Antimicrobial compounds and methods

Abstract

The present disclosure relates to compounds active as antibacterial agents. The compounds are active against gram-positive and gram-negative bacteria and can be used to treat infections caused by gram-positive and gram-negative bacteria. Processes for making the compounds are also disclosed. JPEG2023501575000198.jpg37165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 934,853, filed November 13, 2019, which is incorporated by reference in its entirety.

[0002] Statement of Government Interest This invention was made with Government support under 1R01AI132304-01 awarded by the National Institutes of Health (NIH). The Government has certain rights in the invention.

[0003] The present disclosure relates to compounds that are active as antibacterial agents. The present disclosure also relates to methods of treating bacterial infections using the compounds. [Background technology]

[0004] Antibacterial resistance is a global problem. Both gram-positive and gram-negative bacteria are becoming increasingly resistant to antibiotics.

[0005] Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are resistant to most antibiotics related to penicillin. MRSA strains are commonly associated with infections acquired in health care facilities and can cause infections in the larger community.

[0006] Gram-negative bacteria are thought to be more resistant to antibiotics than gram-positive bacteria because their cell walls are impermeable. According to the National Institutes of Health (NIH), gram-negative bacteria can cause many types of infections and spread to people in a variety of ways. Some species, including Escherichia coli, are common causes of food-borne illnesses. Vibrio cholerae, the causative agent of cholera, is a waterborne pathogen. Gram-negative bacteria can also cause respiratory infections, such as certain types of pneumonia, and sexually transmitted diseases, including gonorrhea. Yersinia pestis, the causative agent of the plague, infects people through the bite of an infected insect or handling an infected animal. See www.niaid.nih.gov / research / gram-negative-bacteria (last viewed on November 6, 2020).

[0007] Several types of Gram-negative bacteria are becoming increasingly resistant to available antibiotics. Some strains are now resistant to many, most, or all available treatments, resulting in increased illness and death from bacterial infections and contributing to rising healthcare costs. Examples of Gram-negative bacteria that exhibit drug resistance include E. coli, which is responsible for the majority of urinary tract infections; Acinetobacter baumanii, which primarily causes disease in healthcare settings; Pseudomonas aeruginosa, which causes bloodstream infections and pneumonia in hospitalized patients and is a common cause of pneumonia in cystic fibrosis patients; Klebsiella pneumoniae, which causes many types of healthcare-associated infections, including pneumonia, urinary tract infections, and bloodstream infections; and Neisseria gonorrhoeae, which causes the sexually transmitted disease gonorrhea, the second most commonly reported infection in the United States.

[0008] Consequently, new drugs are needed to combat Gram-positive and Gram-negative infections. Summary of the Invention [Means for solving the problem]

[0009] These and other needs can be addressed by the present invention, which in one aspect provides a compound of formula I: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, In the formula, ring A is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 and oxo, J is C 1 -C 6 Alkylene or C 3 -C 8 cycloalkylene, any of which may be halo, OH, or C 1 -C 6 Optionally substituted with alkoxy, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO 2 , or replaced by C=O, R x , R y , R x’ , and R y’ However, each independently, H, C 1-C 6 an alkyl or amino protecting group, Y is a bond, OH, or NH 2 , CN, Halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 Alkylene, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, NH, N-(C 1 -C 6 alkyl), N-(C 1 -C 6 Hydroxyalkyl), N-(C 1 -C 6 haloalkyl), N-(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O) or (C=O), Ring B is a 3- to 8-membered monocyclic cycloalkylene, a 3- to 8-membered monocyclic heterocycloalkylene, a 6- to 12-membered bicyclic cycloalkylene, or a 6- to 12-membered bicyclic heterocycloalkylene, each of which is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 Optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl; L is a bond or C 1 -C 6 alkylene, wherein C 1 -C 6Up to two methylene units of the alkylene are independently O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), ring C together with the phenyl ring to which it is fused forms an 8- to 12-membered bicyclic arylene or an 8- to 12-membered bicyclic heteroarylene, the bicyclic heteroarylene having 1 to 3 heteroatoms independently selected from N, O, or S; R 1 , R 2 , and R 3 However, each independently, C 1 -C 6 Alkyl, halo, CN, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , COO(C 1 -C 6 alkyl), CONH 2 , C 1 -C 6 Haloalkyl, oxo, and C 1 -C 6 alkoxy; The present invention provides a compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are each independently 0, 1, 2, or 3.

[0010] In another aspect, the present invention provides a method of using a compound of formula I, or a pharma- ceutically acceptable salt thereof, for the treatment of a bacterial infection.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0012] In a further aspect, the present invention provides a process for making a compound of formula I, or a pharma- ceutically acceptable salt thereof, as shown in the synthetic scheme. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, and suitable methods and materials are described below. In addition, the materials, methods, and examples are only illustrative and are not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including their definitions, will control.

[0014] As used herein, the terms "a," "an," and "the" include not only single member embodiments, but also two or more member embodiments.

[0015] As used herein, the term "about" means "approximately" and is used to modify a numerical value and indicate a defined range around that value. When "X" is the value, "about X" generally indicates a value between 0.95X and 1.05X. Reference to "about X" specifically indicates at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide support by the specification for a claim limitation of, for example, "0.98X". When the quantity "X" includes only integer values ​​(e.g., "X carbons"), "about X" indicates (X-1) to (X+1). In this case, as used herein, "about X" specifically indicates at least the values ​​X, X-1, and X+1.

[0016] When "about" is applied to the beginning of a numerical range, it applies to both ends of that range. Thus, "about 5% to 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0017] As used herein, wavy lines drawn into a structure may be used to indicate a point of attachment for that structure. For example, [ka] So, [ka] indicates the attachment point.

[0018] As used herein, the term "acyl" includes alkanoyl, aroyl, heterocycloyl, or heteroaroyl groups as defined herein. Examples of acyl groups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.

[0019] As used herein, the term "alkanoyl" includes alkyl-C(O)- groups, where alkyl is as defined herein. Examples of alkanoyl groups include, but are not limited to, acetyl and propanoyl.

[0020] As used herein, the term "agent" includes a compound or mixture of compounds that, when added to a composition, tends to have a particular effect on the properties of the composition. For example, a composition that includes a thickening agent is likely to be more viscous than an otherwise identical comparative composition lacking the thickening agent.

[0021] As used herein, the term "alkyl" includes an aliphatic hydrocarbon chain that may be straight or branched. The chain may contain the indicated number of carbon atoms. For example, C 1 -C 10indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Unless otherwise specified, alkyl groups contain 1 to about 20 carbon atoms. In some embodiments, alkyl groups have 1 to about 10 carbon atoms. In some embodiments, alkyl groups ("lower alkyl") have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples can include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, docecyl, cyclopentyl, or cyclohexyl.

[0022] The alkyl group may be an unsubstituted or optionally substituted alkyl group. If optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of the alkyl group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, the alkyl group is an unsubstituted or not an optionally substituted alkyl group.

[0023] As used herein, "alkylene" includes di-substituted alkyl groups. An example is methylene (-CH 2 -), propylene (-CH 2 CH 2 CH 2 -), etc.

[0024] As used herein, the term "alkenyl" includes straight or branched chain hydrocarbons containing at least one carbon-carbon double bond. The chain may contain the number of carbon atoms indicated. For example, "C 1 -C 12 "Alkenyl" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one carbon-carbon double bond. When the indicated number of carbon atoms is 1, C iThe alkenyl is double bonded to the carbon (i.e., the carbon corresponding to the oxo group). In certain embodiments, the chain contains 1 to 12, about 2 to 15, about 2 to 12, about 2 to 8, or about 2 to 6 carbon atoms. The alkenyl group may preferably be in one stereoisomer (i.e., cis- or, alternatively, trans-). Examples of alkenyl groups may include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl, butadienyl, pentadienyl, 3-(1,4-pentadienyl), and hexadienyl.

[0025] The alkenyl group may be an unsubstituted alkenyl group or an optionally substituted alkenyl group. When optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of the alkenyl group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, but the hydrogen atom substituent of the carbon-carbon double bond is not replaced by a hydroxy, amino, or thio group. In some embodiments, the alkenyl group is an unsubstituted alkenyl group or is not an optionally substituted alkenyl group.

[0026] As used herein, "alkenylene" includes di-substituted alkenyl groups. An example is but-2-enylene (-CH 2 CH=CHCH 2 -), etc.

[0027] As used herein, the term "alkoxy" includes straight or branched chain saturated or unsaturated hydrocarbons containing at least one oxygen atom in an ether group (e.g., EtO-). The chain may contain the indicated number of carbon atoms. For example, "C 1 -C 12"Alkoxy" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one oxygen atom. 1 -C 12 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.

[0028] An alkoxy group may be an unsubstituted or an optionally substituted alkoxy group. When optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of an alkoxy group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, but the hydrogen atom alpha to the ether oxygen is not replaced by a hydroxy, amino, or thio group. In some embodiments, an alkoxy group is an unsubstituted or is not an optionally substituted alkoxy group.

[0029] As used herein, the term "alkynyl" includes straight chain, branched, or cyclic hydrocarbons containing at least one carbon-carbon triple bond. Examples can include, but are not limited to, ethynyl, propargyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, or decynyl.

[0030] As used herein, "alkynylene" includes di-substituted alkynyl groups. An example is 2-butynylene (-CH 2 CCCH 2 -), etc.

[0031] An alkynyl group may be an unsubstituted or optionally substituted alkynyl group. When optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of the alkynyl group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, but the sp hybridized hydrogen atom substituents are not replaced by hydroxy, amino, or thio groups. In some embodiments, the alkynyl group is an unsubstituted or optionally substituted alkynyl group.

[0032] As used herein, an "aryl" group refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, dihydroindenyl), and tricyclic (e.g., fluorenyltetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems, where the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. The other ring(s) in the bicyclic or tricyclic ring system can be saturated, partially unsaturated, or fully unsaturated. Bicyclic and tricyclic groups include benzo-fused carbocyclic rings. For example, a benzo-fused group includes a benzene ring fused to one or two 4-8 membered carbocyclic moieties (e.g., 1,2,3,4-tetrahydronaphthalene or 2,3-dihydro-1H-indene ring systems).

[0033] As used herein, "arylene" includes di-substitued aryl groups.

[0034] The aryl group may be an unsubstituted or an optionally substituted aryl group. When optionally substituted, one or more (e.g., 1-5, 1-2, or 1) hydrogen atoms of the aryl group may be independently replaced with a moiety selected from the group consisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, the alkoxy group is an unsubstituted or is not an optionally substituted alkoxy group.

[0035] As used herein, the term "arylalkyl" or "aralkyl" includes an alkyl group, as defined herein, in which at least one hydrogen substituent is replaced with an aryl group, as defined herein. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4-methylbenzyl, and 1,1,-dimethyl-1-phenylmethyl.

[0036] An arylalkyl or aralkyl group, like its constituent groups, may be an unsubstituted or optionally substituted arylalkyl or aralkyl group. For example, but not by way of limitation, the aryl group of an arylalkyl group may be substituted, for example, with 4-methylbenzyl. In some embodiments, the group is an unsubstituted or not an optionally substituted group, particularly when it contains a defined substituent, such as a hydroxyalkyl or alkylaminoalkoxy group.

[0037] As used herein, the term "cycloalkyl" includes non-aromatic saturated monocyclic or polycyclic ring systems that may contain the indicated number of carbon atoms, where none of the rings in the polycyclic ring system are aromatic. For example, C 3 -C 12indicates that the group may have 3 to 12 (inclusive) carbon atoms in it. Unless otherwise specified, cycloalkyl groups contain from about 3 to about 20 carbon atoms. In some embodiments, cycloalkyl groups have 3 to about 12 carbon atoms in the group. In some embodiments, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl. The term "cycloalkyl" also includes polycyclic rings, such as bicyclic cycloalkyls, or tricyclic cycloalkyls, which may be in fused, bridged, or spiro configurations.

[0038] The cycloalkyl group may be an unsubstituted or an optionally substituted cycloalkyl group. When optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of the cycloalkyl group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, the substituted cycloalkyl group may incorporate an exocyclic or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, the cycloalkyl group is an unsubstituted or an optionally substituted cycloalkyl group.

[0039] As used herein, the term "cycloalkylene" includes di-substitued cycloalkyl groups.

[0040] The terms "disorder" and "disease" are used interchangeably herein with respect to the condition of a subject. A disorder is a disturbance or disruption that affects the normal functioning of a subject's body. A disease is a pathological condition of an organ, body part, or system that is characterized by a constellation of identifiable symptoms resulting from a variety of causes, such as infection, genetic defect, or environmental stress. A disorder or disease may also refer to a biofilm-associated disorder characterized by disease-associated bacterial growth or a disorder caused by a planktonic bacterial phenotype.

[0041] As used herein, the term "effective amount" or "effective dosage" includes an amount sufficient to achieve a desired result, and thus depends on the ingredient and the desired result, although once the desired effect has been ascertained, identifying an effective amount is within the skill of one of ordinary skill in the art.

[0042] As used herein, "fluoroalkyl" includes alkyl groups where the alkyl group contains one or more fluoro substituents. Examples include, but are not limited to, trifluoromethyl.

[0043] As used herein, "geminal" substitution includes two or more substituents directly attached to the same atom. An example is 3,3-dimethyl substitution on a cyclohexyl or spirocyclohexyl ring.

[0044] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0045] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms are heteroatoms (e.g., N, O, S, or combinations thereof), and the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. The other ring(s) in the bicyclic or tricyclic ring system can be saturated, partially unsaturated, or fully unsaturated. The heteroaryl group can include a benzo-fused ring system having 2 to 3 rings. For example, the benzo-fused group includes a benzo fused with one or two 4- to 8-membered heterocyclic moieties. Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, puryl, cinnolyl, quinolyl, quinazolinyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinolizinyl, benzo-1,2,5-thiadiazolyl, 1,8-naphthyridinyl, indyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, isoindolinyl, benzo[b]thiophen-yl, quinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzodihydropyranyl, or chromanyl. In some embodiments, the heteroaryl group can include chromanyl, isoindolinyl, and tetrahydroisoquinolinyl.

[0046] As used herein, the term "heteroarylene" includes a heteroaryl group substituted at two positions.

[0047] A heteroaryl group may be an unsubstituted or an optionally substituted heteroaryl group. When optionally substituted, one or more (e.g., 1-5, 1-2, or 1) hydrogen atoms of the heteroaryl group may be independently replaced with a moiety selected from the group consisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, a heteroaryl group is an unsubstituted or an optionally substituted heteroaryl group.

[0048] As used herein, a "heterocycloalkyl" includes a non-aromatic saturated ring of about 3 to about 15 ring atoms (e.g., 5 to about 10 ring atoms, or 3 to about 6 ring atoms), in which one or more atoms of the ring system is an element(s) other than carbon, such as nitrogen, oxygen, or sulfur. A heterocycloalkyl group optionally includes at least one sp 2-hybridized atoms (e.g., rings incorporating carbonyls, endocyclic olefins, or exocyclic olefins). In some embodiments, the nitrogen or sulfur atom of a heterocycloalkyl is optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Monocyclic heterocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered ring that contains at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains 0 or 1 double bond and 1 heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains 0 or 1 double bond and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains 0, 1, or 2 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolin ... These include, but are not limited to, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.

[0049] As used herein, the term "heterocycloalkylene" includes di-substitued heterocycloalkyl groups.

[0050] The term "heterocycloalkyl" also includes polycyclic ring systems, such as bicyclic heterocycles, or tricyclic heterocycles, which may be in fused, bridged, or spiro configurations, and none of the rings of the polycyclic ring system are aromatic. A bicyclic heterocycle can be a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle system in which two non-adjacent atoms of the rings are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or by an alkenylene bridge of 2, 3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.2.0]heptane, (3aR,6aS)-hexahydro-1H-2λ 2 -Cyclopenta[c]pyrrole, (3aR,7aS)-octahydro-2λ 2 -isoindole.

[0051] A heterocycloalkyl group may be an unsubstituted or an optionally substituted heterocycloalkyl group. When optionally substituted, one or more (e.g., 1-4, 1-2, or 1) hydrogen atoms of the group may be independently replaced with a moiety selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, a substituted heterocyclyl group can incorporate an exocyclic or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, a heterocyclyl group is an unsubstituted or an optionally substituted heterocyclyl group.

[0052] The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring, and can be unsubstituted or substituted.

[0053] As used herein, the term "hydrophilic moiety" or "hydrophilic group" includes moieties or functional groups that have a strong affinity for water. Examples may include, but are not limited to, charged moieties, such as cationic or anionic moieties, or polar uncharged moieties, such as alkoxy or amine groups.

[0054] As used herein, the term "hydroxyalkyl" includes an alkyl group in which at least one hydrogen substituent is replaced with an alcohol (-OH) group. In certain embodiments, the hydroxyalkyl group has one alcohol group. In certain embodiments, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain embodiments, the hydroxyalkyl group has one, two, three, four, five, or six alcohol groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0055] When any two substituents or any two instances of the same substituent from a list of alternatives are "independently selected," those groups may be the same or different. For example, R a and R b is independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then two R a Group and two R b In a molecule having groups, all of the groups may be alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a is alkyl and the second R a is fluoro, and the first R b is hydroxyalkyl, and the second R b may be amino (or any other substituent from the group). Alternatively, both R a and the first R b is fluoro and the second R b may be alkyl (i.e., some pairs of substituents may be the same and other pairs may be different).

[0056] An "amino protecting group" is a protecting group suitable for preventing undesired reactions at an amino nitrogen. Representative amino protecting groups include, but are not limited to, formyl, acyl groups, such as alkanoyl groups, e.g., acetyl and trifluoroacetyl, alkoxycarbonyl groups, e.g., tert-butoxycarbonyl (Boc) and methoxycarbonyl, arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc), arylmethyl groups, e.g., benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl.

[0057] A "hydroxyl protecting group" is a protecting group suitable for preventing undesired reactions at a hydroxyl oxygen. Representative hydroxy protecting groups include, but are not limited to, acyl groups, such as alkanoyl groups, e.g., acetyl, arylmethyl groups, e.g., benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl, silyl groups, e.g., trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS or TBS), and the like.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid of amino groups, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0059] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness of the free base and which are not biologically or otherwise objectionable, and are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, orotic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0060] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.)

[0061] As used herein, "or" is generally to be construed as non-exclusive. For example, an embodiment of "a composition comprising A or B" may typically present an embodiment having a composition comprising both A and B. However, "or" should be construed to exclude presented embodiments that cannot be consistently combined (e.g., a composition pH of 9-10 or 7-8).

[0062] As used herein, "spirobibicyclic cycloalkyl" includes cycloalkyl in which geminal substituents on carbon atoms are replaced to participate in the formation of a 1,1-substituted ring. For example, but not limited to, -C(R 1 )(R 2 )-group, R 1 and R 2 But R 1 and R 2 is linked to form a cyclopropyl ring, incorporating the carbon to which it is attached, this can be a spiro bicyclic cycloalkyl group (ie, spirocyclopropyl).

[0063] As used herein, the term "spirobicyclic cycloalkylene" embraces spiro bicyclic cycloalkyl groups which are disubstituted.

[0064] As used herein, "spirobiicyclic heterocycloalkyl" includes heterocycloalkyl in which geminal substituents on carbon atoms are replaced to participate in the formation of a 1,1-substituted ring. For example, but not limited to, -C(R 1 )(R 2 )-group, R 1 and R 2 But R 1 and R 2 is attached to form a pyrrolidine ring, incorporating the carbon to which it is attached, this can be a spiro bicyclic heterocycloalkyl group.

[0065] As used herein, the term "spirobicyclic heterocycloalkylene" embraces 2-point substituted spiro bicyclic heterocycloalkyl groups.

[0066] The compounds disclosed herein are characterized by the presence of an amino functionality, and therefore, those skilled in the art will recognize that the compounds may be isolated as salts in which the nitrogen of the amino functionality has been quaternized.

[0067] As used herein, the terms "treat," "treating," or "treatment" include administering or applying a composition (e.g., a composition described herein) in an amount, manner (e.g., administration schedule), and mode (e.g., route of administration) effective to ameliorate a disorder or a symptom thereof, or to prevent or slow the progression of a disorder or a symptom thereof. Such improvement can include, but is not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of a disease, stabilization of a disease condition (i.e., not worsening), delaying or slowing disease progression, improvement or palliation of a disease condition, reduction in recurrence of a disease, and remission, whether partial or complete, and whether detectable or undetectable.

[0068] Embodiment compound In a first aspect, the present disclosure provides a compound of formula I: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, In the formula, ring A is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl)2 , COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 and oxo, J is C 1 -C 6 Alkylene or C 3 -C 8 cycloalkylene, any of which may be halo, OH, or C 1 -C 6 Optionally substituted with alkoxy, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO 2 , or replaced by C=O, R x , R y , R x’ , and R y’ However, each independently, H, C 1 -C 6 an alkyl or amino protecting group, Y is a bond, OH, or NH 2 , CN, Halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 Alkylene, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, NH, N-(C 1 -C 6 alkyl), N-(C 1 -C 6 Hydroxyalkyl), N-(C 1 -C 6 haloalkyl), N-(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N-(C1-6 alkyl)(C=O) or (C=O), Ring B is a 3- to 8-membered monocyclic cycloalkylene, a 3- to 8-membered monocyclic heterocycloalkylene, a 6- to 12-membered bicyclic cycloalkylene, or a 6- to 12-membered bicyclic heterocycloalkylene, each of which is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), COONH 2 , COONH(C 1 -C 6 Alkyl), COON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 Optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl; L is a bond or C 1 -C 6 alkylene, wherein C 1 -C 6 Up to two methylene units of the alkylene are independently O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), ring C together with the phenyl ring to which it is fused forms an 8- to 12-membered bicyclic arylene or an 8- to 12-membered bicyclic heteroarylene, the bicyclic heteroarylene having 1 to 3 heteroatoms independently selected from N, O, or S; R 1 , R 2 , and R 3 However, each independently, C 1 -C 6 Alkyl, halo, CN, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C1 -C 6 Alkyl) 2 , COO(C 1 -C 6 alkyl), COONH 2 , C 1 -C 6 Haloalkyl, oxo, and C 1 -C 6 alkoxy; The present invention provides a compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are each independently 0, 1, 2, or 3.

[0069] In one embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring A is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 and oxo.

[0070] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring A is [ka] where each R 4 is independently 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 and oxo, and q is 0, 1, or 2.

[0071] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring A is [ka] It is.

[0072] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, J is halo, OH, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 Alkylene, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO 2 , or replaced by C=O.

[0073] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, J is C optionally substituted with OH. 1 -C 6 Alkylene, C 1 -C 6 One methylene unit of the alkylene is replaced by C=O.

[0074] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, J is [ka] It is.

[0075] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, R x and R y is H. In another embodiment, R x is H and R y is C1 -C 6 In another embodiment, R x is H and R y is an amino protecting group. x is H and R y is a Boc group or a methoxycarbonyl group. x and R y are each independently 1 -C 6 In another embodiment, R x and R y are each independently selected from the group consisting of H, Boc, and methoxycarbonyl.

[0076] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] It is.

[0077] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] It is.

[0078] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring C together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic arylene or a 9-10 membered bicyclic heteroarylene, the bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S.

[0079] In another embodiment, ring C together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic arylene or a 9-10 membered bicyclic heteroarylene, wherein the bicyclic heteroaryl has 1-3 heteroatoms independently selected from N and O.

[0080] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] but, [ka] wherein each X 1 But independently, CH 2 , C.H., O., S., SO., SO 2 , N, and NH; R 2 and R 3 However, each independently, C 1 -C 6 Alkyl, halo, or C 1 -C 6 haloalkyl, and n and p are each independently 0, 1, or 2. In another embodiment, each X 1 But independently, CH 2 , CH, O, N, and NH; R 2 and R 3 However, each independently, C 1 -C 6 Alkyl, halo, or C 1 -C 6is a haloalkyl, and n and p are each independently 0 or 1.

[0081] In another embodiment of the compound of formula I, or a single stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof,

Chem.

Chem.

[0082] In another embodiment of the compound of formula I, or a single stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof,

Chem.

Chem.

[0083] In another embodiment,

Chem.

Chem.

[0084] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0085] In another embodiment, [ka] teeth, [ka] It is.

[0086] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Y is a bond.

[0087] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Y is OH, NH 2 , halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 3 Alkylene, C 1 -C 3 A single methylene unit of an alkylene is O, NH, N(C 1 -C 6 alkyl), N(C 1 -C 6 Hydroxyalkyl), N(C 1 -C 6 Haloalkyl), N(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N(C 1-6 alkyl)(C=O), or (C=O).

[0088] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Y is O, NH, NH—C 1-2 Alkylene, N(C 1 -C 6 alkyl), N(C 1 -C 6 Hydroxyalkyl), N(C 1 -C 6 Haloalkyl), N(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N(C 1-6 alkyl)(C=O), and (C=O).

[0089] In another embodiment, Y is O, NH, N(C 1 -C 6 alkyl), N(C 1 -C 6 Hydroxyalkyl), N(C 1 -C 6 Haloalkyl), N(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N(C 1-6 alkyl)(C=O), or (C=O).

[0090] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Y is -NH-, -N(C 1 -C 6 alkyl)- or -N(C 1-6 Alkylene-C 3-8 cycloalkyl)-.

[0091] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Y is -NH-, -N(C 1 -C 3 Alkyl)-, -NH-C 1-2 Alkylene- and -N(C 1-3Alkylene-C 3-6 In another embodiment, Y is selected from the group consisting of -NH-, -NMe-, -NEt-, -NH-CH 2 - and -N(CH 2 -cyclopropyl)-.

[0092] In another embodiment, Y is a bond, —NH—, —N(C 1 -C 3 Alkyl)-, -NH-C 1-2 Alkylene- and -N(C 1-3 Alkylene-C 3-6 In another embodiment, Y is selected from the group consisting of a bond, -NH-, -NMe-, -NEt-, -NH-CH 2 - and -N(CH 2 -cyclopropyl)-.

[0093] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0094] In another embodiment, [ka] teeth, [ka] It is.

[0095] In another embodiment of the compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 4- to 7-membered monocyclic cycloalkylene, a 4- to 7-membered monocyclic heterocycloalkylene, a 6- to 10-membered bicyclic cycloalkylene, or a 6- to 10-membered bicyclic heterocycloalkylene, each of which, the monocyclic heterocycloalkylene and the bicyclic heterocycloalkylene, are independently selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 Optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl.

[0096] In another embodiment, Ring B is a 4-7 membered monocyclic cycloalkylene, a 4-7 membered monocyclic heterocycloalkylene, a 6-10 membered bicyclic cycloalkylene, or a 6-10 membered bicyclic heterocycloalkylene.

[0097] In another embodiment, Ring B is a 4-6 membered monocyclic cycloalkylene, a 4-7 membered monocyclic heterocycloalkylene, or a 6-7 membered bicyclic cycloalkylene, or a 6-7 membered bicyclic heterocycloalkylene.

[0098] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 and optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl.

[0099] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, and C 1 -C 6 and hydroxyalkyl.

[0100] In another embodiment, ring B is a 3-8 membered monocyclic cycloalkylene. In another embodiment, ring B is a 4-7 membered monocyclic cycloalkylene. In another embodiment, ring B is selected from the group consisting of cyclobutylene, cyclopentylene, and cyclohexylene.

[0101] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 and hydroxyalkyl.

[0102] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, and C 1 -C 6 and hydroxyalkyl, and ring B is a 4- to 7-membered monocyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of aryl, aryl, aryl and aryl ; and ring B contains up to two nitrogen atoms.

[0103] In another embodiment, ring B is a 3-8 membered monocyclic heterocycloalkylene. In another embodiment, ring B is a 5-7 membered monocyclic heterocycloalkylene, and ring B contains up to 2 nitrogen atoms. In another embodiment, ring B is a 4-7 membered monocyclic heterocycloalkylene, and ring B contains 1 nitrogen atom. In another embodiment, ring B is a 5-7 membered monocyclic heterocycloalkylene, and ring B contains 1 nitrogen atom.

[0104] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, Halo, C 1 -C 6 Haloalkyl, OH, and C 1 -C6 and optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl.

[0105] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 6-10 membered fused, spiro, or bridged bicyclic cycloalkylene.

[0106] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 6-10 membered fused bicyclic cycloalkylene.

[0107] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 6-10 membered bridged bicyclic cycloalkylene.

[0108] In another embodiment of the compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 6-10 membered spiro bicyclic cycloalkylene. In another embodiment, Ring B is a 7 membered spiro bicyclic cycloalkylene.

[0109] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, Halo, C 1 -C 6 Haloalkyl, OH, and C 1 -C 6 In another embodiment, Ring B is a 6-12 membered bicyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl. In another embodiment, Ring B is a 6-12 membered bicyclic heterocycloalkylene.

[0110] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a 6-12 membered fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms.

[0111] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is a 6-12 membered fused bicyclic heterocycloalkylene containing up to two nitrogen atoms. In another embodiment, ring B is a 6-10 membered fused bicyclic heterocycloalkylene containing two nitrogen atoms. In another embodiment, ring B is a 6-10 membered fused bicyclic heterocycloalkylene containing one nitrogen atom. In another embodiment, ring B is a 6-membered fused bicyclic heterocycloalkylene containing one nitrogen atom.

[0112] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0113] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, Ring B is a bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0114] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, ring B is [ka] is selected from the group consisting of:

[0115] In another embodiment, ring B is [ka] is selected from the group consisting of:

[0116] In another embodiment of a compound of Formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, L is a bond.

[0117] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, L is C 1 -C 6 Alkylene, C 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 It can be replaced by alkyl.

[0118] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, L is C 1 -C 6 It is alkylene.

[0119] In another embodiment, L is -CH 2 -or-CH 2 CH 2 In another embodiment, L is -CH 2 In another embodiment, L is -CH 2 CH 2 -It is.

[0120] In another embodiment, L is a bond or C 1 -C 3 In another embodiment, L is a bond, -CH 2 -, or -CH 2 -CH 2 -It is.

[0121] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, R x’ and R y’ is H. In another embodiment, R x’ is H and R y’ is C 1 -C 6 In another embodiment, R x’ is H and R y’ is an amino protecting group. x’ and R y’ are each independently 1 -C 6 In another embodiment, R x’ and R y’ are each independently selected from the group consisting of H, Boc, and methoxycarbonyl. x’ and R y’ are each independently selected from the group consisting of H and methoxycarbonyl.

[0122] In another embodiment, Y is C 1 -C 3 Alkylene, C 1 -C 3 One methylene unit of an alkylene is -NH-, -N(C 1 -C 6 alkyl)- or -N(C 1-6 Alkylene-C 3-8 cycloalkyl)-, Ring B is a 4- to 6-membered monocyclic cycloalkylene, a 4- to 7-membered monocyclic heterocycloalkylene, a 6- to 9-membered bicyclic cycloalkylene, or a 6- to 9-membered bicyclic heterocycloalkylene; L is a bond or C 1 -C 3 alkylene, R x’ and R y’ are each independently H or an amino protecting group.

[0123] In another embodiment, Y is -NH-, -NMe-, -NEt-, -NH-CH 2 - and -N(CH2 -cyclopropyl)-, and Ring B is selected from the group consisting of [ka] and L is a bond, -CH 2 -, or -CH 2 -CH 2 - and R x’ and R y’ are each independently selected from the group consisting of H, Boc, and methoxycarbonyl.

[0124] In another embodiment of the compound of formula I, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0125] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0126] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , and R 3 are each independently 1 -C 6 Alkyl, halo, C 1 -C 6 Haloalkyl, oxo, and C 1 -C 6alkoxy; and m, n, and p are each independently 0, 1, or 2.

[0127] In another embodiment of the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , and R 3 are each independently 1 -C 6 Alkyl, halo, oxo, or C 1 -C 6 haloalkyl, where m, n, and p are each independently 0 or 1. In another embodiment, m, n, and p are 0.

[0128] In another embodiment, the compound of formula I is a compound of formula IA: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 2 , R 3 , R x , R y , R x’ , R y’ , n, and p have the definitions provided in the paragraph above.

[0129] In another embodiment, the compound of formula I or IA is a compound of formula IA-1: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 2 , R 3 , R x , R y , R x’ , R y’ , n, and p have the definitions given in the preceding paragraph, and each R 4 are independently H, C 1 -C6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, NH 2 and oxo, where q is 0, 1, 2, or 3.

[0130] In another embodiment, the compound of formula I, IA, or IA-1 can be a compound of formula IA-2: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 2 , R 3 , R x , R y , R x’ , R y’ , n, and p have the definitions provided in the preceding paragraph, and K is halo, hydroxyl, or C 1 -C 6 C optionally substituted with an alkoxy group 1 -C 4 It is alkylene.

[0131] In another embodiment, the compound of formula I, IA, IA-1, or IA-2 is a compound of formula IA-3: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 2 , R 3 , R x , R y , R x’ , R y’ , n, and p have the definitions provided in the preceding paragraph, and K is C optionally substituted with hydroxyl. 1 -C 3 It is alkylene.

[0132] In another embodiment, the compound of formula I, IA, IA-1, IA-2, or IA-3 may be a compound of formula IA-4a or IA-4b: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein rings B, L, K, Y, R 2 , R 3 , R x’ , R y’ , n, and p have the definitions provided in the preceding paragraph, and each X 1 are independently 2 , CH, O, S, N, and NH.

[0133] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, or IA-4b is a compound of formula IA-5a or IA-5b: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein rings B, L, K, Y, R x’ , and R y’ has the definition provided in the preceding paragraph, and each X 1 are independently 2 , CH, N, NH, and O. In another embodiment, each X 1 are independently 2 and O.

[0134] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-4b, IA-5a, or IA-5b is a compound of formula IA-6a or IA-6b: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein rings B, L, K, Y, and X are each independently selected from the group consisting of: 1 has the definition provided in the paragraph above.

[0135] In another embodiment, a compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-4b, IA-5a, IA-5b, IA-6a, or IA-6b is selected from the group consisting of a compound of formula IA-7a, formula IA-7b, formula IA-7c, formula IA-7d, formula IA-7e, or formula IA-7f: [ka] Also a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein L, K, Y, and X are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 1 has the definition provided in the preceding paragraph, and each X 2 is independently CH or N, and each s is independently 1, 2, or 3.

[0136] In one embodiment, K is [ka] It is.

[0137] In one embodiment, Y is a bond, —NH—, —NH—(C 1 -C 5 alkylene)-, -N(C 1 -C 6 alkyl)- or -N(C 1 -C 6 Alkylene-C 3 -C 8 cycloalkyl)-.

[0138] In one embodiment, Y is -NH-, -N(C 1 -C 6 alkyl)- or -N(C 1 -C 6 Alkylene-C 3 -C 8cycloalkyl)-.

[0139] In another embodiment, L is a bond or C 1 -C 6 In another embodiment, L is C 1 -C 6 It is alkylene.

[0140] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, IA-7a, or IA-7a is selected from the group consisting of compounds of formula IA-7a-1, formula IA-7a-2, formula IA-7a-3, formula IA-7a-4, formula IA-7a-5, formula IA-7a-6, formula IA-7a-7, or formula IA-7a-8: [ka] or a pharma- ceutically acceptable salt thereof, 1 , and L are as defined herein.

[0141] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, or IA-7c is selected from the group consisting of compounds of formula IA-7c-1, formula IA-7c-2, formula IA-7c-3, formula IA-7c-4, formula IA-7c-5, formula IA-7c-6, formula IA-7c-7, or formula IA-7c-8: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Y, and L are as defined herein.

[0142] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, or IA-7c is selected from the group consisting of compounds of formula IA-7c-9, formula IA-7c-10, formula IA-7c-11, or formula IA-7c-12: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Y, and L are as defined herein.

[0143] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, or IA-7c is selected from the group consisting of compounds of formula IA-7c-13, formula IA-7c-14, formula IA-7c-15, and formula IA-7c-16: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Y, and L are as defined herein.

[0144] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, or IA-7c is selected from the group consisting of a compound of formula IA-7c-17, formula IA-7c-18, formula IA-7c-19, formula IA-7c-20, formula IA-7c-21, formula IA-7c-22, formula IA-7c-23, or formula IA-7c-24: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Y, and L are as defined herein.

[0145] In another embodiment, the compound of formula I, IA, IA-1, IA-2, IA-3, IA-4a, IA-5a, IA-6a, or IA-7c is selected from the group consisting of a compound of formula IA-7c-25, formula IA-7c-26, formula IA-7c-27, or formula IA-7c-28: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Y, and L are as defined herein. paragraph

[0146] In one embodiment, K is C optionally substituted with hydroxyl. 1 -C 3 alkylene, and each X 1 are independently 2 , CH, NH, N, and O; Y is a bond, NH, -NH(C 1 -C 6 alkylene)-, -N(C 1 -C 6 alkyl)- or -N(C 1 -C 6 Alkylene-C 3 -C 8 cycloalkyl)-, and L is a bond or C 1 -C 3 It is alkylene.

[0147] In one embodiment, K is [ka] And each X 1 are independently 2 , CH, NH, N, and O; Y is a bond, -NH-, -NMe-, -NEt-, -NH-CH 2 - and -N(CH 2 -cyclopropyl-, and L is a bond, -CH 2 -, or -CH 2 CH 2 -It is.

[0148] In one embodiment, K is [ka] And each X 1 are independently 2 , CH, NH, N, and O; Y is a bond, -NH-, -NMe-, -NEt-, -NH-CH 2 - and -N(CH 2 -cyclopropyl-, and L is a bond, -CH 2 -, or -CH 2 CH2 and ring B is [ka] is selected from the group consisting of:

[0149] In another aspect, the disclosure provides compounds set forth in Table 1, or pharma- ceutically acceptable salts thereof. In Table 1, both the free base and salt structures of the compounds are shown. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0150] In another aspect, the disclosure provides compounds set forth in Table 2, or pharma- ceutically acceptable salts thereof. In Table 2, both the free base and salt structures of the compounds are shown. [Table 2-1] [Table 2-2] [Table 2-3]

[0151] In another embodiment, the compound of formula I, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is selected from the compounds set forth in any one of Tables 1 and 2.

[0152] In another aspect, the present disclosure provides a compound of formula II: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 1 , R 2 , R 3 , R x’ , R y’ , m, n, and p have the definitions provided in the paragraph above.

[0153] In one embodiment, the compound of formula II, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is selected from the compounds shown in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0154] In another aspect, the present disclosure provides a compound of formula III: [ka] or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: 1 , R 2 , R 3 , R x’ , R y’ , m, n, and p have the definitions provided in the paragraph above.

[0155] In one embodiment, the compound of formula III, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is selected from the compounds shown in Table 4 below. [Table 4-1] [Table 4-2] [Table 4-3]

[0156] Pharmaceutical Compositions and Administration The present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0157] Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid media, dispersion agents, suspension aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., depending on the particular dosage form desired. General introductions to the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0158] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. In general, such methods of preparation include the step of bringing into association a compound of the present invention (the "active ingredient") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multi-dosage unit.

[0159] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dose, for example, one-half or one-third of such a dose.

[0160] The relative amounts of active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0161] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings, and perfumes may also be present in the composition.

[0162] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0163] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0164] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween® 20], polyoxyethylene sorbitan [Tween® 60], polyoxyethylene sorbitan monooleate [Tween® 80], sorbitan monopalmitate [Span® 40], sorbitan monostearate [Span® 60], sorbitan tristearate [Span® 65], glyceryl monooleate, sorbitan monooleate [Span® 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate,Ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0165] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0166] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0167] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0168] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates: malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0169] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0170] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0171] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0172] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.In certain embodiments, the preservative is an antioxidant.In other embodiments, the preservative is a chelating agent.

[0173] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, hydroxyapatite, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0174] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0175] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, croton seed oil, curcuma oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, epilobium oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, melaleuca oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, safflower oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, seabuckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof, but are not limited thereto.

[0176] Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfumes. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with a solubilizing agent, such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0177] Injectables, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectables can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, 1,3-butanediol solutions. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending agents. For this purpose, any brand of fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0178] Sterile injectable compositions, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween® 80) and suspending agents. Sterile injectables can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, 1,3-butanediol solutions. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending agents (for example, synthetic mono- or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants. Other commonly used surfactants, such as Tween® or Span®, or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0179] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a suspension of crystalline or amorphous material that is poorly soluble in water. The rate of absorption of the drug therefore depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0180] Compositions for rectal or vaginal administration will usually be suppositories, which may be prepared by mixing the conjugate of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active ingredient.

[0181] The solid dosage form for oral administration includes capsules, tablets, pills, powders, and granules.In such solid dosage forms, the active ingredient is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) moisturizers, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato, and the like. Potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0182] Solid compositions of a similar type may be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. Solid dosage forms tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, optionally delayed, in a certain part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0183] The active ingredient may be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may contain buffering agents. They may optionally contain opacifying agents and may be of a composition such that they release the active ingredient(s) only, or preferentially, and optionally delayed, in a certain part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0184] Dosage forms for topical and / or transdermal administration of the compounds of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. In general, the active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and / or any necessary preservatives and / or buffers as necessary. In addition, the present invention contemplates the use of transdermal patches, which often have the additional advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled by providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0185] Devices suitable for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices, such as those described in U.S. Patent Nos. 4,886,499, 5,190,521, 5,328,483, 5,527,288, 4,270,537, 5,015,235, 5,141,496, and 5,417,662. Intradermal compositions can be administered by devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication No. WO99 / 34850 and those with comparable functionality. Liquid jet injectors that create a jet that penetrates the stratum corneum and reaches the dermis and / or jet injection devices that deliver liquid vaccines to the dermis through a needle are suitable. Jet injection devices are disclosed, for example, in U.S. Patent Nos. 5,480,381, 5,599,302, 5,334,144, 5,993,412, 5,649,912, 5,569,189, 5,704,911, 5,383,851, 5,893,397, 5,466,220, 5,339, 163, 5,312,335, 5,503,627, 5,064,413, 5,520,639, 4,596,556, 4,790,824, 4,941,880, 4,940,460, and PCT Publication Nos. WO97 / 37705 and WO97 / 13537. A ballistic powder / particle delivery device is suitable, which uses compressed gas to advance the vaccine in powder form through the outer layer of the skin to the dermis. Alternatively or additionally, a conventional syringe can be used in the classical Mantoux method of intradermal administration.

[0186] The pharmaceutical compositions of the invention may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles, which comprise the active ingredient and have a diameter of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration using a device comprising a dry powder reservoir capable of directing a stream of propellant to disperse the powder, and / or using a device comprising a self-propelling solvent / powder dispensing vessel, e.g., a sealed vessel comprising the active ingredient dissolved and / or suspended in a low boiling propellant. Such powders comprise particles in which at least 98% of the particles by weight are greater than 0.5 nanometers in diameter and at least 95% of the particles by number are less than 7 nanometers in diameter. Alternatively, at least 95% of the particles by weight are greater than 1 nanometer in diameter and at least 90% of the particles by number are less than 6 nanometers in diameter. Dry powder compositions may comprise a solid fine powder diluent, e.g., sugar, and are conveniently provided in unit dose form.

[0187] Low boiling point propellants generally include liquid propellants having a boiling point below 65° F. at atmospheric pressure. Generally, the propellant may comprise 50-99.9% (w / w) of the composition and the active ingredient may comprise 0.1-20% (w / w) of the composition. The propellant may further comprise additional components, such as liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size of the same order as the particles containing the active ingredient).

[0188] Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, and may be conveniently administered using an optional nebulizer and / or atomizer device. Such formulations may further include one or more additional ingredients, including, but not limited to, flavoring agents, such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives, such as methyl oxybenzoate. The droplets provided by this route of administration may have a mean diameter of about 0.1 to about 200 nanometers.

[0189] The formulations described herein as useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions of the invention. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient, having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of the powder held close to the nostrils.

[0190] Formulations for nasal administration may, for example, contain as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may include one or more of the additional ingredients described herein. Pharmaceutical compositions of the invention may be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may be, for example, in the form of tablets and / or lozenges manufactured using conventional methods and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the remainder comprising an orally dissolvable and / or disintegrable composition and, optionally, one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powders, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0191] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, one of skill in the art will understand that such compositions are generally suitable for administration to any animal. Modifications to make pharmaceutical compositions suitable for administration to humans into compositions suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0192] The compound provided herein is usually formulated in dosage unit form for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of the composition of the present invention is determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the disease, disorder, or condition being treated and the severity of the disorder, the activity of the specific active ingredient used, the specific composition being used, the age, weight, general condition, sex and diet of the subject, the time of administration, route of administration and excretion rate of the specific active ingredient used, duration of treatment, the drug used in combination with or simultaneously with the specific active ingredient used, and similar factors well known in the medical field.

[0193] To carry out the method of the present invention, the compound or pharmaceutical composition thereof can be administered orally, parenterally, by inhalation spray, topically, rectally, bucally, vaginally, rectally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In general, the most suitable administration route depends on various factors, including the nature of the drug (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0194] The exact amount of compound required to achieve an effective dose will vary between subjects, depending, for example, on the species, age, and general condition of the subject, the severity of the side effects or disorder, the identity of the particular compound(s), the method of administration, etc. The desired dose can be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0195] In certain embodiments, an effective amount of a compound for administration to a 70 kg adult, one or more times per day, may include from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound, per unit dosage form.

[0196] In certain embodiments, the compounds of the invention may be administered orally or parenterally at a dosage level sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, one or more times per day to obtain the desired therapeutic effect.

[0197] It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent may be determined by a physician or by one skilled in the art and may be less than or the same as that administered to an adult.

[0198] It will also be understood that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents.The compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution in the body.It will also be understood that the treatments used can achieve the desired effect on the same disorder and / or they can achieve different effects.

[0199] The compound or composition can be administered simultaneously with, prior to, or after one or more additional therapeutically active agents. Generally, each agent is administered at a dose and / or time schedule determined for that agent. It will be further understood that the additional therapeutically active agents used in this combination can be administered together in a single composition or separately in different compositions. The particular combination for use in a regimen will take into consideration the compatibility of the compound of the present invention with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination are lower than the levels at which they are used individually. Additional therapeutically active agents include antibiotic agents, such as antibiotics useful in the treatment of tuberculosis. Exemplary antibiotics include, but are not limited to, isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

[0200] Kits (e.g., pharmaceutical packs) are also included in the present invention. The kits provided may include a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the kits provided may optionally further include a second container that includes a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the container and the pharmaceutical composition or compound of the present invention provided in the second container are mixed to form one unit dosage form.

[0201] Treatment Uses and Methods In another aspect, the present invention provides a method for treating bacterial infection in a patient in need of such treatment, comprising administering an effective amount of a compound of formula I, or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula I, or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.In certain embodiments, the effective amount is a therapeutically effective amount.In certain other embodiments, the effective amount is a prophylactically effective amount.

[0202] In some embodiments, the compounds of the present invention may have activity against a broad range of both gram-positive and gram-negative bacteria. In these and other embodiments, the compounds of the present invention may be used to treat infections and inhibit the growth of microorganisms. Thus, the compounds of the present invention may be used to treat humans and animals with a broad range of bacterial infections, such as impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infections, diabetic foot ulcers, gastrointestinal infections, and bacteremia. These bacterial infections include Bacillus mycobacterial infections caused by the following bacteria: Staphylococcus aureus, coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, enterococci, beta-hemolytic streptococci, viridans group streptococci, multi-resistant M. tuberculosis and other atypical mycobacteria, such as M. intracellulare and M. avium, as well as emerging gram-negative pathogens, such as Chryseobacterium meningosepticum, Chryseobacterium spp. indologense and other gram-negative pathogens, such as E. coli, Klebsiella, Proteus, Serratia, Citrobacter, Pseudomonas, Burkholderia, Brucella, Yersinia, Francisella, Coxiella, Chlamydia, Salmonella, Rickettsia, Shigella, and Campylobacter.

[0203] In one embodiment, the bacterial infection is tuberculosis. In certain embodiments, the tuberculosis infection is a Mycobacterium tuberculosis infection. In certain embodiments, the tuberculosis infection is a multi-drug resistant tuberculosis (MDR-TB) infection, e.g., resistant to the first-line TB drugs rifampicin and / or isoniazid. In certain embodiments, the tuberculosis infection is an extensively drug resistant tuberculosis (XDR-TB) infection, e.g., resistant to three or more of six classes of second-line drugs (see, e.g., Centers for Disease Control and Prevention (CDC) (2006). "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide, 2000-2004". MMWR Morb Mortal Wkly Rep 55(11):301-5).

[0204] process In some embodiments, compounds and intermediates of the present disclosure can be prepared according to the following general synthetic schemes I and II. 1 , R 2 , R 3 , R x , R y , R x’ , R y’ Variables such as ring A, ring B, ring C, J, L, Y, m, n, and p have the same definitions as in the preceding paragraph, X is a leaving group such as halo, mesylate, tosylate, triflate, etc., and P is a hydroxyl protecting group. In some embodiments, X is halo and P is TBS. [ka]

[0205] In general synthetic scheme I, ketone (a) undergoes reduction to give alcohol (b), and protection of the hydroxyl group affords intermediate (c).

[0206] In step 3 of General Synthetic Scheme I, intermediate (c) is reacted with triisopropyl borate in the presence of a base, such as butyllithium, to provide boronate (d), which in step 4 is cross-coupled with cytosine in the presence of a base, such as a tertiary amine, and a copper reagent, such as a copper(II) reagent, to provide a compound of formula F.

[0207] In step 5 of the general synthetic scheme I, a compound of formula F and a compound of formula (e) are amide coupled to provide intermediate (f). In some processes, about 1.1-2.0 molar equivalents of a compound of formula (e) are mixed with 1 molar equivalent of a compound of formula F in a suitable solvent, such as a polar aprotic solvent. Polar aprotic solvents include solvents such as dichloromethane, dimethylformamide, acetonitrile, and the like. The mixture in the polar aprotic solvent is then reacted at a temperature of about 0° C. to 100° C. for a sufficient time. In some embodiments, the temperature is about 25° C. to 95° C. or about 50° C. to 95° C., and the reaction time is about 1-24 hours, 2-20 hours, or about 5-18 hours.

[0208] In steps 6 and 7, the compound of formula (f) is deprotected to produce the free alcohol, which is then oxidized to the ketone, ie, the compound of formula A.

[0209] In step 8 of the general synthesis scheme I, a compound of formula A is reacted with an amine under reductive amination conditions to give a compound of formula I. The reductive amination can be carried out in the presence of a reducing agent and a suitable solvent. Suitable solvents include protic or aprotic solvents. Protic solvents include, but are not limited to, water and alcohols, such as methanol, ethanol, propanol, and the like. Aprotic solvents include, but are not limited to, solvents such as dichloromethane, dimethylformamide, acetonitrile, and the like. The suitable solvent can also be a combination of two or three solvents. Reducing agents include, but are not limited to, borohydride reagents or metal hydride reagents. Non-limiting examples are lithium borohydride, sodium borohydride, sodium cyanoborohydride. [ka]

[0210] In step 1 of General Synthetic Scheme II, ketone (a) undergoes reductive amination with an amine to give intermediate (g). Conditions for carrying out the reductive amination are provided in the paragraph above.

[0211] In step 2 of General Synthetic Scheme II, intermediate (g) is reacted with triisopropyl borate in the presence of a base, such as butyllithium, to give boronate (h), which in step 3 is cross-coupled with cytosine in the presence of a base, such as a tertiary amine, and a copper reagent, such as a copper(II) reagent, to give a compound of formula III.

[0212] In step 4 of General Synthetic Scheme II, a compound of formula III and a compound of formula (e) are amide coupled to give a compound of formula (I). The conditions for carrying out the amide coupling are similar to those in step 5 of General Synthetic Scheme I.

[0213] In one aspect, the present disclosure provides a compound of formula I: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: Compound of Formula A: [ka] of, Formula B' [ka] or formula C [ka] Compounds of combining under reductive amination conditions to obtain a compound of formula I; In the formula, ring A, ring B, ring C, J, L, R 1 , R 2 , R 3 , R x , R y , R x’ , R y’ , m, n, and p are as defined in the preceding paragraph; Ring B 1 is a nitrogen containing 3-8 membered monocyclic heterocycloalkylene, or a nitrogen containing 6-12 membered bicyclic heterocycloalkylene, each of which is optionally and independently selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6substituted with up to 3 substituents selected from the group consisting of hydroxyalkyl, Y is a bond, or OH, NH 2 , CN, halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 is alkylene, C 1 -C 6 one methylene unit of the alkylene is optionally replaced by NH, N-(C 1 -C 6 alkyl), N-(C 1 -C 6 hydroxyalkyl), N-(C 1 -C 6 haloalkyl), or N-(C 1 -C 6 alkylene-C 3 -C 8 cycloalkyl), Y 1 is a bond, or OH, NH 2 , CN, halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 5 is alkylene, R z is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkylene-C 3 -C 8 cycloalkyl, provides a process.

[0214] In some embodiments, ring B 1 is nitrogen containing a 4- to 7-membered monocyclic heterocycloalkylene, or nitrogen containing a 6- to 9-membered bicyclic heterocycloalkylene, each of which is optionally, independently, C 1 -C 6 alkyl, C1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 and hydroxyalkyl.

[0215] In some embodiments, Ring B 1 is a nitrogen containing 4-7 membered monocyclic heterocycloalkylene, or a nitrogen containing 6-9 membered bicyclic heterocycloalkylene. In some embodiments, ring B 1 is a nitrogen containing 4- to 7-membered monocyclic heterocycloalkylene, or a nitrogen containing 6-membered bicyclic heterocycloalkylene.

[0216] In another embodiment, ring B in formula B' is [ka] is selected from the group consisting of:

[0217] In some embodiments, Ring B 1 teeth, [ka] is selected from the group consisting of:

[0218] In some embodiments, L is a bond, -CH 2 -, or -CH 2 -CH 2 - and R x’ and R y’ are each independently H, Boc, or methoxycarbonyl.

[0219] In some embodiments, Y 1 is a bond, or OH, NH 2 , CN, Halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 3 In some embodiments, Y is an alkylene. 1 is a bond or C 1 -C 3 In some embodiments, Y is an alkylene. 1 is a bond or -CH 2 -It is.

[0220] In some embodiments, R z , H, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 Alkylene-C 3 -C 6 In some embodiments, R z is H, Me, Et, or CH 2 -cyclopropyl.

[0221] In some embodiments, the compound of formula IB is a compound of formula IB', formula IB', or IC: [ka] where the variables are as defined herein.

[0222] In some embodiments, the compound of formula I is a compound of formula IB and formula IC.

[0223] In some embodiments, the compound of formula IB, formula IB', or formula IC is selected from the compounds set forth in Tables 1 and 2.

[0224] In one aspect, the disclosure provides a compound of formula IB: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: coupling a compound of formula A with a compound of formula B under reductive amination conditions to obtain a compound of formula IB; [ka] In the formula, ring A, ring B, ring C, J, L, R 1 , R 2 , R 3 , R x , R y , R z , R x’ , R y’ , m, n, and p have the definitions provided in the paragraphs above.

[0225] In one embodiment, the process further comprises the step of: x , R y , R x’ , and R y’ is an amino protecting group, the method includes removing the amino protecting group.

[0226] In another aspect, the disclosure provides a compound of formula IC: [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: coupling a compound of formula A with a compound of formula C under reductive amination conditions to obtain a compound of formula IC; [ka] In the formula, ring A, ring B 1 , Ring C, J, L, R 1 , R 2 , R 3 , R x , R y, R x’ , R y’ , m, n, and p have the definitions provided in the paragraphs above.

[0227] In one embodiment, the process further comprises the step of: x , R y , R x’ , and R y’ is an amino protecting group, the method includes removing the amino protecting group.

[0228] The process and conditions for carrying out the reductive amination of compounds of formula E are similar to those in the general synthetic scheme.

[0229] In some embodiments, the reductive amination between a compound of formula A and a compound of formula B (or formula B') or between a compound of formula A and a compound of formula C can be carried out in the presence of a reducing agent and a suitable solvent. Suitable solvents include protic or aprotic solvents. Protic solvents include, but are not limited to, water and alcohols, such as methanol, ethanol, propanol, and the like. Aprotic solvents include, but are not limited to, solvents such as dichloromethane, dimethylformamide, acetonitrile, and the like. The suitable solvent may also be a combination of two or three solvents. Reducing agents include, but are not limited to, borohydride reagents or metal hydride reagents. Non-limiting examples are lithium borohydride, sodium borohydride, sodium cyanoborohydride. In some processes, about 1.1-2.0 molar equivalents of a compound of formula B (or B') or C are mixed with 1 molar equivalent of a compound of formula A and 1.0-2.0 molar equivalents of a reducing agent in a suitable solvent. The mixture is then reacted for a sufficient time at a temperature between about 0° C. and 100° C. In some embodiments, the temperature is between about 10° C. and 95° C., or between about 10° C. and 50° C., or room temperature, and the reaction time is between about 1 and 24 hours, between 2 and 20 hours, or between about 5 and 18 hours.

[0230] In some embodiments, the compound of formula A is a compound of formula ID. [ka]

[0231] In another aspect, the disclosure provides a process for preparing compound ID of formula ID, or a pharma- ceutically acceptable salt thereof, comprising: The compound of formula E is [ka] coupling with a compound of formula F, [ka] In the formula, rings C, K, R 1 , R 2 , R 3 , R x , R y , m, n, and p are as defined herein; wherein P is a hydroxyl protecting group.

[0232] The process and conditions for carrying out the amide coupling of a compound of formula E to a compound of formula F are as described in step 5 of general synthetic scheme I.

[0233] In one embodiment, the process further comprises removing the hydroxyl protecting group to provide a compound of formula IE. [ka]

[0234] In some embodiments, the compound of formula IE is [ka] is selected from the group consisting of:

[0235] In another embodiment, the process further comprises oxidizing the hydroxyl group of formula IE to obtain a compound of formula ID. Exemplary oxidizing agents include Dess-Martin periodinane, chromium trioxide, pyridinium chlorochromate, dimethylsulfoxide, oxalyl chloride, and the like.

[0236] In one embodiment, the compound of formula ID is a compound of formula ID-1a or ID-1b: [ka] or a pharma- ceutically acceptable salt thereof, wherein X 1 , K., R. 1 , R 2 , R 3 , R x , R y , m, n, and p have the definitions provided in any of the paragraphs above.

[0237] In another embodiment, the compound of formula ID is a compound of formula ID-2a or ID-2b: [ka] or a pharma- ceutically acceptable salt thereof, wherein R x , R y , X 1 , and K have the definitions provided in the paragraph above.

[0238] In another embodiment, the compound of formula ID is [ka] is selected from the group consisting of: EXAMPLES

[0239] Preparation of compounds The preparation of starting materials that are commercially available, described in the literature, or readily available to those skilled in the art is not described. Those skilled in the art will understand that when compounds are described as being prepared similarly to previous examples or intermediates, reaction times, equivalents of reagents, and temperatures may vary for each specific reaction, and that different work-up or purification techniques may be required or desirable to be used. When reactions are carried out using microwave irradiation, the microwave ovens used were Biotage Initiator or CEM Discover System Model 908005. The actual power supplied was varied during the reaction period to maintain a constant temperature.

[0240] General method Reactions requiring anhydrous conditions were carried out in oven-dried glassware under a positive pressure of either nitrogen or argon. Commercially available reagents were used as received or, otherwise, materials were purified according to the Purification of Laboratory Chemicals. Dichloromethane (CH 2 Cl 2 ), N,N'-dimethylformamide (DMF), toluene, and tetrahydrofuran (THF) were degassed with nitrogen and passed through a solvent purification system (Innovative Technologies Pure Solv). Dry 1,4-dioxane was purchased from Acros Organics in Acros Seal™ bottles. Triethylamine (Et 3 N) and N,N-diisopropylethylamine (DIPEA) were stored over 4 Å molecular sieves or distilled over 4 Å molecular sieves prior to use. Microwave reactions were performed on a CEM Discover System Model 908005. Reactions were monitored by TLC or LCMS, visualized with a dual shortwave / longwave UV lamp, and / or analyzed by KMnO 4, staining with ethanolic solutions of 12-phosphomolybdic acid or other commonly used dyes. Flash chromatography was performed on silica gel Kieselgel 60 (230-400 mesh) from Merck from EM Science using the indicated HPLC grade solvents or an automated medium pressure column chromatography system (Teledyne ISCO CombiFlash® RF75 or CombiFlash® Rf+). Reversed phase HPLC was performed on a Waters HPLC Semi Prep 150B system using a Sunfire C18 Prep Column or an Atlantis T3 Prep Column with isocratic or gradient conditions using HPLC with 12-phosphomolybdic acid or 12-phosphomolybdic acid. 2 O (0.1% TFA) and 10% H 2 O:90 CH 3 CN (0.1% TFA) was used as the eluent.

[0241] Melting points were measured using a Mel-Temp® capillary melting point apparatus. Infrared spectra were obtained using a Nicolet 380-FT IR spectrometer equipped with a Smart Orbit sample system. Optical rotations were obtained at ambient temperature on a Perkin Elmer model 343 polarimeter (Na D line) using a microcell with a path length of 1 decimeter. Mass spectra measured by LCMS were collected on a Thermo Scientific™ UltiMate™ 3000 UHPLC using an electrochemical detector with a fluorescence detector observed at 214 or 254 nm, or a Waters Aquity UPLC H-Class series equipped with a photodiode array detector and a QDa mass detector. 1 H NMR spectra were recorded at 500 MHz, 400 MHz, and 300 MHz. 13 C was recorded at 125 MHz. Proton resonances were determined by the peaks of the deuterated solvent: CDCl 3 7.27 ppm, CD 3 OD 3.31 ppm (center line signal), D6-DMSO 2.50 and D 2The following format was used to report the chemical shifts (δ) [multiplicity (s=singlet, br s=broad singlet, d=doublet, t=triplet, q=quartet, m=multiplet)] relative to 4.79 in CDCl. Carbon resonances are reported as chemical shifts in parts per million (δ) relative to the centerline signal of the respective solvent peak: CDCl 3 77.23 ppm and CD 3 Reported relative to an OD of 49.15 ppm. Commercial chemicals are purchased from multiple sources, including Sigma-Aldrich, Acros, Enamine, TCI America, Combi-Blocks, Alfa-Aesar, Angene, Ark Pharma, PharmaBlock, Strem Chemicals, Frontier Scientific, and AstaTech, Inc.

[0242] Liquid Chromatography Mass Spectrometry Liquid Chromatography Mass Spectrometry A Total ion current (TIC) and DAD UV chromatographic traces as well as MS and UV spectra associated with those peaks were acquired on a UPLC / MS Acquity™ system. The system was equipped with a PDA detector coupled to a Waters single quadrupole mass spectrometer and operated in alternating positive and negative electrospray ionization mode. [LC / MS-ES (+ / -) analysis was performed on an ACQUITY UPLC™ CSH, C18 column (50 x 2.1 mm, 1.7 μm particle size), column temperature 40°C, mobile phase: A-water + 0.1% HCOOH / B-CH 3 CN+0.1% HCOOH, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, negative ES 100-1000, UV detection DAD 210-350 nm.

[0243] Liquid Chromatography Mass Spectrometry B Total ion current (TIC) and DAD UV chromatographic traces as well as MS and UV spectra associated with those peaks were acquired on a UPLC / MS Acquity™ system. The system was equipped with a PDA detector coupled to a Waters single quadrupole mass spectrometer and operated in alternating positive and negative electrospray ionization mode. [LC / MS-ES (+ / -) analysis was performed on an ACQUITY UPLC™ BEH, C18 column (50×2.1 mm, 1.7 μm particle size), column temperature 40° C., mobile phase: A-0.1% v / v aqueous ammonia (aq) solution pH 10 / B-CH 3 CN, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, negative ES 100-1000, UV detection DAD 210-350 nm.

[0244] Liquid Chromatography Mass Spectrometry C LC / MS-ES (+ / -) analysis was performed using an AQUITY with PDA detector and QDA Performance, a C18 column (50 × 2.1 mm, particle size 1.6 μm), column temperature 35 °C, mobile phase: A-Milli Q water (pH = 2.70) containing 0.1% formic acid / B-0.1% formic acid aqueous solution:acetonitrile (10:90), flow rate: 0.8-1.0 mL / min, run time = 4.0 min, gradient: t = 0 min 3% B, t = 2.7 min 98% B, t = 3.0 min 100% B, t = 3.51 min 3% B, stop time 4.0 min.

[0245] Liquid Chromatography Mass Spectrometry D LC / MS-ES (+ / -) analysis was performed using an AQUITY H-class equipped with a PDA detector and a QDA, a C18 column (50 × 2.1 mm, particle size 1.6 μm), column temperature 35 °C, mobile phase: A-Milli Q water (pH = 2.70) containing 0.1% formic acid / B-0.1% formic acid aqueous solution:acetonitrile (10:90), flow rate: 0.8-1.0 mL / min, run time = 4.0 min, gradient: t = 0 min 3% B, t = 2.7 min 98% B, t = 3.0 min 100% B, t = 3.51 min 3% B, stop time 4.0 min.

[0246] Liquid Chromatography Mass Spectrometry LC / MS-ES (+ / -) analysis was performed using an AQUITY H-class equipped with a PDA detector and a QDA, a C18 column (50 x 2.1 mm, particle size 1.6 μm), column temperature 35 °C, mobile phase: A-0.1% formic acid aqueous solution (pH = 2.70) / B-0.1% formic acid aqueous solution:acetonitrile (10:90), run time = 9.0 min, gradient: t = 0 min 1% B, t = 2.5 min 50% B, t = 4.5 min 97.5% B, t = 6.5 min 1% B, stop time 9.0 min.

[0247] Liquid Chromatography Mass Spectrometry F LC / MS-ES (+ / -) analysis was performed using an Agilent Infinity II G6125C LCMS, C18 column (50 × 4.6 mm, particle size 3.5 μm), column temperature 35 °C, mobile phase: A-Milli-Q water (pH = 7.35) containing 5 mM ammonium bicarbonate / B-methanol, run time = 7.0 min, gradient: t = 0 min 8% B, t = 3.0 min 70% B, t = 3.7 min 95% B, t = 4.2 min 100% B, t = 5.21 min 8% B, stop time 7.0 min.

[0248] Liquid Chromatography Mass Spectrometry G LC / MS-ES (+ / -) analysis was performed using a Waters Alliance 2690 and 996 PDA detector equipped with a Micromass ZQ, a C18 column (150 x 4.6 mm, 3.5 μm particle size), column temperature 35°C, mobile phase: A-5 mM ammonium acetate + 0.1% FA in water / B-methanol, run time = 17.0 min, gradient: t = 0 min 10% B, t = 7.0 min 90% B, t = 9.0 min 100% B, t = 14.01 min 10% B, stop time 17.0 min.

[0249] Liquid Chromatography Mass Spectrometry LC / MS-ES (+ / -) analysis was performed using an AQUITY equipped with a PDA detector and QDA Performance, a C18 column (50 x 2.1 mm, particle size 1.6 μm), column temperature 35 °C, mobile phase: A-Milli Q water (pH = 2.70) containing 0.1% formic acid / B-0.1% formic acid in water:acetonitrile (10:90), flow rate: 0.9 mL / min, run time = 3.0 min, gradient: t = 0 min 5% B, t = 1.8 min 98% B, t = 2.0 min 100% B, t = 2.51 min 5% B, stop time 17.0 min.

[0250] Analysis method 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using one of the following instruments: a Bruker Avance400 instrument equipped with probe DUAL 400MHz S1; a Bruker Avance400 instrument equipped with probe 6 S1 400MHz 5mm 1 H- 13 C ID equipped, Bruker Avance III 400 instrument nanobay, equipped with probe Broadband BBFO 5mm direct, 400MHz Agilent Direct Drive instrument, equipped with ID AUTO-X PFG probe, all operating at 400MHz, or Agilent VNMRS500 Direct Drive instrument, 5mm triple resonance 1 H{ 13 C / 15N} Cryoprobe equipped and operated at 500 MHz. Spectra were acquired near room temperature in the solvents stated unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for major peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; br, broad.

[0251] Thin-layer chromatography (TLC) refers to silica gel TLC using silica gel F254 (Merck) plates; f is the distance traveled by the compound divided by the distance traveled by the solvent on the TLC plate. Column chromatography was performed using an automated flash chromatography (Biotage SP1 or Isolera) system with Biotage silica gel cartridges (KP-Sil or KP-NH) or, for reversed-phase chromatography, with Biotage C18 cartridges (KP-C18).

[0252] Preparative HPLC was performed on a Shimadzu LC-20AP, Waters 2545, and Agilent 1260 infinity. Purity was measured with a Waters Alliance e2695-PDA detector 2998 and an Agilent 1260 Infinity-II. (Mobile phase: 0.05% HCl in water / methanol with gradient elution). [Table 5-1] [Table 5-2]

[0253] Synthesis of intermediates [ka] 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (Intermediate 1) [ka] Reagents: 1) 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid, HATU, DIPEA, DMF, room temperature, 16 hours 2) 10% Pd / C, CH 3 OH, room temperature, 16 hours 3) CDI, CH 2 Cl 2 , room temperature, 16 hours 4) MeI, CH 3 CN, room temperature, 16 hours. Step 1: Benzyl 4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate. To a stirred solution of 2-((t-butoxycarbonyl)amino)-2-methylpropanoic acid (35.5 g, 175 mmol) in DMF (350 mL) was added DIPEA (51.2 g, 397 mmol) and HATU (90.6 g, 238 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 45 min. Benzyl piperazine-1-carboxylate (35 g, 158.9 mmol) was added to the reaction mixture at 0° C., which was stirred at room temperature for 16 h. The resulting reaction mixture was subjected to HCl distillation under reduced pressure. 2 O (1500 mL), extracted with EtOAc (3×700 mL), and the combined organics were washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude material obtained was purified by flash chromatography (EtOAc:Hex) to give the desired product (36 g, 55%) as an off-white solid. LCMS [M+H] 406.

[0254] Step 2: t-Butyl (2-methyl-1-oxo-1(piperazin-1-yl)propan-2-yl)carbamate. CH 3To a stirred solution of benzyl 4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate (35.0 g, 86.4 mmol) in OH (500 mL) was added 10% Pd / C (3.5 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The resulting reaction mixture was filtered through Celite® and diluted with CH 3 OH (1500 mL). The filtrate was concentrated under reduced pressure and dried to give the desired product (25.0 g, 100%) as a viscous oil. LCMS [M+H] 272.

[0255] Step 3: t-Butyl (1-(4-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. CH 2 Cl 2 To a stirred solution of t-butyl (2-methyl-1-oxo-1(piperazin-1-yl)propan-2-yl)carbamate (25.0 g, 92.2 mmol) in 10 mL of ethyl acetate was added CDI (17.78 g, 110 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (CH 3 OH:CH 2 Cl 2 ) to give the desired product (30.0 g, 89%) as an off-white solid. LCMS [M+H] 406. 1 H NMR (DMSO-d 6 , 400 MHz): δ 8.04 (s, 1H), 7.48 (s, 1H),7.36 (s, 1H), 7.03 (s, 1H), 3.65-3.52 (m, 4H), 3.51-3.40 (m, 4H), 1.38 (s, 6H),1.30 (s, 9H). LCMS[M+H] 366.3.

[0256] Step 4: 1-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide. CH3 To a stirred solution of t-butyl (1-(4-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (20 g, 55 mmol) in CN (250 mL) was added MeI (20.8 ml, 329 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to give the desired product (30 g, quantitative) as a pale yellow solid. 1 HNMR (DMSO-d 6 , 400 MHz): δ 9.57 9s, 1H), 8.05 (s, 1H), 7.87 (t, 1H), 7.40(s, 1H), 3.93 (s, 3H), 3.78-3.65 (m, 4H), 3.59-3.45 (m, 4H), 1.40 (s, 6H), 1.32(S, 9H). LCMS[M+H] 380.2.

[0257] [ka] tert-Butyl(2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)- 1,2-Dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate (Intermediate 2) [ka] Reagents: 1) NaBH 4 , C.H. 3 OH, room temperature, 3 hours 2) TBDMSCl, imidazole, CH 2 Cl 2 , room temperature, 16 hours 3)n-BuLi, B(OiPr) 3 , THF, -78℃ to room temperature, 3 hours 4) Cytosine, TMEDA, Cu(OAc) 2 H 2 O, C.H. 3 OH:H 2 O(4:1), O 2, room temperature, 16 hours 5) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, CH 3 CN, 90℃, 16 hours 6) MeOH, TsOH, room temperature, 16 hours 7) DMP, CH 2 Cl 2 , room temperature, 3 hours. Step 1: 6-Bromo-1,2,3,4-tetrahydronaphthalen-2-ol. To a stirred solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (10 g, 44 mmol) in MeOH (250 mL) was added NaBH 4 (1.7 g, 44 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 3 h and the volatiles were removed under reduced pressure. The crude solid was dissolved in EtOAc (500 mL) and the reaction mixture was diluted with H 2 The organics were washed with NaO (1×500 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired product (9.0 g, 90%) as a brown solid.

[0258] Step: ((6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane. CH 2 Cl 2 To a stirred solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-ol (49.0 g, 44 mmol) in 1,2-tetrahydronaphthalene-2-ol (500 mL) was added imidazole (3.2 g, 48 mmol) and t-butyldimethylsilyl chloride (7.2 g, 48 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was subjected to H 2 Pour into O (500 mL) and CH 2 Cl 2 (3×700 mL). The combined organics were extracted with Na 2 SO 4It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc:Hex) to give the desired product (85%) as a yellow oil. 1 HNMR (500 MHz, CDCl 3 ) δ 7.24 (s, 1H), 7.22 (d, 1H), 6.93 (d, 1H), 4.15-4.06(m, 1H), 2.99-2.88 (m, 2H), 2.80-2.73 (m, 1H), 2.69 (dd, 1H), 1.98-1.91 (m, 1H), 1.84-1.73 (m, 1H), 0.92 (s, 9H), 0.12 (d, 6H).

[0259] Step 3: Diisopropyl(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)boronate. To a stirred solution of ((6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (3.7 g, 9.5 mmol) in THF (300 mL) was added N 2 Under atmosphere, n-BuLi (2.5 M in hexane, 4.1 mL, 10.4 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Triisopropyl borate (2.4 mL, 10.4 mmol) was added at −78° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting reaction mixture was treated with NH 4 Cl solution (100 mL) and extracted with EtOAc (3×300 mL). 2 SO 4 Drying at rt, filtering and concentrating under reduced pressure gave the desired product (90%) as a clear oil.

[0260] Step 4: 4-amino-1-(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2(1H)-one. MeOH:H 2A solution of diisopropyl(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)boronate (9.9 g, 25 mmol) and cytosine (3.1 g, 28 mmol) in 2H2O (500 mL, 4:1) was stirred at room temperature in air for 30 min. TMEDA (5.1 mL, 34 mmol) and Cu(OAc) 2 H 2 2H2O (5.6 g, 28 mmol) was added and the reaction mixture was stirred at room temperature in air for 48 h. The reaction mixture was concentrated under reduced pressure and cooled to room temperature. 2 O (100 mL) was added to the mixture. The solid was filtered and purified under reduced pressure with H 2 O (3 × 100 mL) and Et 2 The solid was washed with 0 (2×60 mL) and dried to give the desired product (5.5 g, 60%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 ) δ 7.56 (d, 1H), 7.29-7.08 (m, 3H), 7.03 (d, 2H),5.75 (d, 1H), 4.15 (s, 1H), 2.97 (dd, 1H), 2.92-2.82 (m, 1H), 2.81-2.71 (m, 1H), 2.66 (dd, 1H), 1.98-1.85 (m, 1H), 1.78-1.62 (m, 1H), 0.87 (s, 9H), 0.09 (d, 6H). LCMS[M+H]372.2.

[0261] Step 5: tert-Butyl (1-(4-((1-(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. CH 3A mixture of 4-amino-1-(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2(1H)-one (1.5 g, 3.5 mmol) and 1-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (Intermediate 2, 3.1 g, 5.3 mmol) in CN (45 mL) was heated at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by column chromatography (MeOH:CH 2 Cl 2 ) to give the title compound (1.67 g, 80%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ 12.89 (s, 1H),7.22 (d, 1H), 7.12 (d, 1H), 7.03 (d, 1H), 7.02 (s, 1H), 5.77 (d, 1H), 5.02 (br.s, 1H), 4.17-4.02 (m, 1H), 3.83 (br. s, 2H), 3.74 (br., 2H), 3.69 (br. s, 2H), 3.58(br. s, 2H), 3.44 (s, 1H), 2.99-2.86 (m, 2H), 2.81-2.66 (m, 2H), 1.96-1.86 (m, 1H),1.84-1.71 (m, 1H), 1.47 (s, 6H), 1.40 (s, 9H), 1.27-1.15 (m, 1H), 0.87 (s, 9H),0.07 (s, 6H). LCMS[M+H] 669.4.

[0262] Step 6: tert-Butyl (1-(4-((1-(6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of tert-butyl (1-(4-((1-(6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (300 mg, 0.45 mmol) in MeOH (10 mL) was added TsOH (172 mg, 0.90 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and then NaHCO 3 Pour into aqueous solution (25 mL) and CH 2 Cl 2 (3×50 mL). The combined organics were extracted with Na 2 SO 4 Drying at 40° C., filtering, concentrating under reduced pressure, and purifying by column chromatography (MeOH:CH 2 Cl 2 ) to give the desired product (290 mg, 93%) as an off-white solid. LCMS [M+H] 555.3.

[0263] Step 7: tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of tert-butyl (1-(4-((1-(6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (290 mg, 0.42 mmol) in DCM (5 mL) was added Dess-Martin periodinane (259 mg, 0.63 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h and saturated NaHCO 3Pour into aqueous solution (20 mL) and CH 2 Cl 2 (3×50 mL). The combined organics were extracted with Na 2 SO 4 Drying at rt, filtration and concentration under reduced pressure gave the desired product (258 mg, quant.) as an off-white solid. LCMS [M+H] 553.3.

[0264] [ka] 4-((2R,4S)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)-N-(2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide (Intermediate 3) Prepared analogously to Scheme 2 from 1-(4-((2R,4S)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide and 4-amino-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2(1H)-one. LCMS [M+H] 537.3.

[0265] [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(2-oxo-2,3-dihydro-1H-inden-5-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate (Intermediate 4) Prepared analogously to Scheme 2 from benzyl 4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate and 4-amino-1-(2-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)pyrimidin-2(1H)-one. LCMS [M+H] 541.2.

[0266] Compound synthesis [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 9) [ka] Reagents: 1) tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate, Na(OAc) 3 BH, DCE, room temperature, 16 hours 2) HCl / MeOH, room temperature, 4 hours. Step 1: tert-Butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a solution of tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate (8.5 g, 15 mmol) in DCE (500 mL) was added tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (3.4 g, 17 mmol), Na(OAc). 3 BH (4.9 g, 23 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with NaHCO 3 aqueous solution (500 mL), the layers were separated, and the aqueous layer was washed with CH 2 Cl 2 (3×500 mL). The combined organics were extracted with Na 2 SO 4Drying at 400° C., concentrating under reduced pressure, and column chromatography (CH 2 Cl 2 :MeOH:NH 4 OH) to afford the desired compound (75%) as a grey solid. 1 HNMR (500 MHz, CDCl 3 ) δ 7.22 (d, 1H), 7.15 (d, 1H), 7.05 (d,1H), 7.04(s,1H), 5.79 (d, 1H), 4.86 (br. s, 1H), 4.49 (br. s, 1H), 4.08 (br. s, 1H), 3.86(br. s, 2H), 3.76 (br. s, 2H), 3.71 (br. s, 2H), 3.61 (s, 2H), 3.48 (br. s, 1H),3.13-2.98 (m, 2H), 2.96-2.75 (m, 2H), 2.71-2.56 (m, 1H), 2.24-1.98 (m, 3H), 1.91-1.74(m, 2H), 1.64 (s, 1H), 1.51 (s, 6H), 1.43 (d, 20H), 1.28 (s, 1H). LCMS[M+H] 737.8.

[0267] Step 2: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. tert-Butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate was dissolved in HCl / MeOH solution (5 mL) and stirred for 4 h. The volatiles were removed under reduced pressure and the crude solid was purified by reverse phase HPLC (H 2 O:CH 3Purification by CN:TFA) and concentration under reduced pressure. Addition and evaporation under reduced pressure with HCl / MeOH (3×15 mL) gave the desired product. 1 HNMR (400 MHz, D2O) δ 7.76 (d, 1H), 7.20 (d, 1H), 7.09 (d, 2H), 6.68 (d, 1H), 4.03-3.93(m, 1H), 3.83-3.73 (m,1H), 3.63 (s, 4H), 3.58 (s, 6H), 3.23 (d, 1H), 2.88-2.77 (m,3H), 2.33-2.12 (m, 5H), 1.83-1.62 (m, 2H), 1.59 (s, 6H). LCMS[M+H] 537.2.

[0268] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 1) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 HNMR (400 MHz, D 2O) δ 7.87 (d, 1H), 7.30 (d, 1H), 7.21 (s, 2H), 6.80 (d,1H), 4.01 (d, 2H), 3.71 (d, 10 H), 3.33 (s, 1H), 3.09 - 2.87 (m, 4H), 2.83 (s, 1H),2.42 (s, 2H), 2.34 (s, 1H), 1.89 (m, 1H), 1.70 (d, 6H). LCMS[M + H] 535.2。

[0269]

Chem.

[0270]

Chem.

[0271] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((S)-3-(aminomethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 4) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (R)-(pyrrolidin-3-ylmethyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.94 (d, 1H), 7.33 (d, 1H), 7.22 (d, 2H), 6.79 (d,1H), 4.06-3.85 (m, 1H), 3.87-3.27 (m, 12H), 3.25-2.65 (m, 7H), 2.56-2.29 (m, 2H), 2.52-2.30 (m 2H), 1.71 (s, 6H). LCMS[M+H] 537.3.

[0272] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((R)-3-(aminomethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 5) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (S)-(pyrrolidin-3-ylmethyl)carbamate. 1 HNMR (400 MHz, D 2O) δ 8.00 (d, 1H), 7.34 (d, 1H), 7.23 (d, 2H), 6.78 (d,1H), 4.05-3.87 (m, 1H), 3.86-3.27 (m, 12H), 3.27-2.83 (m, 7H), 2.81-2.24 (m, 2H), 2.07-1.72 (m, 2H), 1.70 (s, 6H). LCMS[M+H] 537.4.

[0273] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((cis)-4-aminocyclohexyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 6) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((cis)-4-aminocyclohexyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.92-7.84 (m, 1H), 7.34 (d, 1H), 7.25 (s, 2H), 6.85(d, 1H), 3.89-3.58 (m, 11H), 3.43-3.33 (m, 1H), 3.07-2.94 (m, 3H), 2.44-2.31 (m,1H), 2.17-2.07 (m, 2H), 1.98 (s, 4H), 1.85-1.78 (m, 1H), 1.74 (s, 8H). LCMS[M+H]551.3.

[0274] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 7) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((trans)-4-aminocyclohexyl)carbamate. 1 HNMR (400 MHz, D 2 O) 1H NMR (400 MHz, D2O) δ 7.91 (d, 1H), 7.35 (d, 1H),7.25 (d, 2H), 6.84 (d, 1H), 3.89-3.69 (m, 9H), 3.50 (s, 1H), 3.40-3.23 (m, 2H),3.09-2.92 (m, 3H), 2.32 (s, 3H), 2.23 (s, 2H), 1.98-1.85 (m, 1H), 1.75 (s, 6H),1.68-1.53 ​​(m, 4H). LCMS[M+H] 551.3.

[0275] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((6-aminospiro[3.3]heptan-2-yl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 8) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (6-aminospiro[3.3]heptan-2-yl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.90 (d, 1H), 7.34 (d, 1H), 7.25 (s, 2H), 6.84 (d,1H), 3.99 (s, 1H), 3.86-3.68 (m, 8H), 3.64 (s, 1H), 3.33-3.23 (m, 1H), 2.99 (s, 3H), 2.71-2.56 (m, 2H), 2.56-2.40 (m, 2H), 2.39-2.21 (m, 6H), 1.91 (s, 1H), 1.75(s, 6H). LCMS[M+H] 563.3.

[0276] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1R,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 10) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1S,3R)-3-aminocyclopentyl)carbamate. 1 HNMR (400 MHz, D 2O) δ 7.89 (d, 1H), 7.36 (d, 1H), 7.25 (d, 2H), 6.85 (d,1H), 4.06-3.95 (m, 1H), 3.85-3.68 (m, 10H), 3.39 (d, 1H), 3.07-2.93 (m, 3H), 2.82-2.71(m, 1H), 2.42-2.21 (m, 3H), 2.05-1.89 (m, 3H), 1.89-1.78 (m, 1H), 1.75 (s, 6H). LCMS[M+H]537.3.

[0277] [ka] 4-((S)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 24) Prepared analogously to Scheme 3 from 4-((2R,4S)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)-N-(2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.89-7.84 (m, 1H) 7.36 (d, 1H), 7.25 (d, 2H), 6.86(d, 1H), 4.16 (t, 2H), 3.92 (d, 2H), 3.79 (s, 4H), 3.73 (s, 5H), 3.37 (s, 1H), 3.02(s, 3H), 2.41 (d, 2H), 2.37-2.28 (m, 3H), 1.99-1.86 (m, 1H) 1.87-1.85 (m, 2H), 1.70(s, 3H). LCMS[M+H] 553.5.

[0278] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1R,3R)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 25) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.97 (d, 1H), 7.37 (d, 1H), 7.26 (s, 1H), 7.26 (d,1H), 6.83 (d, 1H), 4.22-4.06 (m, 1H), 4.01-3.86 (m, 1H), 3.79 (s, 4H), 3.74 (s,6H), 3.44-3.33 (m, 1H), 3.07-2.93 (m, 3H), 2.53-2.27 (m, 5H), 2.01-1.76 (m, 2H),1.75 (s, 6H). LCMS[M+H] 537.4.

[0279] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3R)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 26) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 8.03 (d, 1H), 7.37 (d, 1H), 7.26 (d, 2H), 6.82 (d,1H), 4.06-3.96 (m, 1H), 3.80 (s, 5H), 3.75 (s, 6H), 3.44-3.33 (m, 1H), 3.08-2.95(m, 3H), 2.85-2.72 (m, 1H), 2.42-2.19 (m, 3H), 2.05-1.92 (m, 2H), 1.89-1.79 (m,1H), 1.75 (s, 6H). LCMS[M+H] 537.4.

[0280] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-((S)-6-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 27 and Compound 28) tert-Butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate was separated by chiral HPLC to give optically pure stereoisomers. [Table 6]

[0281] First eluting diastereomer 1: 1 HNMR (400 MHz, CDCl 3 ) δ 7.22 (d, 1H), 7.15 (d, 1H), 7.06 (d, 1H), 7.05(s, 1H), 5.79 (d, 1H), 4.85 (br. s, 1H), 4.48 (br. s, 1H), 4.07 (br. s, 1H), 3.86(br. s, 2H), 3.75 (br. s, 2H), 3.71 (br. s, 2H), 3.61 (s, 2H), 3.48-3.38 (m, 1H),3.08-2.95 (m, 2H), 2.95-2.77 (m, 2H), 2.58 (dd, 1H), 2.22-1.99 (m, 3H), 1.85-1.69(m, 2H), 1.63-1.54 (m, 1H), 1.51 (s, 6H), 1.44 (d, 18H), 1.41-1.30 (m, 2H), 1.25(s, 1H). LCMS[M+H] 737.8.

[0282] Compound 27 was prepared in a similar manner as in Step 2 of Scheme 3 from the optically pure first eluting diastereomer 1, tert-butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. 1 HNMR (500 MHz, D 2O) δ 7.97 (d, 1H), 7.38 (d, 1H), 7.28 (s, 1H), 7.26 (d,2H), 6.85 (d, 1H), 4.23-4.11 (m, 1H), 4.01-3.90 (m, 1H), 3.88-3.68 (m, 9H), 3.40(dd, 1H), 3.15-2.96 (m, 3H), 2.54-2.37 (m, 3H), 2.35 (t, 2H), 2.00-1.91 (m, 1H), 1.90-1.78 (m, 2H), 1.76 (s, 6H). LCMS[M+H] 537.4.

[0283] The second dissolution test 2: 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, 1H),7.15 (d, 1H), 7.05 (dd, 2H), 5.78 (d, 1H), 4.86 (br. s, 1H), 4.48 (br. s, 1H), 4.07(br. s, 1H), 3.85 (br. s, 2H), 3.75 (br. s, 2H), 3.71 (br. s, 2H), 3.61 (br. s,2H), 3.47-3.39 (m, 1H), 3.07-2.95 (m, 2H), 2.95-2.77 (m, 2H), 2.57 (dd, 1H), 2.20-1.97(m, 3H), 1.75 (t, 2H), 1.64-1.54 (m, 1H), 1.51 (s, 6H), 1.43 (d, 18H), 1.40-1.31(m, 2H), 1.26 (s, 1H). LCMS[M+H] 737.8.

[0284] Compound 28 was prepared in a similar manner as in Scheme 3, Step 2 from the optically pure second eluting diastereomer 2, tert-butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. 1 HNMR (500 MHz, D 2 O) δ 7.90 (d, 1H), 7.33 (d, 1H), 7.22 (s, 2H), 6.80 (d,1H), 4.14-4.06 (m, 1H), 3.93-3.86 (m, 1H), 3.83-3.64 (m, 10H), 3.37 (dd, 1H), 3.06-2.91(m, 3H), 2.45-2.31 (m, 4H), 2.28 (t, 2H), 1.96-1.85 (m, 1H), 1.86-1.73 (m, 1H),1.71 (s, 6H). LCMS[M+H] 537.4.

[0285] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((trans-3-aminocyclobutyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 29) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (trans-3-aminocyclobutyl)carbamate. 1 HNMR (400 MHz, D 2O) δ 7.86 (d, 1H), 7.35 (d, 1H), 7.25 (d, 1H), 7.24 (d,1H), 6.86 (d, 1H), 4.41-4.29 (m, 1H), 4.17-4.06 (m, 1H), 3.79 (br. s, 3H), 3.73(br. s, 6H), 3.31 (dd, 1H), 3.05-2.93 (m, 3H), 2.90-2.70 (m, 4H), 2.36-2.26 (m,1H), 2.00-1.89 (m, 1H), 1.75 (s, 6H). LCMS[M+H] 523.4.

[0286] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((cis-3-aminocyclobutyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 30) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (cis-3-aminocyclobutyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.88 (d, 1H), 7.35 (d, 1H),7.25 (s, 1H), 7.24 (d,1H), 6.85 (d, 1H), 4.06-3.90 (m, 1H), 3.86-3.66 (m, 10H), 3.36 (dd, 1H), 3.10-2.88(m, 5H), 2.49 (q, 2H), 2.36-2.25 (m, 1H), 2.02-1.91 (m, 1H), 1.75 (s, 6H). LCMS[M+H]523.31.

[0287] [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(6-((((trans)-3-aminocyclobutyl)methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 31) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (trans-3-(aminomethyl)cyclobutyl)carbamate. 1 HNMR (500 MHz, D 2 O) δ 7.93 (d, 1H), 7.39 (d, 1H), 7.29 (d, 1H), 7.28 (d,1H), 6.87 (d, 1H), 4.06-3.97 (m, 1H), 3.82 (s, 4H), 3.76 (s, 5H), 3.71 (s, 1H),3.44 (d, 2H), 3.12-2.95 (m, 3H),2.94-2.85(m, 1H), 2.54-2.45 (m, 2H), 2.45-2.36 (m,3H), 2.00-1.90 (m, 1H), 1.78 (s, 6H). LCMS[M+H] 537.37.

[0288] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((cis-3-aminocyclobutyl)methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 32) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (cis-3-(aminomethyl)cyclobutyl)carbamate. 1 HNMR (500 MHz, D 2 O) δ 7.94 (d, 1H), 7.39 (d, 1H), 7.29 (d, 1H), 7.28 (d,1H), 6.87 (d, 1H), 3.89-3.72 (m, 9H), 3.72-3.63 (m, 1H), 3.43-3.31 (m, 3H), 3.10-2.94(m, 3H), 2.73-2.56 (m, 3H), 2.43-2.32 (m, 1H), 2.13-2.03 (m, 2H), 2.00-1.88 (m,1H), 1.78 (s, 6H). LCMS[M+H] 537.3.

[0289] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3R)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (first eluting diastereomer, compound 33) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate, followed by separation by chiral HPLC and deprotection of the optically pure stereoisomers. 1 HNMR (500 MHz, D 2O) δ 8.04 (d, 1H), 7.40 (d, 1H), 7.30 (s, 1H), 7.29 (d,1H), 6.85 (d, 1H), 4.08-3.99 (m, 1H), 3.86- 3.74 (m, 10H), 3.42 (dd, 1H), 3.11-3.03(m, 3H), 2.85-2.76 (m, 1H), 2.43-2.26 (m, 3H), 2.05 - 1.92 (m, 3H), 1.91-1.83 (m,1H), 1.78 (s, 6H). LCMS[M+H] 537.4.

[0290] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3R)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (second eluting diastereomer, compound 34) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate, followed by separation by chiral HPLC and deprotection of the optically pure stereoisomers. 1 HNMR (500 MHz, D 2O) δ 8.04 (d, 1H), 7.40 (d, 1H), 7.30 (s, 1H), 7.29 (d,1H), 6.85 (d, 1H), 4.08-3.99 (m, 1H), 3.91-3.71 (m, 10H), 3.42 (dd, 1H), 3.12-2.97(m, 3H), 2.86-2.74 (m, 1H), 2.44-2.24 (m, 3H), 2.08-1.92 (m, 3H), 1.92-1.83 (m,1H), 1.78 (s, 6H). LCMS[M+H] 537.4.

[0291] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(2-(((1S,3S)-3-aminocyclopentyl)amino)-2,3-dihydro-1H-inden-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 36) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(2-oxo-2,3-dihydro-1H-inden-5-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate. 1 HNMR (500 MHz, D 2 O) δ 7.94 (d, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.34 (d,1H), 6.88 (d, 1H), 4.36-4.20 (m, 1H), 4.13-4.01 (m, 1H), 3.99-3.92 (m, 1H), 3.82(br. s, 4H), 3.75 (br. s, 4H), 3.57 (dd, 2H), 3.26 (dd, 2H), 2.52-2.39 (m, 2H),2.35 (t, 2H), 1.95-1.79 (m, 2H), 1.78 (s, 6H). LCMS[M+H] 523.3.

[0292] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(2-(((trans-3-aminocyclobutyl)methyl)amino)-2,3-dihydro-1H-inden-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 37) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(2-oxo-2,3-dihydro-1H-inden-5-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (trans-3-(aminomethyl)cyclobutyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.97 (d, 1H), 7.49 (d, 1H), 7.38 (s, 1H), 7.31 (d,1H), 6.84 (d, 1H), 4.24 (t, 1H), 4.02-3.92 (m, 1H), 3.79 (br. s, 3H), 3.74 (br.s, 5H), 3.55 (dd, 2H), 3.36 (d, 2H), 3.23 (dd, 2H), 2.92-2.75 (m, 1H), 2.52-2.41(m, 2H), 2.41-2.31 (m, 2H), 1.75 (s, 6H). LCMS[M+H] 523.3.

[0293] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(2-((trans-4-aminocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 38) Prepared analogously to Scheme 3 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(2-oxo-2,3-dihydro-1H-inden-5-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (trans-4-aminocyclohexyl)carbamate. 1 HNMR (400 MHz, D 2 O) δ 7.92 (d, 1H), 7.49 (d, 1H), 7.38 (s, 1H), 7.31 (d,1H), 6.86 (d, 1H), 4.46-4.35 (m, 1H), 3.79 (br. s, 3H), 3.74 (br. s, 5H), 3.54 (dd,2H), 3.34 (d, 2H), 3.21 (dd, 2H), 2.41-2.16 (m, 4H), 1.75 (s, 6H), 1.68-1.53 ​​(m,4H). LCMS[M+H] 537.3.

[0294] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 15) [ka] Reagents: Step 1) 4 Å molecular sieves, 37% aqueous formaldehyde solution, NaCNBH 3 , MeOH, rt, 16 h 2) 2M HCl in MeOH. Step 1: tert-Butyl ((1r,4r)-4-((6-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-b1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)cyclohexyl)carbamate. To a stirred suspension of tert-butyl ((trans)-4-((6-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)cyclohexyl)carbamate (0.04 g, 0.05 mmol) and 4 Å molecular sieves (1.5 g) in methanol was added formaldehyde (30% in water, 1.5 mL) followed by sodium cyanoborohydride (5 mg, 0.08 mmol) with N 2 The mixture was added under atmospheric pressure and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite® and the solvent was evaporated. Saturated NaHCO 3 Aqueous solution was added and the compound was extracted with ethyl acetate (2×10 mL). The combined organics were washed with Na 2 SO 4 After drying at 40° C., filtering and concentrating under reduced pressure, the crude material was purified by flash column chromatography to afford the title compound (32 mg, 78% yield) as a white solid.

[0295] Step 2: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Compound tert-butyl ((1r,4r)-4-((6-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)cyclohexyl)carbamate (0.03 g, 0.04 mmol) was dissolved in 2M HCl in methanol and stirred at room temperature for 4 hours. The solvent was evaporated and the crude material was purified by HPLC to give the title compound (15 mg, 60% yield) as a brown solid. 1 HNMR (500 MHz, D 2 O): δ 8.00 (d, 1H), 7.40-7.36 (m, 1H), 7.27 (s, 1H),7.26 (s, 1H), 6.82 (d, 1H), 3.98-3.91 (m, 1H), 3.80-3.73 (m, 8H), 3.68-3.61 (m, 1H), 3.33-2.99 (m, 5H), 2.90 (s, 3H), 2.41-2.26 (m, 5H), 2.09-1.92 (m, 1H), 1.81-1.74(m, 1H), 1.73 (s, 6H), 1.72-1.58 (m, 3H). LCMS [M+H] 565.4.

[0296] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((6-aminospiro[3.3]heptan-2-yl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 11) Prepared analogously to Scheme 4 from tert-butyl (1-(4-((1-(6-((6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and formaldehyde. LCMS [M+H] 577.2.

[0297] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,4S)-4-aminocyclohexyl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 19) Prepared analogously to Scheme 4 from tert-butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and formaldehyde. 1 HNMR (500 MHz, D 2 O) δ:7.99 (d, 1H), 7.38-7.34 (m, 1H), 7.25 (s, 2H), 6.80(d, 1H), 4.22-4.15 (m, 1H), 3.99-3.87 (m, 2H), 3.83-3.65 (m, 8H), 3.28-3.16 (m, 2H), 3.15-2.92 (m, 2H), 2.88 (s, 3H), 2.45-2.29 (m, 4H), 2.26-2.18 (m, 1H), 2.17-2.00(m, 1H), 1.99-1.84 (m, 1H), 1.83-1.71 (m, 1H), 1.72 (s, 6H). LCMS [M+H] 551.4.

[0298] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)(ethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 16) [ka] Reagents: Step 1) Acetaldehyde, NaCNBH 3 , MeOH, rt, 16 h 2) 2M HCl in MeOH. Step 1: tert-Butyl ((trans)-4-((6-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(ethyl)amino)cyclohexyl)carbamate. To a stirred solution of tert-butyl ((trans)-4-((6-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)cyclohexyl)carbamate (0.04 g, 0.05 mmol) in methanol was added acetaldehyde (0.5 mL) followed by sodium cyanoborohydride (5 mg, 0.08 mmol) with N 2 The mixture was added under atmospheric pressure and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite® and the solvent was evaporated. Saturated NaHCO 3 Aqueous solution was added to the residue and the compound was extracted with ethyl acetate (2×10 mL). The combined organics were washed with Na 2 SO 4 After drying at 40° C., filtering and concentrating under reduced pressure, the crude material was purified by flash column chromatography to afford the title compound (31 mg, 75% yield) as a white solid.

[0299] Step 2: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)(ethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. tert-Butyl ((trans)-4-((6-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamide)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(ethyl)amino)cyclohexyl)carbamate (0.03 g, 0.04 mmol) was dissolved in 2 M HCl in methanol and stirred at room temperature for 4 h. The solvent was evaporated and the crude material was purified by HPLC to afford the title compound (18 mg, 65% yield) as a brown solid. 1 HNMR (500 MHz, D 2 O): δ 8.04 (d, 1H), 7.37 (d, 1H), 7.27 (s, 1H), 7.26(s, 1H), 6.82 (d, 1H), 3.98-3.91 (m, 1H), 3.81-3.73 (m, 8H), 3.66-3.59 (m, 1H),3.44 (q, 2H), 3.29-2.99 (m, 5H), 2.41-2.26 (m, 5H), 2.09-1.96 (m, 1H), 1.81-1.76(m, 1H), 1.75 (s, 6H), 1.72-1.58 (m, 3H), 1.43 (t, 3H). LCMS [M+H] 579.5.

[0300] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)(ethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 20) Prepared analogously to Scheme 5 from tert-butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and acetaldehyde. 1 HNMR (500 MHz, D 2 O): δ 7.93 (d, 1H), 7.35 (d, 1H), 7.24 (s, 2H), 6.81(d, 1H), 4.26-4.19 (m, 1H), 3.99-3.87 (m, 2H), 3.83-3.65 (m, 8H), 3.60-3.45 (m, 1H), 3.33-3.22 (m, 3H), 3.12-2.93 (m, 2H), 2.51-2.29 (m, 5H), 2.10-1.85 (m, 2H),1.83-1.71 (m, 1H), 1.72 (s, 6H), 1.43 (t, 3H). LCMS [M+H] 565.4.

[0301] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)(cyclopropylmethyl)amino)- 5,6,7,8-Tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 17) [ka] Reagents: Step 1) Cyclopropanecarbaldehyde, NaCNBH 3 , MeOH, rt, 16 h 2) 2M HCl in MeOH. Step 1: tert-Butyl ((trans)-4-((6-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(cyclopropylmethyl)amino)cyclohexyl)carbamate. To a stirred solution of tert-butyl ((trans)-4-((6-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)cyclohexyl)carbamate (0.04 g, 0.05 mmol) in methanol was added cyclopropanecarbaldehyde (0.05 mL) followed by sodium cyanoborohydride (5 mg, 0.08 mmol) with N 2 The mixture was added under atmospheric pressure and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite® and the solvent was evaporated. Saturated NaHCO 3 Aqueous solution was added to the residue and the compound was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with Na 2 SO 4 After drying at rt, filtering and concentrating under reduced pressure, the crude material was purified by flash column chromatography to afford the title compound (29 mg, 70% yield) as a white solid.

[0302] Step 2: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((trans)-4-aminocyclohexyl)(cyclopropylmethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. tert-Butyl ((trans)-4-((6-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamide)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(cyclopropylmethyl)amino)cyclohexyl)carbamate (0.03 g, 0.04 mmol) was dissolved in 2 M HCl in methanol and stirred at room temperature for 4 h. The solvent was evaporated and the crude material was purified by HPLC to give the title compound (17 mg, 70% yield) as a brown solid. 1 HNMR (500 MHz, D 2 O): δ 7.98 (d, 1H), 7.35 (d, 1H), 7.25 (s, 1H), 7.24(s, 1H), 6.80 (d, 1H), 4.19-3.98 (m, 1H), 3.81-3.73 (m, 8H), 3.66-3.61 (m, 1H),3.33-3.19 (m, 5H), 3.17-2.96 (m, 2H), 2.40-2.23 (m, 5H), 2.05-1.98 (m, 1H), 1.85-1.78(m, 2H), 1.72 (s, 6H), 1.68-1.56 (m, 2H), 1.18-1.12 (m, 1H), 0.77 (d, 2H), 0.43(d, 2H). LCMS [M+H] 605.5.

[0303] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)(cyclopropylmethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 21) Prepared analogously to Scheme 6 from tert-butyl (1-(4-((1-(6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and cyclopropanecarbaldehyde. 1 HNMR (500 MHz, D 2 O): δ 7.97 (d, 1H), 7.37-7.35 (m, 1H), 7.24 (s, 1H),7.23 (s, 1H), 6.80 (d, 1H), 4.27-4.19 (m, 1H), 4.06-3.95 (m, 1H), 3.94-3.86 (m, 1H), 3.83-3.63 (m, 8H), 3.38-3.17 (m, 3H), 3.12-2.93 (m, 3H), 2.51-2.29 (m, 5H),2.06-1.91 (m, 2H), 1.83-1.71 (m, 1H), 1.72 (s, 6H), 1.22-1.15 (m, 1H), 0.78 (t,2H), 0.42 (t, 2H). LCMS [M+H] 591.5.

[0304] [ka] Exo-4-(2-amino-2-methylpropanoyl)-N-(1-(3-(-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 12) [ka] Reagents: Step 1) Exo-tert-butyl ((3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate, NaCNBH 3 , DCE, room temperature, 16 hours 2)B 2 Pin 2, KOAc, PdCl(dppf), dioxane, 80°C, 16 hours 3) Cytosine, TMEDA, Cu(OAc) 2 H 2 O, MeOH:H 2 O(4:1), air, room temperature, 20 hours (4) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, CH 3 CN, 80° C., 16 h. (5) 4 M HCl in dioxane, rt, 8 h. Step 1: exo-tert-butyl ((3-(7-bromochroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. To a stirred solution of 7-bromochroman-3-one (0.1 g, 0.5 mmol) in DCE (5 mL) was added exo-tert-butyl ((3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.09 g, 0.5 mmol) and activated 4 Å molecular sieves (0.05 g) at room temperature. The reaction mixture was stirred at room temperature for 2 h. NaCNBH 3 (0.04 g, 0.7 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was poured into water (30 mL) and extracted with DCE (3×15 mL). The combined organic layers were washed with Na 2 SO 4 It was dried at 40° C., filtered, concentrated under reduced pressure and purified by flash chromatography (20% EtOAc in hexanes) to give the title compound (0.1 g, 54%) as a yellow solid. 1 HNMR (400 MHz, MeOD) δ 6.96-6.94 (m, 2H), 6.88 (s, 1H), 4.24 (d,1H), 3.08 (t, 1H),3.13 (t, 1H), 2.93-2.86 (m, 3H), 2.68-2.62 (m, 2H), 2.55-2.52 (m, 2H), 1.46 (s,9H), 1.43-1.33 (m, 2H), 1.30-1.24 (m, 1H), 1.19-1.16 (m, 1H). LCMS [M+H] 423.2.

[0305] Step 2: exo-tert-butyl-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. To a stirred solution of exo-tert-butyl((3-(7-bromochroman-3-yl)-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.1 g, 0.3 mmol) in dioxane (150 mL) was added B 2 Pin 2 (0.12 g, 0.5 mmol) and KOAc (0.07 g, 0.7 mmol) were dissolved in N at room temperature. 2 The reaction mixture was added under N 2 The mixture was degassed for 20 minutes at 40°C. 2 (dppf) (0.02 g, 0.02 mmol) was added and heated at 80° C. for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with Na 2 SO 4 Drying at rt, filtering and concentrating under reduced pressure gave the title compound (0.2 g, quantitative) as a brown gum. LCMS [M+H] 471.2.

[0306] Step 3: tert-Butyl ((exo)-3-(7-(4-amino-2-oxopyrimidin-1(2H)-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. MeOH:H 2 A solution of exo-tert-butyl((3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl) (0.2 g, 0.4 mmol) and cytosine (0.05 g, 0.4 mmol) in 2H2O (6 mL, 4:1) was stirred at room temperature in air for 30 min. TMEDA (0.07 mL, 0.5 mmol) and Cu(OAc) 2 .H 2O (0.08 g, 0.4 mmol) was added and the reaction mixture was stirred at room temperature in air for 20 h. The reaction mixture was concentrated under reduced pressure. The crude material was poured into water (30 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with Na 2 SO 4 It was dried at 40° C., filtered, concentrated under reduced pressure and purified by flash chromatography (10% MeOH in DCM) to give the title compound (0.045 g, 24%) as a brown solid. 1 HNMR: (400 MHz, DMSO-d 6 ): δ 7.53 (d, 1H), 7.19-7.07 (m, 2H), 6.76-6.70(m, 2H), 6.67 (d, 1H), 5.80-5.72 (m, 1H), 4.21 (d, 1H), 3.79 (t, 1H), 3.06-2.99(m, 2H), 2.90 (d, 2H), 2.76-2.73 (m, 2H), 2.66-2.63 (m, 2H), 1.35 (s, 9H), 1.30-1.28(m, 3H), 1.27-1.22 (m, 1H), 1.06-1.04 (m, 1H). LCMS [M+H] 454.9.

[0307] Step 4: exo-tert-butyl ((3-(7-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A stirred solution of tert-butyl ((exo)-3-(7-(4-amino-2-oxopyrimidin-1(2H)-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.05 g, 0.1 mmol) and 1-(4-(2-((tert-butylcarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (0.08 g, 0.2 mmol) in acetonitrile (2 mL) was heated at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by flash chromatography (2% MeOH in DCM) to give the title compound (0.08 g) as a brown gum. LCMS [M+H] 751.

[0308] Step 5: exo-4-(2-amino-2-methylpropanoyl)-N-(1-(3-(-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. To a stirred solution of exo-tert-butyl ((3-(7-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)chroman-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.08 g, 0.1 mmol) in dioxane (1.0 mL) was added 4 M HCl in dioxane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (0.005 g, 8%) as a white solid. 1 HNMR: (400Mz, D 2O): δ 7.91 (d, 1H), 7.42 (d, 1H), 7.13 (q, 1H), 7.07 (d,1H), 6.91 (d, 1H), 4.60-4.55 (m, 1H), 4.55-4.48(m, 1H), 4.13-4.04 (m, 2H), 3.84-3.79(m, 8H),3.68-3.49 (m, 2H), 3.35-3.20 (m, 2H), 3.03 (d, 2H), 2.21-2.04 (m, 2H), 1.80(s, 6H), 1.68-1.55 (m, 1H). LCMS[M+H] 551.3.

[0309] [ka] Exo-4-(2-amino-2-methylpropanoyl)-N-(1-(3-(-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 13) Prepared in a similar manner to Scheme 7 from 7-bromochroman-3-one and exo-tert-butyl (3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 HNMR: (400MHz, D 2 O): δ 7.71 (d, 1H), 7.20 (d, 1H), 6.91 (d, 1H), 6.85 (s,1H), 6.69 (d, 1H), 4.37 (d, 1H), 4.21 (d, 1H), 3.90-3.84 (m, 2H), 3.62-3.50(m, 9H), 3.41-3.31(m, 3H), 3.04-2.91 (m, 2H), 2.32 (s, 2H), 1.58 (s, 6H). LCMS[M+H] 537.3.

[0310] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-((S)-3-(aminomethyl)pyrrolidin-1-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 14) Prepared in a similar manner to Scheme 7 from 7-bromochroman-3-one and (R)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate. 1 HNMR:(400 MHz, D2O): δ 7.70 (d, 1H), 7.21 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 6.69(d, 1H), 4.47 (d, 2H), 4.24 (t, 2H), 3.87 (bs, 1H), 3.69-3.55(m, 7H), 3.45-3.34(m,2H), 3.25-3.18 (m, 1H), 3.12-3.01 (m, 4H), 2.65-2.52 (m, 2H), 2.40-2.26 (m, 2H),1.57 (s, 6H). LCMS[M+2H] / 2 270.2.

[0311] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-((R)-3-(aminomethyl)pyrrolidin-1-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 18) Prepared in a similar manner to Scheme 7 from 7-bromochroman-3-one and (S)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate. 1 HNMR: (400 MHz, D 2O): δ 7.72 (d, 1H), 7.21 (d, 1H), 6.91 (d, 1H), 6.85(s, 1H), 6.68 (d, 1H), 4.46 (d, 2H), 4.23 (t, 2H), 3.86 (bs, 2H), 3.61-3.50 (m,8H), 3.07 (d, 2H), 3.15-2.95 (m, 4H), 2.41-2.26 (m, 2H), 1.56 (s, 6H). LCMS[M+H]539.8.

[0312] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-(4-aminoazepan-1-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 22) Prepared in a similar manner to Scheme 7 from 7-bromochroman-3-one and tert-butyl azepan-4-ylcarbamate. 1 HNMR: (400 MHz, D 2 O): δ 7.76 (d, 1H), 7.25 (d, 1H), 6.95 (d, 1H), 6.89(s, 1H), 6.73-6.71 (m, 1H), 4.56 (d, 2H), 4.32 (t, 1H), 3.96 (bs, 1H), 3.85-3.62(m,4H), 3.60-3.29(m, 9H), 3.28-3.16 (m, 2H), 2.85 (d, 1H), 2.35-2.22 (m, 2H), 2.15-1.90(m, 2H), 1.61 (s, 6H). LCMS[M+H] 553.5.

[0313] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)chroman-7-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 23) Prepared in a similar manner to Scheme 7 from 7-bromochroman-3-one and tert-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 HNMR: (400 MHz, D 2 O):7.76 (d, 1H), 7.19 (d, 1H), 6.90 (d, 1H), 6.84 (s,1H), 6.66 (d, 1H), 4.32-422 (m, 3H), 3.86 (bs, 2H), 3.78-3.47 (m, 11H), 3.35-3.31(m,3H), 3.12-2.80 (m, 3H), 1.92 (bs, 1H), 1.56 (s, 6H), 1.21-0.95 (m, 2H). LCMS[M+H]551.3.

[0314] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(2-(4-aminocyclohexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 35) [ka] Reagents: 1) tert-Butyl (4-oxocyclohexyl)carbamate, Na(OAc) 3 BH, DCE, room temperature for 16 hours 2) Pd(dppf)Cl 2 ·CH 2 Cl 2 ,KOAc,B. 2 Pin 2 , 1,4-dioxane, 105°C, 16 hours, 3) cytosine, Cu(OAc) 2 H 2O, TMEDA, MeOH:H 2 4) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, MeCN, 85° C., 16 hours. 5) HCl, MeOH, rt for 4 hours. Step 1: tert-Butyl (4-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate. To a stirred solution of tert-butyl (4-oxocyclohexyl)carbamate (251 mg, 1.2 mmol) in DCE (10 mL) was added 6-bromo-1,2,3,4-tetrahydroisoquinoline (250 mg, 1.2 mmol) and Na(OAc). 3 BH (375 mg, 1.8 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with CH 2 Cl 2 Dilute with saturated NaHCO 3 (1×15 mL). The aqueous layer was washed with CH 2 Cl 2 (2×20 mL) and the combined organics were washed with Na 2 SO 4 Drying at 400° C., concentrating under reduced pressure, and column chromatography (CH 2 Cl 2 : MeOH) to give the desired product. LCMS [M+H] 411.1.

[0315] Step 2 tert-Butyl (4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate. tert-Butyl (4-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate (512 mg, 1.25 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (30 mg, 0.03 mmol), KOAc (368 mg, 3.75 mmol), and B 2 pin 2The flask containing (349 mg, 1.38 mmol) was evacuated and filled with N 2 The crude reaction mixture was purified by flash chromatography (EtOAc:Hex) to give the desired product. LCMS [M+H] 457.8.

[0316] Step 3: tert-Butyl (4-(6-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate. MeOH:H 2 A suspension of tert-butyl (4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate (500 mg, 1.1 mmol) and cytosine (122 mg, 1.1 mmol) in 2H2O (4:1, 100 mL) was stirred at room temperature for 30 min in air. Cu(OAc) 2 H 2 2O (219 mg, 1.1 mmol) and TMEDA (0.20 mL, 1.3 mmol) were added and the reaction was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and H 2 O was added (150 mL). The solid was collected by filtration and diluted with Et 2 O (25 mL) and cold H 2 Washing with O (25 mL) gave the desired product. LCMS [M+H] 440.3.

[0317] Step 4: tert-Butyl (1-(4-((1-(2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a solution of tert-butyl (4-(6-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl)carbamate (124 mg, 0.28 mmol) in MeCN (20 mL) was added 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (200 mg, 0.39 mmol). The reaction mixture was heated to 85° C. for 16 h. The volatiles were removed under reduced pressure and the crude solid was purified by HPLC using HPLC. 2 Cl 2 (100 mL) and 2 The crude solid was purified by flash chromatography (CH 2 Cl 2 :MeOH:NH 4 OH) to give the desired product.

[0318] Step 5: 4-(2-amino-2-methylpropanoyl)-N-(1-(2-(4-aminocyclohexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. tert-Butyl (1-(4-((1-(2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate was dissolved in HCl / MeOH solution (5 mL) and stirred for 4 h. The volatiles were removed under reduced pressure and the crude solid was purified by reverse phase HPLC (H 2 O:CH 3Purification by CN:TFA) and concentration under reduced pressure. Addition and evaporation under reduced pressure with HCl / MeOH (3×15 mL) gave the desired product. 1 HNMR (500 MHz, D 2 O) δ 8.05 (d, 1H), 7.49-7.37 (m, 3H), 6.87 (dd, 1H),4.64 (d, 2H), 3.99-3.49 (m, 10H), 3.44-3.23 (m, 3H), 2.47-2.28 (m, 2H), 2.26-2.11(m, 2H), 2.03 (d, 2H), 1.87 (d, 1H), 1.78 (s, 6H), 1.73-1.59 (m, 1H). LCMS[M+H] 537.4.

[0319] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(4-(2-aminoethyl)piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 42) [ka] Reagents: 1) DMP, CH 2 Cl 2 , room temperature, 2 hours 8) NaCNBH 3 , DCM, 45° C., 16 h 2) 4M HCl / dioxane, rt, 3 h. Step 8: tert-Butyl (1-(4-((1-(6-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate (0.25 g, 0.45 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (0.15 g, 0.67 mmol) in DCM (10 mL) was added NaBH 3 CN (0.06 g, 0.9 mmol) was dissolved in N at room temperature. 2 The mixture was added under atmospheric pressure. The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (12% MeOH in DCM) to give the title compound (0.1 g, 29%) as an off-white solid. LCMS [M+H] 765.6.

[0320] Step 9: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(4-(2-aminoethyl)piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. To a stirred solution of tert-butyl (1-(4-((1-(6-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (0.1 g, 0.13 mmol) in dioxane (2 mL) was added 4 M HCl in dioxane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title compound (0.025 g, 33%) as a pale yellow solid. 1 HNMR: (400 MHz, D 2 O): δ 7.79 (d, 1H), 7.20 (d, 1H), 7.08 (d, 2H), 6.66(d, 1H), 3.61-3.49 (m, 11H), 3.18-3.14 (m, 1H), 3.07-2.81 (m, 7H), 2.19 (bs, 1H),1.94 (d, 2H), 1.83-1.78 (m, 1H), 1.63-1.51 (m, 9H), 1.43-1.34 (m, 2H). LCMS [M / 2+H]283.3.

[0321] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(7-(4-aminoazepan-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (compound 43) Prepared in a similar manner to Scheme 9 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl azepan-4-ylcarbamate. 1 HNMR: (400 MHz, D 2 O):LCMS [M / 2+H] 276.3.

[0322] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(7-(3-aminoazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 39) Prepared in a similar manner to Scheme 9 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl azetidin-3-ylcarbamate. 1 HNMR: (400 MHz, D 2 O): δ 7.83 (d, 1H), 7.24 (d, 1H), 7.14 (d, 2H), 6.71(d, 1H), 4.70-4.60 (m, 2H), 4.41 (s, 3H), 3.79 (bs, 2H), 3.66-3.54 (m, 7H), 3.24-3.20(m, 1H), 2.87-2.75 (m, 3H), 2.17 (bs, 1H), 1.78-1.72 (m, 1H), 1.62 (s, 6H). LCMS[M+H] 509.5.

[0323] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(7-(3-(aminomethyl)azetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 40) Prepared in a similar manner to Scheme 9 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (azetidin-3-ylmethyl)carbamate. 1 HNMR: (400 MHz, D 2 O): δ 7.82 (d, 1H), 7.23 (d, 1H), 7.14 (d, 2H), 6.71(d, 1H), 4.36 (t, 2H), 4.12-4.07 (m, 2H), 3.66-3.62 (m, 8H), 3.34 (d, 1H), 3.23-3.15(m, 4H), 2.86 (d, 2H), 2.76-2.72 (m, 1H), 2.15 (bs, 1H), 1.70 (m, 1H), 1.62 (s,6H). LCMS [M+H] 523.4.

[0324] [ka] trans-4-(2-amino-2-methylpropanoyl)-N-(1-(7-((3-(aminomethyl)cyclobutyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 41) Prepared in a similar manner to Scheme 9 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (((trans)-3-aminocyclobutyl)methyl)carbamate. 1 HNMR: (400 MHz, D 2 O): δ 7.77 (d, 1H), 7.22 (d, 1H), 7.12 (s, 2H), 6.72(d, 1H), 4.07 (d, 1H), 3.66-3.61 (m, 9H), 3.20-3.10 (m, 3H), 2.91-2.70 (m, 3H), 2.70-2.66 (m, 1H), 2.50-2.44 (m, 2H), 2.26-2.17 (m, 3H), 1.90-1.81 (m, 1H), 1.62(s, 6H). LCMS [M+H] 537.4.

[0325] tert-Butyl(2-methyl-1-oxo-1-(4-((2-oxo-1-(6-oxo- [ka] Cis-4-(2-amino-2-methylpropanoyl)-N-(1-(7-((3-(aminomethyl)cyclobutyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 44) Prepared in a similar manner to Scheme 9 from 5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (((cis)-3-aminocyclobutyl)methyl)carbamate. 1 HNMR: (400 MHz, D 2O): δ 7.75 (d, 1H), 7.22 (d, 1H), 7.12 (s, 2H), 6.73(d, 1H), 3.91 (bs, 1H), 3.67-3.61 (m, 8H), 3.31-3.15 (m, 3H), 3.03-2.88 (m, 4H), 2.57-2.45 (m, 3H), 2.31-2.18 (m, 1H), 2.09-1.96 (m, 2H), 1.90-1.83 (m, 1H), 1.63(s, 6H). LCMS [M / 2+H] 269.3.

[0326] [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(2-((trans)-4-aminocyclohexyl)isoindolin-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride (Compound 46) [ka] Reagents: Step 1) tert-Butyl ((1r,4r)-4-aminocyclohexyl)carbamate, K 2 CO 3 , C.H. 3 CN, 85℃, 16 hours 2)B 2 Pin 2 , KOAc, PdCl 2 (dppf), dioxane, 100°C, 16 hours 3) Cytosine, TMEDA, Cu(OAc) 2 .H 2 O, MeOH:H 2 O(4:1), air, room temperature, 16 hours (4) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, CH 3 CN, 80°C, 16 hours (5)AcCl, MeOH, room temperature, 4 hours. Step 1: tert-Butyl ((trans)-4-(5-bromoisoindolin-2-yl)cyclohexyl)carbamate. CH 3To a stirred solution of 4-bromo-1,2-bis(bromomethyl)benzene (0.31 g, 0.9 mmol) in CN (15 mL) was added tert-butyl((trans)-4-aminocyclohexyl)carbamate (0.21 g, 1.0 mmol) and K 2 CO 3 (0.27 g, 2.0 mmol) was added at room temperature. The reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc in hexanes) to give the title compound (0.2 g, 56%) as a pale yellow solid.

[0327] Step 2: tert-Butyl ((trans)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)cyclohexyl)carbamate. To a stirred solution of tert-butyl ((trans)-4-(5-bromoisoindolin-2-yl)cyclohexyl)carbamate (0.1 g, 0.25 mmol) in dioxane (5 mL), add B 2 Pin 2 (0.08 g, 0.3 mmol) and KOAc (0.07 g, 0.8 mmol) were dissolved in N at room temperature. 2 The reaction mixture was cooled to room temperature and cooled to 40° C. 2 Degass for 20 min at 400 C and add PdCl 2 (dppf) (6.0 mg, 0.03 mmol) was added and the reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (75% EtOAc in hexanes) to give the title compound (0.08 g, 73%) as a brown solid.

[0328] Step 3: tert-Butyl ((trans)-4-(5-(4-amino-2-oxopyrimidin-1(2H)-yl)isoindolin-2-yl)cyclohexyl)carbamate. MeOH:H 2A solution of tert-butyl ((trans)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)cyclohexyl)carbamate (80.0 mg, 0.18 mmol) and cytosine (20 mg, 0.18 mmol) in 2H2O (6 mL, 4:1) was stirred for 30 min. TMEDA (25.0 μL, 0.22 mmol) and Cu(OAc) 2 .H 2 O (36.0 mg, 0.18 mmol) was added and the reaction mixture was stirred at room temperature in air for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was poured into water (30 mL) and CHCl 3 (3×15 mL). The combined organics were extracted with Na 2 SO 4 Drying at 40° C., filtering, concentrating under reduced pressure, and eluting with flash chromatography (8:2:0.2 MeOH:DCM:NH 4 OH) to afford the title compound (32 mg, 44%) as a white solid.

[0329] Step 4: tert-Butyl (1-(4-((1-(2-((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)isoindolin-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of tert-butyl ((trans)-4-(5-(4-amino-2-oxopyrimidin-1(2H)-yl)isoindolin-2-yl)cyclohexyl)carbamate (32 mg, 0.08 mmol) in acetonitrile (4 mL) was added 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (80 mg, 0.15 mmol) and the reaction mixture was irradiated with N 2 The mixture was stirred at 80° C. for 16 h under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (DCM / MeOH) to give the title compound (35 mg, 64%) as a pale yellow solid.

[0330] Step 5: 4-(2-amino-2-methylpropanoyl)-N-(1-(2-((trans)-4-aminocyclohexyl)isoindolin-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Compound tert-butyl (1-(4-((1-(2-((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)isoindolin-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (30 mg, 0.04 mmol) was dissolved in freshly prepared methanolic HCl (4 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by RPHPLC. The desired fractions were collected and evaporated under reduced pressure. To the residue was added HCl in MeOH (2×5 mL) and the solvent was evaporated to give the title compound (11 mg, 50%) as a white solid. 1 HNMR: (400Mz, D 2 O): δ 8.03 (d, 1H), 7.61 (d, 1H), 7.55 - 7.48 (m, 2H),6.85 (d, 1H), 4.98 (d, 2H), 4.73 (d, 3H), 3.80 - 3.73 (m, 8H), 3.67 - 3.59 (m,1H),3.36 - 3.26 (m, 1H), 2.42 (d, 2H), 2.27 (d, 2H), 1.75 (s, 6H), 1.74 - 1.56 (m, 4H). LCMS[M+H]524.3.

[0331] [ka] Methyl ((1S,3S)-3-((6-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)cyclopentyl)carbamate hydrochloride (Compound 45) [ka] Reagents: Step 1) NaHCO 3 , methyl chloroformate, THF, H 2 0°C to room temperature, 2 hours. Step 1: Methyl ((1S,3S)-3-((6-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide)-2-oxopyrimidin-1(2H)-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)cyclopentyl)carbamate: 4-(2-amino-2-methylpropanoyl)-N-(1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide (160 mg, 0.3 mmol) in saturated NaHCO 3 The resulting mixture was dissolved in water (2 ml) and THF (2 ml). Methyl chloroformate (28 mg, 0.3 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solid was filtered and the residue was concentrated under reduced pressure. The residue was dissolved in MeOH (0.5 ml) and 2M HCl in ether (3 ml) was added, the resulting solid was filtered, washed with ether and dried under vacuum to give the title compound (51 mg, 31%) as a white solid. 1HNMR (500 MHz, D 2 O) δ 8.10 (dd, 1H), 7.39 (d, 1H), 7.28 (dd, 2H), 6.82(d, 1H), 4.20 - 4.12 (m, 1H), 4.06 (q, 1H), 3.79 (d, 9H), 3.68 (s, 3H), 3.39 (d,1H), 3.08 - 2.95 (m, 3H), 2.36 (s, 2H), 2.22 (dd, 1H), 2.14 (td, 2H), 1.98 - 1.88(m, 1H), 1.76 (d, 7H), 1.72 - 1.61 (m, 1H). LCMS[M+2H / 2] = 298.3.

[0332] Biological Examples Standard microbiological effects: A certified BSL-2 laboratory was used for testing. Compounds were evaluated against S. aureus (Sa), E. coli (Ec), K. pneumoniae (Kp), A. baumannii (Ab), E. faecalis (Ef), and P. aeruginosa (Pa) using broth microdilution minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays as defined by the Clinical and Laboratory Standards Institute (CLSI) M26-A guidelines.

[0333] E. coli S30 Extract: Inhibition of bacterial protein synthesis was measured using the E. coli S30 Extract System for Circular DNA (Promega Cat. No. L-2010) and Luciferase Assay Reagent (Promega Cat. No. E1500) with minor modifications to published protocols. Fyfe, C., Sutcliffe, JA and Grossman, TH (2012) “Development and characterization of a Pseudomonas aeruginosa in vitro coupled transcription-translation assay system for evaluation of translation inhibitors” J. Microbiol. Methods 90(3), 256-261.

[0334] Compounds were serially diluted in 0.5 mL microcentrifuge tubes by mixing and transferring 50 μL from the highest concentration to 50 μL water, and mixing and transferring 50 μL of this 2-fold dilution to 50 μL water. This mixing and transferring was repeated so that there were a total of 8 tubes with compounds serially diluted at 10-fold the desired screening concentration. These were finally diluted to 1-fold by the addition of S30 luciferase synthesis mix. Compound serial dilutions (2 μL) were added to wells of a black round-bottom 96-well plate. Water (2 μL) was used as a "no inhibitor" control, 4 wells / plate. A control reaction mix without DNA (20 μL, see below) was used as a control for background luminescence, 4 wells / plate. S30 luciferase synthesis mix (18 μL, see below) was added to wells with compound or water mix and incubated at 37° C. for 1 hour. The reaction was stopped by transferring to a 4° C. refrigerator for 5 min, after which 25 μL of luciferase activity mix was added. Luminescence was measured using a BioTek Synergy HTX plate reader. Percent inhibition was determined relative to a no inhibitor control. S30 Luciferase Synthesis Mix: 445 μL of S30 extract, circular 712 μL S30 Premix without amino acids 4.45 μL of pBESTluc™ DNA (1 μg / μL) 78 μL complete amino acid mixture 267 μL water No DNA control: 20 μL of S30 extract, circular 32 μL of S30 premix (no amino acids) 7 μL complete amino acid mixture 21 μL water

[0335] Rabbit reticulocyte lysate Inhibition of eukaryotic protein synthesis was measured using the Rabbit Reticulocyte Lysate System, Nuclease-Treated from Promega (cat. no. L-4960) with minor modifications to the manufacturer's protocol. Compounds were serially diluted in 0.5 mL microcentrifuge tubes by mixing and transferring 50 μL from the highest concentration to 50 μL water, and mixing and transferring 50 μL of this 2-fold dilution to 50 μL water. This mixing and transfer was repeated so that there were a total of eight tubes with compounds serially diluted at 10-fold the desired screening concentration. These were finally diluted to 1-fold by the addition of rabbit reticulocyte luciferase synthesis mix. Serial dilutions of compounds (2.5 μL) were added to wells of a black round-bottom 96-well plate. Water (2.5 μL) was used as a "no inhibitor" control, 4 wells / plate. For background luminescence, a control reaction mix without RNA (2 μL, see below) was used as a control with 4 wells / plate. Rabbit reticulocyte luciferase synthesis mix (22.5 μL, see below) was added to wells with compound or water mix and incubated at 30° C. for 90 minutes. Luciferase assay reagent (25 μL) was added and luminescence was measured using a BioTek Synergy HTX plate reader. % inhibition was determined relative to the no inhibitor control. Rabbit reticulocyte luciferase synthetic mixture: 1,000 μL rabbit reticulocyte lysate 5.7 μL of luciferase control RNA (1 μg / μL) 26 μL complete amino acid mixture 395 μL water No RNA control 70 μL rabbit reticulocyte lysate 2 μL of complete amino acid mixture 28 μL water

[0336] Minimum inhibitory concentration (MIC) MICs were determined using the Clinical Laboratory and Standards Institute (CLSI) broth microdilution method with slight modifications. Clinical and Laboratory Standards Institute (2012). “Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 9th ed. M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA.” Serial two-fold dilutions of compounds are prepared in sterile clear round-bottom 96-well plates.

[0337] To prepare the microdilution tray, two-fold dilutions of antimicrobial agents are prepared in growth medium. Cation-Adjusted Mueller-Hinton Broth (CAMHB) or CAMHB supplemented with sodium bicarbonate (final concentration 6.25 or 25 mM prepared from a 1.0 M stock solution) or CAMHB supplemented with 0-50% heat-inactivated human serum (Fisher catalog number BP2657100) are prepared by adding 200 μL of the highest concentration to be tested (e.g., 64 μg / mL) to row A, mixing and transferring 100 μL from row A to 100 μL of growth medium in row B, and then repeating this mixing and transferring process up to row H of the 96-well plate, discarding the remaining excess 100 μL. This slight modification to the CLSI protocol allows for evaluation of MICs in triplicate on one plate for three compounds, despite only eight compound dilutions (CLSI protocol allows two compounds in triplicate with 10 dilutions). For each bacterium to be evaluated, a 0.5 McFarland suspension (1 × 10 8 Add 5 µL of a 1:10 dilution of the bacterial suspension (CFU / mL) to obtain a final concentration of 5 x 10 4CFU / well. Bacterial suspensions were prepared using the growth method described by CLSI. A sterile loop was used to select well-isolated colonies (3-5 from the agar plate) and used to inoculate tubes containing 4 mL of CAMHB. These cultures were then cultured in a 100 mL tube containing 100 mL of CAMHB. 600nm Incubate at 35 ± 2°C (usually 2-6 hours) until the turbidity reaches or exceeds that of a 0.5 McFarland standard, as determined by measuring the turbidity of the 0.5 McFarland standard. If growth exceeds that of a 0.5 McFarland standard, adjust the turbidity with medium until it is equivalent to that of a 0.5 McFarland standard.

[0338] Compound data are provided in Table 6. IC ≥ 1 μM (% inhibition ≤ 50% at 1 μM) 50 Values ​​(μM) are indicated with "+". IC values ​​are 0.5 μM or more and less than 1 μM. 50 Values ​​(% inhibition >50% and ≦90% at 1 μM) are indicated with "++". IC less than 0.5 μM 50 Values ​​(inhibition %>90% at 1 μM) are indicated with "+++". MIC values ​​(μg / mL) ≥ 32 μg / mL are indicated with "+". MIC values ​​(μg / mL) ≥ 8 μg / mL and < 32 μg / mL are indicated with "++". MIC values ​​(μg / mL) < 8 μg / mL are indicated with "+++". "NA" means not applicable. [Table 7-1] [Table 7-2] [Table 8-1] [Table 8-2]

[0339] The foregoing disclosure has been described in some detail by way of illustrations and examples, for purposes of clarity and understanding. The present invention has been described with reference to various specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the present invention. It will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the above description is intended to be illustrative, rather than limiting. The scope of the present invention should therefore be determined not with reference to the above description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. The present invention provides, for example, the following items. (Item 1) Compounds of Formula I: [ka] or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, In the formula, ring A is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 and oxo, J is C 1 -C 6 Alkylene or C 3 -C 8 cycloalkylene, any of which may be halo, OH, or C 1 -C 6 Optionally substituted with alkoxy, 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO 2 , or replaced by C=O, R x 、R y 、R x’ , and R y’ However, each independently, H, C 1 -C 6 an alkyl or amino protecting group, Y is a bond, OH, or NH 2 , CN, Halo, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 alkylene, 1 -C 6 Up to two methylene units of the alkylene are optionally and independently selected from O, NH, N-(C 1 -C 6 alkyl), N-(C 1 -C 6 Hydroxyalkyl), N-(C 1 -C 6 haloalkyl), N-(C 1-6 Alkylene-C 3-8 Cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O) or (C=O), Ring B is a 3- to 8-membered monocyclic cycloalkylene, a 3- to 8-membered monocyclic heterocycloalkylene, a 6- to 12-membered bicyclic cycloalkylene, or a 6- to 12-membered bicyclic heterocycloalkylene, each of which is selected from the group consisting of C 1 -C 6 Alkyl, C1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, OH, COOH, COO(C 1 -C 6 alkyl), CONH 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 Alkyl) 2 , and C 1 -C 6 Optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl; L is a bond or C 1 -C 6 alkylene, 1 -C 6 Up to two methylene units of the alkylene are independently O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), Ring C together with the phenyl ring to which it is fused forms an 8- to 12-membered bicyclic arylene or an 8- to 12-membered bicyclic heteroarylene, the bicyclic heteroarylene having 1 to 3 heteroatoms independently selected from N, O, or S; R 1 、R 2 , and R 3 However, each independently, C 1 -C 6 Alkyl, halo, CN, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , COO(C 1 -C 6 alkyl), CONH 2 、C 1 -C 6 Haloalkyl, oxo, and C 1 -C 6 alkoxy; The compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are each independently 0, 1, 2, or 3. (Item 2) Ring A is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo, CN, C 1 -C 6 Haloalkyl, phenyl, OH, NH 2 and oxo, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. (Item 3) Ring A is

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Claims

1. Compounds of Formula I: 【Chemistry 136】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, In the formula, ring A is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, phenyl, OH, NH ２ , NH(C １ -C ６ Alkyl), N(C １ -C ６ Alkyl) ２ , COOH, COO(C １ -C ６ alkyl), CONH ２ , CONH(C １ -C ６ alkyl), CON(C １ -C ６ Alkyl) ２ and oxo; J is C １ -C ６ Alkylene or C ３ -C ８ cycloalkylene, any of which is halo, OH, or C １ -C ６ Optionally substituted with alkoxy, １ -C ６ Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO ２ or replaced by C=O, R ｘ , R ｙ , R ｘ’ , and R ｙ’ Each independently represents H, C １ -C ６ an alkyl or amino protecting group; Y is a bond, OH, NH ２ , CN, halo, or C １ -C ６ C optionally substituted with alkoxy １ -C ６ alkylene, １ -C ６ Up to two methylene units of the alkylene are optionally and independently selected from O, NH, N-(C １ -C ６ alkyl), N-(C １ -C ６ Hydroxyalkyl), N-(C １ -C ６ haloalkyl), N-(C １－６ Alkylene-C ３－８ cycloalkyl), NH(C=O), N-(C １－６ alkyl)(C=O) or (C=O); Ring B is a 3- to 8-membered monocyclic cycloalkylene, a 3- to 8-membered monocyclic heterocycloalkylene, a 6- to 12-membered bicyclic cycloalkylene, or a 6- to 12-membered bicyclic heterocycloalkylene, each of which is selected from the group consisting of C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, COOH, COO(C １ -C ６ alkyl), CONH ２ , CONH(C １ -C ６ alkyl), CON(C １ -C ６ Alkyl) ２ , and C １ -C ６ Optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl; L is a bond or C １ -C ６ alkylene, １ -C ６ Up to two methylene units of the alkylene are independently O, NH, (C=O), NH(C=O), N-(C １－６ alkyl)(C=O), (C=NH), NH(C=N), or N-(C １－６ alkyl), Ring C together with the phenyl ring to which it is fused forms an 8- to 12-membered bicyclic arylene or an 8- to 12-membered bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, or S; R １ , R ２ , and R ３ Each independently, C １ -C ６ Alkyl, halo, CN, OH, NH ２ , NH(C １ -C ６ Alkyl), N(C １ -C ６ Alkyl) ２ , COO (C １ -C ６ alkyl), CONH ２ , C １ -C ６ Haloalkyl, oxo, and C １ -C ６ alkoxy; m, n, and p are each independently 0, 1, 2, or 3, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

2. Ring A is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, phenyl, OH, NH ２ and oxo, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

3. Ring A is 【Chemistry 137】 and each R ４ But independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, phenyl, OH, NH ２ and oxo, and q is 0, 1, or 2, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

4. Ring A is 【Chemistry 138】 4. The compound according to any one of claims 1 to 3, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

5. J is halo, OH, or C １ -C ６ C optionally substituted with alkoxy １ -C ６ alkylene, １ -C ６ Up to two methylene units of the alkylene are optionally and independently selected from O, S, SO, SO ２ or C=O, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

6. J is C optionally substituted with OH １ -C ６ alkylene, １ -C ６ 6. The compound according to any one of claims 1 to 5, wherein one methylene unit of the alkylene is replaced by C=O, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

7. J. 【Chemistry 139】 7. The compound according to any one of claims 1 to 6, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

8. R ｘ and R ｙ is H, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

9. 【Fig. 140】 but, 【Chemistry 141】 9. The compound according to any one of claims 1 to 8, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

10. 【Fig. 142】 but, 【Chemistry 143】 10. The compound according to any one of claims 1 to 9, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

11. 【Fig. 144】 but, 【Chemistry 145】 wherein each X １ But independently, CH ２ ,CH,O,S,SO,SO ２ , N, and NH; R ２ and R ３ Each independently, C １ -C ６ Alkyl, halo, or C １ -C ６ 11. The compound of any one of claims 1 to 10, wherein n is haloalkyl, and n and p are each independently 0, 1, or 2, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

12. 【Fig. 146】 but, 【Chemistry 147】 12. The compound according to any one of claims 1 to 11, selected from the group consisting of: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

13. 【Fig. 148】 but, 【Chemistry 149】 13. The compound according to any one of claims 1 to 12, selected from the group consisting of: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

14. 14. The compound of any one of claims 1 to 13, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein Y is a bond.

15. Y is OH, NH ２ , halo, or C １ -C ６ C optionally substituted with alkoxy １ -C ３ alkylene, １ -C ３ One methylene unit of the alkylene is O, NH, N-(C １ -C ６ alkyl), N-(C １ -C ６ Hydroxyalkyl), N-(C １ -C ６ haloalkyl), N-(C １－６ Alkylene-C ３－８ cycloalkyl), NH(C=O), N-(C １－６ 14. The compound of any one of claims 1 to 13, optionally replaced by (C=O), (alkyl), (C=O), or (C=O), or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

16. Y is O, NH, NH-C １－２ Alkylene, N(C １ -C ６ Alkyl), N(C １ -C ６ Hydroxyalkyl), N(C １ -C ６ haloalkyl), N(C １－６ Alkylene-C ３－８ cycloalkyl), NH(C=O), N(C １－６ 16. The compound of claim 15, wherein the compound is selected from the group consisting of (C=O), (alkyl), (C=O), and (C=O), or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

17. Y is NH,N(C １ -C ６ alkyl), NH-C １－２ Alkylene, and N(C １－６ Alkylene-C ３－８ 20. The compound of claim 16, wherein the compound is selected from the group consisting of: aryl, arylcycloalkyl, arylsulfonyl ...

18. Y is -NH-, -NMe-, -NEt-, -NH-CH ２ - and -N(CH ２ 18. The compound of any one of claims 1 to 17, which is selected from the group consisting of: -cyclopropyl)-, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

19. 【Fig. 150】 but, 【Chemistry 151】 19. The compound according to any one of claims 1 to 18, selected from the group consisting of: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

20. Ring B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, COOH, COO(C １ -C ６ alkyl), CONH ２ , CONH(C １ -C ６ alkyl), CON(C １ -C ６ Alkyl) ２ , and C １ -C ６ 20. The compound of any one of claims 1 to 19, which is a 3-8 membered monocyclic cycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

21. Ring B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, and C １ -C ６ 21. The compound of claim 20, which is a 4-6 membered monocyclic cycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

22. B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, COOH, COO(C １ -C ６ alkyl), CONH ２ , CONH(C １ -C ６ alkyl), CON(C １ -C ６ Alkyl) ２ , and C １ -C ６ 20. The compound of any one of claims 1 to 19, which is a 3-8 membered monocyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

23. Ring B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, and C １ -C ６ 23. The compound of claim 22, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein B is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, and B contains up to two nitrogen atoms.

24. Ring B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, C １ -C ６ Haloalkyl, OH, and C １ -C ６ 20. The compound of any one of claims 1 to 19, which is a 6-10 membered bicyclic cycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

25. The compound according to claim 24, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered fused, spiro, or bridged bicyclic cycloalkylene.

26. The compound according to claim 25, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered fused bicyclic cycloalkylene.

27. The compound according to claim 25, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered bridged bicyclic cycloalkylene.

28. The compound according to claim 25, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered spiro bicyclic cycloalkylene.

29. Ring B is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, C １ -C ６ Haloalkyl, OH, and C １ -C ６ 20. The compound of any one of claims 1 to 19, which is a 6-12 membered bicyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of hydroxyalkyl, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

30. The compound according to claim 29, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 9-membered fused, spiro, or bridged bicyclic heterocycloalkylene containing a maximum of 3 nitrogen atoms.

31. The compound according to claim 29 or 30, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 9-membered fused bicyclic heterocycloalkylene containing a maximum of 2 nitrogen atoms.

32. The compound according to claim 29 or 30, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a spiro bicyclic heterocycloalkylene containing a maximum of 2 nitrogen atoms.

33. The compound according to claim 29 or 30, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring B is a bridged bicyclic heterocycloalkylene containing a maximum of 2 nitrogen atoms.

34. Ring B is 【Chemistry 152】 The compound according to any one of claims 1 to 19, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

35. The compound according to any one of claims 1 to 34, or a single stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

36. L is C １ -C ６ alkylene, １ -C ６ Up to two methylene units of the alkylene are optionally and independently selected from O, NH, (C=O), NH(C=O), N-(C １－６ alkyl)(C=O), (C=NH), NH(C=N), or N-(C １－６ 35. The compound of any one of claims 1 to 34, wherein R is substituted with R(s) or R(s) or R(s) or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

37. L is C １ -C ６ 37. The compound of claim 36, which is alkylene, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

38. L is -CH ２ - or -CH ２ CH ２ 38. The compound of claim 37, wherein: -, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

39. R ｘ’ and R ｙ’ is each independently selected from the group consisting of H, Boc, and methoxycarbonyl, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

40. 【Fig. 153】 but, 【Chemistry 154】 40. The compound according to any one of claims 1 to 39, selected from the group consisting of: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

41. R １ , R ２ , and R ３ Each independently, C １ -C ６ Alkyl, halo, C １ -C ６ Haloalkyl, oxo, and C １ -C ６ alkoxy; and m, n, and p are each independently 0, 1, or 2; or a single stereoisomer or mixture of stereoisomers thereof; or a pharma- ceutically acceptable salt thereof.

42. R １ , R ２ , and R ３ Each independently, C １ -C ６ Alkyl, halo, oxo, or C １ -C ６ 42. The compound of claim 41, wherein m, n, and p are each independently 0 or 1, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

43. Compound of formula IA: 【Chemistry 155】 43. The compound of any one of claims 1 to 42, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

44. Compound of formula IA-1: 【Chemistry 156】 wherein each R ４ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, NH ２ and oxo, and q is 0, 1, 2, or 3, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

45. Compound of formula IA-2: 【Chemistry 157】 wherein K is halo, hydroxyl, or C １ -C ６ C optionally substituted with an alkoxy group １ -C ４ 45. The compound of claim 44, which is alkylene, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

46. Compound of formula IA-3: 【Chemistry 158】 wherein K is C optionally substituted with hydroxyl １ -C ３ 46. ​​The compound of claim 45, which is alkylene, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

47. Compound of formula IA-4a or IA-4b: 【Chemistry 159】 wherein each X １ But independently, CH ２ 47. The compound of claim 46, wherein the compound is selected from the group consisting of: CH, O, S, N, and NH, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

48. Compound of formula IA-5a or IA-5b: 【Chemistry 160】 wherein each X １ But independently, CH ２ 48. The compound of claim 47, wherein the compound is selected from the group consisting of: CH, NH, N, and O, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

49. 49. The compound of claim 48, which is a compound of formula IA-6a or IA-6b, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 161】

50. A compound selected from the group consisting of formula IA-7a, formula IA-7b, formula IA-7c, formula IA-7d, formula IA-7e, and formula IA-7f, 【Chemistry 162】 In the formula, each ２ is independently CH or N, and each s is independently 1, 2, or 3, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

51. K. 【Chemistry 163】 51. The compound of any one of claims 45 to 50, which is: or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

52. Y is a bond, NH, NH-(C １ -C ６ alkylene)-, N-(C １ -C ６ alkyl), or N-(C １ -C ６ Alkylene-C ３ -C ８ 51. The compound of any one of claims 43 to 50, wherein R is 0, 1 or 2; R is 1 or 2; and R is 3 or 4. The compound of any one of claims 43 to 50, wherein R is 0, 1 or 2;

53. L is a bond or C １ -C ６ 51. The compound of any one of claims 43 to 50, which is alkylene, or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

54. 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

55. 【Table 2-4】 【Table 2-5】 【Table 2-6】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

56. 56. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

57. 1. A composition for treating a bacterial infection in a patient in need thereof, comprising: (1) A compound according to any one of claims 1 to 55, or a pharma- ceutically acceptable salt thereof; or (2) The pharmaceutical composition according to claim 56. A composition comprising:

58. 58. The composition of claim 57, wherein the bacterial infection is caused by bacteria, including gram-positive and gram-negative bacteria.

59. Compounds of Formula I: 【Chemistry 164】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: Compound of Formula A: 【Chemistry 165】 of, Formula B' 【Chemistry 166】 Or formula C 【Chemistry 167】 under reductive amination conditions to obtain a compound of formula I, In the formula, ring A, ring B, ring C, J, L, R １ , R ２ , R ３ , R ｘ , R ｙ , R ｘ’ , R ｙ , m, n and p are as defined in any one of claims 1 to 53; Ring B １ is a nitrogen containing 3- to 8-membered monocyclic heterocycloalkylene, or a nitrogen containing 6- to 12-membered bicyclic heterocycloalkylene, each of which is optionally and independently selected from C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halo, CN, C １ -C ６ Haloalkyl, OH, COO(C １ -C ６ alkyl), CONH ２ , CONH(C １ -C ６ alkyl), CON(C １ -C ６ Alkyl) ２ , and C １ -C ６ hydroxyalkyl; Y is a bond, OH, NH ２ , CN, halo, or C １ -C ６ C optionally substituted with alkoxy １ -C ６ alkylene, １ -C ６ One methylene unit of the alkylene is NH, N-(C １ -C ６ alkyl), N-(C １ -C ６ Hydroxyalkyl), N-(C １ -C ６ haloalkyl), or N-(C １ -C ６ Alkylene-C ３ -C ８ cycloalkyl), Y １ is a bond, or OH, NH ２ , CN, halo, or C １ -C ６ C optionally substituted with alkoxy １ -C ５ is alkylene, R ｚ But, H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Haloalkyl, or C １ -C ６ Alkylene-C ３ -C ８ The process wherein the alkyl group is cycloalkyl.

60. Compound of Formula ID: 【Chemistry 168】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: The compound of formula E is 【Chemistry 169】 coupling with a compound of formula F 【Chemistry 170】 In the formula, rings C, K, R １ , R ２ , R ３ , R ｘ , R ｙ , m, n and p are as defined in any one of claims 1 to 53; The process wherein P is a hydroxyl protecting group.

61. 61. The process of claim 60, further comprising removing the hydroxyl protecting group to provide a compound of formula IE. 【Chemistry 171】

62. 62. The process of claim 61, further comprising the step of oxidizing said hydroxyl group to obtain a compound of formula ID.

63. Compound of Formula ID: 【Chemistry 172】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein C, K, R １ , R ２ , R ３ , R ｘ , R ｙ 54. The compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are as defined in any one of claims 1 to 53.

64. Compound of Formula II: 【Chemistry 173】 or a single stereoisomer thereof or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: １ , R ２ , R ３ , R ｘ’ , R ｙ’ 54. The compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are as defined in any one of claims 1 to 53.

65. The compound is 【Table 3-5】 【Table 3-6】 【Table 3-7】 【Table 3-8】 65. The compound of claim 64, selected from the compounds shown below: or a pharma- ceutically acceptable salt thereof.

66. Compound of Formula III 【Chemistry 174】 or a single stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein: １ , R ２ , R ３ , R ｘ’ , R ｙ’ 54. The compound, or a single stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein m, n, and p are as defined in any one of claims 1 to 53.

67. The compound is 【Table 4-4】 【Table 4-5】 【Table 4-6】 【Table 4-7】 67. The compound of claim 66, selected from the compounds shown below: or a pharma- ceutically acceptable salt thereof.

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