CDK inhibitors, pharmaceutical compositions and therapeutic uses thereof

Abstract

The present application provides CDK inhibitors, for example, compounds of Formula (I), and pharmaceutical compositions thereof. Also provided is a method for treating, preventing or ameliorating gastrointestinal tract side effects caused by chemotherapy. # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to international application No. PCT / CN2022 / 089004, filed on April 25, 2022, pursuant to 35 U.S.C. 119(a); the entire contents of which are incorporated by reference into this application. Field of the Invention

[0002] The present application provides a CDK inhibitor and a pharmaceutical composition thereof. At the same time, the present application also provides a method for using the preparation to treat, prevent or alleviate gastrointestinal side effects caused by chemotherapy. Background

[0003] Gastrointestinal side effects caused by chemotherapy are a common cancer treatment problem, significantly affecting the morbidity and mortality of cancer patients. 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) caused by traditional chemotherapy drugs such as fluorouracil and irinotecan is as high as 50-80%. 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, have a significantly higher risk of CIP than traditional chemotherapy. Pessi et al., Crit. Rev. Oncol. Hematol. 2014, 90, 165-79; Bossi et al., Ann. Oncol. 2018, 29, iv126-42. CID has been observed in patients receiving small molecule tyrosine kinase inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, multi-target tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, cyclin-dependent kinase (CDK) 4 / 6 inhibitors, and poly (ADP-ribose) polymerase (PARP) inhibitors. 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.

[0004] Gastrointestinal side effects caused by chemotherapy often lead to interruption or change of treatment regimen, thus affecting the patient's prognosis and overall survival. O'Reilly et al., Ther. Adv. Chronic Dis. 2020, 11, 2040622320970354; McQuade et al., Front Pharmacol. 2016, 7, 414. It is reported that CID leads to changes in treatment in approximately 60% of colorectal cancer patients, including dose reduction, delay, and discontinuation of treatment. Arbuckle et al., Oncologist 2000, 5, 250-9; Dranisaris et al., Can. J. Gastroenterol. 2005, 19, 83-7. Currently, the treatment of CID aims to reduce the severity of symptoms rather than counteract the pathophysiological mechanism. Andreyev et al., Lancet Oncol. 2014, 15, e447-e60; McQuade et al., Front Pharmacol. 2016, 7, 414. Therefore, there is a need for an effective therapeutic option to treat, prevent, or alleviate chemotherapy-induced gastrointestinal side effects, such as CID. SUMMARY OF THE INVENTION

[0005] The compound provided in the present application is shown in 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; or a pharmaceutically 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 heterocyclic; (iii) –C(O)R 1a , –C(O)OR 1a , –C(O)NR 1b R 1c , –C(NR 1a )NR 1b R 1c ; R 2 , R 3 , R 4 and R 6Each independently may be one of the following groups: (i) hydrogen, deuterium, cyano, 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 heterocyclic; (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 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 R1c ,–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)2NR 1b R 1c ; Each R 5 are independently: (i) deuterium, cyano, 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 heterocyclic; (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)2NR 1b R 1c ; R 7 Yes (i) C 2-6Alkyl, 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 heterocyclic 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 ; Each R 6a are independently: (i) deuterium, cyano, 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 heterocyclic; (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)NR1b 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 R 1c or –S(O)2NR 1b R 1c ; R 7a Can be 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 One of aralkyl, heteroaryl or heterocyclic; Each R 7b and R 7c They can be hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 One of aralkyl, heteroaryl or heterocyclic group; or R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl or heterocyclyl group; 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 heterocyclic; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, 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 heterocyclic; wherein 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 and heterocyclyl may be matched with one or more, or in one embodiment, one, two, three or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, 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 and heterocyclyl, each of which may be further substituted with one or more substituents, in one embodiment, 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(NRa )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 Rc ,–NR a S(O)2NR b R c ,–SR a , –S(O)R a , –S(O)2R a , –S(O)NR b R c and –S(O)2NR b R c , where each R a , R b , R c and R d are independently represented by one of the following: (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 heterocyclic, each of which is optionally substituted by one or more Q a In one embodiment, one, two, three or four substituent groups Q a (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, optionally substituted by one or more Q a In one embodiment, one, two, three or four substituent groups Q a . Each Q a are independently selected from: (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 ,–ORe 、–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 and –S(O)2NR f R g ; where each R e , R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclic group.

[0006] The present application provides a pharmaceutical composition comprising a compound of formula (I) or its enantiomer, enantiomer mixture, diastereomer, mixture of two or more diastereomers, tautomer or mixture of two or more tautomers, and a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and a pharmaceutically acceptable excipient.

[0007] The present application also provides a method for treating, preventing or alleviating one or more symptoms of a disorder, disease or condition mediated by cyclin-dependent kinase (CDK) in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its enantiomer, enantiomeric mixture, 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] In addition, the present application also provides a method for treating, preventing or alleviating gastrointestinal side effects caused by chemotherapy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its enantiomer, enantiomer mixture, 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.

[0009] The present application also provides a method for treating, preventing or alleviating diarrhea caused by chemotherapy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its enantiomer, enantiomer mixture, 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.

[0010] The present application provides a method for inhibiting the activity of cyclin-dependent kinase (CDK), comprising contacting CDK with a compound of formula (I) or its enantiomer, enantiomer mixture, 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. Detailed description

[0011] In order to better understand what is described in this application, some terms are defined below.

[0012] Generally, the nomenclature used in this application and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacology are well known and widely used in the art. Unless otherwise defined, technical and scientific terms used in this application are generally the same as understood by ordinary technicians in this art.

[0013] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably in this application, for example, for mammalian subjects, such as human subjects. In one embodiment, the subject is a human.

[0014] The terms "treat," "treating," and "treatment method" mean alleviating or eliminating a disorder, disease, or condition, or reducing or eliminating one or more symptoms associated with the disorder, disease, or condition; or reducing or eliminating the cause of the disorder, disease, or condition.

[0015] The terms "preventing," "preventing," and "preventative methods" refer to delaying and / or preventing the onset of a disorder, disease or condition and its attendant symptoms; preventing a subject from developing a disorder, disease or condition; or reducing a subject's risk of developing a disorder, disease or condition.

[0016] The terms "alleviate" and "alleviating" refer to the alleviation or reduction of one or more symptoms (e.g., pain) of a disorder, disease, or condition. The term may also refer to the reduction of adverse reactions associated with an active ingredient. Sometimes, the benefit a subject receives from a preventive or therapeutic drug does not result in a cure of the disorder, disease, or condition.

[0017] The term "contacting" or "contacting" means bringing a therapeutic agent and a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue together so that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In another embodiment, contacting a therapeutic agent with a biomolecule, cell, or tissue comprises administering the therapeutic agent to a receptor having the biomolecule, cell, or tissue to be contacted.

[0018] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound that, when administered, is sufficient to prevent, alleviate, or reduce one or more symptoms of a disease, condition, or disorder being treated. The term "therapeutically effective amount" or "effective amount" also refers to an amount of a compound that is sufficient to elicit a desired biological or medical response in a biomolecule (such as a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is sought by a researcher, veterinarian, physician, or clinician.

[0019] The term "IC 50 ” or “EC 50 The term "inhibitor" refers to the amount, concentration, or dose of a compound required to inhibit a 50% maximum response in an assay measuring a biological response.

[0020] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in that it is compatible with the other ingredients in the pharmaceutical formulation and is suitable for contact with the tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, and is consistent with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulations and Formulations, 1st ed.; Gibson Ed.; CRC Press, 2015.

[0021] The term "about" or "approximately" means an acceptable error for a particular value, which depends on how the value is measured or determined, as determined by a person of ordinary skill. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations of a given value or range. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0022] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents Q described in the present application. 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group consisting of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group consisting of 3 to 6 carbon atoms. 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a linear saturated monovalent hydrocarbon radical consisting of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. In this application, linear C 1-6 and branched chain 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-propyl and isopropyl), butyl (including all isomers, such as n-butyl, isobutyl, sec-butyl and t-butyl), pentyl (including all isomers, such as n-pentyl, isopentyl, sec-pentyl, neopentyl and tert-pentyl) and hexyl (including all isomers, such as n-hexyl, isohexyl and sec-hexyl).

[0023] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group, the main chain of which contains one or more heteroatoms, each of which is independently selected from O, S and N. The heteroalkyl group may be substituted with one or more substituents Q described herein. For example, "C 1-6 "Heteroalkyl" refers to a linear saturated monovalent hydrocarbon group consisting of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group consisting of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl group is composed of 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10) or 1 to 6 (C 1-6 ) carbon atoms, or a linear saturated monovalent hydrocarbon group consisting of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl groups". Examples of heteroalkyl groups include, but are not limited to -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.

[0024] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon double bonds, one, two, three or four in one embodiment, and one in another embodiment. The alkenyl group may be optionally substituted with one or more substituents Q described herein. The term "alkenyl" includes alkenyl groups having "cis" or "trans" configurations or mixtures thereof, or alternatively, "Z" or "E" configurations or mixtures thereof, as is well known to the skilled artisan. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon radical having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and propenyl), butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0025] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon triple bonds, one, two, three or four in one embodiment, and one in another embodiment. Alkynyl groups do not contain carbon-carbon double bonds. The alkynyl group 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 group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is 2 to 20 carbon atoms (C 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 10 carbon atoms (C 2-10 ) or 2 to 6 carbon atoms (C 2-6 ) or a linear monovalent hydrocarbon radical of 4 to 20 carbon atoms (C 4-20 ), 4 to 15 carbon atoms (C 4-15 ), 4 to 10 carbon atoms (C 4- 10 ) or 4 to 6 carbon atoms (C 4-6 ). Examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, such as 1-propynyl, 2-propynyl and propargyl), butynyl (including all isomeric forms, such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl) and hexynyl (including all isomeric forms, such as 1-hexyn-1-yl and 2-hexyn-1-yl).

[0026] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, which may be optionally substituted with one or more substituents Q described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or a bridged or unbridged and / or fused bicyclic group. In certain embodiments, the cycloalkyl has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic; in another embodiment, the cycloalkyl is bicyclic; in another embodiment, the cycloalkyl is tricyclic; in yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, [1.1.1]bicyclopentyl, [2.1.1]bicyclohexyl, [2.2.1]bicycloheptyl, [2.2.2]bicyclooctyl, cyclopentyl, and adamantyl.

[0027] The term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group containing at least one aromatic ring. In certain embodiments, the aryl group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azepanyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl and triphenyl groups. Aryl also refers to a group with two or three carbocyclic rings, one of which is an aromatic ring and the other rings may be saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, indenyl or tetrahydronaphthyl (tetrahydronaphthyl). In one embodiment, aryl is monocyclic. In another embodiment, aryl is dicyclic. In another embodiment, aryl is tricyclic. In another embodiment, aryl is polycyclic. In certain embodiments, aryl can replace one or more groups according to Q described in the application.

[0028] The term "aralkyl" or "aralkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atoms. The example of aralkyl includes but is not limited to benzyl, phenethyl (including all isomeric forms, for example, 1-phenethyl and 2-phenethyl) and phenylpropyl (including all isomeric forms, for example, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, aralkyl is optionally substituted by one or more substituents Q described herein.

[0029] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing 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 heteroaryl groups containing heteroaromatic rings and non-aromatic heterocyclic rings, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms and / or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomeric forms such as furo[2,3-b]pyridinyl, furo[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, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthyridinyl, pyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl In yet another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, piperidinyl, phenanthroline, phenanthridinyl (including all isomeric forms, such as 1,5-phenanthroline, 1,6-phenanthroline, 1,7-phenanthroline, 1,9-phenanthroline and 2,10-phenanthroline), phenazinyl, phenarsazine, phenothiazinyl, phenoxazine and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q described herein.

[0030] The term "heterocyclyl" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more non-aromatic ring atoms are heteroatoms, each independently selected from O, S and N; the remaining ring atoms are carbon atoms. For heterocyclyls comprising heteroaromatic rings and non-aromatic heterocycles, the heterocyclyl is not bonded to the rest of the molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and wherein the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated, or have aromaticity. The term "heterocyclyl" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S and N; the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic rings and non-aromatic heterocycles, the heterocyclyl group is not bonded to the rest of the molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7 or 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may be fused or bridged, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated, or have aromaticity. The heterocyclyl group may be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Examples of heterocyclyl and heterocyclic groups include, but are not limited to, imidazolidinyl, benzophenone ... Pyridine, benzophenone Phenyl, benzofuranonyl, chromanyl, decahydroisoquinolyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isosteres such as 1,4-dihydrobenzo[d][1,3] Oxazine, 3,4-dihydrobenzo[c][1,2]- Oxazine and 3,4-dihydrobenzo[d][1,2] oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithienyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, benzodihydroisopyranyl, isoindolyl, isothiazolidinyl, isothiazolidinyl, Oxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, Oxazolidinyl, oxazolidinyl, oxirane, piperazinyl, piperidinyl, 4-piperidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiazolidinyl, chromanyl, tetrahydroquinolinyl and 1,3,5-terthienyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q described herein.

[0031] The term "halogen," "halide," or "halogen" refers to fluorine, chlorine, bromine, and / or iodine.

[0032] The term "optionally substituted" means that a group or substituent, such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl, may be substituted with one or more substituents Q, wherein each substituent Q is independently selected, for example: (a) deuterium (-D), cyano (-CN), halogen, imino (=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 and heterocyclyl, each of which may be further optionally substituted by one or more substituents Q a In one embodiment, 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)ORa , –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)2NR b R c , where each R a , R b , R c and R d each independently represents (i) hydrogen or deuterium; (ii) C1-6 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 heterocyclic, each of which may be optionally substituted by one or more substituents Q a Substitution, in one embodiment, 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, they form a heterocyclic group which may be optionally substituted by one or more substituents Q a Substitution, in one embodiment, one, two, three or four substituents Q a In the present application, all groups that can be substituted are referred to as "optionally substituted".

[0033] In one embodiment, each Q a can be independently selected from: (a) deuterium, cyano, 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 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 ,–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 ; where each R e , R f , R g and R h can be (i) hydrogen or deuterium alone; (ii) C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclic group.

[0034] In certain embodiments, "optically active" and "enantiomeric activity" refer to a group of molecules having an enantiomeric excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question.

[0035] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about the chiral center. The prefixes (+) and (-) are used to denote the optical rotation 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 has levorotatory properties, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound has dextrorotatory properties, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the sign of the optical rotation (+ / -) has nothing to do with the absolute configuration, R or S, of the compound.

[0036] The term "isotopically enriched" refers to a compound containing an unnatural ratio of isotopes on one or more atoms that make up the compound. In certain embodiments, an isotopically enriched compound contains an unnatural ratio of one or more isotopes, including but not limited to hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 (14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), Fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In certain embodiments, the isotopically enriched compound is in a stable form, i.e., non-radioactive. In certain embodiments, the isotopically enriched compound comprises an unnatural ratio of one or more isotopes, including but not limited to 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( 37Cl), bromine-79( 79 Br), bromine-81( 81 Br) and iodine-127( 127 I). In certain embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In certain embodiments, the isotopically enriched compound contains an unnatural ratio of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11 ( 11 C) Carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 I) It should be understood that in the compounds described, any hydrogen may be 2 H, any carbon can be 13 C, any nitrogen can be 15 N, any oxygen can be 18 O, feasibility is determined based on the judgment of a person of ordinary skill in the art.

[0037] The term "isotopic enrichment" refers to the relative abundance of a common isotope (e.g. 1 H corresponds to the percentage of an isotope at a given position of an element in which a proton of hydrogen or hydrogen-1) is replaced by a less common isotope (e.g., D corresponds to deuterium or hydrogen-2). In this application, when an atom at a particular position in a molecule is designated as a particular less common isotope, it is understood that the abundance of that isotope at that position is much higher than its natural abundance.

[0038] The term "isotopic enrichment factor" refers to the ratio of the isotopic abundance in an isotopically enriched compound to the natural abundance of a particular isotope.

[0039] The term "hydrogen" or the symbol "H" refers to the naturally occurring isotopic composition of hydrogen, consisting of protons ( 1 H), deuterium ( 2 H or D) and tritium ( 3H), their natural abundance. Proton is the most common isotope of hydrogen, with a natural abundance of over 99.98%. Deuterium is a less common isotope of hydrogen, with a natural abundance of approximately 0.0156%.

[0040] The term "deuterium enrichment" refers to the percentage of hydrogen replaced by deuterium at a given position in a molecule. For example, a 1% deuterium enrichment at a given position means that in a given sample, 1% of the molecules contain deuterium at the specified position. Since the naturally occurring distribution of deuterium averages about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials will average about 0.0156%. As used herein, when a particular position in an isotopically enriched compound is specified to have deuterium, it is understood that the abundance of deuterium at that position in the compound is significantly higher than its natural abundance (0.0156%).

[0041] The term "carbon" or the symbol "C" refers to the naturally occurring isotopic composition of carbon, including the natural abundance of carbon-12 ( 12 C) and carbon-13 ( 13 C). Carbon-12 is the most common carbon isotope, with a natural abundance of over 98.89%. Carbon-13 is a less common carbon isotope, with a natural abundance of about 1.11%.

[0042] The term "carbon-13 enriched" or 13 The term "C-enrichment" refers to the percentage of carbon replaced with carbon-13 at a given position in a molecule. For example, a 10% carbon-13 enrichment at a given position means that in a given sample, 10% of the molecules contain carbon-13 at the specified position. Since the naturally occurring distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position in an isotopically enriched compound is specified to have 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%).

[0043] The terms "substantially pure" and "substantially homogeneous" when referring to a substance means sufficiently homogeneous that the presence of impurities cannot be readily detected by standard analytical methods used by ordinary technicians in the general art, including but not limited to thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR) and mass spectrometry (MS); or sufficiently pure that further purification does not significantly change the physical, chemical, biological and / or pharmacological properties of the substance, such as enzymatic activity and biological activity. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules, wherein 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 molecule is a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. In this application, when the atom at a specific position in a specified isotopically enriched compound is a specific less common isotope, a compound containing a non-specified isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a compound having a deuterium at a specific position, a compound containing a proton at the same position is considered an impurity.

[0044] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., compounds provided in the present application) and one or more solvent molecules, which are present in a stoichiometric or non-stoichiometric ratio. Applicable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate has a crystalline form. In another embodiment, the complex or aggregate has an amorphous form. When the solvent is water, the resulting solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0045] For divalent groups described in this application, it is not intended that the orientation of the divalent group be implied. For example, unless a specific orientation is specified, the formula -C(O)NH- can represent both -C(O)NH- and -NHC(O)-.

[0046] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer or two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof” has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer or two or more tautomers of said compound; (ii) a pharmaceutically acceptable salt, solvate, hydrate or prodrug of the compound; or (iii) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer or a pharmaceutically acceptable salt, solvate, hydrate or prodrug of two or more tautomers of the compound" have the same meaning. Compound

[0047] In one embodiment, the present application provides 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 pharmaceutically 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 ; R 2 , R 3 , R 4 and R 6 are independently: (i) hydrogen, deuterium, cyano, 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)R1a 、–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 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)R1a , –S(O)2R 1a , –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; Each R 5 are independently: (i) deuterium, cyano, 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)2NR 1b R 1c ; R 7 Yes (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 ; Each R 6ais independently (i) deuterium, cyano, 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 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 ,–NR1a 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)2NR 1b R 1c ; R 7a It 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 heterocyclic group; 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 heterocyclic; or R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl or heterocyclyl group; 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 heterocyclic group; Each R 1a , R1b , R 1c and R 1d independently may be hydrogen, deuterium, 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 heterocyclic. 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 and heterocyclyl may be optionally substituted with one or more, according to one embodiment, one, two, three or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, nitrosoxy 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 and heterocyclic groups, each of which may be optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a substitution; 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)NRb 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 and –S(O)2NR b R c , where each R a , R b , R c and R d may independently be: (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 heterocyclic, each of which may be optionally substituted by one or more, according to one embodiment, one, two, three or four substituents Q a Replacement; (iii) R b and R c Together with the nitrogen atom to which they are attached, they form a heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or more, according to one embodiment, one, two, three or four substituents Q a replace; Each Q a can be independently selected from the following: (a) deuterium, cyano, halogen, imine, nitro, nitrosoxy 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)2R e 、–OS(O)NR f Rg 、–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 and –S(O)2NR f R g ; where each R e , R f , R g and R h may independently be (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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclic group.

[0048] In another embodiment, the present application provides a compound of formula (Ia): 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 6 and R 7 As defined in this application.

[0049] In another embodiment, a compound of formula (Ib) is provided: 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 6 and R 7 Each is as defined in this application.

[0050] In certain embodiments, in Formula (I), (Ia) or (Ib), R 6 is hydrogen or C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 6 is hydrogen or methyl. In certain embodiments, in Formula (I), (Ia) or (Ib), R 6 In certain embodiments, in Formula (I), (Ia) or (Ib), R 6 It's methyl.

[0051] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes (i) C 2-6 alkyl, heteroaryl or heterocyclyl, each optionally substituted by one or more substituents Q; 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 , where each R 7a , R 7b , R 7c , R 7d and R 7eThe definition of is as described in the application. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is C 2-6 Alkyl, optionally substituted with one or more substituents Q. In certain 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 certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is ethyl or isopropyl.

[0052] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a heteroaryl group, which may be optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a monocyclic heteroaryl group, which may be optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 5-membered heteroaryl group, which may be optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 6-membered heteroaryl group, which may be optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is imidazolyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is imidazol-1-yl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is 1-imidazolyl or 2-aminoimidazol-1-yl.

[0053] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a bicyclic heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 5,5-, 5,6- or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7is a 5,5-fused heteroaryl group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 5,6-fused heteroaryl group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 6,6-fused heteroaryl group, optionally substituted by one, two, or three Q groups.

[0054] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a monocyclic heterocyclic group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 3-membered heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 4-membered heterocyclyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 5-membered heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 6-membered heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a 7-membered heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is azetidinyl, oxazolidinyl, piperidinyl or morpholinyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is azetidin-1-yl, oxazolidin-3-substituted, piperidine-1-substituted or morpholine-4-substituted, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7It is a 3-hydroxyazetidine-1-substituent, a 5-(hydroxymethyl)-2-oxazolidine-3-substituent, a (R)-2-(hydroxymethyl)piperidine-1-substituent or a morpholine-4-substituent.

[0055] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a bicyclic heterocyclic group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a bridged, fused or spiro heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a bridged heterocyclic group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a fused heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is a spiro heterocyclic group, optionally substituted by one, two or three substituents Q.

[0056] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes-OR 7a , where R 7a As defined herein. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes-OR 7a , where R 7a It is C 1-6 Alkyl, C3-10 cycloalkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is C 1-6 Alkoxy is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is methoxy, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is C 3-10 Cycloalkoxy is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is C 6-14 Aryloxy is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R7 is methoxy, ethoxy, propoxy, cyclopentyloxy or phenoxy, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is pivaloyloxymethoxy, benzoyloxymethoxy, isopropoxy, cyclopentyloxy or 4-methylphenoxy.

[0057] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Each is as defined herein. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7 b and R 7c are independently hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7b R 7c , where R 7b and R 7c are independently hydrogen or C 1-6 alkyl, optionally substituted by hydroxycarbonyl, hydroxyl, methoxy or amino. In certain embodiments, in formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c are each independently (i) hydrogen; or (ii) methyl, ethyl, propyl, butyl or pentyl, each optionally substituted with hydroxycarbonyl, hydroxyl, methoxy or amino. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Each is independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, or 1-(hydroxycarbonyl)-2-methylpropyl.

[0058] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R7c Together with the N atom to which they are attached, they form a heteroaryl or heterocyclyl group, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a monocyclic heteroaryl group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 5- or 6-heteroaryl group, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 5-heteroaryl group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached they form a bicyclic heteroaryl group, optionally substituted by one, two or three Q substituents.

[0059] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more. 7 Yes - NR 7b R 7c , where R 7band R 7c Together with the N atom to which they are attached, they form a monocyclic heterocyclic group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 3-, 4-, 5-, 6-, or 7-membered heterocyclic group, each of which is optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), (Ia), or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 5- or 6-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 5-membered heterocyclic group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which they are attached they form a bicyclic heterocyclyl group, optionally substituted by one, two or three Q substituents.

[0060] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7b R 7c , where R 7b and R 7c Together with the N atom to which it is attached, it forms imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazahydroazaheterocycle-1-yl, 2-oxo-5-(hydroxymethyl)oxazolidin-3-yl, 2(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

[0061] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d and R 7e Each is as defined herein. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d is hydrogen; and wherein R 7e It is C 1-6 Alkyl, C 3-10 cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d is hydrogen; and wherein R 7e It is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d is hydrogen; and wherein R 7e It is C 3-10 Cycloalkyl is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d is hydrogen; and wherein R 7e It is a single ring C 3-10 Cycloalkyl is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 Yes - NR 7d C(O)R 7e , where R 7d is hydrogen; where R 7e is a heterocyclic group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)R 7e , where R 7d is hydrogen, R7e is a monocyclic heterocyclic group, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)R 7e , where R 7d is hydrogen, R 7e is a 3-, 4-, 5-, 6- or 7-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)R 7e , where R 7d is hydrogen, R 7e is a 5- or 6-membered heterocyclic group, each of which is optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)R 7e , where R 7d is hydrogen, R 7e is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)R 7e , where R 7d is hydrogen, 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. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is acetamido, 2-aminoacetamido, propionamido, 2-aminopropionamido, 2-amino-3-(imidazol-4-yl)propionamido, butyramido, isobutyramido, 2-aminobutyramido, 2-amino-3-methylbutyramido, 2,6-diaminohexanamido, cyclopropylamino, cyclobutylamino, pyrrolidin-2-ylamino, tetrahydrofuran-2-carboxamido or tetrahydropyran-4-carboxamido. In certain embodiments, in formula (I), (Ia) or (Ib), R 7It is acetamido, 2-aminoacetamido, propionamido, (S)-2-aminopropionamido, (S)-2-amino-3-(imidazol-4-yl)propionamido, butyramido, isobutyramido, (S)-2-aminobutyramido, 2-amino-3-methylbutyramido, (S)-2,6-diaminohexanamido, cyclopropylamino, cyclobutylamino, (S)-pyrrolidin-2-ylamino, tetrahydrofuran-2-carboxamide or tetrahydropyran-4-carboxamide.

[0062] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d and R 7e The definition of is as described in the present application. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e Can be C 1-6 Alkyl, C 3-10 cycloalkyl or heterocyclyl, each of which may be optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e Can be C 1-6 Alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e Can be C 3-10 Cycloalkyl, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e Can be a single ring C 3-10 Cycloalkyl, optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR7e , where R 7d is hydrogen, R 7e is a heterocyclic group, which may be optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e is a monocyclic heterocyclic group, which may be optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e is a 3-, 4-, 5-, 6- or 7-membered heterocyclic group, each of which may be optionally substituted by one, two or three substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7e is a 5- or 6-membered heterocyclic group, each of which may be optionally substituted by one, two or three substituents Q.

[0063] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, 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-methylbutanamido)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. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For-NR 7d C(O)OR 7e , where R 7d is hydrogen, R 7eIt is methyl, hydroxy-formylmethyl, ethoxy-formylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetamidoethyl, 2-(2-aminoacetamido)ethyl, (R)-2-(2-aminopropionamide)ethyl, (S)-2-(2-amino-3-hydroxypropionamide)ethyl, (S)-2-(2-amino-3-methylbutanamide)ethyl, (S)-2-(2-amino-4-(methylthio)butanamide)ethyl, (S)-2-(2-amino-4-methylpentanamide)ethyl, (S)-2-(pyrrolidin-2-ylamino)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl.

[0064] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 methoxycarbonylamino, hydroxymethoxycarbonylhydroxymethoxycarbonylamino, ethoxycarbonylmethoxycarbonylethoxycarbonylamino, ethoxycarbonylamino, 2-hydroxyethoxycarbonylethoxycarbonylamino, 2-methoxyethoxycarbonylethoxycarbonylamino, 2-acetoxyethoxycarbonylethoxycarbonylamino, 2-aminoethoxycarbonylethoxycarbonylamino, 2-acetylaminoethoxycarbonylamino, 2-(2-aminoacetylamide)ethoxycarbonylamino, 2-(2-aminopropionylamide)ethoxycarbonylamino, 2- In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 is methoxycarbonylamino, hydroxymethoxycarbonyl-amino, ethoxycarbonylmethoxycarbonylethoxycarbonylamino, ethoxycarbonylamino, 2-hydroxyethoxycarbonylamino, 2-methoxyethoxycarbonylamino, 2-acetoxyethoxycarbonylamino, 2-aminoethoxycarbonylamino, 2-acetamidoethoxycarbonylamino, 2-(2-aminoacetamide)ethoxycarbonylamino, (R)-2-(2-aminopropionamide)ethoxycarbonylamino, (S)-2-(2-amino-3-hydroxypropionamide) ethoxycarbonylamino, (S)-2-(2-amino-3-methylbutyramide)ethoxycarbonylamino, (S)-2-(2-amino-4-(methylthio)butyramide)ethoxycarbonylamino, (S)-2-(2-amino-4-methylpentanamide)ethoxycarbonylamino, (S)-2-(pyrrolidin-2-ylamino)ethoxycarbonylamino, isopropyloxycarbonylamino, tert-butyloxycarbonylamino, cyclopropyloxycarbonylamino, cyclobutyloxycarbonylamino or tetrahydropyran-4-oxycarbonylamino.

[0065] In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For –NR 7d C(O)NR 7b R 7c , where R 7b , R 7c and R 7d The definition of is as described in the present application. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 For –NR 7d C(O)NR 7b R 7c , where R 7b and R 7d are hydrogen; and R 7c C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), (Ia) or (Ib), R 7 It is N'-isopropylurea group.

[0066] In certain embodiments, in Formula (I), (Ia) or (Ib), R7 is ethyl, isopropyl, imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazetidin-1-yl, 5-(hydroxymethyl)-2-oxooxazolidin-3-yl, (R)-2-(hydroxymethyl)piperidin-1-yl, morpholin-4-yl, azelaylhydroxymethoxy, benzoylhydroxymethoxy, isopropyl, cyclopentyloxy, p-tolyloxy, amino, acetamido, 2-aminoacetamido , 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, cyclopropylamino, cyclobutylamino, (S)-pyrrolidine-2-ylamino, tetrahydrofuran-2-carboxamide, tetrahydropyran-4-carboxamide, methoxycarbonylamino, hydroxymethylcarbonyl oxycarbonylamino, 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-methylbutyramido)ethoxycarbonylamino, (S)-2-(2-amino-4-(methylthio)butyramido)ethoxycarbonylamino, (S)-2-(2-amino-4-methylpentanylamino)ethoxycarbonylamino, (S)-2-(pyrrolidine-2-ylamino)ethoxycarbonylamino, isopropyloxycarbonylamino, tert-butyloxycarbonylamino, cyclopropyloxycarbonylamino, cyclobutyloxycarbonylamino, tetrahydropyran-4-oxycarbonylamino or N'-isopropylurea.

[0067] In another embodiment, the compound provided by the present application is as shown in formula (II): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7b , R 7c , m and n are as defined in this application.

[0068] In another embodiment, the compound provided by the present application is as shown in formula (IIa): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7b and R 7c As defined in this application respectively.

[0069] In another embodiment, the compound provided by the present application is represented by formula (IIb): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7b and R 7c As defined in this application respectively.

[0070] In certain embodiments, according to Formula (II), (IIa) or (IIb), R 6 is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 6 is hydrogen or methyl. In certain embodiments, according to formula (II), (IIa) or (IIb), R 6 In certain embodiments, according to formula (II), (IIa) or (IIb), R 6 It's methyl.

[0071] In certain embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c As defined in the present application, respectively. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c are independently hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7 Yes – NR 7b R 7c , where R 7b and R 7c are independently hydrogen or C1-6 alkyl, optionally substituted by hydroxycarbonyl, hydroxyl, methoxy or amino. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7 Yes – NR 7b R 7c , where R 7b and R 7c are each independently (i) hydrogen; or (ii) methyl, ethyl, propyl, butyl or pentyl, each of which is optionally substituted with hydroxycarbonyl, hydroxyl, methoxy or amino. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Each is independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl or 1-(hydroxycarbonyl)-2-methylpropyl.

[0072] In certain embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl or heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl group, which is optionally substituted by one or more substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a monocyclic heteroaryl group, which is substituted by one, two or three substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached they form a 5-membered heteroaryl group, which is optionally substituted by one, two or three Q substituents.

[0073] In certain embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a heterocyclic group, which may be substituted by one or more substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7cTogether with the N atom to which they are attached, they form a monocyclic heterocyclic substituent, which may be substituted by one, two or three substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a 3-, 4-, 5-, 6- or 7-membered heterocyclic group, and each substituent may be substituted by one, two or three substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a 5- or 6-membered heterocyclic group, each of which may be substituted by one, two or three substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form a 5-membered heterocyclic group, which may be substituted by one, two or three substituents Q. In certain embodiments, according to formula (II), (IIa) or (IIb), R 7b and R 7c Together with the nitrogen atom to which they are attached, they form a 6-membered heterocyclic group, which may be substituted by one, two or three substituents Q.

[0074] In certain embodiments, according to Formula (II), (IIa) or (IIb), R 7b and R 7c Together with the N atom to which they are attached, they form imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazacyclopentadien-1-yl, 2-oxo-5-(hydroxymethyl)oxazolidin-3-yl, 2-(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

[0075] In another embodiment, the compound provided by the present application is as shown in formula (III): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7d , R 7e , m and n are respectively as defined in this application.

[0076] In another embodiment, the compound provided by the present application is as shown in formula (IIIa): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7d and R 7e As defined in this application respectively.

[0077] In another embodiment, the compound provided by the present application is as shown in formula (IIIb): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7d and R 7e As defined in this application respectively.

[0078] In certain 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 certain embodiments, for Formula (III), (IIIa) or (IIIb), R 6 is hydrogen or methyl. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 6 In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 6 It's methyl.

[0079] In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e It is C 1-6 Alkyl, C 3-10 cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e It is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e It is C 3-10Cycloalkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e It is a single ring C 3-10 Cycloalkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e is a heterocyclyl group, optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e is a monocyclic heterocyclyl group, optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e is a 3-, 4-, 5-, 6- or 7-membered heterocyclic group, each of which may be substituted by one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e is a 5- or 6-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrrolyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, for Formula (III), (IIIa) or (IIIb), R 7d is hydrogen; and R 7e It 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.

[0080] In another embodiment, the compound provided by the present application is as shown in formula (IV): 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7d , R 7e , m and n are respectively as defined in this application.

[0081] In another embodiment, the chemical formula of the compound provided herein is (IVa): 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 6 , R 7d and R 7e Each is as defined in this application.

[0082] In another embodiment, the chemical formula of the compound provided herein is (IVb): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7d and R 7e Each is as defined in this application.

[0083] In certain 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 certain embodiments, in Formula (IV), (IVa) or (IVb), R 6 is hydrogen or methyl. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 6 In certain embodiments, in Formula (IV), (IVa) or (IVb), R 6 It's methyl.

[0084] In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is C 1-6 Alkyl, C 3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q; in certain embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is C 3-10 Cycloalkyl is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is a single ring C 3-10 Cycloalkyl, optionally substituted with one, two or three substituents. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e is a heterocyclic group, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e is a monocyclic heterocyclic group, optionally substituted by one, two or three substituents Q. 7e is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (IV), (IVa) or (IVb), 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 certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e is a 5-membered heterocyclic group, optionally substituted by one, two or three substituents Q; in certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e is a 6-membered heterocyclyl group, optionally substituted by one, two or three substituents.

[0085] In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e It is C 1-6 Alkyl, optionally substituted with one, two or three substituents, wherein each substituent is independently -C(O)OR 1a , -OR 1a , -OC(O)R1a , -NR 1b R 1c or -NR 1a C(O)R 1d , where each R 1a , R 1b , R 1c and R 1d As defined herein. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e Is -C(O)OR 1a Substituted C 1-6 Alkyl, where R 1a As defined herein. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e For being-OR 1a Substituted C 1-6 Alkyl, where R 1a As defined herein. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e Is -OC(O)R 1a Substituted C 1-6 Alkyl, where R 1a As defined herein. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e For the 1b R 1c Substituted C 1-6 Alkyl, where R 1b and R 1c are as defined in the present application. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e Is -NR 1a C(O)R 1d Substituted C 1-6 Alkyl, where R 1a and R 1d All are as defined in this application.

[0086] In certain embodiments, in Formula (IV), (IVa) or (IVb), R7 d is hydrogen; R 7e It is an aminoamide substituted C 1-6 In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R7e is a C substituted with an α-aminoamide or β-aminoamide 1-6 In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e It is an α-aminoamide substituted C 1-6 Alkyl, i.e., aminoacetamido, 2-aminopropionamido, 2-amino-3-phenylpropionamido, 2-amino-3-(4-hydroxyphenyl)propionamido, 2-amino-3-(imidazol-4-yl)propionamido, 2-amino-3-(indol-3-yl)propionamido, 2-amino-3-(hydroxycarbonyl)propionamido, 2-amino-3-(aminocarbonyl)propionamido, 2-amino-3-hydroxypropionamido, 2-amino-3- mercaptopropionamide, 2-amino-3-methylbutyramide, 2-amino-3-hydroxybutyramide, 2-amino-4-(methylthio)butyramide, 2-amino-4-hydroxycarbonylbutyramide, 2-amino-4-(aminocarbonyl)butyramide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolin-2-ylcarboxamide. In certain embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is an α-aminoamide substituted C 1-6 Alkyl, i.e., aminoacetamido, (R)-2-aminopropionamido, (R)-2-amino-3-phenylpropionamido, (R)-2-amino-3-(4-hydroxyphenyl)propionamido, (R)-2-amino-3-(imidazol-4-yl)propionamido, (R)-2-amino-3-(indol-3-yl)propionamido, (R)-2-amino-3-(hydroxycarbonyl)propionamido, (R)-2-amino-3-(aminocarbonyl)propionamido, (R)-2-amino-3-hydroxypropionamido, (R)-2-amino-3-thiol In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e C substituted with α-aminoamide 1-6Alkyl, i.e., aminoacetamido, (S)-2-aminopropionamido, (S)-2-amino-3-phenylpropionamido, (S)-2-amino-3-(4-hydroxyphenyl)propionamido, (S)-2-amino-3-(imidazol-4-yl)propionamido, (S)-2-amino-3-(indol-3-yl)propionamido, (S)-2-amino-3-(hydroxycarbonyl)propionamido, (S)-2-amino-3-(aminocarbonyl)propionamido, (S)-2-amino-3-hydroxypropionamido, (S)-2-amino-3-thiol propionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxycarbonylbutanamide, (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)-pyrrolidine-2-ylamide.

[0087] In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e is an aminoamide group substituted with an ethyl group. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e is an α-aminoamide or β-aminoamide substituted by an ethyl group at the 2 position. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; R 7e Yes and R 7e It is an α-aminoamide group substituted by an ethyl group at the 2-position, namely aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxy-phenyl)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-mercaptopropionamide, 2-amino-3-methylbutyramide, 2-amino-3-hydroxybutyramide, 2-amino-4-(methylthio)butyramide, 2-amino-4-hydroxy-carbonylbutyramide, 2-amino-4-(aminocarbonyl)butyramide, 2-amino-3-methylpentanamide, 2-amino-4-methylpentanamide, 2,6-diaminohexanamide, 2-amino-5-guanidinopentanamide or pyrrolin-2-ylcarboxamide. In certain embodiments, in formula (IV), (IVa) or (IV b), R7d is hydrogen; and R 7e It is an α-aminoamide group substituted by an ethyl group at the 2-position, namely, 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 In some embodiments, in formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is an α-aminoamide group substituted by an ethyl group at the 2-position, namely, 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-hydroxycarbonylbutanamide, (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)-pyrrolidine-2-ylamide.

[0088] In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7eis methyl, ethyl, propyl or butyl, each optionally substituted with one, two or three substituents, wherein each substituent is independently hydroxycarbonyl, ethoxycarbonyl, hydroxy, methoxy, acetoxy, amino, acetamido, aminoacetamido, 2-aminopropionamido, 2-amino-3-hydroxy-propionamido, 2-amino-3-methylbutyrylamino, 2-amino-4-(methylthio)butyrylamino, 2-amino-4-methylpentanoylamino or pyrrolidin-2-ylamido. In certain 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-acetylaminoethyl, 2-(2-aminoacetylamino)ethyl, 2-(2-aminopropionylamino)ethyl, 2-(2-amino-3-hydroxypropionylamino)ethyl, 2-(2-amino-3-methylbutyramido)ethyl, 2-(2-amino-4-(methylthio)-butyramido)ethyl, 2-(2-amino-4-methylbutyramido)ethyl, 2-(pyrrolidin-2-ylamido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl. In certain embodiments, in Formula (IV), (IVa) or (IVb), R 7d is hydrogen; and R 7e It is methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-aminoethyl, 2-acetylaminoethyl, 2-(2-aminoacetylamino)ethyl, (R)-2-(2-aminopropionylamino)ethyl, (S)-2-(2-amino-3-hydroxypropionylamino)ethyl, (S)-2-(2-amino-3-methylbutyrylamino)ethyl, (S)-2-(2-amino-4-(methylthio))butyrylamino)ethyl, (S)-2-(2-amino-4-methylpentanoylamino)ethyl, (S)-2-(pyrrolidin-2-ylamino)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl.

[0089] In another embodiment, the compound provided by the present application is as shown in formula (V): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 6a , R 7b , R 7c , R 7d , m and n are each as defined in this application.

[0090] In another embodiment, the compound provided by the present application is as shown in formula (Va): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7b , R 7c and R 7d Each is as defined in this application.

[0091] In another embodiment, the compound provided by the present application is as shown in formula (Vb): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 , R 7b , R 7c and R 7d Each is as defined in this application.

[0092] In certain 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 certain embodiments, in Formula (V), (Va) or (Vb), R 6 is hydrogen or methyl. In certain embodiments, in Formula (V), (Va) or (Vb), R 6 In certain embodiments, in Formula (V), (Va) or (Vb), R 6 It's methyl.

[0093] In certain embodiments, in Formula (V), (Va) or (Vb), R 7b and R 7d are each hydrogen; and R 7c It is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V), (Va) or (Vb), R 7b and R7d Each is hydrogen; R 7c It is isopropyl.

[0094] In another embodiment, the compound provided by the present application is as shown in formula (VI): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7a , m and n are each as defined in this application.

[0095] In another embodiment, the compound provided by the present application is as shown in formula (VIa): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, or a tautomer or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 6 and R 7a Each is as defined in this application.

[0096] In another embodiment, the compound provided by the present application is as shown in formula (VIb): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6 and R 7a Each is as defined in this application.

[0097] In certain 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 certain embodiments, in Formula (VI), (VIa) or (VIb), R 6 In certain embodiments, in Formula (VI), (VIa) or (VIb), R 6In certain embodiments, in Formula (VI), (VIa) or (VIb), R 6 It's methyl.

[0098] In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is C 1-6 Alkyl, C 3-10 Cycloalkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is C 1-6 alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a is methyl, optionally substituted with -OC(O)R 1a Substitution, where R 1a As defined herein. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is C 3-10 Cycloalkyl is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is a single ring C 3-10 Cycloalkyl is optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is C 6-14 aryl, optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a is methyl, ethyl, propyl, cyclopentyl or phenyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, in Formula (VI), (VIa) or (VIb), R 7a It is pivaloyloxymethyl, benzoyloxymethyl, isopropyl, cyclopentyl or 4-methylphenyl.

[0099] The chemical formulae described herein include groups R in (I) to (VI), (Ia) to (VIa) and (Ib) to (VIb) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 6a , R 7a , R 7b , R 7c , R 7d , R 7e , m and n are further defined in the embodiments described in this application. All combinations of the embodiments provided by this application for these groups are within the scope of this disclosure.

[0100] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 In certain embodiments, R 1 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is a single ring C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 1 It is a bicyclic C 4-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 1 Is bridged, fused or spiroC 4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 6-14 aryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 7-15 Aralkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 1 Yes-C(O)R 1a, where R 1a As defined in this application. In certain embodiments, R 1 Yes – C(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 1 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 1 Yes-C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application.

[0101] In certain embodiments, R 1 It is C 1-6 Alkyl or C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 It is C 1-6 Alkyl or monocyclic C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is isopropyl, cyclopentyl or cyclohexyl. In certain embodiments, R 1 It is cyclopentyl.

[0102] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 2 In certain embodiments, R 2 It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is methyl, ethyl, isopropyl, hydroxymethyl or ethoxymethyl. 2 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 2 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 It is C2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 2 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 2 It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is benzyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a heterocyclyl group, optionally substituted by one or more substituents Q.

[0103] In certain embodiments, R 2 Yes – C(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes-C(O)-C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 In certain embodiments, R 2 Yes – C(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 2 Is -COOH or -C(O)OC 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is -COOH or -COOEt. In certain embodiments, R 2 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – C(O)SR 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1cEach is as defined in this application. In certain embodiments, R 2 Yes – C(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – C(S)OR 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – OR 1a , where R 1a As defined in this application. In certain embodiments, R 2 It is C 1-6 Alkoxy is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is 2-ethoxyethoxy. In certain embodiments, R 2 Yes – OC(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OC(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OC(S)OR 1a , where R 1a As defined in this application. In certain embodiments, R2 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined in this application. In certain embodiments, R 2 Yes – OS(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OS(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 is -NH2. In certain embodiments, R 2 Yes – NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(O)SR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R2 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(S)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a C(S)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – SR 1a , where R 1aAs defined in this application. In certain embodiments, R 2 Yes – S(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes –S(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 2 Yes – S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 2 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application.

[0104] In certain embodiments, R 2 is (i) a halogen; (ii) C 1-6 Alkyl or C 7-15 aralkyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , –C(O)OR 1a ,–OR 1a or –NR 1b R 1c , where each R 1a , R 1b and R 1c As defined in this application. In certain embodiments, R 2 is fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, hydroxymethyl, ethoxymethyl, benzyl, acetyl, hydroxy-carbonyl, ethoxycarbonyl, 2-ethoxyethoxy or amino. 2 It's acetyl.

[0105] In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is fluorine or chlorine. In certain embodiments, R 3 In certain embodiments, R 3 It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 3In certain embodiments, R 3 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 3 In certain embodiments, R 3 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 3 It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 3 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 3 It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 3 It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 3 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 3 is hydrogen or methyl.

[0106] In certain embodiments, R 3 Yes – C(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – C(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – C(O)SR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – C(S)R 1a, where R 1a As defined in this application. In certain embodiments, R 3 Yes – C(S)OR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – OR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined in this application. In certain embodiments, R 3 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(S)OR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – OS(O)R 1a , where R 1aAs defined in this application. In certain embodiments, R 3 Yes – OS(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(O)NR 1b R 1c , where R 1a , R 1b and R1c Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(O)SR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR1a C(S)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a C(S)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – SR 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – S(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes –S(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 3 Yes – S(O)NR1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 3 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application.

[0107] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is fluorine. In certain embodiments, R 4 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 1-6 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 1-6 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 2-6 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 2-6 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 3-10 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 6-14 In certain embodiments, R 4 is C optionally substituted by one or more substituents Q 7-15 In certain embodiments, R 4 Heteroaryl is optionally substituted with one or more substituents Q. In certain embodiments, R 4 is a heterocyclyl group optionally substituted by one or more Q substituents.

[0108] In certain embodiments, R 4 Yes – C(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – C(O)OR 1a , where R 1aAs defined in this application. In certain embodiments, R 4 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – C(O)SR 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – C(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments R 4 Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – OR 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(O)OR 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(NR 1a )NR 1b R 1c , where R1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – OC(S)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(S)OR 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – OS(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OS(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(O)NR 1b R 1c, where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(O)SR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(S)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a C(S)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 4 Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4Yes – NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – SR 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – S(O)R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes –S(O)2R 1a , where R 1a As defined in this application. In certain embodiments, R 4 Yes – S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 4 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application.

[0109] In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is fluorine or chlorine. In certain embodiments, R 5 In certain embodiments, R 5 It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is methyl or ethyl. In certain embodiments, R 5 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 5 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 5 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R5 It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 5 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5 Is halogen or C 1-6 Alkyl, optionally substituted with one, two or three substituents Q. In certain embodiments, R 5 is fluorine, chlorine, methyl or ethyl.

[0110] In certain embodiments, R 5 Yes – C(O)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – C(O)OR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – C(O)SR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – C(S)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – C(S)OR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5Yes – OR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(O)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(O)OR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(S)OR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – OS(O)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OS(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – OS(O)2NR 1b R1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(O)R 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(O)SR 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(S)R 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a C(S)NR 1b R1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a S(O)R 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d Each is as described in the present application. In certain embodiments, R 5 Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 yes –NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – SR 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – S(O)R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes –S(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 5 Yes – S(O)NR 1b R 1c , where R 1b and R 1c Each is as described in the present application. In certain embodiments, R 5 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each as described in this application.

[0111] In certain embodiments, R 6 is hydrogen. In certain embodiments, R6 In certain embodiments, R 6 In certain embodiments, R 6 is halogen. In certain embodiments, R 6 is fluorine. In certain embodiments, R 6 In certain embodiments, R 6 It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 In certain embodiments, R 6 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6 In certain embodiments, R 6 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6 It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is hydrogen or methyl.

[0112] In certain embodiments, R 6 Yes – C(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – C(O)OR 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – C(O)SR 1a, where R 1a As described in this application. In certain embodiments, R 6 Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – C(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – C(S)OR 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – OR 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(O)OR 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(S)OR 1a, where R 1a As described in this application. In certain embodiments, R 6 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – OS(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OS(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(O)SR 1d , where R 1a and R 1dEach is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(S)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a C(S)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – SR 1a, where R 1a As described in this application. In certain embodiments, R 6 Yes – S(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes –S(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 6 Yes – S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application.

[0113] In certain embodiments, R 7 It is C 2-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 7 Yes – OR 7a , where R 7a As described in this application. In certain embodiments, R 7 Yes – NR 7b R 7c , where R7b and R 7c Each is as described in the present application. In certain embodiments, R 7 Yes – NR 7d C(O)R 7e , where R 7d and R 7e Each is as described in the present application. In certain embodiments, R 7 Yes – NR 7d C(O)OR 7e , where R 7d and R 7e Each is as described in the present application. In certain embodiments, R 7 Yes – NR 7d C(O)NR 7b R 7c , where R 7b , R 7c and R 7d Each as described in this application.

[0114] In certain embodiments, R 6a In certain embodiments, R 6a In certain embodiments, R 6a is halogen. In certain embodiments, R 6a is fluorine. In certain embodiments, R 6a In certain embodiments, R 6a It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 6a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6ais a heterocyclyl group, optionally substituted by one or more substituents Q.

[0115] In certain embodiments, R 6a Yes – C(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – C(O)OR 1a , wherein R1a is as described herein. In certain embodiments, R 6a Yes – C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – C(O)SR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – C(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – C(S)OR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – OR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(O)OR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(O)NR 1b R 1c , where R 1b and R 1cEach is as defined in this application. In certain embodiments, R 6a Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – OC(S)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(S)OR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OC(S)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – OS(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OS(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R6a Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R 6a Yes – NR 1a C(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1a C(O)SR 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R 6a Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R 6a Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R 6a Yes – NR 1a C(S)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1a S(O)R 1d , where R 1a and R 1d As defined in this application. In certain embodiments, R 6a Yes – NR 1a S(O)2R 1d , where R 1a and R 1dAs defined in this application. In certain embodiments, R 6a Yes – NR 1a S(O)NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – NR 1a S(O)2NR 1b R 1c , where R 1a , R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – SR 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – S(O)R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes –S(O)2R 1a , where R 1a As described in this application. In certain embodiments, R 6a Yes – S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 6a Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined in this application.

[0116] In certain embodiments, R 7a It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a is methyl, optionally substituted with –OC(O)R 1a Substitution, where R 1a As described in this application. In certain embodiments, R 7a is pivaloyloxymethyl, phenacyloxymethyl or isopropyl. 7a It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7a It is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a It is C 2-6 Alkyne, optionally substituted with one or more substituents Q. In certain embodiments, R 7a It is a single ring C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7a In certain embodiments, R 7a It is a bicyclic C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7a It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a is 4-methylphenyl. In certain embodiments, R 7a It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a is a heterocyclyl group, optionally substituted by one or more substituents Q.

[0117] In certain embodiments, R 7b is hydrogen. In certain embodiments, R 7b It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7b is methyl, ethyl, propyl or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is C 7-15Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7b is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 7b It is hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl or 1-(hydroxycarbonyl)-2-methylpropyl.

[0118] In certain embodiments, R 7c is hydrogen. In certain embodiments, R 7c It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c is methyl, ethyl, propyl or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7c is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 7c It is hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl or 1-(hydroxycarbonyl)-2-methylpropyl.

[0119] In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a heteroaryl group, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b and R 7cTogether with the N atom to which they are covalently bonded, they form a monocyclic heteroaryl group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 5-membered or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 5-membered heteroaryl group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 6-membered heteroaryl group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atoms to which they are covalently bonded, they form a 5,5-, 5,6-, or 6,6-fused heterocyclic aryl group, each of which is optionally substituted with one, two, or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form imidazol-1-yl or 2-aminoimidazol-1-yl groups.

[0120] In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a heterocyclic group, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a monocyclic heterocyclic group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 3-, 4-, 5-, 6-, or 7-membered heterocyclic group, each of which is optionally substituted with one, two, or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 5-membered or 6-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a 5-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7cTogether with the N atom to which they are covalently bonded, they form a 6-membered heterocyclic group, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form a bicyclic heterocyclic group, which is optionally substituted with one, two or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atoms to which they are covalently bonded, they form a bridged ring, a fused ring, or a spirocyclic heterocycle, each of which is optionally substituted with one, two, or three substituents Q. In certain embodiments, R 7b and R 7c Together with the N atom to which they are covalently bonded, they form 3-hydroxyazetidin-1-yl, 2-keto-5-(hydroxymethyl)oxazolin-3-yl, 2-(hydroxymethyl)piperidin-1-yl or 4-morpholinyl.

[0121] In certain embodiments, R 7d is hydrogen. In certain embodiments, R 7d It is C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7d It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7d is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7d is a heterocyclyl group, optionally substituted by one or more substituents Q.

[0122] In certain embodiments, R 7e is hydrogen. In certain embodiments, R 7e It is C 1-6 alkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 7eis methyl, ethyl, propyl or butyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e It is C 1-6 Heteroalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7e It is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7e It is C 2-6 Alkynyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7e It is C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7e It is a single ring C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7e is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e It is C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7e It is C 7-15 Aralkyl is optionally substituted with one or more substituents Q. In certain embodiments, R 7e is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7e is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 7e is a monocyclic heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 7e is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, R 7e is a 5- or 6-membered heterocyclyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e is a 5-membered heterocyclyl group, optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e is a 6-membered heterocyclyl group, optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e is pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, R 7e is a biheterocyclic group, optionally substituted with one, two or three substituents Q. In certain embodiments, R 7eis a bridged ring, a fused ring or a spirocyclic heterocycle, each of which is optionally substituted by one, two or three substituents Q.

[0123] In certain embodiments, R 7e It is C 1-6 Alkyl, optionally substituted with one, two or three substituents, 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 R 1a , R 1b , R 1c and R 1d Each is as defined in this application. In certain embodiments, R 7e It is C 1-6 The alkyl group is replaced by –C(O)OR 1a Substitution, where R 1a As described in this application. In certain embodiments, R 7e It is C 1-6 Alkyl is –OR 1a Substitution, where R 1a As described in this application. In certain embodiments, R 7e It is C 1-6 Alkyl is –OC(O)R 1a Substitution, where R 1a As described in this application. In certain embodiments, R 7e It is C 1-6 Alkyl is –NR 1b R 1c Substitution, where R 1b and R 1c Each is as defined in this application. In certain embodiments, R 7e It is C 1-6 Alkyl is –NR 1a C(O)R 1d Substitution, where R 1a and R 1d Each is as defined in this application.

[0124] In certain embodiments, R 7e It is C 1-6 In certain embodiments, R 7e It is C 1-6 The alkyl group is substituted with an α-aminoamide group or a β-aminoamide group. 7e It is C 1-6The alkyl group is substituted with an α-aminoamide group, including aminoacetamide, 2-aminopropionamide, 2-amino-3-phenylpropionamide, 2-amino-3-(4-hydroxy-phenyl)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-mercaptopropionamido, 2-amino-3-methylbutanamido, 2-amino-3-hydroxybutanamido, 2-amino-4-(methylthio)butanamido, 2-amino-4-hydroxy-carbonylbutanamido, 2-amino-4-(aminocarbonyl)butanamido, 2-amino-3-methylpentanamido, 2-amino-4-methylpentanamido, 2,6-diaminohexanamido, 2-amino-5-guanidinopentanamido or pyrrolidine-2-ylcarboxamido. In certain embodiments, R 7e It is C 1-6 The alkyl group is substituted with an α-aminoamide group, including 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- In certain embodiments, R 7e It is C 1-6The alkyl group is substituted with an α-aminoamide group, including 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 The invention also includes the following: (S)-3-mercaptopropionamide, (S)-2-amino-3-methylbutanamide, (S)-2-amino-3-hydroxybutanamide, (S)-2-amino-4-(methylthio)butanamide, (S)-2-amino-4-hydroxycarbonyl-butanamide, (S)-2-amino-4-(aminocarbonyl)butanamide, (S)-2-amino-3-methylpentanamide, (S)-2-amino-4-methylpentanamide, (S)-2,6-diaminohexanamide, (S)-2-amino-5-guanidino-pentanamide or (S)-pyrrolidine-2-ylamide.

[0125] In certain embodiments, R 7e In certain embodiments, R 7e is ethyl substituted at the 2-position by an α-aminoamide or β-aminoamide. 7e The ethyl group is substituted at the 2-position by an α-aminoamide or β-aminoamide, including 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-hydroxy In some embodiments, R 7eThe ethyl group is substituted at the 2-position by an α-aminoamide or β-aminoamide, including 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-mercaptopropionamido, (R)-2-amino-3-methylbutanamido, (R)-2-amino-3-hydroxybutanamido, (R)-2-amino-4-(methylthio)-butanamido, (R)-2-amino-4-hydroxycarbonylbutanamido, (R)-2-amino-4-(aminocarbonyl)butanamido, (R)-2-amino-3-methylpentanamido, (R)-2-amino-4-methylpentanamido, (R)-2,6-diaminohexanamido, (R)-2-amino-5-guanidinopentanamido or (R)-pyrrolidine-2-ylamide. In certain embodiments, R 7e The ethyl group is substituted at the 2-position by an α-aminoamide or β-aminoamide, including 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-hydroxycarbonylbutanamide, (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)-pyrrolidine-2-ylamide.

[0126] In certain embodiments, R 7eis methyl, ethyl, propyl or butyl, each optionally substituted with one, two or three substituents, each of which is independently 4-imidazolyl, hydroxycarbonyl, ethoxycarbonyl, hydroxy, methoxy, acetoxy, amino, acetamido, aminoacetamido, 2-aminopropionamido, 2-amino-3-hydroxypropionamido, 2-amino-3-methylbutanamido, 2-amino-4-(methylthio)butanamido, 2-amino-4-methylpentanamido or pyrrolidin-2-ylamido.

[0127] In certain embodiments, R 7e R 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, 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. In certain embodiments, R 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- 1-(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-methylpentanoylamino)ethyl, (S)-2-(pyrrolidin-2-amido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl or tetrahydropyran-4-yl.

[0128] In certain embodiments, m is an integer of 0. In certain embodiments, m is an integer of 1. In certain embodiments, m is an integer of 2. In certain embodiments, m is an integer of 3.

[0129] 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.

[0130] In one embodiment, the present application provides: 2-Hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[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-pyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonamide A5; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropanamide A6; (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A7; 2-methoxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8; Ethyl 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetate A9; Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetate A10; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetic acid A11; 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13; (S)-2-(2-amino-3-methylbutyramido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A14; 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A16; (S)-2-(2-amino-4-methylpentanoylamino)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A17; (S)-2-(2-amino-3-hydroxypropionamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A18; (S)-2-(2-amino-4-(methylthio)butanamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A19; 2-(2-aminoacetamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A20; (R)-2-(Pyrrolidine-2-carboxamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A21; Tetrahydro-2H-pyran-4-yl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-pyrido[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-pyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-carboxamide A33; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propanamide A35; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butanamide A37; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropanecarboxamide A38; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-carboxamide A39; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide A40; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutanecarboxamide A41; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)piperazine-1-sulfonamide A42; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)piperazine-1-sulfonamide A43; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylpiperazine-1-sulfonamide A47; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylpiperazine-1-sulfonamide A48; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylpiperazine-1-sulfonamide A49; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylpiperazine-1-sulfonamide A50; 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one A51; 6-acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A52; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)piperazine-1-sulfonamide A53; 2-Hydroxyethyl (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 A54; 2-((R)-2-amino-3-methylbutyrylamino)ethyl(((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-methylpiperazin-1-yl)sulfonyl)carbamate A55; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylcarbamoyl)piperazine-1-sulfonamide A56; 6-acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A57; or 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A58; 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.

[0131] In another embodiment, the compound provided herein is: (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1; p-Tolyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[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-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4; 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.

[0132] In another embodiment, the present application provides the following compounds: 6-Acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylpiperazin-1-yl)-2-pyridinyl]-amino]-5-methylpyrido[2,3-d]pyrimidin-7-one C1; or 6-acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-2-yl)-amino)-5-methylpyrido[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, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0133] In certain embodiments, the compounds provided herein are separated or purified. In certain 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 certain embodiments, the compounds provided herein have a purity of at least about 90% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 95% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 98% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 99% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 99.5% by weight.

[0134] Unless specific stereochemistry is specified, the compounds provided herein are intended to encompass all possible stereoisomers. When the compounds provided herein contain alkenyl, the compound may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. For example, in compounds comprising imino, carbonyl or oxime groups, the form of proton tautomerism may be taken; or so-called valence tautomerism in compounds containing aromatic moieties. It can be seen from this that a single compound may exhibit more than one type of isomerism.

[0135] The compounds provided herein may be optically pure, such as a single enantiomer or a single diastereomer, or may be a mixture of stereoisomers, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, one skilled in the art will recognize that administration of a compound in its (R) form is equivalent to administration in its (S) form for compounds that undergo racemization in vivo. Conventional techniques for obtaining single enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from non-chiral starting materials, or separation of enantiomeric mixtures, for example, chiral chromatography, recrystallization, separation, formation of diastereomeric salts, or derivatization to diastereomeric adducts followed by separation.

[0136] When the compounds provided herein contain an acidic or basic moiety, they can also be provided as pharmaceutically acceptable salts. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0137] Suitable acids that can be used in the preparation of pharmaceutically acceptable salts of the compounds provided herein 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, boric acid, (+)-gentisic acid, xiaduo acid, (+)-(1S)-10-sulfogentisic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, saccharinic acid, cyclohexanesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, Acid, α-ketoglutaric acid, glycolic acid, hippuric 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, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic 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, and valeric acid.

[0138] Suitable bases that can be used in the preparation of pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases such as primary, secondary, tertiary, quaternary, aliphatic, and aromatic amines, including, but not limited to, L-arginine, benzylamine, benzylazine, choline, dimethylethanolamine, diethanolamine, diethylamine, dimethylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methylglucamine, hydrazineamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0139] The compounds provided herein can also be provided as prodrugs, which are functional derivatives of compounds and are easily converted into parent compounds in vivo. Prodrugs are generally useful because, in some cases, they are easier to administer relative to the parent compound. For example, prodrugs have bioavailability by oral administration, while the parent compound does not. Prodrugs can also have higher solubility than the parent compound in pharmaceutical compositions. Prodrugs can be converted into parent drugs by various mechanisms, including enzymatic processes and metabolic hydrolysis. Pharmaceutical composition

[0140] In one embodiment, the present application provides a pharmaceutical composition comprising a compound provided herein, such as a compound of formula (I), or an enantiomer thereof, 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and a pharmaceutically acceptable excipient.

[0141] The pharmaceutical composition provided herein can be prepared into a variety of dosage forms, including but not limited to oral dosage forms. The pharmaceutical composition can also be prepared into modified release dosage forms, including delayed release, extended release, long-acting release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release, programmed release and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0142] The pharmaceutical composition provided herein can be provided in unit dosage form or multiple dosage form. As described in the present application, unit dosage form refers to a physically discrete unit suitable for administering to a subject, and is packaged independently as known in the art. Each unit dose contains a predetermined amount of active ingredient (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, and required pharmaceutical excipients. Examples of unit dosage forms include, but are not limited to, independently packaged tablets and capsules. Unit dosage forms can be administered in divided or multiple doses. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles, tablets, or capsules.

[0143] The pharmaceutical composition provided herein can be administered in a single or multiple doses at intervals. It should be understood that the precise dosage and duration of treatment can vary with the age, weight and condition of the subject being treated, and can be determined empirically using known test protocols or by inferring from in vivo or in vitro tests or diagnostic data. It should also be understood that for any particular individual, a specific dosage regimen should be adjusted over time according to the needs of the subject and the professional judgment of the personnel administering or supervising the administration of the pharmaceutical composition. A. Oral administration

[0144] The pharmaceutical composition for oral administration provided by the application can be provided with solid, semisolid or liquid dosage forms for oral administration. As used in the application, oral administration also includes buccal, lingual and sublingual administration. Applicable oral dosage forms include but are not limited to tablets, fast dissolving agents, chewable tablets, capsules, pills, strips, sublingual tablets, lozenges, soft candies, cachets, pellets, medicated chewing gum, loose powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, thin tablets, sprays, elixirs and syrups. In addition to active ingredients, the pharmaceutical composition can also include one or more pharmaceutically acceptable carriers or excipients, including but not limited to adhesives, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, anti-staining agents, sweeteners, flavoring agents, emulsifiers, suspending agents and dispersants, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0145] Suitable binders or granules impart cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granules include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH ); gelatin; sugars such as sucrose, D-glucose and L-glucose, syrups and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, Panwar gum, Ghatti gum, isoflavone husk mucilage, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone (PVP), larch arabinogalactan, tragacanth gum powder, and guar gum; celluloses, such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and microcrystalline cellulose, such as PH-101, PH-103, PH-105 and 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 or filler in the pharmaceutical composition provided herein varies depending on the type of formulation and is easily discernible by one of ordinary skill in the art. The binder or filler may be present in the pharmaceutical composition provided herein at about 50% to about 99% by weight.

[0146] 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 icing sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can impart certain compressed tablets with the property of disintegrating in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical composition provided by the application varies depending on the type of preparation, and is easily distinguishable by those of ordinary skill in the art.

[0147] Suitable disintegrating agents 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 HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethyl cellulose; cross-linked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polyclinic potassium; starches, such as corn starch, potato starch, tapioca starch, pregelatinized starch; clay; and alginate. The amount of disintegrant in the pharmaceutical composition provided herein varies depending on the type of formulation and is easily discernible by a person of ordinary skill in the art. The pharmaceutical composition provided herein may include about 0.5% to about 15% or about 1% to about 5% by weight of a disintegrant.

[0148] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium powder; silicon or silica gel, such as 200 and The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible by one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% lubricant by weight.

[0149] Suitable glidants include, but are not limited to, colloidal silicon dioxide, and asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified water-soluble FD&C dyes, as well as insoluble FD&C dyes and lakes suspended in hydrated alumina. Lakes are insoluble combinations of dye forms formed by the adsorption of water-soluble dyes onto hydrated oxides of heavy metals. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants (such as fruits), and synthetic mixtures of compounds that produce a pleasant taste, such as mint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, gum tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monolaurate ( 20) Sorbitan monooleate polyoxyethylene ether 80 ( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methylparaben and propylparaben, benzoic acid and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol and syrup. Suitable non-aqueous liquids used 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 sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0150] It will be appreciated that many carriers and excipients can serve multiple functions, even within the same formulation.

[0151] The pharmaceutical composition for oral administration provided by the present application can be provided in the form of compressed tablets, ground tablets, chewable tablets, fast-dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that can resist gastric acid but dissolve or disintegrate in the intestine, thereby protecting the active ingredients from the influence of the gastric acid environment. Enteric coatings include but are not limited to fatty acids, fats, phenyl salicylate, wax, shellac, ammoniated shellac and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets wrapped in sugar coatings, which may help to cover up offensive tastes or odors and protect tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer of water-soluble materials or films. Film coatings include but are not limited to hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed compressed tablets are compressed tablets made by multiple compression cycles, including layered tablets and press-coated tablets or dry-coated tablets.

[0152] Tablet dosage forms can be prepared from active ingredients in powder, crystal or granular form 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 agents and sweeteners are particularly suitable for the formation of chewable tablets and lozenges.

[0153] The pharmaceutical composition for oral administration provided by the present application can be provided in the form of soft capsules or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry filled capsules (DFCs), consist of two parts, one part slides over the other part, thereby completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft spherical shells, such as gelatin shells, plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described in the present application, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided by the present application can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. The preparation of capsules containing such solutions can be described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated in a manner known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0154] The pharmaceutical compositions for oral administration provided in the present application can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in another liquid in the form of globules, which can be oil-in-water or water-in-oil. An emulsion may include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier and a preservative. A suspension may include a pharmaceutically acceptable suspending agent and a preservative. An alcohol aqueous solution may include a pharmaceutically acceptable acetal, such as a di(low alkyl) acetal of a low alkyl aldehyde, such as acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. The medicament is a transparent, sweet aqueous alcohol solution. A syrup is a concentrated aqueous solution of sugar (e.g., sucrose) and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate administration.

[0155] Other useful liquid and semisolid dosage forms include, but are not limited to, dosage forms containing the active ingredient and dialkylated mono- or polyethylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium bisulfite, thiodipropionic acid and its esters and dithiocarbamates.

[0156] The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

[0157] The pharmaceutical composition for oral administration provided by the application can be provided in the form of non-effervescent or effervescent, granules and powders, to be re-prepared into liquid dosage forms. The pharmaceutically acceptable carrier and excipient used in the non-effervescent granules or powders can include diluents, sweeteners and wetting agents. The pharmaceutically acceptable carrier and excipient used for effervescent granules or powders can include organic acids and carbon dioxide sources.

[0158] Coloring and flavoring agents can be used in all dosage forms described herein.

[0159] The pharmaceutical composition for oral administration provided in the present application can be prepared into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release dosage forms. B. Regulated release

[0160] The pharmaceutical composition provided in the present application can be prepared into a controlled release formulation. As used in the present application, the term "controlled release" refers to a dosage form in which the position and rate of release of an active ingredient are different from those of an immediate release agent when the same route is used. Controlled release formulations include, but are not limited to, delayed-, sustained-, extended-, sustained-, pulsed-, controlled-, accelerated- and rapid-, targeted-, programmed release, and gastric retention formulations. The controlled release formulation of the pharmaceutical composition can be prepared using a variety of controlled release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multi-particle controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes, and combinations thereof. The rate of release of the active ingredient can also be adjusted by changing the particle size and polymorphic form of the active ingredient. 1. Matrix controlled release device

[0161] The controlled dosage form of the pharmaceutical composition provided herein can be prepared using a matrix controlled release device known to those skilled in the art. See, for example, Takada et al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.

[0162] In certain embodiments, the modified release formulations of the pharmaceutical compositions provided herein are prepared using an erodible matrix device, which is a water-swellable, erodible or soluble polymer, including but not limited to synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0163] Materials that can be used to form the erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agarose, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum gati, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses, such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid Poly (2-hydroxyethyl methacrylate); polylactide; copolymer of L-glutamic acid and L-glutamate ethyl ester; degradable lactic acid-glycolic acid copolymer; 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.

[0164] In certain embodiments, the pharmaceutical compositions provided herein are prepared using 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 non-erodible matrix devices 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, polyethylene terephthalate ionomers, butyl rubber, epichlorohydrin rubber, polyethylene / vinyl alcohol, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicic acid ester copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone, cross-linked partially hydrolyzed polyvinyl acetate, and the like; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0165] In a matrix controlled release system, the desired release kinetics can be controlled, for example, by the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0166] The controlled formulations of the pharmaceutical compositions provided herein can be prepared by methods known to those skilled in the art, including direct tableting, dry or wet granulation followed by tableting, and melt granulation followed by tableting. 2. Osmotic controlled release device

[0167] The controlled release formulation of the pharmaceutical composition provided herein can be prepared using an osmotic controlled release device, including but not limited to a single chamber system, a dual chamber system, an asymmetric membrane technology (AMT) and an extruded core system (ECS). Generally speaking, such a device has at least two components: (a) a core containing an active ingredient; (b) a semipermeable membrane having at least one delivery port, which encapsulates the core. The semipermeable membrane controls water to flow into the core from the aqueous environment used, thereby causing drug release by extrusion of the delivery port.

[0168] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force to transport water from the environment of use to the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinyl pyrrolidone (PVP), cross-linked 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, cross-linked sodium carboxymethylcellulose, 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.

[0169] Another class of osmotic agents is osmotic factors, which are capable of absorbing water to affect an osmotic pressure gradient across the surrounding coating barrier. Suitable osmotic factors 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, D-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, tartaric acid, and the like; urea; and mixtures thereof.

[0170] Osmotic agents with different dissolution rates can be used to affect the speed at which the active ingredient is initially released from the formulation. For example, amorphous sugars such as MANNOGEM can be used. TM EZ etc. provide faster delivery in the first few hours to rapidly produce the desired therapeutic effect and gradually and continuously release the remaining amount to maintain the desired therapeutic or preventive level over a longer period of time. In this case, the active ingredient is released at such a rate to replace the amount of active ingredient that is metabolized and excreted.

[0171] The core may also include various other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0172] Materials that can be used to form the semipermeable membrane include various grades of acrylic resins, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and water-insoluble at physiologically relevant pH values, or that are susceptible to being rendered water-insoluble by chemical changes, such as crosslinking. Examples of suitable polymers that can be used to form the coating 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, CA acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, acetate agar, amylose triacetate, β-glucan ethyl Acid esters, β-glucan triacetate, acetaldehyde dimethyl acetate, carob bean gum triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0173] The semipermeable membrane may also 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 vapor, as disclosed in U.S. Pat. No. 5,798, 119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0174] The delivery ports in the semipermeable membrane can be formed after coating by mechanical or laser drilling. The delivery ports can also be formed in situ by erosion of a plug of water-soluble material or by rupturing a thinner portion of the membrane at a depression in the core. In addition, the delivery ports can be formed during the coating process, such as the type of asymmetric membrane coatings disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0175] The total amount of active ingredient released and the rate of release can be adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0176] The pharmaceutical composition in the form of an osmotic controlled release dosage form may further comprise other conventional excipients or carriers as described herein to facilitate the performance or processing of the formulation.

[0177] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27.

[0178] In certain embodiments, the pharmaceutical composition provided herein is prepared as an AMT controlled release dosage form, which comprises an asymmetric osmotic membrane, which coats a core containing an active ingredient and other pharmaceutically acceptable excipients or carriers. See, for example, U.S. Patent No. 5,612,059 and WO 2002 / 17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct tableting, dry granulation, wet granulation and dip coating.

[0179] In certain embodiments, the pharmaceutical composition provided herein is prepared as an ESC controlled-release dosage form, which comprises a permeable membrane coating a core, wherein the core comprises an active ingredient, hydroxyethylcellulose and other pharmaceutically acceptable excipients or carriers. 3. Multi-particle controlled release device

[0180] The pharmaceutical composition of the controlled release dosage form provided in the present application can be prepared into a multi-particulate controlled release device, which contains a plurality of microparticles, granules, or pellets, with a particle size ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multi-particulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller granulation, melt coagulation, and by spray coating of seed cores. See, for example, Multipartic ulate 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.

[0181] Other excipients or carriers as described herein may be mixed with the pharmaceutical composition to aid in processing and forming multiparticulates. The resulting particles themselves may constitute a multiparticulate device or may be coated with various film-forming materials, such as enteric polymers, water-swellable and water-soluble polymers. The multiparticulates may be further processed into capsules or tablets. 4. Targeted delivery

[0182] The pharmaceutical compositions provided herein can also be prepared to target specific tissues, receptors or other areas of the subject's body to be treated, including delivery systems based on liposomes, resealed red blood cells and antibodies. Examples include, but are not limited to, those disclosed in U.S. Patents Nos. 6316652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542 and 5709874. How to use

[0183] In one embodiment, the present application provides a method for treating, preventing or alleviating one or more symptoms of a disorder, disease or condition mediated by CDK in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0184] In certain embodiments, the CDK is CDK4 or CDK6. In certain embodiments, the CDK is CDK4. In certain embodiments, the CDK is CDK6.

[0185] In certain embodiments, the disorder, disease or condition mediated by a CDK is a gastrointestinal side effect caused by chemotherapy.

[0186] In another embodiment, the present application provides a method for preventing or alleviating gastrointestinal side effects caused by chemotherapy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, such as a compound of formula (I) or its 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 pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0187] In certain embodiments, the chemotherapy-induced gastrointestinal side effect is chemotherapy-induced diarrhea. In certain embodiments, the chemotherapy-induced gastrointestinal side effect is chemotherapy-induced constipation.

[0188] In certain embodiments, the chemotherapy-induced gastrointestinal side effects are caused by fluorouracil (FU-5). In certain embodiments, the chemotherapy-induced gastrointestinal side effects are caused by camptothecin. In certain embodiments, the chemotherapy-induced gastrointestinal side effects are caused by belotecan, irinotecan, topotecan or dextran. In certain embodiments, the chemotherapy-induced gastrointestinal side effects are caused by irinotecan.

[0189] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0190] In certain 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, from about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In one embodiment, 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.

[0191] In one embodiment, the compounds provided herein are administered orally.

[0192] The compound provided by the application can be administered once a day (QD) or divided into multiple daily doses, such as twice a day (BID) or three times a day (TID). In addition, administration can be continuous, i.e., every day, or intermittent. The term "intermittent" or "intermittently" used in the application is intended to indicate regular or irregular intervals to stop and start. For example, the intermittent administration of the compound provided by the application can be weekly administration of one to six days, periodic administration (for example, continuous daily administration for two to eight weeks, then rest period without administration for up to one week), or administration every other day.

[0193] The compounds provided herein may also be combined or used in combination with other therapeutic agents useful for treating and / or preventing the conditions, disorders, or diseases described herein.

[0194] In the present application, the term "combination" includes the use of multiple therapies (for example, one or more preventive agents and / or therapeutic agents). However, the use of the term "combination" does not limit the order of applying therapy (for example, preventive agent and / or therapeutic agent) to the subject suffering from the patient's condition, illness or disease. The first therapy (for example, preventive agent or therapeutic agent, such as the compound provided by the application) can be before the second therapy (for example, preventive agent or therapeutic agent) (for example, 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), while or afterwards (for example, 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later) to the subject. The application also includes triple therapy.

[0195] The route of administration of the compound provided herein is independent of the route of administration of the second therapy. In one embodiment, the compound of the present application is administered orally. Therefore, according to this embodiment, the compound provided herein is administered orally, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomes, via inhalation, vaginally, intraocularly, locally delivered by catheter or stent, subcutaneously, intrafatally, intraarticularly, intrathecally or in a sustained release dosage form. In one embodiment, the compound provided herein and the second therapy are administered orally by the same mode of administration. In another embodiment, the compound provided herein is administered by a mode of administration, such as oral administration, and the second agent (anticancer agent) is administered by another mode of administration, such as parenteral administration.

[0196] In one embodiment, the present application provides a method for inhibiting the activity of cyclin-dependent kinase (CDK), comprising contacting CDK with an effective amount of a compound of formula (I) or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0197] In certain embodiments, the CDK is CDK4 or CDK6. In certain embodiments, the CDK is CDK4. In certain embodiments, the CDK is CDK6.

[0198] The compounds provided herein can also be provided as articles of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0199] In certain embodiments, the present application provides a kit that, when used by a practicing physician, can simplify administration to a subject so as to administer an appropriate amount of a compound provided herein as an active ingredient. In certain embodiments, the present application provides a kit comprising a container and a dosage form of a compound provided herein.

[0200] The kit provided herein may also include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringe drop bags, patches, and inhalers. The kit provided herein may also include a condom for administering the active ingredient.

[0201] The kit provided herein may also include a pharmaceutically acceptable carrier that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in solid form and must be reconstituted 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 particle-free sterile solution suitable for parenteral administration. Examples of pharmaceutically 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; non-aqueous carriers, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0202] The present application will be further illustrated by the following non-limiting examples. Example

[0203] As used herein, the symbols and conventions used in the procedures, schemes, and examples, whether or not a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromole); mmol (millimole); min (minute or minutes); h (hour or hours); ACN (acetonitrile); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); Boc (tert-butyloxycarbonyl). yl); HATU (azabenzotriazole tetramethyluranium hexafluorophosphate); LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); Me (methyl); MeOTf (methyl trifluoromethanesulfonate); Pd(OAc)2 (palladium acetate); tBuOH (tert-butyl alcohol); TBS (tert-butyldimethylsilane); 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).

[0204] For all the following examples, standard post-processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (degrees Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methods described in this application are intended to illustrate applicable chemistry by using specific examples and do not indicate the scope of the present disclosure. Example 1 Preparation of 2-hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1

[0205] The preparation of compound A1 is shown in Scheme 1.

[0206] 2-[tert-Butyl(dimethyl)silyl]oxyethyl N-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-keto-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridine]piperazin-1-yl]sulfonylcarbamate 1.2. 2-tert-Butyl(dimethyl)siloxyethanol (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 slowly added under N2 and 0°C, and stirring was continued at 0°C for 20 minutes, and then pyridine (6.6 g, 83.8 mmol) was added. The mixed solution was stirred at 0°C for another 40 minutes and then added to a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyridin[2,3-d]pyrimidin-7-one 1.1 (15.0 g, 33.5 mmol) and triethylamine (4.2 g, 41.9 mmol) in dichloromethane (20 mL). After stirring at 25°C for 2 hours, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL). The mixed organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1.2 (30 g). The compound was used directly in the next step without further purification. MS (ESI) m / z: 729.8 [M+H] + . Scheme 1

[0207] 2-Hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A1. To a solution of compound 1.2 (15.0 g, 20.5 mmol) in tetrahydrofuran (75 mL) was added HF·pyridine (35.0 mL, 70% purity) at 0°C. After stirring for 1 hour, the reaction was neutralized with saturated aqueous NaHCO3 solution (75 mL), and then extracted with dichloromethane (50 mL x 3). The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Further purification by silica gel column chromatography, eluting with MeOH / DCM, afforded compound A1 (6 g). 1HNMR(400MHz,DMSO-d6)δ11.48(s,1H),10.17(s,1H),8.96(s,1H),8.08(d ,1H,J=4.0Hz),7.89(d,1H,J=10.0Hz),7.52-7.49(m,1H),5.85-5.80(m,1 H),4.87-4.84(m,1H),4.0-4.2(m,2H),3.60-3.45(m,2H),3.40-3.32(m,4 H),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] + . Example 2 Preparation of 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-methylpiperazine-1-yl)sulfonyl)carbamate A2 and (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

[0208] The preparation of compounds A2 and A3 is shown in Scheme 2.

[0209] Tert-butyl (R)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 2.2. A mixed solution of dioxane (1 L) containing 5-chloro-2-nitropyridine (10 g, 63.1 mmol), tert-butyl (S)-3-methylpiperazine-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) was stirred at 100°C for 16 hours under N2 conditions. The reaction mixture was concentrated under vacuum and then purified by silica gel chromatography to obtain compound 2.2 (6.3 g). MS (ESI) m / z: 323.0 [M+H] + .

[0210] 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 for 1 h. The reaction mixture was then filtered and concentrated in vacuo to give compound 2.3 (6.8 g). MS (ESI) m / z: 293.1 [M+H] + .

[0211] Tert-butyl ((S)-4-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-keto-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate 2.5. To a solution of compound 2.3 (555 mg, 1.9 mmol) in anhydrous THF (18 mL) was slowly added dropwise LiHMDS (2.8 mL, 1 M), and the addition was completed within 5 minutes. The mixture was stirred at 0°C for 1 hour, and then a solution of 8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-2-(methylsulfinyl)pyridin[2,3-d]pyrimidin-7(8H)-one 2.4 (1.2 g, 3.4 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise. The reaction was stirred at 0°C for another hour and then neutralized with water (15 mL). The reaction solution was extracted with ethyl acetate (7 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. Compound 2.5 (270 mg) was purified by silica gel chromatography. MS (ESI) m / z: 590.3 [M+H] + . Scheme 2

[0212] (S)-6-acetyl-8-cyclopentyl-5-methyl-2-((5-(2-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin[2,3-d]pyrimidin-7(8H)-one 2.6. Trifluoroacetic acid (1.0 mL) was slowly added dropwise to a solution of compound 2.5 (570 mg, 1.0 mmol) in dichloromethane (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under vacuum and lyophilized to obtain product 2.6 (470 mg). MS (ESI) m / z: 462.3 [M+H] + .

[0213] 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) was slowly added dropwise tert-butyl alcohol (859 mg, 11.6 mmol) at 0°C. After stirring for 30 minutes, the mixture and triethylamine (258 mg, 2.6 mmol) were slowly added to anhydrous dichloromethane (25 mL) containing compound 2.6 (535 g, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give a crude product, which was purified by silica gel chromatography to give product A2 (285 mg). MS (ESI) m / z: 641.3 [M+H] + .

[0214] (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. Triethylamine (1 mL) was slowly added dropwise to a solution of compound A2 (280 mg, 0.4 mmol) in dichloromethane (10 mL) 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). 1 HNMR(400MHz,DMSO-d6)δ10.77(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),1.98-1.8 6(m,2H),1.85-1.73(m,2H),1.66-1.51(m,2H),1.03(d,J=6.0Hz,3H); MS(ESI)m / z:541.3[M+H]+ . Example 3 Preparation of tert-butyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonamide A5

[0215] The preparation of compounds A4 and A5 is shown in Scheme 3. Scheme 3

[0216] Tert-butyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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 dichloromethane (90 mL) was slowly added dropwise tert-butyl alcohol (1.7 g, 22.3 mmol) at 0°C. After the mixture was stirred for 20 minutes, pyridine (3.5 g, 44.7 mmol) was added, and the resulting mixture was stirred for another hour. The mixture was added to a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyridin[2,3-d]pyrimidin-7-one 1.1 (8.0 g, 17.9 mmol) and TEA (2.3 g, 22.3 mmol) in dichloromethane (160 mL) at 0°C. The reaction mixture was stirred at 20°C for 8 hours, then diluted with water (30 mL, and the organic phase was concentrated in vacuo to give a crude product, which was triturated with EtOAc (60 mL) to give Compound A4 (10.5 g). 1H NMR (400MHz, DMSO-d6) δ11.12(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=8.0Hz,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] + .

[0217] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-piperazine-1-sulfonamide A5. Trifluoroacetic acid (1.1 g, 9.6 mmol) was added to a solution of compound A4 (6 g, 9.6 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at 25°C for 2 hours and then concentrated under vacuum to obtain compound A5 (4.8 g). 1 H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 8.10 (d, J = 4.0Hz, 1H), 7.88 (d, J = 8.0Hz, 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] + . Example 4 Preparation of (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropanamide A6

[0218] The preparation of compound A6 is shown in Scheme 4.

[0219] Tert-butyl ((S)-(1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine)-1-sulfonamide-1-oxopropan-2-yl)carbamate 4.1. 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonamide A mixture of A4 (500 mg, 1.0 mmol), tert-butyloxycarbonyl-L-alanine (216 mg, 1.1 mmol), DIPEA (613.0 mg, 4.7 mmol) and HATU (433 mg, 1.1 mmol) in DMF (25 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a crude product, which was purified by silica gel chromatography to obtain compound 4.1 (330 mg). MS (ESI) m / z: 698.3 [M+H] + . Scheme 4

[0220] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropanamide A6. Compound 4.1 (330 mg, 0.5 mmol) was added to a 4M HCl solution in dioxane (10 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to give a crude product. Compound A6 (202 mg) was obtained by purification by silica gel chromatography and reverse phase prep-HPLC. 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),10.29(s,1H),8.97(s,1H),8.16(s,2H),8.08(d,J= 4.0Hz,1H),7.88(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),5.90-5.75(m,1H),3.89(s,1H),3 .41(d,J=6.0Hz,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=8.0Hz,2H),1.58(d,J=6.0Hz,2H),1.40(d,J=8.0Hz,3H); MS(ESI)m / z:598.2[M+H] + . Example 5 Preparation of (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A7

[0221] The preparation of compound A7 is shown in Scheme 5. Scheme 6

[0222] 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 hours, and then concentrated under vacuum to obtain product 5.2 (18 g). The product was used directly in the next step without further purification.

[0223] 6-Acetyl-8-cyclopentyl-2-[[5-(4-imidazol-1-ylsulfonylpiperazin-1-yl)-2-pyridinyl]amino]-5-methylpyridin[2,3-d]pyrimidin-7-one 5.3. 6-Acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyridin[2,3-d]pyrimidin-7-one 1.1 (14 g, 31.3 mmol) was added to a solution of compound 5.2 (10 g, 46.9 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at 25°C for 45 hours and then concentrated under vacuum to obtain a crude product. The product 5.3 (13 g) was purified by silica gel chromatography.

[0224] 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-[4-(3-methylimidazol-3-ium-1-yl)-sulfonylpiperazin-1-yl]-2-pyridyl]amino]pyridin[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 under N2 and 0°C. The reaction mixture was stirred at 0°C for 3 hours and then concentrated under vacuum to obtain compound 5.4 (6.4 g). The product was directly used in the next step without further purification.

[0225] (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[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. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.96(s,1H),8.08(d,J=4.0Hz,1H),7.90(d, J=10.0Hz,1H),7.55-7.46(m,1H),5.83(p,J=8.0Hz,1H),4.82(t,J=6.0Hz,1H),3.7 6-3.43(m,4H),3.28-3.14(m,8H),3.00(t,J=12.0Hz,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] + . Example 6 Preparation of (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1

[0226] The preparation of compound B1 is shown in Scheme 6. Scheme 6

[0227] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-one-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonic acid 6.1. 6-Acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridyl)amino]pyridin[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 under N2 and -30°C. The reaction mixture was stirred at 25°C for 2 hours, then filtered, and the filtrate was concentrated under vacuum to obtain the crude product. Compound 6.1 (550 mg) was purified by reverse phase prep-HPLC. 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.96(s,1H),8.06(d,J=4.0Hz,1H),7.87(d,J=8.0Hz,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] + .

[0228] (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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 heavy ester (477 mg, 2.0 mmol). The mixture was stirred at 25°C for 12 hours, then filtered and concentrated to obtain a crude product. Purification by silica gel column chromatography gave product B1 (120 mg). 1H NMR(400MHz,CCl3D)δ8.83(s,1H),8.40-8.30(m,1H),8.05-7.90(m,1H),7.5 2-7.36(m,1H),5.88(t,J=8.0Hz,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] + . Example 7 6-Acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylpiperazin-1-yl)-2-pyridinyl]-amino]-5-methylpyrido[2,3-d] Preparation of pyrimidin-7-one C1

[0229] The preparation of compound C1 is shown in Scheme 7. Scheme 7

[0230] To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyridin[2,3-d]pyrimidin-7-one (800 mg, 1.8 mmol) and pyridine (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 hours and then concentrated under vacuum to obtain a crude product. The product C1 (80 mg) was purified by silica gel column chromatography and preparative thin layer chromatography. 1H NMR (400MHz, CDCl3) δ8.84-8.82(m,1H),8.82(s,1H),8.35-8.20(m,1H),8.01(d,J=4 .0Hz,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=8.0Hz,6H); MS(ESI)m / z:554.4[M+H] + .

[0231] The following compounds were similarly prepared according to the synthetic procedures or methods exemplified in this application.

[0232] 2-Methoxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8. MS (ESI) m / z: 629.2 [M+H] + .

[0233] 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetic acid ethyl A9. MS (ESI) m / z: 657.3 [M+H] + .

[0234] Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetate A10. MS (ESI) m / z: 657.3 [M+H] + .

[0235] 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetic acid A11. MS (ESI) m / z: 629.2 [M+H] + .

[0236] 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0237] 2-Aminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13. MS (ESI) m / z: 614.1 [M+H] + .

[0238] (S)-2-(2-amino-3-methylbutyramido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A14. MS (ESI) m / z: 713.3 [M+H] + .

[0239] 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A15. MS (ESI) m / z: 656.2 [M+H] + .

[0240] (R)-2-(2-aminopropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A16. MS (ESI) m / z: 685.3 [M+H] + .

[0241] (S)-2-(2-amino-4-methylpentanoylamino)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A17. MS (ESI) m / z: 727.3 [M+H] + .

[0242] (S)-2-(2-amino-3-hydroxypropionamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A18. MS (ESI) m / z: 701.3 [M+H] + .

[0243] (S)-2-(2-amino-4-(methylthio)butyramido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A19. MS (ESI) m / z: 745.3 [M+H] + .

[0244] 2-(2-aminoacetamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A20. MS (ESI) m / z: 671.2 [M+H] + .

[0245] (R)-2-(Pyrrolidine-2-carboxamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A21. MS (ESI) m / z: 711.2 [M+H] + .

[0246] Tetrahydro-2H-pyran-4-yl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin)-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A22. MS (ESI) m / z: 655.3 [M+H] + .

[0247] Cyclobutyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A23. MS (ESI) m / z: 625.3 [M+H] + .

[0248] Cyclopropyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino))pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A24. MS (ESI) m / z: 611.2 [M+H] + .

[0249] Ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A25. MS (ESI) m / z: 599.2 [M+H] + .

[0250] Methyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A26. MS (ESI) m / z: 585.3 [M+H] + .

[0251] Isopropyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin)-3-yl)piperazin-1-yl)sulfonyl)carbamate A27. MS (ESI) m / z: 613.2 [M+H] + .

[0252] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0253] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0254] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0255] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0256] (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0257] (R)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-carboxamide A33. MS (ESI) m / z: 624.3 [M+H] + .

[0258] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)acetamide A34. MS (ESI) m / z: 569.2 [M+H] + .

[0259] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propanamide A35. MS (ESI) m / z: 583.2 [M+H] + .

[0260] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)isobutyramide A36. MS (ESI) m / z: 597.3 [M+H] + .

[0261] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butanamide A37. MS (ESI) m / z: 597.3 [M+H] + .

[0262] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropanecarboxamide A38. MS (ESI) m / z: 595.2 [M+H] + .

[0263] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-carboxamide A39. MS (ESI) m / z: 624.2 [M+H] + .

[0264] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide A40. MS (ESI) m / z: 639.3 [M+H] + .

[0265] N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutanecarboxamide A41. MS (ESI) m / z: 609.3 [M+H]+ .

[0266] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)piperazine-1-sulfonamide A42. MS (ESI) m / z: 571.2 [M+H] + .

[0267] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)piperazine-1-sulfonamide A43. MS (ESI) m / z: 585.3 [M+H] + .

[0268] ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)glycine A44. MS (ESI) m / z: 585.2 [M+H] + .

[0269] ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0270] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-methylpiperazine-1-sulfonamide A46. MS (ESI) m / z: 541.2 [M+H] + .

[0271] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylpiperazine-1-sulfonamide A47. MS (ESI) m / z: 555.2 [M+H] + .

[0272] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylpiperazine-1-sulfonamide A48. MS (ESI) m / z: 569.3 [M+H] + .

[0273] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylpiperazine-1-sulfonamide A49. MS (ESI) m / z: 569.3 [M+H] + .

[0274] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylpiperazine-1-sulfonamide A50. MS (ESI) m / z: 555.2 [M+H] + .

[0275] 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one A51. MS (ESI) m / z: 597.3 [M+H] + .

[0276] 6-Acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A52. MS (ESI) m / z: 583.2 [M+H] + .

[0277] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)piperazine-1-sulfonamide A53. MS (ESI) m / z: 615.3 [M+H] + .

[0278] 2-Hydroxyethyl (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 A54. MS (ESI) m / z: 629.2 [M+H] + .

[0279] 2-((R)-2-amino-3-methylbutyrylamino)ethyl(((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-methylpiperazin-1-yl)sulfonyl)carbamate A55. MS (ESI) m / z: 727.3 [M+H] + .

[0280] 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylcarbamoyl)piperazine-1-sulfonamide A56. MS (ESI) m / z: 612.3 [M+H] + .

[0281] 6-Acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A57. MS (ESI) m / z: 593.2 [M+H] + .

[0282] 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyridin[2,3-d]pyrimidin-7(8H)-one A58. MS (ESI) m / z: 578.2 [M+H] + .

[0283] p-Tolyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B2. MS (ESI) m / z: 618.2 [M+H] + .

[0284] (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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] + .

[0285] Cyclopentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4. MS (ESI) m / z: 596.3 [M+H] + .

[0286] 6-Acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-2-yl)-amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one C2. MS (ESI) m / z: 540.2 [M+H] + . Example B1 Caliper Mobility Shift Analysis of CDK4 and CDK6

[0287] The inhibitory activity of the compounds was detected using the Caliper Mobility Shift assay in the respective kinase buffers (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.

[0288] Pre-incubate the compounds at preset concentrations with CDK4 / Cyclin D1 or CDK6 / Cyclin D1 in a 384-well plate at room temperature for 10 min. FAM-labeled peptides and ATP were then added to initiate the kinase reaction. 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 mM and 230 mM, respectively. The well plate was incubated at 28°C. The kinase reaction was terminated by adding stop buffer (100 mM HEPES, pH 7.5, 0.012% BRIJ-35, 0.2% Coating Reagent 3 (Caliper Life Sciences), and 50 M EDTA). The data were recorded and converted into inhibition rates for each compound to determine the IC50 value. The results are summarized in Table 1. The symbol "***" indicates a value less than or equal to 200 nM, the symbol "**" indicates a value greater than 200 nM but not greater than 500 nM, and the symbol "*" indicates a value greater than 500 nM. Table 1. CDK4 and CDK6 inhibitory activity Example B2 Cell viability assay

[0289] MCF-7 human breast cancer cells under normal growth conditions were assayed for cell viability using the CELLTITER-GLO luminescence method. MCF-7 human breast cancer cells were cultured in an EMEM medium supplemented with 10% FBS and 0.01 mg / mL bovine insulin at 37°C and a 5% CO2 humidified incubator. The cells were seeded at 3,000 cells / well in a 96-well tissue culture plate. Incubate overnight in an incubator to allow the cells to adhere. Preset concentrations of compounds (5 μL) were added to the culture medium. After the cells were incubated at 37°C for 8 days, CELLTITER-GLO detection solution (100 μL) was added. The cells were mixed on an orbital shaker for 5 minutes and then incubated for another 10 minutes. The plate was measured using an ENVISION instrument. The results are summarized in Table 2, where the symbol "+++" indicates a value not greater than 1 μM, the symbol "++" indicates a value greater than 1 μM but not greater than 10 μM, and the symbol "+" indicates a value greater than 10 μM. Table 2. Effects on cell viability Example B3 Apoptosis detection

[0290] The CASPASE-GLO 3 / 7 apoptosis assay was used to detect the protective effect of compounds on cytotoxicity induced by chemotherapy drugs. The COLO205 human colon cancer cells were used for apoptosis experiments. The cells were cultured in PRIM1640 medium supplemented with 10% FBS and 0.01 mg / mL bovine insulin in a humidified incubator at 37°C and 5% CO2. The cells were seeded at 4,000 cells / well in a 96-well tissue culture plate. After incubation overnight, the cells were pretreated with compounds or solvents at preset concentrations for 16 hours, followed by the addition of chemotherapy drugs. After continued culture for 48 hours, CASPASE-GLO 3 / 7 reagent (100 μL / well) was added. The cells were mixed on an orbital shaker for 10 minutes and then incubated at room temperature for 2 hours. The 96-well plate was detected using an ENVISION instrument. According to the formula, the induction factor = (RLU (化合物) -RLU (空白) ) / (RLU (对照) -RLU (空白) ) to calculate the induction fold of the compound on the cells, where RLU is the relative light unit. The relative protection rate of the compound is calculated according to the formula relative protection rate = (induction fold (化疗药物) -Induction multiple (化合物) ) / induction multiple (化疗药物) × 100%. The relative protection rates (RPR) of the compounds against cytotoxicity induced by chemotherapeutic drugs are summarized in Table 3. The results show that the compounds can effectively resist cytotoxicity induced by chemotherapeutic drugs. Table 3. Protection rate of compounds Example B4 5-FU-induced diarrhea model in mice

[0291] The protective effect of the compound on the cytotoxicity induced by the chemotherapeutic drug 5-FU was evaluated using a 5-FU-induced mouse diarrhea model. On day 0, BALB / c mice (20-25g, 7-8 weeks old) were randomly divided into 3 groups (control, 5-FU, compound treatment), with 10 mice in each group. Control group: The mice were gavaged with the same amount of the same solvent as the compound treatment group, and then injected with the same amount of the same solvent as the 5-FU group. 5-FU group: The mice were gavaged with the same amount of the same solvent as the compound treatment group, and then injected with 5-FU (175 mg / kg). Compound treatment group: The mice were gavaged with the compound and then injected with 5-FU (175 mg / kg). The compound was prepared with 0.5% carboxymethyl cellulose (CMC) solution.

[0292] On the 7th day, the diarrhea grade of each mouse was evaluated according to the method described in Kurita et al., Cancer Chemother. Pharmacol. 2000, 46, 211-20, the disclosure of which is incorporated by reference in its entirety into this application. The diarrhea relief rate was calculated by the formula diarrhea relief rate (%) = (5-FU group diarrhea grade - compound treatment group diarrhea grade) / 5-FU group diarrhea grade × 100%. The results are summarized in Table 4, which shows that the compound effectively treats 5-FU-induced cytotoxicity (e.g., diarrhea) by reducing the diarrhea relief rate. Table 4. Effects of compounds on 5-FU cytotoxicity Example B5 Mouse model of irinotecan-induced diarrhea / constipation

[0293] The protective effect of the compounds against chemotherapeutic drug-induced cytotoxicity was evaluated in a mouse model of irinotecan-induced diarrhea / constipation. On day 0, BALB / c mice (20-25g, 7-8 weeks old) were randomly divided into 3 groups (control, irinotecan and compound treatment), with 10 mice in each group. Control group: mice were gavaged with the same amount of the same solvent as the compound treatment group, and then injected with the same amount of the same solvent as the irinotecan group. Irinotecan group: mice were gavaged with the same amount of the same solvent 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 compound was prepared in 0.5% CMC solution.

[0294] On the second day, the feces of the mice were collected within 3 hours and their shape and weight were recorded. The feces reduction rate of each mouse was determined according to the method described in Kim et al., Lab. Anim. Res. 2016, 32, 231-40, the disclosure of which is incorporated herein by reference in its entirety. The feces reduction rate was calculated by the formula feces reduction rate (%) = (control - irinotecan or CDK inhibitor group) / control group × 100%.

[0295] On the 7th day, the diarrhea grade of each mouse was evaluated according to the method described in Kurita et al., Cancer Chemother. Pharmacol. 2000, 46, 211-20, the disclosure of which is incorporated herein by reference in its entirety. The diarrhea relief rate was calculated by the formula diarrhea relief rate (%) = (5-FU group diarrhea grade - compound treatment group diarrhea grade) / 5-FU group diarrhea grade × 100%.

[0296] The results are summarized in Table 5, which show that the compounds significantly reversed irinotecan-induced diarrhea and constipation. Table 5. Effects of compounds on 5-irinotecan cytotoxicity *****

[0297] The above examples are provided to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the disclosure of this application. Modifications that are obvious to those skilled in the art are intended to fall within the scope of the appended claims. All publications, patents, and patent applications cited in this application are incorporated into this application as reference documents, just as if each publication, patent, or patent application was clearly and individually indicated to be incorporated into this specification by reference.

Claims

1. The 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; 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 . R 2 , R 3 , R 4 and R 6 are each independently (i) hydrogen, deuterium, cyano, 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 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 或 -S(O)2NR 1b R 1c ; R 7 Yes (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 ; R 5 and R 6a are each independently (i) deuterium, cyano, 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 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 、 or -S(O)2NR 1b R 1c ; R 7a It 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 heterocyclic group; R 7b and R7c 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 heterocyclic; or R 7b and R 7c Together with the N atom to which they are attached, they form a heteroaryl or heterocyclyl group; 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 heterocyclic group; R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, 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 heterocyclic group; 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 and heterocyclyl is optionally substituted with one or more substituents Q, in one embodiment, one, two, three or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, 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 and heterocyclyl; each of which is further optionally substituted by one or more substituents Q a Substituted, in one embodiment, by 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 and -S(O)2NR b R c , where 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 optionally substituted with one or more, in one embodiment one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, optionally substituted by one or more, in one embodiment one, two, three or four substituents Q a ; Each Q a are independently selected from: (a) deuterium, cyano, halogen, imino, 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 )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 and -S(O)2NR f R g ; where each R e , R f , R g and R h are independently: (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl and heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

2. The compound according to claim 1, wherein R 7 Yes (i) C 2-6 alkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; 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 .

3. The compound according to claim 1 or 2, wherein R 7 It is C 2-6 Alkyl, monocyclic heteroaryl or monocyclic heterocyclyl, each optionally substituted by one or more substituents Q.

4. The compound according to any one of claims 1 to 3, wherein R 7 is ethyl, isopropyl, imidazol-1-yl, 2-aminoimidazol-1-yl, 3-hydroxyazetidin-1-yl, 5-(hydroxymethyl)-2-oxooxazolidine-3-yl yl, (R)-2-(hydroxymethyl)piperidin-1-yl or morpholin-4-yl.

5. The compound according to claim 1 or 2, which has the structure of formula (II): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

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

7. The compound according to claim 1, 5 or 6, wherein R 7b and R 7c Each is independently hydrogen, methyl, hydroxycarbonylmethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl or 1-(hydroxycarbonyl)-2-methylpropyl.

8. The compound according to claim 1 or 5, wherein R 7b and R 7c Together with the N atom to which they are attached they form a heteroaryl or heterocyclyl, each optionally substituted by one or more substituents Q.

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

10. A compound according to any one of claims 1, 5, 8 and 9, wherein R 7b and R 7c Together with the N atom to which they are attached they 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. The compound according to claim 1 or 2, which has the structure of formula (III): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

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

13. The compound according to claim 1, 11 or 12, wherein R 7e It is C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclyl, each optionally substituted by one or more substituents Q.

14. A compound according to any one of claims 1 and 11-13, wherein said R 7e It is C 1-6 Alkyl is optionally substituted with one or more substituents Q.

15. A compound according to any one of claims 1 and 11-13, wherein said R 7e It is C 3-10 Cycloalkyl is optionally substituted with one or more Q substituents.

16. A compound according to any one of claims 1, 11-13 and 15, wherein said R 7e It is a single ring C 3-10 Cycloalkyl is optionally substituted with one or more Q substituents.

17. A compound according to any one of claims 1 and 11-13, wherein said R 7e is a heterocyclyl group, optionally substituted by one or more substituents Q.

18. A compound according to any one of claims 1, 11-13 and 17, wherein said R 7e is a monocyclic heterocyclyl group, optionally substituted by one or more substituents Q.

19. A compound according to any one of claims 1, 11-13, 17 and 18, wherein said R 7e is a 5-membered or 6-membered heterocyclic group, each of which is optionally substituted by one, two or three substituents Q.

20. A compound according to any one of claims 1 and 11-13, wherein said R 7e is methyl, ethyl, propyl, pentyl, cyclopropyl, cyclobutyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one, two or three substituents Q.

21. A compound according to any one of claims 1, 11-13 and 20, wherein R 7e It is methyl, aminomethyl, ethyl, 1-aminoethyl, 1-amino-2-(imidazol-4-yl)ethyl, propyl, isopropyl, 1-amino-propyl, 1-amino-2-methylpropyl, 1,5-diaminopentyl, cyclopropyl, cyclobutyl, pyrrolidin-2-yl, tetrahydrofuran-2-yl or tetrahydropyran-4-yl.

22. The compound according to claim 1 or 2, which has the structure of formula (IV): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

23. The compound according to claim 1 or 22, wherein R 7d It's hydrogen.

24. The compound according to claim 1, 22 or 23, wherein R 7e It is C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclyl, each optionally substituted by one or more substituents Q.

25. according to the compound described in any one of claim 1 and 22-24, wherein said R 7e It is C 1-6 Alkyl is optionally substituted with one or more substituents Q.

26. A compound according to any one of claims 1 and 22-25, wherein said R 7e It is C 1-6 Alkyl, optionally substituted with one, two or three substituents, 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。 27. A compound according to any one of claims 1 and 22-26, wherein said R 7e It is C 1-6 Alkyl, -NR 1a C(O)R 1d replace.

28. A compound according to any one of claims 1 and 22-27, wherein R 7e It is C 1-6 Alkyl, substituted with aminoamide.

29. A compound according to any one of claims 1 and 22-27, wherein R 7e It is an ethyl group, with the 2-position substituted by an aminoamide group.

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

31. according to the compound described in any one of claims 28-30, wherein said aminoamido is aminoacetamido, 2-aminopropionamido, 2-amino-3-phenylpropionamido, 2-amino-3-(4-hydroxy-phenyl)propionamido, 2-amino-3-(imidazol-4-yl)propionamido, 2-amino-3-(indol-3-yl)propionamido, 2-amino-3-(hydroxycarbonyl)propionamido, 2-amino-3-(aminocarbonyl)propionamido, 2-amino-3 2-amino-3-hydroxypropionamido, 2-amino-3-mercaptopropionamido, 2-amino-3-methylbutanamido, 2-amino-3-hydroxybutanamido, 2-amino-4-(methylthio)butanamido, 2-amino-4-hydroxy-carbonylbutanamido, 2-amino-4-(aminocarbonyl)butanamido, 2-amino-3-methylpentanamido, 2-amino-4-methylpentanamido, 2,6-diaminohexanamido, 2-amino-5-guanidinopentanamido or pyrrolidine-2-ylformamide.

32. according to the compound described in any one of claim 1 and 22-24, wherein said R 7e It is methyl, hydroxycarbonylmethyl, ethoxycarbonylmethyl, 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-methyl-butyramido)ethyl, (S)-2-(2-amino-4-)(methylthio)butyramido)ethyl, (S)-2-(2-amino-4-methyl-pentanamido)ethyl, (S)-2-(pyrrolidin-2-ylamido)ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or tetrahydropyran-4-yl.

33. The compound according to claim 1 or 2, which has the structure of formula (V): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

34. according to the compound described in claim 1 or 33, wherein said R 7d It's hydrogen.

35. according to the compound described in claim 1,33 or 34, wherein said R 7b It's hydrogen.

36. A compound according to any one of claims 1 and 33-35, wherein R 7c It is C 1-6 Alkyl is optionally substituted with one or more substituents Q.

37. according to the compound described in any one of claim 1 and 33-36, wherein said R 7c It is isopropyl.

38. A compound according to claim 1 or 2, which has the structure of formula (VI): 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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

39. The compound according to claim 38, wherein R 7a It is C 1-6 Alkyl, C 3-10 Cycloalkyl or C 6-14 Aryl, each optionally substituted with one or more substituents Q.

40. The compound according to claim 38 or 39, wherein said R 7a It is C 1-6 Alkyl is optionally substituted with one, two or three Q substituents.

41. according to the compound described in claim 38 or 39, wherein said R 7a It is C 3-10 Cycloalkyl is optionally substituted with one, two or three Q substituents.

42. according to the compound described in claim 38,39 or 41, wherein said R 7a It is a single ring C 3-10 Cycloalkyl is optionally substituted with one, two or three Q substituents.

43. according to the compound described in claim 38 or 39, wherein said R 7a It is C 6-14 Aryl, optionally substituted with one, two or three Q substituents.

44. according to the compound described in claim 38 or 39, wherein said R 7a is methyl, ethyl, propyl, cyclopentyl or phenyl, each optionally substituted with one, two or three substituents Q.

45. according to the compound described in claim 38,39 or 44, wherein said R 7a It is pivaloyloxymethyl, benzoyloxymethyl, isopropyl, cyclopentyl or 4-methylphenyl.

46. ​​according to the compound described in any one of claims 1-45, wherein said R 1 It is C 1-6 Alkyl or C 3-10 The cycloalkyl groups are each optionally substituted with one or more substituents Q.

47. A compound according to any one of claims 1-46, wherein R 1 It is C 3-10 Cycloalkyl is optionally substituted with one or more Q substituents.

48. A compound according to any one of claims 1 to 47, wherein R 1 It is a single ring C 3-10 Cycloalkyl is optionally substituted with one, two or three Q substituents.

49. according to the compound described in any one of claims 1-46, wherein said R 1 is isopropyl, cyclopentyl or cyclohexyl.

50. A compound according to any one of claims 1-49, wherein R 1 It is cyclopentyl.

51. A compound according to any one of claims 1-50, wherein R 2 is (i) a halogen; (ii) C 1-6 Alkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-OR 1a or -NR 1b R 1c .

52. according to the compound described in any one of claims 1-51, wherein said R 2 Yes-C(O)R 1a .

53. according to the compound described in any one of claims 1-52, wherein said R 2 Yes-C(O)-C 1-6 Alkyl is optionally substituted with one or more substituents Q.

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

55. according to the compound described in any one of claims 1-54, wherein said R 2 It's acetyl.

56. according to the compound described in any one of claims 1-55, wherein said R 3 is hydrogen or C 1-6 Alkyl is optionally substituted with one or more substituents Q.

57. according to the compound described in any one of claims 1-56, wherein said R 3 It's methyl.

58. according to the compound described in any one of claims 1-57, wherein said R 4 It's hydrogen.

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

60. A compound according to any one of claims 1-59, wherein R 5 Is halogen or C 1-6 Alkyl is optionally substituted with one, two or three Q substituents.

61. according to the compound described in any one of claims 1-60, wherein R 5 is fluorine, chlorine, methyl or ethyl.

62. The compound of any one of claims 1-58, wherein m is an integer of 0.

63. according to the compound described in any one of claims 1-62, wherein said R 6 is hydrogen or C 1-6 Alkyl is optionally substituted with one, two or three Q substituents.

64. according to the compound described in any one of claims 1-63, wherein said R 6 It's hydrogen.

65. according to the compound described in any one of claims 1-63, wherein said R 6 It's methyl.

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

67. The compound according to claim 1, wherein the compound is: 2-Hydroxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-piperazine-1-sulfonamide A5; (S)-N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-2-aminopropanamide A6; (R)-6-acetyl-8-cyclopentyl-2-((5-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)-piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A7; 2-methoxyethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A8; Ethyl 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetate A9; Ethyl 2-(((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetate A10; 2-((((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamoyl)oxy)acetic acid A11; 3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A13; (S)-2-(2-amino-3-methylbutyramido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A14; 2-Acetylaminoethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[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-dihydropyrido[2,3-d]pyrimidin)-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A16; (S)-2-(2-amino-4-methylpentanamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A17; (S)-2-(2-amino-3-hydroxypropionamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A18; (S)-2-(2-amino-4-(methylthio)butanamido)ethyl ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-sulfonyl)carbamate A19; 2-(2-aminoacetamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl))amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)carbamate A20; (R)-2-(Pyrrolidine-2-carboxamido)ethyl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)-carbamate A21; Tetrahydro-2H-pyran-4-yl((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-pyrido[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-pyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino))pyridin-3-yl)piperazin-1-yl)sulfonyl)pyrrolidine-2-carboxamide A33; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)propanamide A35; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)butanamide A37; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclopropanecarboxamide A38; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydrofuran-2-carboxamide A39; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide A40; N-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)cyclobutanecarboxamide A41; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)piperazine-1-sulfonamide A42; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-methoxyethyl)piperazine-1-sulfonamide A43; ((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[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-dihydropyrido[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-dihydropyrido[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-ethylpiperazine-1-sulfonamide A47; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-isopropylpiperazine-1-sulfonamide A48; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-propylpiperazine-1-sulfonamide A49; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-dimethylpiperazine-1-sulfonamide A50; 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(4-(morpholinosulfonyl)piperazin-1-yl)-pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one A51; 6-acetyl-8-cyclopentyl-2-((5-(4-((3-hydroxyazetidin-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A52; 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N,N-bis(2-hydroxyethyl)piperazine-1-sulfonamide A53; 2-Hydroxyethyl (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 A54; 2-((R)-2-amino-3-methylbutanamido)ethyl(((S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridinyl)[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-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)-N-(isopropylcarbamoyl)piperazine-1-sulfonamide A56; 6-acetyl-2-((5-(4-((2-amino-1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A57; 2-((5-(4-((1H-imidazol-1-yl)sulfonyl)piperazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one A58; (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)methyl pivalate B1; p-Tolyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B2; Methyl (((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)sulfonyl)oxy)benzoate B3; Cyclopentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-sulfonate B4; 6-Acetyl-8-cyclopentyl-2-[[5-(4-isopropylsulfonylpiperazin-1-yl)-2-pyridinyl]-amino]-5-methylpyrido[2,3-d]pyrimidin-7-one C1; or 6-acetyl-8-cyclopentyl-2-((5-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-2-yl)-amino)-5-methylpyrido[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 pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

68. A pharmaceutical composition comprising a compound of any one of claims 1-67, 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 pharmaceutically acceptable salt, solvate or hydrate thereof; and a pharmaceutically acceptable excipient.

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

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

71. The method of claim 70, wherein the disorder, disease or condition is a gastrointestinal side effect induced by chemotherapy.

72. A method for preventing or alleviating gastrointestinal side effects caused by chemotherapy 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 claim 71 or 72, wherein the chemotherapy-induced gastrointestinal side effects are caused by camptothecin or fluorouracil.

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

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

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

77. A method of inhibiting CDK activity, comprising contacting CDK with an effective amount of a compound of any one of claims 1-67 or a pharmaceutical composition of claim 68 or 69.

Images