CDK inhibitors, pharmaceutical compositions and therapeutic applications thereof

Abstract

The present application provides CDK inhibitors, such as compounds of formula (I), and pharmaceutical compositions thereof. Methods for treating, preventing, or alleviating gastrointestinal side effects caused by chemotherapy are also provided. TIFF2025514839000103.tif44170

Description

[Technical field]

[0001] The present application provides CDK inhibitors and pharmaceutical compositions thereof, as well as methods of using the formulations to treat, prevent, or alleviate chemotherapy-associated gastrointestinal side effects. [Background technology]

[0002] Chemotherapy-related gastrointestinal side effects are a common cancer treatment problem and have a significant impact on morbidity and mortality in cancer patients (see O'Reilly Et al.,Ther. Adv.Chronic Dis. 2020, 11, 2040622320970354; McQuade Et al.,Front Pharmacol. 2016, 7, 414). For example, the incidence of chemotherapy-induced diarrhea (CID) with traditional chemotherapy agents such as fluorouracil and irinotecan reaches 50%-80% (see Stein,Ther. Adv. Med. Oncol. 2010, 2,51-63; McQuade Et al.,Front Pharmacol. 2016, 7, 414). Surprisingly, many targeted therapies, such as tyrosine kinase inhibitors and immunotherapy, carry a significantly higher risk of developing CIP than traditional chemotherapy (see Pessi Et al., Crit. Rev. Oncol. Hematol. 2014, 90, 165-79; Bossi Et al., Ann. Oncol. 2018, 29, iv126-42). CID has been seen in patients who have previously received small molecule tyrosine kinase inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, cyclin-dependent kinase (CDK) 4 / 6 inhibitors, and poly ADP-ribose polymerase (PARP) inhibitors (see Pessi Et al., Crit. Rev. Oncol. Hematol. 2014, 90, 165-79; Bossi Et al., Ann. Oncol. 2018, 29, iv126-42; Secombe Et al., Integr. Cancer Ther. 2020, 19, 1-12).

[0003] Chemotherapy-related gastrointestinal side effects invariably lead to the discontinuation or modification of treatment regimens, affecting patient prognosis and overall survival (see O'Reilly Et al., Ther. Adv.Chronic Dis. 2020, 11, 2040622320970354; McQuade Et al., Front Pharmacol. 2016, 7, 414). CIDs have been reported to lead to treatment modifications, such as dose reductions, delays, or treatment discontinuation, in approximately 60% of colorectal cancer patients (see Arbuckle Et al., Oncologist 2000, 5, 250-9; Dranitsaris Et al., Can. J. Gastroenterol. 2005, 19, 83-7). Currently, treatments for CID aim to reduce the severity of symptoms rather than combating pathophysiological mechanisms (see Andreyev et al., Lancet Oncol. 2014, 15, e447-e60; McQuade et al., Front Pharmacol. 2016, 7, 414). Therefore, effective therapeutic regimens are needed to treat, prevent, and alleviate chemotherapy-related gastrointestinal side effects such as CID. Summary of the Invention

[0004] The present application relates to a compound of formula (I) The present invention provides a compound as set forth in TIFF2025514839000002.tif42170, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: R 1 (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; (iii) -C(O)R1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(NR 1a )NR 1b R 1c and; R 2 , R 3 , R 4 and R 6 are each independently: (i) hydrogen, deuterium, cyanide, halogen, or nitro; 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)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , -S(O)NR 1b R 1c may be one selected from; Each R 5 are independently: (i) deuterium, cyanide, halogen, 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)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)NR 1b R 1c and; R 7 (i)C 2-6 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 (ii) -OR 7a , -NR 7b R 7c , -NR 7d C(O)R 7e , -NR 7d C(O)OR 7e or -NR 7d C(O)NR 7b R 7c and; Each R 6a are independently: (i) deuterium, cyanide, halogen, 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)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 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(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R1a , -S(O)NR 1b R 1c or -S(O)NR 1b R 1c and; R 7a is 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 may be one selected from aralkyl, heteroaryl, or heterocyclyl; Each R 7b and R 7c is hydrogen, 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 R 7b and R 7c may form, together with the nitrogen atom to which they are attached, a heteroaryl or heterocyclyl; Each R 7d and R 7e are each independently hydrogen, 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, heterocyclic aryl, or heterocyclyl; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-14 Aryl, C 7-15 aralkyl, heterocyclic aryl, or heterocyclyl; In the formula, m is an integer of 0, 1, 2, or 3; n is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl is substituted with one or more, or, in some embodiments, one, two, three, or four, substituents Q, where each Q is independently selected from: (a) deuterium, cyanide, halogen, imine, nitro, nitroxy, and oxo; (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 which may be further substituted with one or more substituents, and in certain embodiments, may be substituted with one, two, three, or four substituents Q a 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)2R a , -OS(O)NR b R c , -OS(O)2NR 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)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c Sum-S(O)2NR b Rc, in which each R a , R b , R c and R d are each independently represented as one of the following: (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which may be one or more of Q a and in some embodiments, one, two, three or four substituents Q a and (iii) R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl, and one or more Q a and in some embodiments, one, two, three or four substituents Q a is replaced by; Each Q in the formula a are each independently selected from the following: (a) deuterium, cyanide, halogen, imine, nitro, nitroxy, and carbonyl; (b) 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 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)2R e , -OS(O)NR f R g , -OS(O)2NR 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)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g Sum-S(O)2NR f R g , in which, each R e , R f , R g and R h are each independently (i) hydrogen or deuterium, (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, or (iii) R f and R g together with the nitrogen atom to which they are attached to form a heterocyclyl.

[0005] The present application provides certain pharmaceutical compositions comprising a compound of formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharma-ceutically acceptable excipient.

[0006] The present application also provides a method for treating, preventing, or ameliorating a disease, disorder, or condition associated with one or more symptoms associated with cyclin-dependent kinases (CDKs), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma-ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0007] The present application also provides a method for treating, preventing, or ameliorating chemotherapy-associated gastrointestinal side effects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, or mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0008] The present application provides a method for treating, preventing, or alleviating chemotherapy-associated diarrhea, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0009] The present application provides a method for inhibiting the activity of a cyclin-dependent kinase (CDK), comprising contacting the CDK with a compound according to formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma-ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0010] In order to better understand the present application, several terms are defined below.

[0011] Generally, the nomenclature used in this application and the organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology laboratory procedures are well known and widely adopted in the art. Unless otherwise defined, technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In this application, the two terms "subject" and "patient" are used interchangeably in reference to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0013] The terms "treatment," "treating," and "treatment method" refer to alleviating or eliminating a disease, disorder, or condition, or alleviating or eliminating one or more symptoms associated with the disease, disorder, or condition, or alleviating or eliminating the cause of the disease, disorder, or condition.

[0014] The terms "prevention," "preventing," and "method of preventing" refer to delaying and / or preventing the onset of a disease, disorder, or condition and its associated symptoms, preventing a subject from contracting a disease, disorder, or condition, or reducing a subject's risk of contracting a disease, disorder, or condition.

[0015] The terms "alleviating" and "alleviating" refer to the alleviation or reduction of one or more symptoms (e.g., pain) associated with a disease, disorder, or condition. The term may also refer to the reduction of side effects associated with the active ingredient. The benefit that a subject derives from a prophylactic or therapeutic agent may not result in a cure of the disease, disorder, or condition.

[0016] The term "contact" or "exposure" refers to binding of a therapeutic agent with a biomolecule (such as a protein, enzyme, RNA, DNA, etc.), cell, or tissue, resulting in a physiological and / or chemical effect as a result of such contact. Exposure can occur in vitro, in a test tube, or in a living body. In one embodiment, the 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 a test tube) to determine the effect of the therapeutic agent on the cells. In another embodiment, contacting the therapeutic agent with the biomolecule, cell, or tissue comprises administering the therapeutic agent to a receptor having the biomolecule, cell, or tissue to be contacted.

[0017] The term "therapeutically effective amount" or "effective amount" refers to an administration of a compound that can prevent or alleviate one or more symptoms of the disease, condition, or disease being treated. The term "therapeutically effective amount" or "effective amount" also refers to an amount of a compound sufficient to elicit the desired biological or medical response in a biomolecule (protein, enzyme, RNA, DNA, etc.), cell, tissue, system, animal, or human, as desired by a researcher, veterinarian, physician, or clinician.

[0018] The term "IC50" or "EC50" refers to the amount, concentration, or dose of a compound needed to inhibit 50% of a maximal response in an experiment testing a biological response.

[0019] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or carrier, such as a liquid, solid filler, diluent, excipient, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components in a pharmaceutical formulation and suitable for use in contact with the tissues or organs of a subject (such as a human) without causing excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington The Science and Practice of Pharmacy 23rd Edition; Adejare Ed.;Academic Press, 2020; Handbook of pharmaceutical excipients 9th Edition; Sheskey et. al, Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds.; Synapse InformationResources, 2007; Pharmaceutical Preformulation and Formulation, 1st Edition; Gibson Ed.; See CRC Press, 2015.

[0020] "About" or "approximately" indicates an acceptable error for a value depending on how the value is measured or determined, as judged by one of ordinary skill in the art. In some embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations of a given value or range. In some embodiments, the term "about" or "approximately" means within 25%, within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, within 0.5%, or within 0.05% of a given value or range.

[0021] "Alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkyl is an alkyl group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1-6(C 1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ) or 3~6(C 3-6 ) carbon atoms. 1-6 Or branch C 3-6 Alkyl is also referred to as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers such as n-propanol, isopropyl), butyl (including all isomers such as n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (including all isomers such as n-pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl), and hexyl (including all isomers such as n-hexyl, isohexyl, sec-hexyl).

[0022] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group whose backbone contains one or more heteroatoms, each heteroatom being independently selected from O, S, and N. The heteroalkyl may be substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, heteroalkyl is a cyclic or cyclic group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1-6(C1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ) or 3~6(C 3-6 ) carbon atoms. 1-6 Or branch C 3-6 Heteroalkyl is also referred to as "lower heteroalkyl". Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. By way of example, but not limited to, heteroalkyl can be substituted with -CH2NHC(O)CH3 and -NHC(O)CH2CH3.

[0023] The term "alkenyl" refers, in one embodiment, to a linear or branched monovalent hydrocarbon radical containing one, two, three, or four carbon-carbon double bonds, and in another embodiment, one carbon-carbon double bond. The alkenyl may be optionally substituted with one or more substituents Q as described herein. The term "alkenyl" includes the "cis" or "trans" conformations or mixtures thereof, or alternatively, the "Z" or "E" conformations or mixtures thereof, as known to those skilled in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In some embodiments, the alkenyl is a 2 to 20 (C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ) or 2-6(C 2-6 ) straight-chain monovalent hydrocarbon group consisting of 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ) or 3~6(C 3-6(Alkenyl) refers to a branched monovalent hydrocarbon group of 1 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylene, propenyl (including all isomers such as propenyl-1-yl, propenyl-2-yl, and propenyl), and butenyl (including all isomers such as butenyl-1-yl, butenyl-2-yl, butenyl-3-yl, and 2-butenyl-1-yl).

[0024] The term "alkynyl" refers, in one embodiment, to a linear or branched monovalent hydrocarbon group containing one, two, three, or four carbon-carbon triple bonds, and in another embodiment, one carbon-carbon double bond. Alkynyl does not contain a carbon-carbon double bond. The alkynyl may be substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 4 to 6 carbon atoms. In some embodiments, the alkynyl is a cyclic alkyl radical having 2 to 20 (C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ) or 2-6(C 2-6 ) straight-chain monovalent hydrocarbon group consisting of 4 to 20 (C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ) or 4~6(C 4-6 ) carbon atoms. Illustrative examples of alkynyl groups include, but are not limited to, acetenyl (-C≡CH), propynyl (including all isomers such as 1-propynyl, 2-propynyl, and propargyl), butynyl (including all isomers such as 1-butynyl-1-yl and 2-butynyl-1-yl), pentynyl (including all isomers such as 1-pentynyl-1-yl and 1-methyl-2-pentynyl-1-yl), and hexynyl (including all isomers such as 1-hexynyl-1-yl and 2-hexynyl-1-yl).

[0025] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, a cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In some embodiments, a cycloalkyl is a cyclic group having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ) or 3~7(C 3-7 ) carbon atoms. In one embodiment, cycloalkyl is monocyclic, in another embodiment, cycloalkyl is bicyclic, in another embodiment, cycloalkyl is tricyclic, and in yet another embodiment, cycloalkyl is polycyclic. Illustrative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadiene, cycloheptyl, cycloheptenyl, [1.1.1]bicyclopentyl, [2.1.1]bicyclohexyl, [2.2.1]bicycloheptyl, [2.2.2]bicyclooctyl, bicyclo, and adamantane.

[0026] In this application, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon having one or more aromatic rings. In some embodiments, aryl is a cyclic or polycyclic aromatic hydrocarbon having 6 to 20 (C 6-20 ), 6~15(C 6-15 ), 6~10(C 6-10) ring carbon atoms. Illustrative examples of aryl include, but are not limited to, phenyl, naphthyl, fluorenyl, azabicycloheptyl, anthryl, phenanthryl, pyrenyl, biphenyl, and triphenyl. Aryl also refers to a radical having two or three carbon rings, in which one ring is aromatic and the other ring can be saturated, partially unsaturated, or aromatic, such as dihydronaphthalene, indenyl, indenyl alkyl, or tetralyl. In some embodiments, aryl is monocyclic. In another embodiment, aryl is bicyclic. In another embodiment, aryl is tricyclic. In another embodiment, aryl is polycyclic. In some embodiments, one or more radicals of aryl can be substituted with Q as described in this application.

[0027] The term "aralkyl" refers to a monovalent alkyl substituted with one or more aryls. In some embodiments, the aralkyl is a 7-30 (C 7-30 ), 7~20(C 7-20 ), 7~16(C 7-16 ) carbon atoms. Illustrative examples of aralkyl include, but are not limited to, benzyl, phenethyl (including all isomers such as 1-phenethyl and 2-phenethyl), and phenylpropyl (including all isomers such as 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, aralkyl is optionally substituted with one or more substituents Q as described herein.

[0028] The term "heteroaryl" refers to a monovalent monocyclic aryl or monovalent polycyclic aryl having at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, and N in the ring. For heteroaryls having heteroaryl rings and non-aromatic heterocycles, the heteroaryl is not bonded to the remainder of the molecule through the non-aromatic heterocycle. Each ring of the heteroaryl may contain 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and / or 1 or 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In some embodiments, the heteroaryl is monocyclic. Illustrative examples of monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isothiazole, isoxazole, oxadiazole, xazole, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, thiadiazole, thiazole, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic.Illustrative examples of bicyclic heteroaryls include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazole, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomers of furo[2,3-b]pyridinyl, furan[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[(3,4-b)pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomers of furo[2,3-b]pyridinyl, furan[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,4-c]pyridinyl, and furo[3,4-b]pyridinyl), and aryl groups. imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[4,5-c]pyridinyl, imidazothiazole (including all isomers such as imidazo[2,1-b]thiazole and imidazo[4,5-d]thiazole), indazolyl, indazinyl, indolyl, isobenzofuranyl, isobenzothiophene (i.e. benzo[c]thiophene), isoindolyl, isoquinolinyl, naphthyridinyl (1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,9-naphthyridinyl, 2,10-naphthyridinyl, 2,20-naphthyridinyl, 2,3-naphthyridinyl, 2,4-naphthyridinyl, 2,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, 2,8-naphthyridinyl, 2 ... ,7-naphthyridinyl and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomers such as oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolidinopyridinyl (including pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl and pyrrolo[3,2-c]pyridinyl). Examples of heteroaryl include, but are not limited to, quinolyl, quinoxalinyl, quinoxolinyl, thiadiazolyl, and pyrimidinyl (including all isomers thereof), such as [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridinyl (including all isomers thereof, such as thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, heteroaryl is tricyclic.Illustrative examples of tricyclic heteroaryls include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, piperidine, phenanthrolinyl, phenanthridinyl (including all isomers such as 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl and 2,10-phenanthrolinyl), phenazinyl, phenarsazine, phenothiazinyl, phenoxazinyl and xanthenyl. In some embodiments, heteroaryls are optionally substituted with one or more substituents Q as described herein.

[0029] The term "heterocyclyl" refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring having at least one non-aromatic ring, in which one or more of the non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, and N, and the other ring atoms are carbon atoms. For heterocyclyls that contain heteroaromatic and non-aromatic rings, the heterocyclyl is not linked to the remainder of the molecule by a heteroaromatic ring. In some embodiments, a heterocyclyl or 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 some embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic structure, which may be fused or bridged, and in which N or S atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or have aromatic character. The term "heterocyclyl" refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring having at least one non-aromatic ring, in which one or more of the non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, and N, and the other ring atoms are carbon atoms. For heterocyclyls that contain heteroaromatic and non-aromatic rings, the heterocyclyl is not linked to the remainder of the molecule by a heteroaromatic ring. In some embodiments, a heterocyclyl or 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 some embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic structure, which may be fused or bridged, and in which N or S atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or have aromatic character. The heterocyclyl may be attached to the primary structure at any heteroatom or carbon atom which results in the creation of a stable compound.Illustrative examples of heterocyclyl and heterocyclyl radicals include imidazolidinyl, benzodihydropyridinyl, benzodiphenyl, benzofuranosyl, benzodihydropyran, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazole, dihydrobenzisoxazinyl (including all isosteres such as 1,4-dihydrobenzo[d][1,3]hydrazinyl, 3,4-dihydrobenzo[c][1,2]hydrazinyl and 3,4-dihydrobenzo[d][1,2]hydrazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, Examples of heterocyclyl include, but are not limited to, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolyl, 1,4-dithienyl, furazolidinyl, imidazolidinyl, imidazolinyl, dihydroindolyl, benzodihydroisopyranyl, isodihydroindolyl, isothiazolidinyl, isoxazolidine, morpholino, octahydroindolyl, octahydroisoindolyl, oxazolidine, ethylene oxide, piperazinyl, piperidine, 4-piperidine, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuran, thiomorpholinyl, tetrahydropyran, thiazolidinyl, benzodihydropyran, tetrahydroquinolinyl, and 1,3,5-trithienyl. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0030] The terms "halogen," "halide," or "halo radical" refer to fluorine, chlorine, bromine, and / or iodine.

[0031] The term "optionally substituted" refers to a radical or substituent, such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, that may be substituted with one or more substituents Q, where each substituent Q is independently selected from: (a) deuterium (-D), cyanide (-CN), halogen, imine (=NH), nitro (-NO2), and carbonyl (=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 or heterocyclyl, in which each radical may further comprise one or more substituents Q a or in some embodiments, one, two, three or four substituents Q a 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)2R a , -OS(O)NR b R c , -OS(O)2NR 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)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -P(O)R b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c and -S(O)NR b R c , in which, each R a , R b , R c and R d each independently represents (i) hydrogen or deuterium, 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, in which each radical may be one or more substituents Q a and in certain embodiments, one, two, three or four substituents Q a or (iii) R b and R c together with the nitrogen atom to which they are attached to form a heterocyclyl, which may include one or more substituents Q a In some embodiments, the group is optionally substituted with one, two, three, or four substituents Q a In this application, all radicals that can be substituted are referred to as "optionally substituted."

[0032] In one embodiment, each Q a may each independently be selected from: (a) deuterium, cyanide, halogen, nitro, and carbonyl; (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; 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)2R e 、 -OS(O)NR f R g 、 -OS(O)2NR 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)2R h 、 -NR e S(O)NR f R g 、 -NR e S(O)2NR f R g 、 -P(O)R f R g 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR f R g and -S(O)2NR f R g ; Among them, each R e 、Rf , R g and R h are each 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 taken together with the nitrogen atom to which they are attached may form a heterocyclyl.

[0033] In some embodiments, "optically active" and "enantiomeric activity" refer to a group of molecules having an enantiomeric excess of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, the optically active compound is based on a total weight of the enantiomeric mixture of the discussed mixture that contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer. In some embodiments, the optically active compound is based on a total weight of the enantiomeric mixture of the discussed mixture that contains about 98% or more of one enantiomer and about 2% or less of the other enantiomer. In some embodiments, the optically active compound is based on a total weight of the enantiomeric mixture of the discussed mixture that contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer.

[0034] In describing optically active compounds, the prefixes R and S are used to indicate the absolute conformation of the compound with respect to the chiral center. Additionally, (+) and (-) are used to indicate the rotational properties of the compound, i.e., the direction in which the optically active compound rotates the plane of polarized light. The (-) prefix indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation (+ / -) is independent of the absolute conformation R and S of the compound.

[0035] The term "isotopically enriched" refers to an unnatural proportion of an isotope in one or more atoms that constitute a compound. In some embodiments, an isotopically enriched compound contains one or more unnatural proportions of isotopes, e.g., 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), iodine-131( 131 In some embodiments, the isotopically enriched compound is stable, i.e., non-radioactive. In some embodiments, the isotopically enriched compound contains one or more non-naturally occurring isotopes, such as, for example, hydrogen ( 1 H), deuterium ( 2 H), Carbon-12( 12 C), 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), Iodine-127( 127 In some embodiments, the isotopically enriched compound is non-stable, i.e., radioactive. In some embodiments, the isotopically enriched compound contains one or more non-naturally occurring isotopes, such as 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( 32P), phosphorus-33( 33 P), sulfur-35( 35 S), Chlorine-36( 36 Cl), Iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), iodine-131( 131 I) and the like, but are not limited to these. In such compounds, any hydrogen is 2 H, any carbon 13 C, any nitrogen 15 N, any oxygen 18 It should be understood that the number of possible combinations may vary from 0 to 10, and is based on the judgment of one of ordinary skill in the art to determine feasibility.

[0036] The term "isotopic enrichment" refers to the amount of isotope of an element at a given position in a molecule that is more prevalent (e.g., 1 It refers to the proportion of isotopes (e.g., H corresponds to hydrogen protons or hydrogen-1) that are replaced with less common isotopes (e.g., D corresponds to deuterium or hydrogen-2). In this application, when an atom at a particular location in a molecule is designated as a particular less common isotope, it is understood that the abundance of that isotope at that location is much greater than the natural abundance.

[0037] The term "isotopic enrichment factor" refers to the ratio of the abundance of an isotope in an isotopically enriched compound to the natural abundance of the specified isotope.

[0038] The term "hydrogen" or the symbol "H" refers to a proton ( 1 H), deuterium ( 2 H or D), tritium ( 3 H) and their natural abundance. Proton is the most common hydrogen isotope, with a natural abundance of greater than 99.98%. Deuterium is the less common hydrogen isotope, with a natural abundance of about 0.0156%.

[0039] The term "deuterium enrichment" refers to the percentage of hydrogen replaced by deuterium at a given position in a molecule. For example, 1% enrichment in deuterium at a position means that 1% of the molecules present in a given sample contain deuterium at the specified position. Because the distribution of naturally occurring deuterium averages about 0.0156%, compounds synthesized using non-enriched starting materials will have an average deuterium enrichment of about 0.0156% at any position. As used herein, when a particular position in a given isotopically enriched compound has deuterium, it is understood that the abundance of deuterium at that position in the compound is significantly higher than its natural abundance (0.0156%).

[0040] "Carbon" or the symbol "C" refers to the naturally occurring carbon isotope composition, including the naturally occurring carbon-12 ( 12 C) and Carbon-13 ( 13 Carbon-12 is the most common hydrogen isotope, with a natural abundance of over 98.89%. Carbon-13 is the less common carbon isotope, with a natural abundance of about 1.11%.

[0041] "carbon- 13 Concentrated" or " 13 The term "C enriched" refers to the carbon- 13 Deuterium enrichment refers to the percentage of carbon substituted with carbon-13. For example, 10% enrichment in carbon-13 at a position means that 10% of the molecules present in a given sample contain carbon-13 at the specified position. Because the distribution of naturally occurring carbon-13 averages about 1.11%, compounds synthesized using non-enriched starting materials will have an average deuterium enrichment of about 1.11% at any position. As used herein, when a particular position in a given isotopically enriched compound has carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is significantly higher than its natural abundance (1.11%).

[0042] The terms "substantially pure" and "substantially homogeneous" when used with respect to a substance refer to a substance that is sufficiently homogeneous that impurities cannot be readily detected by standard analytical methods used by those of 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 that is sufficiently pure that further purification would not significantly alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activity. In some embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. In this application, a compound containing a non-specified isotope at a particular position is an impurity associated with the isotopically enriched compound if the atom at that position in the isotopically enriched compound is the specified less common isotope. Thus, a compound designated as deuterium at a particular position is considered an impurity if it contains a proton at that same position.

[0043] The term "solvate" refers to a complex or aggregate formed with one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules, which exists in a stoichiometric or non-stoichiometric ratio. Suitable flow aids include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharma- ceutically acceptable. In some embodiments, the complex or aggregate is in crystalline form. In another embodiment, the complex or assembly has a non-crystalline form. When the solvent is water, the resulting solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0044] For divalent radicals described in this application, no orientation is implied in which the divalent radical is shown. For example, unless a specific orientation is specified, the formula representation of -C(O)NH- may be either -C(O)NH- or -NHC(O)-.

[0045] The term "an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as "(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers of said compound, (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of said compound, or (iii) an enantiomer, a mixture of enantiomers, diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of said compound." In the compound

[0046] In one embodiment, the present application relates to a compound of formula (I): The present invention provides a compound as set forth in TIFF2025514839000003.tif43170, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: R 1 is (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 or -C(NR 1a )NR 1b R 1c and; Each R 2 , R 3 , R 4 and R 6 are independently: (i) hydrogen, deuterium, cyanide, halogen, 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(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1aC(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)NR 1b R 1c and; Each R 5 are independently: (i) deuterium, cyanide, halogen, 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(O)SR 1a , -C(NR 1a )NR 1b R 1c, -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)NR 1b R 1c and; R 7 (i)C 2-6 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 (ii) -OR 7a , -NR 7b R 7c , -NR 7d C(O)R 7e , -NR 7d C(O)OR 7e or -NR 7d C(O)NR 7b R 7c and; Each R 6a are independently: (i) deuterium, cyanide, halogen, 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(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 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(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R1c or -S(O)NR 1b R 1c and; Each R 7a are each independently 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 R 7b and R 7c are independently hydrogen, 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 R 7b and R 7c together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl; Each R 7d and R 7e are independently hydrogen, 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 R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and 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 It may be aralkyl, heteroaryl or heterocyclyl; m is an integer of 0, 1, 2 or 3; n is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl is substituted with one or more, or, in some embodiments, one, two, three, or four, substituents Q, where each Q is independently selected from: (a) deuterium, cyanide, halogen, imine, nitro, nitrooxy, and oxo; (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 which may be further substituted with one or more substituents, or in certain embodiments, with one, two, three, or four substituents Q a 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)2R a , -OS(O)NR b R c , -OS(O)2NR 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)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c Sum-S(O)2NR b R c , in which, each R a , R b , R c and R d may each independently be: (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, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which may have one or more, or in some embodiments, one, two, three, or four, substituents Q a and (iii) R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl, which heterocyclyl may contain one or more, or in some embodiments, one, two, three or four, substituents Q a is replaced by; Each Q in the formula a may each independently be selected from: (a) deuterium, cyanide, halogen, imine, nitro, nitrooxy, and oxo; (b) 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 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)2Re , -OS(O)NR f R g , -OS(O)2NR 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)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g Sum-S(O)2NR f R g , in which, each R e , R f , R g and R h are each 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) Rf and R g taken together with the nitrogen atom to which they are attached may form a heterocyclyl.

[0047] In another embodiment, the present application relates to a compound of formula (Ia): The compound shown in TIFF2025514839000004.tif43170 (wherein R 6 and R 7 (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0048] In another embodiment, the compound of formula (Ib): The compound shown in TIFF2025514839000005.tif46170 (wherein R 6 and R 7 (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0049] In some embodiments, in formula (I), (Ia), or (Ib), R 6 is hydrogen or C 1-6 In some embodiments, in formula (I), (Ia), or (Ib), R 6 is hydrogen or methyl. In some embodiments, in formula (I), (Ia), or (Ib), R 6 is hydrogen. In some embodiments, in formula (I), (Ia) or (Ib), R 6 is methyl.

[0050] In some embodiments, in formula (I), (Ia), or (Ib), R 7 is (i) C, each functional group of which may be optionally substituted with one or more substituents Q2-6 alkyl, heteroaryl, or heterocyclyl; or (ii) -OR 7a , -NR 7b R 7c , -NR 7d C(O)R 7e , -NR 7d C(O)OR 7e or -NR 7d C(O)NR 7b R 7c In this case, each R 7a , R 7b , R 7c , R 7d and R 7e is defined herein. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is C 2-6 In some embodiments, in formula (I), (Ia), or (Ib), R 7 is ethyl, propyl, or butyl, each of which may be optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 is ethyl or isopropyl.

[0051] In some embodiments, in formula (I), (Ia), or (Ib), R 7 is heteroaryl, which may be optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a monocyclic heteroaryl, which may be optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a 5- or 6-membered heteroaryl, each of which may be optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a 5-membered heteroaryl, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7is a 6-membered heteroaryl, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is imidazole, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in Formula (I), (Ia) or (Ib), R7 is imidazol-1-yl, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in Formula (I), (Ia) or (Ib), R 7 is 1-imidazolyl or 2-aminoimidazol-1-yl.

[0052] In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a bicyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a 5,5-fused heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 5,6-fused heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 6,6-fused heteroaryl, optionally substituted with one, two or three substituents Q.

[0053] In some embodiments, in formula (I), (Ia), or (Ib), R 7 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7is 3, 4, 5, 6, or 7-membered heterocyclyl, each of which may be optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a 3-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 4-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 5-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 6-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a 7-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is azabicyclobutyl, oxazolidine, piperidine, or morpholinyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 is an azetidin-1-yl, oxazolidine-3-substituent, piperidine-1-substituent, or morpholine-4-substituent, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 is a 3-hydroxyazetidine-1-substituent, a 5-(hydroxymethyl)-2-oxazolidine-3-substituent, an (R)-2-(hydroxymethyl)piperidine-1-substituent or a morpholine-4-substituent.

[0054] In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7is a bridged, fused, or spiroheterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is a bridged heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is a fused heterocyclyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in formula (I), (Ia) or (Ib), R 7 is spiroheterocyclyl, optionally substituted with one, two or three substituents Q.

[0055] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -OR 7a In this case, R 7a is defined herein. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -OR 7a In this case, R 7a is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is C 1-6 In some embodiments, in formula (I), (Ia), or (Ib), R 7 is methoxy, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is C 3-10 Heteroalkoxy is optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 is C 6-14 aryloxy, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7is methoxy, ethoxy, propoxy, cyclopentyloxy, or phenoxy, each of which is optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 is pivaloyloxymethoxy, benzoyloxymethoxy, isopropoxy, cyclopentyloxy or 4-methylphenoxy.

[0056] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c and R are each defined herein. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c are each independently hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c are each independently hydrogen or C 1-6 In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c are each independently (i) hydrogen, or (ii) methyl, ethyl, propyl, butyl, or amyl, each of which is optionally substituted with hydroxycarbonyl, hydroxy, methoxy, or amino. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7care each independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxymethyl, propyl, isopropyl, or 1-(hydroxycarbonyl)-2-methylpropyl.

[0057] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the nitrogen atom to which they are attached form a monocyclic heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, in Formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a 5- or 6-heteroaryl, each optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7ctogether with the N atom to which they are attached form a 5-heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a bicyclic heteroaryl, optionally substituted with one, two or three Q substituents.

[0058] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the nitrogen atom to which they are attached form a heterocyclyl, which is optionally substituted with one or more. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a monocyclic heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in Formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7ctogether with the N atom to which they are attached form a 5- or 6-membered heterocyclyl, each heterocyclyl optionally substituted with one, two or three substituents Q. In some embodiments, in Formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a 5-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a 6-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the N atom to which they are attached form a bicyclic heterocyclyl, optionally substituted with one, two or three substituents Q.

[0059] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7b R 7c In this case, R 7b and R 7c together with the nitrogen atom to which they are attached form imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazabihydrogenazabiheterocycle-1-yl, 2-oxo-5-(hydroxymethyl)oxazolidin-3-yl, 2(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

[0060] In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)R7e In this case, R 7d and R 7e and R are each defined herein. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen and R 7e is C 1-6 Alkyl, C 3-10 cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen and R 7e is C 1-6 In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen and R 7e is C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen and R 7e is a monocyclic C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is a monocyclic heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is a 5- or 6-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrrolidine, tetrahydrofuran, or tetrahydropyran, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)R 7e In this case, R 7d is hydrogen, and R 7e is methyl, aminomethyl, ethyl, 1-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, propyl, isopropyl, 1-aminopropyl, 1-amino-2-methylpropyl, 1,5-diaminepentyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl, or tetrahydropyran-4-yl. In some embodiments, in Formula (I), (Ia), or (Ib), R 7is acetamide, 2-aminoacetamide, propionamide, 2-aminopropionamide, 2-amino-3-(imidazol-4-yl)propionamide, butyramide, isobutyramide, 2-aminobutyramide, 2-amino-3-methylbutyramide, 2,6-diaminohexanamide, cyclopropylamine, cyclobutylamine, pyrrolidin-2-ylamino, tetrahydrofuran-2-carboxamide, or tetrahydrofuran-2-carboxamide, or tetrahydropyran-4-carboxamide. 7 is acetamide, 2-aminoacetamide, propionamide, (S)-2-aminopropionamide, (S)-2-amino-3-(imidazol-4-yl)propionamide, butyramide, isobutyramide, (S)-2-aminobutyramide, 2-amino-3-methylbutyramide, (S)-2,6-diaminohexanamide, cyclopropylamine, cyclobutylamine, (S)-pyrrolidin-2-ylamino, tetrahydrofuran-2-carboxamide or tetrahydrofuran-2-carboxamide or tetrahydropyran-4-carboxamide.

[0061] In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)OR 7e In this case, R 7d and R 7e is defined herein. In some embodiments, in formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is C 1-6 Alkyl, C 3-10 It may be cycloalkyl or heterocyclyl, each of which may be optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 -NR 7dC(O)OR 7e In this case, R 7d is hydrogen, and R 7e is C 1-6 In some embodiments, in formula (I), (Ia), or (Ib), R 7 Ha-NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is C 3-10 In some embodiments, in Formula (I), (Ia), or (Ib), R 7 Ha-NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is a monocyclic C 3-10 In some embodiments, in Formula (I), (Ia), or (Ib), R 7 Ha-NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is heterocyclyl, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 Ha-NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is a monocyclic heterocyclyl, which may be optionally substituted with one, two or three substituents Q. In some embodiments, in formula (I), (Ia) or (Ib), R 7 Ha-NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7eis a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which may be optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is a 5- or 6-membered heterocyclyl, each of which may be optionally substituted with one, two or three substituents Q.

[0062] In some embodiments, in Formula (I), (Ia), or (Ib), R 7 -NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7e is methyl, hydroxyformylmethyl, ethoxyformylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, 2-(2-aminopropionamido)ethyl, 2-(2-amino-3-hydroxypropionamido)ethyl, 2-(2-amino-3-methylbutyramido)ethyl, 2-(2-amino-4-(methylthio)butanamido)ethyl), 2-(2-amino-4-methylpentanamido)ethyl, 2-(pyrrolidin-2-ylamino)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or tetrahydropyran-4-yl. 7 -NR 7d C(O)OR 7e In this case, R 7d is hydrogen, and R 7eis methyl, hydroxyformylmethyl, ethoxyformylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, (R)-2-(2-aminopropionamido)ethyl, (S)-2-(2-amino-3-hydroxypropionamido)ethyl, (S)-2-(2-amino-3-methylbutyramido)ethyl, (S)-2-(2-amino-4-(methylthio)butanamido)ethyl), (S)-2-(2-amino-4-methylpentanamido)ethyl, (S)-2-(pyrrolidin-2-ylamino)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or tetrahydropyran-4-yl.

[0063] In some embodiments, in Formula (I), (Ia), or (Ib), R 7are methoxycarbonylamino, hydroxymethoxycarbonylhydroxymethoxycarbonylamino, ethoxycarbonylmethoxycarbonylethoxycarbonylamino, ethoxycarbonylamino, 2-hydroxyethoxycarbonylethoxycarbonylamino, 2-methoxyethoxycarbonylethoxycarbonylamino, 2-acetyloxyethoxycarbonylethoxycarbonylamino, 2-aminoethoxycarbonylethoxycarbonylamino, 2-acetamidoethoxycarbonylamino, 2-(2-aminoacetamido)ethoxycarbonylamino, 2-(2-aminopropionamido)ethoxycarbonyl In some embodiments, R in Formula (I), (Ia) or (Ib) is an arylamino, 2-(2-amino-3-hydroxypropionamido)ethoxycarbonylamino, 2-(2-amino-3-methylbutyramido)ethoxycarbonylanamino, 2-(2-amino-4-(methylthio)butyramido)ethoxycarbonylamino, 2-(2-amino-4-methylpentanamido)ethoxycarbonylamino, 2-(pyrrolidin-2-ylamino)ethoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, cyclopropoxycarbonylamino, cyclobutoxycarbonylamino, or tetrahydropyran-4-oxycarbonylamino. 7are methoxycarbonylamino, hydroxymethoxycarbonylamino, ethoxycarbonylmethoxycarbonylethoxycarbonylamino, ethoxycarbonylamino, 2-hydroxyethoxycarbonylamino, 2-methoxyethoxycarbonylamino, 2-acetoxyethoxycarbonylamino, 2-aminoethoxycarbonylamino, 2-acetamidoethoxycarbonylamino, 2-(2-aminoacetamido)ethoxycarbonylamino, (R)-2-(2-aminopropionamido) )ethoxycarbonylamino, (S)-2-(2-amino-3-hydroxypropionamido)ethoxycarbonylamino, (S)-2-(2-amino-3-methylbutanamido)ethoxycarbonylamino, (S)-2-(2-amino-4-(methylthio)butanamido)ethoxycarbonylamino, (S)-2-(2-amino-4-methylpentanamido)ethoxycarbonylamino, (S)-2-(pyrrolidin-2-ylamino)ethoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, cyclopropoxycarbonylamino, cyclobutoxycarbonylamino, or tetrahydropyran-4-oxycarbonylamino.

[0064] In some embodiments, in Formula (I), (Ia), or (Ib), R 7 Ha-NR 7d C(O)NR 7b R 7c In this case, R 7b , R 7c and R 7d is defined herein. In some embodiments, in formula (I), (Ia) or (Ib), R 7 Ha-NR 7d C(O)NR 7b R 7c In this case, R 7b and R 7c is hydrogen and R 7c is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), (Ia), or (Ib), R 7 is N'-isopropyl ureide.

[0065] In some embodiments, in Formula (I), (Ia), or (Ib), R 7are ethyl, isopropyl, imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazetidin-1-yl, 5-(hydroxymethyl)-2-oxazolidin-3-yl, (R)-2-(hydroxymethyl)piperidin-1-yl, morpholin-4-yl, nonanediylhydroxymethoxy, benzoylhydroxymethoxy, isopropoxy, cyclopentyloxy, p-toluyloxy, amine, acetamide, 2-aminoacetamide, propionamide, (S)-2-aminopropionamide, (S)-2 -Amino-3-(imidazol-4-yl)propionamide, butanamide, isobutanamide, (S)-2-aminobutanamide, 2-amino-3-methylbutanamide, (S)-2,6-diaminohexanamide, cyclopropylamino, cyclobutylamino, (S)-pyrrolidin-2-ylamino, tetrahydrofuran-2-carboxamide, tetrahydropyran-4-carboxamide, methoxycarbonylamino, hydroxymethylcarbonylmethoxycarbonylamino, ethoxycarbonylcarbonylmethoxycarbonylamino , ethoxycarbonylamino, 2-hydroxyethoxycarbonylamino, 2-methoxyethoxycarbonylamino, 2-acetoxyethoxycarbonylamino, 2-aminoethoxycarbonylamino, 2-acetamidoethoxycarbonylamino, 2-(2-aminoacetamido)ethoxycarbonylamino, (R)-2-(2-aminopropionamido)ethoxycarbonylamino, (S)-2-(2-amino-3-hydroxypropionamido)ethoxycarbonylamino, (S)-2-(2-amino-3-methylbutanamido (S)-2-(2-amino-4-(methylthio)butanamido)ethoxycarbonylamino, (S)-2-(2-amino-4-methylpentanamido)ethoxycarbonylamino, (S)-2-(pyrrolidin-2-ylamino)ethoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, cyclopropoxycarbonylamino, cyclobutoxycarbonylamino, tetrahydropyran-4-oxocarbonylamino, or N'-isopropylureido.

[0066] In another embodiment, the present application relates to a compound of formula (II): The present invention provides a compound as set forth in TIFF2025514839000006.tif39170, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7b , R 7c , m and n are defined in this application.

[0067] In another embodiment, the present application relates to a compound of formula (IIa): or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6 , R 7b and R 7c are each defined in this application.

[0068] In another embodiment, the present application relates to a compound of formula (IIb): or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6 , R 7b and R 7c are each defined in this application.

[0069] In some embodiments, according to formula (II), (IIa), or (IIb), R 6 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, according to Formula (II), (IIa), or (IIb), R 6 is hydrogen or methyl. In some embodiments, according to Formula (II), (IIa), or (IIb), R 6 is hydrogen. In some embodiments, according to Formula (II), (IIa), or (IIb), R 6 is methyl.

[0070] In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c and R are each defined herein. In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c are each independently hydrogen or C 1-6 and alkyl, which may be optionally substituted with one or more substituents Q. In some embodiments, according to formula (II), (IIa), or (IIb), R 7 -NR 7b R 7c In this case, R 7b and R 7c are each independently hydrogen or C 1-6 In some embodiments, according to Formula (II), (IIa) or (IIb), R 7 -NR 7b R 7c In this case, R 7b and R 7c is each independently (i) hydrogen, or (ii) methyl, ethyl, propyl, butyl, or amyl, each of which is optionally substituted with hydroxycarbonyl, hydroxy, methoxy, or amino. In some embodiments, according to Formula (II), (IIa), or (IIb), R 7b and R 7care each independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxymethyl, propyl, isopropyl, or 1-(hydroxycarbonyl)-2-methylpropyl.

[0071] In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c and together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, according to Formula (II), (IIa), or (IIb), R 7b and R 7c and together with the nitrogen atom to which they are attached form a heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, according to Formula (II), (IIa), or (IIb), R 7b and R 7c and together with the nitrogen atom to which they are attached form a monocyclic heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 5- or 6-heteroaryl, each optionally substituted with one, two or three substituents Q. In some embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 5-membered heteroaryl, optionally substituted with one, two or three substituents Q.

[0072] In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c and together with the nitrogen atom to which they are attached form a heterocyclyl, which may be optionally substituted with one or more substituents Q. In some embodiments, according to Formula (II), (IIa), or (IIb), R 7b and R 7ctogether with the nitrogen atom to which they are attached form a monocyclic heterocyclyl substituent, which may be substituted with one, two or three substituents Q. In some embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which may be substituted with one, two, or three substituents Q. In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl, each of which may be substituted with one, two or three substituents Q. In some embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl, which may be substituted with one, two or three substituents Q. In some embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form a 6-membered heteroaryl, optionally substituted with one, two or three substituents Q.

[0073] In some embodiments, according to formula (II), (IIa), or (IIb), R 7b and R 7c together with the nitrogen atom to which they are attached form imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazacyclopentadecan-1-yl, 2-oxo-5-(hydroxymethyl)oxazolidin-3-yl, 2-(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

[0074] In another embodiment, the present application relates to a compound of formula (III): The compound shown in TIFF2025514839000009.tif41170 (wherein R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 6a , R 7d , R 7e , m and n are each defined herein), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0075] In another embodiment, the present application relates to a compound of formula (IIIa): The compound shown in TIFF2025514839000010.tif43170 (wherein R 6 , R 7d and R 7e (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0076] In another embodiment, the present application relates to a compound of formula (IIIb): The compound shown in TIFF2025514839000011.tif51170 (wherein R 6 , R 7d and R 7e (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0077] In some embodiments, for formula (III), (IIIa), or (IIIb), R 6 is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, for formula (III), (IIIa), or (IIIb), R 6is hydrogen or methyl. In some embodiments, for formula (III), (IIIa) or (IIIb), R 6 is hydrogen. In some embodiments, for formula (III), (IIIa), or (IIIb), R 6 is methyl.

[0078] In some embodiments, for formula (III), (IIIa), or (IIIb), R 7d is hydrogen, and R 7e is C 1-6 Alkyl, C 3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, for formula (III), (IIIa), or (IIIb), R 7d is hydrogen, and R 7e is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7e is C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7e is a monocyclic C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7e is heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7e is monocyclic heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7eis a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which may be substituted with one, two, or three substituents Q. In some embodiments, for formula (III), (IIIa), or (IIIb), R 7d is hydrogen, and R 7e is a 5- or 6-membered heterocyclyl, each radical optionally substituted with one, two or three substituents Q. In some embodiments, for formula (III), (IIIa) or (IIIb), R 7d is hydrogen, and R 7e is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrryl, tetrahydrofuran, or tetrahydropyran, each optionally substituted with one, two, or three substituents Q. In some embodiments, for formula (III), (IIIa), or (IIIb), R 7d is hydrogen, and R 7e is methyl, aminomethyl, ethyl, 1-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, propyl, isopropyl, 1-aminopropyl, 1-amino-2-methylpropyl, 1,5-diaminopentyl, cyclopropyl, cyclobutyl, pyrrolidine-2-substituent, tetrahydrofuran-2-substituent or tetrahydropyran-4-substituent.

[0079] In another embodiment, the present application relates to a compound of formula (IV): The compound shown in TIFF2025514839000012.tif35170 (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7d , R 7e , m and n are each defined herein), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0080] In another embodiment, the present application relates to a compound of formula (IVa): The compound shown in TIFF2025514839000013.tif40170 (wherein R 6 , R 7d and R 7e (each as defined in this application) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0081] In another embodiment, the present application provides a compound of formula (IVb): The compound shown in TIFF2025514839000014.tif45170 (wherein R 6 , R 7d and R 7e (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0082] In some embodiments, in formula (IV), (IVa), or (IVb), R 6 is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (IV), (IVa), or (IVb), R 6 is hydrogen or methyl. In some embodiments, in formula (IV), (IVa) or (IVb), R 6 is hydrogen. In some embodiments, in formula (IV), (IVa) or (IVb), R 6 is methyl.

[0083] In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is C 1-6 Alkyl, C 3-10cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e is C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e is a monocyclic C 3-10 In some embodiments, in Formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e is a monocyclic heterocyclyl, optionally substituted with one, two or three substituents Q. 7e is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents Q. In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is a 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two or three substituents Q. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen and R 7e is a 5-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e is a 6-membered heterocyclyl, optionally substituted with 1, 2 or 3 substituents Q.

[0084] In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is C 1-6 alkyl, optionally substituted with one, two or three substituents Q, wherein each substituent is independently -C(O)OR 1a , -OR 1a , -OC(O)R 1a , -NR 1b R 1c or -NR 1a C(O)R 1d And each R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, in formula (IV), (IVa), or (IVb), 7d is hydrogen, and R 7e -C(O)OR 1a C replaced with 1-6 alkyl, in which R 1a is defined herein. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e -OR 1a C replaced with 1-6 alkyl, in which R 1a is defined herein. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e HA-OC(O)R 1a C replaced with 1-6 alkyl, in which R 1a is defined herein. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e -NR 1b R 1c C replaced with 1-6 alkyl, in which R 1b and R 1cand are both defined herein. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e -NR 1a C(O)R 1d C replaced with 1-6 alkyl, in which R 1a and R 1d are both defined in this application.

[0085] In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is an aminoamide-substituted C 1-6 In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is C substituted with α-aminoamide or β-aminoamide 1-6 In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is an α-amino amide substituted C 1-6Alkyl, i.e., aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxyphenyl)propionamide, 2-amino-3-(imidazol-4-yl)propionamide, 2-amino-3-(indol-3-yl)propionamide, 2-amino-3-(hydroxycarbonyl)propionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, 2-amino- In some embodiments, R in Formula (IV), (IVa) or (IVb) is 3-sulfhydrylpropionamide, 2-amino-3-methylbutanamide, 2-amino-3-hydroxybutanamide, 2-amino-4-(methylsulfanyl)butanamide, 2-amino-4-hydroxycarbonylbutanamide, 2-amino-4-(aminocarbonyl)butanamide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolidin-2-ylformamide. 7d is hydrogen, and R 7e is an α-amino amide substituted C 1-6Alkyl, i.e., aminoacetamide, (R)-2-aminopropionamide, (R)-2-amino-3-phenylpropionamide, (R)-2-amino-3-(4-hydroxyphenyl)propionamide, (R)-2-amino-3-(imidazol-4-yl)propionamide, (R)-2-amino-3-(indol-3-yl)propionamide, (R)-2-amino-3-(hydroxycarbonyl)propionamide, (R)-2-amino-3-(aminocarbonyl)propionamide, (R)-2-amino-3-hydroxypropionamide, (R)-2-amino-3-mercaptopropionamide, (R)-2-amino-3-methylbutanamide, (R)-2-amino-3-hydroxybutanamide, (R)-2-amino-4-(methylthio)butanamide, (R)-2-amino-4-hydroxy In some embodiments, in formula (IV), (IVa) or (IVb), R is selected from the group consisting of (R)-2-amino-4-(aminocarbonyl)butanamide, (R)-2-amino-3-methylpentanamide, (R)-2-amino-4-methylpentanamide, (R)-2,6-diaminohexanamide, (R)-2-amino-5-guanidinopentanamide, and (R)-pyrrolidin-2-ylamide. 7d is hydrogen, and R 7eare aminoacetamide, (S)-2-aminopropionamide, (S)-2-amino-3-phenylpropionamide, (S)-2-amino-3-(4-hydroxyphenyl)propionamide, (S)-2-amino-3-(imidazol-4-yl)propionamide, (S)-2-amino-3-(indol-3-yl)propionamide, (S)-2-amino-3-(hydroxycarbonyl)propionamide, (S)-2-amino-3-(aminocarbonyl)propionamide, (S)-2-amino-3-hydroxypropionamide, (S)-2-amino-3-mercaptopropionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxy C substituted with an α-amino amide, including (S)-2-amino-4-(aminocarbonyl)butanamide, (S)-2-amino-3-methylpentanamide, (S)-2-amino-4-methylpentanamide, (S)-2,6-diaminohexanamide, (S)-2-amino-5-guanidinopentanamide, or (S)-pyrrolidin-2-ylamide. 1-6 It is an alkyl.

[0086] In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is an aminoamide substituted with ethyl. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, and R 7e is an α-amino amide or β-amino amide substituted with ethyl at the 2-position. In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen, R 7e is and R 7eare α-aminoamides substituted with ethyl at the 2-position, i.e., aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxyphenyl)propionamide, 2-amino-3-(imidazol-4-yl)propionamide, 2-amino-3-(indol-3-yl)propionamide, 2-amino-3-(hydroxycarbonyl)propionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, In some embodiments, in Formula (IV), (IVa) or (IVb), R is 2-amino-3-sulfhydrylpropionamide, 2-amino-3-methylbutanamide, 2-amino-3-hydroxybutanamide, 2-amino-4-(methylsulfanyl)butanamide, 2-amino-4-hydroxycarbonylbutanamide, 2-amino-4-(aminocarbonyl)butanamide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolidin-2-ylformamide. 7d is hydrogen, and R 7eis an α-aminoamide substituted with ethyl at the 2-position, i.e., aminoacetamide, (R)-2-aminopropionamide, (R)-2-amino-3-phenylpropionamide, (R)-2-amino-3-(4-hydroxyphenyl)propionamide, (R)-2-amino-3-(imidazol-4-yl)propionamide, (R)-2-amino-3-(indol-3-yl)propionamide, (R)-2-amino-3- (hydroxycarbonyl)propionamide, (R)-2-amino-3-(aminocarbonyl)propionamide, (R)-2-amino-3-hydroxypropionamide, (R)-2-amino-3-mercaptopropionamide, (R)-2-amino-3-methylbutanamide, (R)-2-amino-3-hydroxybutanamide, (R)-2-amino-4-(methylthio)butanamide, (R)-2-amino-4-hydroxy-carbonylbutanamide, (R)-2-amino-4-(aminocarbonyl)butanamide, (R)-2-amino-3-methylpentanamide, (R)-2-amino-4-methylpentanamide, (R)-2,6-diaminohexanamide, (R)-2-amino-5-guanidinopentanamide, or (R)-pyrrolidin-2-ylformamide. In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7eis an α-aminoamide substituted with ethyl at the 2-position, i.e., aminoacetamide, (S)-2-aminopropionamide, (S)-2-amino-3-phenylpropionamide, (S)-2-amino-3-(4-hydroxyphenyl)propionamide, (S)-2-amino-3-(imidazol-4-yl)propionamide, (S)-2-amino-3-(indol-3-yl)propionamide, (S)-2-amino-3- (hydroxycarbonyl)propionamide, (S)-2-amino-3-(aminocarbonyl)propionamide, (S)-2-amino-3-hydroxypropionamide, (S)-2-amino-3-mercaptopropionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxy-carbonylbutanamide, (S)-2-amino-4-(aminocarbonyl)butanamide, (S)-2-amino-3-methylpentanamide, (S)-2-amino-4-methylpentanamide, (S)-2,6-diaminohexanamide, (S)-2-amino-5-guanidinopentanamide, and (S)-pyrrolidin-2-ylamide.

[0087] In some embodiments, in formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is methyl, ethyl, propyl, or butyl, each optionally substituted with one, two, or three substituents Q, each of which is independently hydroxycarbonyl, ethoxycarbonyl, hydroxyl, methoxy, acetoxy, amino, acetamido, aminoacetamido, 2-aminopropionamido, 2-amino-3-hydroxy-propionamido, 2-amino-3-methylbutyrylamido, 2-amino-4-(methylthio)butanoylamido, 2-amino-4-methylpentanoylamido, or pyrrolidin-2-yl-acetylamido. 7d is hydrogen, and R 7eis methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, 2-(2-aminopropionylamino)ethyl, 2-(2-amino-3-hydroxypropionamido)ethyl, 2-(2-amino-3-methylbutanamido)ethyl, 2-(2-amino-4-(methylthio)-butanamido)ethyl, 2-(2-amino-4-methylbutanamido)ethyl, 2-(pyrrolidin-2-ylamido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or tetrahydropyran-4-yl. In some embodiments, in Formula (IV), (IVa), or (IVb), R 7d is hydrogen, and R 7e is methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, (R)-2-(2-aminopropionylamino)ethyl, (S)-2-(2-amino-3-hydroxypropionamido)ethyl, (S)-2-(2-amino-3-methylbutanamido)ethyl, (S)-2-(2-amino-4-(methylthio)-butanamido)ethyl, (S)-2-(2-amino-4-methylpentanoylamido)ethyl, (S)-2-(pyrrolidin-2-ylamido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl.

[0088] In yet another embodiment, the present application relates to a compound of formula (V): The compound shown in TIFF2025514839000015.tif41170 (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7b , R 7c , R 7d, m and n are each defined in this application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0089] In yet another embodiment, the present application relates to a compound of formula (Va): The compound shown in TIFF2025514839000016.tif50170 (wherein R 6 , R 7b , R 7c and R 7d (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0090] In yet another embodiment, the present application provides a compound of formula (Vb): The compound shown in TIFF2025514839000017.tif42170 (wherein R 6 , R 7b , R 7c and R 7d (each as defined in the present application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0091] In some embodiments, in formula (V), (Va), or (Vb), R 6 is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (V), (Va), or (Vb), R 6 is hydrogen or methyl. In some embodiments, in formula (V), (Va), or (Vb), R 6is hydrogen. In some embodiments, in formula (V), (Va), or (Vb), R 6 is methyl.

[0092] In some embodiments, in formula (V), (Va), or (Vb), R 7b and R 7d are hydrogen, and R 7c is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (V), (Va), or (Vb), R 7b and R 7d are hydrogen, and R 7c is isopropyl.

[0093] In yet another embodiment, the present application relates to a compound of formula (VI): The compound shown in TIFF2025514839000018.tif34170 (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7a , m and n are each defined in this application), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0094] In another embodiment, the present application provides a compound of formula (VIa): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, or tautomer, or mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6 and R 7a are each defined in this application.

[0095] In another embodiment, the present application provides a compound of formula (VIb): or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, comprising the compound of formula: 6 and R 7a are each defined in this application.

[0096] In some embodiments, in formula (VI), (VIa), or (VIb), R 6 is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (VI), (VIa), or (VIb), R 6 is hydrogen or methyl. In some embodiments, in formula (VI), (VIa), or (VIb), R 6 is hydrogen. In some embodiments, in formula (VI), (VIa) or (VIb), R 6 is methyl.

[0097] In some embodiments, in formula (VI), (VIa), or (VIb), R 7a is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (VI), (VIa), or (VIb), R 7a is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (VI), (VIa) or (VIb), R 7a is methyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (VI), (VIa), or (VIb), R 7a is methyl, -OC(O)R 1a (In the formula, R 1ais optionally substituted with, as defined herein. In some embodiments, in formula (VI), (VIa), or (VIb), R 7a is C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (VI), (VIa) or (VIb), R 7a is a monocyclic C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (VI), (VIa) or (VIb), R 7a is C 6-14 aryl, optionally substituted with one, two or three substituents Q. In some embodiments, in formula (VI), (VIa) or (VIb), R 7a is methyl, ethyl, propyl, cyclopentyl, or phenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in Formula (VI), (VIa), or (VIb), R 7a is pivaloyloxymethyl, benzoyloxymethyl, isopropyl, cyclopentyl or 4-methylphenyl.

[0098] The formulae described in this application include (I) to (VI), (Ia) to (VIa) and (Ib) to (VIb), in which the radical R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 6a , R 7a , R 7b , R 7c , R 7d , R 7e , m and n are further defined in the embodiments described herein. All combinations of these in the embodiments provided herein are within the scope of the present disclosure.

[0099] In some embodiments, R 1 is hydrogen. In some embodiments, R 1is isopropyl. In some embodiments, R 1 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is a monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is a bicyclic C 4-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is bridged, fused or spiro C 4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 6-14 aryl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 7-15 aralkyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is -C(O)R 1a In this case, R1a is defined herein. In some embodiments, R 1 is -C(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R 1 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 1 is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c are each defined in this application.

[0100] In some embodiments, R 1 is C 1-6 Alkyl or C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 1-6 Alkyl or monocyclic C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is isopropyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is cyclopentyl.

[0101] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is deuterium. In some embodiments, R 2 is cyan. In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluorine, chlorine, bromine, or iodine. In some embodiments, R 2 is nitro. In some embodiments, R 2 is C 1-6alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is methyl, ethyl, isopropyl, hydroxymethyl, or ethoxymethyl. In some embodiments, R 2 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is benzyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is heterocyclyl, optionally substituted with one or more substituents Q.

[0102] In some embodiments, R 2 is -C(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 2 -C(O)-C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is acetyl. In some embodiments, R 2 is -C(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R2 -COOH or -C(O)OC 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is -COOH or -COOEt. In some embodiments, R 2 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 2 is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 2 -C(S)OR 1a Among them, R 1a is defined herein. In some embodiments, R 2 is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -OR 1a In this case, R 1a is defined herein. In some embodiments, R 2 is C 1-6 alkoxy, optionally substituted with one or more substituents Q. In some embodiments, R 2 is 2-ethoxyethoxy. In some embodiments, R 2 is -OC(O)R 1a In this case, R 1ais defined herein. In some embodiments, R 2 is -OC(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R 2 is -OC(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 2 is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 2 -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 2 is -OC(S)NR 1b R 1c In this case, R 1b and R 1c is defined herein. In some embodiments, R 2 -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 2 -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 2 -OS(O)NR 1b R 1c In this case, R 1b and R 1cand R are each defined herein. In some embodiments, R 2 is -OS(O)2NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -NH2. In some embodiments, R 2 -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a C(O)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -NR 1a C(O)SR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 2 -NR1a C(S)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a C(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 2 -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 2 -SR 1a In this case, R 1a is defined herein. In some embodiments, R 2 is -S(O)R1a In this case, R 1a is defined herein. In some embodiments, R 2 is -S(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 2 is -S(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 2 is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0103] In some embodiments, R 2 refers to: (i) halogen, (ii) C 1-6 Alkyl or C 7-15 aralkyl, each of which is substituted with one or more substituents Q; or (iii) —C(O)R 1a , -C(O)OR 1a , -OR 1a or -NR 1b R 1c , in which, each R 1a , R 1b and R 1c are each defined herein. In some embodiments, R 2 is fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, hydroxymethyl, ethoxymethyl, benzyl, acetyl, hydroxycarbonyl, ethoxycarbonyl, 2-ethoxyethoxy, or amino. 2 is acetyl.

[0104] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is cyan. In some embodiments, R 3is halogen. In some embodiments, R 3 is fluorine or chlorine. In some embodiments, R 3 is nitro. In some embodiments, R 3 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is methyl. In some embodiments, R 3 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is trifluoromethyl. In some embodiments, R 3 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is hydrogen or methyl.

[0105] In some embodiments, R 3 is -C(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -C(O)OR 1a Among them, R 1ais defined herein. In some embodiments, R 3 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 3 is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 -C(S)OR 1a Among them, R 1a is defined herein. In some embodiments, R 3 is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -OR 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -OC(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -OC(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R 3 is -OC(O)NR 1b R 1c In this case, R 1b and R 1cis defined herein. In some embodiments, R 3 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -OC(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 3 -OS(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 3 is -OS(O)2NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -NR 1b R 1c In this case, R1b and R 1c and R are each defined herein. In some embodiments, R 3 -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a C(O)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -NR 1a C(O)SR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a C(S)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1aC(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 3 -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 3 -SR 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -S(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -S(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 3 is -S(O)NR 1b R 1c In this case, R 1b and R 1cand R are each defined herein. In some embodiments, R 3 is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0106] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is cyan. In some embodiments, R 4 is halogen. In some embodiments, R 4 is fluorine. In some embodiments, R 4 is nitro. In some embodiments, R 4 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is heterocyclyl, optionally substituted with one or more substituents Q.

[0107] In some embodiments, R 4 is -C(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -C(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R 4 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 4 -C(S)OR 1a Among them, R 1a is defined herein. In some embodiments, R 4 is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -OR 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -OC(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 4is -OC(O)OR 1a Among them, R 1a is defined herein. In some embodiments, R 4 is -OC(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 4 -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -OC(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 4 -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 4 -OS(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4is -OS(O)2NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a C(O)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -NR 1a C(O)SR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a C(S)R 1d In this case, R 1a and R 1dand R are each defined herein. In some embodiments, R 4 -NR 1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a C(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 4 -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 4 -SR 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -S(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 4is -S(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 4 is -S(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 4 is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0108] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is cyan. In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluorine or chlorine. In some embodiments, R 5 is nitro. In some embodiments, R 5 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is methyl or ethyl. In some embodiments, R 5 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 is halogen or C 1-6 alkyl, optionally substituted with one, two, or three substituents Q. In some embodiments, R 5 is fluorine, chlorine, methyl or ethyl.

[0109] In some embodiments, R 5 is -C(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -C(O)OR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 -C(S)OR 1a In this case, R 1ais defined herein. In some embodiments, R 5 is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -OR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -OC(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -OC(O)OR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -OC(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -OC(S)NR 1b R 1c In this case, R 1b and R 1cand R are each defined herein. In some embodiments, R 5 -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 5 -OS(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -OS(O)2NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(O)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -NR 1a C(O)SR 1d In this case, R 1aand R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(S)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a C(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 5 -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5-NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 5 -SR 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -S(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -S(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 5 is -S(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 5 is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0110] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 is cyan. In some embodiments, R 6 is halogen. In some embodiments, R 6 is fluorine. In some embodiments, R 6 is nitro. In some embodiments, R 6 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is methyl. In some embodiments, R 6 is C 1-6Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is trifluoromethyl. In some embodiments, R 6 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 is hydrogen or methyl.

[0111] In some embodiments, R 6 is -C(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -C(O)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 6is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6 is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 -C(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -OR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -OC(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -OC(O)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -OC(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1cand R are each defined herein. In some embodiments, R 6 is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -OC(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 6 -OS(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 is -OS(O)2NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a C(O)OR 1dIn this case, R 1a and R 1d are each defined herein. In some embodiments, R6 is -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -NR 1a C(O)SR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a C(S)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a C(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R6 -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6 -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6 -SR 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -S(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -S(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 6 is -S(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6 is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0112] In some embodiments, R 7 is C 2-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R7 is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 -OR 7a In this case, R 7a is defined herein. In some embodiments, R 7 -NR 7b R 7c In this case, R 7b and R 7c and R are each defined herein. In some embodiments, R 7 -NR 7d C(O)R 7e In this case, R 7d and R 7e and R are each defined herein. In some embodiments, R 7 -NR 7d C(O)OR 7e In this case, R 7d and R 7e and R are each defined herein. In some embodiments, R 7 -NR 7d C(O)NR7b R 7c In this case, R 7b , R 7c and R 7d are each defined in this application.

[0113] In some embodiments, R 6a is deuterium. In some embodiments, R 6a is cyan. In some embodiments, R 6a is halogen. In some embodiments, R 6a is fluorine. In some embodiments, R 6a is nitro. In some embodiments, R 6a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 6a is heterocyclyl, optionally substituted with one or more substituents Q.

[0114] In some embodiments, R 6a is -C(O)R 1aIn this case, R 1a is defined herein. In some embodiments, R 6a is -C(O)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -C(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -C(O)SR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -C(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -C(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a -C(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -C(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -OR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -OC(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -OC(O)OR 1a In this case, R 1ais defined herein. In some embodiments, R 6a is -OC(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -OC(NR 1a )NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -OC(S)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a -OC(S)OR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -OC(S)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -OS(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a -OS(O)2R 1a In this case, R 1a is defined herein. In some embodiments, R 6a -OS(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -OS(O)2NR 1b R 1cIn this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -NR 1a C(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a C(O)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a C(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -NR 1a C(O)SR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a C(NR 1d )NR 1b R 1c In this case, R 1a , R 1b , R 1c and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a C(S)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR1a C(S)OR 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a C(S)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -NR 1a S(O)R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a S(O)2R 1d In this case, R 1a and R 1d and R are each defined herein. In some embodiments, R 6a -NR 1a S(O)NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -NR 1a S(O)2NR 1b R 1c In this case, R 1a , R 1b and R 1c and R are each defined herein. In some embodiments, R 6a -SR 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -S(O)R 1a In this case, R 1a is defined herein. In some embodiments, R 6a is -S(O)2R 1a In this case, R 1ais defined herein. In some embodiments, R 6a is -S(O)NR 1b R 1c In this case, R 1b and R 1c and R are each defined herein. In some embodiments, R 6a is -S(O)NR 1b R 1c In this case, R 1b and R 1c are each defined in this application.

[0115] In some embodiments, R 7a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is methyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is -OC(O)R 1a methyl optionally substituted with, 1a is defined herein. In some embodiments, R 7a is pivaloyloxymethyl, benzoyloxymethyl, or isopropyl. In some embodiments, R 7a is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is C 2-6 alkynylhydroxy, optionally substituted with one or more substituents Q. In some embodiments, R 7a is a monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is cyclopentyl. In some embodiments, R 7a is a bicyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is C6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is phenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is 4-methylphenyl. In some embodiments, R 7a is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is heterocyclyl, optionally substituted with one or more substituents Q.

[0116] In some embodiments, R 7b is hydrogen. In some embodiments, R 7b is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7bis heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b is hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, or 1-(hydroxycarbonyl)-2-methylpropyl.

[0117] In some embodiments, R 7c is hydrogen. In some embodiments, R 7c is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7c is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7cis hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, or 1-(hydroxycarbonyl)-2-methylpropyl.

[0118] In some embodiments, R 7b and R 7c taken together with the nitrogen atom to which they are covalently bonded form a heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7b and R 7c taken together with the nitrogen atom to which they are covalently attached form a monocyclic heteroaryl, optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form a 5- or 6-membered heteroaryl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently bonded form a 5-membered heteroaryl, each of which is optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently bonded form a 6-membered heteroaryl, each of which is optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently bonded form a bicyclic heteroaryl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently bonded form a 5,5-, 5,6-, or 6,6-fused heteroaryl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7ctogether with the nitrogen atom to which they are covalently attached to form imidazol-1-yl or 2-aminoimidazol-1-yl.

[0119] In some embodiments, R 7b and R 7c taken together with the nitrogen atom to which they are covalently attached form a heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7b and R 7c taken together with the nitrogen atom to which they are covalently attached form a monocyclic heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form a 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form a 5-membered heterocyclyl, each of which is optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form a 6-membered heterocyclyl, each of which is optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7c taken together with the nitrogen atom to which they are covalently attached form a bicyclic heterocyclyl, optionally substituted with one, two or three substituents Q. In some embodiments, R 7b and R 7ctogether with the nitrogen atom to which they are covalently attached form a bridged, fused, or spiroheterocyclyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7b and R 7c together with the nitrogen atom to which they are covalently attached form 3-hydroxyazetidin-1-yl, 2-keto-5-(hydroxymethyl)oxazolin-3-yl, 2-(hydroxymethyl)piperidin-1-yl or 4-morpholinyl.

[0120] In some embodiments, R 7d is hydrogen. In some embodiments, R 7d is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7d is heterocyclyl, optionally substituted with one or more substituents Q.

[0121] In some embodiments, R 7e is hydrogen. In some embodiments, R7e is C 1-6 alkyl, each optionally substituted with one or more substituents Q. In some embodiments, R 7e is methyl, ethyl, propyl, or butyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is a monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7e is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents Q. In some embodiments, R 7eis a 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is a 5-membered heterocyclyl, optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is a 6-membered heterocyclyl, optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is pyrrolidine, tetrahydrofuran, or tetrahydropyran, each optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is biheterocyclyl, optionally substituted with one, two, or three substituents Q. In some embodiments, R 7e is a bridged, fused, or spiroheterocyclyl, each optionally substituted with one, two, or three substituents Q.

[0122] In some embodiments, R 7e is C optionally substituted with one, two or three substituents; 1-6 alkyl, wherein each substituent is independently —C(O)OR 1a , -OR 1a , -OC(O)R 1a , -NR 1b R 1c or -NR 1a C(O)R 1d where each R 1a , R 1b , R 1c and R 1d are each defined herein. In some embodiments, R 7e is -C(O)OR 1a C replaced with 1-6 alkyl, in which R 1a is defined herein. In some embodiments, R 7e -OR 1a C replaced with 1-6 alkyl, in which R 1a is defined herein. In some embodiments, R 7e is -OC(O)R 1a C replaced with1-6 alkyl, in which R 1a is defined herein. In some embodiments, R 7e -NR 1b R 1c C replaced with 1-6 alkyl, in which R 1b and R 1c and R are each defined herein. In some embodiments, R 7e -NR 1a C(O)R 1d C replaced with 1-6 alkyl, in which R 1a and R 1d are each defined in this application.

[0123] In some embodiments, R 7e is an aminoamide-substituted C 1-6 In some embodiments, R 7e is C substituted with α-aminoamide or β-aminoamide 1-6 In some embodiments, R 7e are aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxyphenyl)propionamide, 2-amino-3-(imidazol-4-yl)propionamide, 2-amino-3-(indol-3-yl)propionamide, 2-amino-3-(hydroxycarbonyl)propionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, 2-amino-3-sulfhydrylpropionamide C substituted with α-amino amides, including but not limited to 2-amino-3-methylbutanamide, 2-amino-3-hydroxybutanamide, 2-amino-4-(methylsulfanyl)butanamide, 2-amino-4-hydroxycarbonylbutanamide, 2-amino-4-(aminocarbonyl)butanamide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolidin-2-ylformamide.1-6 In some embodiments, R 7e is aminoacetamide, (R)-2-aminopropionamide, (R)-2-amino-3-phenylpropionamide, (R)-2-amino-3-(4-hydroxyphenyl)propionamide, (R)-2-amino-3-(imidazol-4-yl)propionamide, (R)-2-amino-3-(indol-3-yl)propionamide, (R)-2-amino-3-(hydroxycarbonyl)propionamide, (R)-2-amino-3-(aminocarbonyl)propionamide, (R)-2-amino-3-hydroxypropionamide, (R)-2-amino-3-mercaptopropionamide, (R)-2-amino-3-methylbutanamide, (R)-2-amino-3-hydroxybutanamide, (R)-2-amino-4-(methylthio)butanamide, (R)-2-amino-4-hydroxy C substituted with an α-amino amide, including (R)-carbonylbutanamide, (R)-2-amino-4-(aminocarbonyl)butanamide, (R)-2-amino-3-methylpentanamide, (R)-2-amino-4-methylpentanamide, (R)-2,6-diaminohexanamide, (R)-2-amino-5-guanidinopentanamide, or (R)-pyrrolidin-2-ylamide. 1-6 In some embodiments, R 7eare aminoacetamide, (S)-2-aminopropionamide, (S)-2-amino-3-phenylpropionamide, (S)-2-amino-3-(4-hydroxyphenyl)propionamide, (S)-2-amino-3-(imidazol-4-yl)propionamide, (S)-2-amino-3-(indol-3-yl)propionamide, (S)-2-amino-3-(hydroxycarbonyl)propionamide, (S)-2-amino-3-(aminocarbonyl)propionamide, (S)-2-amino-3-hydroxypropionamide, (S)-2-amino-3-mercaptopropionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxy C substituted with an α-amino amide, including (S)-2-amino-4-(aminocarbonyl)butanamide, (S)-2-amino-3-methylpentanamide, (S)-2-amino-4-methylpentanamide, (S)-2,6-diaminohexanamide, (S)-2-amino-5-guanidinopentanamide, or (S)-pyrrolidin-2-ylamide. 1-6 It is an alkyl.

[0124] In some embodiments, R 7e is ethyl substituted with aminoamido. In some embodiments, R 7e is ethyl substituted at the 2-position with an α-aminoamido or β-aminoamido. In some embodiments, R 7eare aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxyphenyl)propionamide, 2-amino-3-(imidazol-4-yl)propionamide, 2-amino-3-(indol-3-yl)propionamide, 2-amino-3-(hydroxycarbonyl)propionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, 2-amino-3-sulfhydrylpropionamide, 2-amino-3-sulfhydrylpropionamide, 2-amino-3-sulfhydrylpropionamide, 2-amino-3-sulfurylpropionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, 2-amino-3-sulfurylpropionamide, 2-amino-3-sulfurylpropionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-sulfuryl ... In some embodiments, R is an ethyl substituted with an α-amino amide or a β-amino amide at the 2-position, including 2-amino-3-methylbutanamide, 2-amino-3-hydroxybutanamide, 2-amino-4-(methylsulfanyl)butanamide, 2-amino-4-hydroxycarbonylbutanamide, 2-amino-4-(aminocarbonyl)butanamide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide, or pyrrolidin-2-ylformamide. 7eis aminoacetamide, (R)-2-aminopropionamide, (R)-2-amino-3-phenylpropionamide, (R)-2-amino-3-(4-hydroxyphenyl)propionamide, (R)-2-amino-3-(imidazol-4-yl)propionamide, (R)-2-amino-3-(indol-3-yl)propionamide, (R)-2-amino-3-(hydroxycarbonyl)propionamide, (R)-2-amino-3-(aminocarbonyl)propionamide, (R)-2-amino-3-hydroxypropionamide, (R)-2-amino-3-mercaptopropionamide, (R)-2-amino-3-methylbutanamide, (R)-2-amino-3-hydroxybutanamide, (R)-2-amino-4-(methylthio)butanamide, (R)-2-amino-4-hydroxy In some embodiments, R is an ethyl substituted with an α-amino amide or a β-amino amide at the 2-position, including (R)-2-amino-4-(aminocarbonyl)butanamide, (R)-2-amino-3-methylpentanamide, (R)-2-amino-4-methylpentanamide, (R)-2,6-diaminohexanamide, (R)-2-amino-5-guanidinopentanamide, or (R)-pyrrolidin-2-ylamide. 7eare aminoacetamide, (S)-2-aminopropionamide, (S)-2-amino-3-phenylpropionamide, (S)-2-amino-3-(4-hydroxyphenyl)propionamide, (S)-2-amino-3-(imidazol-4-yl)propionamide, (S)-2-amino-3-(indol-3-yl)propionamide, (S)-2-amino-3-(hydroxycarbonyl)propionamide, (S)-2-amino-3-(aminocarbonyl)propionamide, (S)-2-amino-3-hydroxypropionamide, (S)-2-amino-3-mercaptopropionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxy and ethyl substituted at the 2-position with an α-amino amide or a β-amino amide, including (S)-2-amino-4-(aminocarbonyl)butanamide, (S)-2-amino-3-methylpentanamide, (S)-2-amino-4-methylpentanamide, (S)-2,6-diaminohexanamide, (S)-2-amino-5-guanidinopentanamide, or (S)-pyrrolidin-2-ylamide.

[0125] In some embodiments, R 7e is methyl, ethyl, propyl, or butyl, each optionally substituted by one, two, or three substituents Q, each of which is independently 4-imidazolyl, hydroxycarbonyl, ethoxycarbonyl, hydroxy, methoxy, acetoxy, amino, acetamido, aminoacetamido, 2-aminopropanamido, 2-amino-3-hydroxypropionamido, 2-amino-3-methylbutanamido, 2-amino-4-(methylthio)butanamido, 2-amino-4-methylpentanamido, or pyrrolidin-2-ylamido.

[0126] In some embodiments, R 7eis methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, aminomethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 1-aminoethyl, 1-amino-2-methylpropyl, 1,5-diaminopentyl, 2-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, 2-(2-aminopropionamido)ethyl, 2-(2-amino-3-hydroxypropionamido)ethyl, 2-(2-amino-3-methylbutanamido)ethyl, 2-(2-amino-4-(methylthio)-butanamido)ethyl, 2-(2-amino-4-methylpentanamido)ethyl, 2-(pyrrolidin-2-ylamido)ethyl, o-propyl, tert-butyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl, or tetrahydropyran-4-yl. 7e is methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, aminomethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 1-aminoethyl, 1-amino-2-methylpropyl, 1,5-diaminopentyl, 2-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, (R)-2-(2-aminopropionamido)ethyl, (S)-2-(2-amino no-3-hydroxypropionamido)ethyl, (S)-2-(2-amino-3-methylbutanamido)ethyl, (S)-2-(2-amino-4-(methylthio)-butanamido)ethyl, (S)-2-(2-amino-4-methylpentanamido)ethyl, (S)-2-(pyrrolidin-2-amido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl or tetrahydropyran-4-yl.

[0127] 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.

[0128] 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.

[0129] In some embodiments, the present application provides: 2-Hydroxyethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1; tert-Butyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A2; (S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-sulfonamide A3; tert-Butyl-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A4; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonamide A5; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropionamide A6; (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A7; 2-Methoxyethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A9; Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A10; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)acetic acid A11; 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-5-(hydroxymethyl)oxazolidin-2-one A12; 2-Aminoethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13; (S)-2-(2-amino-3-methylbutanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A14; 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A15; (R)-2-(2-aminopropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A16; (S)-2-(2-amino-4-methylpentanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A17; (S)-2-(2-amino-3-hydroxypropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A18; (S)-2-(2-amino-4-(methylsulfanyl)butanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A19; 2-(2-aminoacetamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A20; (R)-2-(pyrrolidine-2-formylamino)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A21; Tetrahydro-2H-pyran-4-yl(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A22; Cyclobutyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A23; Cyclopropyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A24; Ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A25; Methyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A26; Isopropyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin)-3-yl)piperazin-1-yl)sulfonyl)carbamate A27; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminobutanamide A28; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminoacetamide A29; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-methylbutanamide A30; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-(1H-imidazol-4-yl)-propionamide A31; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2,6-diaminohexanamide A32; (R)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-formamide A33; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)acetamide A34; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propionamide A35; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)isobutyramide A36; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butyramide A37; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropaneformamide A38; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-formamide A39; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-formamide A40; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutaneformamide A41; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)perazine-1-sulfonamide A42; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)perazine-1-sulfonamide A43; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)glycine A44; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-L-valine A45; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-methylperazine-1-sulfonamide A46; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylperazine-1-sulfonamide A47; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylperazine-1-sulfonamide A48; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylperazine-1-sulfonamide A49; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylperazine-1-sulfonamide A50; 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyridine[2,3-d]pyrimidin-7(8H)-one A51; 6-Acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A52; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)perazine-1-sulfonamide A53; 2-Hydroxyethyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A54; 2-((R)-2-amino-3-methylbutanamido)ethyl(((S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A55; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylaminoformyl)perazine-1-sulfonamide A56; 6-Acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A57; or 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A58; or an enantiomer, a mixture of enantiomers, diastereomer, a mixture of two or more diastereomers, tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0130] In some other embodiments, the present application provides: ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1; p-Methylphenyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B2; ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)benzoic acid methyl ester B3; or Cyclopentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4; or an enantiomer, a mixture of enantiomers, diastereomer, a mixture of two or more diastereomers, tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0131] In yet another embodiment, the present application provides: 6-Acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylperazin-1-yl)-2-pyridine]-amino]-5-methylpyridine[2,3-d]pyrimidin-7-one C1; or 6-Acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)perazin-1-yl)pyridin-2-yl)-amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one C2; or an enantiomer, a mixture of enantiomers, diastereomer, a mixture of two or more diastereomers, tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0132] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, the compounds provided herein have a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. In some embodiments, the compounds provided herein have a purity of at least about 90% by weight. In some embodiments, the compounds provided herein have a purity of at least about 95% by weight. In some embodiments, the compounds provided herein have a purity of at least about 98% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99.5% by weight.

[0133] Unless a particular stereochemistry is specified, the compounds provided in this application are intended to include all possible stereoisomers. When the compounds provided in this application contain an alkenyl, the compounds may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When structural isomers are interconvertible, the compounds may exist as a single tautomer or a mixture of tautomers. For example, compounds containing imino, carbonyl, or oxime may exhibit proton tautomerism, and compounds containing aromatic moieties may exhibit so-called valence tautomerism. This shows that a single compound may exhibit multiple structural isomers.

[0134] The compounds provided in this application may be optically pure, such as a single enantiomer or a single diastereomer, or may be a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of stereoisomers, such as a mixture of two or more diastereomers. Thus, one of skill in the art will recognize that for compounds that undergo racemization in vivo, a compound administered in the (R) form is equivalent to a compound administered in the (S) form. Conventional techniques for obtaining individual enantiomers include synthesis from appropriate optically pure precursors, asymmetric synthesis from achiral starting materials, or isolation of an enantiomeric mixture, e.g., chiral chromatography, recrystallization, isolation, formation of diastereomeric salts, or derivatization to diastereomeric adducts followed by isolation.

[0135] When the compounds provided herein have an acidic or basic moiety, they can also be utilized 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 some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0136] Suitable acids that may be used in the preparation of pharma- ceutically acceptable salts of the compounds provided in the present application include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boronic acid, (+)-chorismic acid, cardonic acid, (+)-(1S)-10-sulfochorismic acid, decanoic acid, capric acid, caprylic acid, cinnamic acid, citric acid, saccharic acid, cyclohexanesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, muconic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, and the like. Acids: nic acid, α-ketoglutaric acid, ethanoic acid, mauric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, whey t-acid, oxalic acid, palmitic acid, bis(hydroxynaphtho)acetic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, glyoxalic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, valeric acid.

[0137] Suitable bases that may be used in the preparation of pharma- ceutically acceptable salts of the compounds provided in the present application include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, and the like; organic bases such as primary, secondary, tertiary, quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benzylamine, benzylidine, choline, dimethylethanolamine, diethanolamine, diethylamine, dimethylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-D-glucamine, hydrazinamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl) Examples of such anamines include pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and aminobutanetriol.

[0138] The compounds provided in the present application may also be provided as prodrugs, which are functional derivatives of the compounds that are readily converted to the parent compound in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent compound. For example, prodrugs are orally bioavailable whereas the parent compound is not. Prodrugs may also be more soluble in pharmaceutical compositions than the parent compound. Prodrugs can be converted to the parent drug by various mechanisms, including enzymatic processes and hydrolytic metabolism.

[0139] Pharmaceutical Compositions In certain embodiments, the present application provides a pharmaceutical composition comprising a compound provided by the present application, such as a compound represented by Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0140] The pharmaceutical compositions provided in the present application may be prepared into various dosage forms, including, but not limited to, dosage forms for oral administration. Pharmaceutical compositions may also be prepared into modified release dosage forms, such as delayed, extended, long-acting, sustained, pulsed, controlled, accelerated, rapid, targeted, programmed, and gastroretentive dosage forms. These dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art. For example, see 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: BocaRaton, FL, 2008.

[0141] The pharmaceutical compositions provided in the present application may be provided in unit dose form or multiple dose form. As described in the present application, a unit dose form is a physically discrete unit suitable for administration to a subject and is individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient (e.g., a compound provided in the present application) sufficient to produce a desired therapeutic effect, and the desired pharmaceutical excipients. Examples of unit dose forms include, but are not limited to, individually packaged tablets and capsules. A unit dose form may be divided or administered in multiple doses. A multiple dose form refers to a plurality of identical unit dose forms packaged in a single container and administered as separate unit dose forms. Examples of multiple dose forms include, but are not limited to, vials, bottled tablets or capsules.

[0142] The pharmaceutical compositions provided in this application may be administered in a single dose or multiple doses at intervals. It should be understood that the exact dosage and duration of treatment may vary according to the age, weight and condition of the subject being treated and may be inferred empirically using known testing protocols or from in vivo or in vitro test or diagnostic data. It should also be understood that for any individual, the specific dosage regimen should be adjusted over time based on the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0143] A. Oral Administration The pharmaceutical compositions for oral administration provided in this application may be provided as solid, semi-solid or liquid formulations for oral administration. Oral administration as used in this application further includes buccal, lingual and sublingual administration. Suitable oral administration forms include, but are not limited to, tablets, fast dissolving, chewable tablets, capsules, tablets, strips, sublingual tablets, lozenges, gummies, wafers, pellet formulations, medicated chewing gum, powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, thin tablets, sprays, elixirs, syrups and the like. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharma- ceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow aids, colorants, dye rearrangement inhibitors, sweeteners, flavorings, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0144] Suitable binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet does not break after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, pregelatinized starch (e.g., STARCH 1500®); gelatin; sugars such as sucrose, D-glucose, L-glucose, syrup, lactose, and the like; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, panwar gum, gum ghatti, isoflavone fruit shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, guar gum, and the like; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and the like; and AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-104, AVICEL® PH-105, AVICEL® PH-106, AVICEL® PH-107, AVICEL® PH-108, AVICEL® PH-109, AVICEL® PH-200, AVICEL® PH-201, AVICEL® PH-202, AVICEL® PH-203, AVICEL® PH-204, AVICEL® PH-205, AVICEL® PH-206, AVICEL® PH-207, AVICEL® PH-208, AVICEL® PH-209, AVICEL® PH-210, AVICEL® PH-211, AVICEL® PH-212, AVICEL® PH-213, AVICEL® PH-214, AVICEL® PH-215, AVICEL® PH Suitable fillers include, but are not limited to, microcrystalline cellulose such as PH-105 and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, L-glucose, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder and filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily determined by one of ordinary skill in the art. The binder and filler in the pharmaceutical compositions provided herein may be present in an amount of about 50 to about 99% by weight.

[0145] Suitable diluents include, but are not limited to, calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, inositol, when present in sufficient amounts, may impart to certain compressed tablets the property of disintegrating in the mouth by chewing. Such compressed tablets may be administered as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible by one skilled in the art.

[0146] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and VEEGUM® HV; citrus pulp; cross-linked celluloses such as cross-linked carboxymethylcellulose; cross-linked polymers such as polyvinylpolypyrrolidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium hydroxyacetate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, pregelatinized starch; clay; and sodium alginate. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily determined by one skilled in the art. The pharmaceutical compositions provided herein for oral administration may contain from about 0.5% to about 15% by weight, or from about 1% to about 5% by weight of disintegrant.

[0147] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; diols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silicones or silica gels, such as AEROSIL® 200 and CAB-O-SIL®. The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily determined by one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of lubricant.

[0148] Suitable flow aids include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, approved certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrate and lakes. Lakes are combinations of water-insoluble dye forms formed by the adsorption of water-soluble dyes to hydrated oxides of heavy metals. Suitable flavoring agents include, but are not limited to, natural flavors derived from plants (e.g., fruits) and synthetic mixtures of compounds that produce a pleasant taste, such as mint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, gum acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate (TWEEN 10001, ... (登録商標) 20), Polyoxyethylene sorbitan monooleate 80 (TWEEN (登録商標)80), and surfactants such as triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM (登録商標) Suitable emulsions include, but are not limited to, gum arabic, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methylparaben, propylparaben, benzoic acid, sodium benzoate, and alcohol. Suitable humectants 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, ethanol, and syrup. 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.

[0149] It should be understood that many carriers and excipients can serve multiple functions, even within the same formulation.

[0150] The pharmaceutical compositions for oral administration provided in this application can be provided in the form of compressed tablets, crushed tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets that are coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating that may be beneficial in masking unpleasant tastes and odors and in protecting the tablet from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalates. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0151] Tablet dosage forms can be prepared from powdered, crystalline, or granular active ingredient alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0152] The pharmaceutical compositions for oral administration provided in this application can be provided as soft or hard capsules made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), are made up of two sections, one over the other, completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, globular shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are as described in this application, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided in this application can be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, and 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. The capsules can also be coated, as known to those skilled in the art, to modify or sustain dissolution of the active ingredient.

[0153] The pharmaceutical compositions for oral administration provided in this application can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, in which one liquid is dispersed in the form of small globules throughout the other liquid, which may be oil-in-water or water-in-oil. Emulsions can include a pharma-ceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can include a pharma-ceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions can include a pharma-ceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. They are clear, sweetened, aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and can also contain a preservative. For a liquid dosage form, for example, the solution in a polyethylene glycol may be conveniently diluted with a sufficient quantity of a pharma- ceutical acceptable liquid carrier, e.g., water, to be measured for administration.

[0154] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol). These formulations 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, bisulfites, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0155] The pharmaceutical compositions for oral administration provided in the present application may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0156] The pharmaceutical compositions for oral administration provided in the present application can be provided as non-effervescent or effervescent granules and powders that will be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and a source of carbon dioxide.

[0157] In all of the above dosage forms, coloring and flavoring agents can be used.

[0158] The pharmaceutical compositions for oral administration provided in the present application can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

[0159] B. Modified release The pharmaceutical compositions provided in the present application can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include delayed release dosage forms, extended release dosage forms, extended release dosage forms, sustained release dosage forms, pulsed release dosage forms, controlled release dosage forms, accelerated and fast release dosage forms, targeted release dosage forms, programmed release dosage forms and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of 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, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by changing the particle size and polymorphism of the active ingredient.

[0160] 1. Matrix Controlled Release Devices The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated using matrix controlled release devices known to those skilled in the art. See, e.g., Takada et.al Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.

[0161] In some embodiments, the pharmaceutical compositions provided in the present application in modified release dosage forms are formulated using erodible matrix devices that are water-swellable, erodible or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0162] Materials useful in forming the erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulose derivatives, 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 methylcellulose (CMC), cellulose acetate butyrate ... poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0163] In some embodiments, the pharmaceutical compositions provided in the present application are formulated with a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, and ionomeric polyethylene terephthalate. , butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0164] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient(s), the ratio of active ingredient(s) to polymer, and other excipients in the composition.

[0165] The pharmaceutical compositions provided in the application in modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.

[0166] 2. Osmotic Controlled Release Devices The pharmaceutical compositions provided in this application in modified release dosage forms can be fabricated using osmotically controlled release devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). In general, such devices have at least two components: (a) a core containing the active ingredient(s); and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from the aqueous environment of use into the core to trigger drug release by extrusion through the delivery port(s).

[0167] In addition to the active ingredient(s), the core of the osmotic device optionally contains an osmotic agent that creates a driving force for the transport of water from the environment of use to the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels," including, but 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), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, copolymers of PVA / PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0168] Another class of osmotic agents are osmogens, which can absorb water and thus affect 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 L-glucose, 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 mixtures thereof.

[0169] Osmotic agents with different dissolution rates can be used to affect how rapidly the active ingredient(s) are initially released from the dosage form. For example, amorphous sugars such as MANNOGEM™ EZ can be used to provide faster delivery during the first two hours to rapidly generate the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) are released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0170] The core can also contain a wide variety of other excipients and carriers as described in this application to enhance the performance of the dosage form or to facilitate stability or processing.

[0171] Materials useful in forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pH or are susceptible to being rendered water insoluble by chemical modification such as crosslinking. Examples of suitable polymers useful in forming coatings include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate 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, agar acetate (agar acetate), and the like. acetate), amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0172] The semipermeable membrane may be a hydrophobic microporous membrane, in which the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water-permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluorides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0173] The delivery port(s) on the semipermeable membrane can be formed after coating by mechanical or laser drilling. The delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over a notch in the core. In addition, the delivery port can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0174] The total amount and release rate of the active ingredient(s) released can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.

[0175] The pharmaceutical composition in an osmotic controlled release dosage form may further comprise additional conventional excipients as described in this application to facilitate performance or processing of the formulation.

[0176] 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.ControlledRelease, 1995, 35, 1-21;Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708;Verma et al., J.ControlledRelease, 2002, 79, 7-27.

[0177] In some embodiments, the pharmaceutical composition provided in the present application is formulated as an AMT controlled release dosage form comprising an asymmetric osmotic membrane coating a core comprising active ingredient(s) and other pharma-ceutical acceptable excipients.See, for example, U.S. Patent No. 5,612,059 and WO2002 / 17918.AMT controlled release dosage form 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 methods.

[0178] In some embodiments, the pharmaceutical compositions provided in the present application are formulated as ESC controlled release dosage forms comprising an osmotic membrane coating a core comprising the active ingredient(s), hydroxyethylcellulose and other pharmaceutically acceptable excipients.

[0179] 3. Multiparticulate controlled release devices The pharmaceutical compositions provided in the present application in modified release dosage form can be fabricated as multiparticulate controlled release devices, including a variety of particles, granules or pellets with diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to 1 mm. Such multiparticulates can be made by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spray coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

[0180] Other excipients as described in this application can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials such as enteric polymers, water-swellable polymers and water-soluble polymers. The multiparticulates can be further processed into capsules or tablets.

[0181] 4. Targeted delivery The pharmaceutical compositions provided in the present application can also be formulated to be targeted to particular tissues, receptors or other areas of the subject's body to be treated, including liposome-based delivery systems, resealed erythrocyte-based delivery systems and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in the following U.S. Patents: 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; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. How to use

[0182] In certain embodiments, the present application provides methods for treating, preventing, or ameliorating one or more symptoms of a CDK-related disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0183] In some embodiments, the CDK is either CDK4 or CDK6. In some embodiments, the CDK is CDK4. In some embodiments, the CDK is CDK6.

[0184] In some embodiments, the CDK-mediated disease, disorder or condition is chemotherapy-associated gastrointestinal side effects.

[0185] In another embodiment, the present application provides a method for preventing or alleviating chemotherapy-associated gastrointestinal side effects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein (e.g., a compound represented by Formula (I)), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0186] In some embodiments, the chemotherapy-related gastrointestinal side effect is chemotherapy-induced diarrhea. In some embodiments, the chemotherapy-related gastrointestinal side effect is chemotherapy-induced constipation.

[0187] In some embodiments, the chemotherapy-related gastrointestinal side effects are caused by 5-fluorouracil (FU-5). In some embodiments, the chemotherapy-related gastrointestinal side effects are caused by camptothecin. In some embodiments, the chemotherapy-related gastrointestinal side effects are caused by belotecan, irinotecan, topotecan, or trastuzumab deruxtecan. In some embodiments, the chemotherapy-related gastrointestinal side effects are caused by irinotecan.

[0188] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human.

[0189] In some embodiments, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 60 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In some embodiments, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 100 mg / kg / day. In another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 50 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 60 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 50 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 25 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 20 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 15 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 10 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 to about 5 mg / kg / day.

[0190] In certain embodiments, the compounds provided herein are administered orally.

[0191] The compounds provided herein can be administered once a day (QD) or in multiple daily doses, e.g., twice a day (BID), three times a day (TID). Furthermore, administration can be continuous (i.e., daily) or intermittent. The terms "intermittent" or "intermittently" as used herein indicate that the intervals between stopping and starting are regular or irregular. For example, the intermittent administration of the compounds provided herein can be 1-6 days a week, cyclical (e.g., daily for 2-8 consecutive weeks followed by a rest period of up to 1 week without administration), or every other day.

[0192] Additionally, the compounds provided herein may be used in conjunction or in combination with other therapeutic agents that may be used in the treatment and / or prevention of the diseases, disorders, or conditions described herein.

[0193] In this application, the term "combination" includes the use of multiple therapies (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which the therapeutic agents (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease, disorder, or condition. A first therapy (e.g., a prophylactic or therapeutic agent, e.g., a compound provided in this application) can precede (e.g., 5 minutes, 15 minutes, 50 minutes, 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 before), simultaneously with, or after (e.g., 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 weeks, 6 weeks, 8 weeks, or 12 weeks after) a second therapy (e.g., a prophylactic or therapeutic agent). This application also includes triple therapy.

[0194] The route of administration of the compound provided in the present application is independent of the route of administration of the second therapy. In an embodiment, the compound provided in the present application is administered orally. Thus, according to this embodiment, the compound provided in the present application is administered orally, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, nasally, liposomally, by inhalation, intravaginally, intraocularly, locally via a catheter or stent, subcutaneously, intraadipose, intraarticularly, intrathecally, or in a sustained release dosage form. In an embodiment, the compound provided in the present application is administered orally using the same administration method as the second therapy. In another embodiment, the compound provided in the present application is administered by one mode of administration, for example, oral administration, and the second agent (anticancer agent) is administered by another mode of administration, for example, parenterally.

[0195] In certain embodiments, the present application provides a method for inhibiting the activity of a cyclin-dependent kinase (CDK), comprising contacting the CDK with an effective amount of a compound represented by Formula (I) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma-ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0196] In some embodiments, the CDK is either CDK4 or CDK6. In some embodiments, the CDK is CDK4. In some embodiments, the CDK is CDK6.

[0197] The compounds provided herein may also be provided as articles of manufacture using packaging materials 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 appropriate for the selected formulation and intended mode of administration and treatment.

[0198] In some embodiments, the present application provides kits that, when used by a medical practitioner, simplify the administration of a pharmaceutical agent to a subject in order to administer an appropriate amount of a compound provided herein as an active ingredient, hi some embodiments, the kit comprises a container containing within the container a dosage form of a compound provided herein.

[0199] The kit provided in the present application may further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, a syringe, a needleless injector, a drip bag, a patch, and an inhaler. The kit provided in the present application may further include a condom used to administer the active ingredient.

[0200] The kits provided herein may also include a pharma- ceutically acceptable carrier for administration of one or more active ingredients. For example, if the active ingredient is provided in a solid form that requires reconstitution for parenteral administration, the kit may include a sealed container of a suitable carrier in which the active ingredient can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Illustrative examples of pharma- ceutically acceptable carriers include, but are not limited to: aqueous carriers including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-soluble carriers including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0201] The present application will be further understood by the following non-limiting examples. EXAMPLES

[0202] In this application, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in contemporary scientific literature, such as, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, the following abbreviations may be used in the Examples and throughout this application, without limitation: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimoles); μM (micromoles); mmol (millimoles); min (minutes); h (hours); ACN (acetonitrile); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); Boc (tert-butoxycarbonyl); HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); Me (methyl); MeOTf (methyl trifluoromethanesulfonate); Pd(OAc)2 (palladium acetate); tBuOH (Tert-Butyl Alcohol); TBS (tert-Butyldimethylsilyl); TEA (Triethylamine); TFA (Trifluoroacetic acid); THF (Tetrahydrofuran); MS (Mass Spectrometry); NMR (Nuclear Magnetic Resonance); prep-TLC (Preparative Thin Layer Chromatography) and prep-HPLC (Preparative High Performance Liquid Chromatography).

[0203] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, all reactions are performed at room temperature. The synthetic methods exemplified in this application are intended to illustrate the applicable chemistry through the use of specific examples and are not indicative of the scope of the present disclosure.

[0204] Example 1 Preparation of 2-hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1 TIFF2025514839000021.tif39170

[0205] A method for preparing compound A1 is shown in Scheme 1.

[0206] 2-[tert-Butyl(dimethyl)silyl]oxymethyl N-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-one-pyridine[2,3-d]pyrimidin-2-yl)amino]-3-pyridine]piperazin-1-yl]sulfonylcarbamate 1.2. 2-tert-Butyl(dimethyl)methylsilyloxyethanol (7.4 g, 41.9 mmol) was dissolved in dichloromethane (150 mL), and N-(hydroxymethyl)sulfonyl chloride (5.9 g, 41.9 mmol, 3.6 mL) was added slowly under nitrogen atmosphere at 0° C., and stirring was continued at 0° C. for 20 minutes, followed by the addition of pyridine (6.6 g, 83.8 mmol). After the mixture was stirred at 0° C. for another 40 min, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-piperazin-1-yl-2-pyridinyl)amino]do[2,3-d]rimidin-7-one 1. 1 (15.0 g, 33.5 mmol) and triethylamine (4.2 g, 41.9 mmol) were added to a dichloromethane solution (20 mL). After stirring at 25° C. for 2 h, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL). The combined organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1.2 (30 g). This compound was used directly in the next reaction step without further purification. MS (ESI) m / z: 729.8 [M+H] + . TIFF2025514839000022.tif61170

[0207] 2-Hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1. Compound 1.2 (15.0 g, 20.5 mmol) was dissolved in tetrahydrofuran (75 mL) at 0° C., and HF pyridine (35.0 mL, 70% purity) was added. After stirring for 1 h, the reaction was neutralized with saturated aqueous NaHCO3 (75 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was further purified by silica gel column chromatography eluted with MeOH / DCM to give compound A1 (6 g). 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.17 (s, 1H), 8.96 (s, 1H), 8.08 (d, 1H, J = 4.0 Hz), 7.89 (d, 1H, J = 10.0 Hz), 7.52-7.49 (m, 1H),5.85-5.80 (m, 1H), 4.87-4.84 (m, 1H), 4.0-4.2 (m, 2H), 3.60-3.45 (m, 2H), 3.40-3.32 (m, 4H), 3.28-3.20 (m, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 2.2-2.3 (m, 2H), 1.88 (br s, 2H), 1.7-1.8 (m, 2H), 1.5-1.6 (m, 2H); MS (ESI) m / z: 615.0 [M+H] + .

[0208] Example 2 Preparation of tert-butyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A2 and (S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-sulfonamide A3 TIFF2025514839000023.tif41170

[0209] A method for preparing compounds A2 and A3 is shown in Scheme 2.

[0210] tert-Butyl (R)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 2.2. A mixture of 5-chloro-2-nitropyridine (10 g, 63.1 mmol), tert-butyl (S)-3-ylpiperazine-1-carboxylate (14 g, 69.4 mmol), K3PO4 (40.2 g, 189.3 mmol), palladium acetate (1.4 g, 6.3 mmol) and BINAP (7.9 g, 12.6 mmol) in dioxane ring (1 L) was stirred at 100 °C under N2 for 16 h. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to give compound 2.2 (6.3 g). MS (ESI) m / z: 323.0 [M+H] + .

[0211] tert-Butyl (R)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylate 2.3. A mixture of compound 2.2 (7.7 g, 23.7 mmol) and Pd / C (5.0 g, 4.7 mmol, 10% purity) in EtOAc (250 mL) was stirred at room temperature under H2 conditions for 1 h. The reaction mixture was filtered and concentrated in vacuo to give compound 2.3 (6.8 g). MS (ESI) m / z: 293.1 [M+H] + .

[0212] tert-Butyl ((S)-4-(6-((8-cyclopentyl-6-(1-ethoxyethylene)-5-methyl-7-one-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate 2.5. LiHMDS (2.8 mL, 1 M) was slowly added dropwise to a solution of compound 2.3 (555 mg, 1.9 mmol) in anhydrous THF (18 mL) at 0 °C, and the reaction was completed within 5 min. The mixture was stirred at 0 °C for 1 h, and then the reaction was cooled to room temperature and cooled to room temperature. A solution of 2.5 (1 mL) was slowly added dropwise. The reaction was stirred at 0° C. for an additional hour and neutralized with water (15 mL). The reaction was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. Purification by silica gel chromatography gave compound 2.5 (270 mg). MS (ESI) m / z: 590.3 [M+H] + . TIFF2025514839000024.tif114170

[0213] (S)-6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(2-methylpiperazin-1-yl)-pyridin-2-yl)amino)pyridine[2,3-d]pyrimidin-7(8H)-one 2.6. To a solution of compound 2.5 (570 mg, 1.0 mmol) in dichloromethane (10 mL) was slowly added dropwise at 0° C. Trifluoroacetic acid (1.0 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo and lyophilized to give product 2.6 (470 mg). MS (ESI) m / z: 462.3 [M+H] + .

[0214] tert-butyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A2. To a solution of N-(hydroxymethyl)sulfonyl chloride (1.6 g, 11.6 mmol) in anhydrous dichloromethane (10 mL) at 0 °C, tert-butanol (859 mg, 11.6 mmol) was slowly added dropwise. After stirring for 30 min, the mixture and triethylamine (258 mg, 2.6 mmol) were slowly added to a solution of compound 2.6 (535 g, 1.2 mmol) in anhydrous dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give product A2 (285 mg). MS (ESI) m / z: 641.3 [M+H] + .

[0215] (S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)-amino)pyridin-3-yl)-3-methylpiperazine-1-sulfonamide A3. To a solution of compound A2 (280 mg, 0.4 mmol) in dichloromethane (10 mL) was slowly added dropwise at 0° C. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under vacuum and lyophilized to give compound A3 (169 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.00 (s, 1H), 8.01 (s, 1H), 7.91-7.68 (m, 2H), 6.89 (s, 2H), 6.02-5.68 (m, 1H), 4.20-4.02 (m, 1H), 3.49-3.39 (m, 2H), 3.23-3.21 (m, 1H), 3.14-3.04 (m, 1H), 2.95-2.92 (m, 1H), 2.82-2.76 (m, 1H), 2.44 (s, 3H), 2.34 (s, 3H), 2.29-2.15 (m, 2H), 1.98-1.86 (m, 2H), 1.85-1.73 (m, 2H), 1.66-1.51 (m, 2H), 1.03 (d, J = 6.0 Hz, 3H); MS (ESI) m / z:541.3 [M+H] + .

[0216] Example 3 Preparation of tert-butyl-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A4 and 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonamide A5 TIFF2025514839000025.tif44170

[0217] A method for preparing compounds A4 and A5 is shown in Scheme 3. TIFF2025514839000026.tif77170

[0218] tert-Butyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A4; To a solution of N-(hydroxymethyl)sulfonyl chloride (3.2 g, 22.3 mmol) in anhydrous dichloromethane (90 mL) at 0 °C, tert-butanol (1.7 mg, 22.3 mmol) was slowly added dropwise. After the mixture was stirred for 20 min, pyridine (3.5 g, 44.7 mmol) was added and the resulting mixture was continued to stir for 1 h. The mixture was added to a dichloromethane solution (160 mL) containing 6-acetyl-8-cyclopentyl-5-methyl-2-[5-piperazin-1-yl-2-pyridinyl)amino]lide[2,3-d]pyrimidin-7-one 1.1 (8.0 g, 17.9 mmol) and TEA (2.3 g, 22.3 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 8 h, diluted with water (30 mL), and the organic phase was concentrated in vacuo to give the crude product, which was triturated with EtOAc (60 mL) to give compound A4 (10.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.20 (s, 1H), 8.98 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.88 (s, 1H), 7.54-7.50 (m, 1H),5.82 (t, J = 8.0 Hz, 1H), 3.50-3.34 (m, 4H), 3.28-3.16 (m, 4H), 2.42 (s, 3H), 2.32 (s, 3H), 2.28-2.18 (m, 2H), 1.96-1.82 (m, 2H), 1.82-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.42 (s, 9H); MS (ESI) m / z: 627.3 [M+H] + .

[0219] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonamide A5. To a solution of compound A4 (6 g, 9.6 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (1.1 g, 9.6 mmol). The reaction mixture was stirred at 25° C. for 2 hours and concentrated in vacuo to give compound A5 (4.8 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 1H),5.92-5.72 (m, 1H), 3.28-3.24 (m, 4H), 3.16-3.02 (m, 4H), 2.42 (s, 3H), 2.32 (s, 3H), 2.25-2.10 (m, 2H), 1.96-1.82 (m, 2H), 1.84-1.72 (m, 2H), 1.66-1.52 (m, 2H); MS (ESI) m / z:527 [M+H] + .

[0220] Example 4 Preparation of (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropionamide A6 TIFF2025514839000027.tif47170

[0221] A method for preparing compound A6 is shown in Scheme 4.

[0222] tert-Butyl ((S)-(1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine)-1-sulfonamido-1-oxypropan-2-yl)carbamate 4.1. A mixture of 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonamide A4 (500 mg, 1.0 mmol), tert-butoxycarbonyl-L-alanine (216 mg, 1.1 mmol), DIPEA (613.0 mg, 4.7 mmol) and HATU (433 mL) in DMF (25 mL) was added. mg, 1.1 mmol) was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give compound 4.1 (330 g). MS (ESI) m / z: 698.3 [M+H] + . TIFF2025514839000028.tif72170

[0223] (S)-N-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropionamide A6. Compound 4.1 (330 mg, 0.5 mmol) was added to a solution of 4M hydrochloric acid in dioxane ring (10 mL) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under vacuum to give the crude product. Purification by silica gel chromatography and reverse phase prep-HPLC gave compound A6 (202 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.29 (s, 1H), 8.97 (s, 1H), 8.16 (s, 2H), 8.08 (d, J = 4.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H),5.90-5.75 (m, 1H), 3.89 (s, 1H), 3.41 (d, J = 6.0 Hz, 4H), 3.28 (s, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.24 (s, 2H), 1.90 (s, 2H), 1.78 (d, J = 8.0 Hz, 2H), 1.58 (d, J = 6.0 Hz, 2H), 1.40 (d, J = 8.0 Hz, 3H); MS (ESI) m / z:598.2 [M+H] + .

[0224] Example 5 Preparation of (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A7 TIFF2025514839000029.tif50170

[0225] A method for preparing compound A7 is shown in Scheme 5. TIFF2025514839000030.tif128170

[0226] 1-(3-Methylimidazol-1-yl)sulfonylimidazole 5.2. 1-Imidazol-1-ylsulfonylimidazole 5.1 (12 g, 60.5 mmol) was dissolved in dichloromethane (120 mL) and methyl trifluoromethanesulfonate (10.9 g, 66.6 mmol) was added. The reaction mixture was stirred at 0° C. for 3 h and concentrated in vacuo to give product 5.2 (18 g). This product was used directly in the next reaction step without further purification.

[0227] 6-Acetyl-8-cyclopentyl-2-[[5-(4-imidazol-1-ylsulfonylperazin-1-yl)-2-pyridine]-amino]-5-methylpyridine[2,3-d]pyrimidin-7-one 5.3. To a solution of compound 5.2 (10 g, 46.9 mmol) in acetonitrile (200 mL) was added 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyrido[2,3-d]pyrimidin-7-one 1.1 (14 g, 31.3 mmol). The reaction mixture was stirred at 25° C. for 45 h and concentrated under vacuum to give the crude product. Purification by silica gel chromatography gave product 5.3 (13 g).

[0228] 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-[4-(3-methylimidazol-3-ium-1-yl)-sulfonylperazin-1-yl]-2-pyridine]amino]pyridine[2,3-d]pyrimidin-7-one 5.4. Compound 5.3 (5 g, 8.6 mmol) was dissolved in dichloromethane (50 mL) and methyl trifluoromethanesulfonate (2.8 g, 17.3 mmol) was added at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 3 hours and concentrated in vacuo to give compound 5.4 (6.4 g). This product was used directly in the next reaction step without further purification.

[0229] (R)-6-Acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A7. To a solution of compound 5.4 (400 mg, 0.5 mmol) in acetonitrile (60 mL) was added (R)-piperidine-2-methanol (93 mg, 0.8 mmol). The reaction mixture was stirred at 25° C. for 16 hours. Compound A7 (155 mg) was obtained by silica gel column chromatography and prep-TLC. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.96 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 10.0 Hz, 1H), 7.55-7.46 (m, 1H),5.83 (p, J = 8.0 Hz, 1H), 4.82 (t, J= 6.0 Hz, 1H), 3.76-3.43 (m, 4H), 3.28-3.14 (m, 8H), 3.00 (t, J = 12.0 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.28-2.16 (m, 2H), 1.99-1.70 (m,5H), 1.66-1.32 (m, 7H); MS (ESI) m / z: 625.2 [M+H] + .

[0230] Example 6 Preparation of ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1 TIFF2025514839000031.tif45170

[0231] A method for preparing compound B1 is shown in Scheme 6. TIFF2025514839000032.tif80170

[0232] 4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonic acid 6.1. 6-Acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyrido[2,3-d]pyrimidin-7-one 1.1 (1.5 g, 3.4 mmol) and DIPEA (866.4 mg, 6.7 mmol) were dissolved in dichloromethane (15 mL) and sulfonyl chloride (390 mg, 3.4 mmol) was added at −30° C. under nitrogen atmosphere. The reaction mixture was stirred at 25° C. for 2 h, and the filtered solution was concentrated under vacuum to give the crude product. Purification by reverse phase prep-HPLC gave compound 6.1 (550 mg). 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.96 (s, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.55-7.49 (m, 1H), 6.90-7.30 (m, 4H),5.90-5.78 (m, 1H), 3.13-3.21 (m, 4H), 2.93-3.01 (m, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 2.18-2.29 (m, 2H), 1.89 (br s, 2H), 1.74-1.84 (m, 2H), 1.56-1.66 (m, 2H); MS (ESI) m / z:528.3 [M+H] + .

[0233] ((((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1. To a solution of compound 6.1 (800 mg, 1.5 mmol) and Ag2O (527 mg, 2.3 mmol) in acetonitrile (15 mL) was added iodomethyl deuterated ester (477 mg, 2.0 mmol). The reaction mixture was stirred at 25 °C for 12 h, filtered and concentrated to give the crude product. Purification by silica gel column chromatography gave product B1 (120 mg). 1 H NMR (400 MHz,CCl3D) δ 8.83 (s, 1H), 8.40-8.30 (m, 1H), 8.05-7.90 (m, 1H), 7.52-7.36 (m, 1H),5.88 (t, J = 8.0 Hz, 1H),5.78 (s, 2H), 3.54-3.48 (m, 4H), 3.33-3.23 (m, 4H), 2.56 (s, 3H), 2.39 (s, 3H), 2.37-2.28 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.86 (m, 2H), 1.73-1.68 (m, 2H), 1.27 (s, 9H); MS (ESI) m / z: 642.4 [M+H] + .

[0234] Example 7 Preparation of 6-acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylperazin-1-yl)-2-pyridine]-amino]-5-methylpyridine[2,3-d]pyrimidin-7-one C1 TIFF2025514839000033.tif50170

[0235] A method for preparing compound C1 is shown in Scheme 7. TIFF2025514839000034.tif46170

[0236] To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyrido[2,3-d]pyrimidin-7-one (800 mg, 1.8 mmol) and pyrido (424 mg, 5.4 mmol) in dichloromethane (10 mL) was added propane-2-sulfonyl chloride (510 mg, 3.6 mmol). The reaction mixture was stirred at 25° C. for 4 h and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography and preparative thin layer chromatography gave product C1 (80 mg). 1 H NMR (400 MHz,CDCl3) δ 8.84-8.82 (m, 1H), 8.82 (s, 1H), 8.35-8.20 (m, 1H), 8.01 (d, J = 4.0 Hz, 1H), 7.45-7.36 (m, 1H),5.96-5.80 (m, 1H), 3.77-3.74 (m, 1H), 3.61-3.53 (m, 4H), 3.25-3.22 (m, 4H), 2.56 (s, 3H), 2.39 (s, 3H), 2.37-2.23 (m, 2H), 2.18-2.01 (m, 2H), 1.90-1.86 (m, 2H), 1.76-1.67 (m, 2H), 1.40 (d, J = 8.0 Hz, 6H); MS (ESI) m / z:554.4 [M+H] + .

[0237] The following compounds were prepared analogously to the examples of synthetic procedures or methods disclosed in this application.

[0238] 2-Methoxyethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8. MS (ESI) m / z: 629.2 [M+H] + . TIFF2025514839000035.tif41170

[0239] 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A9. MS (ESI) m / z: 657.3 [M+H] + . TIFF2025514839000036.tif42170

[0240] Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A10. MS (ESI) m / z: 657.3 [M+H] + . TIFF2025514839000037.tif44170

[0241] 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)acetic acid A11. MS (ESI) m / z: 629.2 [M+H] + . TIFF2025514839000038.tif46170

[0242] 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-5-(hydroxymethyl)oxazolidin-2-one A12. MS (ESI) m / z: 627.2 [M+H] + . TIFF2025514839000039.tif51170

[0243] 2-Aminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13. MS (ESI) m / z: 614.1 [M+H] + . TIFF2025514839000040.tif48170

[0244] (S)-2-(2-amino-3-methylbutanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A14. MS (ESI) m / z: 713.3 [M+H] + . TIFF2025514839000041.tif41170

[0245] 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A15. MS (ESI) m / z: 656.2 [M+H] + . TIFF2025514839000042.tif47170

[0246] (R)-2-(2-aminopropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A16. MS (ESI) m / z: 685.3 [M+H] + . TIFF2025514839000043.tif43170

[0247] (S)-2-(2-amino-4-methylpentanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A17. MS (ESI) m / z: 727.3 [M+H] + . TIFF2025514839000044.tif41170

[0248] (S)-2-(2-amino-3-hydroxypropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A18. MS (ESI) m / z: 701.3 [M+H] + . TIFF2025514839000045.tif40170

[0249] (S)-2-(2-amino-4-(methylsulfanyl)butanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A19. MS (ESI) m / z: 745.3 [M+H] + . TIFF2025514839000046.tif42170

[0250] 2-(2-aminoacetamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A20. MS (ESI) m / z: 671.2 [M+H] + . TIFF2025514839000047.tif42170

[0251] (R)-2-(Pyrrolidine-2-formylamino)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A21. MS (ESI) m / z: 711.2 [M+H] + . TIFF2025514839000048.tif43170

[0252] Tetrahydro-2H-pyran-4-yl(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A22. MS (ESI) m / z: 655.3 [M+H] + . TIFF2025514839000049.tif46170

[0253] Cyclobutyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A23. MS (ESI) m / z: 625.3 [M+H] + . TIFF2025514839000050.tif47170

[0254] Cyclopropyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A24. MS (ESI) m / z: 611.2 [M+H] + . TIFF2025514839000051.tif50170

[0255] Ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A25. MS (ESI) m / z: 599.2 [M+H] + . TIFF2025514839000052.tif44170

[0256] Methyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A26. MS (ESI) m / z: 585.3 [M+H] + . TIFF2025514839000053.tif45170

[0257] Isopropyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin)-3-yl)piperazin-1-yl)sulfonyl)carbamate A27. MS (ESI) m / z: 613.2 [M+H] + . TIFF2025514839000054.tif40170

[0258] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminobutanamide A28. MS (ESI) m / z: 612.3 [M+H] + . TIFF2025514839000055.tif41170

[0259] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminoacetamide A29. MS (ESI) m / z: 584.2 [M+H] + . TIFF2025514839000056.tif46170

[0260] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-methylbutanamide A30. MS (ESI) m / z: 626.3 [M+H] + . TIFF2025514839000057.tif40170

[0261] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-(1H-imidazol-4-yl)-propionamide A31. MS (ESI) m / z: 664.3 [M+H] + . TIFF2025514839000058.tif45170

[0262] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2,6-diaminohexanamide A32. MS (ESI) m / z: 655.3 [M+H] + . TIFF2025514839000059.tif46170

[0263] (R)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-formamide A33. MS (ESI) m / z: 624.3 [M+H] + . TIFF2025514839000060.tif44170

[0264] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)acetamide A34. MS (ESI) m / z: 569.2 [M+H] + . TIFF2025514839000061.tif45170

[0265] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propionamide A35. MS (ESI) m / z: 583.2 [M+H] + . TIFF2025514839000062.tif46170

[0266] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)isobutyramide A36. MS (ESI) m / z: 597.3 [M+H] + . TIFF2025514839000063.tif47170

[0267] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butyramide A37. MS (ESI) m / z: 597.3 [M+H] + . TIFF2025514839000064.tif45170

[0268] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropaneformamide A38. MS (ESI) m / z: 595.2 [M+H] + . TIFF2025514839000065.tif41170

[0269] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-formamide A39. MS (ESI) m / z: 624.2 [M+H] + . TIFF2025514839000066.tif41170

[0270] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-formamide A40. MS (ESI) m / z: 639.3 [M+H] + . TIFF2025514839000067.tif42170

[0271] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutaneformamide A41. MS (ESI) m / z: 609.3 [M+H] + . TIFF2025514839000068.tif44170

[0272] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)perazine-1-sulfonamide A42. MS (ESI) m / z: 571.2 [M+H] + . TIFF2025514839000069.tif44170

[0273] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)perazine-1-sulfonamide A43. MS (ESI) m / z: 585.3 [M+H] + . TIFF2025514839000070.tif44170

[0274] ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)glycine A44. MS (ESI) m / z: 585.2 [M+H] + . TIFF2025514839000071.tif45170

[0275] ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-L-valine A45. MS (ESI) m / z: 627.3 [M+H] + . TIFF2025514839000072.tif44170

[0276] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-methylperazine-1-sulfonamide A46. MS (ESI) m / z: 541.2 [M+H] + . TIFF2025514839000073.tif44170

[0277] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylperazine-1-sulfonamide A47. MS (ESI) m / z: 555.2 [M+H] + . TIFF2025514839000074.tif46170

[0278] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylperazine-1-sulfonamide A48. MS (ESI) m / z: 569.3 [M+H] + . TIFF2025514839000075.tif43170

[0279] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylperazine-1-sulfonamide A49. MS (ESI) m / z: 569.3 [M+H] + . TIFF2025514839000076.tif44170

[0280] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylperazine-1-sulfonamide A50. MS (ESI) m / z: 555.2 [M+H] + . TIFF2025514839000077.tif48170

[0281] 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyridine[2,3-d]pyrimidin-7(8H)-one A51. MS (ESI) m / z: 597.3 [M+H] + . TIFF2025514839000078.tif43170

[0282] 6-Acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A52. MS (ESI) m / z: 583.2 [M+H] + . TIFF2025514839000079.tif47170

[0283] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)perazine-1-sulfonamide A53. MS (ESI) m / z: 615.3 [M+H] + . TIFF2025514839000080.tif50170

[0284] 2-Hydroxyethyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A54. MS (ESI) m / z: 629.2 [M+H] + . TIFF2025514839000081.tif40170

[0285] 2-((R)-2-amino-3-methylbutanamido)ethyl(((S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A55. MS (ESI) m / z: 727.3 [M+H] + . TIFF2025514839000082.tif38170

[0286] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylaminoformyl)perazine-1-sulfonamide A56. MS (ESI) m / z: 612.3 [M+H] + . TIFF2025514839000083.tif43170

[0287] 6-Acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A57. MS (ESI) m / z: 593.2 [M+H] + . TIFF2025514839000084.tif49170

[0288] 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A58. MS (ESI) m / z: 578.2 [M+H] + . TIFF2025514839000085.tif44170

[0289] p-Methylphenyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B2. MS (ESI) m / z: 618.2 [M+H] + . TIFF2025514839000086.tif45170

[0290] ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)benzoic acid methyl ester B3. MS (ESI) m / z: 662.2 [M+H] + . TIFF2025514839000087.tif44170

[0291] Cyclopentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4. MS (ESI) m / z: 596.3 [M+H] + . TIFF2025514839000088.tif47170

[0292] 6-Acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)perazin-1-yl)pyridin-2-yl)-amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one C2. MS (ESI) m / z: 540.2 [M+H] + . TIFF2025514839000089.tif43170

[0293] Example B1 (Caliper Mobility Shift Analysis of CDK4 and CDK6)

[0294] The inhibitory activity of the compounds was detected using Caliper Mobility Shift in each kinase buffer (CDK4: 20 mM HEPES, pH 7.5 and 0.01% Triton X-100; CDK6: 50 mM HEPES, pH 7.5 and 0.0015% BRIJ-35). CDK4 / Cyclin D1 and CDK6 / Cyclin D1 were obtained from PROQINASE and CARNA, respectively. FAM-labeled peptides were obtained from GL.

[0295] Predefined concentrations of compounds were preincubated with CDK4 / Cyclin D1 or CDK6 / Cyclin D1 in 384-well plates for 10 min at room temperature. The kinase reaction was then initiated by adding FAM-labeled peptide and ATP. The final kinase concentrations for CDK4 and CDK6 were 15 nM and 7.5 nM, respectively. The final ATP concentrations for CDK4 and CDK6 were 672 nM and 230 nM, respectively. The well plates were incubated at 28°C. The kinase reaction was terminated by adding termination buffer (100 mM HEPES, pH 7.5, 0.012% BRIJ-35, 0.2% CoatingReagent 3 (Caliper Life Sciences), and 50 M EDTA). Data were recorded and converted to percent inhibition for each compound to determine IC50 values. The results are summarized in Table 1. Among these, the symbol "***" indicates 200 nM or less, the symbol "**" indicates more than 200 nM and 500 nM or less, and the symbol "*" indicates more than 500 nM.

[0296] [Table 1] TIFF2025514839000091.tif126170

[0297] (Example B2) (Cell viability measurement)

[0298] Cell viability of MCF-7 human breast cancer cells under normal growth conditions was measured with the CELLTITER-GLO luminescence assay. MCF-7 human breast cancer cells were cultured in EMEM medium supplemented with 10% FBS, 0.01 mg / mL bovine insulin in a 5% CO2 humidified incubator at 37 °C. Cells were seeded at 3,000 cells / well in 96-well tissue culture plates. Cells were allowed to adhere to the wall after overnight incubation in the incubator. Predefined concentrations of compounds (5 μL) were added to the culture medium. Cells were incubated at 37 °C for 8 days before adding CELLTITER-GLO detection solution (100 μL). Cells were mixed on a rotary shaker for 5 min and incubated for 10 min. Plates were measured on an ENVISION instrument. Results are summarized in Table 2. Among them, the symbol "+++" indicates a value of 1 μM or less, the symbol "++" indicates a value between 1 μM and 10 μM or less, and the symbol "+" indicates a value exceeding 10 μM.

[0299] [Table 2]

[0300] (Example B3) (Apoptosis detection)

[0301] The protective effect of compounds against cytotoxicity by chemotherapeutic agents was tested using the CASPASE-GLO 3 / 7 apoptosis assay. Apoptosis experiments were performed with COLO205 human colon cancer cells. Cells were cultured in PRIM1640 medium supplemented with 10% FBS, 0.01 mg / mL bovine insulin at 37 °C in a 5% CO2 humidified incubator. Cells were seeded at 4,000 cells / well in 96-well tissue culture plates. After overnight culture, cells were pretreated with pre-determined concentrations of compounds or vehicle for 16 h before the addition of chemotherapeutic agents. Incubation was continued for 48 h and Caspase-Glo 3 / 7 reagent was added (100 μL / well). Cells were mixed for 10 min in a gyratory oscillator before incubation for 2 h at room temperature. The 96-well microplates were measured on an ENVISION instrument. The formula (fold induction = (RLU) (化合物) -RLU (ブランク) ) / (RLU (対照) -RLU (ブランク) The compound's induction fold in cells was calculated according to the formula: RLU = (Relative Light Units). The relative protection rate of the compound was calculated as follows: Relative protection rate = (Induction fold) (化学療法剤) -fold induction (化合物) ) / fold induction (化学療法剤) × 100%. The relative protection rates (RPR) of the compounds against chemotherapy-induced cytotoxicity are summarized in Table 3, and the results show that the compounds are effective against chemotherapy-induced cytotoxicity.

[0302] [Table 3] TIFF2025514839000094.tif50170

[0303] (Example B4) (5-FU-induced diarrhea in mice)

[0304] A 5-FU-induced mouse diarrhea model was used to evaluate the protective effect of the compounds against cytotoxicity caused by the chemotherapeutic agent 5-FU. On day 0, BALB / c mice (20-25 g, 7-8 weeks old) were randomly divided into three groups of 10 mice each (control group, 5-FU group, and compound treatment group). Control group: Mice were gavaged with the same volume of the same solvent as the compound treatment group, and then injected with the same volume of the same solvent as the 5-FU treatment group. 5-FU group: Mice were gavaged with the same volume of the solvent as the compound treatment group, and then injected with 5-FU (175 mg / kg). Compound treatment group: Mice were gavaged with the compound, and then injected with 5-FU (175 mg / kg). The compounds were formulated in 0.5% carboxymethylcellulose (CMC) solution.

[0305] On the seventh day, the grade of diarrhea in each mouse was evaluated according to the method described by Kurita et al. (Cancer Chemother. Pharmacol. 2000, 46, 211-20). The diarrhea remission rate was calculated by the formula: diarrhea remission rate (%) = (diarrhea grade in 5-FU group - diarrhea grade in compound treatment group) / diarrhea grade in 5-FU group x 100%. The results are summarized in Table 4 and show that the compounds are effective in treating 5-FU-induced cytotoxicity (e.g., diarrhea) by decreasing the diarrhea remission rate.

[0306] [Table 4]

[0307] (Example B5) (Mouse model of irinotecan-induced diarrhea / constipation)

[0308] The protective effect of the compounds against chemotherapy-induced cytotoxicity was evaluated in irinotecan-induced diarrhea / constipation model mice. On day 0, BALB / c mice (20-25 g, 7-8 weeks old) were randomly divided into three groups of 10 mice each (control group, irinotecan group, and compound treatment group). Control group: Mice were gavaged with the same volume of the same vehicle as the compound treatment group, and then injected with the same volume of the same vehicle as the irinotecan treatment group. Irinotecan group: Mice were gavaged with the same volume of the same vehicle as the compound treatment group, and then injected with irinotecan (240 mg / kg). Treatment group: Mice were gavaged with the compound, and then injected with irinotecan (240 mg / kg). The compounds were formulated in 0.5% CMC solution.

[0309] On the second day, the feces of the mice were collected within 3 hours, and their shape and weight were recorded. The fecal reduction rate was measured with reference to the method of Kim et al. (Lab. Anim.Res. 2016, 32, 231-40, the disclosure of which is incorporated herein by reference in its entirety). The fecal reduction rate was calculated by the formula: Fecal reduction rate (%) = (control group - irinotecan or CDK inhibitor group) / control group x 100%.

[0310] On the 7th day, the grade of diarrhea in each mouse was evaluated according to the method described by Kurita et al. (Cancer Chemother. Pharmacol. 2000, 46, 211-20). The diarrhea remission rate was calculated by the formula: diarrhea remission rate (%) = (diarrhea grade in 5-FU group - diarrhea grade in compound treatment group) / diarrhea grade in 5-FU group x 100%.

[0311] The results are summarized in Table 5 and show that the compounds significantly reversed irinotecan-induced diarrhea and constipation.

[0312] [Table 5]

[0313] The above examples are provided to provide those skilled 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 of this application. Modifications that are obvious to those skilled in the art are intended to be included within the scope of the appended claims. All publications, patents, and patent applications cited in this application are incorporated by reference into this application as if each publication, patent, or patent application was specifically and individually indicated to be incorporated by reference into this application.

Claims

1. Formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, among them, R １ is (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 Or -C(NR １ａ ) N.R. １ｂ R １ｃ and Each R ２ , R ３ , R ４ and R ６ are independently: (i) hydrogen, deuterium, cyanide, halogen, 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(O)SR １ａ , -C(NR １ａ ) N.R. １ｂ R １ｃ , -C(S)R １ａ , -C(S)OR １ａ , -C(S)NR １ｂ R １ｃ , -OR １ａ , -OC(O)R １ａ , -OC(O)OR １ａ , -OC(O)NR １ｂ R １ｃ , -OC(O)SR １ａ , -OC(NR １ａ ) N.R. １ｂ R １ｃ , -OC(S)R １ａ , -OC(S)OR １ａ , -OC(S)NR １ｂ R １ｃ , -OS(O)R １ａ , -OS(O) ２ R １ａ , -OS(O)NR １ｂ R １ｃ , -OS(O) ２ N.R. 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(O)SR １ｄ , -NR １ａ C (NR １ｄ ) N.R. １ｂ R １ｃ , -NR １ａ C(S)R １ｄ , -NR １ａ C(S)OR １ｄ , -NR １ａ C(S)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 N.R. １ｂ R １ｃ , -SR １ａ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ Or -S(O) ２ N.R. １ｂ R １ｃ and R ７ (i) C ２－６ 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 (ii) -OR ７ａ , -NR ７ｂ R ７ｃ , -NR ７ｄ C(O)R ７ｅ , -NR ７ｄ C(O)OR ７ｅ Or -NR ７ｄ C(O)NR ７ｂ R ７ｃ and R ５ and R ６ａ are each independently: (i) deuterium, cyanide, halogen, or nitro; 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(O)SR １ａ , -C(NR １ａ ) N.R. １ｂ R １ｃ , -C(S)R １ａ , -C(S)OR １ａ , -C(S)NR １ｂ R １ｃ , -OR １ａ , -OC(O)R １ａ , -OC(O)OR １ａ , -OC(O)NR １ｂ R １ｃ , -OC(O)SR １ａ , -OC(NR １ａ ) N.R. １ｂ R １ｃ , -OC(S)R １ａ , -OC(S)OR １ａ , -OC(S)NR １ｂ R １ｃ , -OS(O)R １ａ , -OS(O) ２ R １ａ , -OS(O)NR １ｂ R １ｃ , -OS(O) ２ N.R. 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(O)SR １ｄ , -NR １ａ C (NR １ｄ ) N.R. １ｂ R １ｃ , -NR １ａ C(S)R １ｄ , -NR １ａ C(S)OR １ｄ , -NR １ａ C(S)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 N.R. １ｂ R １ｃ , -SR １ａ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ Or -S(O) ２ N.R. １ｂ R １ｃ and R ７ａ is 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 R ７ｂ and R ７ｃ are independently hydrogen, 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 R ７ｂ and R ７ｃ together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl; R ７ｄ and R ７ｅ are each independently hydrogen, 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; R １ａ , R １ｂ , R １ｃ and R １ｄ are each independently hydrogen, deuterium, or 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; m is an integer of 0, 1, 2 or 3; and n is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more, or, in some embodiments, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyanide, halogen, imine, nitro, nitroxy, and carbonyl; (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 which may further comprise one or more substituents Q ａ or in some embodiments, one, two, three or four substituents Q ａ and (c) —C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , -C(O)SR ａ , -C(NR ａ ) N.R. 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 ) N.R. 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 N.R. 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 ) N.R. 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 N.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 N.R. ｂ R ｃ , among which, each R ａ , R ｂ , R ｃ and R ｄ are each 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 radical being one or more, or in some embodiments one, two, three, or four substituents Q ａ or (iii) R ｂ and R ｃ together with the nitrogen atom to which they are attached form a heterocyclyl, which heterocyclyl may contain one or more, or in some embodiments, one, two, three or four, substituents Q ａ is replaced by; Each Q in the formula ａ are each independently selected from the following: (a) deuterium, cyanide, halogen, imine, nitro, nitroxy, and oxo; (b) 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 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 ) N.R. 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 ) N.R. 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 N.R. 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 ) N.R. 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 N.R. ｆ R ｇ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｆ R ｇ Sum-S(O) ２ N.R. ｆ R ｇ , among which, each R ｅ , R ｆ , R ｇ and R ｈ are each independently (i) hydrogen or deuterium, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl and heterocyclyl, or (iii) R ｆ and R ｇ together with the nitrogen atom to which they are attached to form a heterocyclyl.

2. In the formula, R ７ (i) C, each of which is optionally substituted with one or more substituents Q ２－６ alkyl, heteroaryl, or heterocyclyl; or (ii) -OR ７ａ , -NR ７ｂ R ７ｃ , -NR ７ｄ C(O)R ７ｅ , -NR ７ｄ C(O)OR ７ｅ Or -NR ７ｄ C(O)NR ７ｂ R ７ｃ 2. The compound of claim 1 ,

3. The R ７ each of which is optionally substituted with one or more substituents Q ２－６ 3. The compound of claim 1 or 2, which is alkyl, monocyclic heteroaryl or monocyclic heterocyclyl.

4. In the formula, R ７ is ethyl, isopropyl, imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazetidin-1-yl, 5-(hydroxymethyl)-2-oxazolidin-3-yl, (R)-2-(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

5. Formula (II) 3. The compound of claim 1 or 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

6. The R ７ｂ and R ７ｃ are each independently hydrogen or C optionally substituted with one or more substituents Q １－６ 6. The compound of claim 1 or 5, wherein said compound is alkyl.

7. In the formula, R ７ｂ and R ７ｃ 7. The compound of claim 1, 5 or 6, wherein each is independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl or 1-(hydroxycarbonyl)-2-methylpropyl.

8. In the formula, R ７ｂ and R ７ｃ 6. The compound of claim 1 or 5, wherein together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q.

9. In the formula, R ７ｂ and R ７ｃ 9. The compound of claim 1, 5 or 8, wherein together with the nitrogen atom to which they are attached form a monocyclic heteroaryl or monocyclic heterocyclyl, each optionally substituted with one or more substituents Q.

10. In the formula, R ７ｂ and R ７ｃ together with the nitrogen atom to which they are attached form imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazetidin-1-yl, 2-oxo-5-(hydroxymethyl)oxazolidin-3-yl, 2-(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

11. Formula (III) 3. The compound of claim 1 or 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

12. The R ７ｄ The compound according to claim 1 or 11, wherein is hydrogen.

13. The R ７ｅ each of which is optionally substituted with one or more substituents Q １－６ Alkyl, C ３－１０ 13. The compound of claim 1, 11 or 12 which is cycloalkyl or heterocyclyl.

14. The R ７ｅ is optionally substituted with one or more substituents Q １－６ 14. The compound according to any one of claims 1 and 11 to 13, wherein the aryl group is alkyl.

15. The R ７ｅ is optionally substituted with one or more substituents Q ３－１０ The compound of any one of claims 1 and 11 to 13, which is cycloalkyl.

16. The R ７ｅ is a monocyclic ring C optionally substituted with one or more substituents Q ３－１０ The compound of any one of claims 1, 11-13 and 15, which is cycloalkyl.

17. The R ７ｅ A compound according to any one of claims 1 and 11 to 13, wherein is heterocyclyl optionally substituted with one or more substituents Q.

18. The R ７ｅ The compound of any one of claims 1, 11-13 and 17, wherein is monocyclic heterocyclyl optionally substituted with one or more substituents Q.

19. The R ７ｅ 19. The compound of any one of claims 1, 11-13, 17 and 18, wherein is 5- or 6-membered heterocyclyl optionally substituted with one, two or three substituents Q, respectively.

20. In the formula, R ７ｅ is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrrolidine, tetrahydrofuran or tetrahydropyran, each optionally substituted with one, two or three substituents Q.

21. In the formula, R ７ｅ is methyl, aminomethyl, ethyl, 1-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, propyl, isopropyl, 1-aminopropyl, 1-amino-2-methylpropyl, 1,5-diaminopentyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl or tetrahydropyran-4-yl.

22. Formula (IV) 3. The compound of claim 1 or 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

23. In the formula, R ７ｄ 23. The compound of claim 1 or 22, wherein is hydrogen.

24. In the formula, R ７ｅ each of which is optionally substituted with one or more substituents Q １－６ Alkyl, C ３－１０ 24. The compound of claim 1, 22 or 23 which is cycloalkyl or heterocyclyl.

25. The R ７ｅ is optionally substituted with one or more substituents Q １－６ 25. The compound of any one of claims 1 and 22 to 24, wherein the compound is alkyl.

26. In the formula, R ７ｅ C optionally substituted with one, two or three substituents １－６ alkyl, wherein each substituent is independently —C(O)OR １ａ , -OR １ａ , -OC(O)R １ａ , -NR １ｂ R １ｃ Or -NR １ａ C(O)R １ｄ 26. The compound according to any one of claims 1 and 22 to 25,

27. The R ７ｅ Ga-NR １ａ C(O)R １ｄ C replaced by １－６ 27. The compound of any one of claims 1 and 22 to 26, wherein the compound is alkyl.

28. R in the formula ７ｅ is substituted with aminoamide １－６ 28. The compound of any one of claims 1 and 22 to 27, wherein the compound is alkyl.

29. R in the formula ７ｅ 28. The compound of any one of claims 1 and 22-27, wherein is ethyl substituted at the 2-position with an aminoamido.

30. 30. The compound according to claim 28 or 29, wherein the aminoamide is an α-aminoamide.

31. The aminoamide may be aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxyphenyl)propionamide, 2-amino-3-(imidazol-4-yl)propionamide, 2-amino-3-(indol-3-yl)propionamide, 2-amino-3-(hydroxycarbonyl)propionamide, 2-amino-3-(aminocarbonyl)propionamide, 2-amino-3-hydroxypropionamide, 2-amino-3-sulfhydrylpropionamide, 31. The compound according to any one of claims 28 to 30, which is 2-amino-3-methylbutanamide, 2-amino-3-hydroxybutanamide, 2-amino-4-(methylsulfanyl)butanamide, 2-amino-4-hydroxycarbonylbutanamide, 2-amino-4-(aminocarbonyl)butanamide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolidin-2-ylformamide.

32. In the formula, R ７ｅ is methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, (R)-2-(2-aminopropionylamino)ethyl, (S)-2-(2-amino-3-hydroxypropionamido)ethyl, (S)-2-(2-amino-3-methylbutanamido)ethyl, (S)-2-(2-amino-4-(methylthio)butanamido)ethyl, (S)-2-(2-amino-4-methylpentanoylamido)ethyl, (S)-2-(pyrrolidin-2-ylamido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl.

33. Formula (V) 3. The compound of claim 1 or 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

34. The R ７ｄ The compound of claim 1 or 33, wherein is hydrogen.

35. The R ７ｂ 35. The compound of claim 1, 33 or 34, wherein is hydrogen.

36. In the formula, R ７ｃ is optionally substituted with one or more substituents Q １－６ 36. The compound of any one of claims 1 and 33 to 35, wherein the compound is alkyl.

37. The R ７ｃ 37. The compound according to claims 1 and 33-36, wherein is isopropyl.

38. Formula (VI) 3. The compound of claim 1 or 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

39. The R ７ａ each of which is optionally substituted with one or more substituents Q １－６ Alkyl, C ３－１０ Cycloalkyl or C ６－１４ 40. The compound of claim 38 which is aryl.

40. The R ７ａ is optionally substituted with one, two or three substituents Q １－６ 40. The compound of claim 38 or 39, which is alkyl.

41. The R ７ａ is optionally substituted with one, two or three substituents Q ３－１０ 40. The compound of claim 38 or 39, which is cycloalkyl.

42. The R ７ａ is a monocyclic ring C optionally substituted with one, two or three substituents Q ３－１０ 42. The compound of claim 38, 39 or 41, which is cycloalkyl.

43. The R ７ａ is optionally substituted with one, two or three substituents Q ６－１４ 40. The compound of claim 38 or 39, which is aryl.

44. The R ７ａ 40. The compound of claim 38 or 39, wherein is methyl, ethyl, propyl, cyclopentyl or phenyl optionally substituted with one, two or three substituents Q.

45. In the formula, R ７ａ is pivaloyloxymethyl, benzoyloxymethyl, isopropyl, cyclopentyl or 4-methylphenyl.

46. The R １ each of which is optionally substituted with one or more substituents Q １－６ Alkyl or C ３－１０ The compound of any one of claims 1 to 45, which is cycloalkyl.

47. The R １ is optionally substituted with one or more substituents Q ３－１０ The compound of any one of claims 1 to 46, which is cycloalkyl.

48. The R １ is a monocyclic ring C optionally substituted with one, two or three substituents Q ３－１０ The compound of any one of claims 1 to 47, which is cycloalkyl.

49. The R １ The compound according to any one of claims 1 to 46, wherein is isopropyl, cyclopentyl or cyclohexyl.

50. The R １ The compound of any one of claims 1 to 49, wherein is cyclopentyl.

51. In the formula, R ２ (i) halogen; (ii) C １－６ Alkyl or C ６－１４ aryl, each substituted with one or more substituents Q; or (iii) —C(O)R １ａ , -C(O)OR １ａ , -OR １ａ Or -NR １ｂ R １ｃ The compound according to any one of claims 1 to 50,

52. The R ２ But -C(O)R １ａ The compound according to any one of claims 1 to 51,

53. The R ２ is optionally substituted with one or more substituents Q; １－６ The compound of any one of claims 1 to 52, which is alkyl.

54. In the formula, R ２ A compound according to any one of claims 1 to 51, wherein is fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, hydroxymethyl, ethoxymethyl, benzyl, acetyl, hydroxycarbonyl, ethoxycarbonyl, 2-ethoxyethoxy or amino.

55. The R ２ The compound according to any one of claims 1 to 54, wherein is acetyl.

56. The R ３ is hydrogen or C optionally substituted with one or more substituents Q １－６ The compound of any one of claims 1 to 55, which is alkyl.

57. The R ３ The compound according to any one of claims 1 to 56, wherein is methyl.

58. The R ４ The compound according to any one of claims 1 to 57, wherein is hydrogen.

59. 59. The compound according to any one of claims 1 to 58, wherein m is an integer equal to 1.

60. The R ５ is halogen or C optionally substituted with one, two or three substituents Q １－６ 60. The compound of any one of claims 1 to 59, which is alkyl.

61. The R ５ A compound according to any one of claims 1 to 60, wherein is fluorine, chlorine, methyl or ethyl.

62. 59. The compound according to any one of claims 1 to 58, wherein m is an integer equal to 0.

63. The R ６ is hydrogen or C optionally substituted with one, two or three substituents Q １－６ The compound of any one of claims 1 to 62, which is alkyl.

64. The R ６ The compound according to any one of claims 1 to 63, wherein is hydrogen.

65. The R ６ The compound according to any one of claims 1 to 63, wherein is methyl.

66. 66. The compound according to any one of claims 1 to 65, wherein n is an integer equal to 0.

67. wherein the compound is 2-Hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1; tert-Butyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A2; (S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-sulfonamide A3; tert-Butyl-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A4; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-perazine-1-sulfonamide A5; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropionamide A6; (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A7; 2-Methoxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A9; Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)ethyl acetate A10; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)aminoformyl)oxy)acetic acid A11; 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-5-(hydroxymethyl)oxazolidin-2-one A12; 2-aminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13; (S)-2-(2-amino-3-methylbutanamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A14; 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A15; (R)-2-(2-aminopropionamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin)-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A16; (S)-2-(2-amino-4-methylpentanamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A17; (S)-2-(2-amino-3-hydroxypropionamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A18; (S)-2-(2-amino-4-(methylsulfanyl)butanamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A19; 2-(2-aminoacetamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A20; (R)-2-(pyrrolidine-2-formylamino)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)perazin-1-yl)sulfonyl)carbamate A21; Tetrahydro-2H-pyran-4-yl(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A22; Cyclobutyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A23; Cyclopropyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A24; Ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A25; Methyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A26; Isopropyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin)-3-yl)piperazin-1-yl)sulfonyl)carbamate A27; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminobutanamide A28; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminoacetamide A29; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-methylbutanamide A30; (S)—N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-amino-3-(1H-imidazol-4-yl)-propionamide A31; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2,6-diaminohexanamide A32; (R)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-formamide A33; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)acetamide A34; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propionamide A35; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)isobutyramide A36; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butyramide A37; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropaneformamide A38; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-formamide A39; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-formamide A40; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutaneformamide A41; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)perazine-1-sulfonamide A42; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)perazine-1-sulfonamide A43; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)glycine A44; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-L-valine A45; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-methylpiperazine-1-sulfonamide A46; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylperazine-1-sulfonamide A47; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylperazine-1-sulfonamide A48; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylperazine-1-sulfonamide A49; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylperazine-1-sulfonamide A50; 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyridine[2,3-d]pyrimidin-7(8H)-one A51; 6-Acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A52; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)perazine-1-sulfonamide A53; 2-Hydroxyethyl (S)-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A54; 2-((R)-2-amino-3-methylbutanamido)ethyl(((S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl)sulfonyl)carbamate A55; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylaminoformyl)perazine-1-sulfonamide A56; 6-Acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A57; 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)perazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one A58; ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1; p-Methylphenyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B2; ((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)benzoic acid methyl ester B3; Cyclopentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridine[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4; 6-Acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylperazin-1-yl)-2-pyridine]-amino]-5-methylpyridine[2,3-d]pyrimidin-7-one C1; or 6-Acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)perazin-1-yl)pyridin-2-yl)-amino)-5-methylpyridine[2,3-d]pyrimidin-7(8H)-one C2; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

68. 68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; and a pharma- ceutically acceptable excipient.

69. 69. The pharmaceutical composition of claim 68, wherein the composition is in an oral dosage form.

70. A method for treating, preventing or alleviating one or more symptoms of a CDK-related disease, disorder or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 67 or a pharmaceutical composition of claim 68 or 69.

71. 71. The method of claim 70, wherein the disease, disorder or condition is chemotherapy-related gastrointestinal side effects.

72. 70. A method for preventing or alleviating chemotherapy-associated gastrointestinal side effects in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 67 or a pharmaceutical composition according to claim 68 or 69.

73. The method of any one of claims 71 to 72, wherein the chemotherapy-related gastrointestinal side effects are caused by camptothecin or fluorouracil.

74. The method of any one of claims 71 to 73, wherein the chemotherapy-related gastrointestinal side effects are caused by fluorouracil or irinotecan.

75. 75. The method of any one of claims 71 to 74, wherein the chemotherapy-related gastrointestinal side effect is chemotherapy-induced diarrhea or constipation.

76. The method of any one of claims 70 to 75, wherein the subject comprises a human.

77. 70. A method for inhibiting the activity of a CDK comprising contacting said CDK with an effective amount of a compound according to any one of claims 1 to 67 or a pharmaceutical composition according to claim 68 or 69.

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