Rifbutin analogs for use in disease treatment

Abstract

The present invention relates to compounds and pharmaceutical compositions comprising said compounds for use in the treatment, amelioration and / or prevention of diseases. In some embodiments, the disease is a bacterial infection. In some embodiments, the bacterial infection is caused by one or more bacteria belonging to the non-tuberculous Mycobacterium genus, preferably Mycobacterium abscessus.

Description

[0001] The present application relates to compounds for use in the treatment, amelioration and / or prevention of a disease and pharmaceutical compositions comprising said compounds. In some embodiments, the disease is an infection, preferably a bacterial infection. In some embodiments, the bacteria belongs to the following genera or species: Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp., Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis and / or Toxoplasma gondii.

[0002] In some embodiments, the infection is caused by A. baumannii and / or M. abscessus and / or non-tuberculous Mycobacterium (NTM), preferably by M. abscessus. BACKGROUND

[0003] Rifamycins, such as rifabutin, are antibiotics known to have broad-spectrum activity against certain species of Clostridium, Enterococcus, Haemophilus, Legionella, Mycobacterium (both tuberculous and non-tuberculous), Neisseria, Staphylococcus, Streptococcus, Listeria monocytogenes, Moraxella catarrhalis, Bacillus, Bacteroides, Gardnerella vaginalis, Lactobacillus, Mosquitobrachium, 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).

[0004] Recent studies have shown that rifabutin exhibits strong in vitro and in vivo activity against both 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, more effective rifabutin is still needed for the treatment of bacterial infections such as Mycobacterium abscessus and Acinetobacter baumannii infections.

[0005] Invention Summary

[0006] On the one hand, the present invention provides compounds of Formula I or their pharmaceutically acceptable salts, tautomers, solvates, hydrates or enantiomers:

[0007]

[0008] in:

[0009] R 1 and R 2 Each is independently selected from -H, -C1-C6 alkyl, -C3-C 10cycloalkyl, C1-C6 alkylene-C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 3 Replace; or

[0010] R 1 and R 2 Together with the nitrogen atoms to which they are attached, they combine to form 5- to 15-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally bonded by one or more R atoms. 4 replace;

[0011] R 3 Each occurrence is independently -OH, halogen, -CN, -C1-C6 alkoxy, -C1-C6 alkyl, -C3-C 10 Cycloalkyl, -C1-C6 alkylene, -C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-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), wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl may optionally be substituted by one or more -OH, halogen or C1-C6 alkyl groups;

[0012] R 4 Each time it appears, it is independently -C1-C6 alkyl, -OR 5 -C1-C6 alkylene-OR 5 -NR 6 R 7 -C1-C6 alkylene-NR 6 R 7 -C3-C 10 Cycloalkyl, -C1-C6 alkylene, -C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-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), wherein each alkylene is optionally substituted with one or more oxo groups, and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more R groups.8 substituted;

[0013] R 5 independently at each occurrence -H, -Ci-C6alkyl, or -Ci-C6alkylene-OH;

[0014] R 6 and R 7 each occurrence is, independently, -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-Ci0aryl, -Ci-C6alkylene-C6-Ci0aryl, -C6-Ci0aryl-Ci-C6alkylene-, -Ci-C6alkylene-C6-Ci0arylene-, -C6-Ci0arylene-Ci-C6alkylene-, -C6-Ci0arylene-, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, or 5- to 10-membered heteroaryl; and

[0015] R 8 independently at each occurrence -OH, halogen, or -Ci-C6alkyl.

[0016] In one aspect, the present application provides a compound of Formula I:

[0017]

[0018] wherein:

[0019] R 1 and R 2 each is independently selected from -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-Ci0aryl, -Ci-C6alkylene-C6-Ci0aryl, -C6-Ci0aryl-Ci-C6alkylene-, -Ci-C6alkylene-C6-Ci0arylene-, -C6-Ci0arylene-Ci-C6alkylene-, -C6-Ci0arylene-, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 substituted; or

[0020] R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituted;

[0021] R 3 independently at each occurrence -OH, halogen, -Ci-C6alkyl, -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-Ci0aryl, -Ci-C6alkylene-C6-Ci0aryl, -C6-Ci0aryl-Ci-C6alkylene-, -Ci-C6alkylene-C6-Ci0arylene-, -C6-Ci0arylene-Ci-C6alkylene-, -C6-Ci0arylene-, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R10 aryl, -C1-C6alkylene-C6-C10aryl, -C1-C6alkylene-(5- to 10-membered heteroaryl), wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl; 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6alkylene-(5- to 10-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl;

[0022] R 4 independently at each occurrence -C1-C6alkyl, -OR 5 , -C1-C6alkylene-OR 5 , -NR 6 R 7 , -C1-C6alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -C1-C6alkylene-C3-C6cycloalkyl, -C1-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C10aryl, or -C1-C6alkylene-(C6-C10aryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl; 10 3- to 15-membered heterocycloalkyl, -C1-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C10aryl, or -C1-C6alkylene-(C6-C10aryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl; 10 aryl, -C1-C6alkylene-C6-C10aryl, -C1-C6alkylene-(5- to 10-membered heteroaryl), wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl; 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6alkylene-(5- to 10-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or C1-C6alkyl; 8 substituted;

[0023] R 5 independently at each occurrence -H, -C1-C6alkyl, or -C1-C6alkylene-OH;

[0024] R 6 and R 7 each independently at each occurrence -H, -C1-C6alkyl, -C3-C6cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; and 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; and 10 aryl or 5- to 10-membered heteroaryl; and

[0025] R 8 independently at each occurrence -OH, halogen, or C1-C6alkyl.

[0026] In one aspect, the present application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some preferred embodiments, the pharmaceutical composition is effective in treating a disease, preferably an infection, more preferably a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, the genus Staphylococcus and / or the genus Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus Mycobacterium non-tuberculosis (preferably Mycobacterium abscessus). In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium non-tuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0027] In one aspect, the present application provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0028] In one aspect, the present application provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0029] In one aspect, the present application provides the use of a compound or a pharmaceutical composition comprising a compound described herein in the manufacture of a medicament for the treatment of a disease, preferably an infection, more preferably 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 Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or non-tuberculous Mycobacterium, preferably Mycobacterium abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus non-tuberculous Mycobacterium, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genera Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0030] In one aspect, the present application provides a method of treating a disease, preferably an infection, more preferably a bacterial infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or non-tuberculous Mycobacterium, preferably Mycobacterium abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus non-tuberculous Mycobacterium, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genera Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0031] The present application provides rifabutin analogs modified at position C25, and pharmaceutical compositions thereof. The compounds described herein exhibit a broad spectrum of antibacterial activity against a variety of bacterial species, thus retaining the broad spectrum of antibacterial activity characteristic of the rifamycin class of antibiotics. Additional features and advantages of the application will be apparent to those skilled in the art upon reading the detailed description of the application found below. DETAILED DESCRIPTION

[0033] The present application provides rifabutin analogs that are effective in the treatment of bacterial infections, preferably bacterial infections caused by one or more bacteria belonging to the genus non-tuberculous Mycobacterium, preferably Mycobacterium abscessus.

[0034] The technical details are set forth in the description of the specification below. The technology can be practiced with methods and materials similar or equivalent to those described herein, although exemplary methods and materials are now described. Other features, objects, and advantages of the application will be apparent from the description and claims.

[0035] Definitions

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0037] As used herein, the indefinite articles "a" and "an" mean one or more (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0038] The term "and / or", where used herein is used to mean "and" or "or", unless otherwise stated.

[0039] The term "optionally substituted" is understood to mean that the specified chemical moiety (e.g., alkyl) can (but is not required to) be bound to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl can have substituents other than hydrogen. For example, it can be bound to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that the specified chemical moiety has the potential to contain other functional groups, but is not required to contain any other functional groups.

[0040] The term "alkyl" refers to straight chain or branched chain saturated hydrocarbons. C1-C6 alkyl contains 1 to 6 carbon atoms. Examples of -C1-C6 alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, and t-butyl, isoamyl, and neopentyl.

[0041] The term "alkylene" (or "alkylenyl") as used herein refers to a straight chain or branched chain hydrocarbon diradical derived from an alkyl group as defined herein, in which one hydrogen has been cleaved to generate a second radical of the alkylene group. Examples of alkylene groups are illustrated by: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-.

[0042] As used herein, "C1-C6alkoxy" refers to a straight chain or branched saturated -O-C1-C6hydrocarbon, for example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, sec-butoxy, straight chain or branched pentoxy, straight chain or branched hexoxy, straight chain or branched heptoxy, or straight chain or branched octoxy. Preferably, the C1-C6alkoxy is C1-C4alkoxy. "C1-C6alkoxy" can also be denoted as "-O-C1-C6alkyl."

[0043] The term "cycloalkyl" means a monocyclic or bicyclic saturated carbocyclic ring containing 3-10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydro-lH-indene, and decalin.

[0044] The term "aryl" refers to cyclic aromatic hydrocarbon groups having 1 to 2 aromatic rings, including monocyclic or bicyclic groups, such as phenyl or naphthyl. C6-C 10 An aryl group contains 6 to 10 carbon atoms. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, such as 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, OH, or -halogen. The substituents (e.g., alkyl) can themselves be optionally substituted.

[0045] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 15 ring atoms, containing one or more ring heteroatoms selected from N, S, P, and O, with the remainder of the ring atoms being C, wherein each ring of the heteroaryl group contains delocalized pi electrons shared between ring atoms (aromaticity). Preferably, the heteroatoms are selected from N, S, and O, more preferably, from N and O. Preferably, the heteroaryl is a 5-10 membered heteroaryl containing 5 to 10 ring atoms. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, quinolinyl, isothiazolyl, thiazolyl, thiodiazole, indazol, benzimidazolyl, 1,3-dihydro-2H-benzimidazol-2-one, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furano[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, benzothiazolyl, benzofuran, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 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, pyridin-2-one, furano[3,2-c]pyridinyl, furano[2,3-c]pyridinyl, benzoxazolyl, benzisoxazolyl, furano[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [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, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, and thieno[2,3-b]pyrrolyl.

[0046] The term "heterocyclyl" or "heterocycloalkyl" or "heterocycle" means a monocyclic or polycyclic, saturated or partially saturated 3- to 15-membered ring containing carbon and heteroatoms from O, N, and S (preferably O and N), wherein at least one ring does not contain delocalized pi electrons shared between ring carbons or heteroatoms (aromaticity). A 3-10 membered heterocycloalkyl contains 3 to 10 atoms.

[0047] Heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, [l,4]diazepane, [l,2]diazepane, decahydro-[l,6]naphthyridinediazepinyl, octahydro-pyrrolo[l,2-a]pyrazinyl, octahydro-pyrrolo[3,2-c]pyridinyl, and 2,5-diaza- bicyclo[2.2.1]heptyl.

[0048] Heterocyclyl rings or heterocycloalkyl rings can also be fused or bridged, e.g., can be bicyclic or tricyclic. In addition, when containing two or more fused rings, the heterocycloalkyl groups defined herein can have saturated or partially saturated rings fused to aromatic and / or heteroaromatic rings. Exemplary ring systems for such heterocyclyl aryl groups or heterocyclyl heteroaryl groups include indolinyl, indolinonyl, dihydrobenzo-thiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole, and 5,6,7,8-tetrahydro-imidazo[l,2-a]pyrazine.

[0049] Heterocyclyl rings or heterocycloalkyl rings can also be spirocyclic heterocycles or spiroheterocycles. As used herein, spirocyclic heterocycles or spiroheterocycles are understood to mean bicyclic or polycyclic ring systems in which at least two rings are connected by a single atom, and in which at least one ring is a heterocycle (e.g., at least one ring is, e.g., furanyl, morpholinyl, or piperidinyl). One or both rings in a spiroheterocycle can be fused to one or more additional carbocyclic, heterocyclic, aromatic, or heteroaromatic rings to form, e.g., a tricyclic ring system in which two rings are connected by a single atom. Exemplary spiroheterocycles include, but are not limited to, l,3,8-triaza-spiro[4.5]decane, 2,8-diaza-spiro[4.5]decane, 2,9-diaza-spiro[5.5]undecane, 3,9-diaza-spiro[5.5]undecane, l-oxa-4,9-diaza-spiro[5.5]undecane, and 5-oxa-2,8-diaza-spiro[3.5]nonane.

[0050] The term "halo" or "halogen" as used herein means fluoro (F), chloro (CI), bromo (Br), or iodo (I).

[0051] The term "oxo" refers to a carbonyl functional group consisting of a carbon atom double-bonded to an oxygen atom. It can be abbreviated herein as "oxo", C(O), or C=O.

[0052] The term "CN" refers to a cyano group, also known as a nitrile group.

[0053] The present application also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water- insoluble salts such as acetate, amidosulfate (4,4-diamino-stilbene-2,2-disulfate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, 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.

[0054] The term "stereoisomer" refers to a group of compounds that have the same number and type of atoms, and the same connectivity between those atoms, but have different three-dimensional structures. The term "stereoisomer" refers to any one of this group of compounds.

[0055] The term "diastereomer" refers to a group of stereoisomers that are not mirror images of one another and that are not enantiomers. For example, cis and trans double bonds, endo- and exo-substitution on a bicyclic system, and compounds that include multiple chiral centers with different relative configurations are considered diastereomers. The term "diastereomer" refers to either individual member of this group of compounds. In some of the examples presented, the synthetic route can result in a single diastereomer or a mixture of diastereomers. In some cases, these diastereomers are separated, while in other cases, a wavy bond is used to represent a structural element whose configuration can vary.

[0056] The term "enantiomer" refers to a pair of stereoisomers that are mirror images of one another and that are not superimposable. The term "enantiomer" refers to either individual member of this pair of stereoisomers. The term "racemic" refers to a 1 : 1 mixture of a pair of enantiomers.

[0057] The term "tautomer" refers to a group of compounds that have the same number and type of atoms, but different connectivity of those atoms and are in equilibrium with one another. A "tautomer" is an individual member of this group of compounds. Often, a single tautomer is drawn, but it is understood that this single structure is intended to represent all possible tautomers that can exist. Examples include enol-keto tautomers. When a keto form is drawn, it is understood that the enol and keto forms are both part of the present disclosure.

[0058] The term "solvate" refers to complex compounds formed with variable stoichiometry from a solute and solvent. For the purposes of the present invention, such solvents do not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates with water molecules are commonly referred to as "hydrates." Hydrates include compositions containing a stoichiometric amount of water, but also compositions containing variable amounts of water.

[0059] An "effective amount" when used in connection with a compound is an amount effective to treat or prevent a disease in a subject described herein.

[0060] The term "carrier" as used herein in the context of the present disclosure encompasses vehicles, excipients, and diluents, and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

[0061] The term "treatment" with respect to a subject refers to the improvement of the symptoms of a disorder in at least one subject. Treatment includes curing, improving or at least partially arresting a disorder.

[0062] The term "disorder," as used in the present disclosure, means a disease, condition, or illness, and can be used interchangeably with disease, condition, or illness, unless otherwise indicated.

[0063] The term "administer," "administering," or "administration," as used in the present disclosure, means to directly apply a compound of the present disclosure or a pharmaceutically acceptable salt of a compound of the present disclosure or a composition of the present disclosure to a subject, or to apply a prodrug derivative or analog of a compound or a pharmaceutically acceptable salt of a compound or a composition to a subject, which can form an equivalent amount of the active compound in the body of the subject.

[0064] A "patient" or "subject" is a mammal, for example, a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate, such as a monkey, a chimpanzee, a baboon, or a rhesus.

[0065] Compounds of the invention

[0066] In one aspect, the present application provides a compound of Formula I:

[0067]

[0068] wherein:

[0069] R 1 and R 2 each independently is selected from the group consisting of -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, Ci-C6alkylene-C3-C 10 cycloalkyl, 3 to 15 membered heterocycloalkyl, -Ci-C6alkylene-(3 to 15 membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5 to 10 membered heteroaryl, and -Ci-C6alkylene-(5 to 10 membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 ; or

[0070] R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a 5 to 15 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ; and

[0071] R 3independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C6cycloalkyl, -C3-C6cycloalkenyl, -C3-C6halocycloalkyl, -C3-C6halocycloalkenyl, -C6-Ci0aryl, -C6-Cio aryl substituted with one or more R 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C

[0072] R 4 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 5 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 5 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 6 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 7 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 6 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 7 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 8 substituted with one or more R

[0073] R 5 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C

[0074] R 6 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 7 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C 10 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C

[0075] R 8 independently at each occurrence -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3-C

[0076] In one aspect, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof:

[0077]

[0078] wherein:

[0079] R 1 and R 2 are each independently selected from the group consisting of -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 ; or

[0080] R 1 and R 2 , taken together with the nitrogen atom to which they are attached, combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0081] R 3 is independently, at each occurrence, -OH, halogen, -Ci-C6alkyl, -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl;

[0082] R 4 is independently, at each occurrence, -Ci-C6alkyl, -OR 5 , -Ci-C6alkylene-OR 5 , -NR 6 R 7 , -Ci-C6alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-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), wherein each alkylene is optionally substituted with one or more oxo groups, and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more R groups. 8 replace;

[0083] R 5 Each occurrence is independently -H, -C1-C6 alkyl, or -C1-C6 alkylene-OH;

[0084] R 6 and R 7 Each time it appears, it is independently -H, -C1-C6 alkyl, or -C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0085] R 8 Each time it appears, it is independently -OH, halogen, or -C1-C6 alkyl.

[0086] In some implementation schemes, R 1 and R 2 Each is independently selected from -H, -C1-C6 alkyl, -C3-C6-cycloalkyl, C1-C6-alkylene-C3-C6-cycloalkyl, -5 to 6-membered heterocyclic alkyl, -C1-C6-alkylene-(5 to 6-membered heterocyclic alkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 aryl, 5- to 6-membered heteroaryl, and -C1-C6-alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 3 Replace; or

[0087] R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 5- to 15-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally bonded by one or more R atoms. 4 replace;

[0088] R 3Each occurrence is independently -OH, halogen, -CN, -OC1-C6 alkyl, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, 5- to 6-membered heterocyclic alkyl, -C1-C6 alkylene-(5- to 6-membered heterocyclic alkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 Aryl, 5- to 6-membered heteroaryl or -C1-C6 alkylene- (5- to 6-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl may optionally be substituted by one or more -OH, halogen or C1-C6 alkyl groups;

[0089] R 4 Each time it appears, it is independently -C1-C6 alkyl, -OR 5 -C1-C6 alkylene-OR 5 -NR 6 R 7 -C1-C6-alkylene-NR 6 R 7 -C3-C6-cycloalkyl, -C1-C6-alkylene-C3-C6-cycloalkyl, 5- to 6-membered heterocyclic alkyl, -C1-C6-alkylene-(5- to 6-membered heterocyclic alkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 aryl, 5- to 6-membered heteroaryl, or -C1-C6 alkylene- (5- to 6-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo groups, and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more R groups. 8 replace;

[0090] R 5 Each occurrence is independently -H, -C1-C6 alkyl, or -C1-C6 alkylene-OH;

[0091] R 6 and R 7 Each time it appears, it is independently -H, -C1-C6 alkyl, -C3-C6 cycloalkyl, 5- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0092] R 8 Each time it appears, it is independently -OH, halogen, or -C1-C6 alkyl.

[0093] In some implementation schemes, R 1 and R 2each independently selected from -H, -Ci-C6alkyl, -C3-C6-cycloalkyl, Ci-C6-alkylene-C3-C6-cycloalkyl, -5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 3 or R

[0094] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 5- to 15-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more R 4 ;

[0095] R 3 each occurrence is independently -OH, halogen, -Ci-C6alkyl, -C3-C6cycloalkyl, -Ci-C6alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl;

[0096] R 4 each occurrence is independently -Ci-C6alkyl, -OR 5 , -Ci-C6alkylene-OR 5 , -NR 6 R 7 , -Ci-C6alkylene-NR 6 R 7 , -C3-C6cycloalkyl, -Ci-C6alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 10 C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; 8 or R

[0097] R 5independently at each occurrence -H, -Ci-C6alkyl, or -Ci-C6alkylene-OH;

[0098] R 6 and R 7 each independently at each occurrence -H, -Ci-C6-alkyl, -C3-C6-cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0099] R 8 independently at each occurrence -OH, halogen, or -Ci-C6alkyl.

[0100] In some embodiments, R 1 and R 2 each independently is selected from the group consisting of -H, -Ci-C4alkyl, -C3-C 10 cycloalkyl, Ci-C4alkylene-C3-C 10 cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0101] R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ; and

[0102] R 3 independently at each occurrence -OH, halogen, -Ci-C4alkyl, -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl;

[0103] R 4 independently at each occurrence -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4-alkylene-NR 6 R 7 , -C3-C10 cycloalkyl, -Ci-C4-alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4-alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0104] R 5 independently at each occurrence -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0105] R 6 and R 7 each independently at each occurrence -H, -Ci-C4-alkyl, -C3-C 10 cycloalkyl, 5- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; and

[0106] R 8 independently at each occurrence -OH, halogen, or -Ci-C4-alkyl.

[0107] In some embodiments, R 1 and R 2 each is independently selected from -H, Ci-C4alkyl, C3-C6cycloalkyl, -5- to 15- membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituents; or

[0108] R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0109] R 3 independently at each occurrence -OH, halogen, -Ci-C4alkyl, -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl;

[0110] R 4 independently at each occurrence -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ;

[0111] R 5 independently at each occurrence -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0112] R 6 and R 7 each independently at each occurrence -H, -Ci-C4alkyl, -C3-C 10 cycloalkyl, 5- to 6-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; and

[0113] R 8 independently at each occurrence halogen or -Ci-C4alkyl.

[0114] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of -H, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0115] R 1 and R 2together with the nitrogen atom to which they are attached form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituted;

[0116] R 3 independently at each occurrence -OH, halogen, -Ci-C4alkyl, -C3-C 10 cycloalkyl, -Ci-C4-alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl;

[0117] R 4 independently at each occurrence -Ci-C4alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituted;

[0118] R 5 independently at each occurrence -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0119] R 6 and R 7 each independently at each occurrence -H, -Ci-C4alkyl, -C3-C 10 cycloalkyl, 5- to 6-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; and

[0120] R 8halogen or -Ci-C4alkyl at each occurrence.

[0121] R 1 and R 2 are each independently selected from the group consisting of -H, -5- to 12- membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 12-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0122] R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a 5- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0123] R 3 is, at each occurrence, independently -Ci-C4alkyl, -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 12-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 12- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C4alkyl;

[0124] R 4 is, at each occurrence, independently -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C5-C 10 cycloalkyl, -Ci-C4alkylene-C5-C 10 cycloalkyl, 5- to 12-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 12- membered heterocycloalkyl), phenyl, -Ci-C4alkylene-phenyl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 ;

[0125] R 5 is, at each occurrence, independently -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0126] R 6 and R 7 each occurrence is independently -H, -Ci-C4alkyl, -C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0127] R 8 each occurrence is independently halogen or -Ci-C4alkyl.

[0128] In some embodiments, R 1 is -H;

[0129] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0130] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ; and

[0131] R 3 each occurrence is independently -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, -Ci-C2alkylene-C6-aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C2alkyl;

[0132] R 4 each occurrence is independently -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -Ci-C4alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -Ci-C4alkylene-phenyl, 5- to 6-membered heteroaryl, or -Ci-C4alkylene-(5- to 6-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 .

[0133] R 5 independently for each occurrence -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0134] R 6 and R 7 each occurrence is independently -H, -Ci-C4alkyl, -C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0135] R 8 independently for each occurrence halogen or -Ci-C4alkyl.

[0136] in some embodiments, R 1 is -H;

[0137] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0138] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0139] R 3 independently for each occurrence -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6- cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C2alkyl;

[0140] R 4 independently for each occurrence -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7, -C5-C6cycloalkyl, -C1-C4alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C4alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C4alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C4alkylene-(5- to 6-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0141] R 5 independently at each occurrence -H, -C1-C4alkyl, or -C1-C4alkylene-OH;

[0142] R 6 and R 7 are each independently at each occurrence -H, -C1-C4alkyl, -C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0143] R 8 are each independently at each occurrence halogen or -C1-C4alkyl.

[0144] In some embodiments, R 1 is -H;

[0145] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine, piperidine, morpholine, and piperazine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituents; or R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0146] R 3 is independently at each occurrence -C1-C4alkyl, -C3-C6cycloalkyl, -C1-C2-alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6aryl, or -C1-C2alkylene-C6aryl, wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more C1-C2alkyl;

[0147] R 4 is independently at each occurrence -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7, -C5-C6cycloalkyl, -Ci-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -Ci-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0148] R 6 and R 7 are each, independently at each occurrence, -H, -Ci-C2alkyl, -C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0149] R 8 is, at each occurrence, independently halogen or -Ci-C4alkyl.

[0150] In some embodiments, R 1 is -H;

[0151] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituents; or

[0152] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from piperidine, piperazine, and 1,4-diazepane, and wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0153] R 3 is, at each occurrence, independently -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more Ci-C2alkyl;

[0154] R 4 is, at each occurrence, independently -Ci-C6alkyl, -NR 6 R 7 , -Ci-C2alkylene-NR 6 R 7, -C5-C6cycloalkyl, -Ci-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -Ci-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl), wherein each heterocycloalkyl is selected from the group consisting of piperidine, piperazine, and morpholine, wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0155] R 6 and R 7 each occurrence is independently -H, -Ci-C2alkyl, or phenyl; and

[0156] R 8 each occurrence is independently halogen or -Ci-C4alkyl.

[0157] In some embodiments, R 1 is -H;

[0158] R 2 is independently selected from the group consisting of -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from the group consisting of pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or two R 3 substituents; or

[0159] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of piperidine and piperazine, and wherein the heterocycloalkyl is optionally substituted with one R 4 substituent;

[0160] R 3 each occurrence is independently -Ci-C4alkyl, -Ci-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, or -Ci-C2alkylene-C6aryl; wherein each heterocycloalkyl is optionally substituted with one or more Ci-C2alkyl;

[0161] R 4 each occurrence is independently -Ci-C6alkyl, -NR 6 R 7 , -Ci-C2alkylene-NR 6 R 7-C1-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each heterocycloalkyl is selected from the group consisting of piperidine, piperazine, and morpholine, preferably from the group consisting of piperidine and morpholine, and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted;

[0162] R 6 and R 7 each occurrence is independently -H, -C1-C2alkyl, or phenyl.

[0163] In some embodiments, R 1 is -H;

[0164] R 2 is independently selected from the group consisting of -5- to 6-membered heterocycloalkyl and -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from the group consisting of pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or two R 3 ; or

[0165] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of piperidine and piperazine, and wherein the heterocycloalkyl is optionally substituted at the 4-position with one R 4 ;

[0166] R 3 each occurrence is independently -C1-C2alkylene-C6aryl;

[0167] R 4 each occurrence is independently -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -C1-C2alkylene-C5-C6cycloalkyl, phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, phenyl, or heteroaryl is unsubstituted; and

[0168] R 6 and R 7 each occurrence is independently -H, -C1-C2alkyl, or phenyl.

[0169] In some embodiments, R 1 and R 2each independently selected from -H, C1-C4alkyl, C3-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, and -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0170] R 1 ; and R 2 , taken together with the nitrogen atom to which they are attached, form a 5- to 15- membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more R 4 ; or

[0171] R 3 is, at each occurrence, independently -CN, -OC1-C2alkyl, -C1-C4alkyl, -C3-C6cycloalkyl, -C1-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6aryl, -C1-C2alkylene-C6aryl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -C1-C2alkyl;

[0172] R 4 is, at each occurrence, independently -C1-C6alkyl, -OR 5 , -C1-C6alkylene-OR 5 , -NR 6 R 7 , -C1-C6alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -C1-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -C1-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo, and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ; or

[0173] R 5 is, at each occurrence, independently -H, -C1-C6alkyl, or -C1-C6alkylene-OH;

[0174] R 6 ; and R 7each occurrence is independently -H, -Ci-C6alkyl, -C3-C6cycloalkyl, -5- to 6- membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6-aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more R 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; and 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; and

[0175] R 8 each occurrence is independently -OH, halogen, or -Ci-C6alkyl.

[0176] In some embodiments, R 1 and R 2 are independently selected from -H, Ci-C4alkyl, C3-C6cycloalkyl, -5- to 6- membered heterocycloalkyl, and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 ; or

[0177] R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0178] R 3 each occurrence is independently -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6-aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more Ci-C2alkyl;

[0179] R 4 each occurrence is independently -Ci-C6alkyl, -OR 5 , -Ci-C6alkylene-OR 5 , -NR 6 R 7 , -Ci-C6alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10aryl, 5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituted;

[0180] R 5 independently at each occurrence -H, -Ci-C6alkyl, or -Ci-C6alkylene-OH;

[0181] R 6 and R 7 each independently at each occurrence -H, -Ci-C6alkyl, -C3-C6cycloalkyl, Ci-C6alkylene-C3-C6cycloalkyl, -5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, or 5- to 10-membered heteroaryl; and

[0182] R 8 independently at each occurrence -OH, halogen, or -Ci-C6alkyl.

[0183] In some embodiments, R 1 and R 2 each is independently selected from -H, -Ci-C6alkyl, -C3-C6cycloalkyl, Ci-C6alkylene-C3-C6cycloalkyl, -5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, 5- to 6-membered heteroaryl, or -Ci-C6alkylene-(5- to 6-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 substituted.

[0184] In some embodiments, R 1 and R 2 each is independently selected from -H, -Ci-C6alkyl, -C3-C6cycloalkyl, Ci-C6alkylene-C3-C6cycloalkyl, -5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 cycloalkyl, Ci-C6alkylene-C3-C6cycloalkyl, -5- to 6-membered heterocycloalkyl, -Ci-C6alkylene-(5- to 6-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-Cio aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, -Ci-C6alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 10 aryl, 5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 ;

[0185] R 3Each occurrence is independently -OH, halogen, -CN, -OC1-C6 alkyl, -C1-C6 alkyl, -C3-C 10 Cycloalkyl, -C1-C6 alkylene, -C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-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); wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more -OH, halogen or C1-C6 alkyl groups.

[0186] In some implementation schemes, R 1 and R 2 Each is independently selected from -H, -C1-C6 alkyl, -C3-C 10 cycloalkyl, C1-C6 alkylene-C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally surrounded by one or more R 3 replace;

[0187] R 3 Each time it appears, it is independently -OH, halogen, -C1-C6 alkyl, -C3-C 10 Cycloalkyl, -C1-C6 alkylene, -C3-C 10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, -C1-C6 alkylene-(3- to 15-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); wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more -OH, halogen or C1-C6 alkyl groups.

[0188] In some implementation schemes, R 1 and R 2 Each is independently selected from -H, -C1-C4 alkyl, -C3-C 10 Cycloalkyl, C1-C4 alkylene-C3-C 10cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0189] R 3 -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 10 cycloalkyl, -Ci-C4alkylene-C3-C6cycloalkyl, -C6-Cio aryl, -Ci-C4alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl. 10 cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 10 aryl, -Ci-C4alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl. 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl.

[0190] In some embodiments, R 1 and R 2 each is independently selected from -H, Ci-C4alkyl, C3-C6cycloalkyl, -5- to 15- membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0191] R 3 -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 10 cycloalkyl, -Ci-C4alkylene-C3-C6cycloalkyl, -C6-Cio aryl, -Ci-C4alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl. 10 cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 10 aryl, -Ci-C4alkylene-C6-Cio aryl, -5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl. 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl.

[0192] In some embodiments, R 1 and R 2 each is independently selected from -H, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0193] R 3 -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C4alkyl.

[0194] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of -H, -5- to 12-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 12-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ;

[0195] R 3 is independently in each occurrence -Ci-C4alkyl, -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 12-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 12-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C4alkyl.

[0196] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of -H, Ci-C4alkyl, C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from the group consisting of pyrrolidine and piperidine, preferably piperidine, and wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R 3 ;

[0197] R 3independently at each occurrence -CN, -OCi-C2alkyl, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6aryl, -Ci-C2alkylene-C6aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -Ci-C2alkyl.

[0198] In some embodiments, R 1 and R 2 are independently selected from -H, -Ci-C4alkyl, C3-C6cycloalkyl, -5- to 6-membered heterocycloalkyl, and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 ;

[0199] R 3 is -H, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more -Ci-C2alkyl.

[0200] In some embodiments, R 1 is -H;

[0201] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 ;

[0202] R 3 is -H, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, -Ci-C2alkylene-C6aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -Ci-C2alkyl.

[0203] In some embodiments, R 1 is -H;

[0204] R 2independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6- membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0205] R 3 independently at each occurrence -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C2alkyl.

[0206] in some embodiments, R 1 is -H;

[0207] R 2 independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6- membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine, piperidine, morpholine, and piperazine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0208] R 3 independently at each occurrence -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more Ci-C2alkyl.

[0209] in some embodiments, R 1 is -H;

[0210] R 2 independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6- membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituted;

[0211] R 3 independently at each occurrence -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, or -Ci-C2alkylene-C6aryl; wherein each cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more Ci-C2alkyl.

[0212] In some embodiments, R 1 is -H;

[0213] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or two R 3 substituents;

[0214] R 3 is independently -Ci-C4alkyl, -Ci-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, or -Ci-C2alkylene-C6aryl; wherein each heterocycloalkyl is optionally substituted with one or more -Ci-C2alkyl.

[0215] In some embodiments, R 1 is -H;

[0216] R 2 is independently selected from -5- to 6-membered heterocycloalkyl and -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), wherein each heterocycloalkyl is selected from pyrrolidine and piperidine, preferably piperidine, and wherein each heterocycloalkyl is optionally substituted with one or two R 3 substituents;

[0217] R 3 is independently -Ci-C2alkylene-C6aryl.

[0218] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents.

[0219] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0220] R 4 is independently -Ci-C6alkyl, -OR 5 , -Ci-C6alkylene-OR 5 , -NR 6 R 7 , -Ci-C6alkylene-NR 6 R 7 , -C3-C 10cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0221] R 5 independently at each occurrence -H, -Ci-C6alkyl, or -Ci-C6alkylene-OH;

[0222] R 6 and R 7 each independently at each occurrence -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-C 10 aryl, or 5- to 10-membered heteroaryl; and

[0223] R 8 independently at each occurrence -OH, halogen, or -Ci-C6alkyl.

[0224] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0225] R 4 independently at each occurrence -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10aryl, 5- to 10-membered heteroaryl, or -C1-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituted;

[0226] R 5 independently at each occurrence -H, -C1-C4alkyl, or -C1-C4alkylene-OH;

[0227] R 6 and R 7 each independently at each occurrence -H, -C1-C4alkyl, -C3-C 10 cycloalkyl, 5- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; and

[0228] R 8 independently at each occurrence -OH, halogen, or -C1-C4alkyl.

[0229] In some embodiments, R 1 and R 2 combine with the nitrogen atom to which they are attached to form a 5- to 15-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituted;

[0230] R 4 independently at each occurrence -C1-C6alkyl, -OR 5 , -C1-C4alkylene-OR 5 , -NR 6 R 7 , -C1-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -C1-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -C1-C4alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -C1-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 substituted;

[0231] R 5 independently at each occurrence -H, -C1-C4alkyl, or -C1-C4alkylene-OH;

[0232] R 6 and R 7 each occurrence is independently -H, -Ci-C4alkyl, -C3-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, C6-Cio aryl, or 5- to 10-membered heteroaryl; and 10 cycloalkyl, 5- to 6-membered heterocycloalkyl, C6-Cio aryl, or 5- to 10-membered heteroaryl; and 10 aryl or 5- to 10-membered heteroaryl; and

[0233] R 8 each occurrence is independently halogen or -Ci-C4alkyl.

[0234] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 5- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0235] R 4 each occurrence is independently -C5-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C5-C 10 cycloalkyl, -Ci-C4alkylene-C5-C 10 cycloalkyl, 5- to 12-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 12-membered heterocycloalkyl), phenyl, -Ci-C4alkylene-phenyl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 ;

[0236] R 5 each occurrence is independently -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH;

[0237] R 6 and R 7 each occurrence is independently -H, -Ci-C4alkyl, -C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0238] R 8 each occurrence is independently halogen or -Ci-C4alkyl.

[0239] In some embodiments, R 1 and R 2with the nitrogen atom to which they are attached combine to form a 5- to 12- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituted;

[0240] R 4 independently for each occurrence -C1-C6alkyl, -OR 5 , -C1-C4alkylene-OR 5 , -NR 6 R 7 , -C1-C4alkylene-NR 6 R 7 , -C6-C6cycloalkyl, -C1-C4alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C4alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C4alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C4alkylene-(5- to 6-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituted;

[0241] R 5 independently for each occurrence -H, -C1-C4alkyl, or -C1-C4alkylene-OH;

[0242] R 6 and R 7 each independently for each occurrence -H, -C1-C4alkyl, -C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0243] R 8 independently for each occurrence halogen or -C1-C4alkyl.

[0244] In some embodiments, R 1 and R 2 with the nitrogen atom to which they are attached combine to form a 6- to 7- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituted;

[0245] R 4 independently for each occurrence -C1-C6alkyl, -OR 5 , -C1-C4alkylene-OR 5 , -NR 6 R 7 , -C1-C4alkylene-NR 6 R 7, -C5-C6cycloalkyl, -C1-C4alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C4alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C4alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C4alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0246] R 5 each occurrence is independently -H, -C1-C4alkyl, or -C1-C4alkylene-OH;

[0247] R 6 and R 7 each occurrence is independently -H, -C1-C4alkyl, -C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0248] R 8 each occurrence is independently halogen or -C1-C4alkyl.

[0249] In some embodiments, R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 4 substituents;

[0250] R 4 each occurrence is independently -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -C1-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 substituents;

[0251] R 6 and R 7 each occurrence is independently -H, -C1-C2alkyl, -C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0252] R 8 each occurrence is independently halogen or -C1-C4alkyl.

[0253] In some embodiments, R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of piperidine, piperazine, and 1,4-diazepane, and wherein the heterocycloalkyl is optionally substituted with one or more R 4 ;

[0254] R 4 is independently, at each occurrence, -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -C1-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each heterocycloalkyl is selected from the group consisting of piperidine, piperazine, and morpholine, and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 ;

[0255] R 6 and R 7 are each independently, at each occurrence, -H, -C1-C2alkyl, or phenyl; and

[0256] R 8 is independently, at each occurrence, halogen or -C1-C4alkyl.

[0257] In some embodiments, R 1 and R 2 , together with the nitrogen atom to which they are attached, combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of piperidine and piperazine, and wherein the heterocycloalkyl is optionally substituted with one R 4 ;

[0258] R 4 is independently, at each occurrence, -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7-C1-C2alkylene-C5-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -C1-C2alkylene-(5- to 6-membered heterocycloalkyl), phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each heterocycloalkyl is selected from the group consisting of piperidine, piperazine, and morpholine, preferably from the group consisting of piperidine and morpholine, and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted;

[0259] R 6 and R 7 each independently at each occurrence is -H, -C1-C2alkyl, or phenyl.

[0260] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached combine to form a 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of piperidine and piperazine, and wherein the heterocycloalkyl is optionally substituted at the 4-position with one R 4 ;

[0261] R 4 each occurrence is independently -C1-C6alkyl, -NR 6 R 7 , -C1-C2alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -C1-C2alkylene-C5-C6cycloalkyl, phenyl, -C1-C2alkylene-phenyl, 5- to 6-membered heteroaryl, or -C1-C2alkylene-(5- to 6-membered heteroaryl), wherein each alkyl, cycloalkyl, phenyl, or heteroaryl is unsubstituted; and

[0262] R 6 and R 7 each independently at each occurrence is -H, -C1-C2alkyl, or phenyl.

[0263] In one or more embodiments, R 1 and R 2 of the compounds described herein can form one of the structures selected from Table 1 below:

[0264] Table 1. R 1 and R 2 of the embodiments

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] In some embodiments, the compound of Formula I is selected from the group consisting of the compounds shown in Table 2. In one or more embodiments of any of the above aspects, the compound of Formula I is selected from the following Table 2:

[0273] Table 2. Compounds of the Invention

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] In some embodiments, the compound of Formula I is selected from the group consisting of the compounds shown in Table 3. In some embodiments of any of the above aspects, the compound of Formula I is selected from the following Table 3:

[0292] Table 3. Selected compounds of the invention

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] In some embodiments, the compound of Formula I is selected from the group consisting of the compounds shown in Table 4. In some embodiments of any of the above aspects, the compound of Formula I is selected from the group consisting of Table 4:

[0308] Table 4. Selected compounds of the invention

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 17, or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 3, 4, 7, 8, 9, 10, 14, and 17, or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 20, 21, 24, 25, 29, 30, 32a, 36, 37, 38, 41, 43, 44, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 82, and 83, or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 4, 7, 8, 9, 10, 14, 17, 29, 36, 41, 49, 50, 52, 53, 54, 56, 58, 59, 60, 65, 66, 67, 70, 71, and 72, or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound is selected from the group consisting of Compound 1, 2, 4, 7, 8, 9, 10, 14, and 17, or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compound of Formula I is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 6, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 8, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 9, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 10, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 12, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 13, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 14, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 15, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 16, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 17, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 18, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 19, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 20, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 21, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 22, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 23, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 24, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 25, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 26, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 27, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 28, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 29, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 30, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 31, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of Formula I is Compound 32, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 33, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 34, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 35, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 36, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 37, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 38, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 39, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 40, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 41, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 42, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 43, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 44, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 45, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 46, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 47, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 48, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 49, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 50, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 51, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 52, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 53, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 54, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 55, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 56, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 57, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 58, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 59, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 60, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 61, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 62, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of Formula I is Compound 63, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 64, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 65, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 66, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 67, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 68, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 69, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 70, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 71, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 72, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 73, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 74, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 75, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 76, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 77, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 78, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 79, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 80, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 81, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 82, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 83, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 84, or a pharmaceutically acceptable salt thereof.

[0329] In one aspect, the present application provides a pharmaceutical composition comprising at least one compound according to the present application or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0330] Methods of synthesizing the compounds of the disclosure

[0331] The compounds described herein can be prepared by a variety of methods including standard chemical methods. The methods include, but are not limited to, the methods described in the appropriate synthetic routes described in the schemes given below.

[0332] The compounds described herein can be prepared by methods known in the art of organic synthesis, as described in the following synthetic schemes and in the Examples section. In the schemes below, it is well understood that protecting groups will be employed as necessary to protect sensitive or reactive groups, according to general principles or chemistries. The protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage using methods that will be apparent to those skilled in the art. The processes, reaction conditions and order of carrying out the steps are chosen to be consistent with preparation of the compounds described herein.

[0333] One skilled in the art will recognize whether a stereocenter exists in the compounds of Formula I. Accordingly, the present application includes both possible stereoisomers (unless otherwise specified in the synthesis) and we include not only rac mixtures but also individual enantiomers and / or diastereomers. When it is desirable to have a single enantiomer or diastereomer of the compound, it can be obtained by stereo-specific synthesis, or by separation of the final product or any convenient intermediate. The separation of the final product, intermediate, or starting material can be affected by any suitable method known in the art. For example, see "Sterechemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0334] The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0335] Preparation of compounds

[0336] The compounds described herein can be synthesized according to the procedures outlined in the following general synthetic schemes 1, 2, and 3. The starting materials can be commercially available, made by known procedures reported in the literature, or made as illustrated in the following examples.

[0337] Scheme 1. General method for the synthesis of 21,23-oxo-propanedione-25- hydroxy-rifabutin (I-1)

[0338]

[0339] A general method for preparing 21,23-ketal-25-hydroxy-rifabutin I-1 is shown in Scheme 1 above. The C21 and C23 hydroxyl groups are protected using a suitable protecting group (such as dimethoxypropane and camphorsulfonic acid) in a solvent (e.g., DMF) to give the acetal-protected rifabutin. The protected rifabutin is deacetylated using a basic solution (such as sodium methoxide in ether) to give the C25-hydroxyl, C21-C23-protected rifabutin (I-1).

[0340] Scheme 2. Synthesis of 21,23-ketal-25-carbonyl-imidazole-rifabutin (I-2)

[0341]

[0342] The free C25-hydroxyl of intermediate (I-1) can be converted to a C25 imidazole carbamate (i.e., intermediate I-2) using a carbamoylating reagent (such as 1,1'- carbonyldiimidazole) in a suitable solvent (such as dichloromethane (DCM)) as shown in Scheme 2 above.

[0343] Scheme 3. Synthesis of deprotected 25-carbonyl-coupled-rifabutin

[0344]

[0345] Intermediate (I-2) can be substituted with an appropriate amine in the presence of a suitable coupling agent (such as 1-hydroxy-1H-benzotriazole (HOBt)). Subsequent deprotection of the C21-C23 acetal in the coupled rifabutin can be carried out by treatment with an acid (such as camphorsulfonic acid) in a suitable solvent (such as a mixture of THF / water).

[0346] Antibacterial effect of the compounds described in the disclosure

[0347] The compounds described herein are C25-modified analogs of rifabutin that exhibit the broad-spectrum antibacterial activity profile characteristic of the rifamycins. In addition, the compounds described herein unexpectedly show enhanced antibacterial activity against non-tuberculous mycobacteria (including M. abscessus) as compared to currently available antibiotics (e.g., rifabutin).

[0348] As shown in Example 4, Table 6 below, the compounds described herein effectively inhibit bacterial growth of strains of S. aureus, A. baumannii, M. abscessus, M. kansasii, M. xenopi, and M. avium.

[0349] Rifabutin showed moderate activity against the tested strains of M. abscessus with MIC values of 8 mg / L in 7H9 broth and 16 mg / L in hydrolyzed casein peptone broth (Mueller Hinton broth). In contrast, the compounds of the present application showed considerably lower MIC values, corresponding to an increase in activity as much as 132-fold over rifabutin. Thus, the present application teaches compounds that show increased activity against M. abscessus over antibiotics known in the literature. In some embodiments, the compounds described in the present application can be used to treat M. abscessus infections. In some embodiments, the compounds described in the present application can be used to treat M. abscessus infections that are resistant to existing antibiotics.

[0350] Thus, in some embodiments, the compounds of the present application can be used to inhibit bacterial infections, preferably infections caused by non-tuberculous mycobacteria, more preferably infections caused by M. abscessus. In some embodiments, the compounds of the present application can be used to inhibit bacterial infections caused by A. baumannii.

[0351] Methods of using the compounds of the disclosure

[0352] One aspect of the present application relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0353] In one aspect, the present application provides a compound of Formula I according to the present application or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of Formula I according to the present application, for use in a method of preventing or treating a disease in a subject, preferably an infection, further preferably a bacterial infection.

[0354] In one aspect, the present application provides a method of treating a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection, comprising administering to the subject an effective amount of a compound of Formula I according to the present application or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof. In one aspect, the present application provides a method of treating a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of Formula I according to the present application or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0355] In one aspect, the present application provides the use of a compound of formula I, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, as described herein, for the manufacture of a medicament for the treatment of a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection. In one aspect, the present application provides the use of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, as described herein, for the manufacture of a medicament for the treatment of a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection.

[0356] In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, the genus Staphylococcus and / or the genus Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or the species Staphylococcus aureus and / or the genus Mycobacterium non-tuberculosis, preferably Mycobacterium abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium non-tuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or the genus Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0357] In some preferred embodiments, the infection is caused by one or more bacteria belonging to the genus Mycobacterium non-tuberculosis, preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, M. smegmatis, Mycobacterium gordinii and / or Mycobacterium malmoense, more preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii and / or Mycobacterium gordinii, even more preferably Mycobacterium abscessus.

[0358] In some embodiments, the infection is caused by one or more bacteria belonging to the species Mycobacterium abscessus, Acinetobacter baumannii and / or Staphylococcus aureus. In some embodiments, the infection is caused by one or more bacteria belonging to the species Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii.

[0359] In some preferred embodiments, the compounds of the application are used to treat non-tuberculous mycobacteria causing pulmonary infection by non-tuberculous mycobacteria. In some embodiments, the non-tuberculous mycobacteria is M. abscessus, M. avium, M. kansasii, M. smegmatis, M. marinum and / or M. malmoense, preferably M. abscessus, M. avium, M. kansasii and / or M. marinum, more preferably M. abscessus. Thus, in some preferred embodiments, the compounds of the application are used to treat pulmonary infection by non-tuberculous mycobacteria. In some preferred embodiments, the compounds of the application are used to manufacture a medicament for treating pulmonary infection by non-tuberculous mycobacteria. In some preferred embodiments, the application provides a method of treating pulmonary infection by non-tuberculous mycobacteria in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the application.

[0360] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising the compounds of the application and a pharmaceutically acceptable carrier, such as a) diluents, e.g. purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA, or their esters or triglycerides or mixtures thereof), omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; if desired for tablets also c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweetener, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone; d) disintegrants, e.g. starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors and sweeteners; f) emulsifiers or dispersants, e.g. Tween 80, Labrasol, HPMC, DOSS, Capryol 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance the absorption of compounds, such as cyclodextrins, hydroxypropyl cyclodextrins, PEG 400, PEG 200.

[0361] The compounds and pharmaceutical compositions of the present invention can be administered by any suitable route, for example, orally, for example, in the form of a syrup, tablet, capsule, controlled release formulation, fast melt formulation, or lozenge.

[0362] Liquid compositions, particularly injectable liquid compositions, can be prepared by, for example, dissolving, dispersing, etc. For example, a compound of the present disclosure is dissolved or mixed with a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron, or serum proteins, can be used to solubilize a compound of the present disclosure.

[0363] A compound of the present disclosure can also be formulated in suppositories, which can be prepared by using a polyalkylene glycol (e.g., propylene glycol) as a carrier, by using a fatty emulsion or suspension.

[0364] A compound of the present disclosure can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of a drug to form lipid layers encapsulating the drug, as described in U.S. Pat. No. 5,262,564.

[0365] Parenteral injections are generally used for subcutaneous, intramuscular or intravenous injection and infusion. The injection can be prepared in a conventional form, such as a liquid solution or suspension, or a solid form suitable for dissolving in a liquid before injection.

[0366] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can also include excipients, diluents, or surfactants. The compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99% by weight / volume, about 5% to about 90% by weight / volume, or about 1% to about 20% by weight / volume of a compound of the present disclosure.

[0367] The dosage regimen using the compounds of the present disclosure is selected in accordance with a variety of factors, including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular compound of the present disclosure employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount by use of known techniques. The amount of a compound of the present disclosure in the composition will generally be determined by the efficiency of the particular compound employed and the condition being treated.

[0368] An effective dose of a compound of the present disclosure, when used for the indicated effects, is in the range of about 0.5 mg to about 5000 mg depending upon the need of the condition being treated. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of a compound of the present disclosure, or within a range from one amount on the list to another amount. In one embodiment, the composition is in the form of a scoreable tablet.

[0369] Equivalents

[0370] While the technology has been described in connection with specific embodiments thereof, it will be understood that it is capable of numerous alternatives, modifications, and equivalents. All of these alternatives, modifications, and variations are intended to fall within the spirit and scope of the present application. Examples

[0371] The present application will now be illustrated by the following non-limiting examples. While specific embodiments of the application are described below, those skilled in the art will understand that various changes and modifications can be made. Preparations made by reference to similar manners of preparation or by general methods of other preparations can encompass variations in routine parameters such as time, temperature, processing conditions, minor variations in the amounts of reagents, and the like.

[0372] Abbreviations

[0373] The following table provides definitions for certain abbreviations and symbols used herein. It is understood that the list is not exhaustive, but that the meaning of those abbreviations and symbols not defined herein below will be apparent to those skilled in the art. In describing the present application, chemical elements are referred to using the Periodic Table of the Elements.

[0374] ACN acetonitrile

[0375] AcOH acetic acid

[0376] aq. aqueous Ar argon

[0377] CSA camphorsulfonic acid

[0378] DCM dichloromethane

[0379] DMF dimethylformamide

[0380] eq. equivalent

[0381] EtOAc ethyl acetate

[0382] EtOH ethanol

[0383] h hour

[0384] HOBt 1-hydroxy-1H-benzotriazole

[0385] HPLC high performance liquid chromatography

[0386] LC liquid chromatography

[0387] M molar

[0388] MeOH methanol

[0389] MS mass spectrometry

[0390] min minute

[0391] NMR nuclear magnetic resonance spectroscopy

[0392] rt room temperature

[0393] Rt retention time

[0394] sat. saturated

[0395] Unless otherwise stated, the purity and identity of intermediates or example compounds were assessed by state-of-the-art high performance liquid chromatography-mass spectrometry (HPLC-MS). The method is described below.

[0396] Characterization of compounds

[0397] Method A was used for intermediates. Final purity of compounds described herein was determined using Method A or B. Purity (%) was determined by reverse phase HPLC or UPLC using UV detection (254 nm). Structure was confirmed by MS using electrospray ionization positive ion (ESI+) method and reported as [M+H]+, referring to the protonated molecular ion.

[0398] Method A:

[0399] UPLC system: UPLC I BIN SOL MGR equipped with ACQUITY UPLC I-Class eK PDA detector; Chromatographic column: Acquity BEH C18 chromatographic column (particle size 1.7 pm, size 50 mm x 2.1 mm); Mobile phase: A phase (H2O / ammonium formate, pH 3.75 (A) or 9.2 (B)) and B phase (CH3CN + 5% H2O / ammonium formate, pH 3.75 (A) or 9.2 (B)) were used according to the following method:

[0400]

[0401] Mass spectrometer: ACQUITY QDa (Performance) Xevo TQD. Ionization: electrospray (polarity: negative and positive). Analysis lasted 5 min, unless otherwise stated. In some cases, analysis was carried out for 10 min (*) or 30 min (**) as indicated.

[0402] Method B:

[0403] 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 x 4.6 mm); mobile phase: A phase (H2O / ammonium formate, pH 9.2) and B phase (CH3CN + 5% H2O / ammonium formate, pH 9.2) were used according to the following method:

[0404]

[0405] Mass spectrometer: Waters Alliance Micromass ZQ 2000. Ionization: electrospray (polarity: negative and positive).

[0406] NMR analysis

[0407] NMR spectra were recorded on a Bruker DRX-300 spectrometer with TXI probe or BrukeR 500 MHz spectrometer. Chemical shifts are given in parts per million (ppm). Signal assignment was performed using one-dimensional (1D) 1 H and 13 C spectra and two-dimensional (2D) HSQC, HMBC spectra.

[0408] The compound described in the present invention is obtained from the free 25-OH rifabutin (intermediate I-1) prepared from commercially available rifabutin, as shown below.

[0409] Example 1: Synthesis of 21,23-oxo-propanedione-25-hydroxy-rifabutin (I-1)

[0410]

[0411] Synthesis of intermediate I-1:

[0412] Commercially available rifabutin (40.0 g, 47.2 mmol) was dissolved in dry DMF (80 mL) at room temperature under nitrogen atmosphere. 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 nitrogen atmosphere for 26 h. The mixture was then cooled to 0 °C and it was poured into a mixture of saturated aqueous NaHC03solution (700 mL) and water (500 mL). The reaction flask was washed with acetone (100 mL). The resulting suspension was stirred in an ice bath for 10 min and filtered. The filter cake was rinsed with saturated aqueous NaHC03solution (100 mL) and water (50 mL) and dried under vacuum at 40 °C for 24 h. The crude product was purified by flash chromatography (from DCM to a DCM / MeOH / NH4OH 90 / 9 / 1.5 mixture in 50% DCM) to give 21,23-ketal-rifabutin as a purple solid (37.68 g, yield 90%).

[0413] LC / MS A (ESI+): Ret Time = 3.20 min, m / z [M+H] = 887.48, UV purity: 97% (254 nm). +

[0414] 1 H NMR (300 MHz, CDC13): δ 0.39 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H), 0.77-0.88 (m, 9H), 0.89-0.98 (m, 6H), 1.23 (s, 3H), 1.36-1.55 (m, 2H), 1.71-2.18 (m, 6H), 1.77 (s, 3H), 1.96 (s, 3H), 2.04 (s, 3H), 2.22-2.35 (m, 3H), 2.31 (s, 3H), 2.52-2.72 (m, 2H), 2.79 (s, 3H), 2.91-3.09 (m, 2H), 3.06 (dd, J = 10.3, 5.4 Hz, 1H), 3.34 (d, J = 6.7 Hz, 1H), 3.58 (dd, J = 3.1 Hz, 1H), 4.91 (d, J = 7.5 Hz, 1H), 5.08 (dd, J = 12.1, 6.7 Hz, 1H), 5.87 (d, J = 12.2 Hz, 1H), 6.08 (dd, J = 15.5, 6.8 Hz, 1H), 6.16 (dd, J = 10.7, 1.4 Hz, 1H), 6.28 (dd, J = 15.5, 10.7 Hz, 1H), 7.75 (s, 1H), 8.75 (s, 1H), 14.82 (s, 1H).

[0415] 13 ​C NMR (75 MHz, CDC13): δ 7.89, 9.11, 9.99, 12.8, 18.0, 20.2, 20.3, 20.9, 23.5, 25.8, 34.1, 35.4, 36.0, 36.8, 40.8, 41.4, 51.5, 56.2, 66.3, 71.2, 74.6, 76.9, 78.9, 95.0, 100.1, 104.6, 106.1, 108.7, 111.6, 113.7, 115.3, 123.8, 125.5, 131.2, 132.6, 140.8, 140.9, 142.3, 155.2, 168.2, 168.9, 170.5, 172.2, 181.3, 192.7.

[0416] The 21,23-ketal-rifabutin (10.6 g, 11.9 mmol) was dissolved in dry diethyl ether (500 ml). The solution was cooled to -10 °C under argon bubbling. After 15 min, a solution of NaOMe (30 ml, 25 w% in MeOH) was added slowly. A precipitate appeared and another portion of diethyl ether (100 mL) was added to homogenize it. The solution of NaOMe (27.4 mL) was added again. The solution was stirred at -5 °C for 10 min before the ice bath was removed. The reaction mixture was stirred at room temperature for 6 h. A saturated aqueous solution of NaHC03(400 ml) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (400 mL), 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 (from DCM to a mixture DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM 50%). After evaporation, the product was redissolved in acetone and slowly added to water under vigorous stirring. The solid was collected by filtration and dried at 40 °C to give 8.54 g of intermediate 1-1.

[0417] LC / MS A (ESI+): Ret Time = 2.98 min, m / z [M+H] = 845.59, UV purity: 97% (254 nm). +

[0418] 1 ​H NMR (300 MHz, CDC13): δ 0.48 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H), 0.74-0.84 (m, 9H), 0.86-0.96 (m, 6H), 1.04 (s, 3H), 1.23-1.33 (m, IH), 1.43-1.66 (m, 2H), 1.72 (s, 3H), 1.75-2.11 (m, 5H), 2.00 (s, 3H), 2.18-2.29 (m, 3H), 2.21 (s, 3H), 2.47-2.71 (m, 2H), 2.85-3.09 (m, 2H), 3.05-3.14 (m, IH), 3.10 (s, 3H), 3.27-3.35 (m, IH), 3.38-3.51 (m, 2H), 3.55 (dd, J = 9.2, 3.3 Hz, IH), 4.93 (dd, J = 12.5, 9.5 Hz, IH), 5.93 (dd, J = 15.5, 6.5 Hz, IH), 6.05-6.16 (m, 2H), 6.24 (dd, J = 15.5, 11.7 Hz, IH), 7.72 (s, IH), 8.63 (s, IH), 14.83 (s, IH).

[0419] 13 C NMR (75 MHz, CDC13): δ 7.7, 8.4, 12.9, 17.8, 19.9, 20.0, 20.9, 21.0, 24.2, 25.5, 25.8, 34.6, 35.2, 36.3, 39.7, 41.1, 51.4, 51.7, 56.2, 66.3, 71.0, 71.5, 75.5, 83.0, 95.0, 99.6, 104.9, 105.7, 108.6, 111.7, 111.8, 114.3, 124.1, 125.5, 132.0, 132.4, 140.3, 142.6, 142.7, 155.2, 168.2, 169.1, 171.3, 181.6, 191.2.

[0420] Example 2: Synthesis of 25-carbonyl-imidazo-21,23- ketal-rifabutin (I-2)

[0421]

[0422] Intermediate 1-1 (1.00 g, 1.18 mmol, 1 eq) was dissolved in dry DCM (40 ml) under nitrogen atmosphere. To this solution was added carbonyldiimidazole (1.92 g, 11.80 mmol, 10 eq) and the reaction was stirred at room temperature. After 16 hours, the mixture was washed with a saturated aqueous NaHC03solution (40 ml) and brine (40 mL). The organic layer was dried over MgS04, filtered and the DCM evaporated under reduced pressure. The resulting product was purified by flash chromatography (cyclohexane / acetone (from 100 / 0 to 60 / 40 in 20 CV)) to give 25-carbonyl-imidazol-21,23-oxo-acetonide-rifabutin as a black solid (m = 660 mg, yield = 59%).

[0423] LC / MS A (ESI+): Ret Time = 2.29 min, m / z [M+H] = 939.52, UV purity: 99% (254 nm). +

[0424] 1 H NMR (300 MHz, CDC13): δ 0.45 (d, J = 7.0 Hz, 1H), 0.70 - 0.82 (m, 12H), 0.82 - 0.90 (m, 6H), 1.08 (s, 3H), 1.38 - 1.54 (m, 1H), 1.58 - 2.16 (m, 8H), 1.69 (s, 3H), 1.97 (s, 3H), 2.15 - 2.27 (m, 3H), 2.20 (s, 3H), 2.44 - 2.62 (m, 2H), 2.67 (s, 3H), 2.82 - 3.02 (m, 3H), 3.30 (dd, J = 7.4, 1.7 Hz, 1H), 3.51 (dd, J = 10.5, 3.0 Hz, 1H), 4.95 - 5.10 (m, 2H), 5.89 (d, J = 12.1 Hz, 1H), 5.97 (dd, J = 15.6, 6.9 Hz, 1H), 6.07 (dd, J = 10.5, 1.2 Hz, 1H), 6.21 (dd, J = 15.6, 10.6 Hz, 1H), 6.91 - 6.97 (m, 1H), 7.23 - 7.30 (m, 1H), 7.92 - 8.03 (m, 2H), 8.46 - 8.92 (br s, 1H), 14.78 (s, 1H).

[0425] 13 ​C NMR (75 MHz, CDC13): δ 7.6, 9.4, 10.2, 12.7, 17.7, 19.9, 20.74, 20.76, 23.16, 25.4, 25.7, 26.7, 34.0, 35.3, 36.1, 36.6, 40.3, 40.6, 51.2, 51.4, 55.7, 66.2, 70.9, 76.0, 78.7, 79.5, 94.9, 99.9, 104.5, 105.7, 108.4, 111.5, 113.0, 113.7, 116.8, 123.8, 125.2, 130.3, 131.5, 132.0, 136.8, 140.0, 141.7, 142.3, 148.1, 154.9, 168.0, 168.7, 171.6, 181.2, 191.9.

[0426] Example 3: Preparation of compound 4

[0427]

[0428] A stock solution of 25-imidazo-carbonyl-21,23-ketal-rifabutin in DCM (0.025 mol / L) was prepared. Methyl-phenyl-piperidin-4-yl-amine (101 mg, 0.053 mmol, 5 eq) and HOBt (32 mg, 0.213 mmol, 20 eq.) were charged into a Kimble reactor, followed by 400 μL of a solution of 25-imidazo-carbonyl-21,23-ketal-rifabutin (I-2) in DCM (corresponding to 10 mg, 0.010 mmol, 1 eq of 25-imidazo-carbonyl-21,23-ketal-rifabutin). The reaction was stirred at room temperature. After 5 days, DCM was evaporated and 600 μL of THF was added to the mixture, followed by 600 μL of a 0.5 N solution of camphorsulfonic acid in water. The reaction was stirred at room temperature. After 16 h, the mixture was loaded onto a Column PoraPak (Rxn RP 6CC) equilibrated with water. The product was eluted with 5 mL of water, 5 mL of saturated aqueous NaHC03, 5 mL of water / acetonitrile (90 / 10) solution, 5 mL of water and 10 mL of acetonitrile (ACN), and 10 mL of ACN was collected, frozen and lyophilized to give the desired product Compound 4 as a purple powder.

[0429] 1H NMR (300 MHz, CDC13): δ (ppm) 0.00 (d, J = 7.0 Hz, 3H), 0.61 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.5 Hz, 6H), 1.05 (d, J = 6.7 Hz, 3H), 1.47-2.14 (m, 12H), 1.78 (s, 3H), 2.06 (s, 3H), 2.26-245 (m, 3H), 2.32 (s, 3H), 2.63-2.89 (m, 4H), 2.74 (s, 3H), 2.92-3.20 (m, 6H), 3.40 (d, J = 6.1 Hz, 1H), 3.63-3.79 (m, 2H), 3.85 (s, 1H), 4.09-4.38 (m, 2H), 4.59 (d, J = 10.4 Hz, 1H), 4.73 (br s, 1H), 4.96-5.13 (m, 1H), 6.06 (dd, J = 15.6, 6.8 Hz, 1H), 6.17 (d, J = 12.3 Hz, 1H), 6.26 (dd, J = 10.3, 0.8 Hz, 1H), 6.44 (dd, J = 15.6, 10.3 Hz, 1H), 6.72-6.85 (m, 3H), 7.20-7.30 (m, 2H), 8.24 (s, 1H), 8.92 (s, 1H), 14.85 (s, 1H).

[0430] 13 C NMR (75 MHz, CDC13): δ (ppm) 7.7, 8.9, 10.8, 11.6, 17.6, 20.4, 20.9, 21.7, 25.8, 29.1, 31.6, 33.3, 35.3, 36.1, 37.7, 37.8, 38.4, 44.2, 51.4, 51.5, 56.9, 57.1, 66.3, 73.1, 74.7, 77.3, 80.2, 94.4, 104.9, 107.2, 108.6, 112.0, 114.0, 114.1, 114.2, 115.8, 117.6, 124.4, 125.3, 129.3, 130.7, 133.3, 141.2, 142.2, 143.6, 149.8, 155.5, 156.1, 168.4, 168.5, 171.6, 181.4, 192.6.

[0431] The following Table 5 summarizes exemplary compounds of the application prepared according to the protocol of Example 3 above (showing R 1 and R 2Data for compounds 1-17 given in Table 5 were obtained following analytical method B. Data for compounds 20, 21, 24, 25, 29, 30, 32, 36-38, 41, 43, 44, 46, and 48-84 were obtained following analytical method A (*: 10 min analysis; **: 30 min analysis). When the starting amine was initially prepared as a hydrochloride salt, an excess of TEA was added to neutralize the hydrochloride salt prior to the addition of I-2.

[0432] Table 5: Compounds of the application (showing R 1 and R 2 groups)

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] Additional analytical data (NMR) for compound 9 are as follows:

[0440] Compound 9 1 H NMR (300 MHz, CDC13): δ (ppm) -0.12 (d, J = 6.9 Hz, 3H), 0.54 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.84-0.93 (m, 2H), 0.96 (d, J = 6.8 Hz, 3H), 1.00-1.27 (m, 10H), 1.30-1.42 (m, 1H), 1.45-1.83 (m, 7H), 1.70 (s, 3H), 1.96 (s, 3H), 2.00-2.11 (m, 1H), 2.22-2.40 (m, 3H), 2.27 (s, 3H), 2.54-2.84 (m, 10H), 2.90-3.41 (m, 10H), 3.01 (s, 3H), 3.48-3.72 (m, 3H), 4.81 (d, J = 10.5 Hz, 1H), 5.08 (dd, J = 12.6, 7.4 Hz, 1H), 5.91 (dd, J = 15.6, 6.7 Hz, 1H), 6.10 (d, J = 12.6 Hz, 1H), 6.18 (d, J = 9.9 Hz, 1H), 6.33 (dd, J = 15.6, 10.2 Hz, 1H), 8.18 (s, 1H), 9.33 (br s, 1H), 14.72 (s, 1H).

[0441] 13 C NMR (75 MHz, CDC13): δ (ppm) 7.7, 8.8, 10.8, 11.25, 17.3, 20.4, 21.0, 21.9, 24.8, 26.0, 26.4, 31.8, 32.9, 34.3, 37.6, 38.4, 51.5, 51.8, 52.7, 56.9, 58.7, 64.7, 65.2, 72.5, 73.4, 76.7, 80.9, 92.6, 104.4, 107.3, 108.7, 111.8, 114.6, 115.1, 124.3, 124.8, 131.1, 133.1, 140.6, 142.0, 144.3, 156.0, 167.9, 168.2, 170.7, 171.4, 181.5, 192.7.

[0442] Example 4: Preparation of the coupling amine used to synthesize compound 67: synthesis of cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole dihydrochloride salt Step 1

[0443] The amine group is functionalized by alkylation and / or tert-butyloxycarbonyl (Boc) deprotection as needed prior to coupling with the intermediates I-2 described herein.

[0444]

[0445] Step 2 In a glass vial, (3aR,6aS)-tert-butyl 2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4- c]pyrrole-5-carboxylate (150 mg, 0.707 mmol), K2CO3(146 mg, 1.06 mmol) and iodomethylcyclohexane (238 mg, 1.06 mmol) were diluted with 5 ml of DMF and stirred at 70 °C for 36 h. The mixture was diluted with H2O and then extracted twice with EtOAc. The combined organic layers were then washed 5 times with NaCl brine to remove the DMF. The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by flash chromatography with DCM-MeOH (100-0 to 95-5). The product was obtained as a translucent solid, 197 mg, 90% yield.

[0446] 1H NMR (300 MHz, CDC13): δ (ppm) 3.68 - 3.43 (m, 2H), 3.37 - 3.13 (m, 2H), 2.93 - 2.72 (m, 2H), 2.72 - 2.57 (m, 2H), 2.41 - 2.28 (m, 2H), 2.23 (d, J = 7.2 Hz, 2H), 1.89 - 1.58 (m, 5H), 1.46 (s, J = 5.5 Hz, 9H), 1.40 (m, 1H), 1.32 - 1.03 (m, 3H), 0.99 - 0.75 (m, 2H).

[0447] Example 5: Preparation of the coupling amine used to synthesize compound 78: synthesis of 1-tetrahydropyran-4-ylpiperidin-4-amine dihydrochloride salt : The product from Step 1 was dissolved in 1,4-dioxane (2 ml) and then HCl (4N in dioxane, 4 ml) was added dropwise and the mixture was stirred at room temperature for 18 hours. The suspension was then concentrated to dryness to give a white solid, 180 mg, quantitative yield.

[0448] The amine coupling groups of compounds 36, 52, 58, 59, 65, 66, 67, 70, 71 and 72 were prepared as described in this example.

[0449] Step 1 Step 2

[0450] The amine group was functionalized by reductive amination and / or Boc deprotection as needed prior to coupling with intermediate I-2 described herein.

[0451]

[0452] Example 6: Antibacterial activity : A round bottom flask was charged with tert-butyl N-(4-piperidinyl)carbamate (700 mg, 3.49 mmol) and DCE (15 ml) and the mixture was cooled to 0 °C. The mixture was stirred at this temperature for 5 minutes, then tetrahydropyran-4-one (0.389 ml, 4.19 mmol, 1.2 eq) was added and the mixture was stirred at this temperature for 1 h. After this time, sodium triacetoxyborohydride (1.5 g, 7 mmol, 2 eq) was added and the mixture was stirred in a melting ice bath for 18 h. After this time, a minimum amount of MeOH was added and the mixture was concentrated to dryness, then EtOAc (20 ml) was added, the organic phase was washed with H2O and NaCl brine, dried over MgSO4, concentrated to dryness to give a colorless oil, 905 mg, 91% yield.

[0453] Table 6: In vitro activity of the compounds described against Acinetobacter baumannii, Staphylococcus aureus, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium crocolum, and Mycobacterium aviumThe product from the previous step was dissolved in 1,4-dioxane (5 ml) and then HCl (4N in dioxane, 8 ml) was added dropwise and the mixture was stirred at room temperature overnight. After this time, the suspension was concentrated to dryness to give a white solid, 810 mg, yield 90%.

[0454] 1 H NMR (300 MHz, DMSO) δ 11.26 (d, J = 60.4 Hz, 1H), 8.59 (s, 3H), 4.01 - 3.89 (m, 2H), 3.59 - 3.46 (m, 2H), 3.35 - 3.22 (m, 4H), 3.10 - 2.90 (m, 2H), 2.29 - 2.11 (m, 2H), 2.11 - 1.93 (m, 4H), 1.86 - 1.63 (m, 2H).

[0455] The amine coupling groups of compounds 69 and 78 were prepared as described in this example.

[0456] Table 6: In vitro activity of the compounds described against Acinetobacter baumannii, Staphylococcus aureus, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium crocolum, and Mycobacterium avium

[0457] MIC values were determined by broth microdilution method according to CLSI guidelines with the following exceptions: MIC against A. baumannii was determined in RPMI medium supplemented with 10% FCS, MIC against M. abscessus was determined in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement (10%; see column “M. abscessus 7H9”). MIC against M. abscessus was determined for the second time in standard cation-adjusted Mueller Hinton broth without growth supplement (see column “M. abscessus MH”). All other MICs were determined in standard cation-adjusted Mueller Hinton broth, where for slow growing mycobacteria (M. crocina, M. kansasii and M. avium) Middlebrook ADC growth supplement (5%) was added.

[0458] The following procedure was applied for all tested species except M. crocina. From a fresh culture dish (from overnight to several days depending on the bacteria), cells were resuspended in 0.9% (w / v) saline solution and prepared in the respective test medium at a concentration of 5x10 5CFU / mL bacterial inoculum. For M. marinum, the inoculum was prepared from a fresh liquid culture (7H9 + ADC). Appropriate volumes of 10 mg / mL compound solution were dispensed directly into 96-well assay plates using a digital pipettor to prepare two-fold dilution series from 32 to 0.002 μg / mL final concentration for A. baumannii and S. aureus; from 16 to 0.016 μg / mL final concentration for M. abscessus and M. avium; from 1 to 6 x 10 -5 μg / mL final concentration. Finally, 100 μL of bacterial suspension was added to the compounds. The culture dishes were covered and incubated without shaking at 35°C for 20 hours for A. baumannii and S. aureus; at 30°C for 4 days for M. abscessus; at 37°C for 7 days (minimum) for M. kansasii (covered with aluminum foil to avoid light), M. avium, and M. marinum. Antibiotics were included in each experiment as a quality control. MICs were determined visually as the lowest compound concentration that prevented visible growth of bacteria.

[0459] The in vitro activity of the compounds described herein was determined against S. aureus (UAMS-1625 strain), A. baumannii (HUMC1 strain), M. abscessus (ATCC 19977), M. kansasii (ATCC 12478), M. avium (ATCC 25291), and M. marinum (ATCC 19250). MIC values are given in Table 6 below (given in μg / mL).

[0460] ​ ​

[0461]

[0462]

[0463]

Claims

1. A compound of Formula I: ###0001### I or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof, wherein: R1 is H, halogen, -ORa, -NRaRb, -C(O)Rc, -C(O)ORd, -C(O)NRcRd, -CN, -C1-6alkyl, -C1-6alkyl substituted with one or more halogen, -C1-6alkyl substituted with one or more -ORa, -C1-6alkyl substituted with one or more -NRaRb, -C1-6alkyl substituted with one or more -C(O)Rc, -C1-6alkyl substituted with one or more -C(O)ORd, -C1-6alkyl substituted with one or more -C(O)NRcRd, -C1-6alkyl substituted with one or more -CN, -C1-6alkyl substituted with one or more -C3-8cycloalkyl, -C1-6alkyl substituted with one or more -C2-8alkenyl, -C1-6alkyl substituted with one or more -C2-8alkynyl, -C1-6alkyl substituted with one or more -C3-8cycloalkyl substituted with one or more halogen, -C1-6alkyl substituted with one or more -C2-8alkenyl substituted with one or more halogen, -C1-6alkyl substituted with one or more -C2-8alkynyl substituted with one or more halogen, -C1-6alkyl substituted with one or more -C3-8cycloalkyl substituted with one or more -ORa, -C1-6alkyl substituted with one or more -C2-8alkenyl substituted with one or more -ORa, -C1-6alkyl substituted with one or more -C2-8alkynyl substituted with one or more -ORa, -C1-6alkyl substituted with one or more -C3-8cycloalkyl substituted with one or more -NRaRb, -C1-6alkyl substituted with one or more -C2-8alkenyl substituted with one or more -NRaRb, -C1-6alkyl substituted with one or more -C2-8alkynyl substituted with one or more -NRaRb, -C1-6alkyl substituted with one or more -C3-8cycloalkyl substituted with one or more -C(O)Rc, -C1-6alkyl substituted with one or more -C2-8alkenyl substituted with one or more -C(O)Rc, -C1-6alkyl substituted with one or more -C2-8alkynyl substituted with one or more -C(O)Rc, -C1-6alkyl substituted with one or more -C3-8cycloalkyl substituted with one or more -C(O)ORd, -C1-6alkyl substituted with one or more -C2-8alkenyl substituted with one or more -C(O)ORd, -C1-6 ​ R 1 and R 2 are each independently selected from the group consisting of: -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, and -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 3 ; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 15-membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents; R 3 independently at each occurrence: -OH, halogen, -CN, -Ci-C6alkoxy, -Ci-C6alkyl, -C3- 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15- membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more -OH, halogen, or Ci-C6alkyl; R 4 independently for each occurrence: -Ci-C6alkyl, -OR 5 , -Ci-C6alkylene-OR 5 , -NR 6 R 7 , -Ci-C6alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C6alkylene-C3-C 10 cycloalkyl, 3- to 15-membered heterocycloalkyl, -Ci-C6alkylene-(3- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C6alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C6alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo, and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ; R 5 independently for each occurrence: -H, -Ci-C6alkyl, or -Ci-C6alkylene-OH; R 6 and R 7 each occurrence is independently: -H, -Ci-C6alkyl, -C3-C 10 cycloalkyl, 3 to 15 membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; and R 8 each occurrence is independently: -OH, halogen, or -Ci-C6alkyl.

2. The compound of claim 1, wherein, R 1 and R 2 each independently is selected from the group consisting of: -H, -Ci-C4alkyl, -C3-C 10 cycloalkyl, Ci-C4alkylene-C3-C 10 cycloalkyl, -5 to 15 membered heterocycloalkyl, and -Ci-C4alkylene-(5 to 15 membered heterocycloalkyl), wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 3 or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 15-membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents; R 3 independently at each occurrence: -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C4alkylene-C3-C6cycloalkyl, -Ci-C4alkylene-aryl, -Ci-C4alkylene-(5- to 10-membered heteroaryl), -C6-Cio aryl, -Ci-C4alkylene-(C6-Cio aryl), -Ci-C4alkylene-(5- to 10-membered heteroaryl), -Ci-C4alkylene-(5- to 10-membered heteroaryl) substituted with one or more -OH, halogen, or Ci-C4alkyl; 10 independently at each occurrence: -OH, halogen, -Ci-C4alkyl, -C3-C 10 independently at each occurrence: -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C4alkylene-C3-C6cycloalkyl, -Ci-C4alkylene-aryl, -Ci-C4alkylene-(5- to 10-membered heteroaryl), -C6-Cio aryl, -Ci-C4alkylene-(C6-Cio aryl), -Ci-C4alkylene-(5- to 10-membered heteroaryl), -Ci-C4alkylene-(5- to 10-membered heteroaryl) substituted with one or more -OH, halogen, or Ci-C4alkyl; 10 independently at each occurrence: -OH, halogen, -Ci-C4alkyl, -C3-C 10 independently at each occurrence: -OH, halogen, -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci R 4 independently for each occurrence: -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ; R 5 independently for each occurrence: -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH; R 6 and R 7 each occurrence is independently: -H, -Ci-C4alkyl, -C3-C 10 cycloalkyl, 5 to 10 membered heterocycloalkyl, C6-C 10 aryl, or 5 to 10 membered heteroaryl; and R 8 each occurrence is independently: -OH, halogen, or -Ci-C4alkyl.

3. The compound of claim 1 or 2, wherein, R 1 and R 2 each independently is selected from the group consisting of: -H, -5- to 15-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 15-membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents; R 3 Each time it appears, it is independently -OH, halogen, -C1-C4 alkyl, -C3-C 10 Cycloalkyl, -C1-C4 alkylene, -C3-C 10 Cycloalkyl, 5- to 15-membered heterocycloalkyl, -C1-C4 alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl or -C1-C4 alkylene- (5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl may optionally be substituted by one or more -OH, halogen or C1-C4 alkyl groups; R 4 independently for each occurrence: -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C3-C 10 cycloalkyl, -Ci-C4alkylene-C3-C 10 cycloalkyl, 5- to 15-membered heterocycloalkyl, -Ci-C4alkylene-(5- to 15-membered heterocycloalkyl), -C6-C 10 aryl, -Ci-C4alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -Ci-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ; R 5 independently for each occurrence: -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH; R 6 and R 7 each occurrence is independently: -H, -Ci-C4alkyl, -C3-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, C6-Ci0aryl, or 5- to 10-membered heteroaryl; and 10 each occurrence is independently: -H, -Ci-C4alkyl, -C3-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, C6-Ci0aryl, or 5- to 10-membered heteroaryl; and 10 each occurrence is independently: -H, -Ci-C4alkyl, R 8 halogen or -Ci-C4alkyl.

4. The compound according to any one of claims 1 to 3, wherein, R 1 and R 2 Each is independently selected from: -H, -C1-C6 alkyl, -C3-C6 cycloalkyl, C1-C6 alkylene-C3-C6 cycloalkyl, -5-to-6-membered heterocyclic alkyl, -C1-C6 alkylene-(5-to-6-membered heterocyclic alkyl), -C6-C 10 Aryl, -C1-C6 alkylene -C6-C 10 aryl, 5- to 6-membered heteroaryl, or -C1-C6 alkylene- (5- to 6-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 3 replace.

5. The compound according to any one of claims 1 to 4, wherein, R 1 and R 2 each independently is selected from the group consisting of: -H, -5- to 12-membered heterocycloalkyl, and -Ci-C4alkylene-(5- to 12-membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituents; and R 3 Each occurrence is independently: -C1-C4 alkyl, -C3-C 10 Cycloalkyl, -C1-C4 alkylene, -C3-C 10 Cycloalkyl, 5- to 12-membered heterocycloalkyl, -C1-C4 alkylene-(5- to 12-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C4 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl or -C1-C4 alkylene- (5- to 10-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more C1-C4 alkyl groups.

6. The compound according to any one of claims 1 to 5, wherein, R 1 -H; and R is -H. R 2 is independently selected from the group consisting of: -5 to 6 membered heterocycloalkyl and -Ci-C2alkylene-(5 to 6 membered heterocycloalkyl), wherein each heterocycloalkyl is optionally substituted with one or more R 3 substituents; and R 3 independently for each occurrence: -Ci-C4alkyl, -C3-C6cycloalkyl, -Ci-C2alkylene-C3-C6cycloalkyl, 5- to 6-membered heterocycloalkyl, -Ci-C2alkylene-(5- to 6-membered heterocycloalkyl), -C6-aryl, -Ci-C2alkylene-C6aryl, 5- to 6-membered heteroaryl, or -Ci-C2alkylene-(5- to 6-membered heteroaryl); wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Ci-C2alkyl.

7. The compound according to any one of claims 1 to 3, wherein, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 15- membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents.

8. The compound according to any one of claims 1 to 3 or 7, wherein, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 12-membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents; R 4 independently for each occurrence -C1-C6alkyl, -OR 5 , -C1-C4alkylene-OR 5 , -NR 6 R 7 , -C1-C4alkylene-NR 6 R 7 , -C5-C 10 cycloalkyl, -C1-C4alkylene-C5-C 10 cycloalkyl, 5- to 12-membered heterocycloalkyl, -C1-C4alkylene-(5- to 12-membered heterocycloalkyl), phenyl, -C1-C4alkylene-phenyl, 5- to 10-membered heteroaryl, or -C1-C4alkylene-(5- to 10-membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 ; R 5 independently for each occurrence: -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH; R 6 and R 7 each occurrence is independently: -H, -Ci-C4alkyl, -C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and R 8 halogen or -Ci-C4alkyl.

9. The compound according to any one of claims 1 to 3 or 7 to 8, wherein, R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 7- membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with one or more R 4 substituents; R 4 independently for each occurrence: -Ci-C6alkyl, -OR 5 , -Ci-C4alkylene-OR 5 , -NR 6 R 7 , -Ci-C4alkylene-NR 6 R 7 , -C5-C6cycloalkyl, -Ci-C4alkylene-C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, -Ci-C4alkylene-(5- to 6- membered heterocycloalkyl), phenyl, -Ci-C4alkylene-phenyl, 5- to 6- membered heteroaryl, or -Ci-C4alkylene-(5- to 6- membered heteroaryl), wherein each alkylene is optionally substituted with one or more oxo; and wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R 8 ; R 5 independently for each occurrence: -H, -Ci-C4alkyl, or -Ci-C4alkylene-OH; R 6 and R 7 each occurrence is independently: -H, -Ci-C4alkyl, -C5-C6cycloalkyl, 5- to 6- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and R 8 halogen or -Ci-C4alkyl.

10. The compound of claim 1, wherein, ​ 11. The compound of claim 1, wherein, ​ ​ ​ 12. The compound of claim 1, wherein, ​ ​ ​ ​ ​ ​

Images