EA045324B1 - ANTIBACTERIAL COMPOUNDS - Google Patents

Description

Related applications

This application claims benefit from U.S. Provisional Patent Application No. 62/734,173, filed September 20, 2018, and U.S. Provisional Patent Application No. 62/767,313, filed November 14, 2018, each of which is incorporated herein by reference throughout. its completeness.

BACKGROUND OF THE INVENTION

There is a need in the medical field for effective treatment of disease caused by bacterial infection.

Summary of the present invention

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions containing these compounds that are useful in inhibiting the growth of Gram-negative bacteria. In addition, these compounds and compositions are useful for the treatment of bacterial infection such as urinary tract infection and the like.

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

in which n is 0-4; m is 0-4;

A1 is OH or SH; A ₂ represents O or S;

each of R ¹ and R ² independently represents H or optionally substituted alkyl;

or R ¹ and R ² taken together with the carbon to which they are attached form =C(R11) ₂ , =NR11, =O or =S;

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

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0-C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C 4 alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ - C ₄ alkylene)-OR ¹¹ , optionally substituted (Co-C4alkylene)-N(R ¹¹ )2, optionally substituted ( _C0 - _C4 alkylene)-N(R ¹² )-COR ¹¹ , optionally substituted (C0-C4alkylene) -N(R ¹² )-CO2R ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CON(R ¹¹ )2, optionally substituted ( _C0 - _C4 alkylene)-N(R ¹² )-SO2N( R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ )2, optionally substituted (C0-C4 alkylene)-N(R11)-PO(optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-N(R ¹² )-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-O-SO ₂ R ¹¹ , optionally substituted ( C0-C4alkylene)-C(=NOR ¹¹ )(R ¹¹ ) or optionally substituted (C0-C ₄ alkylene)-OR(=O)(OR ¹¹ ) ₂ ,

R ⁴ represents H or optionally substituted alkyl;

or R ³ and R ⁴ taken together with the carbon to which they are attached form =C(R11) ₂ , =NR11, =O or =S;

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

R ⁵ represents H, halogen, optionally substituted alkyl, hydroxyl, alkoxy, cyano, amino or nitro;

ring B is aryl, carbocyclyl, heteroaryl or heterocyclyl;

W represents a bond, -C=C-, bicyclo[1.1.1]pentanylene, -C=C-C=C-, -CH=CH- or -CH ₂ CH ₂ ; ring C is aryl, carbocyclyl, heteroaryl or heterocyclyl;

each X and Y independently represents H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, nitro, -N(R ¹³ ) ₂ or -OR ¹³ ;

or R ³ and one X, taken together with intermediate atoms, form an optionally substituted 5-7 membered carbocyclyl or an optionally substituted 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

Z represents H, halogen, nitro or -L-G;

L represents a bond or optionally substituted C1- _C4 alkylene;

G represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted

- 1 045324 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 );

each R ¹¹ independently represents 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 ny heteroarylalkyl; or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

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 ; or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and each R ¹⁴ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

In accordance with some embodiments presented herein, a compound of formula (I) is a compound of formula (II):

R ⁵ ₂ R ¹ n=<

/=\ /= S—d NH ^z Vn ⁼ WCrM CHG 4^ R ⁴ A! A ₂

Ch ^X t formula (II).

In accordance with some embodiments presented herein, a compound with formula (I) or formula (II) is a compound with formula (III):

n , ^N= ^ /=\ /= y—d NH ^z “Х # ⁼ Ж /ТЧ'рЗ/Ч _r4 K _{0H 0 formula(w)}

In accordance with some embodiments presented herein, a compound of formula (I) or formula (II) or formula (III) is a compound of formula (IV):

In accordance with some embodiments presented herein, a compound of formula (I) or formula (II) or formula (III) is a compound of formula (IVa):

In accordance with some embodiments presented herein, a compound of formula (I) or formula (II) or formula (III) is a compound of formula (IVb):

n , ^Ν =<

/= /= /—ά Ν-Η ^Ζ Ά /7—=—Ά /7—ί

R ³ OH O formula (IVb).

Another aspect relates to a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. In yet another aspect, 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 described herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and pharmaceutically acceptable excipient. In accordance with some embodiments presented herein, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection, and urinary tract infection. In accordance with 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 infections, bladder infections, urethral infections, and kidney infections.

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

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.

Incorporation by reference

All publications, patents and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes identified herein.

Detailed Description of the Invention

As used herein and in the accompanying claims, the singular forms include the corresponding plural forms unless the context clearly dictates otherwise. Thus, for example, a reference to an agent includes a plurality of such agents, and a reference to a cell includes a reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, and so on. When ranges are used herein to describe physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments are intended to be included therein. The term approximately, when applied to a number or range of numerical values, means that the number or a related range of numerical values represents an approximate value within the range of variation in readings from experiment to experiment (or within the statistical error of the experiment), and therefore the number or range of numerical values in some cases will vary from 1% to 15% of the specified number or range of numerical values. The term containing (and related terms such as contain, or contains, or having, or including) is not intended to exclude that, in accordance with other certain embodiments, for example, in an embodiment of any composition of material, composition, method, or the process, or the like, described herein consists of or consists essentially of the elements described.

Definitions

For purposes of this specification and the appended claims, unless otherwise defined, the following terms have the meanings set forth below. Amino refers to the -NH2 radical. Cyano belongs to the CN radical. Nitro refers to the NO2 radical. Oxa refers to -Oradical. Oxo refers to the =O radical. Thioxo belongs to the =S radical. Imino refers to the =N-H radical. Oximo refers to the =N-OH radical. Hydrazino refers to the =N-NH2 radical.

Alkyl refers to a radical with a straight or branched hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, having from one to fifteen carbon atoms (for example, C ₁ -C ₁₅ alkyl). In accordance with certain embodiments, alkyl contains from one to thirteen carbon atoms (eg, C ₁ -C ₁₃ αlkyl). In accordance with certain embodiments, alkyl contains from one to eight carbon atoms (eg, C1- _C8 alkyl). In accordance with other embodiments, alkyl contains from one to five carbon atoms (eg, C ₁ -C ₅ alkyl). In other embodiments, alkyl contains from one to four carbon atoms (eg, C1- _C4 alkyl). In accordance with other embodiments, alkyl contains from one to three carbon atoms (eg, C ₁ -C ₃ alkyl). In other embodiments, alkyl contains one to two carbon atoms (eg, C1- _C2 alkyl). In other embodiments, alkyl contains one carbon atom (eg, C1alkyl). In other embodiments, alkyl contains from five to fifteen carbon atoms (eg, C ₅ -C ₁₅ alkyl). In other embodiments, alkyl contains from five to eight carbon atoms (eg, C ₅ C ₈ alkyl). In accordance with other embodiments, alkyl contains from two to five carbon atoms (eg, C ₂ -C ₅ alkyl). In accordance with other embodiments, alkyl contains from three to five carbon atoms (eg, C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2 -methylpropyl (iso-butyl), 1,1dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule with

- 3 045324 using a single connection. Unless specifically stated otherwise herein, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O) _t N(R ^a )2 (where t is 1 or 2 ), wherein each R ^a 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).

Alkoxy or alkoxy refers to a radical linked through an oxygen atom and having the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having from two to twelve carbon atoms. In accordance with certain embodiments, alkenyl contains from two to eight carbon atoms. In other embodiments, alkenyl contains from two to four carbon atoms. Alkenyl is attached to the rest of the molecule by a single bond, e.g. ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1 ,4-dienyl, etc. Unless specifically stated otherwise herein, the alkenyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), - S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O)tN(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a independently represents 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).

Alkynyl refers to a linear or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In accordance with certain embodiments, the alkynyl contains from two to eight carbon atoms. In other embodiments, the alkynyl contains from two to six carbon atoms. In other embodiments, the alkynyl contains from two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise herein, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O)tN(R ^a )2 (where t is 1 or 2) wherein each R ^a 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).

Alkylene or alkylene chain refers to a linear or branched divalent hydrocarbon chain linking the rest of the molecule with a radical group consisting exclusively

- 4 045324 made mainly of carbon and hydrogen, not containing an unsaturated bond and having from one to two carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are one carbon in the alkylene chain or any two carbons in the chain. In accordance with certain embodiments, the alkylene contains from one to eight carbon atoms (eg, C1C ₈ alkylene). In accordance with other embodiments, the alkylene contains from one to five carbon atoms (eg, C ₁ -C ₅ alkylene). In accordance with other embodiments, the alkylene contains from one to four carbon atoms (eg, C1-C ₄ alkylene). In other embodiments, the alkylene contains from one to three carbon atoms (eg, C1C ₃ alkylene). In accordance with other embodiments, the alkylene contains from one to two carbon atoms (eg, C ₁ -C _g αalkylene). In other embodiments, the alkylene contains one carbon atom (eg, C1alkylene). In accordance with other embodiments, the alkylene contains from five to eight carbon atoms (eg, C ₅ -C ₈ alkylene). In accordance with other embodiments, the alkylene contains from two to five carbon atoms (eg, C ₂ -C ₅ alkylene). In accordance with other embodiments, the alkylene contains from three to five carbon atoms (eg, C ₃ -C ₅ alkylene). Unless otherwise specifically stated herein, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O)tN(R ^a )2 (where t is 1 or 2) wherein each R ^a 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). Alkenylene or alkenylene chain refers to a linear or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In accordance with certain embodiments, alkenylene contains from two to eight carbon atoms (eg, C2- _C8 alkenylene). In accordance with other embodiments, alkenylene contains from two to five carbon atoms (eg, C ₂ -C ₅ alkenylene). In accordance with other embodiments, alkenylene contains from two to four carbon atoms (eg, C ₂ -C ₄ alkenylene). In accordance with other embodiments, alkenylene contains from two to three carbon atoms (eg, C ₂ -C ₃ alkenylene). In other embodiments, alkenylene contains from five to eight carbon atoms (eg, C ₅ C8 alkenylene). In accordance with other embodiments, alkenylene contains from two to five carbon atoms (eg, C ₂ -C ₅ alkenylene). In other embodiments, alkenylene contains three to five carbon atoms (eg, C ₃ -C ₅ alkenylene). Unless otherwise specifically stated herein, the alkenylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O)tN(R ^a )2 (where t is 1 or 2) wherein each R ^a 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).

Alkynylene or alkynylene chain refers to a linear or branched divalent hydrocarbon chain linking the remainder of the molecule molecule with a radical group consisting solely of carbon and hydrogen containing at least one carbon

- 5 045324 carbon triple bond and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In accordance with certain embodiments, the alkynylene contains from two to eight carbon atoms (eg, C ₂ -C ₈ alkynylene). In accordance with other embodiments, the alkynylene contains from two to five carbon atoms (eg, C ₂ -C ₅ alkynylene). In accordance with other embodiments, the alkynylene contains from two to four carbon atoms (eg, C ₂ -C ₄ alkynylene). In other embodiments, the alkynylene contains two to three carbon atoms (eg, C ₂ -C ₃ alkynylene). In other embodiments, the alkynylene contains two carbon atoms (eg, C2alkylene). In accordance with other embodiments, the alkynylene contains from five to eight carbon atoms (eg, C ₅ -C ₈ alkynylene). In accordance with other embodiments, the alkynylene contains from three to five carbon atoms (eg, C ₃ -C ₅ alkynylene). Unless otherwise specifically stated herein, the alkynylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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)tR ^a (where t is 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O)tN(R ^a )2 (where t is 1 or 2) wherein each R ^a 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).

Aryl refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a carbon atom of the ring. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon, from five to eighteen carbon atoms, and at least one of the rings in the ring system is completely unsaturated, i.e. it contains a cyclic system with delocalized (4n+2) π-electrons in accordance with Hückel's theory. The ring system from which aryl groups are derived includes, but is not limited to, groups such as benzene, fluorene, indane, indene, tetraline and naphthalene. Unless specifically stated otherwise herein, the term aryl or the prefix ar (as in the term aralkyl) is intended to include aryl radicals, optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a ) ₂ (where t is 1 or 2), each R ^a independently being 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 each R ^b independently represents a straight link or a straight or branched alkylene or alkenylene chain, and R ^c represents a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

Aralkyl refers to a radical with the formula R ^c -aryl, in which R ^c represents an alkylene chain as defined above, for example, methylene, ethylene and the like. The aralkyl radical portion of the alkylene chain is optionally substituted, as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted, as described above for the aryl group. Aralkenyl refers to the radical with the formula -Rd-aryl, in which Rd represents

- 6 045324 is an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted, as described above for the aryl group.

The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for the alkenylene group.

Aralkynyl refers to a radical with the formula Re-aryl, in which Re is an alkynylene chain as defined above. The aryl portion of the aralkynyl radical is optionally substituted, as described above for the aryl group. The alkynylene chain portion of the aralkynyl radical is optionally substituted as defined above for the alkynylene group.

Aralkoxy refers to a radical linked through an oxygen atom and having the formula -OR ^c aryl, in which R ^c represents an alkylene chain as defined above, for example, methylene, ethylene and the like. The aralkyl radical portion of the alkylene chain is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted, as described above for the aryl group.

Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems having from three to fifteen carbon atoms. In certain embodiments, the carbocyclyl contains from three to ten carbon atoms. In other embodiments, the carbocyclyl contains from five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl is saturated (ie, containing only C-C single bonds) or unsaturated (ie, containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also called a cycloalkyl. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. An unsaturated carbocyclyl is also called a cycloalkenyl. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise herein, the term carbocyclyl is intended to include carbocyclyl radicals that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a ) 2 (where t is 1 or 2), each R ^a independently being 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 independently represents a straight link or linear or branched an alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

Carbocyclylalkyl refers to a radical with the formula -R ^c -carbocyclyl, in which R ^c represents an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above. Carbocyclylalkynyl refers to a radical with the formula -R ^c -carbocyclyl, in which R ^c represents an alkynylene chain as defined above. The alkynylene chain and carbocyclyl radical are optionally substituted as defined above.

Carbocyclylalkoxy refers to a radical linked through an oxygen atom and having the formula -O-R ^c -carbocyclyl, in which R ^c represents an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

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

Halide or halogen refers to bromine, chlorine, fluorine or iodine substituents. Fluoroalkyl refers to an alkyl radical as defined above which is substituted by one or more fluoro radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like. In accordance with some embodiments, the alkyl moiety of the fluoroalkyl radical is optionally substituted, as defined above for an alkyl group. Heterocyclyl refers to a stable 3-18 membered non-aromatic ring radical that contains from two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused, bridged or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical are not necessarily oxidized. One or more nitrogen atoms, if present, are not necessarily quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl , piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl. Unless specifically stated otherwise herein, the term heterocyclyl is intended to include heterocyclyl radicals as defined above and which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, 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)R ^a , -R ^b N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O )tN(R ^a )2 (where t is 1 or 2), each R ^a independently being 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 independently represents a straight link or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

N-heterocyclyl or N-attached heterocyclyl refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and in which the point of attachment of the heterocyclyl radical to the rest of the molecule is the nitrogen atom of the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.

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

Heterocyclylalkyl refers to a radical with the formula -R ^c -heterocyclyl, in which R ^c represents an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain in the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of a heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group. Heterocyclylalkoxy refers to a radical linked through an oxygen atom and having the formula -O-R ^c -heterocyclyl, in which R ^c represents an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain in the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclyl alkoxy radical is optionally substituted as defined above for a heterocyclyl group.

Heteroaryl refers to a radical derived from a 3 to 18 membered aromatic ring radical that contains from two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is completely unsaturated, i.e. it contains a cyclic system with delocalized (4n+2) π-electrons in accordance with Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are not necessarily oxidized. One or more nitrogen atoms, if present, are not necessarily quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzidolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b] [1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2d]pyrimidinyl, benzotriazolyl, benzo[4,6] imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5Hcyclopenta[4,5]thieno[2,3d]pyrimidinyl, 5,6-dihydrobenzo[I]quinazolinyl, 5,6- dihydrobenzo[I]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2c]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-hexahydrocycloocta[c1]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[b]quinazolinyl, 1-phenyl-Spyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[ 3,4d]pyrimidinyl, pyridinyl, pyrido[3,2d]pyrimidinyl, pyrido[3,4d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3d]pyrimidinyl, 5,6,7,8tetrahydropyrido[4,5c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3d]pyrimidinyl, thieno[3,2d]pyrimidinyl, thieno[2,3c]pyridinyl and thiophenyl ( those. thienyl). Unless specifically stated otherwise herein, the term heteroaryl is intended to include heteroaryl radicals as defined above and which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, haloalkenyl, haloalkynyl, 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)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2), each R ^a independently being 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 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 independently represents a straight link or a straight or branched alkylene or alkenylene chain, and R ^c represents a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

N-heteroaryl refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and in which the point of attachment of the heteroaryl radical to the rest of the molecule is the nitrogen atom of the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

C-heteroaryl refers to a heteroaryl radical, as defined above, in which the point of attachment of the heteroaryl radical to the rest of the molecule is the carbon atom of the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. Heteroarylalkyl refers to a radical with the formula -R ^c -heteroaryl, in which R ^c represents an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain in the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of a heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

Heteroarylalkoxy refers to a radical linked through an oxygen atom and having the formula -O-R ^c -heteroaryl, in which R ^c represents an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain in the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

In accordance with some embodiments, the compounds disclosed herein contain one or more asymmetric centers and therefore form enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemical configuration as (R) or (S). Unless otherwise indicated, all stereoisomeric forms of the compounds disclosed herein are intended to be included in the present disclosure. When the compounds described herein contain alkene double bonds, and unless otherwise specified, the present disclosure is intended to include both E- and Z-geometric isomers (eg, cis or trans). Likewise, it is also intended to include all possible isomers, as well as their racemic and optically pure forms and all tautomeric forms. The term geometric isomer refers to E- or Z-geometric isomers (eg, cis or trans) at the alkene double bond. The term positional isomer refers to structural isomers relative to the central ring, such as ortho-, meta-, and para-isomers relative to the benzene ring.

A tautomer refers to a molecule in which the transfer of protons from one atom in the molecule to another atom in the same molecule is possible. In accordance with certain embodiments, the compounds provided herein exist as tautomers. Under conditions where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

In some cases, the heterocyclic LpxC inhibitor compounds disclosed herein exist in tautomeric forms. The structures of these compounds are illustrated in a single tautomeric form for simplicity. The present disclosure expressly includes alternative tautomeric forms, such as, for example, the structures illustrated below.

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In accordance with some embodiments, the compounds disclosed herein are used in various isotopically enriched forms, for example, enriched in ^2H , ^3H , ^nC , ^13C , and/or ^14C . In accordance with one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be prepared using the procedure described in US Pat. Nos. 5,846,514 and 6,334,997. As described in US Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and/or potency, thereby increasing the duration of action of drugs.

Unless otherwise indicated, the structures presented herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having these structures, except for the replacement of hydrogen by deuterium or tritium or the replacement of carbon by ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present disclosure.

The compounds of the present disclosure do not necessarily contain, in one or more of the atoms that constitute such compounds, different atomic isotopes in ratios different from natural ones. For example, the compounds may be labeled isotopes such as, for example, deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). It is also possible to replace isotopes with ² H, "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, ¹²⁵ I. Included within the scope of this disclosure are all isotopic variants of the compounds of the present disclosure, whether radioactive or non-radioactive.

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

Deuterium-substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C; Editor. 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.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to allow the synthesis of deuterium-containing compounds. Large quantities of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethalene-d ₃ (CD ₃ I), are readily available and can be used to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD ₃ I is illustrated, by way of example only, in the reaction schemes below.

Deuterium transfer reagents such as lithium aluminum deuteride (UAlD ₄ ) are used to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD ₄ is illustrated, by way of example only, in the reaction schemes below.

R^ _M „СО,Н ^L ' ^AID4 - V Ϊ LiAID ₄ DR'

DD ^K R OH RR r^oH

Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bridges and to effect reductive substitution of carbon-halogen bonds in aryl, as illustrated, by way of example only, in the reaction schemes below.

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In accordance with one embodiment, the compounds disclosed herein contain one deuterium atom. In accordance with yet another embodiment, the compounds disclosed herein contain two deuterium atoms. In accordance with yet another embodiment, the compounds disclosed herein contain three deuterium atoms. In accordance with yet another embodiment, the compounds disclosed herein contain four deuterium atoms. In accordance with yet another embodiment, the compounds disclosed herein contain five deuterium atoms. In accordance with yet another embodiment, the compounds disclosed herein contain six deuterium atoms. In accordance with yet another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In accordance with yet another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and does not contain non-exchangeable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthesis methods that use deuterated building blocks as the starting material for the synthesis.

In accordance with one embodiment, the compounds disclosed herein contain one or more boron atoms, silicon atoms, or any combination thereof. In accordance with some embodiments, one or more carbon atoms in a compound disclosed herein are replaced with a boron atom, a silicon atom, or any combination thereof.

In accordance with some embodiments, one or more carbon atoms in a compound disclosed herein are replaced with a boron atom. In accordance with some embodiments, one carbon atom in a compound disclosed herein is replaced with a boron atom. In some embodiments, two carbon atoms in a compound disclosed herein are replaced with two boron atoms. In accordance with some embodiments, three carbon atoms in a compound disclosed herein are replaced with three boron atoms. In some embodiments, the four carbon atoms in a compound disclosed herein are replaced with four boron atoms. In some embodiments, the five carbon atoms in a compound disclosed herein are replaced with five boron atoms.

In accordance with some embodiments, one or more carbon atoms in a compound disclosed herein are replaced with a silicon atom. In accordance with some embodiments, one carbon atom in a compound disclosed herein is replaced by a silicon atom. In accordance with some embodiments, two carbon atoms in a compound disclosed herein are replaced by two silicon atoms. In accordance with some embodiments, three carbon atoms in a compound disclosed herein are replaced by three silicon atoms. In accordance with some embodiments, the four carbon atoms in the compound disclosed herein are replaced by four silicon atoms. In some embodiments, the five carbon atoms in a compound disclosed herein are replaced by five silicon atoms. The pharmaceutically acceptable salt includes both acid addition salts and base addition salts. The pharmaceutically acceptable salt of any of the heterocyclic LpxC inhibitor compounds described herein is intended to include any and all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Pharmaceutically acceptable acid addition salt refers to those salts that retain the biological effectiveness and properties of free bases that are not biologically or otherwise undesirable and that 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 which are 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, etc., 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, the illustration

- 12 045324 ratative salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelic acid salts, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, manates, tartrates, methanesulfonates, etc. Amino acid salts such as arginates, gluconates and galacturonates are also provided (see, for example, Berge S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, acid addition salts of base compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to form a salt in accordance with methods and techniques that are familiar to one skilled in the art.

A pharmaceutically acceptable base addition salt refers to those salts that retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. These salts are obtained by adding an inorganic base or an organic base to the free acid. In accordance with some embodiments, pharmaceutically acceptable acid addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts formed with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts formed with 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, Trietidylamine, Tripropylamin, ethanolamine, 2-dimetaminoethanol, 2-deythylaminoethanol, diciclogliwormin, lysine, arginine, histidine, caffeine, n, n-dibenzylethylendiamine, chlorpropaine, hydrogamin, holina, betainamine, ethylendianilin, n. -Methylhlyukamina, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

In the context of this document, treatment, or implementation of treatment, or temporary relief, or attenuation are used interchangeably. These terms refer to an approach to obtaining beneficial or desired results, including, without limitation, beneficial therapeutic effects and/or beneficial prophylactic effects. By beneficial therapeutic effect we mean the elimination or attenuation of the underlying disorder being treated. In addition, a beneficial therapeutic effect is achieved by eliminating or reducing one or more of the physiological symptoms associated with the underlying disorder, such that the patient improves despite the fact that the patient is still affected by the underlying disorder. In some embodiments, the compositions are administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if the disease has not been diagnosed, to provide beneficial prophylactic effects.

A prodrug is intended to mean a compound that, in some embodiments, is converted under physiological conditions or by solvolysis into a biologically active compound described herein. Thus, the term prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable. The prodrug is generally inactive when administered to a subject, but is converted in vivo to the active compound, for example, by hydrolysis. A prodrug compound often offers advantages in solubility, histocompatibility, or sustained release in a mammal (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (Elsevier, Amsterdam). A discussion of prodrugs is presented in Higuchi, T., et al., Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term prodrug also implies the inclusion any covalently linked carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject.Prodrugs of the active compound as described herein are prepared by modifying functional groups present in the active compound such that the modified moieties are cleaved off either standard manipulation, or in vivo to obtain the original active compound. Prodrugs include compounds in which a hydroxy, amino or mercapto group is linked to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxy, free amino or free mercapto 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 compounds and the like.

- 13 045324

LpxC inhibitor compounds.

Presented herein are heterocyclic LpxC inhibitor compounds and pharmaceutical compositions containing the same. These compounds and compositions are useful for inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and for treating bacterial infection.

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

in which n is 0-4;

m is 0-4;

A ₁ represents OH or SH;

A ₂ represents O or S;

each of R ¹ and R ² independently represents H or optionally substituted alkyl;

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

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

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0-C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C 4 alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ - C ₄ alkylene)-OR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2, optionally substituted ( _C0 - _C4 alkylene)-N(R ¹² )-COR ¹¹ , optionally substituted (C0-C4alkylene) -N(R ¹¹ )-CO2R ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2-CON(R ¹¹ ) ₂ , optionally substituted _{(C0C4alkylene )} -N(R ¹² )-SO2N( R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ ) ₂ , optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹¹ )-PO (optionally substituted C1- C4alkyl)2, optionally substituted (C0-C4alkylene)-SO2R ¹¹ , optionally substituted (C0- _C4 alkylene)-O-SO ₂ R ¹¹ , optionally substituted ( _C0 - _C4 alkylene)-N( ^R12 )-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C0-C 4 alkylene)-OR(=O)(OR ¹¹ )2; R ⁴ represents H or optionally substituted alkyl;

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

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

R ⁵ represents H, halogen, optionally substituted alkyl, hydroxyl, alkoxy, cyano, amino or nitro;

ring B is aryl, carbocyclyl, heteroaryl or heterocyclyl;

W represents a bond, -CHC-, bicyclo[1.1.1]pentanylene, -C=C-C=C-, -CH=CH- or -CH2CH2-; ring C is aryl, carbocyclyl, heteroaryl or heterocyclyl;

each X and Y independently represents H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, nitro, -N(R ¹³ ) ₂ or -OR ¹³ ;

or R ³ and one X, taken together with intermediate atoms, form an optionally substituted 5-7 membered carbocyclyl or an optionally substituted 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

Z represents H, halogen, nitro or -L-G;

L represents a bond or optionally substituted C1- _C4 alkylene;

G represents 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 );

each R ¹¹ independently represents H, optionally substituted alkyl, optionally

- 14 045324 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; or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

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 ; or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and each R ¹⁴ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is a monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from O, N, and S, or a monocyclic or bicyclic 512-membered heterocyclyl containing 1-3 heteroatoms selected from O, N, and S. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is phenyl ,

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is phenyl,

or

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring B is phenyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring B is a carbocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring B is heteroaryl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring B is a heterocyclyl.

- 15 045324

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

O

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is a bond. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is C=C-, bicyclo[1.1.1]pentanylene, -C=C-C=C-, -CH =CH- or -CH2CH2-. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -C=C-, -C^C-C^C-, -CH=CH-, or -CH2CH2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -C=C-, -CH=CH-, or -CH2CH2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -C=C-. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is bicyclo[1.1.1]pentanylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -C=C-C^C-. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -CH=CH-. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, W is -CH2CH2-. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is a monocyclic or bicyclic aryl, a monocyclic or bicyclic 3 to 12 membered carbocyclyl, a monocyclic or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from O, N and S, or a monocyclic or bicyclic 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from O, N and S. In accordance with some embodiments of a compound disclosed herein, or its pharmaceutically acceptable salt, solvate, or prodrug, ring C is phenyl, a monocyclic 3-6 membered carbocyclyl, or a monocyclic or bicyclic heteroaryl containing 1 or a heteroatom selected from O, N, and S. In some embodiments of the compound , disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, ring C is phenyl, cyclohexyl,

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is phenyl, cyclohexyl,

Yoon D Yoon

Oh......CF

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is phenyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is a carbocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is a monocyclic cycloalkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is cyclohexane. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is heteroaryl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is a heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is a monocyclic heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is piperidine. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring C is piperazine. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

- 17 045324

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring C is

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring B is phenyl; and ring C is phenyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, a compound of formula (I) has the structure of formula (II):

R ⁵

R ² J ¹ / ^N= ^ ^{Yn X} m formula (II), in which n is 0-4;

m is 0-4;

A ₁ represents OH or SH;

A2 represents O or S;

each of R ¹ and R ² independently represents H or optionally substituted alkyl;

or R ¹ and R ² taken together with the carbon to which they are attached to =C(R ¹¹ )2, =NR11, =O, or =S;

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

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0-C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C 4 alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ - C ₄ alkylene)-OR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2, optionally substituted ( _C0 - _C4 alkylene)-N(R ¹² )-COR ¹¹ , optionally substituted (C0-C4alkylene) -N(R ¹² )-CO2R ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CON(R ¹¹ )2, optionally substituted ( _{C0C4 alkylene} )-N(R ¹² )-SO2N(R ¹¹ )2, optionally substituted ( _C0 - _C4alkylene )-O- _SO2N ( ^R11 )2, optionally substituted (C0-C4alkylene)-N( ^R11 )-PO(optionally substituted C1-C4alkyl) ₂ , optionally substituted ( _C0 - _C4alkylene ) _-SO2R11 , optionally substituted (C0-C4alkylene) ^-OSO2R11 , optionally substituted ( ^C0 - _C4alkylene )-N( ^R12 ) ^-SO2R11 , optionally substituted (C0C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C0-C4alkylene)-OP(=O)(OR ¹¹ )2;

R ⁴ represents H or optionally substituted alkyl;

or R ³ and R ⁴ taken together with the carbon to which they are attached form =C(R ⁿ )2, =NR11, =O or =S;

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

R ⁵ represents H, halogen, optionally substituted alkyl, hydroxyl, alkoxy, cyano, amino or nitro;

each X and Y independently represents H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, hutpo-N(R ¹³ ) ₂ or -OR ¹³ ;

or R ³ and one X, taken together with intermediate atoms, form an optionally substituted 5-7 membered carbocyclyl or an optionally substituted 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S;

Z represents H, halogen, nitro or -L-G;

L represents a bond or optionally substituted C1- _C4 alkylene;

G represents 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 );

each R ¹¹ independently represents 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 ny heteroarylalkyl;

or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

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 ;

or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and each R ¹⁴ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, or nitro. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, optionally substituted alkyl, halogen, cyano, OH, or NH2. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, optionally substituted alkyl, halogen, or cyano. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, halogen, or cyano. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, halogen, cyano, OH, or NH ₂ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H or halogen. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, halogen, OH, or NH2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each independently H, F, or Cl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, X and Y are each H.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X independently represents H, optionally substituted alkyl, halogen, or cyano. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X independently represents H, optionally substituted alkyl, halogen, or cyano. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X independently represents H, halogen, or cyano. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X independently represents H or a halogen. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X independently represents H, F, or Cl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each X is H.

- 19 045324

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y independently represents H, optionally substituted alkyl, halogen, or cyano. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y independently represents H, optionally substituted alkyl, halogen, or cyano. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y independently represents H, halogen, or cyano. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y is independently H or halogen. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y is independently H, F, or Cl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each Y is H.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, m is 0-4. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, m is 0-1, 0-2, 0-3, 0-4, 1-2, 1-3, 14. 2-3, 2-4 or 3-4. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, m is 0, 1, 2, 3, or 4. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, m is 0, 1, 2, 3, or 4. acceptable salt, solvate, or prodrug, m is 0 or 1. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, m is 0. In accordance with some embodiments of a compound disclosed herein , or a pharmaceutically acceptable salt, solvate or prodrug thereof, m is 1.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0-4. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0-1, 0-2, 0-3, 0-4, 1-2, 1-3, 14. 2-3, 2-4 or 3-4. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0, 1, 2, 3, or 4. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, n is 0, 1, 2, 3, or 4. of an acceptable salt, solvate, or prodrug, n is 0 or 1. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0. In accordance with some embodiments of a compound disclosed herein , or a pharmaceutically acceptable salt, solvate or prodrug thereof, n is 1.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A1 is OH. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A1 is SH.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A ₂ is O. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof A2 represents S.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, A1 is OH and _A2 is O.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁵ is H, halogen, optionally substituted alkyl, hydroxyl, or alkoxy. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁵ is H, unsubstituted alkyl, or alkoxy. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R5 is H.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² are independently H or optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² are independently H or unsubstituted alkyl.

- 20 045324

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ is H. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof R ¹ represents optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ is unsubstituted alkyl.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ² is H. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof R ² represents optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ² is unsubstituted alkyl.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² are H.

According to some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached form =C(R ⁿ )2, =NR ⁿ , =O or =S. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, form =C(R ⁿ ) 2 . In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached form an unsubstituted alkenyl group. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, form =NR ⁿ . In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, form =O. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, form =S.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, forms an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted A 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N, and S. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² taken together with the carbon to which they are attached, they form an optionally substituted 3-6-membered carbocyclyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached form an unsubstituted 3- to 6-membered carbocyclyl. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, forms cyclopropyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹ and R ² , taken together with the carbon to which they are attached, forms an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N, and S. In certain embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R1 and ^R2 , taken together with the carbon to which they are attached, form an unsubstituted 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, a compound of formula (I ) or formula (II) has a structure with formula (III):

- 21 045324 n, ^Ν= ^ /=\ /=x,—4 N-n ^Ζ A # = A # Sr3/^

R ^{4 he 0} formula (III), in which

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0- _C4 alkylene)CO ₂ R ¹¹ , optionally substituted (C0-C4alkylene)-CON( ^R11 )2, optionally substituted ( _C0 - _C4 alkylene)-CN optionally substituted ( _C0 - _C4 alkylene)-OR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2, optionally 12x 11 -χΤ/Τχ12χ 11 substituted (C ₀ -C ₄ alkylene)-N(R)-COR, optionally substituted (C ₀ -C ₄ alkylene)-N(R)-CO2R, optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )-CON(R ¹¹ ) ₂ , optionally substituted (C ₀ C ₄ alkylene)-N( R ¹² )-SO2N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ ) ₂ , optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹¹ )- PO (optionally substituted C1-C4alkyl)2, optionally substituted (C0-C4alkylene)-SO2R ¹¹ , optionally substituted (C0- _C4 alkylene)-O-SO ₂ R ¹¹ , optionally substituted ( _C0 - _C4 alkylene)-N (R ¹² )-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C0-C4 alkylene)-OR(=O)(OR ¹¹ )2;

R ⁴ represents H or optionally substituted alkyl;

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

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

Z represents H, halogen, nitro or -L-G;

L represents a bond or optionally substituted C1- _C4 alkylene;

G represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N( ^R13 )2, ^-OR13 , ^-COR13 , -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-SO ₂ N( R ¹³ )2, -N(R ¹⁴ )-SO2-OR ¹³ or -C(=N-OR ¹⁴ )(R ¹³ );

each R ¹¹ independently represents 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 ny heteroarylalkyl;

or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

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 ;

or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and each R ¹⁴ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R3 and ^R4 , taken together with the carbon to which they are attached, form =C( ^R11 )2, =NR11, =O or =S. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R3 and ^R4 , taken together with the carbon to which they are attached, form =C( ^R11 )2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached form an unsubstituted alkenyl group. In accordance with some embodiments of a connection disclosed herein, or

- 22 045324 its pharmaceutically acceptable salt, solvate or prodrug R ³ and R ⁴ taken together with the carbon to which they are attached form =NR ⁿ . In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached, form =O. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached, form =S.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached, forms an optionally substituted 3- to 6-membered carbocyclyl or an optionally substituted A 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N, and S. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ taken together with the carbon to which they are attached, they form an optionally substituted 3-6-membered carbocyclyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached form an unsubstituted 3- to 6-membered carbocyclyl. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached, forms cyclopropyl. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ and R ⁴ , taken together with the carbon to which they are attached, forms an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N, and S. In certain embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R3 and ^R4 , taken together with the carbon to which they are attached, form an unsubstituted 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, N and S. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ⁴ is H In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁴ is an optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁴ is unsubstituted alkyl.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, a compound of formula (I) or formula (II) or formula (III) has the structure of formula (IV):

n _/ ^Ν Λ

7= /=\ d NH ^z— A /—=—A /—( /—

R ³ OH O formula (IV), in which

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0-C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C 4 alkylene)-CON(R ¹¹ )2, optionally substituted (Co-C ₄ alkylene)-CN, optionally substituted (C ₀ -C ₄ αalkylene)-OR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2, optionally substituted ( _C0 - _C4 alkylene)-N(R ¹² )-COR ¹¹ , optionally substituted (Co-C4alkylene)- N(R ¹² )-CO2R ¹¹ , optionally substituted (Co-C4alkylene)-N(R ¹² )-CON( _R ¹¹ )2, optionally substituted ( _C0C4 alkylene)-N(R ¹² )-SO2N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ ) ₂ , optionally substituted (C ₀ -C ₄ αalkylene)-N(R ¹¹ )-PO (optionally substituted C1-C4 alkyl) 2, optionally substituted (C0-C4alkylene)-SO2R ¹¹ , optionally substituted (C0- _C4 alkylene)-O-SO ₂ R ¹¹ , optionally substituted ( _C0 - _C4 αalkylene)-N(R ¹² )-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C0-C 4 alkylene)-OR(=O)(OR ¹¹ )2;

Z represents H, halogen, nitro or -L-G;

L represents a bond or optionally substituted C1- _C4 alkylene;

G represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted

- 23 045324 aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -CN, -N(R ¹³ )j,

-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 );

each R ¹¹ independently represents 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 ny heteroarylalkyl;

or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

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 ;

or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and each R ¹⁴ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the compound has formula (IVa):

n ^N =<

/= /= у—ά NH ^Z Ж /7—=—Ά /7—( /

R ³ OH O formula (IVa).

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the compound has formula (IVb):

n ^N ={ /= /= /—ά NH ^Z Ά /7—=—Ά /7—i /

R ³ OH O formula (IVb).

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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-C4alkylene)COR ¹¹ , optionally substituted (C0- _C4 alkylene)-CO ₂ ^R11 , optionally substituted ( _C0 - _C4 alkylene)CON(R11 ) ₂ , optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ -C ₄ alkylene)OR ¹¹ , optionally substituted (C0-C4 alkylene)-N(R ¹¹ )2, optionally substituted (C ₀ - C ₄ alkylene)N(R ¹² )-COR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CO2R ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CON(R ¹¹ )2 , optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )-SO2N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ ) ₂ , optionally substituted ( C ₀ -C ₄ alkylene)-N(R ¹¹ )PO (optionally substituted C1-C4 alkyl)2, optionally substituted (C0-C4 alkylene)-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-O-SO ₂ R ¹¹ , optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )SO2R ¹¹ , optionally substituted (C0-C4 alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C0C ₄ alkylene)-OR (=O)(OR ¹ 1) ₂ .

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is unsubstituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted carbocyclyl. In accordance with some embodiments of a compound disclosed herein or pharmaceutically

- 24 045324 acceptable salt, solvate or prodrug R ³ is an optionally substituted carbocyclyl alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted heteroaryl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted heteroaralkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted heterocycloalkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted (C0-C4αalkylene)-COR ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-CO ₂ R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-CON(R ¹¹ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted (C0C4alkylene)-CN. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted (C0-C ₄ αalkylene)-OR ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-N(R ¹¹ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4αalkylene)-N(R ¹² )-COR ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C ₄ alkylene)-N(R ¹² )-CO2R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C ₄ alkylene)-N(R ¹² )-CON(R ¹¹ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C ₄ alkylene)-N(R ¹² )-SO2N(R ¹¹ )2. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-O-SO2N(R ¹¹ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted (C0-C4alkylene)-N( ^R11 )PO(optionally substituted C1-C4alkyl) ₂ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-SO2R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C ₄ αalkylene)-O-SO ₂ R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (C0-C4alkylene)-N(R ¹² )-SO2R ¹¹ . According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is optionally substituted (CoC4alkylene)-C(=N-OR ¹¹ )(R ¹¹ ). According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted (C0-C ₄ alkylene)-OR(=O)(OR ¹¹ ) ₂ .

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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 (Co-C4alkylene)COR ¹¹ , optionally substituted (C0-C4alkylene)-CO2R ¹¹ , optionally substituted (C0- _C4 alkylene)CON( ^Rn ) ₂ , optional substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ -C ₄ alkylene)OR ¹¹ , optionally substituted (C0-C4 alkylene) -N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)

- 25 045324

N(R ¹² )-C(R ⁿ , optionally substituted (C ₀ -C ₄ αalkylene)-N(R ¹² )-CO2R ¹¹ , optionally substituted (C0C4alkylene)-N(R ¹² )-CON(R ¹¹ )2, optionally substituted (C0-C4alkylene)-N(R ¹² )-SO2R ¹¹ or optionally substituted ( _C0 - _C4 alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) In accordance with some embodiments of the compound disclosed as used herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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, optional substituted heterocycloalkyl, optionally substituted (C0-C4alkylene)-COR ¹¹ , optionally substituted (C0- _C4 αalkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C4alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ - C ₄ alkylene)-CN, optionally substituted (C ₀ -C ₄ alkylene)-OR ¹¹ , optionally substituted (C0-C4 alkylene)-N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )-COR ¹¹ , optionally substituted (C ₀ -C ₄ alkylene)N(R ¹² )-CO2R ¹¹ , optionally substituted (C0-C ₄ αalkylene)-N(R ¹² )-CON(R ¹¹ ) ₂ or optionally substituted (C ₀ -C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ). According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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-C4alkylene)-COR ¹¹ , optionally substituted (C0- _C4 αalkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C4alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ -C ₄ alkylene)-OR ¹¹ , optionally substituted (C0-C4αalkylene)-N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-N( R ¹² )-COR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CO2R ¹¹ , optionally substituted (C ₀ -C ₄ αalkylene)-N(R ¹² )-CON(R ¹¹ )2, optionally substituted (C0-C4alkylene)-N(R ¹² ) _-SO2R ¹¹ or optionally substituted ( _C0C4 alkylene)-C(=N-OR ¹¹ )(R ¹¹ ). According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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-C4alkylene)-COR ¹¹ , optionally substituted (C0C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C4alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ αalkylene)-CN, optionally substituted (C ₀ -C ₄ alkylene)-OR ¹¹ , optionally substituted (C0C4alkylene)-N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )- COR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-CO2R ¹¹ , optionally substituted (C0-C4αalkylene)-N(R ¹² )-CON(R ¹¹ )2 or optionally substituted (C ₀ -C ₄ alkylene )-C(=N-OR ¹¹ )(R ¹¹ ).

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted alkyl, optionally substituted (C ₀ -C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0 -C4alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ αalkylene)-OR ¹¹ or optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹¹ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted alkyl, optionally substituted (C0C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C4 alkylene) -CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ αalkylene)-OR ¹¹ or optionally substituted (C0-C4alkylene)-N(R ¹¹ )2. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is unsubstituted alkyl, -CO2R ¹¹ , -CON(R ⁿ )2, optionally substituted (C0-C4alkylene)-OR ¹¹ , optionally substituted (C0C ₄ alkylene)-N(R ¹¹ )2, optionally substituted (C0-C4 alkylene)-N(R ¹² )-SO2R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R3 is unsubstituted alkyl, ^CO2R11 , -CON( ^Rn )2, optionally substituted ( _C0 - _C4 alkylene) -OR ¹¹ or optionally substituted (C0C4alkylene)-N(R ¹¹ )2. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C4alkylene)-OH, (C0-C4alkylene)-OME , (C0C4alkylene)-NH2, (C0-C4alkylene)-NHR ¹¹ , (C0- _C4alkylene )-N(R ¹¹ )2 or (C0-C4alkylene)-NH-SO2R ¹¹ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is unsubstituted alkyl, -CO2Me, -CO ₂ Et, (C ₀ -C ₄ alkylene)-OH, (C ₀ -C ₄ alkylene)-OMe, (C ₀ -C ₄ alkylene)-NH ₂ , (C ₀ -C ₄ alkylene)NHR ¹¹ or (C0-C4 alkylene)-N(R ¹¹ )2. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C2alkylene)-OH, (C0-C2alkylene)-OME , (C0-C2alkylene)-NH2, (C0-C2alkylene)-NHR ¹¹ , ⁽ C0-C2alkylene)-N( _R11 ) ₂ or ( _C0 - _C2alkylene )-NH-SO ₂ ^R11 . IN

- 26 045324 in accordance with certain embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof R ³ is unsubstituted alkyl, -CO2Me, -CO2Et, (C0-C2alkylene)-OH, (C0-C2alkylene) -OME, (C0-C2alkylene)-NH2, (C0-C2alkylene)NHMe, (C0-C2alkylene)-NMe2 or (C0-C2alkylene)-NH-SO2Me. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is (C0-C ₂ αalkylene)-NH-SO ₂ Me. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is -NH-SO ₂ Me.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹¹ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted heteroarylalkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹¹ is independently unsubstituted or substituted with a halogen, -CN, -R ^b -OR ^a , -R ^b -C(O) R ^a or -R ^b -S(O) _t R ^a ; where t is 1 or 2; each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹¹ is independently unsubstituted or substituted with -F, -Cl, -CN, -OH, -OME, -SO2Me, or -C (O) Meh.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form an optionally substituted N-heterocyclyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups combined with the nitrogen to which they are attached form an N-heterocyclyl, which is optionally a substituted halogen, oxo, - CN or -R ^b -OR ^a . According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups combined with the nitrogen to which they are attached form an N-heterocyclyl, which is optionally a substituted halogen, oxo, - CN or -R ^b -OR ^a ; wherein each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups coupled to the nitrogen to which they are attached form an N-heterocyclyl that is unsubstituted or substituted with -F, oxo , -CN, -OH or -OMe. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups coupled to the nitrogen to which they are attached form an N-heterocyclyl that is unsubstituted or substituted with -F, - CN, -OH or -OMe. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups coupled to the nitrogen to which they are attached form an N-heterocyclyl that is unsubstituted or substituted with -CN, - OH or -OMe. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form an N-heterocycloalkyl that is unsubstituted or substituted. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form a 4-6 membered N-heterocycloalkyl that is unsubstituted or substituted. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, or unsubstituted or substituted piperazinyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form an unsubstituted or substituted azetidinyl. According to some embodiments, with

- 27 045324 of the compound disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, two R ¹¹ groups combined with the nitrogen to which they are attached form Nheterocycloalkyl, which is substituted. In accordance with some embodiments, the N-heterocycloalkyl is substituted with halogen, oxo, -CN, or -R ^b -OR ^a . In accordance with some embodiments, the N-heterocycloalkyl is substituted with halogen, oxo, -CN, or -R ^b -OR ^a ; wherein each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. In some embodiments, Nheterocycloalkyl is substituted with -F, oxo, -CN, -OH, or -OME. In accordance with some embodiments, N-heterocycloalkyl is substituted with -F, -CN, -OH, or -OME. In accordance with some embodiments, N-heterocycloalkyl is substituted with -CN, -OH, or -OME.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups connected to the nitrogen to which they are attached form an unsubstituted or substituted azetidinyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹¹ groups combined with the nitrogen to which they are attached form a substituted azetidinyl. In accordance with some embodiments, azetidinyl is substituted with halogen, oxo, -CN, or -R ^b -OR ^a . In accordance with some embodiments, azetidinyl is substituted with halogen, oxo, -CN, or -R ^b -OR ^a ; wherein each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. In some embodiments, azetidinyl is substituted with -F, oxo, -CN, -OH, or -OME. In accordance with some embodiments, the azetidinyl is substituted with -F, -CN, -OH, or -OME. In accordance with some embodiments, the azetidinyl is substituted with -CN, -OH, or -OME. In accordance with some embodiments, azetidinyl is substituted with -CN. In accordance with some embodiments, azetidinyl is substituted with OH. In accordance with some embodiments, azetidinyl is substituted with -OME.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹² independently represents H, an optionally substituted alkyl, an optionally substituted carbocyclyl, or an optionally substituted heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹² independently represents H or unsubstituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹² independently represents H or unsubstituted C 1 -C ₄ alkyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ^R3 is:

- 28 045324

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is H. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is a halogen. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is -F, -Cl, or -Br. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is nitro.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Z is -LG.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, L is a bond. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, L is an optionally substituted C1- _C4 alkylene. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, L is an optionally substituted C1- _C2 alkylene. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, L is an unsubstituted C ₁ -C ₂ alkylene. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, L is -CH2-.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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(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 , -oCON(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 accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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 accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug 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 .

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is unsubstituted alkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted carbocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted carbocyclylalkyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is

- 29 045324 optionally substituted heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heterocyclylalkyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heteroaryl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is -N(R ¹³ )2. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is -OR ¹³ . In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -CN. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is -COR ¹³ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is CO ₂ R ¹³ . In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is N(R ¹² )-COR ¹³ .

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -N(R ¹³ )2, -OR ¹³ or - N(R ¹² )-COR ¹³ .

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹³ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl or optionally substituted heteroaryl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹³ independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹³ is independently unsubstituted or substituted with -R ^b -OR ^a , -R ^b -C(O)OR ^a or -R ^b -C(O)R ^a ; wherein each R ^a independently represents hydrogen, alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹³ is independently unsubstituted or substituted with -OH, -OMe, -C(O)CH ₂ OH, -CH ₂ C( O)OH, -C(O)OH, C(O)-cyclopropyl.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, one R ¹³ is H. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. prodrugs, 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.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, one R ¹³ is an optionally substituted heterocyclyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, one R ¹³ is an optionally substituted heterocyclyl selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, thiophenyl, sulfolanyl (1,1 - dioxotetrahydrothiophenyl), 1-imino-1-oxotetrahydrothiophenyl, 1-oxotetrahydrothiophenyl, 1,1-dioxotetrahydrothiopyranyl or 1-imino-1-oxotetrahydrothiopyranyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, one R ¹³ is an optionally substituted heterocyclyl selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl. In accordance with some embodiments of the connection disclosed herein

- 30 045324 menthe, or a pharmaceutically acceptable salt, solvate or prodrug thereof, one R ¹³ is an optionally substituted heterocyclyl, which is a bicyclic heterocycle, which is fused or spirocyclic. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, one R ¹³ is a heterocyclyl that is optionally substituted with 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 ; wherein each R ^a independently represents hydrogen, alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl, or cycloalkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹³ groups coupled to the nitrogen to which they are attached form an optionally substituted N-heterocyclyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹³ groups combined with the nitrogen to which they are attached form an N-heterocyclyl that is unsubstituted or substituted with an optionally substituted alkyl 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) R ^a ; wherein each R ^a independently represents hydrogen, alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, two R ¹³ groups coupled to the nitrogen to which they are attached form an N-heterocyclyl that is unsubstituted or substituted with methyl, oxetanyl, morpholinyl, -OMe, -CH2OH, -NH2, -CH2NH2, -C(O)CH2OH, -CN, -CH2CN, -CH2NHC(O)CH2OH.

According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹⁴ independently represents H, an optionally substituted alkyl, an optionally substituted carbocyclyl, or an optionally substituted heterocyclyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹⁴ independently represents H, unsubstituted alkyl, or unsubstituted heterocyclyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹⁴ is H.

In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heterocyclyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted monocyclic heterocyclyl, fused bicyclic heterocyclyl, or spirobicyclic heterocyclyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted 4-6 membered monocyclic heterocyclyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heterocyclyl selected from morpholinyl, pyrrolidinyl, azetidinyl, piperidinyl, tetrahydropyranyl, and oxetanyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heterocyclyl selected from morpholinyl and pyrrolidinyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted morpholinyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is morpholinyl. In accordance with some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted pyrrolidinyl. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is an optionally substituted heterocyclyl, which is a bicyclic heterocycle that is fused or spirocyclic. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is heterocyclyl, which is optionally substituted with alkyl, -R ^b -CN, heterocyclyl, -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 ; at

- 31 045324 wherein each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is heterocyclyl, which is unsubstituted or substituted with alkyl, optionally substituted with 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)R ^a ; wherein each R ^a independently represents hydrogen, alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl, or carbocyclyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or a straight or branched alkylene. According to some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, G is a heterocyclyl that is unsubstituted or substituted with methyl, oxetane, morpholine, -OMe, -CH2OH, _-NH2 , -CH2NH2 , -C(O)CH ₂ OH, -CN, -CH2CN, -CH2NHC(O)CH2OH.

In accordance with some embodiments, G is optionally substituted morpholinyl. In accordance with some embodiments, G is unsubstituted morpholinyl.

According to some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug Z thereof, is:

- 32 045324

Disclosed herein are LpxC inhibitors other than hydroxamic acid containing a core moiety. In some embodiments, the non-hydroxamic acid LpxC inhibitors contain a core moiety with a pKa of less than 8. In some embodiments, the non-hydroxamic acid LpxC inhibitors contain a core moiety with a pKa of less than 7. In some embodiments An LpxC inhibitor other than hydroxamic acid contains morpholinil.

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

wherein

A is a zinc-binding moiety different from hydroxamate;

each of R ¹ and R ² independently represents a group containing 1-50 atoms other than hydrogen, which are selected from the group consisting of C, N, O, S, P and halogen;

or R ¹ and R ² taken together with the carbon to which they are attached form =C(R ¹¹ ) ₂ , =NR11, =O or =S;

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

R ³ represents 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-C4alkylene)-C OR ¹¹ , optionally substituted (C0-C ₄ alkylene)-CO ₂ R ¹¹ , optionally substituted (C0-C 4 alkylene)-CON(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-CN, optionally substituted (C ₀ - C ₄ alkylene)-OR ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹¹ )2, optionally 12 11 12 11 substituted (C ₀ -C ₄ alkylene)-N(R)-COR, optionally substituted (C ₀ -C ₄ alkylene)-N(R)-CO ₂ R, optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )-CON(R ¹¹ ) ₂ , optionally substituted (C ₀ C ₄ alkylene)-N (R ¹² )-SO2N(R ¹¹ )2, optionally substituted (C ₀ -C ₄ alkylene)-O-SO ₂ N(R ¹¹ ) ₂ , optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹¹ ) -PO(optionally substituted C1-C4alkyl)2, optionally substituted (C0-C4alkylene)-SO2R ¹¹ , optionally substituted (C0- _C4 alkylene)-O-SO ₂ R ¹¹ , optionally substituted ( _C0 - _C4 alkylene)- N(R ¹² )-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted (C ₀ -C ₄ alkylene)-OPO ₂ OR ¹¹ ;

R ⁴ represents H or optionally substituted alkyl;

or R ³ and R ⁴ taken together with the carbon to which they are attached form =C(R ¹¹ ) ₂ , =NR11, =O or =S;

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

ring B is optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;

W represents a bond, -C=C-, bicyclo[1.1.1]pentanylene, -C=C-C=C-, -CH=CH- or -CH ₂ CH ₂ -;

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

each X and Y independently represents H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, nitro, -N(R ¹³ ) 2 or -OR ¹³ ;

each R ¹¹ independently represents 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 ny heteroarylalkyl;

or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl;

- 33 045324 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 ny heteroaryl or optionally substituted heteroarylalkyl;

or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; and n is 0-4;

m is 0-4 and

Z contains a main group with a pKa of less than 8.

In accordance with some embodiments, A is

A ₁ represents OH or SH; A2 represents O or S; and R ⁵ is H, halogen, optionally substituted alkyl, hydroxyl, alkoxy, cyano, amino or nitro. In accordance with some embodiments, R ¹ and R ² are each independently H or optionally substituted alkyl. In accordance with some embodiments, Z contains a basic group with a pKa of less than 7. In accordance with some embodiments, Z contains morpholinyl.

In some embodiments, the LpxC inhibitor other than hydroxamic acid has minimal toxicity. In some embodiments, the non-hydroxamic acid LpxC inhibitor has minimal cardiotoxicity.

In accordance with some embodiments, the LpxC inhibitor heterocyclic compound described herein has the structure shown in Table 1. 1.

Table 1

Compound No. Structure Weight [M+N] 1 O— _h / ^Ν=χ but Racemic mixture 474.4 2 O / ⁼ \ / ⁼ \ /—A ^NH ₀ H but Racemic mixture 446.5 3 O / ⁼ \ / ⁼ \ /—A ^{NH 4} ) OH O but *Separate enantiomer (I ^elution ) 446.5 4 O ^- it is but *Separate enantiomer ( ^2nd elution) 446.5 5 , ^N =\ /=\ /=\ /—ά NH ) he o ^^NH Racemic mixture 491.2 6 О 4J - _О Н ^NH F—' *Separate enantiomer (I ^elution ) 491.2

- 34 045324

7 О / ⁼ \ / ⁼ \ /—A ^NH ' V^z _{he 0} /—NH F— ⁷ *Separate enantiomer ( ^2nd elution) 491.2 8 / ^N= \ oL/\ ⁿ /=\ _ /=\ λΛ / ^ΝΗ it but Racemic mixture 446.2 9 o he /H ''ό hn /—\ * /=\ / ⁼ \ ^HN ^\ 1 /H ) — A /Z but^ *Individual enantiomer (I ^e elution) 446.2 10 % ^he ZA ?Ό HN 7 \ * /=\ /=\ HN—; 1 /A # - A /7 no^ *Separate enantiomer ( ^2nd elution) 446.2 AND oh he z\Z^O nm p—< /=>. /=. HN—ς । HO^ Racemic mixture 446.4 12 O / ⁼ \ / ⁼ \ /—A ^NH vjz^ ₀ /4 ₀ but Racemic mixture 460.5 14 O /=\ /=\ * /—A ^NH onX HN F—^ *Individual enantiomer ( ^2nd elution) 505.6

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15 O ^N /=Х /=Х /—ά ΝΗ _O n about HN ..... Racemic mixture 505.6 16 0—х ( / / ^N =\ ^N /=\ /=\ */—A ^NH _O h^o HN J..... *Individual enantiomer (I ^e elution) 505.4 17 ^ ^Ν=χ ^N /=\ /=\ ./—A NH _{oh o} HN J..... *Separate enantiomer ( ^2nd elution) 505.6 18 O ^N /=\ /=h y—ά NH ₀ H h ₂ n Racemic mixture 445.4 19 О—\ but о О Н 4W/$ _O ^N=/ _f ^nh Racemic mixture 505.6 20 О ъ° ^N /=\ /—( ^Z NH _f ^nh *Individual enantiomer (I ^elution ) 505.6

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21 HO 0 N /HCQ /=\ /—\ NH HWYo ^NH *Separate enantiomer ( ^2nd elution) 505.6 22 0—\ HO 0 O n /=\ /—e nh ^N=/ \=/ 4° ^NH F—( F Racemic mixture 523.4 23 o HH 4W/$ _O ^N=/ —ΝΗ Racemic mixture 473.5 24 D V 4W/tr -O Racemic mixture 474.5 25 O /rx\ /=\ /—( ^Z NH \=/ ^0 ^f n ^/ Y' ^nh Racemic mixture 549.4 26 but 0? >—NH /ghx /=\ /—C NH </Uch ^n=/ \=/ Cho g° Racemic mixture 488.5

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27 BUT oh ? U- NH /llx /=\ /—\ NH -0 Racemic mixture 474.3 28 o y zr^x /=\ z—< ⁷ NH hW/H'f' \=/ ^= ₀ HN ?—— ^N Racemic mixture 512.5 29 F 0 ft >h ⁿ He ^H ° ° Racemic mixture 534.5 thirty F /— ⁷ HN ^^NH ^{4=7 4=7} ho ^z 0 Racemic mixture 505.6 31 but gУУ-^УУ-/ Ν=χ \=/ ^Z ^NH o-/ noc Racemic mixture 460.3 32 £ Vnh ^{4=7 4=7 /ν} Λ, ^ΝΗ HOt) Racemic mixture 460.5

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33 _N \=/ \=/ * ν_Λ _ΝΗ BUT O 455.2 34 NC 6 y^yyy^yyJ^ HN \=/ \=/ S)en Racemic mixture 455.4 35 NC ό = Χ ^Ν НмУ^ * ^=/ \=/ ϋ en *Separate enantiomer ( ^2nd elution) 455.4 36 NC y _N ^o yyy^yyP HN У-' ^= ⁷ ^=/ en Racemic mixture 455.5 37 O^J^NH ^=/ \=/ ^ν Λ,ΝΗ H0t> Racemic mixture 458.3 38 ₌ ΛΑ ^Н <У ^{4=7 4=7 HN} 4?s=o su he δ Racemic mixture 494.2 39 ₌ ⁿ <^* ^{4=7 4=7 HN} 4?s=o en o *Separate enantiomer ( ^2nd elution) 494.2

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40 /=ν°Ύ#Λ = ^{4=7 4=7 HN} 4?s=o en ο *Individual enantiomer (I ^elution ) 494.2 41 ΗΝ^^*^ HN^Q _=q en 0 *Individual enantiomer ( ^2nd elution) 494.2 42 _{= N} \=/ \=/ V/ _NH A /n Racemic mixture 472.6 43 HN—' '—£ NH ΓΛ ns>ъ 0 Racemic mixture 160.3 44 Г y-NH ^=/ \=/ '--NH ^ο ^ ^Ν -/ J HO ^X o no ^x Racemic mixture 503.1 45 o r^ ^NH '>h ⁿ J HO o no *Individual enantiomer ( ^I elution) 503.1 46 Г y-NH ^=/ ^=/ NH ) but o no ^x *Separate enantiomer ( ^2nd elution) 503.1

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47 ΧΛ = gG ^but o Racemic mixture 458.4 48 NHCHH BUT \=/ \=/ X.NH N(e) Racemic mixture 477.5 49 UХХ 0^- NH ^= ⁷ ^= ⁷ Μ NH Н0ь Racemic mixture 432.4 50 0 Oj4NH ^{4=7 4=7} M\ NH no Racemic mixture 474.3 51 _N \=/ \=/ V_Z _NH XX 0 Racemic mixture 501.5 52 Ch ChXX ¹ ' Chn ^= ⁷ ^= ⁷ ΧχΝΗ noХ Racemic mixture 460.6 53 O)-NH ^= ⁷ ^= ⁷ XX ^NH ΗόΧ) Racemic mixture 460.3

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54 _N \=/ \=/ VC _NH HN^ HO o Racemic mixture 445.3 55 OC°nV _N \=/ \=/ * v/. _NH HN^ HO O *Single enantiomer ( ^2nd elution) 445.3 56 ^A ₌ °n=\ ηνΧλ ^{νη 4=7 4=7} 0 HO b Racemic mixture 493.2 57 λα ^А Л ^on 0^ gЛ 7 = \ УЧ N=\ / ^NH ^= ⁷ ^= ^{7 v} AnH Н0ъ Racemic mixture 434.2 58 < ^A ₌ ^NH ^= ⁷ ^= ⁷ ^Λ,ΝΗ but Racemic mixture 430.5 59 / N \=/ \=/ NH BUT o/ Racemic mixture 473.6 60 3Λ^ ^{ΝΗ 4=7 4=7} '—/ ^ΝΗ °' but (E Racemic mixture 478.3

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61 ₌ —NH NH HO Racemic mixture 390.2 62 r\ hnL> ^nh Uch ⁿ nob Racemic mixture 445.3 63 η ₂ ν \=/ \=/ ^Α νη noL Racemic mixture 376.1 64 LA LA L ^he Η ₂ Ν 7 = \ UCH ^Ν =\ AY ^{4=7 4=7} A / ^ΝΗ сА HOt) Racemic mixture 460.2 65 АаъГу _N \=/ \=/ V-/ _NH 0^ HOt) Racemic mixture 431.3 66 F HN Ν=χ O ⁷ noo Racemic mixture 505.5 67 F HN Ν=χ A ^Scientific O ⁷ HO^O \ *Separate enantiomer (I ^elution ) 505.5 68 F $..... ΗΝ ααΑ ν=\ 0 ⁴⁼⁷ Ά, ^νη J HOD *Single enantiomer ( ^2nd elution) 505.5 69 F HN ГУ-У^^ТУ^ Ν=χ ¢4 \=/ n O ⁷ HO O \ *Individual enantiomer (I ^elution ) 505.7 70 FY HN D ^= ⁷ 'MC1H ₀ ' noo *Separate enantiomer ( ^2nd elution) 505.7

- 43 045324

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80 F HN^ N=\ _N \=/ \=/ _NH HOt) *Single enantiomer ( ^2nd elution) 517.6 81 F /=\ _ ΛΑ / ^ΝΗ lch # - \ /A Ζ ^Ν= \ Ν \=/ ν_ζ _ΝΗ NC ^Η0 ° Racemic mixture 500.5 82 F $..... HWjyy _N \=/ * _NH NC ^H °° *Single enantiomer ( ^2nd elution) 500.5 83 F U m \=/ _NH NC^ ^{H0 0} *Separate enantiomer ( ^2nd elution) 500.5 84 F /=\ - ΛΑ / ^N?H lА / - \УХ Z ^N =\ N \=/ _ΝΗ Λ> nH ο- ⁷ Racemic mixture 531.4

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85 F /=\ _ // \\ Γ-NH o- ⁷ *Individual enantiomer ( ^2nd elution) 531.4 86 O. OH b NH AM ⁷ 'U F Racemic mixture 519.7 87 ^^ОН ™Сб У ^N λ/HA ζ=, О NH VzZ •у F ^Z *Individual enantiomer ( ^I elution) 519.4 88 b ^he A NH VjZ F *Separate enantiomer ( ^2nd elution) 519.4

- 46 045324

89 h _he ( ν- ⁷ ΝΗ V# F ^Z Racemic mixture 519.4 90 O. he ( vy----s=^^ NH '“Cs) F ^Z *Single enantiomer ( ^2nd elution) 519.4 91 CN F b S- L-Ν /=\ zr^x ^NH M / \ / ^N= \ BUT (D Racemic mixture 514.3 92 CN ^F O /=\ ^NH M. / \ / ^N=x ^= ^{7 V} 4_NH HO C) Racemic mixture 514.6 93 CN ^F O /=\ /r^x ^NH / \ / ^{N=x 4=7} * ^VA / ^NH but ⁷ O *Separate enantiomer ( ^2nd elution) 514.6

- 47 045324

94 __V ο^νη ^χ = ^/ \=/ ^Λνη ηοΠ) Racemic mixture 491.6 95 I v ^F X ΛΑ ΛΑ Λ ^ΝΗ / - \ UC ^N =\ \=/ \=/ ά NH but ⁷ O Racemic mixture 514.5 96 ΧΛΑ^ΛΑΛ^ NOS) *Single enantiomer ( ^2nd elution) 514.5 97 уУ ⁴ _N \=/ \=/ V/ N _H 0^ HO^) Racemic mixture 512.4 98 уУ ^ы ₌ fy^ ^N ^=\ N \=/ \=/ * NH o^ no * Separate enantiomer (I ^e elution) 512.4

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99 yj3N ^r\ ₌ fy^ ^N ^=\ \=/ \=/ * \—Z W HO OH *Single enantiomer ( ^2nd elution) 512.4 100 = Π ^ΓΝ ^ _N \=/ \=/ * V_Z _z N Η en *Individual enantiomer ( ^2nd elution) 512.4 101 F _Ν \=/ \=/ _{ΝΗ 0} ; ⁿ ° ^m ° Racemic mixture 505.5 102 Ν _χ g Ν=\ _Ν \=/ \=/ ν_ζ _ΝΗ HOb Racemic mixture 510.4 103 N, V ^and N Ν=χ _N \=/ \=/ 'V/ _NH HOt) *Individual enantiomer (I ^elution ) 510.4

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104 Ν _χ V % NUMM' N=\ HOb *Separate enantiomer ( ^2nd elution) 510.4 105 _g -G\ ₌ \=/ \=/ NH O—' but o Racemic mixture 505.6 106 _Ν \=/ \=/ * V/ _ΝΗ ΗΟΪ) *Individual enantiomer (I ^elution ) 505.6 107 _Г Т\ = ГИ^ \=/ \=/ 'Η _N H O ^- ' HO O *Separate enantiomer ( ^2nd elution) 505.6 108 O»on n\Ul /=\ /=\ ^Η / ^Ν Τ^Ο F * Racemic mixture 505.4 109 Ο _χχ he /=\ /=\ ^Η , ^Ν Τ^Ο \ _k j \ * / \ / \ / (rVV-— ^N / А V ~ А V F * *Separate enantiomer ( ^2nd elution) 505.4

-50045324

110 O OH /U ?^0 ην Ud /=d /=d ^41 ^Ν /L / - A F * Racemic mixture 505.5 111 o he <Χ _Ο _ /=\ uch? ^Ν /X y - y χ F * *Individual enantiomer ( ^2nd elution) 505.5 112 A ΗΝ IHY Ν=χ сХ noХ) Racemic mixture 535.6 FROM A HN X _Ν \=/ \=/ ΝΗ HOt) *Individual enantiomer (I ^elution ) 535.6 114 A ΗΝ ν=\ _Ν \=/ \=/ * ν/ _ΝΗ noХ) *Separate enantiomer ( ^2nd elution) 535.6

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115 F _N \=/ \=/ V/ _NH sU NoUe Racemic mixture 509.3 116 42 o HN Str * /=\ za Н^СН \ __^NH F *Individual enantiomer (I ^elution ) 509.3 117 42 About HN 'K. /=\ /gd. УУ - \=Ч F^__/NH F *Separate enantiomer ( ^2nd elution) 509.3 118 уУ ₌ fyy ^N C _N \=/ \=/ VJ' _NH >У НУ) Racemic mixture 485.5 119 уУ = fyy ^N C _N \=/ \=/ * V_z _NH сУ but О *Individual enantiomer ( ^I elution) 485.5 120 уу = fyy ^N y _N \=/ \=/ NH оУ НОУ) *Separate enantiomer ( ^2nd elution) 485.5

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121 MeO CM) A <M mu^yyU ^{4=7 4=7} * but ⁷ O *Separate enantiomer (I ^e elution) 529.3 122 MeO ..... b oM Mumub ^{4=7 4=7} * ^V A ^NH but ⁷ O *Separate enantiomer ( ^2nd elution) 529.3 123 F ΜΜΜ ^Ν ί AU Racemic mixture 518.6 124 U b /=\ l-ъ ^ΝΗ X / \ / ^Ν=χ \=/ mu _ΝΗ HC)O Racemic mixture 517.7 125 a MU—UHM _Ν \=/ \=/ m\ΝΗ M H(Eb /0 Racemic mixture 536.2

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126 % V. /=\ ^ΝΗ X # ~ \ / \ X ^=/ ^v 4nh but ⁷ 0 Racemic mixture 531.7 127 Ch V UL = \=/ \=/ Χά _NH but ⁷ O Racemic mixture 531.5 128 o .X _N \=/ \=/ XY _NH (X HOt) Racemic mixture 551.6 129 X _N \=/ \=/ x; _NH o^ ⁷ noL Racemic mixture 489.5 130 Г= Г\-Г^ _N \=/ \=/ Xf _NH о^ ⁷ HOt) Racemic mixture 498.4

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136 F o TH /0 *Individual enantiomer ( ^I elution) 519.7 137 F Q Λ /0 *Single enantiomer ( ^2nd elution) 519.7 138 F ^{4=7 4=7} NH H0t> Racemic mixture 519.3 139 F HDB Racemic mixture 491.4 140 F ^У^УУч^ _N \=/ \=/ *M n _H H0t) *Individual enantiomer ( ^2nd elution) 491.4 141 F^/ \=/ \=/ Uch ⁿ NO^Z Racemic mixture 491.7

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142 ₌ <GUCH ⁿ n=\ _N \=/ \=/ , V-0 _NH but O *Separate enantiomer ( ^2nd elution) 491.7 143 F $..... m \=/ /V_Z_ _NH -O ⁷ HO 0 Racemic mixture 519.6 144 yjDH ^VnH ^= ⁷ ^= ⁷ HO' 0 Racemic mixture 503.6 145 NH ₂ \=/ \=/ v/' _NH n0b Racemic mixture 459.3 146 NH ₂ \=/ \=/ 'M. _NH HO t) *Single enantiomer ( ^I elution) 459.3 147 NH ₂ \=/ \=/ 'Η _NH noU *Separate enantiomer ( ^2nd elution) 459.3

- 57 045324

148 ΧηχΧ nh ₂ \=/ \=/ A/ _NH nob Racemic mixture 459.3 149 av av _NH Hdb Racemic mixture 507.2 150 0 V- NH ^but H } C^l = Ox ( \=/ \=/ _HN ......../ j he X-o NH Racemic mixture 493.2 151 V- NH ^but y? ) ll = ll _h / \=/ \=/ 5 he X=o NH Racemic mixture 493.2 152 but nA but^o N Racemic mixture 503.2 153 V- NH ^N °H ) ) LL = AL _x / \=/ \=/ ......../ | OH ^ ^Ν ·^Ο 513.3

- 58 045324

154 /HE vs jCQ X) o HO || nm—' ΌΗ Racemic mixture 503.2 155 Ο ьМ ИН /О “ Ox /О / -V -V _Н №-< j he Racemic mixture 489.2 156 0 V- ΝΗ HO—4 ( ^=/ ¹ ^=/ ¹ |\........Lu Ън X oХ)Н Racemic mixture 503.2 157 Vn^JHNH ^{4=7 4=7} * ΧχΝΗ ^but noХ) *Separate enantiomer ( ^2nd elution) 517.4 158 ^H0 O Η Λ-Ν ^{4=7 4=7} _ζ ΝΗ X noP) Racemic mixture 517.2 159 h Ν=χ _Ν \=/ \=/ *V_Z _ΝΗ -O ⁷ NOS) *Individual enantiomer (I ^e elution) 503.5

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160 N=\ _N \=/ \=/ *V/ NH -ς> HO 0 *Separate enantiomer ( ^2nd elution) 503.5 161 £ HN Ν=χ UC 0^ NS) 0 Racemic mixture 515.6 162 Ρ ΗΝ Ν=Χ ^-Ν C-U HOC) *Individual enantiomer (I ^elution ) 515.6 163 £ HN N=x \=/ \=/ M^NH noo *Separate enantiomer ( ^2nd elution) 515.6 164 \ $° HN ИУ^УУ^ n=x ^-N \=/.V_Tm _H o-'HC>0 *Individual enantiomer (I ^elution ) 503.3

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165 0 HN Ν=χ A = ⁷ Α/ ^νη сЛ noо *Individual enantiomer ( ^2nd elution) 503.3 166 O ΗΝ Ν=\ \=/ \=/ Η _Ν Η BUT O Racemic mixture 515.6 167 G ΗΝ ν=\ \=/ \=/ ΝΗ 0^ BUT 0 Racemic mixture 503.4 168 g HN _N \=/ \=/ * V-KnH o^ ⁷ but ⁷ © *Separate enantiomer (I ^e elution) 503.4 169 g HN Ν=χ /— N '—''—' * '—£ NH 0^ HO ⁷ © *Separate enantiomer ( ^2nd elution) 503.4

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170 C HN \=/ * >H ^H no^o *Separate enantiomer (I ^e elution) 503.4 171 C HN Ν=χ _N \=/ \=/ * v_z _NH 0^ HO <0 *Separate enantiomer ( ^2nd elution) 503.4 172 = O-/ ^N N=\ HO 0 Racemic mixture 507.3 173 ΛΑ / ^NH2 ₀ -\ / = \ lЧ , ^N= \ l4J> _N H ^=/ \=/ ^ν Λ_ΝΗ but ⁷ 0 Racemic mixture 431.3 174 -PL- \=/ \=/ ^^ΝΗ but eh -O Racemic mixture 459.1

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180 'b gUU^UU^ N=\ 0 Uch ⁿ HO C) \ *Individual enantiomer (I ^elution ) 503.4 181 ъ ^<У^<у7 N=x ₀ ' NOS) *Separate enantiomer ( ^2nd elution) 503.4 182 ^O O HN _{N=x N} \=/ \=/ *M N _H 0^ HO^O *Individual enantiomer (I ^elution ) 556.7 183 ^0 0 HN r/W/b? Ν=χ <G noo *Individual enantiomer ( ^2nd elution) 556.7 184 HN—/ HN N=\ VV · M^NH HO C) *Individual enantiomer (I ^elution ) 525.6 185 О hn-У HN ^У^УУ/ Ν=χ /—N ^= ⁷ ^= ^{7 ν} Λ.ΝΗ 0^ HO 0 *Separate enantiomer ( ^2nd elution) 525.6 186 o.,p HN n=x /-N ^=/ \=/ 'Μ.NH 0^ NOS) *Individual enantiomer (I ^elution ) 563.5 187 o.,p £ HN ИУ^УУ^ Ν=χ ^N ^=/ \=/ * >Ч ^Н 0^ but o *Separate enantiomer ( ^2nd elution) 563.5

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188 <UR HN aau n=x qA nose" *Individual enantiomer ( ^I elution) 563.7 189 o.p HN N=\ A ^= ⁷ \=/ 'Μ ΝΗ o- ⁷ NOO *Separate enantiomer ( ^2nd elution) 563.7 190 o ⁷ ААУЧ ν=\ A ΝΗ сА HO(E Racemic mixture 460.1 191 F Y ΗΝ TA >0 pL 7 = 4 J, nA n=\ Г; b H ⁿ 0^ HO b Racemic mixture 567.2 192 / 0 >0 A ⁷ 7 = 4 J. nA n=\ C) A At HO b Racemic mixture 518.3

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193 BUT A/ = ODN4 N=\ G? Ό ^Η but b Racemic mixture 490.4 194 N^\ // \\ <“ ^0Н \=/ ^V ANH Hot) Racemic mixture 435.3 195 OD = fX°N=\ _N \=/ \=/ V/ _NH 0^ NoD Racemic mixture 447.5 196 УУ^/Ul _N \=/ \=/ V/ _NH HOt) Racemic mixture 447.4 197 να _ λα Λ ⁰ ' /7—==—\ 7—\ ^N =\ \=/ V/'YiH HOt) Racemic mixture 351.2 198 GA LA L ^on g Vnh ^=/ y-( N=\ 0-'' \=/ V-Λ _ΝΗ H0t) Racemic mixture 448.5 199 F ^Χ Ν-Λ - ΛΑ Λ ^Ν 11 №=/ noD Racemic mixture 396.2

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200 Ν Ch - /X / ^{Ν N} 2 _M X - SKA, nsHo Racemic mixture 336.1 201 X - X Γ°Ν 4=/ VJ nh ⁰ noH Racemic mixture 393.2 202 nXXXX m ? - \ / \ ,Х \=/ Μ _ΝΗ Ο-j noХ) Racemic mixture 421.3 203 l /X A ^he g~\ m XX O hX XX Vn^z V/ _NH o UCH HO O Racemic mixture 480.2 204 o he X · /=\ o ....... ^/N he * Separate enantiomer 452.6 205 Ci ^hn ^X ₌ lu? _Ν=χ νΧ NS'0 Racemic mixture 466.3

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206 $ ^F HN N^/ \==/ V_A _NH but <o Racemic mixture 480.2 207 F $ HN fT ^N C^ - \ / ^N= \ N\y ⁴⁼⁷ уУ ^Н HO> 0 Racemic mixture 431.41 208 F $ HN _n= . V/\ _H o-/ )-4 HO 0 Racemic mixture 438.3 209 ^Ts _N 0^ HOO 442.3 210 0 = yy ^NH n=\ \=/ \=/ 4 _w O± HO 0 457.3 211 HO gUL = <УN-( N=\ 0^HO 0 Racemic mixture 463.3

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212 HO >0 /—\ G~\ 7—(\ J. N—( N=\ NH but ⁷ 0 Racemic mixture 494.2 213 HO GU/X N=\ \=/ \=/ ό NH but ⁷ 0 Racemic mixture 323.4 214 O^ul^y/y^ ^= ⁷ M\nH but ⁷ o Racemic mixture 421.1 215 ъ ^/ —СУ — СУ —\ / ^Ν=χ y ^N = ^{7 W} '4nH but'сз *Individual enantiomer (I ^elution ) 503.6 216 У ХУ—= ΟΧ _z ⁿ⁼ \ HOC) *Separate enantiomer ( ^2nd elution) 503.6 217 % d ⁿ U yY - *Individual enantiomer ( ^2nd elution) 446.3

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218 Ν 1 ν Ο Υ X /=х /=х \ # - А / ^Ν=χ HC) 0 *Separate enantiomer ( ^2nd elution) 510.4 219 < A O -N X /=x /=x ) ) - A / ^N=x * 4\/ ^NH Ho'o *Separate enantiomer (I ^elution ) 499.7 220 X „ _ ⁴ -A # - A , ^N= \ *γ. NH HOC) *Single enantiomer ( ^2nd elution) 499.7 221 < to О HN /=х /=х ) ) — А # \ / ^N=x * 4\, ^NH but ⁷ О *Separate enantiomer (I ^elution ) 519.5 222 / F b HN ⁷ ^ x, ? — у Λλ, ^ν =\ * ^V £/ ^NH ΗΟ^Ο *Separate enantiomer ( ^2nd elution) 519.5

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228 < ? X HN /=х /=х ) — У # \ / ^N=x * X / ^NH HO (D *Separate enantiomer ( ^2nd elution) 499.6 229 HO _ts Α”θ - Χχχ o^ but ⁷ o *Separate enantiomer (I ^elution ) 501.5 230 y X = O~?N=\ \=/ -CA O± noo *Separate enantiomer ( ^2nd elution) 501.5 231 HO - <xX^\ _Z ^N= \ NX/ X *X\ NH < ) FX 0^ HO 0 *Separate enantiomer ( ^2nd elution) 519.4 232 HO O ί> ^{Η 4=7 4=7} Χ ^ΝΗ Ί no'se Racemic mixture 487.5 233 HO X ί >-NH ^= ⁷ ^= ⁷ * '—(\ NH ° _V XX 1 HO 0 *Individual enantiomer ( ^I elution) 487.5

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239 l /=\ /=\ \J - but ⁷ O *Separate enantiomer ( ^2nd elution) 549.3 240 HO ^=/ _NH nsa )- ⁷ NOS) Chin O Racemic mixture 517.3 241 HO = ^< HC\ ^N =\ _N \=/ ChL Λλ' _ΝΗ HO—\ HOC) Vnh 0 *Individual enantiomer (I ^elution ) 517.3 242 HO HO—y ) - ⁷ ΗΟΌ 4NH O *Separate enantiomer ( ^2nd elution) 517.3 243 Cho HO—\ HO ^N =\ ^{4=7 4=7} * M, NH HO^C) *Separate enantiomer ( ^2nd elution) 490.3 244 b ^{he ην} ΓΚ ° ^N /==> ci ΝΗ V4 ΗΟ ^/ \ F Racemic mixture 521.6

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245 h/V _ O NH ......1 but' *Separate enantiomer ( ^2nd elution) 503.3 246 Vv ^OH Un O ^UCHU—O ⁷ \ ⁴⁼⁷ NH ......1 HO *Separate enantiomer ( ^I elution) 503.6 247 0 OH o ⁿ \U-/=\U N but ⁷ *Separate enantiomer (I ^elution ) 503.4 248 O OH o nOH · /=\ U N but ⁷ *Separate enantiomer ( ^2nd elution) 503.4 249 0 OH ⁿ CC U NH Vy U ^he F Racemic mixture 521.3

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250 \ 0 OH ^h nV^*/=\ ζ-λ. Ν ³ ΝΗ *Individual enantiomer ( ^I elution) 499.3 251 \ ο _ν he Ρ Η ο ΗΝ Ъ*/=\ ζτ^χ Ν J— ΝΗ *Separate enantiomer ( ^2nd elution) 499.3 252 O OH ΗN y—x * /=\ /=\ OH / \ ^— a HN^ ^OH / *Separate enantiomer ( ^2nd elution) 466.5 253 o he ⁿ \ M· /=\ /=\ V HN—< J ° he *Separate enantiomer (I ^e elution) 523.3 254 o he /k / A # A # ' ζ Ν 'l / HN—< J ^υ OH *Separate enantiomer ( ^2nd elution) 523.3 255 o he ^ΗΝ νΤ~Λ V /L / ^— \ / L / ΗΝ—Ζ J ° he Racemic mixture 523.3

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256 η ⁿ /1 j /^Ν—\ no^h^m 1 / γσ Ύγ ΌΗ Racemic mixture 513.3 257 χ ^ΟΗ ΗΝ^Ο ΟΗ ζ 1 ς /=\ ν—' /у+7 0 he Racemic mixture 503.3 258 0 V- ΝΗ ^Η0 Λ ) A ^he p nh ₂ Racemic mixture 475.2 259 V- pln—X / ^N \ll = ll _x ς \=/ \=/ _ΗΝ —/ _ΝΗ he '—' Racemic mixture 459.3 260 A? - €>l.....r \>n / ^ ^ΝΗ Racemic mixture 459.2

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261 O VNH ^H °-Q OH Racemic mixture 459.3 262 0 y—ΝΗ ⁿ ° y_ _ G ^! uO - he Racemic mixture 502.2 263 0 VNH ^N °H /> / ^Ν \ /=\ /—\ /° /L? - (/ \ ( ^λ - ^{7 v} nh ₂ he Racemic mixture 411.1 264 0 У—NH ^Η θ4 /) / ^Ν < ΛΑ X /? ( ^= ⁷ ' ^—7 '—OH he Racemic mixture 412.1 265 —NH ^but L ) / ^N ) ll = ll _x HN \=/ \=/ HN........< I \ Vo Racemic mixture 445.2

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266 oi X TA___/AU/ /=m /—( )—=—( UA nh hn \' * \=/ \=/ '— ^/ 0 he *Separate enantiomer ( ^2nd elution) 446.3 267 0 OH ^ΝΗ *Separate enantiomer ( ^2nd elution) 475.3 268 O OH ^hn CVa* HA _ HA ^but \ / \=/ \=/ he θ ^ΝΗ *Separate enantiomer ( ^2nd elution) 475.3 269 ^rn ---ryJ HN >— ⁷ * ^=/ ^= ⁷ o ⁷ OH *Separate enantiomer ( ^2nd elution) 490.3 270 o he HN ?-у /=\ /=\ ^ОН / V? ^— (OH he *Separate enantiomer ( ^2nd elution) 407.4 271 °D % t = T ^Η/Ν θ HN 7- ⁷ \=/ \=/ ^N Racemic mixture 432.3

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272 ^OH ην % O OH /—< O HO^ )=/ ^=/ F *Separate enantiomer ( ^2nd elution) 535.4 273 y ^he gY° HN V—, )=d/gd, hr but—* ^= ⁷ *Separate enantiomer ( ^2nd elution) 476.6 274 OH /=Ch /A # - C HN 4 ⁷ ^ ⁷ N—। US ^F O- O OH 'CN Racemic mixture 473.3 275 0 OH HN \ /=\ Ud, he *Separate enantiomer ( ^2nd elution) 519.4 276 41 O he *Separate enantiomer ( ^2nd elution) 519.6 277 O _h OH ^0 H \ O HN Sp /=\ Sp, N—' he *Separate enantiomer ( ^2nd elution) 519.5

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278 0, OH _l o n \ O ^HN ch. /=\ '= ^N 7 F *Single enantiomer ( ^2nd elution) 521.3 279 CN F *Single enantiomer ( ^2nd elution) 522.5 280 Hl V O VO = νΛ аЧ F *Individual enantiomer ( ^2nd elution) 523.6 281 N ill o he _F Yes ΗΝΌ-α 5=\ /Г^ уУУУУУ F^__/NH F *Separate enantiomer ( ^2nd elution) 536.5 282 1 p F^__/NH F *Single enantiomer ( ^2nd elution) 527.3

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283 __^NH F *Single enantiomer ( ^2nd elution) 527.6 284 V ^H HH. h η Р ^N pJXP Ν U no *Individual enantiomer ( ^2nd elution) 521.5 285 O. he ΗΝ р--\ /=\ /=\ ΗΝ^ 1 у _о J4J - X *Separate enantiomer ( ^2nd elution) 460.3 286 O HN р--у /=\ /=\ N—' uech/ - BUT^p^ but^\\ 0 * Single enantiomer 526.2 287 A_on /A .'^ΝΗ ΗΝ p--< /=\ /=\ ΗΝ—k J ChUkh/ - C/ *Separate enantiomer ( ^2nd elution) 459.4 288 0,__on ^ΗΝ Уа /=\ /=\ ^ΗΝ ^Τ *Separate enantiomer ( ^2nd elution) 459.4

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289 W с о ⁷ \ *Individual enantiomer ( ^I elution) 509.2 290 HO 0 /—< /=4 /=\ * NH '—' OH^—. NH / ⁸ ¾ *Single enantiomer (I ^elution ) 509.3 291 HN^ HO 0 O _n ^47 - C-$ _n / ⁸ ¾ * Individual enantiomer 538.4 292 o V—NH ^but H /) / ^N ne - ° ⁿ h ₂ n Racemic mixture 445.3 293 o V— NH ^no -r yO - O/ ⁷ he Racemic mixture 418.2

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294 Urn n/U Η' V/M Α/χρ ΝΗ V\ ._. '/ ^ν ο F Racemic mixture 518.53 295 Χ O* ^S \mu χ χ * o- ⁷ but U *Separate enantiomer ( ^2nd elution) 508.45 296 HO O /—\ / ⁼ \ / ⁼ \ /—\ ^{NH ΗΝ} νλν/^1Χ ^{Ν=/ 4} ---' OH o _Z NH / o *Single enantiomer ( ^2nd elution) 508.54 297 ΗΝ—\ HO O O UN \ ) — U /M OH ^““o / ^ΝΗ / o *Separate enantiomer ( ^2nd elution) 537.54 298 o¥ SUM «=\ \=/ \==/ *\--ΝΗ BUT Y) *Individual enantiomer ( ^2nd elution) 409.45 299 \//° O* ^S \ γΓ\ = ГУп ^Н X / \ / \ / * \ / х _ N ''>'' (\ NH pH O\ ^{H0 0} *Individual enantiomer ( ^2nd elution) 508.51

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300 A Ο ^f m (X but 0 *Separate enantiomer ( ^2nd elution) 532.52 301 cX HO ⁷ % *Single enantiomer ( ^2nd elution) 518.60 302 —N x * Ax 0^ HO b *Separate enantiomer ( ^2nd elution) 498.46 303 У HN x /—N '— ⁷ '— ⁷ '—ά NH сХ no'b *Separate enantiomer ( ^2nd elution) 486.55 304 OX /X HN but 0 *Separate enantiomer ( ^2nd elution) 522.61 305 XN x Y> * M ^NH but ⁷ Y * Separate enantiomer ( ^2nd elution) 509.56

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Names of compounds in table. 1 are as follows:

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

-hydroxy-6-(3 -hydroxy-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(K)-5-hydroxy-6-(3-hydroxy-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(8)-5-hydroxy-6-(3-hydroxy-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

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

(R)-6-(3-((2-φτopethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(3-((2-fluoroethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

5-hydroxy-6-(3-hydroxy-2-(4-((4-((((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

(R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-τeτpahydropyran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

(8)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((K)-tetrahydrofuran-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

-hydroxy-6-(3 -hydroxy-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)pyrimidin-4(3H)-one;

6-((K)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-((8)-3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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

6-((R)-3 -(((R)-1 -fluoropropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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6-((8)-3-(((R)-l-fluoropropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(ZN)-on;

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

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

(K)-M-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propanamide;

(8)-M-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propanamide;

18G-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide ;

3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-K-methyl-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide;

methyl 3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanoate;

N-(3,3-d iforocyclobutyl)-3-(5-hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4((4-(morpholinomethyl)phenyl)ethynyl)phenyl )propanamide;

ethyl-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)-2-(4-((4(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl )phenyl)propanoate;

methyl-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl) phenyl)propanoate;

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

K-(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;

K-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((((8)tetrahydrofuran-3-yl )amino)methyl)phenyl)ethynyl)phenyl)propanamide;

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

5-hydroxy-6-(3-hydroxy-2-methyl-2-(4-((4-((((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

1-(4-((4-((8)-1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)propan2-yl)phenyl)ethynyl)benzyl )pyrrolidine-3-carbonitrile;

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-(4-((4-((R)-1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2-yl)phenyl)ethynyl)benzyl)pyrrolidin- 3-carbonitrile;

(3 S)-1 -(4-((4-(1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4yl)propan-2-yl)phenyl)ethynyl) benzyl)pyrrolidine-3-carbonitrile;

(3 S)-1 -(4-((4-(1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4yl)propan-2-yl)phenyl)ethynyl) benzyl)pyrrolidine-3-carbonitrile;

(S)-1 -(4-((4-((8)-1 -hydroxy-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl )benzyl)pyrrolidine-3-carbonitrile;

(S)-1 -(4-((4-((R)-1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4yl)propan-2-yl)phenyl )ethynyl)benzyl)pyrrolidine-3-carbonitrile;

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

6-(2-(4-((4-(((3-oxabicyclo[3.1.0]heκcan-6-yl)amino)methyl)φenyl)ethynyl)φenyl)3-hydroxypyripidine)-5-hydroxypyrimidine-4( ZH)-on;

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

6-(2-(4-((4-((((8)-1,1-dioxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidine-4( ZN)on;

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

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

6-(2-(4-((4-((((R)-1,1-dioxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidine-4( ZN)on;

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

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

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

5-hydroxy-6-(3-hydroxy-2-(4-((4-(2-(((8)-tetrahydrofuran-3yl)amino)ethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((K)-1 -(2-hydroxyacetyl)pyrrolid in-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl )pyrimidin-4(3N)-one;

-hydroxy-6-((K)-3 -hydroxy-2-(4-((4-((((K)-1 -(2-hydroxyacetyl)pyrrolid in-3 yl)amino)methyl)phenyl)ethynyl )phenyl)propyl)pyrimidin-4(3H)-one;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-((((K)-1-(2-hydroxyacetyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl) phenyl)propyl)pyrimidin-4(3H)-one;

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

-hydroxy-6-(3 -hydroxy-2-(4-((4(hydroxymethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

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

ethyl-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)-2-(4-((4-((oxetan-3 ylamino)methyl)phenyl)ethynyl)phenyl) propanoate;

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

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((tetrahydrofuran-3 - yl)methyl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N)- He;

5-hydroxy-6-(3-hydroxy-2-(4-((4-(((tetrahydro-2H-pyran-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

-hydroxy-6-(3 -hydroxy-2-(4-((4-(piperazin-1 ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(K)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(8)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -imino-1 -oxidotetrahydro-1 Η-116-thiophen3-yl)amino)methyl)phenyl)ethynyl)phenyl)propyl )pyrimidin-4(3N)-one;

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

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

-hydroxy-6-(3 -hydroxy-2-(4-((4-(4-methylpiperazin-1 carbonyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -oxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4((methylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((K)-pyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

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

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

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

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;

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;

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;

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;

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;

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;

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

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

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

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

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

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

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

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

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

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

1-(4-((4-(1-(((8)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propan- 2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

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

-(4-((4-((8)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3 -(5-hydroxy-6-oxo-1,6dihydropyrimidin-4-yl )propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

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

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

1-(4-((4-((8)-1 -(((R)-1 -fluoropropan-2-yl)amino)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidine-4- yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

6-(3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol5(3H)- yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((2К)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4с]pyrrol-5 (3H)-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

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

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

- 91 045324

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

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

6-(3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-(((8)-3 -methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl) phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((R)-3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-(((8)-3 -methoxypyrrolidin-1 yl)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((8)-3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-(((8)-3 -methoxypyrrolidin-1 yl)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

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

(3 S)-1 -(4-((4-(1-(((8)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6dihydropyrimidine-4 -yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

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

(S)-1 -(4-((4-((8)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3 -(5-hydroxy-6-oxo-1, 6dihydropyrimidin-4-yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile;

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

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

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

2-( 1 -(4-((4-((8)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidine -4-yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile;

-((3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butanenitrile;

(3 S)-3 -((3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl )amino)butanenitrile;

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

(S)-3-(((R)-3-(5-hydroxy-6-oκco-l,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanenitrile;

- 92 045324 (3R)-3 -((3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl) propyl)amino)butanenitrile;

(K)-3-(((8)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanenitrile;

(R)-3 -(((R)-3 -(5 -hydroxy-6-oxo-1,6-dihydropyrimide in-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl) phenyl)propyl)amino)butanenitrile;

6-(3 -((2-fluoropropyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H )-He;

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

(R)-1 -(3 -(5 -hydroxy-6-oxo-1, 6-d ihydropyrimide in-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl) azetidine-3-carbonitrile;

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

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

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

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

6-(3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((K)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl )phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((K)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((K)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((8)-3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-((((K)-tetrahydrofuran-3 yl)amino)methyl )phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-(3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-((((8)-tetrahydrofuran-3 yl)amino)methyl)phenyl)ethynyl )phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((K)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((8)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((8)-3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-((((8)-tetrahydrofuran-3 yl)amino)methyl )phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-(3 -((3,3-d iforocyclobutyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

- 93 045324 (R)-6-(3 -((3, 3-d fluorocyclobutyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4( ZN)-on;

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

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

(R)-6-(3-((2,2-diφτopethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one ;

(8)-6-(3-((2,2-difluoroethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one ;

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

(R)-6-(3-(cycloπpoπlamino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(3-(cyclopropylamino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(4 S)-3 -(3 -(5 -hydroxy-6-oxo-1, 6-d ihydropyrimide in-4-yl)-2-(4-((4-((3 methoxyase etidin-1-yl )methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

(S)-3 -((S)-3 -(5 -hydroxy-6-oxo-1, 6-d ihydropyrimidin-4-yl)-2-(4-((4-((3 methoxyase etidine-1 -yl)methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

(S)-3 -((R)-3 -(5 -hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3 methoxyase etidine-1- yl)methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one;

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

6-(2-(4-((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((8)1-fluoropropane- 2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-(3 -((2-chloropπpoπyl)amino)-2-(4-((4-(((R)-3 -methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(ZN)-on;

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;

6-(2-(4-((4-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)phenyl)ethynyl)phenyl)-3-(((8)1-fluoropropane- 2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

-hydroxy-6-(3 -((2-(methyl sulfonyl)ethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

- 94 045324

-hydroxy-6-(3 -((2-hydroxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-((3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)propanenitrile;

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

6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((8)1-fluoropropane- 2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((K)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3(((8)- 1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((8)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3(((8)- 1-fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

-((2-(4-((4-((3 -(cyanomethyl)azetide in-1 -yl)methyl)phenyl)ethynyl)phenyl)-3 -(5hydroxy-6-oxo-1,6-dihydropyrimidine- 4-yl)propyl)amino)propanenitrile;

6-(3 -((2-φτopπpoπyl)amino)-2-(4-((4-(((R)-3 -methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(ZN)-on;

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

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

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

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

(R)-6-(2-((3-φτopπpoπyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(2-((3-fluoropropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one;

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

6-((2R)-2-((l-φτopπpoπan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3N) -He;

6-((2 8)-2-(( 1 -fluoropropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3N )-He;

- 95 045324

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;

5-hydroxy-6-(3-(((8)-1-hydroxypropan-2-yl)amino)-2-(4-((4-((((8)tetrahydrofuran-3-yl)amino)methyl )phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

6-(2-(4-((4-(((8)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3N)- He;

6-((K)-2-(4-((4-(((8)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)3-hydroxypropyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-((8)-2-(4-((4-(((8)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)3-hydroxypropyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-(2-(4-((4-(((K)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3N)- He;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -imino-1 -oxidohexahydro-116-thiopyran-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine- 4(ZN)-on;

5-hydroxy-6-(3 -hydroxy-2-(4-((4-(((( 1 S,3R)-1 -imino-1 -oxidotetrahydro- 1H-116thiophen-3-yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-(((( 1R, 3 S)-1 -imino-1 -oxidotetrahydro-1 Η-116thiophen-3-yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((4-(2-hydroxyacetyl)piperazin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

6-(2-(4-((4-(((^)-1-(cyclopropanecarbonyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidine-4(3H )He;

2-hydroxy-M-(4-((4-(1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)πpopan-2-yl)φenyl)ethynyl)benzyl)- N-((R)-πpyrrolidin-3-yl)acetamide;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((R)-1 -(2-hydroxyethyl)pyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3N)-one;

2-((3R)-3 -((4-((4-( 1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4yl)propan-2-yl)phenyl )ethynyl)benzyl)amino)pyrrolidin-1-yl)acetic acid;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -(2-hydroxyacetyl)piperidin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

(R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((l-(2-hydroxyacetyl)pipipiridin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3N)-one;

(8)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3N)-one;

- 96 045324

2-hydroxy-X-(((28)-1 -(4-((4-(1 -hydroxy-3-(5-hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propan-2-yl )phenyl)ethynyl)benzyl)pyrrolidin-2yl)methyl)acetamide;

6-(3 -(3-fluoroazetidin-1 -yl)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4( ZN)-on;

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

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

5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3N)- He;

5-hydroxy-6-((R)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3-yl)amino)propyl)pyrimidine-4 (ZN)-on;

5-hydroxy-6-((S)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3-yl)amino)propyl)pyrimidine-4 (ZN)-on;

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

(R)-5-hydroxy-6-(3-((2-methocyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(8)-5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((8)tetrahydrofuran-3-yl)amino)propyl)pyrimidin-4(3N)- He;

5-hydroxy-6-(3-(((8)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3N )-He;

-hyde pokch-6-((R)-3 -(((S)-1 -hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

5-hydroxy-6-((8)-3-(((8)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

-hydroxy-6-(3 -(((R)-1 -hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3N) -He;

-hyde pokch-6-((R)-3 -(((R)-1 -hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

-hydroxy-6-((8)-3 -(((R)-1 -hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin- 4(ZN)-on;

- 97 045324

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

6-(2-amino-2-(4-((4-((((K)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one ;

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

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

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

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

6-(2-(4-((4-(((1,1-otetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((8)-1-fluoropropane-2- yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

6-((2R)-2-(4-((4-(((l, 1-dioxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((8)-1-fluoropropane -2-yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

6-((2 8)-2-(4-((4-((( 1,1-dioxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((8)-1- fluoropropan-2-yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

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

6-((R)-3 -(((S)-1 -acetylpyrrolidin-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-((8)-3 -(((S)-1 -acetylpyrrolidin-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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

6-((R)-3 -(((1 H-pyrazol-5 -yl)methyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-((8)-3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4 (ZN)-on;

6-(3 -(((R)-1,1 -dioxidotetrahydrothiophen-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4( ZN)-on;

- 98 045324

6-((R)-3 -(((R)-1,1-otetrahydrothiophen-3-yl)amino dioxide)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5 -hydroxypyrimidin-4(3H)-one;

6-((S)-3-(((R)-1,1-dioxide otetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5 -hydroxypyrimidin-4(3H)-one;

6-(3-(((S)-1,1-dioxide otetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4 (ZN)-on;

6-((R)-3-(((S)-1,1-dioxide otetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5 -hydroxypyrimidin-4(3H)-one;

6-((S)-3-(((S)-1,1-otetrahydrothiophen-3-yl)amino dioxide)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5 -hydroxypyrimidin-4(3H)-one;

-hydroxy-6-(3-methoxy-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

T\G-(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;

methyl-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(6-((4(morpholinomethyl)phenyl)ethynyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3N)-yl)propanoate;

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

-hydroxy-6-(3 -hydroxy-2-(4-(( 1 -((tetrahydro-2H-pyran-4-yl)methyl)-1 H-pyrazol4-yl)ethynyl)phenyl)propyl)pyrimidin-4 (ZN)-on;

-hydroxy-6-(3 -hydroxy-2-(4-((6-(morpholinomethyl)pyridin-3 yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

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

-hydroxy-6-(3 -hydroxy-2-(4-(( 1 -methyl-1 H-pyrazol-4yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

5-hydroxy-6-(3-hydroxy-2-(4-((E)-4-((((8)-tetrahydrofuran-3yl)amino)methyl)styryl)phenyl)propyl)pyrimidine-4(3H) -He;

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

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

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

- 99 045324

-hydroxy-6-(3 -hydroxy-2-(4-(( 1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4yl)ethynyl)phenyl)propyl)pyrimidin-4(3N) -He;

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;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((trans-4(morpholinomethyl)cyclohexyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

5-hydroxy-6-((R)-3-hydroxy-2-(4-((τpans-4(morpholinomethyl)cyclohexyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

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

6-(3-((2-fluoroethyl)amino)-2-(4-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol4-yl)ethynyl)phenyl)propyl) -5-hydroxypyrimidin-4(3H)-one;

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

6-(3 -((2-fluoroethyl)amino)-2-(4-(( 1 -(oxetan-3 -yl)-1 H-pyrazol-4yl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4 (ZN)-on;

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

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

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

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

6-(2-((1,1'-biphenyl]-4-yl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one;

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

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

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

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

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

- 100 045324 (8)-5-hydroxy-6-(3 -hydroxy-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4( ZN)-on;

(R)-5 -hydroxy-6-(3 -hydroxy-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- He;

(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;

(R)-1 -(3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)-2-(4-((4-((3 methoxyazetidin-1 -yl)methyl )phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile;

6-(3 -(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -He;

(R)-6-(3 -(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

(8)-6-(3 -(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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;

(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;

(8)-6-(3 -((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyase etidin-1 yl)methyl)phenyl)ethynyl )phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

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

(R)-6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -He;

(8)-6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -He;

6-(3 -(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3N) -He;

(R)-6-(3 -(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

(8)-6-(3 -(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidin-4(3N)- He;

- 101 045324 (R)-6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5- hydroxypyrimidin-4(3H)-one;

(S)-6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)-2-methylpropyl)-5-hydroxypyrimidine-4 (ZN)-on;

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

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

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

6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(R)-6-(2-(2-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N) -He;

(8)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H) -He;

6-(2-(4-((4-(((R)-l-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3N)- He;

6-((R)-2-(4-((4-((((R)-1 -acetylpyrrolidin-3 -yl)amino)methyl)phenyl)ethynyl)phenyl)3-hydroxypropyl)-5-hydroxypyrimidin- 4(ZN)-on;

6-((S)-2-(4-((4-((((R)-l-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)3-hydroxypropyl)-5-hydroxypyrimidin- 4(ZN)-on;

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

(S)-1 -(4-((4-((8)-1 -(3 -cyanoazetidin-1 -yl)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propane -2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3fluoropropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3fluoropropyl)amino)propyl)-5-hydroxypyrimidine-4(3H)- He;

(R)-6-(2-(2-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-((3fluoropropyl)amino)propyl)-5-hydroxypyrimidine-4(3H)- He;

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;

- 102 045324

6-((K)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3(((8)-1-fluoropropane- 2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((8)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3 (((8)-1-fluoropropane- 2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-(2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)yl)methyl)phenyl)ethynyl)phenyl)-3-( ((8)-1-fluoropropan-2-yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

6-((2K)-2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)yl)methyl)phenyl)ethynyl)phenyl) -3-(((8)-1-fluoropropan-2-yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

6-((28)-2-(2-fluoro-4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)yl)methyl)phenyl)ethynyl)phenyl) -3-(((8)-1-fluoropropan-2-yl)amino)propyl)-5hydroxypyrimidin-4(3H)-one;

2-hydroxy-M-( 1 -(4-((4-(1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl) benzyl)piperidin-4-yl)acetamide;

(K)-2-hydroxy-M-( 1-(4-((4-(1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propan-2-yl) phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide;

(8)-2-hydroxy-b1-(1 -(4-((4-(1 -hydroxy-3-(5-hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propan-2-yl) phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3N)-one;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3N)-one;

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;

5-hydroxy-6-((8)-3-(((8)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

5-hydroxy-6-((K)-3-(((8)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

5-hydroxy-6-((K)-3-(((K)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

5-hydroxy-6-((8)-3-(((K)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-He;

6-(3 -((2-fluoro-3-hydroxypropyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(ZN)-on;

- 103 045324 (K)-5-hydroxy-6-(2-(4-((4-((3-methoxyase ethid in-1-yl)methyl)phenyl)ethynyl)phenyl)3 -((1-methylcyclopropyl )amino)propyl)pyrimidin-4(3N)-one;

(8)-5-hydroxy-6-(2-(4-((4-((3-methoxyase etidin-1-yl)methyl)phenyl)ethynyl)phenyl)3 -((1 -methylcyclopropyl)amino)propyl )pyrimidin-4(3N)-one;

6-(2-(4-((4-( 1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3 -(((S)-1 -fluoropropan-2yl)amino)propyl)-5-hydroxypyrimidine-4 (ZN)-on;

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

6-((28)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((8)-1-fluoropropan-2 yl)amino)propyl) -5-hydroxypyrimidin-4(3H)-one;

5-hydroxy-6-((K)-3-hydroxy-2-(4-((4-((((K)-1 -(methylsulfonyl)pyrrolid in-3 yl)amino)methyl)phenyl)ethynyl) phenyl)propyl)pyrimidin-4(3N)-one;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-((((K)-1-(methylsulfonyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3N)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((K)-1 -(methyl sulfonyl)pyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

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

2-hydroxy-M-((3K)-1 -(4-((4-( 1 -hydroxy-3 -(5-hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propan-2-yl) phenyl)ethynyl)benzyl)pyrrolidin-3-yl)acetamide;

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

-hydroxy-6-(3 -hydroxy-2-(4-((4-((piperidin-4ylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3N)-one;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((methyl((K)-pyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N) -He;

-hydroxy-6-(3 -hydroxy-2-(4-((4-((((K)-1 -methylpyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-He;

6-(2-(4-((4-(((K)-1-glycylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3H)- He;

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

-hydroxy-6-(3 -hydroxy-2-(4-(( 1 -(2-hydroxyacetyl)piperide in-4yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

- 104 045324

5-hydroxy-6-(2-(methylamino)-2-(4-((4-((((R)-τeτpahydropyran-3yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)pyrimidine-4(ZH )-He;

-hydroxy-6-(3 -hydroxy-2-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(8)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one;

(R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxy piperid and n-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N )-He;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-(((K)-2-(hydroxymethyl)piperazin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-(((8)-2-(hydroxymethyl)piperazin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(ZN)-on;

5-hydroxy-6-(3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((K)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin- 4(ZN)-on;

5-hydroxy-6-((8)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((K)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3N)-one;

5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-τeτpahydropyran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3N)-one;

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

6-((28)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one;

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

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

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

(R)-N-( 1 -(4-((3 -fluoro-4-( 1 -hydroxy-3 -(5 -hydroxy-6-oxo-1, 6-d ihydropyrimidin-4yl)propan-2-yl )phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide;

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

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

- 105 045324 (8)-6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2fluorophenyl)-3-hydroxypropyl )-5-hydroxypyrimidin-4(3H)-one;

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

(3R)-1 -(4-((3 -fluoro-4-( 1 -hydroxy-3 -(5 -hydroxy-6-oxo-1,6-dihydropyrimide in-4yl)propan-2-yl)phenyl) ethynyl)benzyl)pyrrolidine-3-carbonitrile;

6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N) -He;

(R)-6-(2-(4-((2-φτop-4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N) -He;

6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyaz etidin1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3 -(3 hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N )-He;

(R)-6-(2-(4-((3-φτop-4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N) -He;

6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyaz etidin1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(8)-6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3 -(3 hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3N )-He;

(R)-6-(2-(3-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(3hydroxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H) -He;

6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroaz ethid in-1yl)propyl)-5-hydroxypyrimidin-4(3H)-one ;

(8)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin1-yl)propyl)-5-hydroxypyrimidine-4(3H) -He;

(R)-6-(2-(2-φτop-4-((4-(morpholinomethyl)phenyl)ethynyl)φenyl)-3-(3-φτopazetidin1-yl)propyl)-5-hydroxypyrimidine-4(3N) -He;

1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin4-yl)propan-2-yl)-3 -fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile;

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

- 106 045324 (R)-1 -(4-((4-( 1 -((2,2-difluoroethyl)amino)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidin-4-yl)propane -2-yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3carbonitrile;

6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((K)-1-fluoropropan-2yl)amino)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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

6-((S)-2-(2-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(((R)-lfluoropropan-2-yl)amino)propyl)-5 -hydroxypyrimidin-4(3H)-one;

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

(R)-1 -(4-((4-((8)-1 -((2,2-d iforoethyl)amino)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidin-4-yl )propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3carbonitrile;

(R)-1 -(4-((4-((R)-1 -((2,2-d iforoethyl)amino)-3 -(5 -hydroxy-6-oxo-1,6dihydropyrimidin-4-yl )propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3carbonitrile;

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;

(8)-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;

(R)-6-(3 -((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyase ethid in-1yl)methyl)phenyl)ethynyl)phenyl )propyl)-5-hydroxypyrimidin-4(3H)-one;

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

(8)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4( ZN)-on;

(K)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4( ZN)-on;

6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(^)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one;

6-((S)-2-(2-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(((R)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidine-4 (ZN)-on;

- 107 045324

6-(A)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((A)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidine-4(3N )-He;

-hydroxy-6-(3-methoxy-2-(4-((4-((((8)-tetrahydrofuran-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N)- He;

5-hydroxy-6-((8)-3-methoxy-2-(4-((4-((((8)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

5-hydroxy-6-((R)-3-methooxy-2-(4-((4-(((S)-τeτpahydropyran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

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

(S)-3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate;

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

-hydroxy-6-(3-methoxy-2-(4-((4-((((8)-pyrrolid in-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3N) -He;

5-hydroxy-6-((8)-3-methoxy-2-(4-((4-((((8)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

5-hydroxy-6-(U)-3-methoxy-2-(4-((4-((((8)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4( ZN)-on;

-hydroxy-6-(3 -m6tokch-2-(4-((4-(((R)-p yrrol ide and n-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

5-hydroxy-6-((8)-3-methoxy-2-(4-((4-((((A)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4( ZN)-on;

5-hydroxy-6-((R)-3-meτocy-2-(4-((4-((((R)-πppolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (ZN)-on;

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

(R)-N-(2-(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)-1-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl) methanesulfonamide;

(8)^-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1 -(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

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

- 108 045324 (R)-N-(2-(5-hydroxy-6-oκco-l,6-d ihydropyrimide in-4-yl)-1 -(4-((4-(4hydroxypiperidin-4-yl) phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

(8)-M-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1 -(4-((4-(4hydroxypiperidin-4-yl)phenyl)ethynyl)phenyl )ethyl)methanesulfonamide;

N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1 -(4-((4-(((8)-2(hydroxymethyl)piperazin-1-yl) methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

M-((K)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(((8)-2(hydroxymethyl)piperazin- 1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

X-((8)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1 -(4-((4-(((8)-2(hydroxymethyl)piperazin- 1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide;

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

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

6-(3 -(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-(2morpholinoethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(ZN )-He;

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

(R)-N-(l-([l,Γ-biphenyl]-4-yl)-2-(5-hydroxy-6-oκco-l,6-dihydropyrimidin-4yl)ethyl)methanesulfonamide;

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

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

(R)-N-(2-(5-hydroxy-6-oκco-l,6-dihydropyrimidin-4-yl)-l-(4-((4-((3methoxyazetidin-1-yl)methyl)phenyl) ethynyl)phenyl)ethyl)methanesulfonamide;

(8)-M-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1 -(4-((4-((3 methoxyazetidin-1-yl)methyl)phenyl )ethynyl)phenyl)ethyl)methanesulfonamide;

6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin1-yl)propyl)-5-hydroxypyrimidin-4(3H)-one;

(R)-6-(2-(2-φτop-4-((4-(morpholinomethyl)φenyl)ethynyl)φenyl)-3-(3methoxyazetidin-1-yl)propyl)-5-hydroxypyrimidin-4(3H) -He;

(8)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3methoxyazetidin-1 -yl)propyl)-5-hydroxypyrimidin-4(3N) -He;

- 109 045324

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

(K)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

(S)-6-(3 -((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(ZN)-on;

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

(8)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one;

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

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

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

(R)-1 -(3 -(5 -hydroxy-6-oxo-1,6-d ihydropyrimide in-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl) Azetidine-3-yl acetate;

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

(8)-H-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide;

(R)-N-(3-(5-hydroxy-6-oκco-l,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide;

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

(8)-H-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide;

(R)-N-(3-(5-hydroxy-6-oκco-l,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide;

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

(8)-5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4( ZN)-on; and (R)-5 -hydroxy-6-(3 -(2-methyl-1 H-imidazol-1 -yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin- 4(ZN)-on.

Receiving connections

The compounds used in the chemical reactions described herein are prepared in accordance with organic synthesis techniques known to those skilled in the art, starting from commercially available chemical products and/or compounds described in the chemical literature. Commercially available chemical products are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA, USA), Aldrich Chemical (Milwaukee, WI, USA, 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, Pennsylvania, USA), Crescent Chemical Co. (Haappauge, New York, USA), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, New York, USA), Fisher Scientific Co. (Pittsburgh, PA, USA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT, USA), ICN Biomedicals, Inc. (Costa Mesa, California, USA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, New Hampshire, USA), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah, USA), Pfaltz & Bauer, Inc. (Waterberry, CT, USA), Polyorganix (Houston, TX, USA), Pierce Chemical Co. (Rockford, IL, USA), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, New Jersey, USA), TCI America (Portland, Oregon, USA), Trans World Chemicals, Inc. (Rockville, MD, USA) and Wako Chemicals USA, Inc. (Richmond, Virginia, USA). Suitable references and textbooks that detail the synthesis of reagents useful in the preparation of the compounds described herein or provide references to articles that describe the preparation include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc. ., New York; S. R. Sandier et al., Organic Functional Group Preparations, 2nd Ed., Academic Press, New York, 1983; H. O. House, Modern Synthetic Reactions, 2nd Ed., W. A. Benjamin, Inc. Menlo

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Park, Calif. 1972; T. L. Gilchrist, Heterocyclic Chemistry, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., Wiley Science, New York, 1992. Additional relevant references and textbooks that detail the synthesis of reagents useful in preparing the compounds described herein, or references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527- 29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. 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: 3-52729871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Functional Groups (1992) Interscience ISBN: 0-47193022-9; Solomons, T. W. G. Organic Chemistry 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-190950; Stowell, J.C., Intermediate Organic Chemistry 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-574562; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, over 55 volumes; and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes. Alternatively, specific and similar reagents can be identified by using the American Chemical Society's Chemical Abstract Service indexes of known chemical products and reactions, which are available in most public and university libraries, and by available real-time databases (contact American Chemical Society, Washington, D.C. for more information). Chemicals that are known but not commercially available in catalogs are not necessarily produced by specialty chemical synthesis laboratories, and many of the standard chemical supply laboratories (such as the suppliers listed above) provide specialty synthesis services. A reference to the preparation and selection of pharmaceutical salts of the heterocyclic LpxC inhibitor compound described herein is given in P. H. Stahl & C. G. Wermuth Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical compositions.

In certain embodiments, a heterocyclic LpxC inhibitor compound as described herein is administered as a pure chemical product. In other embodiments, a heterocyclic LpxC inhibitor compound described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, physiologically acceptable (or acceptable) excipient, or physiologically acceptable (or acceptable) carrier) selected based on the chosen 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) )).

Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitor compound as described herein, or a stereoisomer, pharmaceutically acceptable salt or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) are acceptable or suitable if the carrier is compatible with the other ingredients of the composition and does not cause an adverse effect on the recipient of the composition (i.e. subject or patient).

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.

In accordance with certain embodiments, the heterocyclic LpxC inhibitor compound disclosed herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% other organic small molecules, such as unreacted intermediates or synthesis by-products that are formed, for example, in one or more steps of the synthesis process.

Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or other suitable material that readily dissolves in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, which include, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, pharmaceutical grade magnesium carbonate, etc. .P. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, ^21st Ed. Mack Pub. Co., Easton, PA (2005)). The dose of a composition containing at least one heterocyclic compound is the LpxC inhibitor that is described herein differs depending on the patient's condition, that is, the stage of the disease, general health, age and other factors.

Pharmaceutical compositions are administered in a manner that is appropriate to the disease being treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration will be determined by 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 route of administration. In general, an appropriate dosage and treatment regimen will provide the composition(s) in an amount sufficient to provide beneficial therapeutic and/or prophylactic effects (eg, improved clinical outcome) or reduce the severity of symptoms. Optimal doses are usually determined using experimental models and/or clinical trials. The optimal dose depends on the patient's body weight, weight, or blood volume. Oral dosages typically range from about 1.0 mg to about 1000 mg one to four times daily or more frequently.

LpxC, lipid A and gram-negative bacteria.

Metalloproteins influence a wide range of biological systems, biological processes and diseases. For example, UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) is an essential enzyme involved in the first step of lipid A biosynthesis for Gram-negative bacteria. Lipid A is an essential component of the outer membrane of gram-negative bacteria. LpxC is a zinc(II)-dependent metalloenzyme in which two histidines and an aspartic acid residue bind to a zinc(II) ion. The structures of LpxC show a zinc(II) ion bound to two water molecules, both of which have been implicated in the enzyme's mechanism of action. LpxC is highly conserved among Gram-negative bacterial strains, making LpxC an attractive target for the treatment of Gram-negative bacterial infections. In recent years, there has been an increase in the number of resistant and multi-resistant strains of bacteria. Therefore, there is a need for new antibiotics, especially those with new mechanisms of action. There remains a need for LpxC metalloprotein modulators useful in therapeutic, diagnostic and research applications.

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

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.

Methods of treatment.

Disclosed herein are methods of treating a disease in which bacterial growth is inhibited. This disease involves infection with gram-negative bacteria. In some embodiments, a method of treating a gram-negative bacterial infection 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 some embodiments, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infections, and urinary tract infection. In some embodiments, the gram-negative bacterial infection is a urinary tract infection (UTI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP), or intra-abdominal infection (IAI). In some embodiments, the gram-negative bacterial infection is selected from chronic urinary tract infections, complicated urinary tract infections, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections, and kidney infections. In accordance with some embodiments, the compounds described herein are used to

- 112 045324 treatment of chronic urinary tract infections. In accordance with some embodiments, the compounds described herein are used to treat complicated urinary tract infections. In other embodiments, the compounds described herein are used to treat complicated intra-abdominal infections. In accordance with some embodiments, the compounds described herein are used to treat chronic intra-abdominal infection. 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 to treat an existing infection. In accordance with some embodiments, administration is provided as prophylaxis.

In some embodiments, a heterocyclic LpxC inhibitor compound as described herein is used to treat conditions caused by endotoxin production by bacteria and, in particular, gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin. In some embodiments, a method of treating a condition caused by endotoxin or LPS exposure 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. substance. In another embodiment, the heterocyclic LpxC inhibitor compounds that are described herein are useful in the treatment of conditions that are caused or exacerbated by bacterial production of lipid A and LPS or endotoxin, such as sepsis, septic shock, systemic inflammation, localized inflammation , chronic obstructive pulmonary disease (COPD) and acute attacks of chronic bronchitis (AECB). In some embodiments, a method of treating a condition caused by endotoxin or LPS exposure 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. substance, wherein the condition caused by exposure to endotoxin or LPS is selected from sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute attacks of chronic bronchitis (AECB).

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 pulmonary and hospital-acquired infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Staphylococcus aureus, Shigella sonnet, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum , Providencia sluarlii and Citrobacter freundi, Haemophilus influenzae, species from Kluyvera spp., Legionella spp., Moraxella catarrhalis, Enterobacter spp., Acinetobacter spp., Klebsiella spp., Burkholderia spp., and Proteus spp., and infections caused by other bacterial species such as Neisseria spp. , species of the genus Shigella, species of the genus Salmonella, Helicobacler pylori, Vibrionaceae and species of the genus Bordetella, as well as infections caused by species of the genus Brucella, Francisella tularensis and/or Yersiniapestis.

In accordance with 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. . One embodiment relates to a method wherein the infection with gram-negative bacteria is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection and urinary tract infection.

One embodiment relates to a method wherein the infection with gram-negative bacteria is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections and kidney infections. One embodiment relates to a method in which the infection with gram-negative bacteria is a chronic urinary tract infection. One embodiment relates to a method in which the infection with gram-negative bacteria is a complicated urinary tract infection. One embodiment relates to a method in which the administration is to treat an existing infection. One embodiment relates to a method in which administration is provided as prophylaxis.

One embodiment relates to a method of treating an infection with gram-negative bacteria in a patient in need thereof, comprising administering to the patient a pharmaceutical

- 113 045324 of a composition containing a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient. In accordance with one embodiment, the infection with gram-negative bacteria is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection and urinary tract infection. In another embodiment, the gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections, and kidney infections. In accordance with one embodiment, the infection with gram-negative bacteria is a chronic urinary tract infection. In another embodiment, the infection with gram-negative bacteria is a complicated urinary tract infection. In accordance with one embodiment, the administration is to treat an existing infection. According to a further embodiment, administration is provided as prophylaxis.

In accordance with other embodiments, the compounds of the present disclosure are not active against gram-positive bacteria. In accordance with some embodiments, the compounds of the present disclosure are not active against Staphylococcus aureus.

Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are presented only as illustrations of various embodiments, and they will not be construed as limiting the present invention in any way.

Examples

I. Chemical synthesis.

Unless otherwise stated, reagents and solvents used were obtained from commercial suppliers. Anhydrous solvents and oven-dried laboratory glassware were used for synthetic reactions sensitive to moisture and/or oxygen. The outputs were not optimized. Reaction times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated. Spectra are presented as ppm (parts per million) (δ) and coupling constants, J is presented in hertz. For proton spectra, solvent peaks were used as the reference peak.

The following abbreviations and terms have the meanings indicated in this document: AcOH = acetic acid

B2pin ₂ = bis-(pinacolato)dibor

Boc = tert-butoxycarbonyl

DCC = dicyclohexylcarbodiimide

DIEA = X^diisopropylethylamine

DMAP = 4-dimethylaminopyridine

EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. = equivalent(s) Et = ethyl

EtOAc or EA = ethyl acetate

EtOH = ethanol g = grams

h. or hour = hour

HBTU = O-(benzotriαzol-1-yl)-N,N,N',N'-tetraαmethyluronium hexafluorophosphate

HOBt = hydroxybenzotriazole

HPLC = high pressure liquid chromatography kg = kilogram l = liter

LC/MS = LCMS = liquid chromatography-mass spectrometry

LRMS = low resolution mass spectrometry m/z = mass to charge ratio Me = methyl

MeOH = methanol mg = milligram min. = minute ml = milliliter mmol = millimole NaOAc = sodium acetate PE = petroleum ether

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Ph = phenyl

Prep = preparative quant. = quantitative

RP-HPLC = reverse phase high pressure liquid chromatography rt or RT = room temperature

THF = tetrahydrofuran

UV = ultraviolet

Example 1. Synthesis of 6-(3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl )propyl)-5-hydroxypyrimidin-4(3H)-oneα (compound 68)

Step 1. Synthesis of 4,5-bis-(benzyloxy)-6-(iodomethyl)pyrimidine

To a solution of 1 (35 g, 0.107 mmol) in DMF (350 ml) was added tributylvinyltin (37.4 g, 0.0117 mol) and purged with nitrogen for 10 min. PdCl ₂ (PPh ₃ ) ₄ (7.5 g, 0.010 mol) was added to this reaction mixture and heated to 100°C for 6 hours. After completion of the reaction, the reaction mixture was cooled, diluted with water and extracted with EtOAc (2-750 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography to obtain pure 1a as a colorless liquid. Yield: 23 g, 76%

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 completion of the reaction, the reaction mixture was bubbled with oxygen for 10 minutes. Dimethyl sulfide (12 ml) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was warmed to -30°C and sodium borohydride (5.34 g, 0.144 mol) was carefully added portionwise and stirred for 10 minutes. The solvent was removed and the reaction mixture was dissolved in dichloromethane and washed with water (100 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 2 as an off-white solid. Yield: 16 g, 69.5%. LC_MS = calculated value for C ₁₉ H ₁₈ N ₂ O ₃ is 322.36, observed = 323.2.

To a cooled to 0°C solution of 2 (4 g, 0.0124 mol) in DCM (40 ml) was added triethylamine (2.5 g, 0.0248 mol) followed by the addition of methanesulfonyl chloride (2.1 g, 0.0186 mol ). After completion of the reaction, the reaction mixture was washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 4.96 g of crude product. The crude product (4.96 g, 0.0124 mol) was dissolved in acetone (50 ml) and cooled to 0°C, and NaI (3.7 g, 0.0248 mol) was added to this mixture and stirred at 0°C within 30 min. After completion of the reaction, the reaction mixture was dissolved in water and extracted using DCM. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3 as a pale yellow solid. Yield: 4.0 g, 74.7%. LCMS= calculated value for C ₁₉ H ₁₇ IN ₂ O ₂ is 432.26, observed = 433.1.

Step 2. Synthesis of (R)-3-(5,6-bis-(benzyloxy)pyrimidin-4-yl)-2-(4-iodophenyl)propan-1-olα

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 Et ₃ N (5.34 ml, 38.3 mmol ) and heated the reaction mixture to 80°C. To this 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 hours. After completion of the reaction, the reaction mixture was diluted EtOAc and washed with 10% NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , 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% LCMS = calculated value for C ₁₈ H ₁₆ INO ₃ is 421.23, observed = mass not ionized.

A solution of 2 (2.0 g, 4.74 mmol) in THF (20 ml) was cooled to -78°C. To this cooled reaction mixture was slowly added NaHMDS (1M in THF, 4.74 mL, 4.74 mmol) followed by the addition of 4,5bis-(benzyloxy)-6-(iodomethyl)pyrimidine (2.05 g, 4.74 mmol) and stirred the reaction mixture for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated NH ₄ Cl. The layers were separated, the organic layer was washed with saline and dried over Na ₂ SO ₄ , 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 value for C ₃₇ H ₃₂ IN ₃ O ₅ is 725.58, observed = 726.1.

A solution of 3 (1.8 g, 2.48 mmol) in diethyl 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 completion of the reaction, the reaction mixture was quenched with a saturated solution of NH ₄ Cl and diluted with water. The reaction mixture was extracted with EtOAc (150 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, 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 4 as an off-white solid Yield 0.9 g, 66.6% LC_MS = calculated value for _C27 H ₂₅ IN ₂ O ₃ is 552.41, observed = 553.1.

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

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 over 20 minutes and the reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was filtered on a celite pad and the pad was washed with DCM. The filtrate was washed with 10% NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , 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% purity). LC_MS = calculated value for C ₂₇ H ₂₃ IN ₂ O ₃ is 550.40, observed = 551.0.

AcOH (5 ml) was added to a solution of 2 (85 g, 0.154 mol) and (S)-1-fluoropropane-2-amine hydrochloride (21 g, 0.185 mol) in MeOH (800 ml) and the reaction mixture was stirred for 12 hours. MP-CNBH3 resin (load 2.45 mmol/g, 64.1 g, 0.154 mol) was then added and the reaction mixture was stirred for 1 hour. After completion of the reaction, the resin was filtered and washed with 10% MeOH in DCM (200 ml) and the filtrate was concentrated. The resulting crude mass was dissolved in DCM and washed with 10% NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure to obtain the crude product. To a solution of the above crude product (65 g, 0.00116 mol) in THF (700 ml) under N ₂ was added Et ₃ N (21.4 g, 0.212 mol) and di-tert-butyl bicarbonate (46.3 g , 0.212 mol) and stirred at 25 °C for 12 hours. After completion of the reaction, the reaction mixture was diluted in water and extracted using EtOAc (2x500 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (230-400 mesh, 15-50% EtOAc in petroleum ether) to give racemic mixture 3, which was separated by chiral SFC purification. yielding 4a and 4b.

Yield: (42 g, 58%). 4a: ISOMER-I: 17 g 4b: ISOMER-II: 17 g LCMS = calculated value for

C ₃₀ H ₃₁ FIN ₃ O ₂ is 711.62, observed = 712.2.

To a solution of 4b (17 g, 0.023 mol) in DCM (200 ml) was added 4N HCl in 1,4-dioxane (200 ml) and the reaction mixture was stirred at 25°C for 14 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was dissolved in water and neutralized using 10% NaHCO ₃ and extracted using EtOAc (500 mlx2). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

The resulting compound was taken up in DCM (100 ml), BCl ₃ (1M in DCM, 100 ml) was added to this mixture and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was carefully quenched with MeOH (100 ml) and stirred. After 10 min. the reaction mixture was concentrated under reduced pressure. The crude product was triturated with DCM and the solid was filtered and dried to give pure 5 as a white solid. Yield: (10.5 g, 94%). LC_MS = calculated value for C ₁₆ H ₁₉ FIN ₃ O ₂ is 431.25, observed = 432.1.

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 Et ₃ N (33.9 ml, 0.243 mol) and the reaction mixture was degassed under a nitrogen atmosphere for 10 min. PdCl ₂ (PPh ₃ ) ₂ (0.34 g, 0.00048 mol), CuI (0.27 g, 0.0014 mol) was then added and the reaction mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was filtered over a celite pad and the pad was washed with excess EtOAc. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC purification [YMC-ACTUS-TRIART C18 (250x30) mm, 5 µm; using ACN/water (A) and 0.1% HCOOH (B) with flow rate = 20 ml/min., λ = 210 nm; using a step gradient from 8% to 20% (B) in 0-15 min. and 100% after 16 minutes; t _R =14.7 min.) fractions were lyophilized to obtain the pure title compound as an off-white solid. Yield: (4.8 g, 39.3%). LC MS = calculated value for C ₂₉ H ₃₃ FN ₄ O ₃ is 504.61, observed = 505.3. The compounds described herein were prepared by organic synthesis similar to those presented in Example 1, as well as by other techniques known to those skilled in the art, starting with commercially available chemicals and/or compounds described in the chemical literature . LC-MS data for each compound are presented in Table. 1.

II. Assessment of biological properties.

Example 1: In vitro assays for screening compounds and metalloprotein modulators.

Bacterial sensitivity study.

Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Briefly, suspensions of organisms were adjusted to 0.5 standard McFarland units to yield a final inoculum of 3x105 to 7x105 colony forming units (CFU)/ml. Dilutions of drug and inocula were performed in sterile Mueller-Hinton cationic balanced broth (Beckton Dickinson). An inoculum volume of 100 μL was added to wells containing 100 μL of broth with 2-fold serial dilutions of the drug. All inoculated microdilution plates were incubated in ambient air at 35°C for 18–24 hours. After incubation, the lowest drug concentration that prevented visible growth (OD at 600 nm <0.05) was recorded as the MIC. The assay was monitored using quality control laboratory strains and levofloxacin, a compound with a defined MIC spectrum, according to CLSI guidelines.

Exemplary in vitro assay data for selected bacteria for compounds according to embodiments of the present disclosure are presented in Table. 2.

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Connection No. MIC for E. coli MIC for K. pneumoniae 1 IN IN 2 A A 3 A A 4 A A 5 IN IN 6 IN D 7 IN IN 8 A IN 9 IN WITH 10 A IN AND A IN 12 IN IN 14 A A 15 A A 16 A IN 17 A A 18 IN D 19 A IN 20 A IN 21 IN IN 22 A IN 23 A IN 24 A IN 25 IN IN 26 IN D 27 IN IN 28 V D 29 A IN

table 2

Connection No. MIC for E. coli MIC for K. pneumoniae thirty IN WITH 31 A IN 32 A IN 33 A A 34 A IN 35 A A 36 A IN 37 A IN 38 A V 39 A V 40 IN With 41 IN V 42 A V 43 A V 44 A V 45 IN With 46 A V 47 IN V 48 A V 49 A V 50 IN V 51 IN With 52 IN With 53 IN With 54 IN V 55 IN D 56 IN With 57 IN With

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58 IN D 59 IN WITH 60 IN WITH 61 V D 62 V D 63 V D 64 V WITH 65 A IN 66 A IN 67 A IN 68 A A 69 A WITH 70 A A 71 A A 72 A IN 73 A A 74 A A 75 A A 76 A IN 77 IN WITH 78 IN IN 79 A V 80 A A 81 A A 82 A A 83 A A 84 A IN 85 A IN 86 A V 87 IN With 89 A V 90 A V

91 A A 92 A A 93 A A 94 A IN 95 A IN 96 A A 97 A IN 98 A IN 99 A A 100 A A 101 A IN 102 A A 103 A IN 104 A A 105 A A 106 IN WITH 107 A A 108 A IN 109 A IN 110 A IN 111 A V 112 A V FROM IN With 114 IN V 115 A A 116 IN IN 117 A A 118 A IN 119 A IN 120 IN D 121 IN WITH 122 A IN

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123 A V 124 IN V 125 IN D 126 IN WITH 127 V IN 128 V WITH 129 V WITH 130 V WITH 131 V IN 132 A IN 133 A A 134 WITH D 135 V WITH 136 D D 137 IN WITH 138 IN IN 139 A A 140 A IN 141 A IN 142 A A 143 A IN 144 IN WITH 145 IN WITH 146 IN With 147 V V 148 V With 149 V With 150 V With 151 V With 152 A V 153 A V 154 WITH D

155 IN D 156 D D 157 IN IN 158 IN IN 159 A IN 160 A IN 162 IN WITH 163 A IN 164 IN WITH 165 IN IN 166 A IN 167 A IN 168 IN D 169 A IN 170 IN D 171 A IN 172 A A 173 A IN 174 A IN 175 IN WITH 176 A V 177 A With 178 IN V 179 IN V 180 WITH With 181 V A 182 V WITH 183 A V 184 IN With 185 V With 186 A V 187 A V

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188 A IN 189 A IN 190 A A 191 A IN 192 IN With 193 IN With 194 IN With 195 V With 196 V D 197 With D 198 With D 199 V WITH 200 V D 201 V D 202 V D 203 V D 204 With D 205 V D 206 V WITH 207 V WITH 208 V D 209 V D 210 V WITH 211 With D 212 D D 214 With D 215 A A 216 A A 217 A A 218 A IN 219 A IN 220 A A

221 A IN 222 A A 223 A A 224 IN WITH 225 A IN 226 A IN 227 IN D 228 A A 229 IN D 230 A IN 231 A IN 232 A IN 233 IN WITH 234 A IN 235 A IN 236 A A 237 A A 238 A A 239 A A 240 A IN 241 IN WITH 242 A IN 243 A V 244 IN With 245 A V 246 IN With 247 IN With 248 A V 249 IN V 250 A V 251 A V 252 A V

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253 IN D 254 A IN 255 A IN 256 A WITH 257 IN IN 258 IN WITH 259 IN D 260 V WITH 261 V D 262 With D 263 D D 264 D D 265 A WITH 266 IN WITH 267 IN WITH 268 IN WITH 269 V IN 270 V IN 271 A IN 273 A IN 275 A IN 276 IN IN 277 A IN 278 A A

279 A IN 280 A A 281 A IN 282 A IN 283 A IN 285 A A 287 IN WITH 288 IN With 289 A A 292 IN WITH 293 A V 294 A A 295 A A 296 WITH D 297 WITH D 298 D D 299 A IN 300 A A 301 A A 302 A A 303 A IN 304 A IN 305 A A

Note: Microbiological activity data are presented within the following ranges:

A: >1 µg/ml C: from >8.0 µg/ml to >32 µg/ml,

B: >1 µg/ml to >8.0 µg/ml D: >32 µg/ml.

LpxC binding assay.

IC ₅₀ values for E. coli LpxC were determined using the Raipid Fire MS assay as previously described in J. Med. Chem. 2012, 55, 1662-1670.

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Table 3 Exemplary in vitro assay data for E. coli LpxC for compounds according to embodiments of the present disclosure

Connection No. IC50 for LpxC E. coli 7 A 14 IN 17 A 19 D 20 A 23 IN 38 A 43 IN 44 IN 54 IN 56 V 57 V 60 V 61 With 62 D 63 D 64 IN 65 A 68 IN 71 IN 101 IN 130 A 135 D 138 IN 139 A 141 A 145 D 148 IN 149 D 169 A

Connection No. IC50 for LpxC E. coli 171 A 172 A 173 IN 174 IN 177 IN 191 A 192 IN 193 A 194 IN 199 IN 200 D 201 IN 202 IN 203 D 205 D 206 D 208 WITH 209 IN 210 IN 211 IN 212 D 240 A 241 IN 242 IN 287 IN 288 V 289 A 296 IN 297 V 298 D

299 A

Note: IC ₅₀ data are presented within the following ranges: A: >10 nM C: >50 nM to >100 nM,

B: >10 nM to >50 nM D: >100 nM to 1 µM.

III. Preparation of pharmaceutical dosage forms.

Example. Capsule for oral administration.

The active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof. An oral capsule is prepared by mixing 1-1000 mg of the active ingredient with starch or other suitable powder mixture. The mixture is included in an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

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Claims (15)

CLAIM 1. A compound or a pharmaceutically acceptable salt thereof characterized by the structure of formula (II) % Xch Formula (II) where n is 0 or 1; m represents 0 or 1; A ₁ represents OH; A ₂ represents O; R ¹ and R ² represent H; 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-C4alkylene)COR 11, optional substituted (C0-C4alkylene)CO2R ¹¹ , optionally substituted (C0- _C4alkylene )CON(R ¹¹ )2, optionally substituted (C0-C4alkylene)-CN, optionally substituted (C0-C4alkylene)-OR11, optionally substituted (C0- C4alkylene)-N( ^R11 )2, optionally substituted ( _C0 - _C4alkylene )-N( ^R12 ) ^-COR11 , optionally substituted (C0-C4alkylene)-N( ^R12 ) _-CO2R11 , optionally substituted ( C ₀ -C ₄ alkylene)-N(R ¹² )-CON(R ¹¹ )2, optionally substituted (C0-C4alkylene)-N(R ¹² )SO2N(R ¹¹ )2, optionally substituted (C0-C4alkylene)-OSO2N (R ¹¹ )2 optionally substituted (C0-C ₄ alkylene)-N(R ¹¹ )-PO(optionally substituted C1-C4 alkylene)2, optionally substituted (C0-C4 alkylene)-SO2R ¹¹ , optionally substituted (C0-C ₄ alkylene )-O-SO ₂ R ¹¹ , optionally substituted (C0-C4alkylene)-N(R ¹² )-SO2R ¹¹ , optionally substituted (C0-C4alkylene)-C(=N-OR ¹¹ )(R ¹¹ ) or optionally substituted ( C0-C ₄ alkylene)-OR(=O)(OR ¹¹ ) ₂ ; R ⁴ represents H or optionally substituted alkyl; R ⁵ represents H; each X and Y independently represents H, optionally substituted alkyl, halogen, fluoroalkyl, cyano, nitro, -N(R ¹³ ) 2 or -OR ¹³ ; Z represents -L-G; L represents a bond or optionally substituted C1- _C2 alkylene; G represents optionally substituted alkyl, optionally substituted carbocyclyl, 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 or -N(R ¹⁴ )-SO2R ¹³ ; each R ¹¹ independently represents 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 ny heteroarylalkyl; or two R ¹¹ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; each R ¹² independently represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; each R ¹³ is H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹³ on one nitrogen atom, taken together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl; each R ¹⁴ independently represents H, unsubstituted alkyl or unsubstituted heterocyclyl; where each cyano represents -CN; each nitro is -NO ₂ ; alkyl is independently a straight or branched chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds and containing from one to fifteen carbon atoms; each alkenyl is independently a straight or branched chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, having from two to twelve carbon atoms; - 124 045324 each alkynyl is independently a straight or branched chain hydrocarbon radical consisting exclusively of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms; each aryl is independently an aromatic monocyclic or polycyclic hydrocarbon ring system containing only hydrogen and five to eighteen carbon atoms, where at least one of the rings in the ring system is completely unsaturated; each aralkyl independently represents a radical of the formula -(C1-C ₁₂ alkylene)aryl; each carbocyclyl is independently a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems containing from three to fifteen carbon atoms; each carbocyclylalkyl is independently a radical of the formula -(C 1 -C ₁₂ alkylene)carbocyclyl; each halogen is independently -Br, -Cl, -F or -I; each fluoroalkyl independently represents an alkyl radical substituted by one or more fluoro radicals; each heterocyclyl independently represents a stable 3-18 membered non-aromatic ring radical containing from two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur; and each N-heterocyclyl independently represents a heterocyclyl radical containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl radical to the rest of the molecule passes through a nitrogen atom in the heterocyclyl radical; each heterocyclylalkyl independently represents a radical of the formula -(C1-C ₁₂ alkylene)heterocyclyl; each heteroaryl independently represents a radical derived from a 3-18 membered aromatic ring radical that contains from two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur; each heterocyclyl and heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, fluoroalkyl, cyano, carbocyclyl, heterocyclyl, 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)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t means 1 or 2), -R ^b -S(O) tR ^a (where t means 1 or 2), -R ^b -S(O)tOR ^a (where t means 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t means 1 or 2), where each R ^a independently represents hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl or cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R ^b independently represents a direct bond or linear or a branched alkylene chain and R ^c represents a linear or branched alkylene chain; each heteroarylalkyl independently represents a radical of the formula -(C1-C ₁₂ alkylene)heteroaryl and the term optionally substituted, unless specifically defined, means that said group is substituted by one or two additional groups individually and independently selected from halogen, -CN, - NH2, -OH, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently H, F or Cl and R ⁴ represents H. 3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (IV) Formula (IV). 4. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, where the compound is characterized by the structure of formula (IVa) or formula (IVb) >—£ N-H Formula (IVa) Formula (IVb) 5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, where R ³ represents an optionally substituted alkyl, optionally substituted (C ₀ -C ₄ alkylene)-CO ₂ R ^Π , optionally - 125 045324 optionally substituted ( _C0 - _C4alkylene )CON( _R11 ) ₂ , optionally substituted ( _C0 - _C4alkylene ) ^-OR11 , optionally substituted (C0-C4alkylene)-N( ^R11 )2 or optionally substituted (C ₀ -C ₄ alkylene)-N(R ¹² )SO ₂ Rn. 6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ represents H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroarylalkyl; or two R ¹¹ groups combined with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl. 7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is independently unsubstituted or substituted with a halogen, -CN, -R ^b -OR ^a , -R ^b -C(O)R ^a or -R ^b -S (O)tR ^a ; wherein t is 1 or 2; each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or straight or branched alkylene; or two R ¹¹ groups combined with the nitrogen to which they are attached form N-heterocyclyl, which is optionally substituted with halogen, oxo, -CN or -R ^b -OR ^a ; wherein each R ^a independently represents hydrogen or alkyl, which is optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl; and each R ^b independently represents a straight link or straight or branched alkylene; and each R ¹² independently represents H or unsubstituted alkyl. 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein G is an optionally substituted 4-6 membered monocyclic heterocyclyl. 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, where n is 0; m means 0; R ⁴ represents H; R ³ represents - 126 045324 Z represents 10. Connection selected from 5-hydroxy-6-(3-hydroxy-3-methyl-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; - 127 045324 6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; (R)-6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(3-((2-fluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)pyrimidin-4(3H)one; 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin- 4(3H)-ona; 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidine-4 (3H)-she; 6-(3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)- she; 6-((R)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin- 4(3H)-ona; 6-((S)-3-(((R)-1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin- 4(3H)-ona; 6-(3-amino-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)one; K-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide; (R)-N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propanamide; (S)-N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propanamide; K-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide ; 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-K-methyl-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide; methyl 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanoate; K-(3,3-difluorocyclobutyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide ; ethyl 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(((tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propanoate; methyl-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-(((tetrahydrofuran-3 yl)amino)methyl)phenyl)ethynyl)phenyl )propanoate; K-(1-cyanoethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide; K-(2,2-difluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((2(hydroxymethyl)-1 H -imidazol-1 -yl)methyl)phenyl)ethynyl)phenyl)propanamide; N-(2-fluoroethyl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((((S)tetrahydrofuran3-yl)amino )methyl)phenyl)ethynyl)phenyl)propanamide; 5-hydroxy-6-(3-hydroxy-2-methyl-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-methyl-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 1 -(4-((4-((S)-1 -hydroxy-3-(5 -hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl)benzyl)pyrrolidine -3-carbonitrile; 1-(4-((4-((R)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl)benzyl)pyrrolidine -3-carbonitrile; (3S)-1 -(4-((4-(1 -hydroxy-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl)benzyl)pyrrolidine -3-carbonitrile; - 128 045324 (3S)-1 -(4-((4-(1 -hydroxy-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl) benzyl)pyrrolidine-3-carbonitrile; (S)-1-(4-((4-((S)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl )benzyl)pyrrolidine-3-carbonitrile; (S)-1-(4-((4-((R)-1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl )benzyl)pyrrolidine-3-carbonitrile; (3R)-1 -(4-((4-( 1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl)benzyl)pyrrolidine -3-carbonitrile; 6-(2-(4-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3H )-she; 6-(2-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-((((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3H )-she; 6-((R)-2-(4-((4-((((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3 hydroxypropyl)-5- hydroxypyrimidin-4(3H)-one; 6-((S)-2-(4-((4-((((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidine -4(3H)-she; 6-(2-(4-((4-((((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4(3H )-she; 6-((R)-2-(4-((4-((((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidine -4(3H)-she; 6-((S)-2-(4-((4-((((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3 hydroxypropyl)-5- hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-((5-oxa-2-azaspiro[3.4]octan-2-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H) -she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(2-(((S)-tetrahydrofuran-3yl)amino)ethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyacetyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3H)-one; 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyacetyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl) phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyacetyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl) phenyl)propyl)pyrimidin-4(3H)-one; 6-(2-(4-((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H) -she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((oxetan-3ylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; ethyl 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((oxetan-3ylamino)methyl)phenyl)ethynyl)phenyl)propanoate; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((3 -morpholinoazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((tetrahydrofuran-3yl)methyl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((tetrahydro-2H-pyran-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(piperazin-1ylmethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -imino-1 -oxidotetrahydro-1H-1 I6-thiophen-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((2methoxyethyl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 6-(2-(4-((4-(((cyclopropylmethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-methylpiperazin-1carbonyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; - 129 045324 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -oxidotetrahydrothiophen-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((methylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 6-(2-(4-((4-(aminomethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-amino-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5-hydroxypyrimidin-4(3H)-one; 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; 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; 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; 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; 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; 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; 5-hydroxy-6-(3 -(3-methoxyazetidin-1 -yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (R)-5-hydroxy-6-(3-(3-methoxyazetidin-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; (S)-5-hydroxy-6-(3 -(3-methoxyazetidin-1 -yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-(3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-((R)-3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin-4(3H)-one ; 6-((S)-3-((cis-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin-4(3H)-one ; 6-(3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-((R)-3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one ; 6-((S)-3-((trans-3-fluorocyclobutyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one ; 1 -(4-((4-( 1-(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)propan- 2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 1-(4-((4-((R)-1-(((S)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 1 -(4-((4-((S)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 1-(4-((4-(1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)propan- 2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 1-(4-((4-((R)-1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 1-(4-((4-((S)-1-(((R)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 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[3,4с]pyrrol-5 (3H)yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((2S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((tetrahydro-1H-furo[3,4с]pyrrol-5 (3H)yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 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; - 130 045324 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; 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; 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; 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; 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; (3R)-1 -(4-((4-( 1-(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (3S)-1 -(4-((4-(1 -(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (S)-1 -(4-((4-((R)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (8)-1-(4-((4-((8)-1-(((8)-1-fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; 6-(3-(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-((oxetan-3ylamino)methyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 2-(1 -(4-((4-(1 -(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl )propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile; 2-(1 -(4-((4-((R)- 1-(((S)-1 -fluoropropan-2-yl)amino)-3-(5-hydroxy-6-oxo-1,6 -dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile; 2-(1 -(4-((4-((S)-1 -(((S)-1 -fluoropropan-2-yl)amino)-3-(5 -hydroxy-6-oxo-1,6 -dihydropyrimidin-4yl)propan-2-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetonitrile; 3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)butanonitrile; (38)-3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino )butanonitrile; (8)-3-(((8)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanonitrile; (8)-3-(((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanonitrile; (3R)-3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino )butanonitrile; (R)-3-(((8)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanonitrile; (R)-3-(((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl )propyl)amino)butanonitrile; 6-(3-((2-fluoropropyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H )-she; 1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin-3-carbonitrile; (R)-1 -(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin- 3-carbonitrile; (8)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin- 3-carbonitrile; 6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (8)-6-(3-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 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; 6-((R)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((R)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((8)-3-(((8)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((R)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-(((S)-1 -fluoropropan-2-yl)amino)-2-(4-((4-((((8)-tetrahydrofuran-3 yl)amino)methyl)phenyl)ethynyl )phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; - 131 045324 6-((R)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((S)-3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl) phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin-4(3H)-one ; (S)-6-(3-((3,3-difluorocyclobutyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-(3-(cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-(cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(3-(cyclopropylamino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (4S)-3-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl) ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one; (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; (S)-3-((R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4-((3-methoxyazetidin-1yl) methyl)phenyl)ethynyl)phenyl)propyl)-4-methyloxazolidin-2-one; (3S)-1 -(4-((4-(1 -((2,2-difluoroethyl)amino)-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2- yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; 6-(2-(4-((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropane -2yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-((2-chloropropyl)amino)-2-(4-((4-(((R)-3 -methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(3H)-she; 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; 6-(2-(4-((4-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropane -2yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3-((2-(methylsulfonyl)ethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-((2-hydroxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 3-((3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)amino)propanenitrile; 6-(3-((2,2-difluoroethyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)butyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropane -2yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((R)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S) -1fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((S)-2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S) -1fluoropropan-2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3 -methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(3H)-she; 6-((2R)-3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)- 5-hydroxypyrimidin-4(3H)-one; 6-((2S)-3-((2-fluoropropyl)amino)-2-(4-((4-(((R)-3-methoxypyrrolidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl) -5-hydroxypyrimidin-4(3H)-one; 6-(3-((2-fluoropropyl)amino)-2-(4-((4-(2-morpholinoethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one; - 132 045324 (R)-6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one ; (S)-6-(2-((3-fluoropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one; 6-((2R)-2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)- she; 6-((2S)-2-((1-fluoropropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)- she; 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; 5-hydroxy-6-(3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4-((((S)tetrahydrofuran-3yl)amino)methyl)phenyl )ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 6-(2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)5-hydroxypyrimidin-4(3H) -she; 6-((R)-2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4 (3H)-she; 6-((S)-2-(4-((4-(((S)-2-(aminomethyl)pyrrolidin-1 -yl)methyl)phenyl)ethynyl)phenyl)-3 hydroxypropyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-(2-(4-((4-(((R)-2-(aminomethyl)pyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)5-hydroxypyrimidin-4(3H) -she; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((( 1 -imino-1 -oxidohexahydro-116-thiopyran-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-(((( 1S,3R)-1 -imino-1 -oxidotetrahydro- 1H-116-thiophen-3yl)amino)methyl)phenyl )ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-(((( 1R,3S)-1 -imino-1 -oxidotetrahydro- 1H-116-thiophen-3yl)amino)methyl)phenyl )ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((4-(2-hydroxyacetyl)piperazin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 6-(2-(4-((4-((((R)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4( 3H)-she; 2-hydroxy-K-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl)benzyl)- N-((R)-pyrrolidin-3-yl)acetamide; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((((R)-1-(2-hydroxyethyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3H)-one; 2-((3R)-3-((4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl )benzyl)amino)pyrrolidin-1-yl)acetic acid; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4( 3H)-she; (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3H)-one; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(((1-(2-hydroxyacetyl)piperidin-4yl)amino)methyl)phenyl)ethynyl)phenyl)propyl) pyrimidin-4(3H)-one; 2-hydroxy-N-(((2S)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2-yl )phenyl)ethynyl)benzyl)pyrrolidin-2-yl)methyl)acetamide; 6-(3-(3-fluoroazetidin-1 -yl)-2-(4-((4-((3-methoxyazetidin-1 -yl)methyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin-4( 3H)-she; (R)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; (S)-6-(3 -(3-fluoroazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3yl)amino)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((R)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3yl)amino)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-((S)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)tetrahydrofuran-3yl)amino)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (R)-5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; - 133 045324 (S)-5-hydroxy-6-(3-((2-methoxyethyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H) -she; 5-hydroxy-6-(2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((S)tetrahydrofuran-3yl)amino)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H )-she; 5-hydroxy-6-((R)-3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-((S)-3-(((S)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-(3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H )-she; 5-hydroxy-6-((R)-3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-((S)-3-(((R)-1-hydroxypropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 6-(2-((3-chloropropyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-amino-2-(4-((4-((((R)-tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one ; 6-(2-amino-2-(4-((4-((4-methoxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)ethyl)-5hydroxypyrimidin-4(3H)-one; (R)-5-rugpoKcu-6-(3 -(3-methoxyazetidin-1-yl)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl )pyrimidin-4(3H)-one; (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; 6-(3-(azetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1fluoropropan-2-yl) amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((2R)-2-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-(((S)1-fluoropropane -2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((2S)-2-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3 -(((S)-1 fluoropropane -2-yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-(((S)-1 -acetylpyrrolidin-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4(3H) -she; 6-((R)-3-(((S)-1 -acetylpyrrolidin-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-((S)-3-(((S)-1 -acetylpyrrolidin-3 -yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-(3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one ; 6-((R)-3-((( 1 H-pyrazol-5 -yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin- 4(3H)-ona; 6-((S)-3-(((1H-pyrazol-5-yl)methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidine-4 (3H)-she; 6-(3-(((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4( 3H)-she; 6-((R)-3-(((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 6-((S)-3-(((R)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 6-(3-(((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin-4( 3H)-she; 6-((R)-3-(((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 6-((S)-3-(((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5- hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3-methoxy-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin4(3H)-one; 6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; - 134 045324 (R)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)- she; (S)-6-(3-(3-fluoroazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; (R)-5-rugpoKcu-6-(3 -hydroxy-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; (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; (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; 6-(3-(cycloproyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -she; (R)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; (S)-6-(3 -(cyclopropyl(methyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)- 5-hydroxypyrimidin-4(3H)-one; (R)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl )propyl)-5-hydroxypyrimidin-4(3H)-one; (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; 6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -she; (S)-6-(3 -(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -she; 6-(3-(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine-4(3H) -she; (R)-6-(3-(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; (S)-6-(3 -(cyclopropylamino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2methylpropyl)-5-hydroxypyrimidin-4(3H)-one ; (R)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2methylpropyl)-5-hydroxypyrimidin-4( 3H)-she; (S)-6-(3-(cyclopropylamino)-2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2methylpropyl)-5-hydroxypyrimidin-4( 3H)-she; 5-hydroxy-6-(3-(3-hydroxyazetidin-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (R)-5-hydroxy-6-(3 -(3 -hydroxyazetidin-1 -yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; (S)-5-hydroxy-6-(3-(3-hydroxyazetidin-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; 6-(2-(4-((4-(((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)5-hydroxypyrimidin-4(3H) -she; 6-((R)-2-(4-((4-((((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4 (3H)-she; 6-((S)-2-(4-((4-((((R)-1-acetylpyrrolidin-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4 (3H)-she; - 135 045324 (S)-1 -(4-((4-((R)-1 -(3-cyanoazetidin-1-yl)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin- 4yl)propan-2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (S)-1 -(4-((4-((S)-1 -(3-cyanoazetidin-1-yl)-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)propane -2-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5hydroxypyrimidine-4(3H)- she; (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-((3-fluoropropyl)amino)propyl)-5hydroxypyrimidine-4(3H)- she; 6-(2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2yl)amino )propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((R)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropane2 -yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 6-((S)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropane2 -yl)amino)propyl)-5-hydroxypyrimidin-4(3H)-one; 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; 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; 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; 2-hydroxy-N-(1 -(4-((4-(1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl) benzyl)piperidin-4-yl)acetamide; (R)-2-hydroxy-N-(1 -(4-((4-( 1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2-yl) phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide; (S)-2-hydroxy-N-(1 -(4-((4-(1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl) phenyl)ethynyl)benzyl)piperidin-4-yl)acetamide; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 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; 5-hydroxy-6-((S)-3-(((S)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-((R)-3-(((S)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-((R)-3-(((R)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-she; 5-hydroxy-6-((S)-3-(((R)-2-hydroxypropyl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H )-she; 6-(3-((2-fluoro-3-hydroxypropyl)amino)-2-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidine -4(3H)-she; (R)-5-hydroxy-6-(2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((1methylcyclopropyl)amino)propyl)pyrimidine -4(3H)-she; (S)-5-hydroxy-6-(2-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((1methylcyclopropyl)amino)propyl)pyrimidine -4(3H)-she; 6-(2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2-yl)amino)propyl)-5hydroxypyrimidine-4 (3H)-she; 6-((2R)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3 -(((S)-1 -fluoropropan-2yl)amino)propyl)-5 -hydroxypyrimidin-4(3H)-one; 6-((25)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-(((S)-1-fluoropropan-2yl)amino)propyl)-5 -hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-((((R)-1-(methylsulfonyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-((((R)-1-(methylsulfonyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((R)-1-(methylsulfonyl)pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin- 4(3H)-ona; N-((3R)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl) benzyl)pyrrolidin-3-yl)cyclopropanecarboxamide; - 136 045324 2-hydroxy-N-((3R)-1-(4-((4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydronirimidin-4-yl)pronαn2-yl) phenyl)ethynyl)benzyl)pyrrolidin-3-yl)acetamide; 6-(2-(4-((4-((2-(aminomethyl)morpholino)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((piperidin-4ylamino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(3-hydroxy-2-(4-((4-((methyl((R)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H) -she; 5-hydroxy-6-(3 -hydroxy-2-(4-((4-((((R)-1 -methylpyrrolidin-3 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4( 3H)-she; 5-hydroxy-6-(3-hydroxy-2-(4-((1-(2-hydroxyacetyl)piperidin-4yl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-(2-(methylamino)-2-(4-((4-((((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)pyrimidine-4(3H )-she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (S)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; (R)-5-hydroxy-6-(3-hydroxy-2-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((R)-2-(hydroxymethyl)piperazin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1yl)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine -4(3H)-she; 5-hydroxy-6-(3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidin- 4(3H)-ona; 5-hydroxy-6-((S)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 5-hydroxy-6-((R)-3-hydroxy-2-(4-((4-(((2-hydroxyethyl)((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl) propyl)pyrimidin-4(3H)-one; 6-(2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one; 6-((2S)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypronyl)-5hydroxypyrimidin-4(3H)-one; 6-((2R)-2-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-hydroxy-2-(4-((4-((((R)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)ethyl)pyrimidine-4,5-diol; N-(1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropprimidin-4-yl)propan-2yl)phenyl)ethynyl) benzyl)piperidin-4-yl)-2-hydroxyacetamide; (R)-N-(1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl) phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide; (S)-N-(1 -(4-((3-fluoro-4-( 1 -hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl) phenyl)ethynyl)benzyl)piperidin-4-yl)-2-hydroxyacetamide; 6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3hydroxypropyl)-5-hydroxypyrimidin-4 (3H)-she; (S)-6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3hydroxypropyl)-5 -hydroxypyrimidin-4(3H)-one; (R)-6-(2-(4-((4-((1-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)ethynyl)-2-fluorophenyl)-3hydroxypropyl)-5 -hydroxypyrimidin-4(3H)-one; (3R)-1-(4-((3-fluoro-4-(1-hydroxy-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)phenyl)ethynyl )benzyl)pyrrolidine-3-carbonitrile; 6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; (R)-6-(2-(4-((2-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; 6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; (R)-6-(2-(4-((3-fluoro-4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3 -(3-hydroxyazetidine-1 - 137 045324 yl)propyl)-5-hydroxypyrimidine- 4(3H)-ona; 6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-hydroxyazetidin-1yl)propyl)-5-hydroxypyrimidine-4(3H) -she; (R)-6-(2-(3-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3 -(3-hydroxyazetidin-1 yl)propyl)-5-hydroxypyrimidine-4(3H )-she; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H) -she; (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-fluoroazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H) -she; 1 -(4-((4-( 1 -((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl)-3 -fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile; (S)-1 -(4-((4-(1 -((2,2-difluoroethyl)amino)-3 -(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2- yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile; (R)-1-(4-((4-(1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan2- yl)-3-fluorophenyl)ethynyl)benzyl)azetidine-3-carbonitrile; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2yl)amino)propyl)-5-hydroxypyrimidine-4 (3H)-she; 6-((R)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2yl)amino)propyl)-5 -hydroxypyrimidin-4(3H)-one; 6-((S)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-1-fluoropropan-2yl)amino)propyl)-5 -hydroxypyrimidin-4(3H)-one; R)-1 -(4-((4-(1 -((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)propan-2yl )-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (R)-1-(4-((4-((S)-1-((2,2-difluoroethyl)amino)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl) propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; (R)-1 -(4-((4-((R)-1 -((2,2-difluoroethyl)amino)-3-(5 -hydroxy-6-oxo-1,6-dihydropyrimidin-4yl) propan-2-yl)-3-fluorophenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile; 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; (S)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl)propyl )-5-hydroxypyrimidin-4(3H)-one; (R)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-((3-methoxyazetidin-1yl)methyl)phenyl)ethynyl)phenyl)propyl )-5-hydroxypyrimidin-4(3H)-one; 6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidine-4( 3H)-she; (R)-6-(3-((2,2-difluoroethyl)amino)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidine-4( 3H)-she; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidine-4(3H)- she; 6-((S)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidine-4 (3H)-she; 6-((R)-2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(((R)-2hydroxypropyl)amino)propyl)-5-hydroxypyrimidine-4 (3H)-she; 5-hydroxy-6-(3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((S)-tetrahydrofuran-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate; (S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate; (R)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl dihydrogen phosphate; 5-hydroxy-6-(3-methoxy-2-(4-((4-(((S)-pyrrolidin-3- 138 045324 yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((S)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((S)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-(3-methoxy-2-(4-((4-(((R)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4(3H)- she; 5-hydroxy-6-((S)-3-methoxy-2-(4-((4-((((R)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; 5-hydroxy-6-((R)-3-methoxy-2-(4-((4-((((R)-pyrrolidin-3yl)amino)methyl)phenyl)ethynyl)phenyl)propyl)pyrimidine-4 (3H)-she; N(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide; (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide; (S)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide; N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl)ethyl)methanesulfonamide ; (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl )ethyl)methanesulfonamide; (S)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(4-hydroxypiperidin-4yl)phenyl)ethynyl)phenyl )ethyl)methanesulfonamide; N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-(((S)-2-(hydroxymethyl)piperazin-1yl)methyl )phenyl)ethynyl)phenyl)ethyl)methanesulfonamide; 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; 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; 6-(2-(4-((4-(((R)-3-aminopyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5hydroxypyrimidin-4(3H)-one; 6-(2-(4-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)phenyl)-3-hydroxypropyl)-5-hydroxypyrimidin-4(3H)-one; 6-(3-(((S)-1-fluoropropan-2-yl)amino)-2-(4-((4-(2-morpholinoethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidine-4(3H )-she; N-(1-([1,1'-biphenyl]-4-yl)-2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4yl)ethyl)methanesulfonamide; N-(2-(5-rugpoKcu-6-oKco-1,6-dihydropyrimidin-4-yl)-1-(4-((4-((3-methoxyazetidin-1 yl)methyl)phenyl)ethynyl)phenyl )ethyl)methanesulfonamide; (R)-N-(2-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-1-(4-((4-((3-methoxyazetidin-1yl)methyl)phenyl) ethynyl)phenyl)ethyl)methanesulfonamide; (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; 6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)5-hydroxypyrimidin-4(3H )-she; (S)-6-(2-(2-fluoro-4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-(3-methoxyazetidin-1-yl)propyl)5-hydroxypyrimidin-4(3H )-she; 6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)5-hydroxypyrimidin-4(3H) -she; (R)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; (S)-6-(3-((1-fluoro-2-methylpropan-2-yl)amino)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5-hydroxypyrimidin- 4(3H)-ona; 6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (S)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; (R)-6-(3-(cyclopropyl(methyl)amino)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-5hydroxypyrimidin-4(3H)-one; 1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin-3-ylacetate; - 139 045324 (S)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl )azetidin-3-ylacetate; (R)-1-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidin- 3-yl acetate; K-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide; (S)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide; (R)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)acetamide; N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide; (S)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide; (R)-N-(3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)methanesulfonamide; 5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4(3H)-one ; (S)-5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)pyrimidin-4( 3H)-one and (R)-5-hydroxy-6-(3-(2-methyl-1H-imidazol-1-yl)-2-(4-((4(morpholinomethyl)phenyl)ethynyl)phenyl)propyl )pyrimidin-4(3H)-one; or a pharmaceutically acceptable salt thereof. 11. Connection selected from I - 140 045324 or a pharmaceutically acceptable salt thereof. 12. Connection selected from I - 141 045324 its pharmaceutically acceptable salt. 13. A pharmaceutical composition containing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the treatment of an infection with gram-negative bacteria in a patient in need thereof. 15. Use according to claim 14, wherein the infection with gram-negative bacteria is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection and urinary tract infection; or infection with gram-negative bacteria is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections and kidney infections. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 142-