Antibacterial compounds

Abstract

Provided herein are heterocyclic derivative compounds useful for inhibiting the growth of Gram-negative bacteria and pharmaceutical compositions comprising the compounds. In addition, the compounds and compositions of the present invention can be used to treat bacterial infections, such as urinary tract infections, and the like.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 734,173, filed on September 20, 2018, and U.S. Provisional Patent Application No. 62 / 767,313, filed on November 14, 2018, each of which is incorporated herein by reference in its entirety. Background Art

[0003] There is a need in the medical field for effective treatments for diseases caused by bacterial infections. Summary of the invention

[0004] Provided herein are heterocyclic derivative compounds useful for inhibiting the growth of Gram-negative bacteria and pharmaceutical compositions comprising the compounds. In addition, the compounds and compositions of the present invention can be used to treat bacterial infections, such as urinary tract infections, and the like.

[0005] Provided herein is a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a structure of formula (I):

[0006]

[0007] in,

[0008] n is 0-4;

[0009] m is 0-4;

[0010] A1 is OH or SH;

[0011] A2 is O or S;

[0012] R 1 and R 2 are each independently H or optionally substituted alkyl;

[0013] or R 1 and R 2 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S;

[0014] or R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0015] R 3is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2;

[0016] R 4 is H or optionally substituted alkyl;

[0017] or R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S; or R 3 and R 4Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0018] R 5 is H, halogen, optionally substituted alkyl, hydroxy, alkoxy, cyano, amino or nitro;

[0019] Ring B is aryl, carbocyclic, heteroaryl or heterocyclic;

[0020] W is a bond, -C≡C-, bicyclo[1.1.1]pentylene, -C≡CC≡C-, -CH=CH- or -CH2CH2;

[0021] Ring C is aryl, carbocyclyl, heteroaryl or heterocyclyl;

[0022] Each X and Y is independently H, optionally substituted alkyl, halo, fluoroalkyl, cyano, nitro, -N(R 13 )2OR 13 ;

[0023] or R 3 and one X together with the intervening atoms form an optionally substituted 5- to 7-membered carbocyclyl or an optionally substituted 5- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0024] Z is H, halo, nitro or -LG;

[0025] L is a bond or an optionally substituted C1-C4 alkylene group;

[0026] G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R 14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R 14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 );

[0027] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0028] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0029] Each R 12 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

[0030] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0031] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0032] Each R 14 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0033] In some embodiments provided herein, the compound of formula (I) is a compound of formula (II):

[0034]

[0035] In some embodiments provided herein, the compound of formula (I) or formula (II) is a compound of formula (III):

[0036]

[0037] In some embodiments provided herein, the compound of formula (I) or formula (II) or formula (III) is a compound of formula (IV):

[0038]

[0039] In some embodiments provided herein, the compound of formula (I) or formula (II) or formula (III) is a compound of formula (IVa):

[0040]

[0041] In some embodiments provided herein, the compound of formula (I) or formula (II) or formula (III) is a compound of formula (IVb):

[0042]

[0043] Another aspect provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0044] On the other hand, there is provided herein a method for treating a Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient. In some embodiments provided herein, the Gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intraperitoneal infection, skin infection and urinary tract infection. In some embodiments provided herein, the Gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urethral infection and kidney infection.

[0045] In another aspect, provided herein is a method of inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase comprising contacting the enzyme with a compound described herein.

[0046] In another aspect, provided herein is a method of treating a bacterial infection in a patient in need thereof, comprising administering to the patient a composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0047] Incorporation by reference

[0048] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes described herein. DETAILED DESCRIPTION

[0049] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so on. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. The term "about" used when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error range), so in some cases, the number or numerical range will vary between 1% and 15% of the number or numerical range. The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude that, in certain other embodiments, for example, embodiments of any composition of matter, composition, method or process, etc. described herein "consists of" or "consists essentially of" the features.

[0050] definition

[0051] As used in this specification and the appended claims, the following terms have the meanings set forth below unless indicated otherwise.

[0052] "Amino" refers to a -NH2 group.

[0053] "Cyano" refers to a -CN group.

[0054] "Nitro" refers to a -NO2 group.

[0055] "Oxa" refers to an -O- group.

[0056] "Oxo" refers to a =0 group.

[0057] "Thio" refers to a =S group.

[0058] "Imino" refers to a =NH group.

[0059] "Oximo" refers to a =N-OH group.

[0060] "Hydrazino" refers to the =N-NH2 radical.

[0061] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains 1 to 13 carbon atoms (e.g., C1-C 13In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1,1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise expressly specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0062] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom wherein alkyl is an alkyl chain as defined above.

[0063] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond and having 2-12 carbon atoms. In certain embodiments, alkenyl comprises 2 to 8 carbon atoms. In other embodiments, alkenyl comprises 2 to 4 carbon atoms. The alkenyl is connected to the rest of the molecule by a single bond, for example, vinyl, prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise expressly specified in the specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each Ra and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0064] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2-12 carbon atoms. In certain embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group contains 2 to 6 carbon atoms. In other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise expressly specified in the specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0065] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, does not contain unsaturation and has 1-12 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and to the group is through a carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group comprises 1 to 8 carbon atoms (for example, C1-C8 alkylene). In other embodiments, the alkylene group comprises 1 to 5 carbon atoms (for example, C1-C5 alkylene). In other embodiments, the alkylene group comprises 1 to 4 carbon atoms (for example, C1-C4 alkylene). In other embodiments, the alkylene group comprises 1 to 3 carbon atoms (for example, C1-C3 alkylene). In other embodiments, the alkylene group comprises 1 to 2 carbon atoms (for example, C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise expressly specified in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0066] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which is composed only of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 12 carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond, and is connected to the group by a single bond. In certain embodiments, the alkenylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise expressly specified in the specification, alkenylene chains are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0067] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which is composed only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond, and is connected to the group by a single bond. In certain embodiments, the alkynylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene comprises 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, the alkynylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise expressly specified in the specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0068] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, wherein at least one ring of the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl radicals are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is intended to include aryl groups optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(Ra )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2)(where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, wherein each of the above substituents is unsubstituted.

[0069] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl group is optionally substituted as described above for the aryl group.

[0070] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain part of the aralkenyl group is optionally substituted as described above for alkenylene.

[0071] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for aryl. The alkynylene chain part of the aralkynyl group is optionally substituted as described above for alkynylene chains.

[0072] "Aralkyloxy" refers to a group of the formula -OR c - an aryl group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl group is optionally substituted as described above for the aryl group.

[0073] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including condensed rings or bridged ring systems, with 3 to 15 carbon atoms. In certain embodiments, the carbocyclyl comprises 3 to 10 carbon atoms. In other embodiments, the carbocyclyl comprises 5 to 7 carbon atoms. The carbocyclyl is connected to the rest of the molecule by a single bond. The carbocyclyl is saturated (i.e., only comprising a single C-C bond) or unsaturated (i.e., containing one or more double bonds or triple bonds). Fully saturated carbocyclyl groups are also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -Rb -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2)(where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, wherein each of the above substituents is unsubstituted.

[0074] "Carbocyclylalkyl" refers to a group of the formula -R c -Carbocyclic group, where R cis an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0075] "Carbocyclylalkynyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl group are optionally substituted as described above.

[0076] "Carbocyclylalkoxy" refers to a group of the formula -OR c - a carbocyclic group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as described above.

[0077] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0078]

[0079] wait.

[0080] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0081] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorinated groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl is optionally substituted as described above for the alkyl group.

[0082] "Heterocyclyl" refers to a stable 3 to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise expressly stated in the specification, the heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a condensed ring, a bridged ring or a spirocyclic ring system. The heteroatoms in the heterocyclyl group are optionally oxidized. If there are one or more nitrogen atoms, it is optionally quaternized. The heterocyclyl is partially or completely saturated. The heterocyclyl is connected to the rest of the molecule through any atom in the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)Ra , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2)(where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, wherein each of the above substituents is unsubstituted.

[0083] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through the nitrogen atom in the heterocyclyl group. N-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0084] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl group as defined above containing at least one heteroatom, and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. C-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0085] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclic radical is a nitrogen-containing heterocyclic radical, the heterocyclic radical is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic radical alkyl group is optionally substituted as described above for the alkylene chain. The heterocyclic radical moiety of the heterocyclic radical alkyl group is optionally substituted as described above for the heterocyclic radical.

[0086] "Heterocyclylalkoxy" refers to a group of the formula -OR c - a heterocyclic group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. If the heterocyclic radical is a nitrogen-containing heterocyclic radical, the heterocyclic radical is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic radical alkoxy group is optionally substituted as described above for the alkylene chain. The heterocyclic moiety of the heterocyclic radical alkoxy group is optionally substituted as described above for the heterocyclic radical.

[0087] "Heteroaryl" refers to a group derived from a 3 to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom in the ring. Examples of heteroaryl groups include, but are not limited to, aza- benzo[b][1,4]dioxolane, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolane, benzo[d]thia ... benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydro benzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methoxy-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepine yl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl oxazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(Ra )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2)(where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, wherein each of the above substituents is unsubstituted.

[0088] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0089] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for a heteroaryl group.

[0090] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, wherein R cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl.

[0091] "Heteroarylalkoxy" refers to a group of the formula -OR c - a heteroaryl group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0092] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise indicated, the disclosure is intended to relate to all stereoisomeric forms of compounds disclosed herein. When the compounds described herein contain olefin double bonds, unless otherwise indicated, the present invention is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers are also intended to be included, as well as their racemic forms and optically pure forms, and all tautomeric forms. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of olefin double bonds. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0093] "Tautomers" refer to molecules in which it is possible for a proton to move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. In situations where tautomerism is possible, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0094]

[0095] In some cases, the heterocyclic LpxC inhibitory compounds disclosed herein exist in tautomeric forms. For clarity, the structures of the compounds are illustrated in one tautomeric form. Alternative tautomeric forms are explicitly included in the present disclosure, for example, the structures shown below.

[0096]

[0097] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14 In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0098] Unless otherwise stated, structures shown herein are intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C- or 14 Compounds having the present structures other than C-enriched carbon substitutions are also within the scope of the present disclosure.

[0099] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Label the compound. 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 18 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br, 125Isotopic substitutions are contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0100] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0101] Various methods are used to synthesize deuterium substituted compounds, such as those described in: Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2), 9-32.

[0102] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0103] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions.

[0104] By way of example only, the use of CD3I is shown in the following reaction scheme.

[0105]

[0106] Deuterium is transferred to the reaction substrate using a deuterium transfer reagent such as lithium aluminum deuteride (LiAlD4) under reducing conditions. By way of example only, the use of LiAlD4 is shown in the following reaction scheme.

[0107]

[0108] By way of example only, as shown in the following reaction scheme, deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aromatic carbon-halogen bonds.

[0109]

[0110] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atom. In one embodiment, the level of deuterium incorporation is determined by the synthesis method using deuterated synthetic building blocks as starting materials.

[0111] In one embodiment, the compounds disclosed herein contain one or more boron atoms, silicon atoms, or any combination thereof. In some embodiments, one or more carbon atoms in the compounds disclosed herein are replaced by boron atoms, silicon atoms, or any combination thereof.

[0112] In some embodiments, one or more carbon atoms in the compounds disclosed herein are replaced by boron atoms. In some embodiments, one carbon atom in the compounds disclosed herein is replaced by a boron atom. In some embodiments, two carbon atoms in the compounds disclosed herein are replaced by two boron atoms. In some embodiments, three carbon atoms in the compounds disclosed herein are replaced by three boron atoms. In some embodiments, four carbon atoms in the compounds disclosed herein are replaced by four boron atoms. In some embodiments, five carbon atoms in the compounds disclosed herein are replaced by five boron atoms.

[0113] In some embodiments, one or more carbon atoms in the compounds disclosed herein are replaced by silicon atoms. In some embodiments, one carbon atom in the compounds disclosed herein is replaced by a silicon atom. In some embodiments, two carbon atoms in the compounds disclosed herein are replaced by two silicon atoms. In some embodiments, three carbon atoms in the compounds disclosed herein are replaced by three silicon atoms. In some embodiments, four carbon atoms in the compounds disclosed herein are replaced by four silicon atoms. In some embodiments, five carbon atoms in the compounds disclosed herein are replaced by five silicon atoms.

[0114] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. Any pharmaceutically acceptable salt of the heterocyclic LpxC inhibitory compounds described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0115] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, 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, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to procedures and techniques familiar to skilled artisans.

[0116] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from organic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic 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, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0117] As used herein, "treat" or "treating" or "alleviate" or "improve" are used interchangeably. These terms refer to a means of obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. By "therapeutic benefit" is meant the elimination or amelioration of the underlying condition being treated. Additionally, therapeutic benefit may also be achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that improvement is observed in the patient, although the patient is still suffering from the underlying condition. For preventive benefit, in some embodiments, the composition is administered to a patient at risk for developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0118] "Prodrug" is intended to mean a compound that, in some embodiments, is converted under physiological conditions or by solvolysis into a biologically active compound as described herein. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted into active compounds in vivo, for example, by hydrolysis. Prodrug compounds generally have advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

[0119] A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0120] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such a prodrug is administered to a mammalian subject. As described herein, a prodrug of an active compound is prepared by modifying a functional group present in the active compound in a manner that allows the modification to be cleaved into the parent active compound in routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0121] LpxC inhibitory compounds

[0122] Provided herein are heterocyclic LpxC inhibitory compounds and pharmaceutical compositions comprising the compounds. The compounds and compositions of the present invention can be used to inhibit UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and to treat bacterial infections.

[0123] Also provided herein is a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a structure of formula (I):

[0124]

[0125] in,

[0126] n is 0-4;

[0127] m is 0-4;

[0128] A1 is OH or SH;

[0129] A2 is O or S;

[0130] R 1 and R 2 are each independently H or optionally substituted alkyl;

[0131] or R 1 and R 2 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S; or R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0132] R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2; R 4 is H or optionally substituted alkyl;

[0133] or R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S;

[0134] or R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0135] R 5 is H, halogen, optionally substituted alkyl, hydroxy, alkoxy, cyano, amino or nitro;

[0136] Ring B is aryl, carbocyclic, heteroaryl or heterocyclic;

[0137] W is a bond, -C≡C-, bicyclo[1.1.1]pentylene, -C≡CC≡C-, -CH=CH- or -CH2CH2-;

[0138] Ring C is aryl, carbocyclyl, heteroaryl or heterocyclyl;

[0139] Each X and Y is independently H, optionally substituted alkyl, halo, fluoroalkyl, cyano, nitro, -N(R 13 )2OR 13 ;

[0140] or R 3 and one X together with the intervening atoms form an optionally substituted 5- to 7-membered carbocyclyl or an optionally substituted 5- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0141] Z is H, halo, nitro or -LG;

[0142] L is a bond or an optionally substituted C1-C4 alkylene group;

[0143] G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R 14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R 13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 );

[0144] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0145] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0146] Each R 12 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

[0147] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0148] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0149] Each R 14 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0150] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is a monocyclic or bicyclic aryl group, a monocyclic or bicyclic heteroaryl group containing 1 or 2 heteroatoms selected from O, N, and S, or a monocyclic or bicyclic 5- to 12-membered heterocyclyl group containing 1 to 3 heteroatoms selected from O, N, and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is a phenyl group, In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is phenyl,

[0151] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is phenyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is a carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is a heteroaryl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is a heterocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring B is

[0152] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, W is a bond. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, W is -C≡C-, bicyclo[1.1.1]pentylene, -C≡CC≡C-, -CH=CH-, or -CH2CH2-. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, W is -C≡C-, -C≡CC≡C-, -CH=CH-, or -CH2CH2. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, W is -C≡C-, -CH=CH-, or -CH2CH2. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, W is -C≡C-. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, W is bicyclo[1.1.1]pentanylene. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, W is -C≡CC≡C-. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, W is -CH=CH-. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, W is -CH2CH2-.

[0153] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is a monocyclic or bicyclic aryl group, a monocyclic or bicyclic 3 to 12-membered carbocyclyl group, a monocyclic or bicyclic heteroaryl group containing 1 or 2 heteroatoms selected from O, N, and S, or a monocyclic or bicyclic 5 to 12-membered heterocyclyl group containing 1 to 3 heteroatoms selected from O, N, and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is phenyl, a monocyclic 3 to 6-membered carbocyclyl group, or a monocyclic or bicyclic heteroaryl group containing 1 or 2 heteroatoms selected from O, N, and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is phenyl, cyclohexyl, In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is phenyl, cyclohexyl, In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is phenyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is a carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is a monocyclic cycloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is cyclohexane. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is a heteroaryl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is a heterocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is a monocyclic heterocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, ring C is piperidine. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is piperazine. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Ring C is

[0154] In some embodiments of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring B is phenyl; and Ring C is phenyl.

[0155] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the compound of formula (I) has the structure of formula (II):

[0156]

[0157] in,

[0158] n is 0-4;

[0159] m is 0-4;

[0160] A1 is OH or SH;

[0161] A2 is O or S;

[0162] R 1 and R 2 are each independently H or optionally substituted alkyl;

[0163] or R 1 and R 2 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S; or R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0164] R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2;

[0165] R 4 is H or optionally substituted alkyl;

[0166] or R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S; or R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0167] R 5 is H, halogen, optionally substituted alkyl, hydroxy, alkoxy, cyano, amino or nitro;

[0168] Each X and Y is independently H, optionally substituted alkyl, halo, fluoroalkyl, cyano, nitro-N(R 13 )2OR 13 ;

[0169] or R 3 and one X together with the intervening atoms form an optionally substituted 5- to 7-membered carbocyclyl or an optionally substituted 5- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0170] Z is H, halo, nitro or -LG;

[0171] L is a bond or an optionally substituted C1-C4 alkylene group;

[0172] G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R 14 )-COR 13 、-SO2R 13-、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R 14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R 13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 );

[0173] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0174] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0175] Each R 12 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

[0176] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0177] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0178] Each R 14 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0179] In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H, optionally substituted alkyl, halo, fluoroalkyl, cyano or nitro. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H, optionally substituted alkyl, halo, cyano, OH or NH2. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H, optionally substituted alkyl, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H, halo, cyano, OH or NH2. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X and Y is independently H or halo. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each X and Y is independently H, halo, OH, or NH2. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each X and Y is independently H, F, or Cl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each X and Y is H.

[0180] In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is independently H, optionally substituted alkyl, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is independently H, optionally substituted alkyl, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is independently H, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is independently H or halo. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is independently H, F or Cl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each X is H.

[0181] In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is independently H, optionally substituted alkyl, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is independently H, optionally substituted alkyl, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is independently H, halo or cyano. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is independently H or halo. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is independently H, F or Cl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, each Y is H.

[0182] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 0 to 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 0 to 1, 0 to 2, 0 to 3, 0 to 4, 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 0, 1, 2, 3, or 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 0 or 1. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 0. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, m is 1.

[0183] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 0 to 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 0 to 1, 0 to 2, 0 to 3, 0 to 4, 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 0, 1, 2, 3, or 4. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 0 or 1. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 0. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, n is 1.

[0184] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, A1 is OH. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, A1 is SH.

[0185] In some embodiments of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A2 is O. In some embodiments of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A2 is S.

[0186] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, A1 is OH and A2 is O.

[0187] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 5 is H, halogen, optionally substituted alkyl, hydroxyl or alkoxy. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 5 is H, unsubstituted alkyl or alkoxy. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 5 For H.

[0188] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 is independently H or optionally substituted alkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 is independently H or unsubstituted alkyl.

[0189] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 is H. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 is an unsubstituted alkyl group.

[0190] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 2 is H. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 2In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 2 is an unsubstituted alkyl group.

[0191] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 For H.

[0192] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form =C(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form an unsubstituted alkenyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form =NR 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form =0. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached they form =S.

[0193] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 and R 2Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form an unsubstituted 3 to 6 membered carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form a cyclopropyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 1 and R 2 Together with the carbon to which they are attached, they form an unsubstituted 4- to 7-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N and S.

[0194] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the compound of Formula (I) or Formula (II) has the structure of Formula (III):

[0195]

[0196] in,

[0197] R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2;

[0198] R 4 is H or optionally substituted alkyl;

[0199] or R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S; or R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0200] Z is H, halo, nitro or -LG;

[0201] L is a bond or an optionally substituted C1-C4 alkylene group;

[0202] G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13、-CON(R 13 )2、-N(R 14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R 14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R 13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 );

[0203] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0204] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0205] Each R 12 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

[0206] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0207] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0208] Each R 14is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0209] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an unsubstituted alkenyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form =NR 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form =0. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached they form =S.

[0210] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an unsubstituted 3 to 6 membered carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R3 and R 4 Together with the carbon to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form a cyclopropyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 and R 4 Together with the carbon to which they are attached, they form an unsubstituted 4- to 7-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N and S.

[0211] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 4 is H. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 4 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 4 is an unsubstituted alkyl group.

[0212] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the compound of Formula (I) or Formula (II) or Formula (III) has the structure of Formula (IV):

[0213]

[0214] in,

[0215] R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11, optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2;

[0216] Z is H, halo, nitro or -LG;

[0217] L is a bond or an optionally substituted C1-C4 alkylene group;

[0218] G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R 14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R 13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 );

[0219] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0220] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0221] Each R 12 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

[0222] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0223] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0224] Each R 14 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0225] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the compound has Formula (IVa):

[0226]

[0227] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the compound has Formula (IVb):

[0228]

[0229] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2.

[0230] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted carbocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted carbocyclylalkyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted heteroarylalkyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted heterocyclic group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-COR 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-CO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-CON(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-CN. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-OR 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 11) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-SO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted (C0-C4 alkylene)-O-SO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an optionally substituted (C0-C4 alkylene)-OP(=O)(OR 11 )2.

[0231] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 or optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11, optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2 or optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 or optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11, optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2 or optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ).

[0232] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-OR 11 or optionally substituted (C0-C4 alkylene)-N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is optionally substituted alkyl, optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-OR 11 or optionally substituted (C0-C4 alkylene)-N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is an unsubstituted alkyl group, -CO2R 11 、-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is an unsubstituted alkyl group, -CO2R 11 、-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-OR 11 or optionally substituted (C0-C4 alkylene)-N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C4 alkylene)-OH, (C0-C4 alkylene)-OMe, (C0-C4 alkylene)-NH2, (C0-C4 alkylene)-NHR 11 、(C0-C4 alkylene)-N(R 11 )2 or (C0-C4 alkylene)-NH-SO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C4 alkylene)-OH, (C0-C4 alkylene)-OMe, (C0-C4 alkylene)-NH2, (C0-C4 alkylene)-NHR 11 or (C0-C4 alkylene)-N(R 11 ) 2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C2 alkylene)-OH, (C0-C2 alkylene)-OMe, (C0-C2 alkylene)-NH2, (C0-C2 alkylene)-NHR 11 、(C0-C2 alkylene)-N(R 11 )2 or (C0-C2 alkylene)-NH-SO2R 11 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C2 alkylene)-OH, (C0-C2 alkylene)-OMe, (C0-C2 alkylene)-NH2, (C0-C2 alkylene)-NHMe, (C0-C2 alkylene)-NMe2 or (C0-C2 alkylene)-NH-SO2Me. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3is (C0-C2 alkylene)-NH-SO2Me. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, R 3 It is -NH-SO2Me.

[0233] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 11 R is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted heteroarylalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 11 are independently unsubstituted or substituted with halogen, -CN, -R b -OR a , -R b -C(O)R a or -R b -S(O) t R a substituted; wherein t is 1 or 2; each R a are independently hydrogen or alkyl optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R b is independently a direct bond or a straight or branched alkylene group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 11 Independently unsubstituted or substituted with -F, -Cl, -CN, -OH, -OMe, -SO2Me or -C(O)Me.

[0234] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, both R 11 The groups are joined to the nitrogen to which they are attached to form an optionally substituted N-heterocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 11 The groups are joined with the nitrogen to which they are attached to form a radical optionally substituted with halogen, oxo, -CN or -R b -OR a In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, two R 11 The groups are joined with the nitrogen to which they are attached to form a radical optionally substituted with halogen, oxo, -CN or -R b -OR a substituted N-heterocyclic group; wherein each R a are independently hydrogen or alkyl optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R bare independently a direct bond or a straight or branched alkylene group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form an N-heterocyclyl group which is unsubstituted or substituted with -F, oxo, -CN, -OH or -OMe. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, the two R 11 The groups are joined to the nitrogen to which they are attached to form an N-heterocyclyl group which is unsubstituted or substituted with -F, -CN, -OH or -OMe. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, the two R 11 The groups are joined with the nitrogen to which they are attached to form an N-heterocyclyl which is unsubstituted or substituted with -CN, -OH or -OMe.

[0235] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, both R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted N-heterocycloalkyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted 4- to 6-membered N-heterocycloalkyl group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted azetidinyl, an unsubstituted or substituted pyrrolidinyl, an unsubstituted or substituted piperidinyl, an unsubstituted or substituted morpholinyl, or an unsubstituted or substituted piperazinyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted azetidinyl, an unsubstituted or substituted pyrrolidinyl, or an unsubstituted or substituted piperidinyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted azetidinyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form a substituted N-heterocycloalkyl. In some embodiments, the N-heterocycloalkyl is replaced by halogen, oxo, -CN or -R b -OR a In some embodiments, the N-heterocycloalkyl group is substituted by halogen, oxo, -CN or -Rb -OR a replaced by; where each R a are independently hydrogen or alkyl optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R b is independently a direct bond or a straight or branched alkylene. In some embodiments, the N-heterocycloalkyl is substituted with -F, oxo, -CN, -OH or -OMe. In some embodiments, the N-heterocycloalkyl is substituted with -F, -CN, -OH or -OMe. In some embodiments, the N-heterocycloalkyl is substituted with -CN, -OH or -OMe.

[0236] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, both R 11 The groups are joined to the nitrogen to which they are attached to form an unsubstituted or substituted azetidinyl group. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, the two R 11 The groups are joined to the nitrogen to which they are attached to form substituted azetidinyl groups. In some embodiments, the azetidinyl group is replaced by halogen, oxo, -CN or -R b -OR a In some embodiments, the azetidinyl group is substituted with halogen, oxo, -CN or -R b -OR a replaced by; where each R a are independently hydrogen or alkyl optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R b Independently a direct bond or a straight or branched alkylene. In some embodiments, the azetidinyl is substituted with -F, oxo, -CN, -OH or -OMe. In some embodiments, the azetidinyl is substituted with -F, -CN, -OH or -OMe. In some embodiments, the azetidinyl is substituted with -CN, -OH or -OMe. In some embodiments, the azetidinyl is substituted with -CN. In some embodiments, the azetidinyl is substituted with -OH. In some embodiments, the azetidinyl is substituted with -OMe.

[0237] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 12 R is independently H, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 12is independently H or unsubstituted alkyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 12 are independently H or unsubstituted C1-C4 alkyl.

[0238] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, R 3 for:

[0239]

[0240]

[0241] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Z is H. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Z is halo. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Z is -F, -Cl, or -Br. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Z is nitro.

[0242] In some embodiments of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is -LG.

[0243] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, L is a bond. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, L is an optionally substituted C1-C4 alkylene. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, L is an optionally substituted C1-C2 alkylene. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, L is an unsubstituted C1-C2 alkylene. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, L is -CH2-.

[0244] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R 13 )2.-OR 13 、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2、-N(R 14 )-SO2R 13 、-N(R 14 )-CON(R 13 )2、-N(R 14 )-CO2R 13 、-O-CON(R 13 )2-、-N(R 14 )-SO2N(R 13 )2、-O-SO2N(R 13 )2、-N(R 14 )-SO2-OR 13 OR-C(=N–OR 14 )(R 13 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -N(R 13 )2.-OR 13 、-CN、-COR 13 、-CO2R 13 、-CON(R 13 )2、-N(R 14 )-COR 13 、-SO2R 13 -、-SO2N(R 13 )2 or -N(R 14 )-SO2R 13 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -N(R 13 )2.-OR 13 、-CON(R 13 )2 or -N(R 14 )-COR 13 .

[0245] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted alkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is unsubstituted alkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted carbocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted carbocyclylalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted heterocyclyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted heterocyclylalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted heteroaryl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is -N(R 13 )2. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is -OR 13 In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is -CN. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is -COR 13 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is -CO2R 13 In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is -N(R 12 )-COR 13 .

[0246] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, G is optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -N(R 13 )2.-OR 13 or -N(R 12 )-COR 13 .

[0247] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 13R is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaryl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 13 is independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

[0248] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 13 Independently unsubstituted or -R b -OR a , -R b -C(O)OR a or -R b -C(O)R a replaced by; where each R a are independently hydrogen, alkyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl; and each R b is independently a direct bond or a straight or branched alkylene group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 13 Independently unsubstituted or substituted with -OH, -OMe, -C(O)CH2OH, -CH2C(O)OH, -C(O)OH, -C(O)-cyclopropyl.

[0249] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, one R 13 is H. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, one R 13 is H and the other R 13 is H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaryl.

[0250] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, one R 13 is an optionally substituted heterocyclic group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, one R 13is an optionally substituted heterocyclic group selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, thienyl, sulfolane (1,1-dioxotetrahydrothienyl), 1-imino-1-oxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or 1-imino-1-oxotetrahydrothiopyranyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, one R 13 is an optionally substituted heterocyclic group selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, one R 13 is an optionally substituted heterocyclic group, which is a fused or spirocyclic bicyclic heterocyclic ring. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, one R 13 is optionally oxo-, imino-, -R b -N(R a 2. -R b -OR a , -R b -C(O)R a , -R b -C(O)OR a or -R b -N(R a )C(O)R a substituted heterocyclic group; wherein each R a are independently hydrogen, alkyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl, or cycloalkyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl; and each R b are independently a direct bond or a straight or branched chain alkylene group.

[0251] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, both R 13 The groups are joined to the nitrogen to which they are attached to form an optionally substituted N-heterocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 13 The groups are joined with the nitrogen to which they are attached to form an unsubstituted or substituted alkyl, optionally substituted heterocyclyl, -R b -OR a , -R b -N(R a 2. -R b -C(O)R a , -R b -CN or -R b -N(R a )C(O)Ra substituted N-heterocyclic group; wherein each R a are independently hydrogen, alkyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl; and each R b are independently a direct bond or a straight or branched alkylene group. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, the two R 13 The groups are joined to the nitrogen to which they are attached to form an N-heterocyclyl which is unsubstituted or substituted with methyl, oxetanyl, morpholinyl, -OMe, -CH2OH, -NH2, -CH2NH2, -C(O)CH2OH, -CN, -CH2CN, -CH2NHC(O)CH2OH.

[0252] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each R 14 R is independently H, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 14 is independently H, unsubstituted alkyl or unsubstituted heterocyclyl. In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, each R 14 For H.

[0253] In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted heterocyclic group. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted monocyclic heterocyclic group, a fused bicyclic heterocyclic group or a spirobicyclic heterocyclic group. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted 4 to 6-membered monocyclic heterocyclic group. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted heterocyclic group selected from morpholinyl, pyrrolidinyl, azetidinyl, piperidinyl, tetrahydropyranyl and oxetane. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted heterocyclic group selected from morpholinyl and pyrrolidinyl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted morpholinyl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is morpholinyl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted pyrrolidinyl. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is an optionally substituted heterocyclic group, which is a fused or spirocyclic bicyclic heterocyclic ring. In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is optionally substituted by alkyl, -R b -CN, heterocyclic group, -R b -N(R a 2. -R b -OR a , -R b -C(O)R a or -R b -N(R a )C(O)R a substituted heterocyclic group; wherein each R a are independently hydrogen or alkyl optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R b In some embodiments of the compounds disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof, G is unsubstituted or substituted with alkyl, optionally substituted heterocyclyl, -R b -OR a , -R b -N(R a 2. -R b -C(O)R a , -R b -CN or -Rb -N(R a )C(O)R a substituted heterocyclic group; wherein each R a are independently hydrogen, alkyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl; and each R b In some embodiments of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or prodrugs, G is a heterocyclyl group which is unsubstituted or substituted with methyl, oxetane, morpholine, -OMe, -CH2OH, -NH2, -CH2NH2, -C(O)CH2OH, -CN, -CH2CN, -CH2NHC(O)CH2OH.

[0254] In some embodiments, G is optionally substituted morpholinyl. In some embodiments, G is unsubstituted morpholinyl.

[0255] In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, Z is:

[0256]

[0257]

[0258] Disclosed herein are non-hydroxamic acid LpxC inhibitors comprising a basic moiety. In some embodiments, the non-hydroxamic acid LpxC inhibitor comprises a basic moiety with a pKa of less than 8. In some embodiments, the non-hydroxamic acid LpxC inhibitor comprises a basic moiety with a pKa of less than 7. In some embodiments, the non-hydroxamic acid LpxC inhibitor comprises a morpholinyl group.

[0259] In some embodiments, the non-hydroxamic acid LpxC inhibitor is a compound of formula (A), or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0260]

[0261] in,

[0262] A is a non-hydroxamic acid zinc-binding moiety;

[0263] R 1 and R 2 Each is independently a group containing 1 to 50 non-hydrogen atoms selected from C, N, O, S, P and halogen;

[0264] or R 1 and R 2 Together with the carbon to which they are attached, they form =C(R11 )2, =NR 11 , =O or =S; or R 1 and R 2 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0265] R 3 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted (C0-C4 alkylene)-COR 11 , optionally substituted (C0-C4 alkylene)-CO2R 11 , optionally substituted (C0-C4 alkylene)-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 11 , optionally substituted (C0-C4 alkylene)-N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-COR 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-CON(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2N(R 11 )2. Optionally substituted (C0-C4 alkylene)-O-SO2N(R 11 )2, optionally substituted (C0-C4 alkylene)-N(R 11 )-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R 11 , optionally substituted (C0-C4 alkylene)-O-SO2R 11 , optionally substituted (C0-C4 alkylene)-N(R 12 )-SO2R 11 , optionally substituted (C0-C4 alkylene)-C(=N-OR 11 )(R 11 ) or optionally substituted (C0-C4 alkylene)-OPO2OR 11 ;

[0266] R 4is H or optionally substituted alkyl;

[0267] or R 3 and R 4 Together with the carbon to which they are attached, they form =C(R 11 )2, =NR 11 , =O or =S;

[0268] or R 3 and R 4 Together with the carbon to which they are attached, they form an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

[0269] Ring B is optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

[0270] W is a bond, -C≡C-, bicyclo[1.1.1]pentylene, -C≡CC≡C-, -CH=CH- or -CH2CH2-;

[0271] Ring C is optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

[0272] Each X and Y is independently H, optionally substituted alkyl, halo, fluoroalkyl, cyano, nitro, -N(R 13 )2OR 13 ;

[0273] Each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0274] or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl;

[0275] Each R 13 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

[0276] or two R on the same nitrogen atom 13 together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; and

[0277] n is 0-4;

[0278] m is 0-4; and

[0279] Z comprises a basic group having a pKa of less than 8.

[0280] In some embodiments, A is A1 is OH or SH; A2 is O or S; and R 5 is H, halogen, optionally substituted alkyl, hydroxy, alkoxy, cyano, amino or nitro. 1 and R 2 Each is independently H or optionally substituted alkyl. In some embodiments, Z comprises a basic moiety with a pKa of less than 7. In some embodiments, Z comprises a morpholinyl group.

[0281] In some embodiments, the non-hydroxamic acid LpxC inhibitor has minimal toxicity. In some embodiments, the non-hydroxamic acid LpxC inhibitor has minimal cardiotoxicity.

[0282] In some embodiments, the heterocyclic LpxC inhibiting compounds described herein have the structures provided in Table 1.

[0283] Table 1

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334] The compounds in Table 1 are named:

[0335] 5-Hydroxy-6-(3-hydroxy-3-methyl-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)pyrimidin-4(3H)-one;

[0336] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0337] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0338] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0339] 6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0340] (R)-6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0341] (S)-6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0342] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0343] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0344] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0345] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0346] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)pyrimidin-4(3H)-one;

[0347] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0348] 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0349] 6-(3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0350] 6-((R)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0351] 6-((S)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0352] 6-(3-amino-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0353] N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0354] (R)-N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0355] (S)-N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0356] N-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0357] 3-(5-Hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-N-methyl-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0358] 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanoic acid methyl ester;

[0359] N-(3,3-difluorocyclobutyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0360] Ethyl 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propanoate;

[0361] 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propanoic acid methyl ester;

[0362] N-(1-cyanoethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

[0363] N-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((2-(hydroxymethyl)-1H-imidazol-1-yl)methyl)phenyl)ethynyl)phenyl)propanamide;

[0364] N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propanamide;

[0365] 5-Hydroxy-6-(3-hydroxy-2-methyl-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0366] 5-hydroxy-6-(3-hydroxy-2-methyl-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0367] 1-(4-((4-((S)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0368] 1-(4-((4-((R)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0369] (3S)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0370] (3S)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0371] (S)-1-(4-((4-((S)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0372] (S)-1-(4-((4-((R)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0373] (3R)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0374] 6-(2-(4-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0375] 6-(2-(4-((4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0376] 6-(2-(4-((4-((((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0377] 6-((R)-2-(4-((4-((((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0378] 6-((S)-2-(4-((4-((((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0379] 6-(2-(4-((4-((((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0380] 6-((R)-2-(4-((4-((((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0381] 6-((S)-2-(4-((4-((((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0382] 6-(2-(4-((4-((5-oxa-2-azaspiro[3.4]octan-2-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0383] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(2-(((S)-tetrahydrofuran-3-yl)amino)ethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0384] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((((R)-1-(2-hydroxyacetyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0385] 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyacetyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0386] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyacetyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0387] 6-(2-(4-((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0388] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0389] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((oxetan-3-ylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0390] Ethyl 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((oxetan-3-ylamino)methyl)phenyl)ethynyl)phenyl)propanoate;

[0391] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((3-morpholinoazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0392] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((tetrahydrofuran-3-yl)methyl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0393] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0394] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0395] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0396] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0397] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-imino-1-oxotetrahydro-1H-16-thiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0398] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((2-methoxyethyl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0399] 6-(2-(4-((4-(((cyclopropylmethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0400] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(4-methylpiperazine-1-carbonyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0401] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-oxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0402] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-((methylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0403] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0404] 6-(2-(4-((4-(aminomethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0405] 6-(2-(4-((4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0406] 6-(2-amino-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0407] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0408] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0409] 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0410] 6-(3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0411] 6-((R)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0412] 6-((S)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0413] 5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0414] (R)-5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0415] (S)-5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0416] 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0417] 6-(3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0418] 6-((R)-3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0419] 6-((S)-3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0420] 6-(3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0421] 6-((R)-3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0422] 6-((S)-3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0423] 1-(4-((4-(1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0424] 1-(4-((4-((R)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0425] 1-(4-((4-((S)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0426] 1-(4-((4-(1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0427] 1-(4-((4-((R)-1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0428] 1-(4-((4-((S)-1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0429] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((2R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0430] 6-((2S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0431] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0432] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0433] 6-((S)3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0434] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((S)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0435] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((S)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0436] 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(((S)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0437] (3R)-1-(4-((4-(1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0438] (3S)-1-(4-((4-(1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0439] (S)-1-(4-((4-((R)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0440] (S)-1-(4-((4-((S)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0441] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((oxetan-3-ylamino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0442] 2-(1-(4-((4-(1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile;

[0443] 2-(1-(4-((4-((R)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile;

[0444] 2-(1-(4-((4-((S)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile;

[0445] 3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0446] (3S)-3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0447] (S)-3-(((S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0448] (S)-3-(((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0449] (3R)-3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0450] (R)-3-(((S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0451] (R)-3-(((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butyronitrile;

[0452] 6-(3-((2-fluoropropyl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0453] 1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

[0454] (R)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

[0455] (S)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

[0456] 6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0457] (R)-6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0458] (S)-6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0459] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0460] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0461] 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0462] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0463] 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0464] 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0465] 6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0466] (R)-6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0467] (S)-6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0468] 6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0469] (R)-6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0470] (S)-6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0471] 6-(3-(Cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0472] (R)-6-(3-(cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0473] (S)-6-(3-(cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0474] (4S)-3-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

[0475] (S)-3-((S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

[0476] (S)-3-((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

[0477] (3S)-1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0478] 6-(2-(4-((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0479] 6-(3-((2-chloropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0480] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-(oxetan-3-yl)azetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0481] 6-(2-(4-((4-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0482] 5-hydroxy-6-(3-((2-(methylsulfonyl)ethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0483] 5-Hydroxy-6-(3-((2-hydroxyethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0484] 3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)propionitrile;

[0485] 6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)-5-hydroxypyrimidin-4(3H)-one;

[0486] 6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0487] 6-((R)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0488] 6-((S)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0489] 3-((2-(4-((4-((3-(cyanomethyl)azetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propyl)amino)propionitrile;

[0490] 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0491] 6-((2R)-3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0492] 6-((2S)-3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0493] 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(2-morpholinoethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0494] 6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0495] (R)-6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0496] (S)-6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0497] 6-(2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0498] 6-((2R)-2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0499] 6-((2S)-2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0500] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidin-4(3H)-one;

[0501] 5-hydroxy-6-(3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0502] 6-(2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0503] 6-((R)-2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0504] 6-((S)-2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0505] 6-(2-(4-((4-(((R)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0506] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-imino-1-oxohexahydro-116-thiopyran-4-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0507] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((1S,3R)-1-imino-1-oxotetrahydro-1H-16-thiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0508] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((1R,3S)-1-imino-1-oxotetrahydro-1H-16-thiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0509] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0510] 6-(2-(4-((4-((((R)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0511] 2-Hydroxy-N-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)-N-((R)-pyrrolidin-3-yl)acetamide;

[0512] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((((R)-1-(2-hydroxyethyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0513] 2-((3R)-3-((4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)amino)pyrrolidin-1-yl)acetic acid;

[0514] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0515] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0516] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0517] 2-Hydroxy-N-(((2S)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidin-2-yl)methyl)acetamide;

[0518] 6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0519] (R)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0520] (S)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0521] 5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3H)-one;

[0522] 5-hydroxy-6-((R)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3H)-one;

[0523] 5-hydroxy-6-((S)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3H)-one;

[0524] 5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0525] (R)-5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0526] (S)-5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0527] 5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((S)-tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3H)-one;

[0528] 5-hydroxy-6-(3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0529] 5-hydroxy-6-((R)-3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0530] 5-hydroxy-6-((S)-3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0531] 5-hydroxy-6-(3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0532] 5-hydroxy-6-((R)-3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0533] 5-hydroxy-6-((S)-3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0534] 6-(2-((3-chloropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0535] 6-(2-amino-2-(4-((4-(((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0536] 6-(2-amino-2-(4-((4-((4-methoxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0537] (R)-5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0538] (S)-5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0539] 6-(3-(azetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0540] 6-(2-(4-((4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0541] 6-((2R)-2-(4-((4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0542] 6-((2S)-2-(4-((4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0543] 6-(3-(((S)-1-acetylpyrrolidin-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0544] 6-((R)-3-(((S)-1-acetylpyrrolidin-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0545] 6-((S)-3-(((S)-1-acetylpyrrolidin-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0546] 6-(3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0547] 6-((R)-3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0548] 6-((S)-3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0549] 6-(3-(((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0550] 6-((R)-3-(((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0551] 6-((S)-3-(((R)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0552] 6-(3-(((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0553] 6-((R)-3-(((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0554] 6-((S)-3-(((S)-1,1-dioxotetrahydrothiophen-3-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0555] 5-Hydroxy-6-(3-methoxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0556] N-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(6-((4-(morpholinomethyl)phenyl)ethynyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)propanamide;

[0557] 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(6-((4-(morpholinomethyl)phenyl)ethynyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)propanoic acid methyl ester;

[0558] 2-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-6-((4-(morpholinomethyl)phenyl)ethynyl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one;

[0559] 5-hydroxy-6-(3-hydroxy-2-(4-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0560] 5-Hydroxy-6-(3-hydroxy-2-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0561] 5-Hydroxy-6-(3-hydroxy-2-(5-((4-(morpholinomethyl)phenyl)ethynyl)pyridin-2-yl)propyl)pyrimidin-4(3H)-one;

[0562] 5-Hydroxy-6-(3-hydroxy-2-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0563] 5-hydroxy-6-(3-hydroxy-2-(4-((E)-4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenylvinyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0564] 6-(3-((2-fluoroethyl)amino)-2-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0565] 6-(2-amino-2-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0566] 5-hydroxy-6-(3-hydroxy-2-(4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0567] 5-hydroxy-6-(3-hydroxy-2-(4-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0568] 2-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-6-(4-(2-morpholinoethyl)phenyl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one;

[0569] 5-Hydroxy-6-((S)-3-hydroxy-2-(4-((trans-4-(morpholinomethyl)cyclohexyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0570] 5-Hydroxy-6-((R)-3-hydroxy-2-(4-((trans-4-(morpholinomethyl)cyclohexyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0571] 6-(3-((2-fluoroethyl)amino)-2-(4-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0572] 6-(3-((2-fluoroethyl)amino)-2-(4-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0573] 6-(3-((2-fluoroethyl)amino)-2-(4-(imidazo[1,5-a]pyridin-7-ylethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0574] 6-(3-((2-fluoroethyl)amino)-2-(4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0575] 5-Hydroxy-6-((5-((4-(morpholinomethyl)phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)methyl)pyrimidin-4(3H)-one;

[0576] 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-6-((4-(morpholinomethyl)phenyl)ethynyl)isoindolin-1-one;

[0577] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)-2-oxopyridin-1(2H)-yl)propyl)pyrimidin-4(3H)-one;

[0578] 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(6-(4-(2-morpholinoethyl)phenyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)propanoic acid;

[0579] 6-(2-([1,1'-biphenyl]-4-yl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one; 6-(2-amino-2-(4'-(2-morpholinoethyl)-[1,1'-biphenyl]-4-yl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

[0580] 6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0581] (R)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0582] (S)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0583] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0584] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0585] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0586] (S)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

[0587] (R)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

[0588] 6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0589] (R)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0590] (S)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0591] 6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0592] (R)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0593] (S)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0594] 6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0595] (R)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0596] (S)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0597] 6-(3-(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0598] (R)-6-(3-(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0599] (S)-6-(3-(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0600] 6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidin-4(3H)-one;

[0601] (R)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidin-4(3H)-one;

[0602] (S)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidin-4(3H)-one;

[0603] 5-hydroxy-6-(3-(3-hydroxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0604] (R)-5-hydroxy-6-(3-(3-hydroxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0605] (S)-5-hydroxy-6-(3-(3-hydroxyazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0606] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0607] (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0608] (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0609] 6-(2-(4-((4-((((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0610] 6-((R)-2-(4-((4-((((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0611] 6-((S)-2-(4-((4-((((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0612] (S)-1-(4-((4-((R)-1-(3-cyanoazetidin-1-yl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0613] (S)-1-(4-((4-((S)-1-(3-cyanoazetidin-1-yl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0614] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0615] (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0616] (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0617] 6-(2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0618] 6-((R)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0619] 6-((S)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0620] 6-(2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0621] 6-((2R)-2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0622] 6-((2S)-2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0623] 2-Hydroxy-N-(1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide;

[0624] (R)-2-hydroxy-N-(1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide;

[0625] (S)-2-hydroxy-N-(1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide;

[0626] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0627] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0628] 6-(3-((1-fluoro-3-hydroxypropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0629] 5-hydroxy-6-((S)-3-(((S)-2-hydroxypropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0630] 5-hydroxy-6-((R)-3-(((S)-2-hydroxypropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0631] 5-Hydroxy-6-((R)-3-(((R)-2-hydroxypropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0632] 5-Hydroxy-6-((S)-3-(((R)-2-hydroxypropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0633] 6-(3-((2-fluoro-3-hydroxypropyl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0634] (R)-5-hydroxy-6-(2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((1-methylcyclopropyl)amino)propyl)pyrimidin-4(3H)-one;

[0635] (S)-5-hydroxy-6-(2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((1-methylcyclopropyl)amino)propyl)pyrimidin-4(3H)-one;

[0636] 6-(2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0637] 6-((2R)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0638] 6-((2S)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0639] 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-((((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0640] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-((((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0641] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0642] N-((3R)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidin-3-yl)cyclopropanecarboxamide;

[0643] 2-Hydroxy-N-((3R)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidin-3-yl)acetamide;

[0644] 6-(2-(4-((4-((2-(aminomethyl)morpholino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0645] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((piperidin-4-ylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0646] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((methyl((R)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0647] 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-1-methylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0648] 6-(2-(4-((4-((((R)-1-glycylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0649] 6-(2-(4-((1-glycylpiperidin-4-yl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0650] 5-Hydroxy-6-(3-hydroxy-2-(4-((1-(2-hydroxyacetyl)piperidin-4-yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0651] 5-hydroxy-6-(2-(methylamino)-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)pyrimidin-4(3H)-one;

[0652] 5-Hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0653] (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0654] (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0655] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((R)-2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0656] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0657] 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0658] 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0659] 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0660] 6-(2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0661] 6-((2S)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0662] 6-((2R)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0663] 6-(2-hydroxy-2-(4-((4-(((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)pyrimidine-4,5-diol;

[0664] N-(1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide;

[0665] (R)-N-(1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide;

[0666] (S)-N-(1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide;

[0667] 6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0668] (S)-6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0669] (R)-6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0670] (3R)-1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0671] 6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0672] (S)-6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0673] (R)-6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0674] 6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0675] (S)-6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0676] (R)-6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0677] 6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0678] (S)-6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0679] (R)-6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0680] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0681] (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0682] (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0683] 1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0684] (S)-1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0685] (R)-1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

[0686] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0687] 6-((R)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0688] 6-((S)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0689] (R)-1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0690] (R)-1-(4-((4-((S)-1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0691] (R)-1-(4-((4-((R)-1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

[0692] 6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0693] (S)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0694] (R)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0695] 6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0696] (S)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0697] (R)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0698] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2-hydroxypropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0699] 6-((S)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2-hydroxypropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0700] 6-((R)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2-hydroxypropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0701] 5-hydroxy-6-(3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0702] 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0703] 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0704] 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate;

[0705] (S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate;

[0706] (R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate;

[0707] 5-hydroxy-6-(3-methoxy-2-(4-((4-((((S)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0708] 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((S)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0709] 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((S)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0710] 5-hydroxy-6-(3-methoxy-2-(4-((4-((((R)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0711] 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((R)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0712] 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((R)-pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0713] N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0714] (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0715] (S)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0716] N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0717] (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0718] (S)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0719] N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0720] N-((R)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0721] N-((S)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0722] 6-(2-(4-((4-(((R)-3-aminopyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0723] 6-(2-(4-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

[0724] 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(2-morpholinoethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0725] N-(1-([1,1'-biphenyl]-4-yl)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)ethyl)methanesulfonamide;

[0726] (R)-N-(1-([1,1'-biphenyl]-4-yl)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)ethyl)methanesulfonamide;

[0727] (S)-N-(1-([1,1'-biphenyl]-4-yl)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)ethyl)methanesulfonamide;

[0728] N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0729] (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0730] (S)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

[0731] 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0732] (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0733] (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0734] 6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0735] (R)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0736] (S)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0737] 6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0738] (S)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0739] (R)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

[0740] 1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin-3-yl acetate;

[0741] (S)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin-3-yl acetate;

[0742] (R)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin-3-yl acetate;

[0743] N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide;

[0744] (S)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide;

[0745] (R)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide;

[0746] N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide;

[0747] (S)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide;

[0748] (R)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide;

[0749] 5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

[0750] (S)-5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; and

[0751] (R)-5-Hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one.

[0752] Preparation of compounds

[0753] The compounds used in the chemical reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” were obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

[0754] Suitable reference books and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein, or providing references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; T L Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry", 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes.

[0755] Alternatively, specific and similar reactants are identified by the known chemicals and reactions index compiled by the Chemical Abstract Service of the American Chemical Society, which is available from most public and university libraries and through online databases (contact the American Chemical Society, Washington, DC for more details). Known but not commercially available chemicals in the catalog are optionally prepared by custom chemical synthesis houses, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the heterocyclic LpxC inhibitory compounds described herein is P.H. Stahl and C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0756] Pharmaceutical composition

[0757] In certain embodiments, the heterocyclic LpxC inhibitory compounds described herein are administered as the pure chemical. In other embodiments, the heterocyclic LpxC inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0758] Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitory compound described herein, or a stereoisomer, a pharmaceutically acceptable salt or an N-oxide thereof, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject or patient) of the composition.

[0759] One embodiment provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

[0760] In certain embodiments, the heterocyclic LpxC inhibitory compounds disclosed herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products produced in one or more steps of the synthetic methods.

[0761] Suitable oral dosage forms include, for example, tablets, pills, capsules, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that is easily soluble in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition. Mack Pub. Co., Easton, PA (2005)).

[0762] The dosage of the composition comprising at least one heterocyclic LpxC inhibitory compound described herein will vary depending on the patient's condition, ie, disease stage, general health, age, and other factors.

[0763] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Appropriate dosage and suitable duration and frequency of administration will depend on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, appropriate dosage and treatment regimen provide compositions in an amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical results) or alleviate the severity of symptoms. Typically, experimental models and / or clinical trials are used to determine the optimal dose. The optimal dose depends on the patient's body mass, body weight or blood volume.

[0764] Oral dosages are generally in the range of about 1.0 mg to about 1000 mg, one to four times a day or more.

[0765] LpxC, lipid A, and Gram-negative bacteria

[0766] Metalloproteins affect a wide variety of biological systems, biological processes, and diseases. For example, for Gram-negative bacteria, UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) is an important enzyme involved in the first critical step of lipid A biosynthesis. Lipid A is an important component of the outer membrane of Gram-negative bacteria. LpxC is a zinc (II)-dependent metalloenzyme with two histidine and aspartic acid residues that bind to zinc (II) ions. The structure of LpxC shows that the zinc (II) ion is bound to two water molecules, both of which are involved in the mechanism of the enzyme. LpxC is highly conserved among Gram-negative bacterial strains, which makes LpxC an attractive target for the treatment of Gram-negative infections.

[0767] In recent years, resistance and multidrug-resistant strains of bacteria have increased. Therefore, new antibiotics are needed, especially antibiotics with new mechanisms of action. There is still a need for metalloprotein modulators of LpxC that are useful in the fields of therapy, diagnosis and research.

[0768] One embodiment provides a method of inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase comprising contacting the enzyme with a compound disclosed herein.

[0769] One embodiment provided herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

[0770] Treatment

[0771] Disclosed herein is a method for treating a disease, wherein inhibition of bacterial growth is shown. Such diseases include gram-negative bacterial infections. In some embodiments, the method for treating a gram-negative bacterial infection in a patient in need includes administering to the patient a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient. In some embodiments, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intraperitoneal infection, skin infection and urinary tract infection. In some embodiments, the gram-negative bacterial infection is urinary tract infection (UTI), hospital-acquired / ventilator-associated pneumonia (HAP / VAP) or intraperitoneal infection (IAI). In some embodiments, the gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urinary tract infection and kidney infection. In some embodiments, the compound described herein is used to treat chronic urinary tract infection. In some embodiments, the compound described herein is used to treat complicated urinary tract infection. In other embodiments, the compounds described herein are used to treat complicated intra-abdominal infections. In some embodiments, the compounds described herein are used to treat chronic intra-abdominal infections. In other embodiments, the compounds described herein are used to treat hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). In some embodiments, the administration is used to treat existing infections. In some embodiments, the administration is provided as prevention.

[0772] In some embodiments, the heterocyclic LpxC inhibitory compounds described herein are used to treat conditions caused by bacterial production of endotoxins, particularly those caused by Gram-negative bacteria and bacteria that use LpxC in lipopolysaccharide (LPS) or endotoxin biosynthesis. In some embodiments, a method for treating a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof and a pharmaceutically acceptable excipient. In another embodiment, the heterocyclic LpxC inhibitory compounds described herein can be used to treat conditions caused or aggravated by bacterial production of lipid A and LPS or endotoxins, such as sepsis, septic shock, systemic inflammation, local inflammation, chronic obstructive pulmonary disease (COPD), and acute exacerbation of chronic bronchitis (AECB). In some embodiments, a method of treating a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient, wherein the condition caused by endotoxin or LPS is selected from sepsis, septic shock, systemic inflammation, local inflammation, chronic obstructive pulmonary disease (COPD), and acute exacerbation of chronic bronchitis (AECB).

[0773] In other embodiments, the compounds of the present disclosure can be used to treat severe or chronic respiratory tract infections or complicated urinary tract infections, including severe lung infections and nosocomial infections, such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Staphylococcus aureus, Shigella sonnei, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providenciasluarlii, and Citrobacter freundi, Haemophilus influenzae, Kluyvera species, Legionella species, Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella species, Burkholderia species) and Proteus species,and infections caused by other bacterial species such as Neisseria species, Shigella species, Salmonella species, Helicobaclerpylori, Vibrionaceae and Bordetella species, as well as infections caused by Brucella species, Francisella tularensis and / or Yersinia pestis.

[0774] In one embodiment, provided herein is a method of treating a Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0775] One embodiment provides a method wherein the Gram-negative bacterial infection is selected from the group consisting of pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection, and urinary tract infection.

[0776] One embodiment provides a method wherein the Gram-negative bacterial infection is selected from the group consisting of chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urethral infection, and kidney infection.

[0777] One embodiment provides a method wherein the Gram-negative bacterial infection is a chronic urinary tract infection. One embodiment provides a method wherein the Gram-negative bacterial infection is a complicated urinary tract infection. One embodiment provides a method wherein the administration is for the treatment of an existing infection. One embodiment provides a method wherein the administration is provided as prophylaxis.

[0778] One embodiment provides a method of treating a Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0779] In one embodiment, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection and urinary tract infection. In other embodiments, the gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urethral infection and kidney infection.

[0780] In one embodiment, the gram-negative bacterial infection is a chronic urinary tract infection. In another embodiment, the gram-negative bacterial infection is a complicated urinary tract infection. In one embodiment, the administration is for the treatment of an existing infection. In another embodiment, the administration is provided as prevention.

[0781] In other embodiments, the compounds of the present disclosure are inactive against Gram-positive bacteria. In some embodiments, the compounds of the present disclosure are inactive against Staphylococcus aureus.

[0782] Other embodiments and uses will be apparent to those skilled in the art from this disclosure.The following examples are provided merely to illustrate various embodiments and should not be construed as limiting the invention in any way.

[0783] Example

[0784] I. Chemical Synthesis

[0785] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations that were sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ), and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0786] The following abbreviations and terms have the indicated meanings throughout the text:

[0787] AcOH = acetic acid

[0788] B2pin2=Bis(pinacol)diboron

[0789] Boc=tert-butyloxycarbonyl

[0790] DCC = dicyclohexylcarbodiimide

[0791] DIEA=N,N-diisopropylethylamine

[0792] DMAP = 4-dimethylaminopyridine

[0793] EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0794] eq = equivalent

[0795] Et=ethyl

[0796] EtOAc or EA = ethyl acetate

[0797] EtOH = ethanol

[0798] g = grams

[0799] h or hr = hours

[0800] HBTU = O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0801] HOBt = Hydroxybenzotriazole

[0802] HPLC = High Pressure Liquid Chromatography

[0803] kg or Kg = kilogram

[0804] L or l = liter

[0805] LC / MS = LCMS = Liquid Chromatography-Mass Spectrometry

[0806] LRMS = Low Resolution Mass Spectrometry

[0807] m / z = mass-to-charge ratio

[0808] Me = methyl

[0809] MeOH = methanol

[0810] mg = milligrams

[0811] min = minutes

[0812] mL = milliliters

[0813] mmol = millimole

[0814] NaOAc = Sodium acetate

[0815] PE = Petroleum Ether

[0816] Ph = Phenyl

[0817] Prep=Preparation

[0818] quant.=quantitative

[0819] RP-HPLC = Reverse Phase High Pressure Liquid Chromatography

[0820] rt or RT = room temperature

[0821] THF = Tetrahydrofuran

[0822] UV = Ultraviolet

[0823] Example 1: Synthesis of 6-(3-(((S)-1-fluoropropane-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one (Compound 68)

[0824]

[0825] Step 1: Synthesis of 4,5-bis(benzyloxy)-6-(iodomethyl)pyrimidine

[0826]

[0827] To a solution of 1 (35 g, 0.107 mmol) in DMF (350 mL) was added tributyl vinyl tin (37.4 g, 0.0117 mol) and purged with nitrogen for 10 min. PdCl2(PPh3)4 (7.5 g, 0.010 mol) was added to the reaction mixture and heated to 100 ° C for 6 h. After the reaction was completed, the reaction mixture was cooled, diluted with water, and extracted with EtOAc (2*750 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to give pure 1a as a colorless liquid. Yield: 23 g, 76%

[0828] A solution of 1a (23 g, 0.072 mol) in DCM: MeOH (500 mL) was cooled to -78 ° C and treated with ozone for 30 min. After the reaction was completed, the reaction mixture was bubbled with oxygen for 10 min. Dimethyl sulfide (12 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was warmed to -30 ° C, and sodium borohydride (5.34 g, 0.144 mol) was carefully added in batches and stirred for 10 min. The solvent was removed, and the reaction mixture was dissolved in dichloromethane, washed with water (100 mL) and brine solution, dried over Na2SO4, filtered and concentrated to give 2 as an off-white solid. Yield: 16 g, 69.5%. LC_MS=calculated for C19H18N2O3 322.36, found=323.2 To a solution of 2 (4 g, 0.0124 mol) in DCM (40 mL) cooled at 0°C was added triethylamine (2.5 g, 0.0248 mol), followed by methanesulfonyl chloride (2.1 g, 0.0186 mol). After completion of the reaction, the reaction mixture was washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4.96 g of crude product.

[0829] The crude product (4.96 g, 0.0124 mol) was dissolved in acetone (50 mL) and cooled to 0 ° C. NaI (3.7 g, 0.0248 mol) was added thereto and stirred at 0 ° C for 30 min. After the reaction was completed, the reaction mixture was dissolved in water and extracted with DCM. The organic layer was washed with saline solution and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3 as a light yellow solid. Yield: 4.0 g, 74.7%. LCMS = calculated for C19H17IN2O2 is 432.26, found = 433.1.

[0830] Step 2: Synthesis of (R)-3-(5,6-bis(benzyloxy)pyrimidin-4-yl)-2-(4-iodophenyl)propan-1-ol

[0831]

[0832] To a solution of 1 (1.7 g, 9.5 mmol) in toluene (20 mL) was added 4-iodophenylacetic acid (5 g, 19.1 mmol) and Et3N (5.34 mL, 38.3 mmol), and the reaction mixture was heated at 80°C. To the hot reaction mixture was added a solution of pivaloyl chloride (2.31 g, 19.1 mmol) in toluene (5 mL), and heated to 110°C for 2 h. After the reaction was complete, the reaction mixture was diluted with EtOAc and washed with 10% NaHCO3, water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, 15-20% EtOAc in petroleum ether) to give 2. Yield: 2.1 g, 77%.

[0833] LC_MS = Calculated for C18H16INO3 421.23, Found = unionized mass.

[0834] A solution of 2 (2.0 g, 4.74 mmol) in THF (20 mL) was cooled to -78 ° C. NaHMDS (1 M in THF, 4.74 mL, 4.74 mmol) was slowly added to the cooled reaction mixture, followed by 4,5-bis(benzyloxy)-6-(iodomethyl)pyrimidine (2.05 g, 4.74 mmol), and the reaction mixture was stirred for 1 h. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl. The layers were separated, the organic layer was washed with brine solution and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, 15-20% EtOAc in petroleum ether) to give 3. Yield: 1.8 g, 52.3%. LC_MS = calculated for C37H32IN3O5 is 725.58, found = 726.1.

[0835] A solution of 3 (1.8 g, 2.48 mmol) in ether (10 mL) and EtOH (20 mL) was cooled to 0 ° C, LiBH4 (2M in THF, 12.4 mL, 12.4 mmol) was added and stirred for 30 min. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution and diluted with water. The reaction mixture was extracted with EtOAc (150 mL * 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, 15-20% EtOAc in petroleum ether) to obtain 4 as an off-white solid. Yield: 0.9 g, 66.6%. LC_MS = calculated for C27H25IN2O3 is 552.41, and found = 553.1.

[0836] Step 3: Synthesis of 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one

[0837]

[0838] To a solution of 1 (120 g, 0.21 mol) in DCM (2.5 L) was added Dess-Martin periodinane (92 g, 0.434 mol) in portions at 0°C for 20 min and the reaction mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was filtered over a Celite bed and the bed was washed with DCM. The filtrate was washed with 10% NaHCO3, water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was passed through silica gel (230-400 mesh, 15-20% EtOAc in petroleum ether) to give 2. Yield: (85 g, 66% pure). LC_MS = Calculated for C27H23IN2O3 550.40, found = 551.0

[0839] To 2 (85g, 0.154mol) and (S) -1- fluoropropane -2- amine hydrochloride (21g, 0.185mol) in MeOH (800mL) solution, add AcOH (5mL) and stir reaction mass 12h. Then add MP-CNBH resin (loading 2.45mmol / g, 64.1g, 0.154mol), and stir reaction mass 1h. After reaction was completed, resin was filtered and washed with 10%MeOH (200mL) in DCM, and filtrate was concentrated. The crude material obtained was dissolved in DCM, and washed with 10%NaHCO and saline solution. The organic layer is through Na SO Drying, filtered, and concentrated under reduced pressure to crude product.

[0840] To a solution of the above crude product (65 g, 0.00116 mol) in THF (700 mL) under N2 was added Et3N (21.4 g, 0.212 mol) and di-tert-butyl carbonate (46.3 g, 0.212 mol) and stirred at 25°C for 12 h. After the reaction was complete, the reaction mixture was dissolved in water and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (230-400 mesh, 15-50% EtOAc in petroleum ether) to give a racemic mixture 3, which was separated by chiral SFC purification to give 4a and 4b.

[0841] Yield: (42 g, 58%). 4a: Isomer-I: 17 g. 4b: Isomer-II: 17 g. LC_MS = Calculated for C30H31FIN3O2: 711.62, Found = 712.2

[0842] 4N HCl (200 mL) in 1,4-dioxane was added to a solution of 4b (17 g, 0.023 mol) in DCM (200 mL), and the reaction mixture was stirred at 25 ° C for 14 h. The reaction mixture was then concentrated under reduced pressure. The crude product was dissolved in water, neutralized with 10% NaHCO3, and extracted with EtOAC (500 mLx2). The combined organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure.

[0843] The obtained compound was dissolved in DCM (100 mL), BCl3 (1M in DCM, 100 mL) was added thereto, and the reaction mixture was stirred at 25 ° C for 2 h. After the reaction was completed, the reaction mixture was carefully quenched and stirred with MeOH (100 mL). After 10 min, the reaction mixture was concentrated under reduced pressure. The crude product was ground with DCM, the solid was filtered, and dried to give pure 5 as a white solid. Yield: (10.5 g, 94%). LC_MS = calculated for C16H19FIN3O2 is 431.25, found = 432.1.

[0844] To a solution of 5 (10.5 g, 0.024 mol), 1-(4-ethynylbenzyl)-3-methoxyazetidine (9.79 g, 0.048 mol) in DMF (60 mL) was added Et3N (33.9 mL, 0.243 mol), and the reaction mixture was degassed under nitrogen for 10 min. PdCl2(PPh3)2 (0.34 g, 0.00048 mol), CuI (0.27 g, 0.0014 mol) were then added, and the reaction mixture was stirred at 25°C for 30 min. After the reaction was complete, the reaction mixture was filtered over a celite bed, and the bed was washed with excess EtOAc. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC [YMC-ACTUS-TRIART C18 (250X30) mm, 5 μm; using ACN / water (A) and 0.1% HCOOH (B) flow rate = 20 mL / min, λ = 210 nm; using a step gradient of 8% to 20% (B) at 0-15 min, 100% at 16 min; t R =14.7 min), the fractions were lyophilized to give the pure title compound as an off-white solid. Yield: (4.8 g, 39.3%). LC MS = Calculated for C29H33FN4O3 504.61, found = 505.3.

[0845] The compounds described herein were prepared following organic syntheses analogous to those in Example 1, as well as other techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. LC-MS data for each compound are shown in Table 1.

[0846] II. Biological Evaluation

[0847] Example 1: In vitro assays for screening compounds and metalloprotein modulators

[0848] Bacterial susceptibility testing

[0849] Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Briefly, the biological suspension was adjusted to a 0.5 McFarland standard to yield 3 x 10 5 Up to 7x 10 5 The final inoculum of colony forming units (CFU) / mL.Drug dilutions and inoculum were prepared in sterile, cation-regulated Mueller-Hinton Broth (BecktonDickinson). An inoculum volume of 100 μL was added to a well containing 100 μL liquid culture medium containing 2 times of serial dilution of the drug. All inoculated microdilution plates were incubated at 35 °C for 18-24h in ambient air. After incubation, the lowest drug concentration that prevented visible growth (OD600 nm<0.05) was recorded as MIC. According to the CLSI guidelines, the performance of the test was monitored by using laboratory quality control strains and levofloxacin (a compound with a determined MIC spectrum).

[0850] Table 2 provides exemplary in vitro assay data for compounds according to embodiments of the present disclosure against selected bacteria.

[0851] Table 2

[0852]

[0853]

[0854]

[0855]

[0856] Note: Microbiological activity data are given within the following ranges:

[0857] A: ≤1μg / mL C: >8.0μg / mL to ≤32μg / mL

[0858] B: >1 μg / mL to ≤8.0 μg / mL D: >32 μg / mL LpxC binding assay

[0859] The IC against E. coli LpxC was determined using the Raipid FireMS assay as previously described in J. Med. Chem. 2012, 55, 1662-1670. 50 value.

[0860] Table 3. Exemplary in vitro assay data for compounds of embodiments of the present disclosure against E. coli LpxC.

[0861] Table 3

[0862]

[0863]

[0864] Note: IC 50 Data are given in the following ranges:

[0865] A: ≤10nM C: >50nM to ≤100nM

[0866] B: >10nM to ≤50nM D: >100nM to 1μM III. Preparation of pharmaceutical dosage forms

[0867] Example 1 : Oral capsule

[0868] The active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof. Capsules for oral administration are prepared by mixing 1-1000 mg of the active ingredient with starch or other suitable powder blends. The mixture is introduced into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV): in, R 3 is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C4 alkylene)-OH, (C0-C4 alkylene)-OMe, (C0-C4 alkylene)-NH2, (C0-C4 alkylene)-NHR 11 or (C0-C4 alkylene)-N(R 11 )2; Z is -LG; L is a bond or an unsubstituted C1-C2 alkylene group; G is an optionally substituted 4- to 6-membered monocyclic heterocyclyl, wherein G is optionally substituted with methyl, oxetanyl, morpholinyl, -OMe, -CH2OH, -NH2, -CH2NH2, -C(O)CH2OH, -CN, -CH2CN, or -CH2NHC(O)CH2OH; Each R 11 is independently H, alkyl, carbocyclyl, heterocyclyl or heteroarylalkyl, wherein each R 11 independently unsubstituted or substituted by -F, -Cl, -CN, -OH, -OMe, -SO2Me or -C(O)Me, wherein the heterocyclyl is a C2-C ... 12 Heterocyclic group; or two R on the same nitrogen atom 11 together with the nitrogen to which they are attached form an N-heterocyclyl, which is optionally substituted with -F, oxo, -CN, -OH or -OMe; in: Each alkyl group is a C1-C4 alkyl group; each carbocyclyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Each N-heterocyclic group is a C2-C 12 Heterocyclyl, wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom; each heteroaryl is a monocyclic heteroaryl selected from furanyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and Each heteroarylalkyl is -(C1-C2alkylene)-heteroaryl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (IVa) or Formula (IVb):

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 3 is (C0-C4 alkylene)-N(R 11 )2.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Two R's 11 The groups are joined with the nitrogen to which they are attached to form an N-heterocyclyl optionally substituted with -OH, -CN or -OMe.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: L is an unsubstituted C1-C2 alkylene group.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein: L is a C1-C2 alkylene group; G is morpholinyl or pyrrolidinyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: G is a morpholinyl group.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Two R's 11 The groups are joined with the nitrogen to which they are attached to form an azetidinyl group optionally substituted with -OH, -CN or -OMe.

9. A compound selected from the following, or a pharmaceutically acceptable salt thereof as well as 10. A compound selected from the following, or a pharmaceutically acceptable salt thereof: as well as 11. A compound selected from the following, or a pharmaceutically acceptable salt thereof: as well as 12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Gram-negative bacterial infection in a patient in need thereof.

14. The use according to claim 13, wherein the Gram-negative bacterial infection is selected from pneumonia, sepsis, intra-abdominal infection, skin infection and urinary tract infection.

15. The use according to claim 13, wherein the Gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urethral infection and kidney infection.

16. The use according to any one of claims 13 to 15, wherein the Gram-negative bacterial infection is a chronic urinary tract infection.

17. The use according to any one of claims 13 to 15, wherein the Gram-negative bacterial infection is a complicated urinary tract infection.

Images