Rifabutin analogues for the treatment of diseases

Abstract

The present disclosure relates to compounds and pharmaceutical compositions comprising the same for treating, ameliorating and / or preventing disease. In some embodiments, the disease is bacterial infection. In some embodiments, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria genus, preferably M. abscessus.

Description

[Technical Field]

[0001] The present disclosure relates to compounds and pharmaceutical compositions comprising the same for the treatment, amelioration, and / or prevention of diseases. In some embodiments, the disease is a bacterial infection, preferably caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or the genus Nontuberculous Mycobacteria (NTM), preferably M. abscessus. [Background technology]

[0002] Rifamycins, such as rifabutin, are effective against Clostridium species, Enterococcus species, Haemophilus species, Legionella species, Mycobacterium species (tuberculous and nontuberculous mycobacteria), Neisseria species, Staphylococcus species, Streptococcus species, Listeria monocytogenes, Moraxella catarrhalis, Bacillus species, Bacteroides species, Gardnerella vaginalis, and other bacterial and fungal infections. It is a known antibiotic active against a broad spectrum of pathogens, including Lactobacillus vaginalis, Lactobacillus species, Mobiluncus species, Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and Toxoplasma gondii (Kunin, Clin. Infect. Dis., 1996; Farr and Mandell, Med. Clin. North. Am., 1982; Thornsberry et al., Rev. Infect. Dis., 1983; Hoover et al., Diagn. Microbiol. Infect. Dis., 1993; Kerry et al., J. Antimicrob. Chemother., 1975).

[0003] Rifabutin has recently been shown to have potent in vitro and in vivo activity against Mycobacterium abscessus (Aziz et al., Antimicrob. Agents Chemother., 2017; Dick et al., Antimicrob. Agents Chemother., 2020) and Acinetobacter baumannii (Luna et al., Nat. Microbiol., 2020; Trebosc et al., Drug Discov. Today, 2021; Trebosc et al., J. Antimicrob. Chemother., 2020). However, A. baumannii can exhibit reduced susceptibility to rifabutin through mechanisms such as mutations in the RNA polymerase β-subunit (RpoB) gene or expression of the ADP-ribosyltransferase (Arr) enzyme (Trebosc et al., J. Antimicrob. Chemother., 2020). The Arr enzyme ribosylates rifabutin at the C23 carbon, and mutations in the RpoB subunit limit the ability of rifabutin to interact with and inhibit the RpoB subunit. Furthermore, M. abscessus endogenously encodes a gene encoding the Arr enzyme, which makes it naturally less susceptible to treatment with rifabutin (Schaffle et al., Antimicrob. Agents Chemother., 2021). Thus, there is a need for more effective rifamycins for the treatment of bacterial infections such as M. abscessus and A. baumannii infections. Summary of the Invention

[0004] In one aspect, the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or enantiomer thereof: [ka] (In the formula, Y 1 (CR 1 R 2 ) n wherein n is an integer from 1 to 6, and R 1 and R 2 is independently, at each occurrence, selected from the group consisting of hydrogen, —C1-C6 alkyl, and —C1-C6 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, wherein each cycloalkyl is optionally further substituted with one or more halogens; X 1 -OR 11 , or -NR 51 R 52 and R 11 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 12A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 and R 12A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 20A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or -S(O)2NR 18 R 19 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 20 and optionally substituted by R 16 and R 16A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 20A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 17 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 18 R 19 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 20 and optionally substituted by R 17 , R 18 and R 19are each independently hydrogen, halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 23A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or S(O)2NR 21 R 22 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 23 and optionally substituted by R 20 and R 20A are each independently halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 23A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -S(O)2(C1-C6 alkyl), or S(O)2NR 21 R 22 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 23 and optionally substituted by R 21 and R 22 are each independently hydrogen or -C1-C6 alkyl; R 23 and R 23A are each independently -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, or cyano; R 51 and R 52are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 and R 53A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -CO2R 58 , -S(O)2(C1-C6 alkyl), -S(O)2(C6-C 10 aryl), or -S(O)NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 57 and R 57A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64 , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or S(O)2NR 62 R 63 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 61 and R 61A are each independently halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -S(O)2(C1-C6 alkyl), or S(O)2NR 62 R 63 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 62 and R 63 are each independently hydrogen and -C1-C6 alkyl; R 64 and R 64A are each independently -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, halogen, or cyano.

[0005] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein (preferably a compound of Formula I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some preferred embodiments, the pharmaceutical composition is effective for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or nontuberculous Mycobacteria, preferably M. abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0006] In one aspect, the present disclosure provides a compound described herein (preferably a compound of Formula I) or a pharmaceutically acceptable salt thereof for use in a method for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or nontuberculous Mycobacteria, preferably M. abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0007] In one aspect, the present disclosure provides use of a compound described herein (preferably a compound of Formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, in the manufacture of a medicament for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or nontuberculous Mycobacteria, preferably M. abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0008] In one aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (preferably a compound of Formula I) or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or nontuberculous Mycobacteria, preferably M. abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0009] The present disclosure provides C25 acetate-modified rifabutin analogs and pharmaceutical compositions thereof. The compounds of the present invention exhibit broad antibacterial activity against a wide range of bacterial species, thus maintaining the broad antibacterial activity characteristic of the rifamycin class of antibiotics. Furthermore, the compounds exhibited unexpectedly enhanced activity against various strains of M. abscessus and A. baumannii compared to currently available antibiotics, including rifabutin and rifamycins such as rifampicin. In preferred embodiments, the compounds of the present invention are particularly active against strains harboring resistance mutations that render them resistant to current antibiotics. In preferred embodiments, the resistance mechanism is a mutation in the RpoB gene and / or expression of the Arr enzyme. Additional features and advantages of the present technology will be apparent to those skilled in the art upon reading the detailed description below. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure provides analogs of rifabutin that are effective in treating bacterial infections, preferably bacterial infections caused by one or more bacteria belonging to the nontuberculous Mycobacteria genus, preferably M. abscessus.

[0011] Details of the present technology are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present technology, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0013] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0014] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0015] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bound to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be bound at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have additional functional groups.

[0016] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. 10An aryl group contains 6 to 10 carbon atoms. When it contains two aromatic rings (such as a bicyclic ring), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or may be fused (e.g., naphthyl). The aryl group may be substituted at any point with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-Ci-C alkyl, -Ci-C alkyl, -O-Ci-C alkenyl, -O-Ci-C alkynyl, -Ci-C alkenyl, -Ci-C alkynyl, -OH, -O-P(O)(OH), -OC(O)Ci-C alkyl, -C(O)Ci-C alkyl, -OC(O)O-C ​​alkyl, -NH, -NH(Ci-C alkyl), -N(Ci-C alkyl), -S(O)-Ci-C alkyl, -S(O)NHCi-C alkyl, and -S(O)N(Ci-C alkyl). The substituents themselves may be substituted. Furthermore, when containing two fused rings, an aryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0017] Unless otherwise specifically defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, or a polycyclic aromatic radical containing one or more ring heteroatoms selected from N, S, P, and O, with the remaining ring atoms being C. 5- to 15-membered heteroaryl groups contain 5 to 15 atoms, while 5- to 10-membered heteroaryl groups contain 5 to 10 atoms. Heteroaryl, as defined herein, also refers to a bicyclic heteroaromatic group in which the heteroatoms are selected from N, S, P, and O, preferably N, S, and O, more preferably N and O. The aromatic radical may be independently substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, Triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiamine Azolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl nyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl These include pyridinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.

[0018] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. A -C1-C6 alkyl group contains 1 to 6 carbon atoms. Examples of -C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, and tert-butyl, isopentyl, and neopentyl.

[0019] The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight-chained or branched. A -C2-C6 alkenyl group is an alkenyl group containing 2 to 6 carbon atoms. Some alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. As used herein, the term "alkenyl" includes groups containing a carbon-carbon double bond anywhere within the carbon chain.

[0020] The term "alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and may be straight-chained or branched. A -C2-C6 alkynyl group is an alkynyl group containing 2 to 6 carbon atoms. Some alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. As used herein, the term "alkynyl" includes groups containing a carbon-carbon triple bond anywhere within the carbon chain.

[0021] The term "alkylene" or "alkylenyl," as used herein, refers to a biradical of a straight or branched hydrocarbon chain derived from an alkyl, as defined herein, where one hydrogen of the alkyl is cleaved to produce a second radical of the alkylene. Examples of alkylene include, by way of illustration, CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-CH-, or -CH(CHCH)-.

[0022] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. -C3-C6 cycloalkyl contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. -C3-C8 cycloalkyl is a cycloalkyl group containing 3 to 8 carbon atoms. Cycloalkyl groups can be fused (e.g., decalin) or bridged (e.g., norbornane).

[0023] The term "cycloalkenyl" refers to a monocyclic non-aromatic unsaturated carbocyclic ring containing 5 to 18 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. -C5-C8 cycloalkenyl is a cycloalkenyl group containing 5 to 8 carbon atoms.

[0024] The terms "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refer to a monocyclic or polycyclic 3- to 24-membered ring system containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur (preferably oxygen and nitrogen), where at least one ring does not contain delocalized π-electrons shared among the ring carbons or heteroatoms (aromaticity). 3- to 15-membered heterocycloalkyl groups contain 3- to 15-membered atoms, and 3- to 10-membered heterocycloalkyl groups contain 3- to 10-membered atoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.

[0025] Heterocyclyl or heterocycloalkyl rings can also be fused or bridged, for example, bicyclic or tricyclic rings. Furthermore, when containing two or more fused rings, heterocycloalkyl groups as defined herein can have an unsaturated or partially saturated ring fused to an aromatic or heteroaromatic ring or fused aromatic or heteroaromatic ring system. Exemplary ring systems of such heterocycle-aryl or heterocycle-heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0026] Heterocyclyl ring or heterocycloalkyl ring can also be spirocyclic heterocycle or spiro heterocycle.As used herein, spirocyclic heterocycle or spiro heterocycle is understood to mean a bicyclic or polycyclic ring system, in which at least two rings are bonded via a single atom, and at least one of the rings is a heterocycle (for example, at least one of the rings is furanyl, morpholinyl or piperazinyl).One or both rings of spiro heterocycle can be fused with one or more additional carbocyclic rings, heterocyclic rings, aromatic rings or heteroaromatic rings, for example, to form a tricyclic ring system, in which two of the rings are bonded via a single atom.

[0027] As used herein, the term "halo" or "halogen" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0028] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluoro, chloro, bromo, and iodo, each of which is preferably a fluoro atom. It is understood that the maximum number of halogen atoms is limited by the number of available bonding sites and, therefore, depends on the number of carbon atoms comprising the alkyl portion of the haloalkyl group. "Haloalkyl" can refer to, for example, CF, CHF, CHF, CFCH, CHCF, CHCHF, CHCFCH, CHCFCF, or CH(CF). Highly preferred "haloalkyl" substituents on compounds of the invention are CF, CHF, and CHCF, with CF and CHF being even more preferred.

[0029] The term "carbonyl" refers to a functional group consisting of a carbon atom double-bonded to an oxygen atom, which may be abbreviated herein as "oxo," C(O), or C=O.

[0030] As used herein, "C1-C6-alkoxy" refers to a "substituted hydroxyl" of the formula (-OR'), where R' is an optionally substituted -C1-C6 alkyl as defined herein, and the oxygen moiety is directly attached to the parent molecule; thus, the term "C1-C6 alkoxy" as used herein refers to a straight-chain or branched -C1-C6 alkoxy, which can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight-chain or branched pentoxy, straight-chain or branched hexyloxy. -C1-C4 alkoxy and -C1-C3 alkoxy are preferred.

[0031] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, hydroxybenzoate ... Salts include phosphate, setionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0032] The term "stereoisomers" refers to a series of compounds that have the same number and kinds of atoms and share the same bond connectivity between those atoms, but differ in three-dimensional structure. The term "stereoisomer" refers to any member of this series of compounds.

[0033] The term "diastereomer" refers to a series of stereoisomers that are not superimposable by rotation about a single bond. For example, compounds containing cis- and trans-double bonds, endo- and exo-substitution on a bicyclic ring system, and multiple stereocenters with different relative configurations are considered diastereomers. The term "diastereomer" refers to any member of this series of compounds. In some examples presented, synthetic routes may produce a single diastereomer or a mixture of diastereomers. In some cases, these diastereomers are separated, and in other cases, wavy bonds are used to indicate structural elements with variable configurations.

[0034] The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to a single member of the pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0035] The term "tautomer" refers to a series of compounds that have the same number and type of atoms but differ in bond connectivity and are in equilibrium with each other. A "tautomer" is a single member of this series of compounds. Typically, a single tautomer is depicted, but it is understood that this single structure is meant to represent all possible tautomers that may exist. An example includes enol-ketone tautomerism. When a ketone is depicted, it is understood that both the enol form and the ketone form are part of this disclosure.

[0036] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease of interest as described herein.

[0037] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0038] The term "treating," with respect to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0039] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0040] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or composition directly to a subject, or administering to a subject a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt of the compound or composition, which is capable of forming an equivalent amount of the active compound in the subject's body.

[0041] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of this disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which water is the solvent molecule is typically called a "hydrate." Hydrates include compositions containing stoichiometric amounts of water and compositions containing variable amounts of water.

[0042] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0043] As used herein, "Arr" enzyme refers to an ADP-ribosyltransferase enzyme. In a preferred embodiment, the Arr enzyme ribosylates rifamycin and rifamycin derivatives at the C23 carbon. In some embodiments, the compounds of Formula I can be used to treat bacterial infections caused by bacteria that express or overexpress Arr.

[0044] As used herein, "RpoB" refers to an RNA polymerase β-subunit, preferably a bacterial RNA polymerase β-subunit. In some embodiments, the compounds of Formula I can be used to treat bacterial infections caused by bacteria with resistance mutations in the RpoB gene.

[0045] Compounds of the Invention In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or enantiomer thereof: [ka] (In the formula, Y 1 (CR 1 R 2 ) n wherein n is an integer from 1 to 6, and R 1 and R 2 is independently, at each occurrence, selected from the group consisting of hydrogen, —C1-C6 alkyl, and —C1-C6 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, wherein each cycloalkyl is optionally further substituted with one or more halogens; X 1 -OR 11 , or -NR 51 R 52 and R 11 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 12A, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 and R 12A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 20A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or -S(O)2NR 18 R 19and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 20 and optionally substituted by R 16 and R 16A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 20A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 17 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 18 R 19 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 20 and optionally substituted by R 17 , R 18 and R 19 are each independently hydrogen, halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 23A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or S(O)2NR 21 R 22 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 23 and optionally substituted by R 20 and R 20Aare each independently halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 23A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -S(O)2(C1-C6 alkyl), or S(O)2NR 21 R 22 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 23 and optionally substituted by R 21 and R 22 are each independently hydrogen or -C1-C6 alkyl; R 23 and R 23A are each independently -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, or cyano; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53and optionally substituted by R 53 and R 53A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -CO2R 58 , -S(O)2(C1-C6 alkyl), -S(O)2(C6-C 10 aryl), or -S(O)NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 57 and R 57A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64 , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -S(O)2(C1-C6 alkyl), or S(O)2NR 62 R 63 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 61 and R 61A are each independently halogen, -OH, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -S(O)2(C1-C6 alkyl), or S(O)2NR 62 R 63 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 62 and R 63 are each independently hydrogen and -C1-C6 alkyl; R 64 and R 64A are each independently -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, halogen, or cyano.

[0046] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer from 1 to 5, and R 1 and R 2 is independently, at each occurrence, selected from hydrogen, —C1-C4 alkyl, and —C1-C4 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, and each cycloalkyl is optionally further substituted with one or more halogens.

[0047] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer from 1 to 4, and R 1 and R 2 is independently, at each occurrence, selected from hydrogen, —C1-C4 alkyl, and —C1-C4 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, and each cycloalkyl is optionally further substituted with one or more halogens.

[0048] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer of 1 to 3, and R 1 and R 2 is independently, at each occurrence, selected from hydrogen, —C1-C4 alkyl, and —C1-C4 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, and each cycloalkyl is optionally further substituted with one or more halogens.

[0049] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer of 1 to 3, and R 1 and R 2 is independently, at each occurrence, selected from hydrogen, —C1-C2 alkyl, and —C1-C2 alkoxy, wherein each alkyl is optionally substituted by one or more fluorine, chlorine, or —C3-C6 cycloalkyl, and each cycloalkyl is optionally further substituted by one or more fluorine or chlorine.

[0050] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer of 1 to 3, and R 1 and R 2 is independently, at each occurrence, selected from hydrogen, and —C1-C2 alkyl, where each alkyl is optionally substituted by one or more fluorine, chlorine, or —C3-C6 cycloalkyl, and each cycloalkyl is optionally further substituted by one or more fluorine or chlorine.

[0051] In some embodiments, Y 1 (CR 1 R 2 ) nwherein n is an integer of 1 to 3, and R 1 and R 2 is independently at each occurrence selected from hydrogen, and —C1-C2 alkyl, where each alkyl is optionally substituted with one —C3-C6 cycloalkyl, where the cycloalkyl is optionally substituted with one to three, preferably one or two, halogens selected from fluorine and chlorine, or where each alkyl is optionally substituted with one to three, preferably one or two, halogens selected from fluorine and chlorine.

[0052] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer of 1 to 3, and R 1 and R 2 is independently at each occurrence selected from -H, methyl, and ethyl, wherein each methyl and ethyl may be substituted by one or more fluorines or chlorines.

[0053] In some embodiments, Y 1 (CR 1 R 2 ) n wherein n is an integer of 1 to 3, and R 1 and R 2 is independently at each occurrence selected from -H, methyl, and ethyl.

[0054] In some embodiments, the compound is of formula IA: [ka] During the ceremony, X 1 is as defined in Formula I above, or in subsequent embodiments herein; m is an integer of 0 to 4, preferably 0 to 3, and more preferably 0 to 2; R 3is selected from -H and -C1-C6 alkyl, preferably -H and -C1-C3 alkyl, more preferably -H, methyl, and ethyl.

[0055] In one embodiment, m is an integer from 0 to 3, preferably m is an integer from 0 to 2, and R 3 is selected from -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, and even more preferably methyl. In one embodiment, m is an integer from 0 to 3, preferably m is an integer from 0 to 2, and R 3 is hydrogen.

[0056] In some embodiments, the compound is of formula IB, formula IC, formula ID, formula IE, formula IF, or formula IG: [ka] In the formula, X 1 is as defined for formula I.

[0057] In some preferred embodiments of any of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, or Formula IG, R 11 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 12A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 and R 12A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C6 alkyl; R 16 and R 16A are each independently -C1-C6 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 and R 53A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 57 and R 57A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, or -C1-C6 haloalkyl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 61 , R 61A , R 64 and R 64A are each independently -OH, halogen, -CN, -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, or phenyl.

[0058] In some embodiments, R 11 are independently -C1-C6 alkylene-R 12A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10aryl, or 5- to 10-membered heteroaryl, and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 and R 12A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C6 alkyl; R 16 and R 16A are each independently -C1-C6 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 and R 53A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R57 and R 57A are each independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, or -C1-C6 haloalkyl, and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 61 , R 61A , R 64 and R 64A are each independently -C1-C6 alkyl or phenyl.

[0059] In one embodiment, R 11 are independently -C1-C6 alkylene-R 12A, -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 16 and optionally substituted by R 12A are independently -C1-C6 alkylene-R 16A , -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl; R 16 and R 16Aare each independently -C1-C4 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 53A are independently -C1-C6 alkylene-R 57A , -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-10 membered heterocycloalkyl, -C6-C 10Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3-8 membered heterocycloalkyl, -C6-C 10 Aryl, 5-6 membered heteroaryl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 57Aare independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, -C6-C 10 aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, or -C1-C6 haloalkyl, and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 64 and optionally substituted by R 61 , R 61A , R 64 and R 64A are each independently -C1-C6 alkyl or phenyl.

[0060] In some embodiments, R 11 are independently -C1-C6 alkylene-R 12A, -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 16 and optionally substituted by R 12A are independently -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, cycloalkenyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl; R 16 and R 16A are each independently -C1-C4 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A, -C5-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, phenyl, or heteroaryl may be selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C3-C6 cycloalkyl, -C5-C6 cycloalkenyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy may be selected from one or more R 57 and optionally substituted by R 53A are independently -C1-C6 alkylene-R 57A , -C5-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C4 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 54, R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -C6-C 10 Aryl, 5-6 membered heteroaryl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 57A are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 64A , -C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C2 alkoxy, or -C1-C2 haloalkyl, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy may be selected from the group consisting of one or more R 64 and optionally substituted by R 61 , R 61A , R 64 and R 64A are each independently -C1-C6 alkyl or phenyl.

[0061] In one embodiment, R 11 are independently -C1-C6 alkylene-R 12A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each alkylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 16A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 16 and optionally substituted by R 12Aare independently -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl; R 16 and R 16A are each independently -C1-C4 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may be selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C1-C6 alkylene-R 57A , -C5-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C4 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 57A are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, —C1-C6 alkyl, —C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, —C1-C2 alkoxy, or —C1-C2 haloalkyl, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy may be selected from the group consisting of one or more R 64 and optionally substituted by R 61 , R 61A , R 64 and R 64A are each independently -C1-C6 alkyl or phenyl.

[0062] In some embodiments, R 11 are independently -C1-C6 alkylene-R 12A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may be selected from the group consisting of one or more R 12 and optionally substituted by R 12are independently -C1-C6 alkyl, -C1 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and R 12A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl; R 16 is -C1-C4 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, preferably R 51 and R 52 at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A, -C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C1-C6 alkylene-R 57A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C4 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A, -C3-C6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 57A are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, —C1-C6 alkyl, —C3-C6 cycloalkyl, or phenyl, and each alkyl, cycloalkyl, and phenyl is selected from the group consisting of one or more R 64 and optionally substituted by R 61 , R 61A and R 64 are each independently -C1-C6 alkyl or phenyl.

[0063] In one embodiment, R 11 are independently -C1-C6 alkylene-R 12A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, and each alkylene, cycloalkyl, heterocycloalkyl, or phenyl may be selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C6 alkyl, -C1 haloalkyl, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and R 12A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl; R 16 is -C1-C4 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A, -C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or phenyl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C1-C6 alkylene-R 57A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C4 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkoxy is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C3-C6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R.59 R 60 , -S(O)2(C1-C6 alkyl), or -S(O)2NR 59 R 60 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 57A are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1-C2 alkoxy, -C1-C2 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, and alkoxy is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, —C1-C6 alkyl, —C3-C6 cycloalkyl, or phenyl, and each alkyl, cycloalkyl, and phenyl is selected from the group consisting of one or more R 64 and optionally substituted by R 61 , R 61A and R 64 are each independently -C1-C6 alkyl or phenyl.

[0064] In some embodiments, R 11 are independently -C1-C6 alkylene-R 12A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, and each alkylene, cycloalkyl, heterocycloalkyl, or phenyl may be selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -OR 13, -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or phenyl, -C1 alkoxy, -C1 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C1-C4 alkylene-R57A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1-C4 alkoxy, -C1 haloalkyl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkylene, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1 haloalkyl, -CO2R 58 , -S(O)2(C6-C 10 aryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl may be selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, -C1-C2 alkylene-R 61A , -C1 alkoxy, -C1 haloalkyl, halogen, cyano, oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C2 alkyl), or -S(O)2NR 59 R 60 and each alkyl and alkylene is selected from one or more R 61 and optionally substituted by R 57A are independently -C1-C6 alkyl, -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1 alkoxy, -C1 haloalkyl, -OR 58 , N.R. 59 R 60 and each alkyl, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R58 , R 59 and R 60 are each independently hydrogen, -C1-C4 alkyl, and phenyl, and each alkyl and phenyl is selected from one or more R 64 and optionally substituted by R 64 are independently -C1-C6 alkyl; R 61 and R 61A are each independently -C1-C6 alkyl or phenyl.

[0065] In one embodiment, R 11 are independently -C1-C6 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene and heterocycloalkyl being selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or phenyl, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1-C4 alkoxy, oxo, -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -CO2R 58 , -S(O)2(phenyl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl may be selected from one or more R 61 and optionally substituted by R 57are independently -C1-C6 alkyl, -C1-C2 alkylene-R 61A , oxo, -OR 58 , N.R. 59 R 60 , -S(O)2(C1-C2 alkyl), or -S(O)2NR 59 R 60 and each alkyl and alkylene is selected from one or more R 61 and optionally substituted by R 57A are independently -C1-C4 alkyl, -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -C1 alkoxy, -C1 haloalkyl, -OR 58 , N.R. 59 R 60 and each alkyl, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen, -C1-C4 alkyl, and phenyl, and each alkyl and phenyl is selected from one or more R 64 and optionally substituted by R 64 are independently -C1-C6 alkyl; R 61 and R 61A are each independently -C1-C4 alkyl or phenyl.

[0066] In some embodiments, R 11 are independently -C1-C4 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene or heterocycloalkyl being selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -OR 13 , -CO2R 13, or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16 and optionally substituted by R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C1-C6 alkylene-R 57A , -C3-C6 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -C1-C4 alkoxy, oxo, -CO2R 54, or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 61A , phenyl, -CO2R 58 , -S(O)2(phenyl), and each alkyl, alkylene, and phenyl is selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C6 alkyl, oxo, NR 59 R 60 , -S(O)2(C1-C2 alkyl), or -S(O)2NR 59 R 60 and each alkyl and alkylene is selected from one or more R 61 and optionally substituted by R 57A are independently -C1-C4 alkyl, -C5-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -OR 58 , N.R. 59 R 60 and each alkyl, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen and -C1-C2 alkyl; R 61 and R 61A are each independently -C1-C2 alkyl, or phenyl.

[0067] In one embodiment, R 11 are independently -C1-C4 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene or heterocycloalkyl being selected from one or more R12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16 wherein the 5- to 6-membered heterocycloalkyl does not contain heteroatoms other than O and N, preferably the 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and still more preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine; R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C4 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C4 alkyl, -C1-C4 alkylene-R 57A, -C5C6 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -C1-C4 alkoxy, -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-R 61A , phenyl, -CO2R 58 , -S(O)2(phenyl), wherein the phenyl is selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C4 alkyl, oxo, NR 59 R 60 , -S(O)2(C1-C2 alkyl), or -S(O)2NR 59 R 60 and R 57A are independently -C1-C4 alkyl, -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, and phenyl, and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen or -C1-C2 alkyl; R 61are independently -C1-C2 alkyl; R 61A is independently phenyl.

[0068] In one embodiment, R 11 are independently -C1-C4 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene or heterocycloalkyl being selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16 wherein the 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and still more preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine; R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 53 or R 51 and R52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C4 alkyl, -C1-C3 alkylene-R 57A , -C5-C6 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -C1-C2 alkoxy, -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C2 alkyl, -C1-C2 alkylene-R 61A , phenyl, -CO2R 58 , -S(O)2(phenyl), wherein the phenyl is selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C2 alkyl, oxo, NR 59 R 60 , or -S(O)NR 59 R 60 and R 57A are independently -C1-C2 alkyl, -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, and phenyl, and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen or -C1-C2 alkyl; R 61 are independently -C1-C2 alkyl; R 61A are independently phenyl; The 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and still more preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine.

[0069] In one embodiment, R 11 are independently -C1-C4 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene or heterocycloalkyl being selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16 wherein the 5- to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and N, preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine; R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51and R 52 are each independently hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C4 alkyl, -C1-C3 alkylene-R 57A , -C5-C6 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -C1-C2 alkoxy, -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C2 alkyl, -C1-C2 alkylene-R 61A , phenyl, -CO2R 58 , -S(O)2(phenyl), wherein the phenyl is selected from one or more R 61and optionally substituted by R 57 are independently -C1-C2 alkyl, oxo, NR 59 R 60 , or -S(O)NR 59 R 60 and R 57A are independently -C1-C2 alkyl, 5- to 6-membered heterocycloalkyl, and each heterocycloalkyl is selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen or -C1-C2 alkyl; R 61 are independently -C1-C2 alkyl; R 61A are independently phenyl; The 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and still more preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine.

[0070] In one embodiment, R 11 are independently -C1-C4 alkylene-R 12A or 5-6 membered heterocycloalkyl, each alkylene or heterocycloalkyl being selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C2 alkyl; R 12A are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more R 16wherein the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine, preferably the 5- to 6-membered heterocycloalkyl is pyrrolidine; R 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl; R 16 is -C1-C2 alkyl, R 51 and R 52 are each independently hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-R 53A , -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of is hydrogen, and each cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 and optionally substituted by R 53 are independently -C1-C4 alkyl, -C1-C3 alkylene-R 57A , -C5-C6 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 53A are independently -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, -C1-C2 alkoxy, -CO2R 54 , or -NR 55 R56 and each cycloalkyl, heterocycloalkyl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C2 alkyl, -C1-C2 alkylene-R 61A , phenyl, -CO2R 58 , -S(O)2(phenyl), wherein the phenyl is selected from one or more R 61 and optionally substituted by R 57 are independently -C1-C2 alkyl, oxo, NR 59 R 60 , or -S(O)NR 59 R 60 and R 57A are independently -C1-C2 alkyl, 5- to 6-membered heterocycloalkyl, and each heterocycloalkyl is selected from one or more R 61 and optionally substituted by R 58 , R 59 and R 60 are each independently hydrogen or -C1-C2 alkyl; R 61 are independently -C1-C2 alkyl; R 61A are independently phenyl; The 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and still more preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine.

[0071] In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or enantiomer thereof: [ka] (In the formula, Y 1 (CR 1 R 2 ) n wherein n is an integer from 1 to 6, and R 1 and R 2 is independently, at each occurrence, selected from the group consisting of hydrogen, —C1-C6 alkyl, and —C1-C6 alkoxy, wherein each alkyl is optionally substituted with one or more halogens, or —C3-C6 cycloalkyl, wherein each cycloalkyl is optionally further substituted with one or more halogens; X 1 -OR 11 , or -NR 51 R 52 and R 11 are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5-10 membered heteroaryl, or -C1-C6 alkylene-5-10 membered heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be selected from one or more R 12 and optionally substituted by R 12 are independently -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and R 13 , R 14 and R 15 are each independently hydrogen, -C1-C6 alkyl, or -C6-C 10 is aryl, R 51 and R 52are each independently hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-5- to 10-membered heteroaryl; Each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 73 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 54 , -C(O)R 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 are independently hydrogen or -C1-C6 alkyl; R 55 and R 56are each independently hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 haloalkyl, -CO2C1-C6 alkyl, -S(O)2(C1-C6 alkyl), or -S(O)2(C6-C 10 aryl), each alkyl optionally substituted with one or more phenyl; R 57 is -C1-C6 alkyl, R 73 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; each alkylene may be optionally substituted by one or more oxo or -OH; each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one or more -C1-C6 alkyl, -C1-C6 haloalkyl, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, -OCH3, -OCH2CH2OH, -SONH2, phenyl, or oxo; R 75 and R 76 are each independently -H, -C1-C6 alkyl, -CO2C1-C6 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl, halogen -OC1-C6 alkyl, or -CN; R74 are independently -H, -C1-C6 alkyl, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C6 alkyls.

[0072] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 and each 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl or -C1-C6 alkylene-C6-C 10 is aryl, Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C6 alkylene-phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkylene-5- to 6-membered heterocycloalkyl, and the 5- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C6 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 73 and optionally substituted by R 73 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; each alkylene may be optionally substituted by one or more oxo or -OH; each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one or more -C1-C6 alkyl, -C1-C6 haloalkyl, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, -OCH3, -OCH2CH2OH, -SONH2, phenyl, or oxo; R 75 and R 76 are each independently -H, -C1-C6 alkyl, -CO2C1-C6 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl, halogen -OC1-C6 alkyl, or -CN; R 74 are independently -H, -C1-C6 alkyl, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C6 alkyls.

[0073] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 each 5- to 6-membered heterocycloalkyl contains no heteroatoms other than O and N, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52are each independently hydrogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl or -C1-C4 alkylene-C6-C 10 is aryl, Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C4 alkylene-phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl or -C1-C4 alkylene-5-6 membered heterocycloalkyl, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C4 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 73and optionally substituted by R 73 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; the -C1-C6 alkyl is optionally substituted by one or more -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl, -C1-C6 haloalkyl, phenyl, halogen, -OH, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C6 alkyl, —C1-C6 haloalkyl, or halogen; R 75 and R 76 are each independently -H, -C1-C6 alkyl, -CO2C1-C6 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl, halogen -OC1-C6 alkyl, or -CN; R 74 are independently -H, -C6-C 10aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C6 alkyls.

[0074] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 by, preferably exactly one R 12 each 5- to 6-membered heterocycloalkyl selected from pyrrolidine, piperidine, piperazine, and morpholine, and each 5- to 6-membered heterocycloalkyl optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C4 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C4 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C4 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or -C1-C4 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkylene-5-6-membered heterocycloalkyl, and the 5-6-membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C4 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 73 and optionally substituted by R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C4 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; the -C1-C4 alkyl is optionally substituted by one or more of -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C4 alkyl, -C1-C4 haloalkyl, phenyl, halogen, -OH, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C4 alkyl, —C1-C4 haloalkyl, or halogen; R 75 and R 76 are each independently -H, -C1-C4 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C4 alkyl, halogen-OC1-C4 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C4 alkyls.

[0075] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 73 and optionally substituted by R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C4 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C4 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C4 alkyl, -C1-C4 haloalkyl, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C4 alkyl, —C1-C4 haloalkyl, or halogen; R 75 and R 76are each independently -H, -C1-C4 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C4 alkyl, halogen-OC1-C4 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C4 alkyls.

[0076] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine, and morpholine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 73 and optionally substituted by R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -C1-C2 haloalkyl, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —C1-C2 haloalkyl, or halogen; R 75 and R 76 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen, -OC1-C2 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0077] In some embodiments, R 11is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine, and morpholine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine and morpholine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 1,4-membered heterocycloalkyl, the heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, the azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane optionally fused to one or more additional aryl or heteroaryl rings, or the heterocycloalkyl being attached by a single atom to another cycloalkyl or heterocycloalkyl to form a 10- to 15-membered spirocyclic heterocycle, or the heterocycle is piperidine which may contain a C2-bridged alkylene, the heterocycloalkyl being selected from one or more, preferably one or two, R 73 may be further substituted by R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 75 and R 76 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0078] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, and piperazine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine and piperazine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a 1,4-membered heterocycloalkyl, the heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, the azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane optionally fused to one or more additional aryl or heteroaryl rings, or the heterocycloalkyl being attached by a single atom to another cycloalkyl or heterocycloalkyl to form a 10- to 15-membered spirocyclic heterocycle, or the heterocycle is piperidine which may contain a C2-bridged alkylene, the heterocycloalkyl being selected from one or more, preferably one or two, R 73 wherein when the heterocycloalkyl is azetidine, the azetidine is substituted at the 3-position, and when the heterocycloalkyl is piperidine or piperazine, the piperidine or piperazine is substituted at the 4-position; R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 75 and R 76 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen, -OC1-C2 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0079] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 is hydrogen and R 52are independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, and piperazine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine and piperazine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a 1,4-membered heterocycloalkyl selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, wherein the azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane is optionally fused to one or more additional aryl or heteroaryl rings, or the heterocycloalkyl is attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, wherein the heterocycloalkyl is optionally joined to one or more, preferably one or two, R 73 wherein when the heterocycloalkyl is azetidine, the azetidine is substituted at the 3-position, and when the heterocycloalkyl is piperidine or piperazine, the piperidine or piperazine is substituted at the 4-position; R 73 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 75 and R 76 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0080] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl; R 51 is hydrogen and R 52are independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, and piperazine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine and piperazine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl; R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a membered heterocycloalkyl, said heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, said heterocycloalkyl being selected from one or more, preferably one or two, R 73 may be further substituted by R 73is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 75 R 76 , -OR 74 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 75 and R 76 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 74 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0081] In some embodiments, X1 HA-OR 11 is.

[0082] In some embodiments, the compound is of formula I-B1, formula I-C1, formula I-D1, formula I-E1, I-F1, or I-G1: [ka] In the formula, R 11 is as defined in Formula I.

[0083] In some embodiments of any of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, Formula IG, Formula I-A1, Formula I-B1, Formula I-C1, Formula I-D1, Formula I-E1, Formula I-F1, or Formula I-G1, R 11 is -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, and each alkyl, alkenyl, or alkynyl is selected from one or more, preferably one or two, and more preferably exactly one R 12 and preferably R 11 is -C1-C4 alkyl, -C2-C4 alkenyl, or -C2-C4 alkynyl, and each alkyl, alkenyl, or alkynyl is selected from one or more, preferably one or two, and more preferably exactly one R 12 and more preferably, R 11 is -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl, and each alkyl, alkenyl, or alkynyl is selected from one or more, preferably one or two, and more preferably exactly one R 12 and even more preferably, R 11 is -C1-C2 alkyl, -C2 alkenyl, or -C2 alkynyl, and each alkyl, alkenyl, or alkynyl is selected from one or more, preferably one or two, and more preferably exactly one R 12 may be substituted by

[0084] In some embodiments, R 11 is one or more, preferably one or two, more preferably exactly one R 12 and preferably, R 11 is one or more, preferably one or two, more preferably exactly one R 12 and more preferably, R 11 is one or more, preferably one or two, more preferably exactly one R 12 and even more preferably, R 11 is one or more, preferably one or two, more preferably exactly one R 12 is -C1-C2 alkyl optionally substituted by

[0085] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or 3- to 10-membered heterocycloalkyl, and each alkyl or heterocycloalkyl may be selected from one or more R 12 R may be substituted by 12 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R 16 may be substituted by

[0086] In some embodiments, R 11is —C1-C4 alkyl, preferably —C1-C3 alkyl, or 3- to 10-membered heterocycloalkyl, and each alkyl or heterocycloalkyl may be selected from one or more R 12 R may be substituted by 12 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, halogen, cyano, oxo, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or heteroaryl is selected from one or more, preferably one or two, preferably exactly one R 16 R may be substituted by 13 , R 14 and R 15 are each independently hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, or 5- to 10-membered heteroaryl, and each cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more, preferably one or two, and more preferably exactly one R 20 R may be substituted by 16 and R 20 are independently selected from -C1-C4 alkyl, halogen, cyano, -C1-C4 alkoxy, or -C1-C2 haloalkyl.

[0087] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or 3- to 6-membered heterocycloalkyl, and each alkyl may be selected from one or more R 12and each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, and R 12 are independently -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C1-C4 alkoxy, -C1-C4 haloalkyl, halogen, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each cycloalkyl, cycloalkenyl, heterocycloalkyl, phenyl or heteroaryl is selected from one or more, preferably one or two, preferably exactly one R 16 R may be substituted by 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl, and R 16 are independently selected from -C1-C4 alkyl, halogen, cyano, -C1-C4 alkoxy, or -C1-C2 haloalkyl.

[0088] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or 3- to 6-membered heterocycloalkyl, and each alkyl may be selected from one or more R 12 and each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, and R 12 are independently 3 to 6-membered heterocycloalkyl, phenyl, -OR 13 , -CO2R 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is selected from one or more, preferably one or two, preferably exactly one R 16 R may be substituted by 13 , R 14 and R 15 are each independently hydrogen or -C1-C4 alkyl, and R 16 is independently —C1-C4 alkyl.

[0089] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or 5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 and each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; and R 12 are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is present in exactly one R 16 R may be substituted by 13 , R 14 and R 15 are each independently hydrogen or -C1-C2 alkyl, and R 16 is independently -C1-C2 alkyl, preferably methyl.

[0090] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, containing 1 or 2 heteroatoms selected from N and O, or 5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 and each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; and R 12 are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is present in exactly one R 16 The heterocycloalkyl does not contain heteroatoms other than O and N, and preferably the 5- to 6-membered heterocycloalkyl contains 1 to 4 heteroatoms, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, and R 13 , R 14 and R15 are each independently -C1-C2 alkyl, and R 16 is independently -C1-C2 alkyl, preferably methyl.

[0091] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or a 5- to 6-membered heterocycloalkyl selected from piperidine, piperazine, and pyrrolidine, and each alkyl is selected from one or more R 12 and each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; and R 12 are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is present in exactly one R 16 wherein the heterocycloalkyl does not contain heteroatoms other than O and N, and preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperazine, or morpholine, and R 13 , R 14 and R 15 are each independently -C1-C2 alkyl, and R 16 is independently -C1-C2 alkyl, preferably methyl.

[0092] In some embodiments, R 11 is —C1-C4 alkyl, preferably —C1-C3 alkyl, or a heterocycle selected from piperidine and pyrrolidine, and each alkyl is selected from one or more R 12 and each piperidine or pyrrolidine is optionally substituted by one methyl, and R 12 are independently 5- to 6-membered heterocycloalkyl, phenyl, -COR 13 , or -NR 14 R 15 and each heterocycloalkyl or phenyl is present in exactly one R 16wherein the heterocycloalkyl does not contain heteroatoms other than O and N, preferably the 5- to 6-membered heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine or morpholine, more preferably the 5- to 6-membered heterocycle is selected from pyrrolidine and piperidine, and R 13 , R 14 and R 15 are each independently -C1-C2 alkyl, and R 16 is independently -C1-C2 alkyl, preferably methyl.

[0093] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 and each 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl.

[0094] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 each 5- to 6-membered heterocycloalkyl contains no heteroatoms other than O and N, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl.

[0095] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 by, preferably exactly one R 12 each 5- to 6-membered heterocycloalkyl selected from pyrrolidine, piperidine, piperazine, and morpholine, and each 5- to 6-membered heterocycloalkyl optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl.

[0096] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, and each alkyl is selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 is phenyl, -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14and R 15 are each independently -C1-C2 alkyl.

[0097] In some embodiments, R 11 is selected from -C1-C4 alkyl, 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-5- to 6-membered heterocycloalkyl, or -C1-C2 alkylene-phenyl, each alkyl being selected from one or more R 12 by, preferably exactly one R 12 wherein each 5- to 6-membered heterocycloalkyl is selected from pyrrolidine and piperidine, and each 5- to 6-membered heterocycloalkyl is optionally further substituted by one or more —C1-C2 alkyl; R 12 -CO2R 13 , and -NR 14 R 15 are independently selected from R 13 , R 14 and R 15 are each independently -C1-C2 alkyl.

[0098] In some embodiments, X 1 Ha-NR 51 NR 52 is.

[0099] In some embodiments, the compound is of formula I-B2, formula I-C2, formula I-D2, formula I-E2, formula I-F2, or formula I-G2: [ka] In the formula, R 51 and R 52 is as defined in Formula I.

[0100] In some embodiments of any of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, Formula IG, Formula I-A2, Formula I-B2, Formula I-C2, Formula I-D2, Formula I-E2, Formula I-F2, or Formula I-G2, R51 and R 52 are each independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, 3- to 10-membered heterocycloalkyl, or —C6-C 10 aryl, and each alkyl, heterocycloalkyl, or aryl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 may be substituted by

[0101] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, 3- to 10-membered heterocycloalkyl, or —C6-C 10 aryl, and each alkyl, heterocycloalkyl, or aryl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, -C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, halogen, cyano, oxo, -OR 54 , -CO2R 54 , or -NR 55R 56 and each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl may be selected from one or more R 57 may be substituted by

[0102] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, 3- to 10-membered heterocycloalkyl, or —C6-C 10 aryl, and each alkyl, heterocycloalkyl, or aryl is selected from one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R 57 may be substituted by

[0103] In some embodiments, R 51 is hydrogen or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R57 may be substituted by

[0104] In some embodiments, R 51 is hydrogen and R 52 are independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, 3- to 10-membered heterocycloalkyl, or phenyl, and each alkyl, heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, and the heterocycloalkyl or heteroaryl may be joined by one or more R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from one or more R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, —C1-C6 alkyl, or phenyl, and the —C1-C6 alkyl is selected from one or more R 61 or R 55 and R 56 can be combined to produce one or more R 57 R forms a 5- to 6-membered heterocycloalkyl optionally substituted by 57 -C1-C6 alkyl, oxo, -NR 59 R 60 or SO2NH2, and the -C1-C6 alkyl is selected from one or more R61 may be substituted by

[0105] In some embodiments, R 51 is hydrogen and R 52 are independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, 5- to 6-membered heterocycloalkyl, or phenyl, and each alkyl, heterocycloalkyl, or phenyl is selected from one or more, preferably one or two, and preferably exactly one R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl is selected from the group consisting of one or more, preferably one or two, and preferably exactly one R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from one or more, preferably one or two, and more preferably exactly one R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, or phenyl, and the -C1-C6 alkyl is selected from the group consisting of one or more R 61 or R 55 and R 56 can be combined to produce one or more R57 R forms a 5- to 6-membered heterocycloalkyl optionally substituted by 57 -C1-C6 alkyl, oxo, -NR 59 R 60 , SO2NH2, and the -C1-C6 alkyl is selected from one or more R 61 may be substituted by

[0106] In some embodiments, R 51 is hydrogen and R 52 are independently hydrogen, -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, 5- to 6-membered heterocycloalkyl containing 1 to 4 or less, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, or phenyl, and each alkyl, heterocycloalkyl, or phenyl is selected from one or more, preferably 1 or 2, preferably exactly one R 53 or R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 5-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 4 or less, preferably 1 to 3, and more preferably 1 or 2 heteroatoms selected from O and N, and has one or more, preferably 1 or 2, and preferably exactly one R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1 to 4 or less, preferably 1 to 3, more preferably 1 or 2 heteroatoms selected from O and N, phenyl, -OR 54 , -CO2R 54 , or -NR 55 R 56and each alkyl, cycloalkyl, heterocycloalkyl or phenyl is selected from one or more, preferably one or two, and more preferably exactly one R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, or phenyl, and the -C1-C6 alkyl is selected from the group consisting of one or more R 61 or R 55 and R 56 can be combined to produce one or more R 57 R forms a 5- to 6-membered heterocycloalkyl optionally substituted by 57 -C1-C6 alkyl, oxo, -NR 59 R 60 or SO2NH2, and the -C1-C6 alkyl is selected from one or more R 61 may be substituted by

[0107] In some embodiments, R 51 is hydrogen and R 52 are independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, piperidine, piperazine, morpholine, or phenyl, and each alkyl, piperidine, piperazine, morpholine, or phenyl is selected from one or more, preferably one or two, and preferably exactly one R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine, which piperidine, piperazine or morpholine has one or more, preferably one or two, preferably exactly one R 53 and optionally substituted by R 53are independently -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, cyclohexane, piperidine, piperazine, morpholine, phenyl, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each cyclohexane, piperidine, piperazine, morpholine or phenyl has one or more, preferably one or two, more preferably exactly one R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, or phenyl, or R 55 and R 56 combine to form a 5-6 membered heterocycloalkyl substituted by oxo and methyl, R 57 -C1-C6 alkyl, oxo, -NR 59 R 60 , SO2NH2, and the -C1-C6 alkyl is selected from one or more R 61 R may be substituted by 59 and R 60 are independently hydrogen or R 64 is —C1-C3 alkyl optionally substituted by R 61 is a 6-membered heterocycloalkyl, and R 62 is -C1-C3 alkyl, preferably -C1-C2 alkyl, preferably methyl, and R 64 is methyl or phenyl.

[0108] In some embodiments, R 51 is hydrogen and R 52are independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, piperidine, piperazine, morpholine, or phenyl, and each alkyl, piperidine, piperazine, morpholine, or phenyl is selected from one or more, preferably one or two, and preferably exactly one R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine, which piperidine, piperazine or morpholine has one or more, preferably one or two, preferably exactly one R 53 and optionally substituted by R 53 are independently -C1-C6 alkyl, preferably -C1-C4 alkyl, more preferably -C1-C3 alkyl, cyclohexane, piperidine, piperazine, morpholine, phenyl, -OR 54 , -CO2R 54 , or -NR 55 R 56 and each cyclohexane, piperidine, piperazine, morpholine, phenyl or heteroaryl has one or more, preferably one or two, more preferably exactly one R 57 and optionally substituted by R 54 , R 55 and R 56 are each independently hydrogen, —C1-C6 alkyl, preferably —C1-C4 alkyl, more preferably —C1-C3 alkyl, or phenyl, wherein the —C1-C6 alkyl is optionally substituted with one or more phenyl; R 57 -C1-C6 alkyl, oxo, -NR 59 R 60 , or SO2NH2.

[0109] In some embodiments, R 51 is hydrogen and R 52 is a 3- to 10-membered heterocycloalkyl.

[0110] In some embodiments, R 51 is hydrogen and R 52 is a 5-6 membered heterocycloalkyl optionally substituted by one or more, preferably one or two, preferably exactly one methyl.

[0111] In some embodiments, R 51 is hydrogen and R 52 is piperidine, piperazine or morpholine optionally substituted by one or more, preferably one or two, preferably exactly one methyl.

[0112] In some embodiments, R 51 is hydrogen and R 52 is optionally substituted -C3-C6 cycloalkyl, preferably optionally substituted -C5-C6 cycloalkyl.

[0113] In some embodiments, R 51 is hydrogen and R 52 is one or more, preferably one or two, preferably exactly one R 53 is a cyclohexane optionally substituted by R 53 is NR 55 R 56 and R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, preferably methyl, and each -C1-C6 alkyl may be substituted by phenyl.

[0114] In some embodiments, R 51 and R 52 are independently -C6-C 10 aryl, preferably R 51 and R 52 are each independently phenyl.

[0115] In some embodiments, R 51 and R52 are each independently hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, or -C1-C6 alkylene-C6-C 10 is aryl, Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C6 alkylene-phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C6 alkylene-5- to 6-membered heterocycloalkyl, which 5- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C6 alkylene-phenyl.

[0116] In some embodiments, R 51 and R 52 are each independently hydrogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, or -C1-C4 alkylene-C6-C 10 is aryl, Each alkyl and cycloalkyl may be one or more R 53and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C4 alkylene-phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, which 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C4 alkylene-phenyl.

[0117] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C4 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C4 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C4 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or -C1-C4 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C4 alkyl, or -C1-C4 alkylene-5-6-membered heterocycloalkyl, wherein the 5-6-membered heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl; R 53 are independently -OR 54, -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C4 alkyl, R 55 and R 56 are each independently -H, -C1-C4 alkyl, phenyl, or -C1-C4 alkylene-phenyl.

[0118] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl.

[0119] In some embodiments, R 51 and R52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine, and morpholine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl.

[0120] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine, and morpholine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from pyrrolidine, piperidine, piperazine and morpholine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl.

[0121] In some embodiments, R 51 and R 52 are each independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, and piperazine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine and piperazine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54 , -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl.

[0122] In some embodiments, R 51 is hydrogen and R 52 are independently hydrogen, —C1-C4 alkyl, —C5-C6 cycloalkyl, —C1-C3 alkylene-C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, —C1-C3 alkylene-5- to 6-membered heterocycloalkyl, —C6 aryl, or —C1-C3 alkylene-C6 aryl; Each alkyl and cycloalkyl may be one or more R 53 and optionally substituted by each heterocycloalkyl is selected from pyrrolidine, piperidine, and piperazine, and each heterocycle is optionally substituted by one or more -C1-C2 alkyl, or -C1-C2 alkylene-phenyl; each -C6 aryl is optionally substituted by one or more -C1-C2 alkyl, or -C1-C4 alkylene-5-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine and piperazine, and the 5-6 membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl; R 53 are independently -OR 54, -CO2R 54 , or -NR 55 R 56 and R 54 is -C1-C2 alkyl, R 55 and R 56 are each independently -H, -C1-C2 alkyl, phenyl, or -C1-C2 alkylene-phenyl.

[0123] In some embodiments, R 51 and R 52 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl, preferably an optionally substituted 5- to 6-membered heterocycloalkyl.

[0124] In some embodiments, R 51 and R 52 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which can be formed by one or more R 53 may be substituted by

[0125] In some embodiments, R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 5-6 membered heterocycloalkyl, the heterocycloalkyl containing 1 to 4, preferably 1 to 3, more preferably 1 to 2 heteroatoms selected from O and N, and one or more R 53 may be substituted by

[0126] In some embodiments, R 51 and R 52 combine with the nitrogen atom to which they are attached to form piperidine, piperazine, or morpholine, and in piperidine, piperazine, or morpholine, one or more R 53 may be substituted by

[0127] In some embodiments, R51 and R 52 combine with the nitrogen atom to which they are attached to form piperidine, piperazine, or morpholine, and in piperidine, piperazine, or morpholine, one or more R 53 R may be substituted by 53 are independently —C1-C6 alkyl, (preferably —C1-C3 alkyl, preferably methyl), phenyl, or NR 59 R 60 wherein the phenyl is optionally substituted by —SO 2 NH 2 ; R 59 and R 60 are independently methyl or phenyl, or R 59 and R 60 combine to form an oxo- and methyl-substituted piperazine.

[0128] In some embodiments, R 51 is hydrogen and R 52 is optionally substituted -C6-C 10 The aryl, preferably the optionally substituted aryl, is optionally substituted phenyl.

[0129] In some embodiments, R 51 is hydrogen and R 52 is phenyl, which is optionally substituted by -C1-C6 alkyl, preferably -C1-C3 alkyl, which is optionally substituted by piperidine or piperazine, each of which is optionally substituted by methyl.

[0130] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are each independently hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-R 53A, -C5-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R 51 and R 52 at least one of R is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, or phenyl is selected from one or more, preferably one or two, R 53 or R 51 and R 52 together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which heterocycloalkyl is selected from one or more, preferably one or two, R 53 may be substituted by

[0131] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, which is a heterocycloalkyl group containing one or more R 53 may be substituted by

[0132] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which heterocycloalkyl is selected from one or more, preferably one or two, R 53 or the heterocycle is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is substituted with one or more, preferably one or two, R 53or the heterocycle is attached at a single atom to another cycloalkyl or heterocycloalkyl to form a 10-15 membered spirocyclic heterocycle, the spirocyclic group being optionally substituted by one or more, preferably one or two R 53 may be substituted by

[0133] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which heterocycloalkyl is selected from the group consisting of one or more R 53 may be substituted by

[0134] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which is fused to one or more additional aryl or heteroaryl rings to form a 10- to 15-membered heteroaryl, which is fused to one or more R 53 may be substituted by

[0135] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which is attached to another cycloalkyl or heterocycloalkyl through a single atom to form a 10- to 15-membered spirocyclic heterocycle, which spirocyclic group is formed by one or more R 53 may be substituted by

[0136] In some embodiments, X 1Ha-NR 51 R 52 and R 51 and R 52

[0049] In another embodiment, the heterocycloalkyl is piperidine. In another embodiment, the heterocycloalkyl is morpholine. In another embodiment, the heterocycloalkyl is 1,4-diazepane. In another embodiment, the heterocycloalkyl is piperazine. In another embodiment, the heterocycloalkyl is azetidine.

[0137] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, and (i) the heterocycloalkyl is piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine, and the piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine is selected from the group consisting of one or more R 53 or (ii) the heterocycle is piperidine fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which fused to one or more R 53 or (iii) the heterocycle is piperidine, which is attached at a single atom to another cycloalkyl or heterocycloalkyl to form a 10- to 15-membered spirocyclic heterocycle, and the spirocyclic group is optionally substituted with one or more R 53 may be substituted by

[0138] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycloalkyl being piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine, and the piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine is selected from the group consisting of one or more R 53 or the piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is substituted with one or more R 53 or the piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine is attached at a single atom to another cycloalkyl or heterocycloalkyl to form a 10-15 membered spirocyclic heterocycle, the spirocyclic group being optionally substituted by one or more R 53 may be substituted by

[0139] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine, said heterocycloalkyl being selected from one or more R 53 In another embodiment, the heterocycloalkyl is piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine, and the heterocycle is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is optionally substituted with one or more R 53In another embodiment, the heterocycloalkyl is piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine, and the heterocycle is linked to another cycloalkyl or heterocycloalkyl at a single atom to form a 10-15 membered spirocyclic heterocycle, which is optionally substituted by one or more R 53 may be substituted by

[0140] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52 together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being piperidine, said piperidine being selected from one or more R 53 In another embodiment, the heterocycloalkyl is piperidine, which is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is optionally substituted with one or more R 53 In another embodiment, the heterocycloalkyl is piperidine, which is attached to another cycloalkyl or heterocycloalkyl through a single atom to form a 10-15 membered spirocyclic heterocycle, which is optionally substituted with one or more R 53 may be substituted by

[0141] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52 together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycloalkyl being morpholine, and the morpholine being one or more R 53In another embodiment, the heterocycloalkyl is morpholine, which is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is optionally substituted with one or more R 53 In another embodiment, the heterocycloalkyl is morpholine, which is attached to another cycloalkyl or heterocycloalkyl at a single atom to form a 10-15 membered spirocyclic heterocycle, which is optionally substituted with one or more R 53 may be substituted by

[0142] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycloalkyl being a 1,4-diazepane, the 1,4-diazepane being one or more R 53 In another embodiment, the heterocycloalkyl is a 1,4-diazepane, which is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is fused to one or more R 53 In another embodiment, the heterocycloalkyl is a 1,4-diazepane, which is attached to another cycloalkyl or heterocycloalkyl through a single atom to form a 10-15 membered spirocyclic heterocycle, which may be substituted with one or more R 53 may be substituted by

[0143] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycloalkyl being a piperazine, and the piperazine may be one or more R 53 In another embodiment, the heterocycloalkyl is piperazine, which is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is optionally substituted with one or more R 53 In another embodiment, the heterocycloalkyl is piperazine, which is attached to another cycloalkyl or heterocycloalkyl at a single atom to form a 10-15 membered spirocyclic heterocycle, which may be substituted with one or more R 53 may be substituted by

[0144] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R 52 together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being azetidine, said azetidine being selected from one or more R 53 In another embodiment, the heterocycloalkyl is azetidine, which is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, which is optionally substituted with one or more R 53 In another embodiment, the heterocycloalkyl is azetidine, which is attached to another cycloalkyl or heterocycloalkyl at a single atom to form a 10-15 membered spirocyclic heterocycle, which is optionally substituted with one or more R 53 may be substituted by

[0145] In another embodiment, X 1 Ha-NR 51 R 52 and R 51 and R52 together with the nitrogen atom to which they are attached to form a heterocycloalkyl, said heterocycloalkyl being piperidine.

[0146] In another preferred embodiment, X 1 Ha-NR 51 R 52 and R 53 and R 53A are independently -C1-C4 alkyl, -C1-C3 alkylene-R 57A , 5- to 15-membered heterocycloalkyl, 5- to 15-membered heteroaryl, or phenyl, -OR 54 , -C(O)R 54 , -CO2R 54 , oxo, or -NR 55 R 56 and each alkylene, heterocycloalkyl, heteroaryl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 are independently hydrogen, -C1-C4 alkyl, -C5-C6 cycloalkyl, or phenyl, and each alkyl, cycloalkyl, or phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R 55 and R 56 are each independently hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-R 61A , phenyl, -CO2C1-C6 alkyl, -S(O)2(phenyl), and phenyl or cycloalkyl may be one or more R 61 may be substituted by

[0147] In another preferred embodiment, X 1 Ha-NR 51 R 52 and R 53 and R 53A are independently -C1-C4 alkyl, -C1-C3 alkylene-R 57A , 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl, or phenyl, -OR 54 , -C(O)R54 , -CO2R 54 , oxo, or -NR 55 R 56 and each alkylene, heterocycloalkyl, heteroaryl, and phenyl is selected from the group consisting of one or more R 57 and optionally substituted by R 54 are independently hydrogen, —C1-C2 alkyl, —C6 cycloalkyl, or phenyl, and each alkyl, cycloalkyl, or phenyl is selected from the group consisting of one or more R 61 and optionally substituted by R 55 and R 56 are each independently hydrogen, -C1-C2 alkyl, -C1-C3 alkylene-R 61A , phenyl, -CO2C1-C2 alkyl, -S(O)2(phenyl), and phenyl or cycloalkyl may be one or more R 61 may be substituted by

[0148] In another preferred embodiment, X 1 Ha-NR 51 R 52 and R 57 and R 57A are independently -C1-C6 alkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, halogen, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 61 may be substituted by

[0149] In another preferred embodiment, X 1 Ha-NR 51 R 52 and R 57 and R 57A are independently -C1-C2 alkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, halogen, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 61may be substituted by

[0150] In another preferred embodiment, X 1 Ha-NR 51 R 52 and R 61 and R 61A is independently —C1-C2 alkyl, phenyl, —C1-C2 alkoxy, —C1-C2 haloalkyl, or halogen.

[0151] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a piperazine or piperidine, each piperazine or piperidine containing one or more R 53 R may be substituted by 53 is -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -OR 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 57 R may be substituted by 54 are independently hydrogen, -C6-C 10 aryl, or -C5-C6 cycloalkyl, each aryl or cycloalkyl being selected from one or more R 61 R may be substituted by 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C6-C 10 Aryl, -S(O)C-C 10 aryl, or —C(O)O—C1-C6 alkyl, each alkyl or aryl being selected from one or more R 61 R may be substituted by 57are independently -C1-C6 alkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, 5- to 10-membered heteroaryl, oxo, halogen, —OH, or —SO2NH2, and each alkyl, heterocycloalkyl, aryl, and heteroaryl may be one or more R 61 R may be substituted by 61 are independently -C1-C6 alkyl, -C6-C 10 It is aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, or halogen.

[0152] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a piperidine which is substituted with one or more R 53 R may be substituted by 53 is -C1-C6 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 Aryl, 5-10 membered heteroaryl, -OR 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 57 R may be substituted by 54 are independently hydrogen or -C6-C 10 aryl, and R 55 and R 56 are each independently hydrogen, -C1-C6 alkyl, -C6-C 10 Aryl, -S(O)C-C 10 aryl, or —C(O)OC1-C6 alkyl, each alkyl or aryl being selected from one or more R 61 R may be substituted by 57are independently -C1-C6 alkyl, 3- to 10-membered heterocycloalkyl, -C6-C 10 aryl, 5- to 10-membered heteroaryl, oxo, halogen, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, aryl, and heteroaryl may be one or more R 61 R may be substituted by 61 are independently -C1-C6 alkyl, -C6-C 10 It is aryl, 5-10 membered heteroaryl, -C1-C6 alkoxy, -C1-C6 haloalkyl, or halogen.

[0153] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a piperidine which is substituted with one or more R 53 R may be substituted by 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -OR 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from the group consisting of one or more R 57 R may be substituted by 54 are independently hydrogen or phenyl, and R 55 and R 56 are each independently hydrogen, —C1-C4 alkyl, phenyl, —S(O)2 phenyl, or —C(O)OC1-C4 alkyl; R 57 are independently -C1-C4 alkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, fluorine, chlorine, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of one or more R 61 R may be substituted by61 is independently -C1-C4 alkyl, phenyl, 5- to 10-membered heteroaryl, -C1-C4 alkoxy, -C1-C4 haloalkyl, fluorine, or chlorine.

[0154] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a piperidine which is substituted with one or more R 53 R may be substituted by 53 is -C1-C2 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -OR 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from one or more R 57 R may be substituted by 54 are independently hydrogen or phenyl, and R 55 and R 56 are each independently hydrogen, —C1-C2 alkyl, phenyl, —S(O)2 phenyl, or —C(O)OC1-C4 alkyl; R 57 are independently -C1-C2 alkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, fluorine, chlorine, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 61 R may be substituted by 61 is independently -C1-C2 alkyl, phenyl, 5- to 10-membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, fluorine, or chlorine.

[0155] In some preferred embodiments, X 1 Ha-NR 51 R 52and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being piperidine, which is selected from the group consisting of one or two R 53 and preferably the piperidine is substituted at the 4-position only, with R 53 is -C1-C2 alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -OR 54 , or -NR 55 R 56 and each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is selected from one or more R 57 R may be substituted by 54 are independently hydrogen or phenyl, and R 55 and R 56 are each independently hydrogen, —C1-C2 alkyl, phenyl, —S(O)2 phenyl, or —C(O)OC1-C4 alkyl; R 57 are independently -C1-C2 alkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, fluorine, chlorine, -OH, or -SO2NH2, and each alkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of one or more R 61 R may be substituted by 61 is independently -C1-C2 alkyl, phenyl, 5- to 10-membered heteroaryl, -C1-C2 alkoxy, -C1-C2 haloalkyl, fluorine, or chlorine.

[0156] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycle being a piperidine which has exactly one R at the 4-position 53 is replaced by R 53 Ha-NR55 R 56 and R 55 and R 56 are each independently -C1-C2 alkyl, or phenyl.

[0157] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, the heterocycle being piperidine fused to indole to form 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, which is fused to one or more R 53 In some embodiments, the heterocycloalkyl is piperidine fused to indole to form 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

[0158] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, which heterocycle is attached at a single atom to another cycloalkyl or heterocycloalkyl to form a 10-15 membered spirocyclic heterocycle, which spirocyclic heterocycle is a piperidine which is joined at a single atom to one or more R 53 may be substituted by

[0159] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, the heterocycle being piperidine attached at the 4-position to form a 10- to 15-membered spirocyclic heterocycle, the spirocyclic heterocycle being joined by one or more R 53 may be substituted by

[0160] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, the heterocycle being piperidine attached at the 4-position to form a 10- to 15-membered spirocyclic heterocycle, the spirocyclic heterocycle being joined by one or more R 53 R may be substituted by 53 is phenyl.

[0161] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being an azetidine, which is selected from the group consisting of one or more R 53 may be substituted by

[0162] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being an azetidine, which is selected from the group consisting of one or more R 53 R may be substituted by 53 is a 5- to 10-membered heteroaryl, or -NR 55 R 56 and R 55 and R 56are each independently hydrogen or phenyl, and the phenyl may be substituted by halogen, preferably fluorine or chlorine, more preferably fluorine.

[0163] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being an azetidine, which is selected from the group consisting of one or more R 53 and R 53 is a 5- to 10-membered heteroaryl, or -NR 55 R 56 and R 55 and R 56 are each independently hydrogen or phenyl, and the phenyl may be substituted by halogen, preferably fluorine or chlorine, more preferably fluorine.

[0164] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a 1,4-diazepane, which is a 1,4-diazepane having one or more R 53 may be substituted by

[0165] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl, the heterocycle being a 1,4-diazepane, the 1,4-diazepane being one or more R 53 R may be substituted by 53is phenyl, which may be substituted by halogen, preferably fluorine or chlorine, more preferably fluorine.

[0166] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is -C5-C6 heterocycle, -C6-C 10 Aryl, -C1-C6 alkylene-C5-C6 heterocycle, or -C1-C4 alkylene-C6-C 10 aryl, and each heterocycle or aryl may be one or more R 53 may be substituted by

[0167] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is piperidine, piperazine, morpholine, pyrrolidine, -C1-C4 alkylene-piperidine, -C1-C4 alkylene-piperazine, -C1-C4 alkylene-morpholine, or -C1-C4 alkylene-pyrrolidine, and each piperidine, piperazine, morpholine, or pyrrolidine may be substituted by one or more -C1-C2 alkyl groups.

[0168] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is piperidine, piperazine, morpholine, pyrrolidine, -C1-C2 alkylene-piperidine, -C1-C2 alkylene-piperazine, -C1-C2 alkylene-morpholine, or -C1-C2 alkylene-pyrrolidine, and each piperidine, piperazine, morpholine, or pyrrolidine may be substituted by one or more -C1-C2 alkyl groups.

[0169] In some preferred embodiments, X1 Ha-NR 51 R 52 and R 51 is -H and R 52 is piperidine, piperazine, morpholine, pyrrolidine, -C1-C2 alkylene-piperidine, -C1-C2 alkylene-piperazine, -C1-C2 alkylene-morpholine, or -C1-C2 alkylene-pyrrolidine, and each piperidine, piperazine, or pyrrolidine is optionally substituted at the 4-position by one or more -C1-C2 alkyls.

[0170] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is piperidine, or -C1-C2 alkylene-piperidine, each piperidine being optionally substituted at the 4-position by one or more -C1-C2 alkyls.

[0171] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is phenyl, or -C1-C4 alkylene-phenyl, and each phenyl is selected from one or more R 53 may be substituted by

[0172] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is phenyl, or -C1-C4 alkylene-phenyl, and each phenyl is selected from one or more R 53 R may be substituted by 53 is —C1-C2 alkyl optionally substituted by one or more —C5-C6 heterocycloalkyl, which heterocycloalkyl may be further substituted by one or more —C1-C2 alkyl.

[0173] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is phenyl, or -C1-C3 alkylene-phenyl, and each phenyl is selected from one or more R 53 R may be substituted by 53 is —C1-C2 alkyl optionally substituted with one or more piperidines or piperazines, which may be further substituted with one or more —C1-C2 alkyls.

[0174] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is —C1-C4 alkyl, each alkyl optionally substituted by one or more —CO2C1-C4 alkyl, —OC1-C4 alkyl, —N(C1-C4 alkyl)2, or —C5-C6 heterocycloalkyl, preferably the heterocycloalkyl optionally substituted by one or more —C1-C2 alkyl.

[0175] In some preferred embodiments, X 1 Ha-NR 51 R 52 and R 51 is -H and R 52 is -C1-C4 alkyl, each alkyl optionally substituted by one or more -CO2C1-C4 alkyl, -OC1-C4 alkyl, -N(C1-C4 alkyl)2, piperidine, morpholine, or piperazine, preferably the piperidine or piperazine optionally substituted at the 4-position by one or more -C1-C2 alkyl.

[0176] In some embodiments, X 1 Ha-NR 51 R 52 and R51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 53 and optionally substituted by R 53 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; each alkylene may be optionally substituted by one or more oxo or -OH; each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one or more -C1-C6 alkyl, -C1-C6 haloalkyl, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, -OCH3, -OCH2CH2OH, -SONH2, phenyl, or oxo; R 55 and R 56 are each independently -H, -C1-C6 alkyl, -CO2C1-C6 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl, halogen -OC1-C6 alkyl, or -CN; R 54 are independently -H, -C1-C6 alkyl, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C6 alkyls.

[0177] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 53 and optionally substituted by R 53 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C6 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; the -C1-C6 alkyl is optionally substituted by one or more -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C6 alkyl, -C1-C6 haloalkyl, phenyl, halogen, -OH, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C6 alkyl, —C1-C6 haloalkyl, or halogen; R 55 and R 56 are each independently -H, -C1-C6 alkyl, -CO2C1-C6 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl, halogen -OC1-C6 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C6 alkyls.

[0178] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 53 and optionally substituted by R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C4 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; the -C1-C4 alkyl is optionally substituted by one or more of -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C4 alkyl, -C1-C4 haloalkyl, phenyl, halogen, -OH, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C4 alkyl, —C1-C4 haloalkyl, or halogen; R 55 and R 56are each independently -H, -C1-C4 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C4 alkyl, halogen-OC1-C4 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C4 alkyls.

[0179] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 53 and optionally substituted by R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, -C(O)-C-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C4 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C4 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56, -OR 54 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C4 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C4 alkyl, -C1-C4 haloalkyl, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C4 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C4 alkyl, —C1-C4 haloalkyl, or halogen; R 55 and R 56 are each independently -H, -C1-C4 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C4 alkyl, halogen-OC1-C4 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C4 alkyls.

[0180] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a 3- to 15-membered heterocycloalkyl, which may be optionally fused to one or more additional aryl or heteroaryl rings, or which may be attached to another cycloalkyl or heterocycloalkyl by a single atom to form a 10- to 15-membered spirocyclic heterocycle, or which may comprise a C2-bridged alkylene, and which may be optionally fused to one or more, preferably one or two, R 53 and optionally substituted by R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -C1-C2 haloalkyl, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —C1-C2 haloalkyl, or halogen; R 55 and R 56are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0181] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, the heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, the azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane optionally fused to one or more additional aryl or heteroaryl rings, or the heterocycloalkyl being attached by a single atom to another cycloalkyl or heterocycloalkyl to form a 10- to 15-membered spirocyclic heterocycle, or the heterocycle is piperidine which may contain a C2-bridged alkylene, the heterocycloalkyl being selected from one or more, preferably one or two, R 53 may be further substituted by R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C-C 10Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 55 and R 56 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0182] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, the heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, the azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane optionally fused to one or more additional aryl or heteroaryl rings, or the heterocycloalkyl being attached by a single atom to another cycloalkyl or heterocycloalkyl to form a 10- to 15-membered spirocyclic heterocycle, or the heterocycle is piperidine which may contain a C2-bridged alkylene, the heterocycloalkyl being selected from one or more, preferably one or two, R 53 wherein when the heterocycloalkyl is azetidine, the azetidine is substituted at the 3-position, and when the heterocycloalkyl is piperidine or piperazine, the piperidine or piperazine is substituted at the 4-position; R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 55 and R 56 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen, -OC1-C2 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0183] In some embodiments, X 1 Ha-NR 51 R 52 and R 51 and R 52 are combined together with the nitrogen atom to which they are attached to form a heterocycloalkyl, said heterocycloalkyl being selected from azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, or 1,4-diazepane, said heterocycloalkyl being selected from one or more, preferably one or two, R 53 may be further substituted by R 53 is -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 Aryl, -C(O)-C6-C 10Aryl, 3- to 10-membered heterocycloalkyl, -C1-C3 alkylene-3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C1-C3 alkylene-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -NR 55 R 56 , -OR 54 or oxo; The -C1-C4 alkyl may be substituted by one or more -N(C1-C2 alkyl)2, -OH, -OCH2CH2OH, or phenyl; each aryl is optionally substituted by one or more -C1-C2 alkyl, -CF3, phenyl, halogen, -OCH3, or -SO2NH2; each heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl, or oxo; each heteroaryl is optionally substituted by one or more oxo, —C1-C2 alkyl, —CF3, or halogen; R 55 and R 56 are each independently -H, -C1-C2 alkyl, -CO2C1-C4 alkyl, -SO2 phenyl, -C6-C 10 aryl, or 5- or 6-membered heteroaryl, each -C6-C 10 The aryl or 5- to 6-membered heteroaryl may be substituted by one or more -C1-C2 alkyl, halogen-OC1-C2 alkyl, or -CN; R 54 are independently -H, -C6-C 10 aryl, or -C5-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more -C1-C2 alkyls.

[0184] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the present disclosure or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient.

[0185] In one aspect, the present invention provides a compound according to the present disclosure or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of the present disclosure, for use in a method for preventing or treating a disease, preferably an infection, more preferably a bacterial infection, even more preferably a bacterial infection caused by one or more bacteria belonging to the genus non-tuberculous Mycobacteria, preferably M. abscessus, in a subject.

[0186] In one aspect, the present invention provides a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof. In one aspect, the present invention provides a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof.

[0187] In one aspect, the present invention provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, in the manufacture of a medicament for treating a bacterial infection in a subject in need thereof. In one aspect, the present invention provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, in the manufacture of a medicament for treating a bacterial infection in a subject in need thereof.

[0188] In some embodiments, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria genus, preferably M. abscessus. In some embodiments, the bacterial infection is caused by A. baumannii. In some embodiments, the bacterial infection is caused by an A. baumannii strain having a resistance mutation in the RpoB gene. In some preferred embodiments, the resistance mutation is H535Q, H535C, or H535L.

[0189] In one or more embodiments, X in the compounds of the invention 1 can form one of the structures selected from Table 1 below:

[0190] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0191] In one or more embodiments of any of the above aspects, the compound of Formula I is selected from Table 2 below: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

[0192] In one or more embodiments of any of the above aspects, the compound of Formula I is selected from Compound 44, Compound 49, Compound 52, Compound 67, Compound 85, Compound 90, Compound 91, Compound 98, Compound 105, Compound 106, Compound 109, Compound 110, Compound 118, and Compound 121.

[0193] In one or more embodiments of any of the above aspects, the compound of formula I is selected from Compound 67, Compound 90, Compound 98, and Compound 106.

[0194] Methods of synthesizing compounds of the present invention The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes shown below.

[0195] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes and examples. In the schemes described below, it is fully understood that protecting groups for sensitive or reactive groups are used where necessary according to general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Buts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selected processes and reaction conditions and the order of their execution shall be consistent with the preparation of the compounds of the present disclosure.

[0196] Those skilled in the art will recognize whether a stereocenter exists in compounds of formula I. Thus, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. In a preferred embodiment, the present disclosure provides compounds of formula I, wherein X 1 and Y 1 This includes enantiomers and / or diastereomers within. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0197] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0198] The compounds of the present disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present disclosure can be synthesized using the methods described below, along with synthetic methods known in the field of synthetic organic chemistry, or variations thereof recognized by those skilled in the art.These methods include, but are not limited to, the methods described below.The compounds of the present disclosure can be synthesized according to the steps outlined in general schemes 1, 2 and 3.Starting materials are commercially available or are prepared by procedures known in the published literature or as illustrated.

[0199] Scheme 1. General synthesis of C21-C23-acetal-25-OH rifabutin (I-1) [ka] A general method for preparing C21-C23-acetal-25-OH rifabutin is shown in Scheme 1 above. Protection of the C21 and C23 hydroxy groups using dimethoxypropane and camphorsulfonic acid in DMF afforded acetal-protected rifabutin. Deacetylation of the protected rifabutin using an ethereal solution of sodium methoxide afforded 25-OH rifabutin with protected C21 and C23 hydroxy groups (I-1).

[0200] Scheme 2. Preparation of 25-OH rifabutin ester (I-2) [ka] C21-C23 protected 25-OH rifabutin (I-1) can be esterified with a suitable carboxylic acid, such as malonic acid, in the presence of a coupling reagent such as DCC. Other dicarboxylic acids (e.g., glutaric acid, succinic acid, adipic acid, methylmalonic acid, or ethylmalonic acid) can be used.

[0201] Scheme 3. Preparation of deprotected 25-ester or 25-amide conjugate rifabutin [ka] The C25-esterified, protected rifabutin can be coupled to an appropriate alcohol or amine using a coupling reagent such as EDCI or COMU (preferably, EDCI is used for coupling to alcohols and COMU is used for coupling to amines). Deprotection of the C21-C23 acetal in the conjugated rifabutin can be carried out by treatment with an acid such as camphorsulfonic acid in an alcohol such as methanol.

[0202] Antibacterial efficacy of the disclosed compounds The compounds of the present invention are C25-modified analogs of rifabutin that exhibit broad-spectrum antibacterial activity characteristic of the rifamycin class. Furthermore, the compounds of the present invention unexpectedly exhibit enhanced antibacterial activity against nontuberculous mycobacteria, including M. abscessus, compared to currently available antibiotics (e.g., rifabutin). The compounds of the present invention also retain antibacterial activity against A. baumannii and unexpectedly exhibit enhanced antibacterial activity against certain strains of A. baumannii, such as A. baumannii that have one or more resistance mutations that render them resistant to currently available antibiotics (e.g., rifabutin).

[0203] As shown in Example 7, Table 5 below, compounds of the present disclosure are effective in inhibiting bacterial growth in S. aureus, A. baumannii, and M. abscessus strain complexes, as well as other non-tuberculous Mycobacteria, namely, M. kansasii, M. xenopi, and M. avium. Table 9 shows that compounds of the invention (e.g., Compound 3) are effective in inhibiting bacterial growth in E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, M. tuberculosis, S. pyogenes, H. influenzae, and M. smegmatis strains.

[0204] Example 7, Tables 6, and 7 show the activity of compounds of the present invention against specific isolates of M. abscessus compared with currently available antibiotics. Table 6 shows the activity of compounds of the present invention in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement. Table 7 shows the activity of compounds of the present invention in cation-adjusted Mueller Hinton broth. Rifampicin exhibited MIC values ​​greater than 32 mg / L and was not considered active against M. abscessus strains. Rifabutin and 3-(4-morpholinyl)rifamycin S, unmodified at the C25 position, exhibited moderate activity against the M. abscessus strains tested, with MIC values ​​ranging from 2 to 16 mg / L and 4 to 32 mg / L, respectively. In contrast, compound 3 exhibited MIC values ​​of 0.5-2 mg / L, corresponding to 8-16 times greater activity than rifabutin in four of the five M. abscessus strains tested. Furthermore, the C25-modified compound CGP 4832 exhibited lower activity than compound 3 (MIC of 2-8 mg / L). Similarly, additional compounds of the present invention (e.g., compounds 85, 90, and 98) exhibited enhanced activity (e.g., 4-16-fold increase in activity) compared to rifabutin in the M. abscessus isolates tested, as shown in Table 7. Thus, the present disclosure teaches compounds that exhibit increased activity against M. abscessus beyond that of antibiotics known in the literature. In some embodiments, compounds of the present invention can be used to treat M. abscessus infections. In some embodiments, the M. abscessus infection is resistant to current antibiotics.

[0205] As shown in Example 7, Table 8, compounds of the present invention (e.g., Compound 3) retained strong antibacterial activity against wild-type A. baumannii strains and overcame antibiotic resistance mechanisms such as ADP-ribosyltransferase (Arr)-mediated resistance and RpoB mutation-mediated resistance mechanisms. In contrast to the activity of Compound 3, CGP4832 did not exhibit strong activity against wild-type A. baumannii and lost activity against RpoB mutant strains compared to rifabutin.

[0206] Thus, in some embodiments, compounds of the present invention can be used to inhibit bacterial infections, preferably infections caused by nontuberculous mycobacteria, more preferably M. abscessus. In some embodiments, compounds of the present invention can be used to inhibit bacterial infections caused by A. baumannii. In some preferred embodiments, compounds of the present invention can be used to treat bacterial infections caused by bacterial strains that possess one or more resistance genes or mechanisms to currently available antibiotics (e.g., rifampicin and / or rifabutin). In some preferred embodiments, compounds of the present invention can be used to inhibit bacterial infections caused by A. baumannii, which possess resistance mechanisms, preferably resistance mutations in the RpoB gene and / or expression of the ADP-ribosyltransferase (Arr) enzyme. In some preferred embodiments, the resistance mutation in the RpoB gene is H535Q, H535C, or H535L.

[0207] Methods of Use of the Disclosed Compounds One aspect of the present disclosure relates to a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof. One aspect of the present disclosure relates to a compound (or a pharmaceutically acceptable salt) or pharmaceutical composition described herein for use as a medicament. One aspect of the present disclosure relates to a compound (or a pharmaceutically acceptable salt) or pharmaceutical composition described herein for use in a method of treating a bacterial infection in a subject. One aspect of the present disclosure relates to the use of a compound (or a pharmaceutically acceptable salt) or pharmaceutical composition described herein in the manufacture of a medicament for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by a bacterial strain harboring one or more resistance genes or mechanisms to currently available antibiotics (e.g., rifampicin and / or rifabutin).

[0208] In some embodiments, the infection is caused by Mycobacterium spp., Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes spp., Moraxella catarrhalis spp., Bacillus spp., Bacteroides spp., Gardnerella vaginalis, or any of the following: It is caused by one or more bacteria belonging to the genera Lactobacillus vaginalis, Lactobacillus species, Mobiluncus species, Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis and / or Toxoplasma gondii.

[0209] In some embodiments, the infection is caused by one or more bacteria belonging to the species M. abscessus, M. kansasii, M. xenopi, M. avium, A. baumannii, S. aureus, E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, M. tuberculosis, S. pyogenes, H. influenzae, and / or M. smegmatis.

[0210] In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii and / or S. aureus and / or nontuberculous Mycobacteria, preferably M. abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0211] In some preferred embodiments, the infection is caused by one or more bacteria belonging to the non-tuberculous Mycobacterium genus, preferably M. abscessus, M. avium, M. kansasii, M. xenopi and / or M. malmoense, and even more preferably M. abscessus.

[0212] In some embodiments, the infection is caused by one or more bacteria belonging to the species M. abscessus, A. baumannii, and / or S. aureus. In some embodiments, the infection is caused by one or more bacteria belonging to the species M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the species A. baumannii.

[0213] In some embodiments, the infection is caused by one or more bacteria belonging to an M. abscessus subsp. abscessus strain, e.g., M. abscessus subsp. abscessus strain ID number ATCC 19977, strain ID number CCUG 71636, or strain ID number CCUG 71382; M. abscessus subsp. bolletii, e.g., strain ID number CCUG 50184; and / or M. abscessus subsp. massiliense, e.g., strain ID number CCUG 48898.

[0214] In some preferred embodiments, compounds of the present disclosure can be used to inhibit bacterial infections caused by A. baumannii, preferably A. baumannii possesses a resistance mechanism that makes it resistant to current antibiotics, preferably the resistance mechanism is a mutation in the RpoB gene and / or expression of the ADP-ribosyltransferase (Arr) enzyme. In some embodiments, the infection is caused by one or more bacteria belonging to the A. baumannii wild-type strain, the A. baumannii Arr-2 strain, the A. baumannii RpoB H535Q mutant strain, the A. baumannii RpoB H535C mutant strain, and / or the A. baumannii RpoB H535L mutant strain.

[0215] In some preferred embodiments, the compounds of the present disclosure are used to treat nontuberculous mycobacteria causing nontuberculous mycobacterial pulmonary infections. Accordingly, one aspect of the present disclosure relates to a method of treating a nontuberculous mycobacterial pulmonary infection in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. One aspect of the present disclosure relates to a compound (or a pharmaceutically acceptable salt thereof) or pharmaceutical composition described herein for use in the method of treating a nontuberculous mycobacterial pulmonary infection in a subject. One aspect of the present disclosure relates to the use of a compound (or a pharmaceutically acceptable salt thereof) or pharmaceutical composition described herein in the manufacture of a medicament for treating a nontuberculous mycobacterial pulmonary infection in a subject. In some embodiments, the non-tuberculosis Mycobacterium is M. abscessus, M. avium, M. kansasii, M. xenopi, and / or M. malmoense.

[0216] Exemplary pharmaceutical compositions include a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, e.g., hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, e.g., EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids, or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) in tablets, a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol, c) binders, if desired, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, for example glucose or beta-lactose, corn sweeteners, natural and synthetic gums, for example acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, d) disintegrating agents, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colorants, flavors and sweeteners, f) emulsifiers or dispersing agents, for example Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier, and / or g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0217] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds can be dissolved or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0218] The disclosed compounds may also be formulated as suppositories which may be prepared from fatty emulsions or suspensions using polyalkylene glycols, such as propylene glycol, as the carrier.

[0219] The disclosed compounds can also be administered in the form of liposome delivery system, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.Liposome can be formed from various phospholipids containing cholesterol, stearylamine or phosphatidylcholine.In some embodiments, the film of lipid components is hydrated with an aqueous solution of drug to form a lipid layer that encapsulates the drug, as described in U.S. Patent No. 5,262,564.

[0220] Injectable parenteral administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or in solid form suitable for dissolving in liquid prior to injection.

[0221] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0222] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0223] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the particular disclosed compound being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0224] Effective dosages of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5,000 mg of the disclosed compounds as needed to treat a condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or a range of amounts within the dosage list. In one embodiment, the composition is in the form of a scoreable tablet.

[0225] equivalent While the present technology has been described in conjunction with the specific embodiments outlined above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

[0226] example The present disclosure will now be illustrated by the following non-limiting examples. Specific embodiments of the present disclosure are described below, but those skilled in the art will understand that various changes and modifications can be made. References to preparations made in the same manner as, or by common methods for, other preparations may include variations in routine parameters such as time, temperature, workup conditions, slight changes in reagent amounts, and the like.

[0227] Abbreviation The following list provides definitions of certain abbreviations and symbols used herein. It is understood that this list is not exhaustive, but that the meaning of abbreviations and symbols not defined below will be readily apparent to one of ordinary skill in the art. In describing this disclosure, chemical elements are identified according to the Periodic Table of the Elements. [Table 3]

[0228] Compound characterization Unless otherwise specified, the purity and identity of intermediates or exemplary compounds were assessed by state-of-the-art LC / MS. Methods for reaction monitoring and compound purity determination were performed by liquid chromatography / mass spectrometry (LC / MS) as described below. Method A was used to characterize intermediates I-1 through I-6. Method B was used to characterize compounds of the present invention and confirm their purity. Percent purity was determined by reverse-phase HPLC or UPLC using UV detection (254 nm). Compound structures were confirmed by MS using electrospray ionization positive (ESI+) method and are reported as [M+H]+, referring to the protonated molecular ion.

[0229] Method A UPLC system: UPLC I BIN SOL MGR equipped with ACQUITY UPLC I-Class eK PDA Detector; Column: Acquity BEH C18 column (particle size 1.7 μm, dimensions 50 mm × 2.1 mm); Mobile phase: Phase A (HO / ammonium formate, pH 3.75 or 9.2) and Phase B (CH3CN + 5% HO / ammonium formate, pH 3.75 or 9.2) were used according to the following method: [Table 4]

[0230] Mass spectrometry: ACQUITY QDa (Performance) Xevo TQD. Ionization: electrospray (polarity: negative and positive).

[0231] Method B HPLC system: Waters 2695 LC equipped with a photodiode array detector Waters 996; Column: XBridge C18 column (particle size 3.5 μm, dimensions 50 mm × 4.6 mm); Mobile phase: Phase A (HO / ammonium formate, pH 9.2) and Phase B (CH3CN + 5% HO / ammonium formate, pH 9.2) were used according to the following method: [Table 5]

[0232] Mass spectrometry: Waters Alliance Micromass ZQ 2000. Ionization: electrospray (polarity: negative and positive).

[0233] NMR spectra were recorded using a Bruker DRX-300 spectrometer or a Bruker 500 MHz spectrometer equipped with a TXI probe. Chemical shifts were measured in parts per million (ppm). One-dimensional (1D) 1 H and 13 The assignment was made using C spectra as well as two-dimensional (2D) HSQC and HMBC spectra.

[0234] All commercially available reagents and solvents were used without further purification. Normal-phase purification was performed using an Interchim PuriFlash 430 equipped with a prepacked column (FlashPure, BUCHI®, silica 40 μm irregular). Reverse-phase purification was performed by HPLC prep (Buchi Pure C-830, column: OmniSphere C18 Dynamax) using HO (0.1% HCOOH) / ACN (0.1% HCOOH) as the mobile phase.

[0235] Example 1: Synthesis of C21-C23 acetal 25-OH rifabutin (intermediate I-1) As shown below, compounds of the present invention were prepared from free 25-OH rifabutin (intermediate I-1), which was prepared from commercially available rifabutin. [ka]

[0236] Synthesis of intermediate I-1: Rifabutin (40.0 g, 47.2 mmol) was dissolved in dry DMF (80 mL) under a nitrogen atmosphere at room temperature. 2,2-Dimethoxypropane (58.1 mL, 472 mmol) and camphorsulfonic acid (12.6 g, 54.3 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 26 hours. The mixture was then cooled to 0 °C and poured into a mixture of saturated aqueous NaHCO3 (700 mL) and water (500 mL). The reaction flask was washed with acetone (100 mL). The resulting suspension was stirred on an ice bath for 10 minutes and filtered. The cake was rinsed with saturated aqueous NaHCO3 (100 mL) and water (50 mL) and dried under vacuum at 40 °C for 24 hours. The crude product was purified by flash chromatography (DCM to 50% mixture DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM) to give the desired product as a purple solid (37.68 g, 90% yield).

[0237] 21,23-Dimethylacetonide-rifabutin (10.6 g, 11.9 mmol) was dissolved in dry diethyl ether (500 mL). The solution was cooled to -10 °C using Ar bubbling. After 15 min, a solution of NaOMe (30 mL, 25 wt % in MeOH) was slowly added. A precipitate formed, and another portion of diethyl ether (100 mL) was added to homogenize. NaOMe solution was added again (27.4 mL). The solution was stirred at -5 °C for 10 min, and then the ice bath was removed. The reaction mixture was stirred at room temperature for 6 h. NaHCO 3A saturated aqueous solution of (400 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (400 mL), and the combined organic layers were washed with brine (300 mL) and evaporated to give the desired crude product as a black-purple powder. The product was purified by flash chromatography (DCM to 50% mixture DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM). After evaporation, the product was redissolved in acetone and slowly added to water with vigorous stirring. The solid was collected by filtration and dried at 40 °C to give the deacetylated analog of rifabutin intermediate I-1 (97% purity).

[0238] Example 2: Synthesis of 25-malonate trifabutin (intermediate I-2) [ka] Intermediate I-1 (1 equiv.) and malonic acid (3 equiv.) were dissolved in THF and cooled to 0 °C. DCC (3 equiv.) was added and the reaction was stirred at 0 °C for 1.5 h. Dicyclohexylurea was removed by filtration, and the filtrate was evaporated in vacuo. The crude product was purified by flash chromatography (CHCl3 / MeOH) to give intermediate I-2 as a black solid.

[0239] Example 3: Synthesis of 25-methyl-malonate trifabutin (intermediate I-3) [ka] Intermediate I-1 (500 mg, 0.59 mmol, 1 equiv.) and 2-methylpropanedioic acid (210 mg, 1.78 mmol, 3 equiv.) were dissolved in DCM (10 mL). DCC (366 mg, 1.78 mmol, 3 equiv.) was then added, and the reaction was stirred at room temperature. After 1 h, the mixture was filtered, and the DCM was evaporated. The resulting oil was solubilized in EtOAc (30 mL) and washed with a 1N aqueous solution of HCl (30 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting solid was purified by flash chromatography (CHCl3 / MeOH, 100 / 0 to 95 / 5) to afford intermediate I-3, obtained as a mixture of diastereoisomers, as a black solid (m = 395 mg, yield = 70%). LC / MS A(ESI+):T R =2.15 min, m / z[M+H] + =945.52, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (Mixture of diastereoisomers) δ 0.35 (d, J = 7.0 Hz, 1.5H), 0.41 (d, J = 7.0 Hz, 1.5H), 0.62-0.73 (m, 3H), 0.73-0.88 (m, 9H), 0.99-1.10 (m, 6H), 1.16-1.25 (m, 3H), 1.25-1.36 (m, 3H), 1.40-1.55 (m, 3H), 1.64-1.91 (m, 3H), 1.74 (s, 1.5H), 1.75 (s, 1.5H), 1.99 (s, 3H), 2.05-2.16 (m, 1H), 2.16-2.26 (m, 1H), 2.30 (s, 1.5H), 2.31 (s, 1.5H), 2.68 (s, 1.5H), 2.73 (s, 1.5H), 2.77-3.00 (m, 4H), 3.01-3.66 (m, 8H), 4.90-5.08 (m, 2H), 5.72-5.86 (m, 1H), 6.02 (dd, J = 15.4, 6.8 Hz, 1H), 6.14 (d, J = 10.5 Hz, 1H), 6.19-6.34 (m, 1H), 7.66 (s, 0.5H), 7.67 (s, 0.5H), 8.70 (brs, 1H), 14.61 (s, 0.5H), 14.62 (s, 0.5H). 13C NMR (75 MHz, CDCl3): (mixture of diastereoisomers) δ 7.8, 8.2, 8.6, 9.8, 10.1, 12.8, 14.3, 14.4, 15.3, 17.7, 20.1, 20.2, 20.3, 20.7, 20.8, 23.8, 23.9, 24.5, 25.8, 33.0, 33.7, 34.3, 36.2, 39.9, 40.5, 41.5, 41.7, 44.7, 47.4, 47.6, 50.9, 51.1, 55.7, 55.9, 64.4, 64.7, 70.7, 70.8, 75.1, 75.5, 76.9, 77.3, 78.6, 78.8, 91.9, 100.0, 100.1, 104.9, 106.1, 108.5, 111.4, 111.5, 114.1, 114.2, 114.9, 115.1, 123.7, 124.9, 125.0, 130.4, 130.5, 133.3, 133.5, 140.6, 140.8, 140.9, 141.5, 141.6, 156.1, 156.2, 168.1, 168.7, 168.8, 171.0, 171.2, 172.3, 172.4, 174.55, 174.58, 177.1, 181.7, 181.8, 193.0, 193.1.

[0240] Example 4: Synthesis of 25-succinate trifabutin (intermediate I-4) [ka] Intermediate I-1 (1 g, 1.18 mmol, 1 equiv.), succinic anhydride (591.5 mg, 5.92 mmol, 5 equiv.), and DMAP (722.2 mg, 5.92 mmol, 5 equiv.) were dissolved in 10 mL of CHCl3, and the reaction was stirred at 60 °C. After 70 h, the mixture was diluted with 50 mL of DCM and washed with a 0.5 N aqueous solution of HCl (2 × 30 mL), a saturated aqueous solution of NaHCO3 (2 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO4 and evaporated under vacuum. The resulting solid was purified by flash chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate I-4 as a black solid (791 mg, 71% yield). LC / MS A(ESI+):T R =2.14 min, m / z[M+H] + =945.60, UV purity: 99% (254nm). 1 H NMR (300 MHz, CDCl3):δ 0.29 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H), 0.79-0.85 (m, 9H), 1.16-1.26 (m, 9H), 1.31-1.72 (m, 5H), 1.75 (s, 3H), 2.00 (s, 3H), 2.18-2.29 (m, 2H), 2.31 (s, 3H), 2.53-2.59 (m, 4H), 2.80 (s, 3H), 2.96-3.08 (m, 3H), 3.30-3.72 (m, 8H), 4.92 (d, J = 8.1 Hz, 1H), 5.04 (dd, J = 12.1, 6.2 Hz, 1H), 5.85 (d, J = 11.5 Hz, 1H), 5.99-6.35 (m, 3H), 7.62 (s, 1H), 8.72 (s, 1H), 14.62 (s, 1H). 13C NMR (75 MHz, CDCl3):δ 7.79, 8.98, 9.84, 12.79, 17.68, 20.16, 20.24, 21.19, 21.23, 23.67, 24.47, 25.73, 29.09, 29.16, 32.49, 33.30, 34.26, 36.30, 40.70, 41.18, 51.72, 51.37, 56.26, 65.02, 70.98, 74.69, 76.93, 78.38, 91.42, 99.90, 104.79, 106.09, 108.44, 111.50, 114.25, 115.27, 123.84, 124.87, 130.51, 133.39, 140.53, 140.85, 141.68, 156.46, 168.13, 168.66, 171.46, 172.19, 176.15, 182.05, 193.17.

[0241] Example 5: Synthesis of 25-glutarate trifabutin (I-5) [ka] Intermediate I-1 (1 g, 1.18 mmol, 1 equiv.), glutaric anhydride (675 mg, 5.92 mmol, 5 equiv.), and DMAP (723 mg, 5.92 mmol, 5 equiv.) were dissolved in 10 mL of CHCl. ​​The reaction was stirred at 60 °C. After 22 h, glutaric anhydride (675 mg, 5.92 mmol, 5 equiv.) and DMAP (723 mg, 5.92 mmol, 5 equiv.) were added, and the mixture was stirred at 60 °C. After 24 h, the mixture was diluted with 50 mL of DCM and washed with a 0.5 N aqueous solution of HCl (2 × 30 mL), a saturated aqueous solution of NaHCO (2 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO and evaporated in vacuo. The resulting solid was purified by flash chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to afford intermediate I-5 as a black solid (554 mg, 49% yield). LC / MS A(ESI+):T R =2.19 min, m / z[M+H] += 959.65, UV purity: 99% (254 nm). 1 H NMR (300 MHz, CDCl3): δ 0.33 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H), 0.80 - 0.86 (m, 9H), 1.14 (dd, J = 2.1, 6.5 Hz, 6H), 1.22 (s, 3H), 1.36 - 1.41 (m, 1H), 1.51 (m, 2H), 1.67 - 1.80 (m, 5H), 1.85 - 1.91 (m, 2H), 2.02 (s, 3H), 2.15 - 2.40 (m, 9H), 2.80 (s, 3H), 2.92 (d, J = 6.6 Hz, 2H), 3.02 - 3.08 (m, 1H), 3.10 - 3.71 (m, 8H), 4.91 (d, J = 7.6 Hz, 1H), 5.04 (dd, J = 12.1, 6.4 Hz, 1H), 5.85 (d, J = 12.1 Hz, 1H), 6.05 (dd, J = 15.5, 6.1 Hz, 1H), 6.16 (dd, J = 10.7, 1.1 Hz, 1H), 6.29 (dd, J = 15.6, 10.6 Hz, 1H), 7.75 (s, 1H), 8.69 (s, 1H), 14.65 (s, 1H). 13C NMR (75 MHz, CDCl3):δ 7.92, 9.09, 10.08, 12.92, 17.86, 20.26, 20.34, 21.29, 21.33; 23.75, 25.87, 32.95, 33.53, 33.64, 33.77, 34.35, 36.52, 40.78, 41.43, 51.39, 51.64, 56.31, 65.19, 71.12, 74.54, 77.05, 78.66, 91.99, 100.05, 104.96, 106.19, 108.58, 111.62, 114.30, 115.26, 123.93, 125.06, 130.77, 133.33, 140.74, 140.94, 141.79, 156.38, 168.25, 168.78, 172.31, 172.39, 177.06, 182.04.

[0242] Example 6: Synthesis of 25-ethyl-malonate trifabutin (I-6) [ka] A solution of intermediate I-1 (1.00 g, 1.18 mmol, 1 equiv.) in 20 mL of dry DCM was added to ethyl malonate (469 mg, 3.55 mmol, 3.0 equiv.) and DCC (732 mg, 3.55 mmol, 3.0 equiv.). The mixture was stirred at 40 °C for 2 h 30 min and then cooled to 0 °C. The precipitated DCC was filtered off and rinsed with DCM. The filtrate was concentrated in vacuo to give a crude residue, which was purified by flash chromatography (solids were dissolved in DCM, 80 g of Buchi, 1 / 0 to 96 / 4 DCM / MeOH gradient, 40 min). Intermediate I-6 was obtained as a purple solid (104 mg, 9%) as a mixture of diastereoisomers. MS A(ESI+): m / z [M+H] + =957.70, UV purity: 99% (254nm).

[0243] Example 7: General procedure for the synthesis of ester conjugates [ka] A solution of the desired intermediate (I-2, I-3, I-4, I-5, or I-6) in THF (0.07 M) was prepared. The corresponding alcohol (0.064 mmol, 3 equiv.) and EDCI (12.5 mg, 0.64 mmol, 3 equiv.) were charged into a Kimble reactor, and 300 μL of a THF solution of the rifabutin intermediate (corresponding to 1 equiv. of the rifabutin intermediate) was added. The reaction was stirred at room temperature. After 24 h, 600 μL of an aqueous camphorsulfone solution (0.5 N) was added to the mixture. The reaction tube was stirred at 4 °C for 16 h. The mixture was then loaded onto a PoraPak column (Rxn RP 6CC) equilibrated with water. Elution was carried out with 5 mL of water, 5 mL of a water / ACN solution (90 / 10), and 10 mL of ACN. 10 mL ACN fractions were collected, frozen, and lyophilized to give the desired product as a purple powder.

[0244] Example 8: General procedure for the synthesis of amide conjugates [ka] A solution of the desired intermediate (I-2, I-3, I-4, I-5, or I-6) in THF (0.07 M) was prepared. The corresponding amine (0.043 mmol, 2 equiv.) and COMU (18 mg, 0.43 mmol, 2 equiv.) were charged into a Kimble reactor, and 300 μL of a THF solution of the rifabutin intermediate (equivalent to 1 equiv. of rifabutin intermediate) was added, followed by DIEA (15 μL, 0.082 mmol, 4 equiv.). The reaction was stirred at room temperature. After 3 h, 600 μL of an aqueous solution of camphorsulfone (0.5 N) was added to the mixture. The reaction was stirred at 4 °C for 16 h. The mixture was then loaded onto a PoraPak (Rxn RP 6CC) column equilibrated with water. The elution was carried out with 5 mL of water, 5 mL of saturated aqueous NaHCO3, 5 mL of a solution of water / ACN (90 / 10), 5 mL of water, and 10 mL of ACN. 10 mL ACN fractions were collected, frozen, and lyophilized to give the desired product as a purple powder.

[0245] Table 3 below summarizes exemplary compounds of the invention prepared according to the protocols of Examples 7 and 8 above. The data shown in Table 3 was obtained according to Analytical Method B.

[0246] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13]

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 6-19

Table 6-20

Table 6-21

Table 6-22

Table 6-23

Table 6-24

Table 6-25

Table 6-26

Table 6-27

Table 6-28

Table 6-29

Table 6-30

Table 6-31

Table 6-32

Table 6-33

Table 6-34

Table 6-35

Table 6-36

Table 6-37

Table 6-38

Table 6-39

Table 6-40

[0247] Example 9: Synthesis of Compound 3 [ka] To a solution of I-2 (200 mg, 0.21 mmol, 1 equiv.) in THF (5 mL) was added (1-methyl-3-piperidyl)methanol (55 μL, 0.43 mmol, 2 equiv.) and EDCI (113 mg, 0.64 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 18 h, filtered, and the solvent was evaporated. The resulting solid was redissolved in DCM (40 mL) and washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The organic phase was then evaporated under vacuum. The resulting solid was purified by flash chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give a black solid (yield: 71.5%, Rt: 2.77 min, purity (254 nm): 99%, MS (ESI+) m / z = 1042.69 [M+H]). + , 521.96 [M+2H]2+). C21-C23 protected compound 3 (160 mg, 0.15 mmol) was dissolved in 5 mL of a THF / 0.5 N acid camphorsulfone solution in water (1 / 1). The reaction was stirred at room temperature for 4 h, followed by the addition of 40 mL of DCM. The mixture was washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and evaporated under vacuum. The resulting solid was purified by flash chromatography (DCM / MeOH: 100 / 0 to 90 / 10) to give compound 3 as a black solid (yield: 52%, Rt: 2.43 min, purity (254 nm) = 99%, MS (ESI+) m / z = 1002.71 [M+H] + , 501.95[M+2H] 2+ ).

[0248] Compound 3 was further synthesized as follows: To a solution of I-2 (150 mg, 0.16 mmol, 1 equiv.) in THF (5 mL), (1-methyl-3-piperidyl)methanol (0.32 mmol, 2 equiv.), DIEA (110 μL, 0.64 mmol, 4 equiv.), and COMU (137 mg, 0.32 mmol, 2 equiv.) were added. The reaction was stirred at room temperature. After 3 h, the solvent was evaporated under vacuum. The resulting solid was dissolved in DCM (40 mL) and washed with a 0.5 N aqueous solution of HCl (3 × 40 mL), a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The DCM was evaporated under vacuum. The resulting solid was then dissolved in 5 mL of a 0.5 N aqueous solution of THF / camphorsulfonic acid (1 / 1). The reaction mixture was stirred at room temperature. After 24 hours, the mixture was diluted with 50 mL of DCM and washed with saturated aqueous NaHCO3 (3 x 50 mL), brine (50 mL), and dried over MgSO4. The solvent was evaporated under vacuum, and the resulting solid was purified by preparative HPLC to give compound 3 as a purple solid (yield = 23%). LC / MS A(ESI+):T R =1.73 min, m / z[M+H] + =1002.56, UV purity: 99% (254nm). HRMS(Maldi-TOF):[M+H] + Calculated m / z for = 1002.5434, found 1002.5461. 1H NMR (300 MHz, CDCl3): (Mixture of diastereoisomers) δ -0.12 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.5 Hz, 6H), 1.02 (d, J = 6.8 Hz, 3H), 1.33-1.45 (m, 1H), 1.60-2.22 (m, 14H), 1.71 (s, 3H), 2.02 (s, 3H), 2.24-2.45 (m, 3H), 2.28 (s, 3H), 2.41 (d, J = 12.1 Hz, 3H), 2.55-2.79 (m, 2H), 2.90-3.08 (m, 4H), 3.05 (s, 3H), 3.11 (d, J = 10.1 Hz, 1H), 3.20-3.34 (m, 3H), 3.37-3.60 (m, 2H), 3.66 (dd, J = 9.8 Hz, 2.8 Hz, 1H), 3.89-4.09 (m, 2H), 4.86 (dd, J = 9.83 Hz, 1H), 5.12-5.24 (m, 1H), 5.96 (dd, J = 15.5 Hz, 6.3 Hz, 1H), 6.10-6.41 (m, 3H), 8.22 (s, 0.5H), 8.23 ​​(m, 0.5H), 9.16 (s, 1H), 14.67 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of diastereoisomers) δ 7.87, 7.91, 8.98, 11.28, 11.38, 11.42, 17.53, 17.58, 20.45, 20.46, 21.07, 21.08, 22.22, 22.27, 23.78, 23.96, 25.96, 26.13, 33.17, 35.17, 35.38, 36.28, 37.73, 38.02, 38.61, 41.70, 41.79, 45.49, 45.72, 51.56, 51.62, 55.27, 55.42, 56.88, 56.93, 57.80, 58.00, 66.35, 67.38, 67.69, 72.58, 72.58, 72.65, 74.30, 74.38, 76.55, 76.69, 81.23, 81.43, 94.67, 94.71, 104.77, 107.60, 107.63, 109.20, 109.22, 111.90, 114.54, 114.60, 116.07, 116.22, 124.14, 124.17, 125.28, 131.62, 131.69, 133.23, 133.34, 141.04, 141.09, 142.12, 142.21, 144.81, 144.95, 155.39, 166.77, 166.78, 167.20, 167.33, 168.36, 168.38, 168.64, 168.95, 171.65, 181.14, 181.21, 192.68.

[0249] Example 10: Synthesis of Compound 5 [ka] To a solution of I-2 (150 mg, 0.16 mmol, 1 equiv.) in THF (5 mL) were added (1-methyl-4-piperidyl)methanamine (27 μL, 0.19 mmol, 1.2 equiv.), DIEA (110 μL, 0.64 mmol, 4 equiv.), and COMU (137 mg, 0.32 mmol, 2 equiv.). After 1 h, the solvent was evaporated in vacuo. The resulting solid was dissolved in DCM (40 mL) and washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The solvent was then evaporated in vacuo to give a black solid (quantitative yield), which was used without further purification (Rt: 2.65 min, MS (ESI+) m / z = 1041.70 [M+H]). + The obtained C21-C23 protected compound 5 (160 mg, 0.15 mmol) was dissolved in a solution of THF / 0.5 N camphorsulfone in water (1 / 1). The reaction mixture was stirred at room temperature for 3 h, and 40 mL of DCM was added. The mixture was washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The solvent was evaporated under vacuum, and the resulting solid was purified by flash chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give compound 5 as a black solid (yield: 51%, Rt: 2.28 min, purity (254 nm): 99%, MS (ESI+) m / z = 1001.7 [M+H]). + , 501.4[M+2H] 2+ ).

[0250] Compound 5 was further synthesized as follows: To a solution of I-2 (150 mg, 0.16 mmol, 1 equiv.) in THF (5 mL), (1-methyl-4-piperidyl)methanamine (27 μL, 0.19 mmol, 1.2 equiv.), DIEA (110 μL, 0.64 mmol, 4 equiv.), and COMU (137 mg, 0.32 mmol, 2 equiv.) were added. After 1 h, the solvent was evaporated in vacuo. The resulting solid was dissolved in DCM (40 mL) and washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The solvent was then evaporated in vacuo to give a black solid (quantitative yield), which was used without further purification (Rt: 2.65 min, MS (ESI+) m / z = 1041.70 [M+H]). + ).

[0251] The obtained C21-C23 protected compound 5 (160 mg, 0.15 mmol) was dissolved in a solution of THF / 0.5 N camphorsulfone in water (1 / 1). The reaction mixture was stirred at room temperature for 3 h, and 40 mL of DCM was added. The mixture was washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The solvent was evaporated under vacuum, and the resulting solid was purified by flash chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give compound 5 as a black solid (yield: 51%, Rt: 2.28 min, purity (254 nm): 99%, MS (ESI+) m / z = 1001.7 [M+H]). + , 501.4[M+2H] 2+ ).

[0252] Example 11: Synthesis of Compound 14 [ka] To a solution of I-2 (150 mg, 0.16 mmol, 1 equiv.) in THF (5 mL) were added methyl-phenyl-piperidin-4-yl-amine (0.32 mmol, 2 equiv.), DIEA (110 μL, 0.64 mmol, 4 equiv.), and COMU (137 mg, 0.32 mmol, 2 equiv.). The reaction was stirred at room temperature. After 3 h, the solvent was evaporated under vacuum. The resulting solid was dissolved in DCM (40 mL) and washed with a 0.5 N aqueous solution of HCl (3 × 40 mL), a saturated aqueous solution of NaHCO3 (3 × 40 mL), brine (40 mL), and dried over MgSO4. The DCM was evaporated under vacuum. The resulting solid was then dissolved in 5 mL of a 0.5 N aqueous solution of THF / camphorsulfonic acid (1 / 1). The reaction mixture was stirred at room temperature. After 24 hours, the mixture was diluted with 50 mL of DCM and washed with saturated aqueous NaHCO3 (3 x 50 mL), brine (50 mL), and dried over MgSO4. The solvent was evaporated under vacuum, and the resulting solid was purified by preparative HPLC to give compound 14 as a purple solid (yield = 64%). LC / MS A(ESI+):T R =2.33 min, m / z[M+H] + =1063.61, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3):δ -0.06 (d, J = 7.1 Hz, 1.2H), -0.05 (d, J = 7.1 Hz, 1.8H), 0.83 (d, J = 6.8 Hz, 3H), 0.61 (d, J = 6.9 Hz, 3H), 0,96 (d, J = 6.6 Hz, 6H), 1.03 (d, J = 6.8 Hz, 1.2H), 1.04 (d, J = 6.9 Hz, 1.8H), 1.49-1.38 (m, 1H), 1.70-1.53 (m, 2H), 1.72 (s, 1.8H), 1.74 (s, 1.2H), 1.99-1.76 (m, 7H), 2.04 (s, 3H), 2.10-2.03 (m, 3H), 2.32 (s, 1.2H), 2.33 (s, 1.8H), 2.42-2.33 (m, 3H), 2.66-2.54 (m, 1H), 2.74 (s, 1.2H), 2.79-2.68 (m, 2H), ), 2.81 (s, 1.8H), 3.05-2.95 (m, 2H), 3.07 (s, 1.8H), 3.09 (s, 1.2H), 3.27-3.10 (m, 3H), 3.36-3.28 (m, 1H), 3.48-3.38 (m, 3H), 3.66 (d, J = 9.9 Hz, 1H), 3.88-3.74 (m, 2H), 4.73 (d, J = 13.0 Hz, 1H), 4.82 (t, J = 12.3 Hz, 1H), 5.18 (dd, J = 12.7 Hz, 7.7 Hz, 0.4H), 5.23 (dd, J = 12.6 Hz, 8.0 Hz,0.6H), 5.23 (dd, J = 12.6 Hz, 8.0 Hz,0.6H), 5.95 (t, J = 6.2 Hz, 0.4H), 5.95 (t, J = 6.2 Hz, 0.4H), 6.00 (t, J = 6.3 Hz, 0.6H), 6.17 (d, J = 12.5 Hz, 0.4H), 6.19 (d, J = 12.6 Hz), 6.25 (d, J = 10.5 Hz, 1H), 6.37 (dd, J = 15.2 Hz, 10.0 Hz, 1H), 6.75 (td, J = 7.3 Hz, 0.9 Hz, 1H), 6.86-6.78 (m, 2H), 7.24 (t, J = 7.8 Hz, 2H), 8.24 (s, 0.4H), 8.25 (s, 0.6H), 9.11 (brs, 0.4H), 9.20 (brs, 0.6H), 14.69 (s, 1H). 13 C NMR (75 MHz, CDCl3):δ 7.6, 8.9, 11.19, 11.22, 11.3, 11.5, 17.4, 17.5, 20.32, 20.34, 20.98, 20.99, 22.1, 22.2, 25.8, 28.7, 29.45, 29.48, 31.6, 31.7, 32.9, 33.0, 35.2, 36.1, 37.4, 37.7, 37.8, 38.4, 38.5, 41.4, 41.9, 42.0, 46.4, 51.5, 56.7, 56.8, 56.9, 57.0, 66.3, 72.4, 72.6, 74.1, 74.2, 76.6, 81.1, 81.8, 94.4, 104.7, 104.8, 107.5, 107.6, 109.0, 109.1, 111.8, 114.0, 114.1, 114.5, 114.6, 115.4, 115.6, 117.5, 117.7, 124.1, 125.0, 125.08, 125.1, 129.3, 131.40, 131.43, 133.1, 133.2, 140.9, , 141.9, 142.0, 144.7, 145.3, 149.8, 149.9, 155.3, 164.2, 164.3, 168.3, 168.37, 168.43, 168.5, 171.4, 171.5, 181.0, 181.2, 192.5, 192.6.

[0253] Example 12: Synthesis of Compound 40 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=33%). LC / MS A(ESI+):T R=2.37 points, m / z[M+H] + =1077.65, UV purity: 92% (254nm). HRMS (Maldi-TOF): [M+H] + The calculated value of Hakoseki m / z is 1077.5907, and the measured value is 1077.5912. 1 H NMR (300 MHz, CDCl3): (diestereoisomer and rotary isomer and mixture) δ -0.12-0.00 (m, 3H), 0.51-0.67 (m, 3H), 0.76-0.86 (m, 3H), 0.92-1.06 (m, 9H), 1.26-1.51 (m, 4H), 1.45-2.10 (m, 16H), 2.11-2.45 (m, 6H), 2.46-2.64 (m, 3H), 2.65-3.50 (m, 13H), 3.55-3.71 (m, 2H), 3.56-3.87 (m, 1H), 3.89-4.06 (m, 1H), 4.64-4.88 (m, 2H), 5.08-5.27 (m, 1H), 5.88-6.06 (m, 1H), 607-6.47 (m, 3H), 6.69-6.88 (m, 3H), 7.16-7.30 (m, 2H), 8.16-8.27 (m, 1H), 8.75-9.29 (m, 1H), 14.54-14.75 (m, 1H). 13C NMR (75 MHz, CDCl3): (mixture of diastereoisomers and rotamers) δ 7.68, 8.81, 8.88, 8.97, 10.51, 11.02, 11.23, 11.26, 11.31, 11.67, 13.87, 14.02, 14.05, 14.16, 17.18, 17.27, 17.42, 20.21, 20.32, 20.82, 20.84, 21.74, 22.02, 22.08, 22.22, 25.34, 25.39, 28.65, 28.79, 28.84, 29.54 29.60, 29.65, 31.59, 32.82, 32.94, 33.02, 34.53, 35.41, 37.15, 37.71, 37.81, 37.91, 38.08, 38.33, 38.39, 38.51, 42.12, 42.18, 42.25, 42.79, 43.07, 43.44, 43.54, 45.73, 46.05, 46.08, 46.17, 51.11, 56.46, 56.60, 56.70, 56.86, 56.91, 56.96, 57.02, 65.48, 65.54, 72.11, 72.52, 72.60, 72.74, 73.52, 73.64, 73.68, 74.12, 76.53, 76.75, 79.78, 80.98, 81.34, 81.99, 93.38, 93.53, 104.74, 104.90, 104.94, 107.23, 107.41, 107.46, 107.66, 108.78, 108.82, 108.99, 111.64, 111.78, 113.83, 114.09, 114.15, 114.37, 114.63, 114.66, 114.89, 115.02, 115.19, 115.40, 117.26, 117.65, 123.94, 124.19, 124.79, 124.87, 125.03, 129.24, 130.88, 130.99, 131.29, 133.21, 133.27, 140.79, 140.90, 140.96, 141.50, 141.68, 141.74, 141.91, 143.76, 144.47, 144.76, 145.47, 149.75, 149.91, 155.48, 155.60, 155.64, 167.71, 167.79, 167.85, 168.12, 168.26, 168.41, 168.47, 168.65, 170.97, 171.08, 171.36, 171.41, 171.48, 181.01, 181.38, 181.43, 192.48, 192.58, 192.62, 192.69.

[0254] Example 13: Synthesis of Compound 50 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=15%). LC / MS A(ESI+):T R =2.38 min, m / z[M+H]+=1048.67, UV purity: 99% (254nm). HRMS(Maldi-TOF):[M+H] + Calculated m / z for = 1048.5647, found 1048.5693. 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.06 (dd, J = 6.2 Hz, 62 Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.91-1.03 (m, 9H), 1.11-1.25 (m, 2H), 1.36-1.51 (m, 1H), 1.64-2.07 (m, 10H), 1.73 (s, 3H), 2.03 (s, 3H), 2.26-2.40 (m, 6H), 2.51-2.58 (m, 2H), 2.61-3.10 (m, 6H), 3.06 (s, 3H), 3.13-3.24 (m, 1H), 3.30-3.39 (m, 3H), 3.45-3.74 (m, 4H), 4.46-4.60 (m, 1H), 4.81 (dd, J = 10.4 Hz, 10.4 Hz, 1H), 5.07-5.20 (m, 1H), 5.95 (dd, J = 6.6 Hz, 6.6 Hz, 0.5H), 6.00 (dd, J = 6.6 Hz, 6.6 Hz, 0.5H), 6.09-6.29 (m, 2H), 6.34 (dd, J = 15.4 Hz, 10.4Hz, 1H), 7.10-7.30 (m, 5H), 8.22 (s, 0.5H), 8.24 (s, 0.5H), 9.06 (s, 1H), 14.72 (s, 0.5H), 14.73 (s, 0.5H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.66, 7.71, 8.79, 10.83, 11.09, 11.17, 11.19, 17.31, 17.38, 20.28, 20.80, 21.90, 22.06, 25.69, 31.61, 32.26, 32.34, 32.91, 32.96, 35.16, 36.03, 37.47, 37.58, 37.64, 38.00, 38.17, 38.20, 38.28, 41.21, 42.24, 42.31, 42.84 42.91, 46.66, 46.69, 51.41, 51.47, 56.70, 56.82, 66.17, 72.57, 72.66, 74.07, 74.15, 76.57, 80.50, 81.00, 94.26, 94.30, 104.69, 107.29, 107.43, 108.89, 111.74, 111.77, 114.32, 114.36, 115.19, 115.54, 124.12, 124.16, 125.00, 125.06, 126.10, 128.33, 129.09, 131.04, 131.08, 133.11, 139.75, 139.88, 140.87, 140.93, 141.86, 141.98, 144.20, 144.71, 155.29, 164.04, 164.09, 168.23, 168.26, 168.30, 168.38, 168.58, 168.63, 171.34, 171.42, 181.10, 181.15, 192.50, 192.56.

[0255] Example 14: Synthesis of Compound 57 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=42%). LC / MS A(ESI+):T R =2.27 min, m / z[M+H] + =1050.56, UV purity: 99% (254nm). HRMS(Maldi-TOF):[M+H]+ The calculated value of Hoseki m / z is 1050.5434, and the measured value is 1050.5505. 1 H NMR (300 MHz, CDCl3): (Mixture of isomers) δ -0.05 (dd, J = 1.6 Hz, J = 7.0 Hz, 3H), 0.60 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 6H), 1.0 (d, J = 6.6 Hz, 3H), 1.36-1.50 (m, 1H), 1.66-2.18 (m, 11H), 1.69 (s, 1.5H), 1.73 (s, 1.5H), 2.03 (s, 3H), 2.28-2.43 (m, 3H), 2.30 (s, 1.5H), 2.31 (s, 1.5H), 2.73-2.90 (m, 2H), 2.98-3.11 (m, 2H), 3.07 (s, 1.5H), 3.08 (s, 1.5H), 3.18 (t, J = 9 Hz, 1H), 3.27-3.41 (m, 4H), 3.48-3.88 (m, 6H), 4.50-4.62 (m, 1H), 4.80 (dd, J = 9.6, 5.7 Hz, 1H), 5.14 (quad d, J = 4.5 Hz, 12.5 Hz, 1H), 5.96 (ddd, J = 2.6 Hz, 6.6 Hz, 15.6 Hz, 1H), 6.17 (dd, J = 3.8 Hz, 12.5 Hz, 1H), 6.24 (d, J= 9.9 Hz, 1H), 6.36 (dd, J = 15.6 Hz, 10.4 Hz, 1H), 6.86-6.99 (m, 3H), 7.23-7.32 (m, 2H), 8.20 (s, 0.5H), 8.21 (s, 0.5H), 9.05 (s, 0.5H), 9.07 (s, 0.5H), 14.68 (s, 0.5H), 14.69 (s, 0.5H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.67, 8.81, 11.06, 11.17, 11.20, 17.29, 17.32, 20.26, 20.82, 20.83, 21.95, 22.10, 25.56, 29.68, 29.85, 29.99, 30.75, 30.81, 32.90, 32.94, 34.92, 35.79, 37.40, 37.50, 37.66, 38.31, 38.36, 38.52, 41.21, 41.24, 42.84, 43.06, 51.26, 51.30, 56.70, 56.72, 65.88, 70.79, 71.03, 72.50, 72.54, 74.11, 74.17, 76.56, 80.95, 81.21, 93.98, 104.73, 107.39, 107.46, 108.92, 111.70, 111.72, 114.44, 114.50, 115.04, 115.13, 116.05, 116.07, 121.23, 124.11, 124.94, 129.65, 131.11, 133.12, 140.88, 141.76, 141.81, 144.68, 144.88, 155.37, 156.94, 156.96, 164.19, 164.25, 168.10, 168.22, 168.29, 168.32, 168.49, 171.30, 171.36, 181.11, 181.15, 192.48, 192.56.

[0256] Example 15: Synthesis of Compound 66 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=38%). LC / MS A(ESI+):T R =2.23 min, m / z[M+H] + =1067.61, UV purity: 97% (254nm). HRMS(Maldi-TOF):[M+H] + Calculated m / z for = 1067.5500, found 1067.5509. 1 H NMR (300 MHz, CDCl3): (Mixture of rotating isomers) δ -0.08 (d, J = 7.7 Hz, 3H), 0.56 (d, J = 5.0 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.5 Hz, 6H), 1.01 (d, J = 6.9 Hz, 3H), 1.35-1.47 (m, 1H), 1.66-2.06 (m, 7H), 1.73 (s, 3H), 2.03 (s, 3H), 2.12-2.32 (m, 2H), 2.29 (s, 3H), 2.32-2.42 (m, 1H), 2.46 (d, J = 6.7 Hz, 2H), 2.81-3.81 (m, 19H), 3.06 (s, 1.5H), 3.07 (s, 1.5H), 4.77-4.84 (m, 1H), 5.12-5.20 (m, 1H), 5.96 (dd, J = 6.5, 15.4 Hz, 1H), 6.16 (dd, J = 4.5, 12.6 Hz, 1H), 6.24 (d, J =10.4 Hz, 1H), 6.36 (ddd, J = 4.3, 10.7, 15.2 Hz, 1H), 6.57-6.65 (m, 2H), 6.87-6.95 (m, 2H), 8.25 (s, 1H), 8.98 (s, 1H), 14.65 (s, 0.5H), 14.67 (s, 0.5H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.73, 8.86, 10.99, 11.09, 11.21, 17.40, 20.37, 20.91, 22.03, 22.06, 24.37, 25.51, 26.27, 32.99, 34.73, 35.61, 37.37, 37.65, 37.72, 38.37, 38.46, 40.68, 41.27, 45.24, 46.03, 47.61, 47.87, 47.94, 49.07, 50.10, 51.01, 51.23 51.26, 56.81, 56.84, 65.72, 72.56, 72.64, 74.10, 74.17, 76.57, 80.84, 81.06, 93.78, 104.84, 104.89, 107.44, 107.47, 108.94, 109.00, 111.77, 111.82, 112.73, 112.82, 112.91, 114.59, 114.62, 115.41, 115.93, 116.01, 116.22, 116.30, 124.13, 124.22, 125.02, 131.11, 131.26, 133.20, 133.26, 140.94, 140.96, 141.93, 143.54, 143.57, 143.80, 143.82, 144.47, 144.64, 153.73, 153.77, 155.55, 155.58, 156.85, 156.89, 165.59, 165.89, 168.27, 168.32, 168.40, 171.46, 171.48, 181.31, 181.37, 192.70, 192.72.

[0257] Example 16: Synthesis of Compound 82 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=42%). LC / MS A(ESI+):T R =2.29 min, m / z[M+H] +=1077.54, UV purity: 99% (254nm). HRMS (Maldi-TOF): [M+H] + The calculated value of Hakoseki m / z is 1077.5907, and the measured value is 1077.5912. 1 H NMR (300 MHz, CDCl3): (Mixture of isomers) δ -0.04 (d, J = 7.0 Hz, 1.5H), -0.03 (d, J = 7.0 Hz, 1.5H), 0.62 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.5 Hz, 6H), 1.02 (d, J = 6.9 Hz, 3H), 1.38-1.47 (m, 1H), 1.60-1.84 (m, 7H), 1.73 (s, 3H), 1.90-2.22 (m, 4H), 2.03 (s, 3H), 2.26-2.76 (m, 10H), 2.28 (s, 3H), 2.73 (d, J = 13.8 Hz, 3H), 2.86-3.00 (m, 2H), 3.01-3.17 (m, 1H), 3.05 (s, 3H), 3.17-3.30 (m, 1H), 3.35 (dd, J = 2.1 Hz, 7.1 Hz, 1H), 3.57-3.84 (m, 4H), 3.95 (d, J = 13.3 Hz, 1H), 4.27 (d, J = 13.3 Hz, 1H), 4.76 (dd, J = 8.7 Hz, 9.1 Hz, 1H), 5.16 (dd, J = 12.6 Hz, 7.2 Hz, 1H), 5.97 (dd, J = 15.5 Hz, 6.8 Hz, 1H), 6.15, (d, J = 12.5 Hz, 1H), 6.23 (d, J = 10.1 Hz, 0.8 Hz, 1H), 6.36 (dd, J = 15.6 Hz, 10.2 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 2H), 7.17-7.26 (m, 2H), 8.23 ​​(s, 1H), 8.97 (s, 1H), 14.79 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.87, 7.99, 9.11, 11.09, 11.16, 11.34, 17.61, 20.62, 21.10, 22.24, 26.08, 28.12, 28.25, 29.05, 29.58, 29.67, 31.76, 31.80, 33.20, 33.24, 35.65, 36.52, 37.74, 37.77, 37.85, 38.51, 42.02, 42.18, 45.28, 45.42, 51.62, 51.72 57.05, 57.21, 66.54, 73.18, 73.41, 73.46, 76.83, 80.76, 80.91, 94.86, 104.95, 107.54, 107.56, 109.12, 112.11, 114.15, 114.26, 114.40, 115.48, 115.63, 117.63, 117.78, 124.43, 125.39, 129.49, 131.24, 133.22, 141.32, 142.35, 144.26, 144.40, 150.03, 150.08, 155.47, 168.53, 168.58, 169.78, 169.90, 171.55, 171.60, 174.28, 174.43, 181.48, 192.76.

[0258] Example 17: Synthesis of Compound 85 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=35%). LC / MS A(ESI+):T R =2.29 min, m / z[M+H] + =1091.57, UV purity: 99% (254nm). HRMS(Maldi-TOF):[M+H] + Calculated m / z for = 1091.6063, found 1091.6069. 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.05 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.5 Hz, 6H), 1.05 (d, J = 7.0 Hz, 3H), 1.37-1.51 (m, 1H), 1.62-2.08 (m, 13H), 1.74 (s, 1.5H), 1.75 (s, 1.5H), 2.07 (s, 3H), 2.29-2.46 (m, 7H), 2.34 (s, 3H), 2.56-2.71 (m, 3H), 2.77 (s, 3H), 2.94-3.17 (m, 4H), 3.08 (s, 1.5H), 3.08 (s, 1.5H), 3.32 (dd, J = 7.4 Hz, 2.2 Hz, 1H), 3.45 (s, 1H), 3.64-3.74 (m, 2H), 3.75-3.88 (m, 1H), 3.94-4.08 (m, 1H), 4.68-4.84 (m, 2H), 5.17 (dd, J = 7.6 Hz, 4.7 Hz, 0.5H), 5.21 (dd, J = 7.6 Hz, 4.7 Hz, 0.5H), 6.02 (dd, J = 15.3 Hz, 6.0 Hz, 1H), 6.19 (d, J = 12.3 Hz, 1H), 6.23-6.45 (m, 2H), 6.76 (t, J = 7.1 Hz, 1H), 6.84 (d, J = 8.25 Hz, 2H), 7.22-7.31 (m, 2H), 8.22 (s, 1H), 9.17 (s, 1H), 14.75 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.86, 9.04, 11.26, 11.35, 11.50, 17.62, 20.47, 20.64, 21.08, 22.17, 26.07, 29.07, 29.83, 31.78, 32.51, 32.63, 33.24, 33.69, 35.58, 36.48, 37.70, 37.75, 37.91, 38.50, 38.55, 41.86, 45.61, 51.61, 51.70, 56.98, 57.24, 66.52, 72.84, 73.09, 73.16, 77.10, 81.16, 81.36, 94.94, 104.76, 107.56, 109.19, 111.92, 114.19, 114.50, 116.00, 117.66, 124.21, 125.33, 131.58, 131.62, 133.20, 141.14, 142.24, 144.59, 144.71, 150.07, 155.32, 168.35, 168.64, 170.76, 170.81, 171.65, 174.31, 174.37, 181.18, 192.63.

[0259] Example 18: Synthesis of Compound 90 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=47%). LC / MS A(ESI+):T R =1.76 min, m / z[M+H] + =1063.51, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.10 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.4 Hz, 6H), 1.03 (d, J = 6.8 Hz, 3H), 1.24-1.32 (m, 1H), 1.44-1.59 (m, 2H), 1.71-2.20 (m, 11H), 1.72 (s, 3H), 2.04 (s, 3H), 2.27-2.45 (m, 3H), 2.34 (s, 3H), 2.60-2.83 (m, 4H), 2.89-3.13 (m, 4H), 3.02 (s, 3H), 3.16-3.27 (m, 3H), 3.37 (s, 1H), 3.50 (s, 2H), 3.65 (d, J = 9.7 Hz, 2H), 3.72-3.90 (m, 1H), 4.81 (d, J = 10.4 Hz, 1H), 5.32 (dd, J = 12.6 Hz, 9.2 Hz, 1H), 5.86-6.00 (m, 1H), 6.18-6.35 (m, 3H), 7.24-7.33 (m, 5H), 8.24 (s, 1H), 9.47 (s, 1H), 14.55 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.65, 8.79, 10.92, 12.02, 17.18, 20.11, 20.82, 20.84, 22.32, 25.81, 31.73, 31.84, 32.73, 35.19, 36.12, 37.04, 38.04, 38.93, 41.70, 46.30, 51.43, 51.98, 56.14, 63.10, 66.26, 71.85, 73.50, 76.32, 83.00, 94.74, 104.27, 107.66 109.29, 111.43, 114.79, 115.63, 123.47, 124.82, 127.08, 128.23, 129.21, 132.28, 132.73, 138.15, 140.57, 141.75, 146.09, 154.89, 164.67, 167.91, 168.33, 169.29, 171.36, 180.56, 192.33.

[0260] Example 19: Synthesis of Compound 91 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=35%). LC / MS A(ESI+):T R =2.01 min, m / z[M+H] + =1049.57, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.06 (d, J = 7.0 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.7 Hz, 6H), 1.01 (d, J = 6.9 Hz, 3H), 1.35-1.52 (m, 1H), 1.68-2.14 (m, 7H), 1.73 (s, 3H), 2.03 (s, 3H), 2.27-2.48 (m, 7H), 2.31 (s, 3H), 2.60-2.75 (m, 2H), 2.91-3.03 (m, 2H), 3.06 (s, 3H), 3.18 (d, J = 9.9 Hz, 1H), 3.27-3.47 (m, 6H), 3.48-3.59 (m, 4H), 3.59-3.70 (m, 2H), 4.81 (d, J = 10.6 Hz, 1H), 5.14 (dd, J = 12.5 Hz, 7.6 Hz, 1H), 5.98 (dd, J = 15.6 Hz, 6.6 Hz, 1H), 6.16 (d, J = 12.5 Hz, 1H), 6.24 (d, J = 10.3 Hz, 1H), 6.37 (dd, J = 15.6 Hz, 10.4 Hz, 1H), 7.24-7.33 (m, 5H), 8.25 (s, 1H), 9.09 (s, 1H), 14.73 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 8.01, 9.10, 11.35, 11.47, 17.63, 20.57, 21.14, 22.30, 26.06, 33.22, 35.55, 36.41, 37.80, 37.91, 38.55, 41.42, 42.20, 46.60, 51.65, 51.71, 52.80, 53.17, 57.03, 63.11, 66.49, 72.85, 74.46, 76.84, 81.20, 94.77, 104.93, 107.66 109.20, 112.06, 114.64, 115.60, 124.41, 125.35, 127.63, 128.66, 129.44, 131.45, 133.35, 137.76, 141.14, 142.27, 144.89, 155.51, 164.51, 168.55, 168.65, 168.68, 171.67, 181.37, 192.81.

[0261] Example 20: Synthesis of Compound 95 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=45%). LC / MS A(ESI+):T R =2.02 min, m / z[M+H] + =1075.60, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.10 (d, J = 6.8 Hz, 3H), 0.60 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 1.18 (d, J = 6.4 Hz, 6H), 1.28-1.48 (m, 2H), 1.60-1.80 (m, 2H), 1.65 (s, 3H), 1.81-1.95 (m, 1H), 1.99 (s, 3H), 2.17-2.39 (m, 2H), 2.29 (s, 3H), 2.65-2.91 (m, 4H), 2.97 (d, J = 7.0 Hz, 2H), 3.04-3.14 (m, 1H), 3.07 (s, 3H), 3.15-3.43 (m, 10H), 3.45-3.75 (m, 10H), 3.94-4.04 (m, 1H), 4.78 (d, J = 10.7 Hz, 1H), 5.20 (dd, J = 12.4 Hz, 8.8 Hz, 1H), 5.88 (dd, J = 15.1 Hz, 6.7 Hz, 1H), 6.12-6.36 (m, 3H), 7.08-7.23 (m, 4H), 8.25 (s, 1H), 8.98 (s, 1H), 14.47 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 8.09, 9.18, 11.37, 11.66, 17.38, 20.55, 21.57, 22.46, 24.83, 32.79, 33.04, 33.71, 36.06, 36.19, 36.72, 38.02, 39.01, 40.66, 41.41, 45.05, 50.71, 51.42, 51.77, 51.88, 56.87, 65.35, 67.12, 72.53, 74.09, 76.74, 82.09, 91.36, 105.51, 108.02, 109.27, 111.85, 115.02, 115.44, 124.47, 124.68, 124.72, 124.77, 127.33, 131.84, 133.13, 140.23, 140.54, 141.70, 145.63, 156.69, 164.54, 168.17, 168.35, 171.45, 182.05, 193.05.

[0262] Example 21: Synthesis of Compound 98 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=56%). LC / MS A(ESI+):T R =2.01 min, m / z[M+H] + =1055.58, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.05 (d, J = 7.0 Hz, 3H), 0.59 (d, J = 6.9 Hz, 3H), 0.78-0.95 (m, 2H), 0.81 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.5 Hz, 6H), 1.02 (d, J = 7.0 Hz, 3H), 1.14-1.21 (m, 2H), 1.37-1.53 ​​(m, 2H), 1.63-1.87 (m, 9H), 1.73 (s, 3H), 1.89-2.00 (m, 2H), 2.01-2.16 (m, 4H), 2.03 (s, 3H), 2.23-2.41 (m, 7H), 2.30 (s, 3H), 2.53-2.71 (m, 2H), 2.87-3.01 (m, 2H), 3.07 (s, 3H), 3.14-3.22 (m, 1H), 3.29-3.41 (m, 5H), 3.42-3.57 (m, 3H), 3.58-3.70 (m, 2H), 4.79 (dd, J = 10.7 Hz, 0.9 Hz, 1H), 5.13 (dd, J = 12.6 Hz, 7.6 Hz, 1H), 5.98 (dd, J = 15.6 Hz, 6.6 Hz, 1H), 7.17 (d, J = 12.5 Hz, 1H), 6.24 (dd, J = 10.3 Hz, 1.0 Hz, 1H), 6.38 (dd, J = 15.6 Hz, 10.4 Hz, 1H), 8.21 (s, 1H), 9.11 (s, 1H), 14.73 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 8.02, 9.11, 11.40, 11.50, 17.64, 20.56, 21.13, 21.15, 22.33, 26.15, 26.38, 27.07, 32.09, 33.25, 35.25, 35.71, 36.56, 37.82, 37.92, 38.54, 41.46, 42.26, 46.64, 51.70, 51.77, 53.36, 53.91, 57.04, 65.70, 66.60, 72.87, 74.51 76.90, 81.25, 94.92, 104.91, 107.68, 109.20, 112.08, 114.62, 115.57, 124.43, 125.37, 131.44, 133.38, 141.20, 142.23, 145.00, 155.47, 164.42, 168.57, 168.67, 168.83, 171.66, 181.30, 192.76.

[0263] Example 22: Synthesis of Compound 99 [ka] Following the procedure described above for compound 14, the title compound was obtained as a purple solid (yield=23%). LC / MS A(ESI+):T R =2.00 min, m / z[M+H] + =1036.54, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): (mixture of isomers) δ -0.05 (d, J = 7.1 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.5 Hz, 6H), 1.02 (d, J = 7.0 Hz, 3H), 1.36-1.48 (m, 1H), 1.72-2.11 (m, 7H), 1.72 (s, 3H), 2.03 (s, 3H), 2.23-2.31 (m, 2H), 2.28 (s, 3H), 2.31-2.42 (m, 1H), 2.50-2.75 (m, 2H), 2.86-3.02 (m, 2H), 3.09 (s, 3H), 3.13-3.23 (m, 1H), 3.34 (dd, J = 7.8 Hz, 2.5 Hz, 1H), 3.40-3.70 (m, 12H), 3.73-3.84 (m, 1H), 4.81 (dd, J = 10.6 Hz, 1.0 Hz, 1H), 5.17 (dd, J = 12.6 Hz, 7.9 Hz, 1H), 5.96 (dd, J = 15.5 Hz, 6.6 Hz, 1H), 6.15-6.28 (m, 2H), 6.36 (dd, J = 15.6 Hz, 10.4 Hz, 1H), 6.63-6.70 (m, 2H), 7.49 (dd, J = 7.2 Hz, 1.9 Hz, 0.5H), 7.52 (dd, J = 7.2 Hz, 1.9 Hz, 0.5H), 8.19 (dd, J = 5.1 Hz, 1.8 Hz, 1H), 8.24 (s, 1H), 9.16 (s, 1H), 14.71 (s, 1H). 13C NMR (75 MHz, CDCl3): (mixture of rotamers) δ 7.97, 9.12, 11.47, 11.58, 17.61, 20.55, 21.13, 21.15, 22.39, 26.12, 33.21, 35.65, 36.51, 37.70, 37.99, 38.65, 41.54, 41.87, 45.34, 45.43, 46.23, 51.70, 51.76, 56.99, 66.58, 72.73, 74.48, 76.85, 81.63, 94.92, 104.85, 107.60 107.74, 109.26, 112.02, 114.34, 114.72, 115.51, 124.34, 125.31, 131.61, 133.31, 138.03, 141.09, 142.21, 145.30, 148.32, 155.43, 159.29, 164.85, 168.52, 168.55, 168.64, 171.62, 181.24, 192.74.

[0264] Example 23: Antibacterial activity of compounds of the present invention MIC values ​​were determined by broth microdilution according to CLSI guidelines. Unless otherwise noted, MICs for A. baumannii were performed in RPMI medium supplemented with 10% FCS. MICs for S. pneumoniae and S. pyogenes were performed in cation-adjusted Mueller Hinton broth supplemented with 5% laked horse blood. MICs for H. influenzae were performed in Hemophilus test medium broth. MICs for M. abscessus, M. tuberculosis, and M. smegmatis were performed in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement (10%). All other MICs were performed in standard cation-adjusted Mueller Hinton broth supplemented with Middlebrook ADC growth supplement (5%) for slow-growing mycobacteria (M. xenopi, M. kansasii, and M. avium).

[0265] The following procedure applies to all species tested, except for M. tuberculosis and M. smegmatis. Resuspend cells from plate cultures (overnight to 7-day cultures, depending on the species) in 0.9% (w / v) saline solution and add a bacterial inoculum of 5 x 10 5CFU / mL were prepared in the respective test media. For M. xenopi, inocula were prepared from fresh liquid cultures (7H9+ADC) instead of plates. Using a digital dispenser, appropriate volumes of 10 mg / mL compound solution were directly dispensed into 96-well assay plates to create two-fold dilution series with final concentrations ranging from 32 to 0.00006 μg / mL (range adapted depending on species). Finally, 100 μL of bacterial suspension was added to the compound. Plates were covered and incubated without shaking at 35°C for 20 hours to 7 days or longer, depending on the species. Antibiotics were included in all experiments as quality controls. MICs were determined visually as the lowest concentration of compound that prevented visible bacterial growth.

[0266] Inocula were prepared from exponentially growing cultures and grown to OD of 0.02 and 0.002 for M. tuberculosis and M. smegmatis, respectively. 600 Similar procedures were used for M. tuberculosis and M. smegmatis, except that the MICs were set at 100°C. MICs at 90% growth inhibition were determined using a GFP reporter after 5 days of incubation for M. tuberculosis and using the BacTiter-Glo kit (Promega) after 20 hours of incubation for M. smegmatis.

[0267] The in vitro activity of the compounds described herein was determined against S. aureus (strain UAMS-1625), A. baumannii (strain HUMC1), M. abscessus (ATCC 19977), M. kansasii (ATCC 12478), M. avium (ATCC 25291), and M. xenopi (ATCC 19250). MIC values, expressed in μg / mL, are shown in Table 4 below.

[0268] [Table 7-1] [Table 7-2] [Table 7-3]

[0269] In vitro activity against M. abscessus complex Compound 3, rifabutin, rifampicin, 3-(4-morpholinyl)rifamycin S, and CGP4832 were tested for MIC activity against the following five isolates of the Mycobacterium abscessus complex: (1) M. abscessus subsp. abscessus; strain ID number ATCC 19977; (2) M. abscessus subsp. abscessus; strain ID number CCUG 71636; (3) M. abscessus subsp. abscessus; strain ID number CCUG 71382; and (4) M. abscessus subsp. bolletii; strain ID number CCUG 50184; and (5) M. abscessus subsp. massiliense; strain ID number CCUG 48898. The structures of rifabutin, rifampicin, 3-(4-morpholinyl)rifamycin S, and CGP4832, as well as the results, are shown below. [ka]

[0270] [Table 8]

[0271] Additionally, compounds 85, 90, and 98 were tested in CAMHB medium against the same five isolates of the Mycobacterium abscessus complex used above in Table 5. The data are shown below in Table 6.

[0272] [Table 9]

[0273] In vitro activity against A. baumannii Compound 3, rifabutin, rifampicin, 3-(4-morpholinyl)rifamycin S, and CGP4832 were tested for MIC activity against the following isolates of A. baumannii: wild-type (WT); Arr-2, RpoB H535Q mutant; RpoB H535C mutant; and RpoB H535L mutant. The results are shown in Table 7 below.

[0274] [Table 10]

[0275] In vitro activity against additional bacterial species Additionally, compound 3, rifabutin, rifampicin, 3-(4-morpholinyl)rifamycin S, and CGP4832 were tested for MIC activity against strains from the following species: Enterococcus faecium (strain NCTC 12204), Enterococcus faecalis (strain ATCC 51575), Staphylococcus epidermidis (strain ATCC 12228), Streptococcus pneumoniae (strain ATCC 49619), Streptococcus pyogenes (strain IHMA 1117021), and Haemophilus influenzae (strain ATCC 12228). 49247), Mycobacterium tuberculosis (H37Rv, ATCC 27294 strain), and M. smegmatis (ATCC 700084 strain). The results are shown in Table 8 below.

[0276] [Table 11]

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof: 【Chemistry 1】 (In the formula, Y １ But (CR １ R ２ ) ｎ where n is an integer from 1 to 6; R １ and R ２ independently at each occurrence, hydrogen, -C １ -C ６ Alkyl, and -C １ -C ６ alkoxy, each alkyl being selected from the group consisting of one or more halogens, or -C ３ -C ６ each cycloalkyl may be further substituted by one or more halogens; X １ But, -OR １１ or -NR ５１ R ５２ and R １１ But independently, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R １２Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R １２ may be substituted by R １２ and R １２Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R １６Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -OR １３ , -CO ２ R １３ or -NR １４ R １５ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R １６ may be substituted by R １３ , R １４ and R １５ are each independently hydrogen, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ２０Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, -S(O) ２ (C １ -C ６ alkyl), or -S(O) ２ N.R. １８ R １９ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ２０ may be substituted by R １６ and R １６Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ２０Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -OR １７ , -S(O) ２ (C １ -C ６ alkyl), or -S(O) ２ N.R. １８ R １９ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ２０ may be substituted by R １７ , R １８ and R １９ are each independently hydrogen, halogen, —OH, —C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ２３Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, -S(O) ２ (C １ -C ６ alkyl), or S(O) ２ N.R. ２１ R ２２ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ２３ may be substituted by R ２０ and R ２０Ａ each independently represents a halogen, —OH, —C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ２３Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -S(O) ２ (C １ -C ６ alkyl), or S(O) ２ N.R. ２１ R ２２ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ２３ may be substituted by R ２１ and R ２２ are each independently hydrogen or -C １ -C ６ is alkyl, R ２３ and R ２３Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkoxy, -C １ -C ６ haloalkyl, halogen, or cyano; R ５１ and R ５２ are each independently hydrogen, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ５３Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R ５３ or R ５１ and R ５２ together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl or a 5- to 15-membered heteroaryl, said heterocycloalkyl or heteroaryl being selected from one or more R ５３ may be substituted by R ５３ and R ５３Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ５７Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -OR ５４ , -C(O)R ５４ , -CO ２ R ５４ or -NR ５５ R ５６ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ５７ may be substituted by R ５４ , R ５５ and R ５６ are each independently hydrogen, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ６１Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, —CO ２ R ５８ , -S(O) ２ (C １ -C ６ alkyl), -S(O) ２ (C ６ -C １０ aryl), or -S(O) ２ N.R. ５９ R ６０ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ６１ may be substituted by R ５７ and R ５７Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ６１Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -OR ５８ , N.R. ５９ R ６０ , -S(O) ２ (C １ -C ６ alkyl), or -S(O) ２ N.R. ５９ R ６０ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ６１ may be substituted by R ５８ , R ５９ and R ６０ are each independently hydrogen, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ６４ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, -S(O) ２ (C １ -C ６ alkyl), or S(O) ２ N.R. ６２ R ６３ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ６４ may be substituted by R ６１ and R ６１Ａ each independently represents a halogen, —OH, —C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ６４Ａ , -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, -C ３ -C ６ Cycloalkyl, -C ５ -C ８ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkyl, halogen, cyano, oxo, -S(O) ２ (C １ -C ６ alkyl), or S(O) ２ N.R. ６２ R ６３ and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy is selected from one or more R ６４ may be substituted by R ６２ and R ６３ are each independently hydrogen, and -C １ -C ６ is alkyl, R ６４ and R ６４Ａ Each independently represents -C １ -C ６ Alkyl, -C １ -C ６ Alkoxy, -C １ -C ６ haloalkyl, phenyl, halogen, or cyano.

2. The compound is of formula IA: 【Chemistry 2】 During the ceremony, m is an integer from 0 to 4; R ３ is selected from -H, methyl, and ethyl, preferably the compound is of formula I-B, formula IC, formula ID, formula IE, formula IF, or formula IG: 【Chemistry 3】

3. X １ Ga-OR １１ 3. The compound according to claim 1 or claim 2,

4. X １ -NR ５１ N.R. ５２ 3. The compound according to claim 1 or claim 2,

5. R ５１ and R ５２ are each independently hydrogen, -C １ -C ６ Alkyl, -C １ -C ６ Alkylene-R ５３Ａ , -C ５ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, or phenyl, preferably R ５１ and R ５２ at least one of is hydrogen, and each alkyl, alkylene, cycloalkyl, heterocycloalkyl or phenyl is selected from one or more, preferably one or two, R ５３ or R ５１ and R ５２ together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl, said heterocycloalkyl containing one or more, preferably one or two, R ５３ The compound of claim 4, optionally substituted by:

6. R ５１ and R ５２ together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocycloalkyl, said heterocycloalkyl containing one or more, preferably one or two, R ５３ or said heterocycle is fused to one or more additional aryl or heteroaryl rings to form a 10-15 membered heteroaryl, said 10-15 membered heteroaryl being substituted by one or more, preferably one or two, R ５３ or said heterocycle is attached at a single atom to another cycloalkyl or heterocycloalkyl to form a 10-15 membered spirocyclic heterocycle, said spirocyclic group being optionally substituted by one or more, preferably one or two, R ５３ The compound of claim 4, optionally substituted by:

7. The compound of claim 6, wherein the 3- to 15-membered heterocycloalkyl is piperidine, morpholine, 1,4-diazepane, piperazine, or azetidine.

8. The compound of claim 6 , wherein the heterocycloalkyl is piperidine.

9. R ５３ and R ５３Ａ But independently, -C １ -C ４ Alkyl, -C １ -C ３ Alkylene-R ５７Ａ , 5- to 15-membered heterocycloalkyl, 5- to 15-membered heteroaryl, or phenyl, —OR ５４ , -C(O)R ５４ , -CO ２ R ５４ , oxo, or -NR ５５ R ５６ and each alkylene, heterocycloalkyl, heteroaryl, and phenyl is selected from one or more R ５７ may be substituted by R ５４ are independently hydrogen, -C １ -C ４ Alkyl, -C ５ -C ６ cycloalkyl, or phenyl, each alkyl, cycloalkyl, or phenyl being selected from one or more R ６１ may be substituted by R ５５ and R ５６ are each independently hydrogen, -C １ -C ４ Alkyl, -C １ -C ４ Alkylene-R ６１Ａ , phenyl, -CO ２ C １ -C ６ Alkyl, -S(O) ２ (phenyl), wherein phenyl or cycloalkyl is selected from one or more of R ６１ Optionally, The compound according to any one of claims 4 to 8.

10. R ５７ and R ５７Ａ But independently, -C １ -C ６ Alkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, oxo, halogen, -OH, or -SO ２ N.H. ２ and each alkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from one or more R ６１ The compound according to any one of claims 4 to 9, optionally substituted by:

11. R ６１ and R ６１Ａ But independently, -C １ -C ２ Alkyl, phenyl, -C １ -C ２ Alkoxy, -C １ -C ２ The compound according to any one of claims 4 to 10, which is haloalkyl or halogen.

12. X １ The compound of claim 1, wherein is selected from the group consisting of: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】

13. The compound of claim 1 selected from the group consisting of: 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【Table 2-15】 【Table 2-16】 【Table 2-17】 【Table 2-18】 【Table 2-19】 【Table 2-20】 【Table 2-21】 【Table 2-22】 【Table 2-23】

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient.

15. A compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 14, for use as a medicament, preferably for use in a method for treating a bacterial infection.

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