (XIII) to (XVI), R ⁶ is 2,2-dimethyl-5-(nitrooxy)-pentylyl.

In certain embodiments, in any of formulas (XIII) to (XVI), R ^is -C(O)-C _6-14 aryl, optionally substituted by one or more substituents Q replace. In certain embodiments, in any of formulas (XIII) to (XVI), R ⁶ is benzyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (XIII) to (XVI), ^R6 is benzyl. In certain embodiments, in any one of formulas (XIII) to (XVI), R ⁶ is benzyl, which is substituted with one substituent Q. In certain embodiments, in any one of formulas (XIII) to (XVI), R ⁶ is benzyl, which is substituted with two substituents Q. In certain embodiments, in any of formulas (XIII) to (XVI), R ⁶ is benzyl, which is substituted with three substituents Q. In certain embodiments, in any of formulas (XIII) to (XVI), R ⁶ is benzyl, which is substituted with four substituents Q. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ⁶ is dimethylbenzoyl. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ⁶ is 2,4-dimethylbenzoyl. In certain embodiments, in any of Formulas (XIII) to (XVI), R ^is -C(O)-bicycloC _8-14 aryl, optionally substituted with one or more substituents Q replaced. In certain embodiments, in any of formulas (XIII) to (XVI), R ⁶ is -C(O)-naphthyl, optionally substituted with one or more substituents Q.

In certain embodiments, in any of Formulas (XIII) to (XVI), R ⁶ is -C(O)-heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ^is -C(O)-monocyclic heteroaryl, optionally substituted with one or more substituents Q . In certain embodiments, in any one of Formulas (XIII) to (XVI), R is ^-C (O)-(5- or 6-membered heteroaryl), each of which is optionally Or multiple substituents Q substituted. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ^is -C(O)-thienyl or -C(O)-pyridyl, each of which is optionally Or multiple substituents Q substituted. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ^is -C(O)-(bicyclic heteroaryl), optionally substituted by one or more substituents Q replace. In certain embodiments, in any one of Formulas (XIII) to (XVI), R ⁶ is -C(O)-(5,5-, 5,6- or 6,6-fused hetero aryl), each of which is optionally substituted by one or more substituents Q.

In yet another embodiment, provided herein is a compound of formula (XXI): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , R ^6a , L, X, Y , Z, m, n and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XXII): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , R ^6a , L, X, Y, Z, m, n and p are each as defined herein .

In yet another embodiment, provided herein is a compound of formula (XXIII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , R ^6a , L, X, Y , Z, m, n and p are each as defined herein.

In yet another embodiment, provided herein is a compound of formula (XXIV): Or its diastereomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable form A salt, solvate, hydrate or prodrug; wherein R ¹ , R ² , R ³ , R ⁵ , R ^4b , R ^6a , L, X, Y, Z, m, n and p are each as defined herein .

In certain embodiments, in any of formulas (XIII) to (XXIV), X is a bond. In certain embodiments, in any of Formulas (XIII) to (XXIV), X is C(R ^4a ), wherein R ^4a is as defined herein. In certain embodiments, in any of formulas (XIII) to (XXIV), X is C(H). In certain embodiments, in any of formulas (XIII) to (XXIV), X is N.

In certain embodiments, in any of formulas (XIII) to (XXIV), Y is CR ^4a , N, or S, wherein R ^4a is as defined herein. In certain embodiments, in any of Formulas (XIII) to (XXIV), Y is CR ^4a or S, wherein R ^4a is as defined herein. In certain embodiments, in any of Formulas (XIII) to (XXIV), Y is C(R ^4a ), wherein R ^4a is as defined herein. In certain embodiments, in any of formulas (XIII) to (XXIV), Y is C(H). In certain embodiments, in any of Formulas (XIII) to (XXIV), Y is C(CH ₃ ). In certain embodiments, in any of formulas (XIII) to (XXIV), Y is S.

In certain embodiments, in any of formulas (XIII) to (XXIV), Z is CR ^4a , N, or S, wherein R ^4a is as defined herein. In certain embodiments, in any of formulas (XIII) to (XXIV), Z is CR ^4a or N, wherein R ^4a is as defined herein. In certain embodiments, in any of Formulas (XIII) to (XXIV), Z is C(R ^4a ), wherein R ^4a is as defined herein. In certain embodiments, in any of formulas (XIII) to (XXIV), Z is C(H). In certain embodiments, in any of formulas (XIII) to (XXIV), Z is N.

In certain embodiments, in any one of formulas (XIII) to (XXIV), X is a bond, C(R ^4a ) or N; Y is C(R ^4a ) or S; and Z is C( R ^4a ) or N; wherein each R ^4a is as defined herein. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is C(R ^4a ) or N; wherein R ^4a is as described herein definition. In certain embodiments, in any of Formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is C(R ^4a ); wherein R ^4a is as defined herein. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is N. In certain embodiments, in any one of formulas (XIII) to (XXIV), X is C(R ^4a ); Y is C(R ^4a ); and Z is C(R ^4a ) or N; wherein each R ^4a is as defined herein. In certain embodiments, in any one of formulas (XIII) to (XXIV), X is C(R ^4a ); Y is C(R ^4a ); and Z is C(R ^4a ); wherein each R ^4a is as defined herein. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is C(R ^4a ); Y is C(R ^4a ); and Z is N; wherein each R ^4a is as as defined herein.

In certain embodiments, in any one of formulas (XIII) to (XXIV), X is a bond, C(H) or N; Y is C(H) or S; and Z is C(H) or N. In certain embodiments, in any one of formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is C(H) or N. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is C(H) or C(CH ₃ ). In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is a bond; Y is S; and Z is N. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is C(H); Y is C(H); and Z is C(H) or N. In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is C(H); Y is C(H); and Z is C(H). In certain embodiments, in any one of Formulas (XIII) to (XXIV), X is C(H); Y is C(H); and Z is N.

In certain embodiments, in any one of formulas (XIII) to (XXIV), p is an integer of 0. In certain embodiments, in any one of formulas (XIII) to (XXIV), p is an integer of 1; and R ^4b is halo or C _1-6 alkyl, optionally modified by one or more substituted by substituent Q. In certain embodiments, in any one of formulas (XIII) to (XXIV), p is an integer of 1; and R ^4b is fluorine, chlorine, methyl or ethyl.

In certain embodiments, in any of Formulas (I) to (XXIV), ^R1 is hydrogen.

In certain embodiments, in any of Formulas (I) to (XXIV), ^R2 is hydrogen.

In certain embodiments, in any of Formulas (I) to (XXIV), ^R3 is hydrogen.

In certain embodiments, in any one of Formulas (I) to (XXIV), L is C _1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XXIV), L is methylene.

In certain embodiments, in any one of formulas (I) to (XXIV), m is an integer of 0.

In certain embodiments, in any of formulas (V) to (VIII) and (XVII) to (XX), A is C _1-6 alkylene, optionally substituted with one or more Base Q substitution. In certain embodiments, in any of formulas (V) to (VIII) and (XVII) to (XX), A is butanediyl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (V) to (VIII) and (XVII) to (XX), A is butan-1,4-diyl, which is optionally modified by one or more Substituent Q substitutes. In certain embodiments, in any of formulas (V) to (VIII) and (XVII) to (XX), A is pentadiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any of formulas (V) to (VIII) and (XVII) to (XX), A is pentyl-2,5-diyl, optionally modified by one or more Substituent Q substitutes. In certain embodiments, in any of Formulas (V) to (VIII) and (XVII) to (XX), A is 2-methylpentan-2,5-diyl.

In certain embodiments, in any of formulas (IX) to (XII) and (XXI) to (XXIV), n is an integer of 2. In certain embodiments, in any of formulas (IX) to (XII) and (XXI) to (XXIV), n is an integer of 2; and each R ^6a is independently a C _1-6 alkyl group , which is optionally substituted by one or more substituents Q. In certain embodiments, in any of formulas (IX) to (XII) and (XXI) to (XXIV), n is an integer of 2; and each R ^6a is methyl.

In certain embodiments, in any one of formulas (XIII) to (XXIV), p is an integer of 1; and R ^4b is halo or C _1-6 alkyl, optionally modified by one or more substituted by substituent Q. In certain embodiments, in any one of formulas (XIII) to (XXIV), p is an integer of 1; and R ^4b is fluorine, chlorine, methyl or ethyl.

The groups R ¹ , R ² , R ³ , R 4 , R ⁵ , R ⁶ , R ^4a , ^{R 4b ,} R ^4c , R in the formulas described herein (including formulas (I) to (XXIV)) ^6a , A, L, X, Y, Z, m, n and p are further defined in the examples described herein. All combinations of the examples provided herein for these groups are within the scope of this invention.

In certain embodiments, ^R1 is hydrogen. In certain embodiments, R ¹ is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R1 is methyl. In certain embodiments, R ¹ is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is trifluoromethyl. In certain embodiments, R ¹ is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is C _6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R ¹ is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ¹ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ¹ is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ¹ is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ¹ is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ¹ is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ¹ is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ¹ is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ¹ is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, ^R2 is hydrogen. In certain embodiments, R ² is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R2 is methyl. In certain embodiments, R ² is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R2 is trifluoromethyl. In certain embodiments, R ² is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ² is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ² is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ² is C _6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R ² is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R2 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, ^R2 is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ² is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ² is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ² is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ² is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ² is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ² is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ² is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ² is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, ^R3 is hydrogen. In certain embodiments, R ³ is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R3 is methyl. In certain embodiments, R ³ is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ³ is trifluoromethyl. In certain embodiments, R ³ is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ³ is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ³ is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ³ is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ³ is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R3 is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R3 is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ³ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ³ is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ³ is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ³ is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ³ is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ³ is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ³ is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ³ is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, R ⁴ is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is bicyclic C _8-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is naphthyl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is naphth-2-yl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ⁴ is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is monocyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is thienyl or pyridyl, each optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is bicyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is 5,5-, 5,6-, or 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is 5,5-fused heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is 5,6-fused heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is thieno[2,3- c ]pyridyl or thiazolo[5,4- c ]pyridyl, each optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is thieno[2,3- c ]pyridin-2-yl or thiazolo[5,4- c ]pyridin-2-yl, each optionally substituted with one or more Base Q substitution. In certain embodiments, R ⁴ is benzo[ d ]isothiazolyl or benzo[ d ][1,2,3]thiadiazolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is benzo[ d ]isothiazol-6-yl or benzo[ d ][1,2,3]thiadiazol-6-yl, each of which is optionally modified by one or more substituted by substituent Q. In certain embodiments, R ⁴ is 6,6-fused heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is isoquinolinyl or 1,6-didinyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁴ is isoquinolin-6-yl or 1,6-tridin-2-yl, each of which is optionally substituted with one or more substituents Q.

In certain embodiments, R ⁴ is thieno[2,3- c ]pyridin-2-yl, 4-fluorothieno[2,3- c ]pyridin-2-yl, 4-chlorothieno[2 ,3- c ]pyridin-2-yl, 4-methylthieno[2,3- c ]pyridin-2-yl, 4-chloro-3-methylthieno[2,3- c ]pyridine-2 -yl, thiazolo[5,4- c ]pyridin-2-yl, 4-fluorothiazolo[5,4- c ]pyridin-2-yl, 4-chlorothiazolo[5,4- c ]pyridin- 2-yl, 4-methylthiazolo[5,4- c ]pyridin-2-yl, benzo[ d ]isothiazol-6-yl, 3-cyanobenzo[ d ]isothiazol-6-yl , 3-methylbenzo[ d ]isothiazol-6-yl, 3-fluoromethylbenzo[ d ]isothiazol-6-yl, 3-hydroxybenzo[ d ]isothiazol-6-yl, 3 -Methoxybenzo[ d ]isothiazol-6-yl, 3-ethoxybenzo[ d ]isothiazol-6-yl, benzo[ d ][1,2,3]thiadiazole-6 -yl, isoquinolin-6-yl, 1,6-tridin-2-yl, 8-fluoro-1,6-tridin-2-yl, 8-chloro-1,6-tridin-2-yl base, 8-methyl-1,6-tridin-2-yl, or 8-ethyl-1,6-tridin-2-yl.

In certain embodiments, ^R5 is deuterium. In certain embodiments, ^R5 is cyano. In certain embodiments, ^R5 is halo. In certain embodiments, ^R5 is fluorine. In certain embodiments, ^R5 is chlorine. In certain embodiments, ^R5 is nitro. In certain embodiments, R ⁵ is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R5 is methyl. In certain embodiments, R ⁵ is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R5 is trifluoromethyl. In certain embodiments, R ⁵ is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁵ is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁵ is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁵ is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁵ is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, ^R5 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, ^R5 is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ⁵ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is methoxy. In certain embodiments, R ⁵ is -OC(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -OC(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -OC(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -OC(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -OS(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -OS(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -OS(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -OS(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a C(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a C(O)OR ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a C(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a C(NR ^1d )NR ^1b R ^1c , wherein R ^1a , R ^1b , R ^1c , and R ^1d are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a S(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a S(O) ₂ R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a S(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -NR ^1a S(O) ₂ NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -SR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁵ is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ⁵ is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is nitro. In certain embodiments, R ⁶ is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is methyl. In certain embodiments, R ⁶ is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is C _6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ⁶ is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ⁶ is -C(O)R ^1a , wherein R ^1a is C _1-6 alkyl, C _6-14 aryl or heteroaryl, each optionally substituted with one or more Base Q substitution. In certain embodiments, R ⁶ is -C(O)-C _1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is 5-(nitrooxy)pentyl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is 2,2-dimethyl-5-(nitrooxy)pentyl.

In certain embodiments, R ⁶ is -C(O)R ^1a , wherein R ^1a is C _6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-C _6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is benzyl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is benzyl. In certain embodiments, R ⁶ is benzyl, which is substituted with one substituent Q. In certain embodiments, R ⁶ is benzyl, which is substituted with two substituents Q. In certain embodiments, R ⁶ is dimethylbenzoyl. In certain embodiments, R ⁶ is 1,4-dimethylbenzoyl. In certain embodiments, R ⁶ is benzyl, which is substituted with three substituents Q. In certain embodiments, R ⁶ is benzyl, which is substituted with four substituents Q. In certain embodiments, R ⁶ is -C(O)-bicycloC _8-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-naphthyl, optionally substituted with one or more substituents Q.

In certain embodiments, R ⁶ is -C(O)-heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-monocyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-(5- or 6-membered heteroaryl), each of which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-thienyl or -C(O)-pyridyl, each optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-(bicyclic heteroaryl), which is optionally substituted with one or more substituents Q. In certain embodiments, R ⁶ is -C(O)-(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted by one or more substituents Q replace.

In certain embodiments, R ^4a is hydrogen. In certain embodiments, R ^4a is deuterium. In certain embodiments, R ^4a is cyano. In certain embodiments, R ^4a is halo. In certain embodiments, R ^4a is fluorine. In certain embodiments, R ^4a is chlorine. In certain embodiments, R ^4a is nitro. In certain embodiments, R ^4a is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is methyl. In certain embodiments, R ^4a is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is trifluoromethyl. In certain embodiments, R ^4a is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4a is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ^4a is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is methoxy. In certain embodiments, R ^4a is -OC(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -OC(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -OC(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -OC(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -OS(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -OS(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -OS(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -OS(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -NR ^1a C(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4a is -NR ^1a C(O)OR ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4a is -NR ^1a C(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -NR ^1a C(NR ^1d )NR ^1b R ^1c , wherein R ^1a , R ^1b , R ^1c and R ^1d are each as defined herein. In certain embodiments, R ^4a is -NR ^1a S(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4a is -NR ^1a S(O) ₂ R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4a is -NR ^1a S(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -NR ^1a S(O) ₂ NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -SR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4a is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4a is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, R ^4b is deuterium. In certain embodiments, R ^4b is cyano. In certain embodiments, R ^4b is halo. In certain embodiments, R ^4b is fluorine. In certain embodiments, R ^4b is chlorine. In certain embodiments, R ^4b is nitro. In certain embodiments, R ^4b is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is methyl or ethyl. In certain embodiments, R ^4b is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is trifluoromethyl. In certain embodiments, R ^4b is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is heterocyclyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4b is fluorine, chlorine, methyl or ethyl.

In certain embodiments, R ^4b is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is methoxy. In certain embodiments, R ^4b is -OC(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -OC(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -OC(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -OC(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -OS(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -OS(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -OS(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -OS(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -NR ^1a C(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4b is -NR ^1a C(O)OR ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4b is -NR ^1a C(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -NR ^1a C(NR ^1d )NR ^1b R ^1c , wherein R ^1a , R ^1b , R ^1c and R ^1d are each as defined herein. In certain embodiments, R ^4b is -NR ^1a S(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4b is -NR ^1a S(O) ₂ R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^4b is -NR ^1a S(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -NR ^1a S(O) ₂ NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -SR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4b is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4b is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, R ^4c is hydrogen. In certain embodiments, R ^4c is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is methyl or ethyl. In certain embodiments, R ^4c is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is trifluoromethyl. In certain embodiments, R ^4c is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^4c is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ^4c is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4c is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4c is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4c is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4c is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4c is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^4c is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^4c is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, R ^6a is deuterium. In certain embodiments, R ^6a is cyano. In certain embodiments, R ^6a is halo. In certain embodiments, R ^6a is fluorine. In certain embodiments, R ^6a is chlorine. In certain embodiments, R ^6a is nitro. In certain embodiments, R ^6a is nitrooxy. In certain embodiments, R ^6a is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is methyl. In certain embodiments, R ^6a is C _1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is trifluoromethyl. In certain embodiments, R ^6a is C _2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is C _2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is C _3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is C _6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is C _7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R ^6a is heterocyclyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, R ^6a is -C(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -C(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -C(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -C(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is methoxy. In certain embodiments, R ^6a is -OC(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -OC(O)OR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -OC(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -OC(NR ^1a )NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -OS(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -OS(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -OS(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -OS(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -NR ^1a C(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^6a is -NR ^1a C(O)OR ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^6a is -NR ^1a C(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -NR ^1a C(NR ^1d )NR ^1b R ^1c , wherein R ^1a , R ^1b , R ^1c and R ^1d are each as defined herein. In certain embodiments, R ^6a is -NR ^1a S(O)R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^6a is -NR ^1a S(O) ₂ R ^1d , wherein R ^1a and R ^1d are each as defined herein. In certain embodiments, R ^6a is -NR ^1a S(O)NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -NR ^1a S(O) ₂ NR ^1b R ^1c , wherein R ^1a , R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -SR ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -S(O)R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -S(O) ₂ R ^1a , wherein R ^1a is as defined herein. In certain embodiments, R ^6a is -S(O)NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein. In certain embodiments, R ^6a is -S(O) ₂ NR ^1b R ^1c , wherein R ^1b and R ^1c are each as defined herein.

In certain embodiments, A is C _1-6 alkylene, which is optionally substituted with one or more substituents Q. In certain embodiments, A is methyldiyl, ethylenediyl, propylenediyl, butanediyl, pentyldiyl, or hexanediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, A is methyl-1,1-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, A is ethyl-1,2-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, A is prop-1,3-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, A is butyl-1,4-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, A is pentyl-1,5-diyl, optionally substituted with one or more substituents Q. In certain embodiments, A is pentyl-2,5-diyl, optionally substituted with one or more substituents Q. In certain embodiments, A is 2-methylpentan-2,5-diyl. In certain embodiments, A is hex-1,6-diyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, L is C _1-6 alkylene, which is optionally substituted with one or more substituents Q. In certain embodiments, L is methyldiyl, ethylenediyl, propylenediyl, butanediyl, pentyldiyl, or hexanediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, L is methyl-1,1-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, L is ethyl-1,2-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, L is prop-1,3-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, L is butan-1,4-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, L is pentyl-1,5-diyl, which is optionally substituted with one or more substituents Q. In certain embodiments, L is 1-methylpentan-1,5-diyl. In certain embodiments, L is hex-1,6-diyl, which is optionally substituted with one or more substituents Q.

In certain embodiments, X is a bond. In certain embodiments, X is CR ^4a , wherein R ^4a is as defined herein. In certain embodiments, X is CH. In certain embodiments, X is N.

In certain embodiments, Y is CR ^4a , wherein R ^4a is as defined herein. In certain embodiments, Y is CH. In certain embodiments, Y is O. In certain embodiments, Y is NR ^4c , wherein R ^4c is as defined herein. In certain embodiments, Y is NH. In certain embodiments, Y is N. In certain embodiments, Y is S.

In certain embodiments, Z is CR ^4a , wherein R ^4a is as defined herein. In certain embodiments, Z is CH. In certain embodiments, Z is C(CH ₃ ). In certain embodiments, Z is O. In certain embodiments, Z is NR ^4c , wherein R ^4c is as defined herein. In certain embodiments, Z is NH. In certain embodiments, Z is N. In certain embodiments, Z is S.

In some embodiments, m is an integer of 0. In some embodiments, m is an integer of 1. In some embodiments, m is an integer of 2. In some embodiments, m is an integer of 3. In some embodiments, m is an integer of 4.

In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4. In some embodiments, n is an integer of 5.

In some embodiments, p is an integer of 0. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. In some embodiments, p is an integer of 3.

In one embodiment, provided herein is a compound of formula (I), wherein: R ¹ , R ² and R ³ are each hydrogen; R ⁴ is thieno[2,3- c ]pyridin-2-yl, 4- Fluorothio[2,3- c ]pyridin-2-yl, 4-chlorothieno[2,3- c ]pyridin-2-yl, 4-methylthieno[2,3- c ]pyridin-2 -yl, 4-chloro-3-methylthieno[2,3- c ]pyridin-2-yl, thiazolo[5,4- c ]pyridin-2-yl, 4-fluorothiazolo[5,4 - c ]pyridin-2-yl, 4-chlorothiazolo[5,4- c ]pyridin-2-yl, 4-methylthiazolo[5,4- c ]pyridin-2-yl, benzo[ d ]isothiazol-6-yl, 3-cyanobenzo[ d ]isothiazol-6-yl, 3-methylbenzo[ d ]isothiazol-6-yl, 3-fluoromethylbenzo[ d ] Isothiazol-6-yl, 3-hydroxybenzo[ d ]isothiazol-6-yl, 3-methoxybenzo[d]isothiazol-6-yl, 3-ethoxybenzo[ d ]isothiazol- 6 -yl Thiazol-6-yl, benzo[ d ][1,2,3]thiadiazol-6-yl, isoquinolin-6-yl, 1,6-tridine-2-yl, 8-fluoro-1 ,6-㖠din-2-yl, 8-chloro-1,6-㖠din-2-yl, 8-methyl-1,6-㖠din-2-yl, or 8-ethyl-1,6 -Didin-2-yl; R ⁶ is 2,4-dimethylbenzoyl or 2,2-dimethyl-5-(nitrooxy)pentyl; L is methyldiyl; and m is an integer of 0.

In one embodiment, provided herein are the following compounds: ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (thieno[2,3- c ]pyridine- 2-yl)-propamide-2- d A1 ; ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (isoquinolin-6-yl)-propyl Amide-2- d A2 ; ( S )-2,4-dimethylbenzoic acid 4-(3-amino-1-side oxy-1-(thieno[2,3- c ]pyridine-2 -Amino)propan-2-yl-2- d ) benzyl ester A5 ; or ( S )-2,4-dimethylbenzoic acid 4-(3-amino-1-(isoquinoline-6- methylamino)-1-side oxyprop-2-yl-2- d ) benzyl ester A6 ; or its tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable Acceptable salts, solvates, hydrates or prodrugs.

In another embodiment, provided herein are the following compounds: ( S )-2,2-dimethyl-5-(nitrooxy)pentanoate 4-(3-amino-1-pendantoxy- 1-(thieno[2,3- c ]pyridin-2-ylamino)propan-2-yl-2- d )benzyl ester A3 ; or ( S )-2,2-dimethyl-5-( Nitrooxy)valerate 4-(3-amino-1-(isoquinolin-6-ylamine)-1-side oxypropan-2-yl-2- d ) benzyl ester A4 ; or its Tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

In certain embodiments, compounds provided herein have a ratio of no less than about 3,200 (about 50% deuterium enriched), no less than about 4,800 (about 75% deuterium enriched), no less than about 5,130 (about 80% deuterium enriched). ), not less than approximately 5,450 (approximately 85% deuterium enriched), not less than approximately 5,770 (approximately 90% deuterium enriched), not less than approximately 6,090 (approximately 95% deuterium enriched), not less than approximately 6,220 (approximately 97% deuterium enriched) deuterium enrichment), a deuterium enrichment factor of not less than about 6,280 (about 98% deuterium enrichment), not less than about 6,350 (about 99% deuterium enrichment), or not less than about 6,380 (about 99.5% deuterium enrichment). Deuterium concentration can be measured using conventional analytical methods known to those of ordinary skill (including mass spectrometry and nuclear magnetic resonance spectroscopy).

In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 3,200. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 4,800. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 5,130. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 5,450. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 5,770. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 6,090. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 6,220. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 6,280. In certain embodiments, compounds provided herein have a deuterium enrichment factor of no less than about 6,350. In certain embodiments, compounds provided herein have a deuterium concentration factor of no less than about 6,380.

In certain embodiments, compounds provided herein have no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98% deuterium at the specified atoms. Concentrate. In certain embodiments, compounds provided herein have no less than about 50% deuterium enrichment at a specified atom. In certain embodiments, compounds provided herein have deuterium enrichment at no less than about 70% of the specified atoms. In certain embodiments, compounds provided herein have no less than about 80% deuterium enrichment at a specified atom. In certain embodiments, compounds provided herein have deuterium enrichment at no less than about 90% of the specified atoms. In certain embodiments, compounds provided herein have no less than about 98% deuterium enrichment at a specified atom.

In certain embodiments, each position represented by D in the compounds provided herein has no less than about 3,200, no less than about 4,800, no less than about 5,130, no less than about 5,450, no less than about 5,770, no less than about 6,090, a deuterium enrichment factor of not less than about 6,220, not less than about 6,280, not less than about 6,350, or not less than about 6,380. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 3,200. In certain embodiments, each position represented by D in the compounds provided herein has a deuterium concentration factor of no less than about 4,800. In certain embodiments, each position represented as D in the compounds provided herein has a deuterium concentration factor of no less than about 5,130. In certain embodiments, each position represented as D in the compounds provided herein has a deuterium concentration factor of no less than about 5,450. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 5,770. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 6,090. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 6,220. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 6,280. In certain embodiments, each position designated D in the compounds provided herein has a deuterium concentration factor of no less than about 6,350. In certain embodiments, each position represented by D in the compounds provided herein has a deuterium concentration factor of no less than about 6,380.

In certain embodiments, each position represented by D in the compounds provided herein has no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98% deuterium enriched. In certain embodiments, each position designated D in the compounds provided herein has a deuterium enrichment of no less than about 50%. In certain embodiments, each position designated D in the compounds provided herein has a deuterium enrichment of no less than about 70%. In certain embodiments, each position designated D in the compounds provided herein has a deuterium enrichment of no less than about 80%. In certain embodiments, each position designated D in the compounds provided herein has a deuterium enrichment of no less than about 90%. In certain embodiments, each position designated D in the compounds provided herein has a deuterium enrichment of no less than about 98%.

In certain embodiments, compounds provided herein are isolated or purified. In certain embodiments, compounds provided herein have a purity of at least about 90% by weight, at least about 95% by weight, at least about 98% by weight, at least about 99% by weight, or at least about 99.5% by weight. In certain embodiments, compounds provided herein have a purity of at least about 90% by weight. In certain embodiments, compounds provided herein have a purity of at least about 95% by weight. In certain embodiments, compounds provided herein have a purity of at least about 98% by weight. In certain embodiments, compounds provided herein have a purity of at least about 99% by weight. In certain embodiments, compounds provided herein have a purity of at least about 99.5% by weight.

Unless a specific stereochemistry is specified, the compounds provided herein are intended to encompass all possible stereoisomers. Where a compound provided herein contains an alkenyl group, the compound may exist as one of or a mixture of geometric cis / trans (or Z / E ) isomers. In the case where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This may take the form of proton tautomerism in compounds containing, for example, imino, ketone or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. It follows that a single compound can exhibit more than one type of tautomerism.

The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be a mixture of stereoisomers, such as a mixture of enantiomers, e.g. , a racemic mixture of two enantiomers; or a mixture of two or more diastereoisomers. Thus, one of ordinary skill will be aware that, with respect to a compound that undergoes epimerization in vivo, administration of a compound in its ( R ) form is equivalent to administration of a compound in its ( S ) form. Conventional techniques for the preparation/separation of individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from non-chiral starting materials or the analysis of enantiomeric mixtures, e.g. Chromatography, recrystallization, resolution, diastereomeric salt formation or derivatization to diastereomeric adducts, followed by separation.

When the compounds provided herein contain acidic or basic moieties, they may also be provided as pharmaceutically acceptable salts. See, Berge et al., J. Pharm. Sci. 1977 , 66 , 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use , 2nd ed.; Stahl and Wermuth, eds.; John Wiley & Sons, 2011. In certain embodiments, pharmaceutically acceptable salts of the compounds provided herein are solvates. In certain embodiments, pharmaceutically acceptable salts of compounds provided herein are hydrates.

Suitable acids for preparing pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, chelated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S )-camphor-10-sulfonate Acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- Hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-side oxyglutaric acid, Glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydriodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactouronic acid, lauric acid, maleic acid, (-)-L-apple Acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid , oleic acid, orotic acid, oxalic acid, palmitic acid, parapic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, hard Fatty acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.

Suitable bases for preparing pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and Organic bases, such as primary amines, secondary amines, tertiary amines and quaternary ammoniums, aliphatic amines and aromatic amines, including (but not limited to) L-arginine, benzethamine, benzathine ), choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine Propylamine, N -methyl-glucosamine, hydrabamine, 1 H -imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine , piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N -methyl- D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol and tromethamine.

The compounds provided herein may also be provided as prodrugs, which are functional derivatives of the compounds and can be readily converted to the parent compound in vivo. Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent compound. It may be bioavailable, for example, by oral administration, whereas the parent compound is not bioavailable. Prodrugs may also have enhanced solubility in pharmaceutical compositions over the parent compound. Prodrugs can be converted to the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Pharmaceutical composition

In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of formula (I)) or an enantiomer thereof, a mixture of enantiomers, a diastereomer Isomers, mixtures of two or more diastereoisomers, tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts or solvates thereof , hydrates or prodrugs; and pharmaceutically acceptable excipients.

The pharmaceutical compositions provided herein may be formulated in a variety of dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. Pharmaceutical compositions can also be formulated in modified release dosage forms (including delayed release, sustained release, extended release, sustained release, pulse release, controlled release, accelerated release, rapid release, targeted release, programmed release and gastric retention dosage forms). These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy , supra; Modified-Release Drug Delivery Technology , 2nd ed.; Rathbone et al., eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

In one embodiment, the pharmaceutical compositions provided herein are formulated for oral administration. In another embodiment, the pharmaceutical compositions provided herein are formulated for parenteral administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for intravenous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for intramuscular administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for subcutaneous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for topical administration.

Pharmaceutical compositions provided herein may be provided in unit dosage form or in multiple dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for administration to individuals and individually packaged as is known in the art. Each unit dosage contains a predetermined amount of an active ingredient (eg, a compound provided herein) sufficient to produce the desired therapeutic effect in combination with the desired pharmaceutical excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may be administered in portions or multiples thereof. A multi-dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or pint or gallon bottles.

The pharmaceutical compositions provided herein can be administered once or multiple times at timed intervals. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the individual being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. . It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time based on the individual's needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A. Oral administration

For Oral Administration The pharmaceutical compositions provided herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include (but are not limited to) lozenges, fast-melt, chewable lozenges, capsules, pills, strips, throat lozenges, buccal lozenges, pills, cachets, medicinal chewing gum, bulk powders, bubbles Effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient(s), the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including (but not limited to) binders, fillers, diluents, disintegrants, and wetting agents. , lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

The binder or granulating agent imparts cohesion to the tablet and ensures that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starches (eg, STARCH 1500®); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose ; Natural and synthetic gums, such as gum arabic, algin, alginate, Irish moss extract, Panwar gum, Ghatti gum, lilac bark mucus, carboxymethylcellulose, methylcellulose, cellulose, polyvinylpyrrolidone (PVP), VEEGUM®, pine arabinogalactan, powdered tragacanth and guar gum; cellulose such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose Vegetarian calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and microcrystalline cellulose, Such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105 and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies with the type of formulation and is readily identifiable to one of ordinary skill. Binders or fillers may be present in the pharmaceutical compositions provided herein from about 50 to about 99% by weight.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and myo-inositol, can impart properties to some compressed tablets which, when present in sufficient amounts, permit disintegration in the mouth by chewing. These compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies with the type of formulation, and is readily recognized by one of ordinary skill.

Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; algae; gums, such as guar gum and VEEGUM ® HV; citrus pomace; cross-linked cellulose, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; Polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starches; clays; and algins. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily recognized by one of ordinary skill. Pharmaceutical compositions provided herein may contain from about 0.5 to about 15% by weight or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol ( PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut, cottonseed, sunflower, sesame, olive, corn and soybean oil; zinc stearate; ethyl oleate; ethyl laurate ester; agar; starch; lycopodium; and silica or silica gel, such as AEROSIL ^® 200 and CAB-O-SIL ^® . The amount of lubricant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily recognized by one of ordinary skill. Pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of lubricant.

Suitable glidants include, but are not limited to, colloidal silica, CAB-O- ^SIL® , and asbestos-free talc. Suitable colorants include, but are not limited to, any of approved water-soluble FD&C dyes and water-insoluble FD&C dyes and lakes suspended on alumina hydrate. Lakes are a combination of water-soluble dyes adsorbed to hydrated oxides of heavy metals, which results in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce pleasant taste sensations, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate ( ^TWEEN® 20), polyoxyethylene sorbitan monooleate Oleate 80 (TWEEN ^® 80) and triethanolamine oleate. Suitable suspending and dispersing agents include (but are not limited to) sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidine ketone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid and sodium benzoate, and alcohols. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethylene glycol, and syrups. Suitable non-aqueous liquids for use in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.

It will be appreciated that many carriers and excipients can serve several functions, even within the same formulation.

For oral administration, the pharmaceutical compositions provided herein may be in the form of compressed tablets, ground tablets, chewable buccal tablets, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated or Supplied as film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient(s) from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, aminated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multi-compressed tablets are compressed tablets prepared by more than one compression cycle, including layered tablets and compression-coated tablets or dry-coated tablets.

Tablet dosage forms may consist of the active ingredient in powder, crystalline or granular form, alone or with one or more carriers or excipients described herein (including binders, disintegrants, controlled release polymers, lubricants, diluent and/or colorant). Flavoring and sweetening agents are particularly useful in formulating chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administration may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) consist of two parts, one sliding over the other, thus completely enclosing the active ingredient(s). Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propylparabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be enclosed in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. In order to modify or sustain the dissolution of the active ingredient(s), the capsules may also be coated as is known to those skilled in the art.

Pharmaceutical compositions provided herein for oral administration may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of small beads in another liquid, which can be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. The suspension may contain pharmaceutically acceptable suspending agents and preservatives. The aqueous alcoholic solution may include pharmaceutically acceptable acetals, such as bis(lower alkyl)acetals of lower alkyl aldehydes, for example, acetaldehyde diethyl acetal; and water having one or more hydroxyl groups Miscible solvents such as propylene glycol and ethanol. The elixir is a clear, sweet-tasting, hydroalcoholic solution. Syrups are concentrated aqueous solutions of sugar (eg, sucrose) and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (eg, water) to facilitate convenient measurement for administration.

Other available liquid and semi-solid dosage forms include (but are not limited to) formulations containing the active ingredient and dialkylated mono- or polyalkylene glycols (including 1,2-dimethoxymethane, diglyme, triglyme, Glyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether), etc., Among them, 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. Such dosage forms may further include one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin , ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

Pharmaceutical compositions provided herein for oral administration may be provided as non-effervescent or effervescent granules and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents may be used in all dosage forms described herein.

Pharmaceutical compositions provided herein for oral administration may be formulated in immediate or modified release dosage forms (including delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release forms). B. Parenteral administration

For local or systemic administration, the pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

For parenteral administration, the pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including (but not limited to) solutions, suspensions, emulsions, micelles, liposomes, micron Spheres, nanosystems and solid forms suitable for solution or suspension in liquid prior to injection. These dosage forms can be prepared according to conventional methods known to those skilled in medical science and technology. See, for example, Remington: The Science and Practice of Pharmacy , supra.

Pharmaceutical compositions provided herein for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non- Aqueous vehicles, antibacterial agents or preservatives for the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, isolating agents Or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters and inert gases.

Suitable aqueous vehicles include (but are not limited to) water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, non-volatile oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil medium chain triglycerides and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N -methyl base-2-pyrrolidone, N,N- dimethylacetamide and dimethylsulfoxide.

Suitable antibacterial agents or preservatives include (but are not limited to) phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride benzalkonium (eg, benzethonium chloride), methyl-paraben and propyl-paraben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable clamping or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin. Butyl ether 7-β-cyclodextrin (CAPTISOL ^® ).

When the pharmaceutical compositions provided herein are formulated for multi-dose administration, the multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antibacterial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product (including lyophilized powder and subcutaneous injection tablets) to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

Pharmaceutical compositions provided herein for parenteral administration may be formulated in immediate or modified release dosage forms (including delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release forms).

For administration as an implanted depot, the pharmaceutical compositions provided herein for parenteral administration may be formulated as suspensions, solids, semi-solids, or thixotropic liquids. In one embodiment, a pharmaceutical composition provided herein is dispersed in a solid internal matrix via an outer polymeric film that is insoluble in body fluids but allows diffusion of the active ingredient(s) in the pharmaceutical composition. surrounded.

Suitable internal matrices include (but are not limited to) polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyterephthalate Ethylene glycol formate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, polysilicone rubber, polydimethylsiloxane, polysiloxane Carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic acid and methacrylic acid), collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric films include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, polysilicone rubber, polydimethylsiloxy Alkane, chloroprene, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber , epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/ethyleneoxyethanol copolymer. C. Partial investment

The pharmaceutical compositions provided herein can be administered topically to the skin, pores, or mucous membranes. As used herein, topical administration includes cutaneous (intra), conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be suitable for topical administration in any dosage form for local or systemic effects, including (but not limited to) emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusts, Powders, dressings, elixirs, lotions, suspensions, tinctures, ointments, foams, films, aerosols, douches, sprays, suppositories, bandages and skin patches. Topical formulations of the pharmaceutical compositions provided herein may also include liposomes, micelles, microspheres, and nanosystems.

Pharmaceutically acceptable carriers and excipients suitable for topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antibacterial or preservatives directed against the growth of microorganisms, stabilizing agents Agent, solubility enhancer, isotonic agent, buffer, antioxidant, local anesthetic, suspending and dispersing agent, wetting or emulsifying agent, complexing agent, isolating or chelating agent, penetration enhancer, cryoprotectant, lyoprotectant , thickeners and inert gases.

Pharmaceutical compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, sonotophoresis, or microneedle or needle-free injection (such as POWDERJECT™ and BIOJECT™).

Pharmaceutical compositions provided herein may be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles including lard, benzoated lard, olive oil, cottonseed oil, and other oils (white petrolatum); emulsifying or adsorbable vehicles such as hydrophilic petrolatum, sulfuric acid Hydroxystearin and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, including cetyl alcohol, glyceryl monostearate , lanolin and stearic acid water-in-oil (W/O) emulsion or oil-in-water (O/W) emulsion. See, for example, Remington: The Science and Practice of Pharmacy , supra. These vehicles are emollient, but generally require the addition of antioxidants and preservatives.

A suitable cream base can be oil-in-water or water-in-oil. A suitable cream vehicle may be washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also known as the "internal" phase, generally contains petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. Although not necessarily present, the aqueous phase usually exceeds the oil phase in volume and typically contains a wetting agent. Emulsifiers in cream formulations can be nonionic, anionic, cationic or amphoteric surfactants.

Gel is a semi-solid, suspension-type system. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid vehicle. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers such as carbomers, carboxypolyolefins and ^CARBOPOL® ; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers and Polyvinyl alcohol; cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as yellow Acanthus gum and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersing agent (such as alcohol or glycerin) can be added, or the gelling agent can be dispersed by grinding, mechanical mixing and/or stirring.

The pharmaceutical compositions provided herein may be suppositories, pessaries, bougies, plasters or poultice, ointments, powders, dressings, creams, plasters, contraceptive pills, ointments, solutions, lotions, suspensions, tampons Administer rectally, transurethral, transvaginally, or transvulvally in the form of , gel, foam, spray, or enema. Such dosage forms may be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy (supra).

Rectal, urethral and vaginal suppositories are solids inserted into an orifice of the body that are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifice. Pharmaceutically acceptable carriers for rectal and vaginal suppositories include bases or vehicles such as hardeners which, when formulated with the active ingredient, produce a melting point near body temperature; and antioxidants as described herein, including sub- Hydrogen sulfate and sodium metabisulfite. Suitable vehicles include (but are not limited to) cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and monoglycerides and diglycerides of fatty acids. Suitable mixtures of esters and triglycerides and hydrogels (such as polyvinyl alcohol, hydroxyethyl methacrylate and polyacrylic acid). Combinations of various media can also be used. Rectal and vaginal suppositories may be prepared by compression or molding. Typical weights for rectal and vaginal suppositories are about 2 to about 3 g.

The pharmaceutical compositions provided herein may be administered ocularly in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

The pharmaceutical compositions provided herein may be administered to the respiratory tract either intranasally or by inhalation. Pharmaceutical compositions may be provided in the form of aerosols or solutions for use with pressurized containers, pumps, sprays, nebulizers (such as those using electrohydrodynamics to produce a fine mist) or nebulizers alone or with a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) delivered in combination. Pharmaceutical compositions may also be provided as dry powders for insufflation, alone or in combination with inert carriers such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may contain bioadhesive agents including chitosan or cyclodextrin.

Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers or nebulizers may be formulated to contain ethanol, aqueous ethanol or suitable substitutes for dispersion, solubilization or prolonged release of the active ingredient; e.g. solvent propulsion agents; and/or surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

Pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of these sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters, and cartridges for use in inhalers or insufflators may be formulated to contain a powder mixture of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l -Leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Pharmaceutical compositions provided herein for inhalation/intranasal administration may further comprise suitable flavors, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.

Pharmaceutical compositions provided herein for topical administration may be formulated for immediate release or modified release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. D. Modified release

The pharmaceutical compositions provided herein can be formulated into modified release dosage forms. As used herein, the term "modified release" refers to a dosage form that releases the active ingredient at a different rate or location than an immediate release dosage form when administered by the same route. Modified release dosage forms include (but are not limited to) delayed release, sustained release, extended release, sustained release, pulsatile release, controlled release, accelerated release and rapid release, targeted release, programmed release and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can use various modified release devices and methods known to those skilled in the art, including (but not limited to) matrix controlled release devices, osmotic controlled release devices, multi-particle controlled release devices, ion exchange resins, Enteric coating, multilayer coating, microspheres, liposomes and their combination preparation. The release rate of the active ingredient(s) can also be improved by changing the particle size and polymorphism of the active ingredient(s). 1. Matrix controlled release device

The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using matrix controlled release devices known to those skilled in the art. See, for example, Takada et al., Encyclopedia of Controlled Drug Delivery , edited by Mathiowitz; Wiley, 1999; Vol. 2.

In certain embodiments, pharmaceutical compositions provided herein in modified release dosage forms are formulated using an erodible matrix device that is a water-swellable, erodible or soluble polymer, including (but not limited to) Synthetic polymers and naturally occurring polymers and derivatives (such as polysaccharides and proteins).

Materials that can be used to form the erodible matrix include (but are not limited to) chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, gum tragacanth, Carrageenan, ghati gum, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates ; Propylene glycol alginate; Gelatin; Collagen; Cellulose, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC ), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl Methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyethylene Alcohol; polyvinyl acetate; glyceryl fatty acid ester; polyacrylamide; polyacrylic acid; copolymer of ethylacrylic acid or methacrylic acid (EUDRAGIT ® ); poly(2-hydroxyethyl-methacrylate); poly Lactide; copolymer of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives , such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate Chloride homopolymers and copolymers.

In certain embodiments, pharmaceutical compositions provided herein are formulated using non-erodible matrix devices. The active ingredient(s) are dissolved or dispersed in an inert matrix and are initially released by diffusion through a single administration of the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polymethylmethacrylate Butyl acrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, vinyl chloride and Vinyl acetate, vinylidene chloride, copolymer of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate /Vinyl alcohol terpolymer, ethylene/ethyleneoxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polysilicone rubber, polydimethylsiloxy alkane and polysiloxycarbonate copolymers; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, Microcrystalline wax and triglycerides.

In matrix-controlled release systems, the desired release kinetics may be determined, for example, by the type of polymer used, the viscosity of the polymer, the particle size of the polymer and/or the active ingredient(s), the relative size of the active ingredient(s) The ratio of polymers to polymers, and other excipients or carriers in the composition are controlled.

Pharmaceutical compositions provided herein in modified release dosage forms may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression. 2. Osmosis controlled release device

Pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including, but not limited to, single chamber systems, two chamber systems, asymmetric membrane technology (AMT), and extrusion core systems ( ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the flow of water from the aqueous use environment into the core to cause release of the drug by extrusion through the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic device optionally contains a osmotic agent, which creates a driving force for transporting water from the environment of use to the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, which are also known as "osmotic polymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (such as calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG) ), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, copolymers of PVA/PVP and hydrophobic monomers (such as methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, Cross-linked sodium carboxymethylcellulose, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) ) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

Another class of penetrants are osmogens, which absorb water to influence the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, Potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, Benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and its mixture.

Penetrants with different dissolution rates can be used to affect how quickly the active ingredient(s) are initially delivered from the dosage form. For example, an amorphous sugar (such as MANNOGEM ^™ EZ) can be used to provide faster delivery during the first few hours to produce the desired therapeutic effect in a timely manner, and to gradually and continue to release the remaining amount to maintain treatment over an extended period of time or Required level of preventive effect. In this case, the active ingredient(s) are released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

The core may also contain a wide variety of other excipients and carriers, as described herein, to enhance the performance of the dosage form or to facilitate stability or processing.

Materials that can be used to form semi-permeable membranes include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water permeable and insoluble in water at physiologically relevant pH or readily chemically Alterations (such as cross-linking) render it insoluble in water. Examples of suitable polymers that may be used to form the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, nitrocellulose, acetic acid Cellulose butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA Ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, acetic acid agar, amylose triacetate, β-glucan B Acid ester, beta glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitopolymer Sugar, collagen, gelatin, polyolefin, polyether, polyether, polyetherether, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural wax and synthetic wax.

Semipermeable membranes can also be hydrophobic microporous membranes in which the pores are substantially filled with gas and are not wetted by an aqueous medium, but are permeable to water vapor, as disclosed in US Pat. No. 5,798,119. This hydrophobic but water vapor permeable membrane typically contains hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polystyrene, polyetherstyrene, polystyrene, Polyvinyl halide, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

The delivery port(s) in the semi-permeable membrane can be formed after coating by mechanical or laser drilling. The delivery port may also be formed in situ by corrosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane on the indentation of the core. Additionally, the delivery port may be formed during the coating process, such as in the case of asymmetric film coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220.

The total amount and rate of release of the active ingredient(s) released can be substantially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.

Pharmaceutical compositions in osmotic controlled release dosage forms may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the formulation.

Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy , supra; Santus and Baker, J. Controlled Release , 1995 , 35 , 1-21; Verma et al., Drug Dev. Ind. Pharm. , 2000 , 26 , 695 -708; Verma et al., J. Controlled Release , 2002 , 79 , 7-27.

In certain embodiments, the pharmaceutical compositions provided herein are formulated in an AMT controlled release dosage form, which dosage form includes an asymmetric permeable membrane coating a core containing the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, for example, US Patent No. 5,612,059 and WO 2002/17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (including direct compression, dry granulation, wet granulation and dip coating).

In certain embodiments, the pharmaceutical compositions provided herein are formulated in an ESC controlled release dosage form, which dosage form includes a permeable membrane coating a core that includes the active ingredient(s), hydroxyethyl cellulose, and others. Pharmaceutically acceptable excipients or carriers. 3.Multi-particle controlled release device

The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured as a multiparticulate controlled release device comprising a diameter ranging from about 10 µm to about 3 mm, from about 50 µm to about 2.5 mm, or from about 100 µm to about 1 The diversity of particles, granules or pellets in mm. Such multiparticulates may be prepared by methods known to those skilled in the art, including wet or dry granulation, extrusion/spheronization, rolling, melt-freezing and coating of seed cores by spraying. See, for example, Multiparticulate Oral Drug Delivery ; Ghebre-Sellassie, ed.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1994; and Pharmaceutical Palletization Technology ; Ghebre-Sellassie, ed.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

Other excipients or carriers, as described herein, may be blended with the pharmaceutical compositions to aid processing and formation of multiparticulates. The resulting particles may themselves constitute multiparticulate devices or may be coated with various film-forming materials such as enteric polymers, water-swellable and water-soluble polymers. The multigranules can be further processed into capsules or tablets. 4. Targeted delivery

The pharmaceutical compositions provided herein may also be formulated to be targeted to specific tissues, receptors, or other areas of the body of the individual to be treated, including liposome, resealed red blood cell, and antibody-based delivery systems. Examples include (but are not limited to) U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,04 No. 8,736, No. 6,039,975 No. 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874. Instructions

In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a ROCK-mediated disorder, disease, or condition in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of (I) Compounds, or their enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or both A mixture of one or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, the ROCK-mediated disorder, disease or condition is an ocular disease. In certain embodiments, the ROCK-mediated disorder, disease or condition is a neurodegenerative eye disease.

In certain embodiments, the ROCK is ROCK1. In certain embodiments, the ROCK is ROCK2.

In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of an ocular disease in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound provided herein (e.g., , compound of formula (I)), or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers , or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, the ocular disease is ocular hypertension. In certain embodiments, the eye disease is glaucoma.

In certain embodiments, the eye disease is primary glaucoma. In certain embodiments, the eye disease is open-angle glaucoma. In certain embodiments, the ocular disease is normal tension glaucoma. In certain embodiments, the eye disease is angle-closure glaucoma. In certain embodiments, the eye disease is congenital glaucoma.

In certain embodiments, the eye disease is secondary glaucoma. In certain embodiments, the ocular disease is neovascular glaucoma. In certain embodiments, the eye disease is pigmentary glaucoma. In certain embodiments, the ocular disease is exfoliative glaucoma. In certain embodiments, the ocular disease is uveitic glaucoma.

In yet another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of neurodegenerative eye disease in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound provided herein ( For example, compounds of formula (I)), or their enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers isomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, the neurodegenerative eye disease is glaucoma. In certain embodiments, the neurodegenerative eye disease is primary glaucoma. In certain embodiments, the neurodegenerative eye disease is open angle glaucoma. In certain embodiments, the neurodegenerative eye disease is normal tension glaucoma. In certain embodiments, the neurodegenerative eye disease is angle-closure glaucoma. In certain embodiments, the neurodegenerative eye disease is congenital glaucoma.

In certain embodiments, the neurodegenerative eye disease is secondary glaucoma. In certain embodiments, the neurodegenerative eye disease is neovascular glaucoma. In certain embodiments, the neurodegenerative eye disease is pigmentary glaucoma. In certain embodiments, the neurodegenerative eye disease is exfoliative glaucoma. In certain embodiments, the neurodegenerative eye disease is uveitis glaucoma.

In yet another embodiment, provided herein is a method of reducing intraocular pressure in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), or an enantiomer, enantiomer thereof. Mixtures of isomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or mixtures of two or more tautomers; or pharmaceuticals thereof Above acceptable salts, solvates, hydrates or prodrugs.

In certain embodiments, the individual is a mammal. In certain embodiments, the individual is a human.

In certain embodiments, a therapeutically effective amount of a compound provided herein ranges from about 1 µg/day to about 1 mg/day, from about 1 µg/day to about 500 µg/day, from about 1 µg/day to About 200 µg/day, about 1 µg/day to about 100 µg/day, about 2 µg/day to about 50 µg/day, or about 2 µg/day to about 20 µg/day. In one embodiment, a therapeutically effective amount of a compound provided herein ranges from about 1 µg/day to about 1 mg/day. In another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 1 µg/day to about 500 µg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein ranges from about 1 µg/day to about 200 µg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 1 µg/day to about 100 µg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein ranges from about 2 µg/day to about 50 µg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 2 µg/day to about 20 µg/day.

Depending on the disorder, disease or condition to be treated and the condition of the individual, the compounds provided herein may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous , CIV, intracisternal injection or infusion , subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) administration. The compounds provided herein may be formulated in appropriate dosage units with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles suitable for each route of administration.

In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered parenterally. In yet another embodiment, the compounds provided herein are administered intravenously. In yet another embodiment, the compounds provided herein are administered intramuscularly. In yet another embodiment, the compounds provided herein are administered subcutaneously. In yet another embodiment, the compounds provided herein are administered topically. In yet another embodiment, a compound provided herein is administered by local instillation.

The compounds provided herein can be delivered as a single dose, such as, for example, a single bolus injection or oral administration as a lozenge or pill; or over time, such as, for example, a continuous infusion over time or divided bolus doses over time. If necessary, the compounds provided herein can be administered repeatedly, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.

The compounds provided herein can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). Additionally, administration can be continuous (i.e., daily) or intermittent. As used herein, the terms "intermittently" or "intermittently" are intended to mean stopping and starting at regular or irregular intervals. For example, compounds provided herein may be administered on an intermittent basis from 1 to 6 days per week, administered in cycles (e.g., daily administration for 2 to 8 consecutive weeks followed by a rest period, no administration for up to week) or on alternate days.

The compounds provided herein may also be used in combination with or in combination with other therapeutic agents for the treatment and/or prevention of the conditions, disorders, or diseases described herein.

As used herein, the term "combination" includes the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). However, use of the term "combination" does not limit the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to an individual suffering from the condition, disorder, or disease. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein) may be administered (e.g., 5 minutes, 15 minutes, 50 minutes) before the second therapy (e.g., a prophylactic or therapeutic agent) is administered to the individual , 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago ), simultaneously or subsequently (for example, 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5, 6, 8, or 12 weeks later). Triple therapy is also considered in this article.

The route of administration of the compounds provided herein is independent of the route of administration of the secondary therapy. In one embodiment, the compounds provided herein are administered orally. In another embodiment, a compound provided herein is administered intravenously. In another embodiment, the compounds provided herein are administered topically. Thus, according to these embodiments, the compounds provided herein are administered orally, intravenously, or topically, and the second therapy can be orally, parenterally, intraperitoneally, intravenously, intraarterially, Transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, via inhalation, transvaginal, intraocular, local delivery via catheter or stent, subcutaneous, intrafatal, Administer intra-articularly, intrathecally, topically, or in a slow-release dosage form. In one embodiment, a compound provided herein and a second therapy are administered topically by the same mode of administration. In another embodiment, a compound provided herein is administered by one mode of administration (e.g., via topical), while the second agent (anticancer agent) is administered by another mode of administration (e.g., orally) Invest.

In one embodiment, provided herein is a method for inhibiting the activity of ROCK, which includes combining ROCK with an effective amount of a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, two or More mixtures of diastereoisomers, tautomers, or mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof .

In certain embodiments, the ROCK is ROCK1. In certain embodiments, the ROCK is ROCK2.

The compounds provided herein may also be provided in articles using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,525,907, 5,052,558, and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

In certain embodiments, provided herein is a kit that, when used by a medical practitioner, can simplify administration to an individual of a suitable amount of a compound provided herein as an active ingredient. In certain embodiments, kits provided herein include a container and a dosage form of a compound provided herein.

Kits provided herein may further comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringe drip bags, patches, and inhalers. Kits provided herein may also include condoms for administration of the active ingredients.

Kits provided herein can further comprise a pharmaceutically acceptable vehicle for administering one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container in a suitable vehicle in which the active ingredient can be dissolved to form a form suitable for parenteral administration. Granular sterile solution. Examples of pharmaceutically acceptable vehicles include (but are not limited to): aqueous vehicles, including (but are not limited to) water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose injection, Sugar and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, including (but not limited to) ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including (but not limited to) ) corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

The invention will be further understood by the following non-limiting examples. Example

As used herein, whether or not specific abbreviations are explicitly defined, the symbols and conventions used in these methods, reaction diagrams, and examples are consistent with contemporary scientific literature, such as the Journal of the American Chemical Society, Journal of Medicinal Chemistry, or Journal of Biological They are the same as used in Chemistry. Specifically, but not limiting, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (millilitre); μL (microliter); mM (millimol); μM. (micromoles); mmol (millimoles); min (minutes); h (hours); Bn (benzyl); t- Bu (tertiary butyl); DCM (dichloromethane); DIPEA ( N , N -diisopropylethylamine); DMF (dimethylformamide); DMSO (dimethyltrisoxide); EtOAc (ethyl acetate); EtOH (ethanol); HBTU (benzotriazole tetrafluorophosphate hexafluorophosphate) Methylureonium); LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); PE (petroleum ether); PhtN (phthalimide); TBAF (tetra-n-butylammonium fluoride) ; THF (tetrahydrofuran); TIPS (triisopropylsilyl); MS (mass spectrometry); NMR (nuclear magnetic resonance); and preparative HPLC (preparative high performance liquid chromatography).

For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. All temperatures are expressed in °C (Celsius) unless otherwise specified. All reactions were performed at room temperature unless otherwise specified. The synthetic methods described herein are intended to illustrate applicable chemistry through the use of specific examples and are not indicative of the scope of the invention. Example 1 Preparation of ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (thieno[2,3- c ]pyridin-2-yl)-propanamide-2 - d A1

Compound A1 was prepared as shown in Reaction Scheme 1.

Step A: Methyl 2-(4-(hydroxymethyl)phenyl)acetate 1.2 . To 2-(4-(hydroxymethyl)phenyl)acetic acid 1.1 (9.5 g) in MeOH under nitrogen, To the solution of 52.8 mmol), thionite chloride (2 mL) was added dropwise. After the reaction mixture was stirred at 50°C for 2 hours, water (200 mL) was added. The reaction mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (200 mL), dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 1.2 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.29 - 7.18 (m, 4H), 5.12 (s, 1H), 4.47 (s, 2H), 3.65 (s, 2H), 3.61 (s, 3H).

Step B: Methyl 2-(4-((triisopropylsiloxy)methyl)phenyl)acetate 1.3 . To compound 1.2 (7.7 g, 42.8 mmol) in anhydrous DCM under nitrogen 2,6-lutidine (8.3 g, 77.0 mmol) and triisopropylsilyl triflate (15.7 g, 51.3 mmol) were added to the solution in sequence. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 100:1) to obtain compound 1.3 (11 g) with a yield of 77%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.33 - 7.17 (m, 4H), 4.78 (s, 2H), 3.64 (s, 2H), 3.61 (s, 3H), 1.21 - 1.11 (m, 3H ), 1.05 (d, J = 6.9 Hz, 18H). Reaction diagram 1

Step C: 2-(4-(((triisopropylsiloxy)methyl)phenyl)ethyl-2,2- d ₂ acid 1.4 . Carefully dissolve sodium metal (1.1 g, 10%) in in anhydrous CH ₃ OD (50 mL) while stirring in an ice bath under nitrogen until the sodium metal was completely consumed. Then a solution of compound 1.3 (11 g, 29.6 mmol) in CH ₃ OD was slowly added. The mixture was stirred at room temperature. 12 h and concentrated. The residue was dissolved in CH ₃ OD (50 mL) and the resulting solution was stirred for a further 12 h. The reaction was then quenched by adding deuterated water (5 mL). The mixture was stirred for 3 h, and then Adjust to pH 4.0 with 20% HCl and extract twice with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ and concentrated. The residue is purified by silica column chromatography (DCM:MeOH = 10:1) , compound 1.4 (7.6 g) was obtained with a yield of 72%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 - 7.21 (m, 4H), 4.82 (s, 2H), 1.20 - 1.03 (m, 21H). Deuterium isotope purity is 97.5%.

Step D: ( R )-4-benzyl-3-(2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)acetyl- d ₂ )oxazolidine- 2-Keto 1.5 . To a solution of compound 1.4 (6.8 g, 19.4 mmol) in anhydrous DCM at 0 °C was slowly added chloride chloride (2.7 g, 21.3 mmol) to form a chloride solution. To a solution of ( R )-4-benzyloxazolidin-2-one (3.8 g, 21.3 mmol) in anhydrous THF (150 mL) at -78 °C was slowly added n -BuLi (2.5 m , 8.5 mL). The resulting solution was stirred at -78°C for 2 hours. Then add the chloride solution slowly through the syringe. After the reaction mixture was stirred at -78°C for 2 hours and then allowed to warm to room temperature, saturated aqueous _NH4Cl (150 mL) was added to quench the reaction. The reaction mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (300 mL), dried over _{anhydrous Na2SO4} , and concentrated. The residue was purified by silica gel column chromatography to obtain compound 1.5 (2.1 g) with a yield of 24%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.37 - 7.15 (m, 7H), 7.15 - 7.06 (m, 2H), 4.81 (s, 2H), 4.74 - 4.60 (m, 1H), 4.35 (t , J = 8.6 Hz, 1H), 4.20 (dd, J = 8.9, 2.9 Hz, 1H), 2.95 (dd, J = 14.9, 5.3 Hz, 2H), 1.21 - 1.12 (m, 3H), 1.07 (d, J = 6.9 Hz, 18H). Deuterium isotope purity is 98.0%.

Step E: 2-((S)-3-((R)-4-benzyl-2-side oxyoxazolidin-3-yl)-3-side oxy-2-(4-((( Triisopropylsilyl)oxy)methyl)phenyl)propyl-2- d )isoindoline-1,3-dione 1.6 . At -78°C, under nitrogen, add to anhydrous solution To a solution of compound 1.5 (3.0 g, 6.2 mmol) in THF (30 mL) was added LiHMDS (1 M, 74 mL) slowly. After the mixture was stirred at -78°C for 1 hour, N -(bromomethyl)phthalimide (1.8 g, 7.4 mmol) in anhydrous THF (50 mL) was slowly added. The reaction mixture was stirred at -78°C for 3 hours and then at room temperature overnight. The reaction was quenched with saturated aqueous _NH4Cl (100 mL) and the reaction mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous HCl ( ₁₀₀ mL), dried over _Na2SO4 , and concentrated. The residue was recrystallized from EtOAc/PE to obtain compound 1.6 (2 g) in 50% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 - 7.70 (m, 4H), 7.32 - 7.16 (m, 7H), 7.15 - 7.10 (m, 2H), 4.73 (s, 2H), 4.71 - 4.60 (m, 1H), 4.28 - 4.19 (m, 2H), 4.15 (dd, J = 9.0, 2.7 Hz, 1H), 4.03 (d, J = 14.0, 1H), 3.03 (dd, J = 13.5, 3.1 Hz , 1H), 2.89 (dd, J = 13.5, 7.5 Hz, 1H), 1.16 - 1.05 (m, 3H), 1.01 (d, J = 7.0 Hz, 18H). Deuterium isotope purity is 98.0%.

Step F: ( S )-3-(1,3-bisoxyisoindolin-2-yl)-2-(4-(((triisopropylsilyl)oxy)methyl)benzene To a solution of compound 1.6 (2.0 g, 3.0 mmol) in THF (30 mL) and water (10 mL) at -10 ° C was added H ₂ O ₂ ( 30%, 0.72 mL, 12 mmol), followed by the dropwise addition of LiOH (72 mg, 3 mmol) in water (1 mL). The reaction mixture was stirred at -5°C to -10°C for 2 hours, and then adjusted to approximately pH 5 with 2M aqueous HCl and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous HCl ( ₅₀ mL), dried over _Na2SO4 , and concentrated. The residue was purified by silica column chromatography to obtain compound 1.7 (1.1 g) with a yield of 73%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 - 7.73 (m, 2H), 7.70 - 7.62 (m, 2H), 7.35 - 7.25 (m, 4H), 4.77 (s, 2H), 4.20 (d, J = 8.1 Hz, 2H), 1.17 - 1.08 (m, 3H), 1.05 (d, J = 6.6 Hz, 18H). Deuterium isotope purity is 98.0%.

Step G: ( S )-3-(1,3-bisoxyisoindolin-2-yl) -N- (thieno[2,3- c ]pyridin-2-yl)-2-( 4-(((triisopropylsilyl)oxy)methyl)phenyl)propanamide-2- d 1.8 . To compound 1.7 (1.0 g, 2.0 mmol) in DMF (20 mL) DIPEA (516 mg, 4 mmol) and HATU (917 mg, 2.4 mmol) were added to the solution. After the mixture was stirred at 0 °C for 10 min, thieno[2,3- c ]pyridin-2-amine (330 mg, 2.2 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour and then poured into water (50 mL). The precipitate was filtered, washed with water, dried, and purified by silica column chromatography to obtain compound 1.8 (594 mg) with a yield of 47%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.00 (s, 1H), 9.02 (s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.81 (m, 4H), 7.60 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 4.72 (s, 2H), 4.17 (d, J = 2.7 Hz, 2H), 1.14 - 1.04 (m, 3H), 0.99 (d, J = 7.0 Hz, 18H); MS (ESI) m/z : 615 [M+H] ⁺ . Deuterium isotope purity is 98.0%.

Step H: ( S )-3-(1,3-dilateral oxyisoindolin-2-yl)-2-(4-(hydroxymethyl)phenyl) -N- (thieno[2, 3- c ]pyridin-2-yl)propanamide-2- d 1.9 . To a solution of compound 1.8 (400 mg, 0.84 mmol) in THF (5 mL) was added TBAF (4.2 mL, 4.2 mmol, 1 M is contained in THF). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with water (5 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and concentrated. The residue was purified by silica gel column chromatography to obtain compound 1.9 (203 mg) with a yield of 51%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97 (s, 1H), 9.01 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.87 - 7.77 (m, 4H), 7.59 ( d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.94 (s, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.42 (d, J = 5.7 Hz, 2H), 4.17 (s, 2H); MS (ESI) m/z : 459 [M+H] ⁺ . Deuterium isotope purity is 98.0%.

Step I: ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (thieno[2,3- c ]pyridin-2-yl)propanamide-2- d A1 . To a solution of compound 1.9 (200 mg, 0.42 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.3 mL, 6.0 mmol). The reaction mixture was stirred at 55°C for 3 hours and then concentrated. The residue was purified by reverse phase preparative HPLC to obtain compound A1 (105 mg) in a yield of 76%. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90 (s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 7.58 (dd, J = 5.5, 1.0 Hz, 1H), 7.37 (s, 4H ), 6.93 (s, 1H), 4.59 (s, 2H), 3.39 (d, J = 13.0 Hz, 1H), 3.02 (d, J = 12.9 Hz, 1H); MS (ESI) m/z : 329.1 [ M+H] ⁺ . Deuterium isotope purity is 98.0%. Example 2 Preparation of ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (isoquinolin-6-yl)-propanamide-2- d A2

Compound A2 was prepared as shown in Scheme 2 according to the procedure described in Example 1. MS (ESI) m/z : 323 [M+H] ⁺ . Deuterium isotope purity is 98.0%. Reaction diagram 2 Example 3 Preparation of ( S )-2,2-dimethyl-5-(nitrooxy)pentanoic acid 4-(3-amino-1-side oxy-1-(thieno[2,3- c ]pyridin-2-ylamino)propan-2-yl-2- d )benzyl ester A3

Compound A3 was prepared as shown in Reaction Scheme 3. Reaction diagram 3

Step A: ( S )-2,2-dimethyl-5-(nitrooxy)pentanoic acid 4-(3-(1,3-bisoxyisoindolin-2-yl)-2 -Deutero-1-pendantoxy-1-(thieno[2,3- c ]pyridin-2-ylamino)propan-2-yl-2- d )benzyl ester 3.1 . Add to dry DCM (20 To a solution of 2,2-dimethyl-5-(nitrooxy)pentanoic acid (2.0 g, 10.6 mmol) in mL), add anhydrous DMF (4 drops), followed by oxalate chloride (2.7 mL, 31.7 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated to form 2,2-dimethyl-5-(nitrooxy)penteryl chloride. The residue was redissolved in THF (1 mL); and compound 1.9 (251 mg, 0.53 mmol), DIPEA (342) in anhydrous DMF (20 mL) and anhydrous THF (10 mL) was slowly added at 0°C. mg, 2.6 mmol) and DMAP (34 mg, 0.26 mmol). The reaction mixture was stirred until TLC showed no compound 1.9 remained. The reaction mixture was then diluted with saturated aqueous NH ₄ Cl solution (5 mL) and extracted twice with EtOAc. The combined organic layers were washed five times with water and saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by silica column chromatography to obtain compound 3.1 (175 mg) with a yield of 51%. MS (ESI) m/z : 649.1 [M+H] ⁺ .

Step B: ( S )-2,2-dimethyl-5-(nitrooxy)valerate 4-(3-amino-1-sideoxy-1-(thieno[2,3- c ]pyridin-2-ylamino)-prop-2-yl-2- d )benzyl ester A3 . To a solution of compound 3.1 (150 mg, 0.23 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.15 mL, 3.0 mmol). The reaction mixture was stirred at 55°C for 3 hours and then concentrated. The residue was purified by reverse phase preparative HPLC to obtain compound A3 (86 mg) in 75% yield. ¹ H NMR (401 MHz, DMSO- d ₆ ) δ 12.82 (s, 1H), 9.49 (s, 1H), 8.55 (d, J = 6.5Hz, 1H), 8.13 (t, J = 13.8 Hz, 1H) , 8.03 (s, 3H), 7.30 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 5.2 (s, 2H), 2.83 - 2.80 ( m, 2H), 2.61 - 2.59 (m, 2H), 1.96 - 1.90 (m, 4H), 1.36 (s, 6H); MS (ESI) m/z : 502.1 [M+H] ⁺ . Deuterium isotope purity is 98.0%. Example 4 Preparation of ( S )-2,2-dimethyl-5-(nitrooxy)valerate 4-(3-amino-1-(isoquinolin-6-ylamine)-1-side Oxyprop-2-yl-2- d )benzyl ester A4

Compound A4 was prepared as shown in Scheme 4 according to the procedure described in Example 3. MS (ESI) m/z : 496.2 [M+H] ⁺ . Deuterium isotope purity is 98.0%. Reaction graph 4 Example 5 Preparation of ( S )-2,4-dimethylbenzoic acid 4-(3-amino-1-side oxy-1-(thieno[2,3- c ]pyridin-2-ylamino) Propan-2-yl-2- d )benzyl ester A5

Compound A5 was prepared as shown in Scheme 5 according to the procedure described in Example 3. MS (ESI) m/z : 461.2 [M+H] ⁺ . Deuterium isotope purity is 98.0%. Reaction diagram 5 Example 6 Preparation of ( S )-2,4-dimethylbenzoic acid 4-(3-amino-1-(isoquinolin-6-ylamino)-1-side oxypropan-2-yl-2 - d ) Benzyl ester A6

Compound A6 was prepared as shown in Scheme 6 according to the procedure described in Example 3. MS (ESI) m/z : 455.2 [M+H] ⁺ . Deuterium isotope purity is 98.0%. Reaction diagram 6 Example B1 ROCK2 Kinase Assay

Add 4 nM of ROCK2 kinase (2.5 μL) and 4x compound (2.5 μL) at target concentrations (e.g., ranging from 5 pm to 100 nM) to the wells of a 384-well plate. After the plate was centrifuged at 1,000 rpm for 1 minute, 2.0 μM STK2 substrate (CISBIO) (2.5 μL) was added to the wells and the plate was centrifuged at 1,000 rpm for 1 minute. Then 24 μM ATP (2.5 μL) was added and the plate was centrifuged at 1,000 rpm for 1 minute to initiate the kinase reaction. The plate was incubated at 25°C for 1.5 hours and the kinase reaction was stopped by adding 5 μL of 4x streptavidin-XL665 to each well. After centrifuging the plate at 1,000 rpm for 1 minute, 4x STK Antibody-cryptate detection buffer (5 μL) was added to each well. The plate was centrifuged at 1,000 rpm for 1 minute and then incubated at room temperature for 1 hour. Read the plate in HTRF mode using the ENVISION® Plate Reader. The _IC50 values of the compounds were calculated and the results are summarized in Table 1. Table 1. ROCK2 Kinase Inhibition Compound number IC ₅₀ (nM) A1 0.88 A2 0.62 A3 88 Example B2 Stability Study

A clear solution of compound A1 (0.02 wt%) was prepared in buffer pH 7.2 containing 100 mg sodium citrate in 100 mL water. The corresponding protium compound of compound A1 (0.02 wt%), i.e., ( S )-3-amino-2-(4-(hydroxymethyl)-phenyl) -N- (thieno A clear solution of [2,3- c ]pyridin-2-yl)-propionamide ("Protium Reference Compound"). Place the two solutions into a stability test chamber at 40°C. Elimination of the product 2-(4-(hydroxymethyl)phenyl) -N by analytical HPLC on a C18 column (XBRIDGE SHIELD RP18) at 0 and 48 hours against the parent compound (compound A1 or protium reference compound) An aliquot of each solution was analyzed for -(thieno[2,3- c ]pyridin-2-yl)acrylamide and total impurities. The results are summarized in Table 2. Table 2. Stability at 40°C at pH 7.2 Protium reference Compound A1 time 0 48 hours 0 48 hours parent compound 95.3% 78.02% 97.60% 86.62% elimination products 0.78% 11.91% 0.46% 7.73% total impurities 4.3 21.7 2.2 13.2 * * * * *

The examples set forth above are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of the disclosure herein. Modifications obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent publication was specifically and individually indicated to be incorporated by reference.

Claims (73)

A compound of formula (I): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, or two or more A mixture of tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: R ¹ , R ² and R ³ are each independently (i) hydrogen; (ii) C _{1 -6} alkyl, C _1-6 heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl _, Heteroaryl or heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , - S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁴ is C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; each R ⁵ is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl , C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or Heterocyclyl; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , - OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S (O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ⁶ is (i) hydrogen or nitro; (ii) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; (iii) -C(O)R ^1a , -C (O)-A-ONO ₂ , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -S(O)R ^1a , -S(O ) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR 1b R ^1c ; each R ^1a , ^{R 1b ,} R ^1c and R ^1d are independently hydrogen, deuterium, C _1-6 alkane Base, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl Or heterocyclyl; A and L are each independently C _1-6 alkylene; and m is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl , alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl optionally via one or more, in one embodiment, via one, two, three or four substituents Q Substituted, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, nitrooxy and pendant oxy; (b) C _1-6 alkyl, C _{1- 6} heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl, Each of them is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents ^Qa ; and (c) -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C(S)NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC (NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS( O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C (S)R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , - NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -P(O)R ^b R ^c , -SR ^a , -S(O)R ^a , -S(O ) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen or deuterium; ( ii) C _1-6 alkyl, C _1-6 heteroalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl _, C _6-14 aryl, C _7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more, in one embodiment, by one, two, three or four substituents ^Qa ; or (iii) R ^b and R ^c together with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted by one or more, in one embodiment, by one, two, three or four substituents Q ^a ; wherein Each Q ^a is independently selected from: (a) deuterium, cyano, halo, nitro, nitrooxy and pendant oxy; (b) C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C (O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(O)SR ^e , -C(NR ^e )NR ^f R ^g , -C(S)R ^e , -C(S)OR ^e , -C(S)NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , - OC(O)SR ^e , -OC(NR ^e )NR ^f R ^g , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)( OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h ) NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -P(O)R ^f R ^g , -SR ^e , -S( O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g and -S(O) ₂ NR ^f R ^g ; where each R ^e , R ^f , R ^g and R ^h are independently It is (i) hydrogen or deuterium; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7- 15} aralkyl, heteroaryl or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are attached form a heterocyclyl group; and wherein the compound has a deuterium enrichment factor of not less than about 3,200 or not Less than about 50% deuterium enrichment. The compound of claim 1, wherein R ⁶ is -C(O)-A-ONO ₂ . The compound of claim 1, wherein R ⁶ is -C(O)R ^1a . The compound of claim 3, wherein R ⁶ is -C(O)-C _6-14 aryl or -C(O)-heteroaryl, each of which is substituted by one or more substituents Q as appropriate. Such as the compound of claim 3 or 4, wherein R ⁶ is -C(O)-C _6-14 aryl, which is optionally substituted by one or more substituents Q. The compound of any one of claims 3 to 5, wherein R ⁶ is -C(O)-(bicyclic C _8-14 aryl), which is optionally substituted by one or more substituents Q. The compound of claim 3 or 4, wherein R ⁶ is -C(O)-heteroaryl, which is optionally substituted by one or more substituents Q. The compound of claim 3, 4 or 7, wherein R ⁶ is -C(O)-(monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. Such as the compound of claim 3, 4 or 7, wherein R ⁶ is -C(O)-(bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 9, wherein R ⁴ is a C _6-14 aryl, heteroaryl or heterocyclyl group, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 10, wherein R ⁴ is a C _6-14 aryl or heteroaryl group, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 11, wherein R ⁴ is a heteroaryl group, which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12, wherein R ⁴ is a monocyclic heteroaryl group, which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 13, wherein R ⁴ is a 5- or 6-membered heteroaryl group, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12, wherein R ⁴ is a bicyclic heteroaryl group, which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12 and 15, wherein R ⁴ is 5,5-, 5,6- or 6,6-fused heteroaryl, each of which is optionally substituted by one or more substituents Q replaced. The compound of any one of claims 1 to 12, 15 and 16, wherein R ⁴ is a 5,6-fused heteroaryl group, which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12 and 15 to 17, wherein R ⁴ is thieno[2,3- c ]pyridyl, thiazolo[5,4- c ]pyridyl, benzo[ d ] Isothiazolyl or benzo[ d ][1,2,3]thiadiazolyl, each optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12 and 15 to 18, wherein R ⁴ is thieno[2,3- c ]pyridin-2-yl, thiazolo[5,4- c ]pyridin-2-yl , benzo[ d ]isothiazol-6-yl, or benzo[ d ][1,2,3]thiadiazol-6-yl, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 12, 15 and 16, wherein R ⁴ is a 6,6-fused heteroaryl group, which is optionally substituted by one or more substituents Q. Such as the compound of any one of claims 1 to 12, 15, 16 and 20, wherein R ⁴ is isoquinolyl or 1,6-didinyl, each of which is optionally substituted by one or more substituents Q. For example, the compound of any one of claims 1 to 12, 15, 16, 20 and 21, wherein R ⁴ is isoquinolin-6-yl or 1,6-tridin-3-yl, each of which is subjected to a Or multiple substituents Q substituted. The compound of any one of claims 1 to 9, which has the structure of formula (XIII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, two or more mutual A mixture of isomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein: X is a bond, CR ^4a or N; Y and Z are each independently CR ^4a , O, NR ^4c , N or S; each R ^4a is independently hydrogen or R ^4b ; each R ^4b is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl , C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or Heterocyclyl, each optionally substituted by one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C (NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O )R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , - NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S( O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; each R ^4c is independently (i) hydrogen; (ii) C _1-6 alkyl, C _{1 -6} heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl , each of which is optionally substituted by one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; and p is 0, 1 , an integer of 2 or 3. Such as the compound of claim 23, which has the structure of formula (XV): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereoisomers, tautomers, two or more mutual Mixtures of isomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof. For example, the compound of claim 23 or 24 has the structure of formula (XX): or its diastereomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its medicines Above acceptable salts, solvates, hydrates or prodrugs. The compound of claim 25, wherein A is pentadiyl, which is optionally substituted by one or more substituents Q. Such as the compound of claim 25 or 26, wherein A is pentyl-2,5-diyl, which is optionally substituted by one or more substituents Q. The compound of any one of claims 25 to 27, wherein A is 2-methylpentan-2,5-diyl. For example, the compound of claim 23 or 24 has the structure of formula (XXIV): or its diastereomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its medicines Above acceptable salts, solvates, hydrates or prodrugs; wherein: each R ^6a is independently (i) deuterium, cyano, halo or nitro; (ii) C _1-6 alkyl, C _{1 -6} heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl , each of which is optionally substituted by one or more substituents Q; or (iii) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(NR ^1a )NR ^1b R ^1c , -OS( O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; and n is an integer of 0, 1, 2, 3, 4 or 5. Such as the compound of claim 29, wherein n is an integer of 2. The compound of claim 29 or 30, wherein each R ^6a is independently C _1-6 alkyl or C _1-6 heteroalkyl, each of which is substituted by one or more substituents Q as appropriate. The compound of any one of claims 29 to 31, wherein each R ^6a is independently a C _1-6 alkyl group, which is optionally substituted by one or more substituents Q. The compound of any one of claims 29 to 32, wherein each R ^6a is methyl. The compound of any one of claims 23 to 33, wherein X is a bond. The compound of any one of claims 23 to 33, wherein X is CR ^4a . The compound of any one of claims 23 to 33 and 35, wherein X is CH. The compound of any one of claims 23 to 33 and 35, wherein X is C(CH ₃ ). The compound of any one of claims 23 to 37, wherein Y is CR ^4a . The compound of any one of claims 23 to 38, wherein Y is CH. The compound of any one of claims 23 to 37, wherein Y is S. The compound of any one of claims 23 to 40, wherein Z is CR ^4a . The compound of any one of claims 23 to 41, wherein Z is CH. The compound of any one of claims 23 to 40, wherein Z is N. The compound of any one of claims 23 to 33, wherein X is a bond; Y is S; and Z is CR ^4a . The compound of any one of claims 23 to 33 and 44, wherein X is a bond; Y is S; and Z is CH. The compound of any one of claims 23 to 33, wherein X is a bond; Y is S; and Z is N. The compound of any one of claims 23 to 33, wherein X, Y and Z are each independently CR ^4a . The compound of any one of claims 23 to 33 and 47, wherein each of X, Y and Z is CH. The compound of any one of claims 23 to 33, wherein X is N; and Y and Z are each independently CR ^4a . The compound of any one of claims 23 to 33 and 49, wherein X is N; and each of Y and Z is CH. The compound of any one of claims 23 to 50, wherein p is an integer of 0. A compound according to any one of claims 23 to 50, wherein p is an integer of 1. The compound of any one of claims 23 to 50 and 52, wherein each R ^4b is independently halo or C _1-6 alkyl, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 23 to 50, 52 and 53, wherein each R ^4b is independently fluorine, chlorine, methyl or ethyl. The compound of any one of claims 1 to 54, wherein ^R1 is hydrogen. The compound of any one of claims 1 to 55, wherein R ² is hydrogen. The compound of any one of claims 1 to 56, wherein R ³ is hydrogen. The compound of any one of claims 1 to 57, wherein L is methyldiyl, ethylenediyl or propylenediyl, each of which is optionally substituted by one or more substituents Q. The compound of any one of claims 1 to 58, wherein L is methyldiyl. The compound of any one of claims 1 to 59, wherein m is an integer of 0. Such as the compound of claim 1, wherein: R ¹ , R ² and R ³ are each hydrogen; R ⁴ is thieno[2,3- c ]pyridin-2-yl, 4-fluorothio[2,3- c ]pyridin-2-yl, 4-chlorothieno[2,3- c ]pyridin-2-yl, 4-methylthieno[2,3- c ]pyridin-2-yl, 4-chloro-3- Methylthieno[2,3- c ]pyridin-2-yl, thiazolo[5,4- c ]pyridin-2-yl, 4-fluorothiazolo[5,4- c ]pyridin-2-yl, 4-Chlorothiazolo[5,4- c ]pyridin-2-yl, 4-methylthiazolo[5,4- c ]pyridin-2-yl, benzo[ d ]isothiazol-6-yl, 3 -Cyanobenzo[ d ]isothiazol-6-yl, 3-methylbenzo[ d ]isothiazol-6-yl, 3-fluoromethylbenzo[ d ]isothiazol-6-yl, 3- Hydroxybenzo[ d ]isothiazol-6-yl, 3-methoxybenzo[ d ]isothiazol-6-yl, 3-ethoxybenzo[ d ]isothiazol-6-yl, benzo[ d ][1,2,3]thiadiazol-6-yl, isoquinolin-6-yl, 1,6-tridin-2-yl, 8-fluoro-1,6-tridin-2-yl , 8-chloro-1,6-tridin-2-yl, 8-methyl-1,6-tridin-2-yl, or 8-ethyl-1,6-tridin-2-yl; R ⁶ is 2,4-dimethylbenzoyl or 2,2-dimethyl-5-(nitrooxy)pentyl; L is methyldiyl; and m is an integer of 0. The compound of claim 1 or 61, wherein the compound is: ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (thieno[2,3- c ]pyridine -2-yl)-Propanamide-2- d A1 ; ( S )-3-amino-2-(4-(hydroxymethyl)phenyl) -N- (isoquinolin-6-yl)- Propamide-2- d A2 ; ( S )-2,2-dimethyl-5-(nitrooxy)pentanoic acid 4-(3-amino-1-side oxy-1-(thieno [2,3- c ]pyridin-2-ylamino)propan-2-yl-2- d )benzyl ester A3 ; ( S )-2,2-dimethyl-5-(nitrooxy)pentan Acid 4-(3-amino-1-(isoquinolin-6-ylamine)-1-side oxypropan-2-yl-2- d ) benzyl ester A4 ; ( S )-2,4- Dimethylbenzoic acid 4-(3-amino-1-pendantoxy-1-(thieno[2,3- c ]pyridin-2-ylamino)propan-2-yl-2- d )benzyl Ester A5 ; or ( S )-2,4-dimethylbenzoic acid 4-(3-amino-1-(isoquinolin-6-ylamine)-1-side oxypropan-2-yl- 2- d ) Benzyl ester A6 ; or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or precursors Medicine. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 62, or an enantiomer thereof, a mixture of enantiomers, a diastereomer, or two or more non-stereoisomers. Mixtures of enantiomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; and pharmaceutically acceptable salts, solvates or hydrates thereof; Acceptable excipients. The pharmaceutical composition of claim 63, wherein the composition is in a topical dosage form. A method of treating, preventing or ameliorating one or more symptoms of a ROCK-mediated disorder, disease or condition in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of any one of claims 1 to 62 The compound of claim 63 or the pharmaceutical composition of claim 64. Claim the method of claim 65, wherein the disorder, disease or condition is an eye disease. A method of treating, preventing or ameliorating one or more symptoms of an eye disease in an individual, comprising administering to the individual in need a therapeutically effective amount of a compound as claimed in any one of claims 1 to 62 or as claimed in claim 63 or 64 pharmaceutical compositions. For example, claim the method of item 66 or 67, wherein the eye disease is ocular hypertension or glaucoma. A method of treating, preventing or ameliorating one or more symptoms of neurodegenerative eye disease in an individual, comprising administering to the individual in need a therapeutically effective amount of a compound as claimed in any one of claims 1 to 62 or as claimed 63 or 64 pharmaceutical composition. The method of claim 69, wherein the neurodegenerative eye disease is glaucoma. A method of reducing intraocular pressure in an individual, comprising administering to the individual in need a therapeutically effective amount of a compound of any one of claims 1 to 62 or a pharmaceutical composition of claim 63 or 64. The method of any one of claims 65 to 71, wherein the individual is a human. A method of inhibiting the activity of ROCK, which includes contacting the ROCK with an effective amount of a compound as claimed in any one of claims 1 to 62 or a pharmaceutical composition as claimed in claim 63 or 64.