IL326691A - Tricyclic heteroaromatic KLK5 inhibitors - Google Patents

Tricyclic heteroaromatic KLK5 inhibitors

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IL326691A
IL326691A IL326691A IL32669126A IL326691A IL 326691 A IL326691 A IL 326691A IL 326691 A IL326691 A IL 326691A IL 32669126 A IL32669126 A IL 32669126A IL 326691 A IL326691 A IL 326691A
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compound
pct
alkyl
ring
cycloalkyl
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IL326691A
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Biocryst Pharm Inc
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (16)

1. WO 2025/0493 CLAIMS PCT / US2024 / 0436 What is claimed is : 1 . A compound of formula ( I ) , or a pharmaceutically acceptable salt thereof : ( RA ) m wherein : ring B ring ( RD ) á A ( RB ) n B T - RT K ( I ) ; A is a tricyclic ring system comprising at least one aromatic or heteroaromatic ring ; is aryl , heteroaryl , cycloalkyl , cycloalkenyl , heterocycloalkyl , or heterocycloalkenyl ; B wherein J and ring are bonded to the same ring within the tricyclic ring system A ring of ring is aryl , heteroaryl , cycloalkyl , or heterocycloalkyl ; J represents –HN– , -CH2- , -C ( O ) - , -O- , -S- , -S ( O ) - , -SO2- , -N ( alkyl ) - , -CH ( alkyl ) — , -CH ( CF3 ) - , -CH ( aryl ) - , -C ( alkyl ) 2- , -CH ( cycloalkyl ) - , ^ , or is absent ; K represents -C ( O ) — , —O— , –HN– , -CH2- , -S- , -S ( O ) - , -SO2- , -N ( alkyl ) — , –2HCHN— , -CH ( alkyl ) - , -CH ( cycloalkyl ) - , or is absent ; wherein at least one of J and K is absent , or is -C ( O ) - , -CH2- , -CH ( alkyl ) - , or - CH ( aryl ) - ; Y represents -H , 2HN₂HC- , -C ( = NH ) ( NH2 ) , -C ( O ) NH2 , -NH2 , -CN , halo , -CH2C ( O ) OH , -C ( O ) OH , -S ( O ) 2NH2 , -CH2CN , -NHBoc , 3HCHN₂HC- , -CH ( CH3 ) NH2 , -CH2NHCH = NOH , HO₂HC- , amino - substituted cycloalkyl , or optionally substituted alkyl , alkenyl , aryl , arylalkyl , arylalkenyl , heteroaryl , or heteroarylalkyl ; V is -C ( O ) RE or H ; - 1006 - WO 2025/0493 IZ PCT / US2024 / 0436 RE is -OH , -NH - OH , O– ( alkyl ) , C– ( O ) ( haloalkyl ) , or N- N ﻢﮩﻴﻨﮨ T is a bond , or represents -C ( O ) - , -C ( O ) —HN , C— ( O ) N ( alkyl ) - , -C ( O ) —O , —HN₂HC— , — CH2O- , -CH ( CF3 ) -NH- , -NH - CH ( CF3 ) - , or -NHC ( O ) - ; RT represents H , halo , -CH2C ( O ) NH2 , -CH2C ( O ) OH , or optionally substituted alkyl , hydroxyalkyl , alkoxyalkyl , haloalkyl , aminoalkyl , cycloalkyl , heterocycloalkyl , spirocycloalkyl , heterospirocycloalkyl , ( cycloalkyl ) alkyl , ( heterocycloalkyl ) alkyl , aryl , arylalkyl , heteroaryl , or heteroarylalkyl ; RA , independently for each occurrence , represents alkyl , halo , -NHBoc , tosyl , hydroxyalkyl , aminoalkyl , or alkoxyalkyl ; RB , independently for each occurrence , represents halo , -C ( O ) OH , -C ( O ) NH2 , – C ( O ) NH ( alkyl ) , -C ( O ) NH ( aminoalkyl ) , oxo , cyano , hydroxy , or optionally substituted alkyl , alkoxy , haloalkyl , hydroxyalkyl , cycloalkyl , heterocycloalkyl , aryl , or heteroaryl ; RD , independently for each occurrence , represents hydroxy , halo , -CN , C– ( O ) OH , C– ( O ) NH ( alkyl ) , -C ( O ) NH ( cycloalkyl ) , -CH2C ( O ) ( alkyl ) , -CH2C ( O ) ¹DRO , - CH2C ( O ) ¹DRHN , -O [ ( CH2 ) xO ] y ( alkyl ) , -O ( CH2 ) xCOOH , ( hydroxy ) alkoxy , ( halo ) alkoxy , ( alkoxy ) alkoxy , arylalkoxy , ( cycloalkyl ) alkoxy , or optionally substituted alkyl , alkenyl , aryl , arylalkyl , arylalkenyl , heteroaryl , heteroarylalkyl , alkoxy , hydroxyalkyl , or haloalkyl ; ¹DR , independently for each occurrence , represents H , alkyl , cycloalkyl , ( cycloalkyl ) alkyl , heterocycloalkyl , ( heterocycloalkyl ) alkyl , aryl , arylalkyl , heteroaryl , or heteroarylalkyl ; m , n , and q are each integers independently selected from 0-3 ; and x and y are each integers independently selected from 1-10 .
2. The compound of claim 1 , having the structure of formula ( Ia ) : - 1007 - WO 2025/0493 wherein : ( RA ) m( RA ) mA3 A( RB ) n ( RD ) á K B T - RT ( Ia ) ; PCT / US2024 / 0436 ring A2 Aand ring are each independently selected from aryl , heteroaryl , cycloalkyl , heterocycloalkyl , partially unsaturated cycloalkyl , or partially unsaturated heterocycloalkyl ; m1 and m2 are each integers selected from 0-3 ; and the sum of ml and m2 is 3 or less .
3. The compound of claim 2 , having the structure of formula ( Ia - 1 ) : ( RA ) m( RA ) m A3 A ( RD ) á ( RB ) n B T - RT K - 1008 - ( Ia - 1 ) . WO 2025/0493 ( RA ) m( RA ) ²m A3 A
4 . The compound of claim 3 , wherein M ( RA ) m1 ( RA ) m A ( RA ) m( RA ) m A PCT / US2024 / 0436 has the following structure :
5 . The compound of claim 4 , wherein viv is selected from the group consisting of : ( RA ) mN RA ( RA ) m-NH ( RA ) m( RA ) m1 ( RA ) m , ( RA ) m( RA ) m and www ww , ﺲﻳﺩ - 1009 - ﻭ ﻭ WO 2025/0493 ( RA ) m( RA ) ²m A3 A PCT / US2024 / 0436
6 . The compound of claim 3 , wherein M has the following structure : ( RA ) mZ A wherein : Z1 , Z2 , and ³Z are each independently selected from S , CH , and CRA ; and one and only one of ¹Z , ²Z , and ³Z is S.
7 . The compound of claim 6 , wherein consisting of : ( RA ) m( RA ) m ( RA ) m ( RA ) m1 ( RA ) m ﺲﺑﺩ RA , ( RA ) m A is selected from the group ( RA ) m ( RA ) m1 || ¯1m ( RA ) m ﻭ ﺱﺭ N ( RA ) m ( RA ) m ﺲﻧﺩ , - 1010 - ww ņw , WO 2025/0493 ( RA ) ²m ( RA ) m ( RA ) m
8 .
9 . ﺐﻨﻳ , ( RA ) m ( RA ) m The compound of claim 6 , wherein ( RA ) m w ( RA ) m ( RA ) m A ( RA ) m A The compound of claim 6 , wherein ( RA ) m ( RA ) m( RA ) ²m consisting of ﻊﻨﻳ ( RA ) m - 1011 - ﺱﺩ PCT / US2024 / 0436 NH ( RA ) mN - RA m , , and has the following structure : is selected from the group ( RA ) m , and ( RA ) mww WO 2025/0493
10 . Z The compound of claim 6 , wherein ³Z ( RA ) m A ﺲﻧﺩ
11 . ww mi m The compound of claim 6 , wherein ( RA ) m ZZO AZ ﺐﻧﺩ ( RA ) m consisting of ,
12 . ( RA ) m m PCT / US2024 / 0436 has the following structure : m is selected from the group ( RA ) m ﻭ and ( RA ) m ( RA ) ²m A3 A ww ( RA ) m( RA ) m The compound of claim 3 , wherein
13 . The compound of claim 3 , wherein is ( RA ) ( RA ) ²m ( RmmA3 A - 1012 - ﺲﻧﺩ is ﺏﺭ w WO 2025/0493
14 . The compound of claim 3 , wherein PCT / US2024 / 0436 ( RA ) m( RA ) m( RA ) ²m A3 A( RA ) m M is
15. The compound of any one of claims 1-14 , wherein RA , independently for each occurrence , represents alkyl .
16 . The compound of any one of claims 2-15 , wherein each occurrence of m1 and m2 is ( 0 . B . The compound of any one of claims 1-16 , wherein ring is a bicyclic ring . B . The compound of any one of claims 1-16 , wherein ring is a monocyclic ring . ( RB ) n W B T - RT . The compound of any one of claims 1-16 , wherein T - RT is ( RB ) n and W is N or CH . 20 . The compound of claim 19 , wherein W is N. 21 . The compound of claim 19 , wherein W is CH . V ( RB ) N B RT 22 . The compound of any one of claims 1-16 , wherein T - RT is ( RB ) n 23 . The compound of any one of claims 1-22 , wherein V is -C ( O ) RE . 24 . The compound of claim 23 , wherein RE is -OH or -O ( methyl ) . 25 . The compound of claim 23 , wherein RE is -OH . 26 . The compound of any one of claims 1-25 , wherein n is 0 . - 1013 - WO 2025/049326 PCT / US2024 / 0436 27 . The compound of any one of claims 1-26 , wherein -T - RT is H. 28. The compound of any one of claims 1-26 , wherein T is a bond , and RT is optionally substituted aryl , heteroaryl , heterocycloalkyl , or cycloalkyl . 29 . The compound of any one of claims 1-26 , wherein T is -C ( O ) - , -C ( O ) NH- , or -C ( O ) N ( alkyl ) - . 30 . The compound of any one of claims 1-26 , wherein T is -C ( O ) - , and RT is optionally substituted heterocycloalkyl , preferably optionally substituted N - linked heterocycloalkyl . 31 . The compound of any one of claims 1-26 , wherein T is -C ( O ) –HN . 32. The compound of claim 31 , wherein RT is optionally substituted alkyl , hydroxyalkyl , haloalkyl , ( cycloalkyl ) alkyl , ( heterocycloalkyl ) , arylalkyl , or heteroarylalkyl . 33 . 34 . The compound of claim 32 , wherein RT is optionally substituted alkyl . The compound of claim 31 , wherein RT is optionally substituted cycloalkyl , heterocycloalkyl , aryl , or heteroaryl . 35 . The compound of claim 34 , wherein RT is optionally substituted cycloalkyl . 36. The compound of any one of claims 1-35 , wherein -J - K- is selected from the group consisting of -C ( O ) —HN- , C— ( O ) -N ( CH3 ) — , C— ( O ) –2HCHN- , -CH2 - —O , and ₂HC— - –HN . 37 . The compound of claim 36 , wherein -J - K- is -C ( O ) –HN- . D . The compound of any one of claims 1-37 , wherein ring is a bicyclic ring . D . The compound of any one of claims 1-37 , wherein ring is a monocyclic ring . D . ✓ is selected from the The compound of any one of claims 1-39 , wherein ring group consisting of phenyl , pyrazinyl , pyridinyl , pyriminyl , thiophenyl , tetrahydroisoquinolinyl , benzoimidazolyl , indolyl , bicyclo [ 1.1.1 ] pentanyl , bicyclo [ 2.2.2 ] octanyl , cyclohexyl , isoindolinyl , isoquinolinyl , or naphthalenyl . - 1014 - WO 2025/0493 D . The compound of claim 40 , wherein ring is phenyl . D . The compound of claim 40 , wherein ring is pyridinyl . PCT / US2024 / 0436 D . The compound of claim 40 , wherein ring isoquinolinyl . is benzoimidazolyl , indolyl , or D . The compound of any one of claims 1-37 , wherein ring is represented by : vir v viv RD vir N 45 . NH -NH ﻭ RD -NH The compound of claim 44 , wherein Y is -NH2 . or RD D . The compound of any one of claims 1-37 , wherein ring is represented by ( RD ) a D . The compound of any one of claims 1-37 , wherein ring is represented by - ( RD ) a 48. The compound of claim 46 or 47 , wherein Y is selected from the group consisting of 2HN2HC— , C– ( = NH ) ( NH2 ) , and C– ( O ) NH2 . 49 . The compound of claim 48 , wherein Y is -CH2NH2 . - 1015 - WO 2025/049326 PCT / US2024 / 0436 D . The compound of any one of claims 1-37 , wherein ring is represented by - ( RD ) a 51 . The compound of claim 50 , wherein Y is 2HN₂HC- . 52 . The compound of any one of claims 1-51 , wherein RD , independently for each occurrence , represents hydroxy , halo , -C ( O ) NH ( alkyl ) , or optionally substituted alkyl , alkoxy , hydroxyalkyl , or haloalkyl . 53 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof , selected from the following table : S COOH HN HN HN . HN . HN ₂HNÌ OH HN ₂HN HN HN HN . HN NH - 1016 - OMe HN NH OH HN . WO 2025/0493 HN HN OMe NH F HN ` NH OH HN . OH HN PCT / US2024 / 0436 HN HN . NH OH HN HN . HN . OH N HN HN . HN NH HN N NH NH OH HN NH NH COOH HN . OH HN ' HN . HN . - 1017 - HN ₂HN WO 2025/0493 .OH PCT / US2024 / 0436 OH N N HN HN HN . HN . HN NH .OH ₂HN OH N HN HN HN . HN HN ₂HN .OH ₂HN .OH N N HN HN ' HN . HN HN NH HN N NH NH .OH HN . - 1018 - N₂H HN NH .OH HN . WO 2025/0493 HN OMe HN ₂HN OH PCT / US2024 / 0436 HN HN . HN . OH HN NH OH N N HN HN ' HN . HN HN NH OH HN HN " OH HN ₂HN OH S. N HN HN . HN NH - 1019 - HN NH .OH HN HN . HN NH .OH N HN HN . NH2 WO 2025/049326 PCT / US2024 / 0436 S OH OH HN HN . HN NH N₂H NH N₂H HO .OH N HN HN . HN NH OH HN HN . HN . N₂H OH N N HN HN HN HN .OH N HN NH NH HN - 1020 - N₂H HN NH N = ₂HN OH N HN . WO 2025/0493 HN NH NH PCT / US2024 / 0436 S .OH OH HN . OH HN- N HN NH NH N COOH N HN HN N₂H HN- N₂H N₂H N HN HN HN HN N NH ₂HN .OH COOH N HN N N COOH COOH N N HN HN HN . HN . - 1021 - N₂H WO 2025/0493 IL F S .OH HN HN- NH HN NH H₂OC S .OH HN N₂H PCT / US2024 / 0436 H₂OC HN HN H₂OC HN HN HN HN OH N NH NH HN HN . HN- .OH HN N₂H ` ₂HN - 1022 - HN N NH .OH WO 2025/0493 S. S. HN HN ₂HN HN OH HN ` N ' HN NH NH NH NH NH OH .OH IZ OH N₂H S HN PCT / US2024 / 0436 OH .OH OH HN HN OH HN OH - 1023 - NH NH .N . OH OH OH OH OH ﻢﮨ WO 2025/0493 .OH N OH HN N₂H S S HN HN OH ' N ' .OH NH NH OH PCT / US2024 / 0436 .OH HN ' N N₂H HN N HN N₂H HN NH HN N₂H IN - 1024 - ₂HN .OH .OH IN OH ' N ' HN HN- WO 2025/0493 N₂H Br HN OH PCT / US2024 / 0436 .OH HN HN . HN HN- OH OH N N HN HN HN . Br HN . HN- OH -NH .OH HN HN HN Br HN . -NH .OH -NH H₂OC N N HN HN HN Br HN . -NH - 1025 - HN- WO 2025/0493 OH N HN Br HN . HN- H₂OC OH Br PCT / US2024 / 0436 .OH HN HN -NH .OH HN HN Br HN . Br HN . ‍NH Br HN -NH HN -NH HN- OH N N HN Br .OH -NH OH N HN HN HN . -NH .OH N HN HN HO HN . Br -NH - 1026 - -NH .OH WO 2025/0493 HN & NH ₂HN N₂H HN .OH .OH IN OH PCT / US2024 / 0436 OH HN E NH NH N Cl HN -NH .OH HN OH N HN HN HN . HN . HO d -NH .OH -NH .OH N HN HN HN HN N -NH - 1027 - -NH WO 2025/049326 PCT / US2024 / 0436 CO2H N CO2H N HN ' HN HN . HN -NH CO2H -NH CO2H ﻡﻮﻧﺓ HN HN . HN ' -NH CO2H HN . -NH CO2H Labe N HN HN . HN HN . -NH -NH HN -NH CO2H H₂OC N HN HN . CI . e HN . -NH - 1028 - WO 2025/0493 F OH HN . HN H₂OC .OH PCT / US2024 / 0436 .OH HN . OH HN . F HN HN . HN of HO Dage HN HO .OH - 1029 - HN of HO HN OH HN OH .OH WO 2025/0493 OH HN ' Br .OH OH HN . OH HN PCT / US2024 / 0436 .OH IZ HN % HN N HN OH HN eas S. OH Br - 1030 - S HN NH OH .NH WO 2025/049326 PCT / US2024 / 0436 OH N HN HN NH HO -NH -NH N HN HN HN HN . NH HO N HN HN NH HN NH NH HO HN . .OH HN HN . HN NH HN NH HO NH ` ₂HN HN . - 1031 - HO . NH HN . NH NH WO 2025/0493 N₂H N₂H N₂H HN HO HO PCT / US2024 / 0436 HN HN HN . .OH NH OH N N HN HN HN . HN . HN N₂H .OH OH HN HN . - 1032 - N₂H N₂H OH N HN N₂H HN HO HN WO 2025/0493 N₂H HN N₂H N₂H HN N₂H HN N₂H HN HO OH OH .OH N₂H PCT / US2024 / 0436 OH N HN HN . OH N HN HN HN . N₂H HO N HN HN HN . N₂H .OH HN HN . OH HN " OH N₂H OH HN HN .OH N HN HN . ﺂﺗے NH HO . " OH - 1033 - N₂H WO 2025/0493 NC . HN N₂H N₂H -NH OH OH N HN HN HN Br NH PCT / US2024 / 0436 OH HN . OH N HN HN . HN . HO OH ' N ' H2N OH HN N HN HN HN NH ₂HN .OH .OH - 1034 - N₂H HN NH HN € ₂HN OH N .OH N .OH N WO 2025/0493 N₂H .OH HN CF N₂H N₂H N₂H HN HN HN HN NH F .OH .OH .OH OH N₂H HN PCT / US2024 / 0436 OH OH N HN HN . N ` ₂HN HO . NH HN . HN . - 1035 - N₂H HN HN ' NH NH .OH .OH WO 2025/0493 HN HN HN N₂H HN ' N₂H OH HN NHN₂H OH OH .OH - 1036 - HN N₂H HN N₂H CF PCT / US2024 / 0436 OH OH OH IZ OH N NH HN ₂HN WO 2025/0493 HN N₂H HN N₂H HN N₂H HN OH NH OMe OH OMe OMe PCT / US2024 / 0436 ₂HN OH .OH N HN HN . OH OH IZ - 1037 - N₂H F HN .OH N HN F NH N HN NH OH N IN WO 2025/0493 N₂H HN HN HO PCT / US2024 / 0436 HO N HN HN . HN . OH N₂H HO N N HN HN N HN . HN . NH HN F ₂HN ₂HN- .OH N₂H N N - N N -CFHN -N ` ´N -CF .OH NH .OH N H .N . HN - 1038 - N₂H WO 2025/0493 N₂H HN ' OH .OH N OH HN ﺢﻣﺩ HO HN N HN NH OH N HN N H2N NH HO . IZ N₂H NH NH HO . PCT / US2024 / 0436 -OH N .N . OH N HN HN N HN HN . OH N₂H - 1039 - HN HO . N HN . OH WO 2025/0493 N₂H HO . HN N N₂H N₂H HN HO . PCT / US2024 / 0436 HN HN . HN . OMe HO NH OH OMe N₂H OMe OMe HN -CFN ₂HN HO . N HN ' N ' -CFN HN N₂H NH HO HN N NH - 1040 - N₂H HN N₂H HO . NH NH WO 2025/0493 N₂H HO HN N ' S ' HO . N₂H N₂H HN HN . N₂H HN HO HO PCT / US2024 / 0436 HN . N HN HN HN . OH N HN HN . OH HO N₂H H .N . OH N HN HN . .OH N HN HN .CI HN . CI HN NH -Ts .OH HN N NH NH .OH N .N . HN HN . - 1041 - 2 = WO 2025/0493 S. HN NH .OH N HN Br PCT / US2024 / 0436 .OH N HN ` ₂HN HN OH S. .OH HN HN . ` NH OH HN HN ` ₂HN .OH N N HN HN ' N ' HN . ` NH .OH ₂HN HO . N HN HN ' N ' H2N NH HO HN ' N NH N₂H N₂H - 1042 - HN ' HO . .NH NH WO 2025/0493 HO HN N N₂H .OH NH HN 0 = 5 = HN ' N ' N₂H NH .OH NH PCT / US2024 / 0436 OH ` N ' OH OH HN HN ' N ' HN BocHN OH NH HO N N HN HN . HN N₂H N₂H HN HO HN . N₂H HO . N HN N₂H - 1043 - NH WO 2025/0493 N₂H HO HN ' N HO . HN N CI N₂H N₂H HO HN N HN . .OH .NH HN NH HO . PCT / US2024 / 0436 OH N ' N ' N HN HN . .NH N₂H S. HO N HN HN . N₂H OH N N HN HN HN HN NH - 1044 - ₂HN WO 2025/0493 N₂H HO . HN N HN . N₂H N₂H N₂H HO HN N HO HN N HO NH N₂H HN N₂H HN HO HO . HO PCT / US2024 / 0436 N N N HN NH N₂H HN HN NH - 1045 - N₂H HO . N NH .NH .NH NH WO 2025/0493 N₂H N₂H HO HN N N₂H N₂H HN HN HN NH HO . HO HO OH HN . N HN N NH N₂H HO PCT / US2024 / 0436 HN N N₂H HN HO HO N NỀ HN NH N₂H HO . .NH .NH NH HN .NH .NH N₂H HO N HN NH - 1046 - N₂H NH WO 2025/0493 N₂H N₂H N₂H N₂H N₂H HO . HN N HO HN N HO N HN HO NH NH N₂H N₂H HN HN HO HO HO . PCT / US2024 / 0436 N N N HN NH N₂H HO N HN HN NH HN HO N₂H HN NH CN - 1047 - N₂H HO NH NH NH NH NH Et- WO 2025/0493 HO N₂H HN NH HN N₂H HN N₂H N₂H N₂H HN HO HO HO N₂H HO PCT / US2024 / 0436 HN HN A OH HO N HN HN . HN N HN HO N₂H HO HN HN NH NH H2N HO N HN NH N₂H NH Et- HO HN .NH NH CN - 1048 - N₂H HN__ WO 2025/0493 N₂H N₂H N₂H N₂H HN HO HO HN N HO HN N HO . HN N NH NH N₂H N₂H HN HN HO HO . HO PCT / US2024 / 0436 N HN HN NH N₂H HO . N HN NH - 1049 - N₂H .NH NH .NH H₂OC WO 2025/0493 N₂H HO . HN N N₂H N₂H HN N₂H HN HO HO HN N NH .OH OH N HN NH H₂OC N₂H HN HO HO . PCT / US2024 / 0436 N N HN NH NH N₂H N₂H HN HO F N OH N HN NC . HN . N₂H OH N F HN F. HN HN . F OH - 1050 - N₂H NH NH NH WO 2025/0493 N₂H N₂H N₂H OH PCT / US2024 / 0436 .OH N N HN HN HN HN HO HN N HN HO OH HN . HN OH N₂H N₂H HN ' HO . HO . HN HN HN . , HN N₂H F3C HO N HN N N₂H ' NH N₂H N₂H HN ' NH HNẢ HN - 1051 - NH HO OH N .NH WO 2025/0493 N₂H N₂H OH PCT / US2024 / 0436 OH N N HN HN HN HN . HN -NH NH HO . H .OH HO F N HN HN 、 HN . N HN ' HN . H N₂H HO NH HO HN N HN OH N HN HN .F HN . HN . N₂H N N₂H HN .OH HN . - 1052 - N₂H N₂H HN OH HN WO 2025/0493 S PCT / US2024 / 0436 OH N HN HN HN . HN . HN N₂H NH HO .OH HN . HN N N₂H .OH N₂H HO HN N N₂H F F HN NH HN . NH OH N HN HN HN . HN . N₂H S OH HN HN . ` ₂HN N₂H OH N HN HN . NH- 1053 - WO 2025/0493 N₂H N₂H .OH HN N NH HO HN N HN .OH N N₂H HN HO . PCT / US2024 / 0436 HN . OH HN ' NH COOH HN . ´N₂H .OH N HN HN CI HN . HN . N₂H OH N HN HN - 1054 - N₂H .OH N HN HN NH2 WO 2025/0493 HN ₂HN PCT / US2024 / 0436 OH N HN HN OH ₂HNÌ HO HN . N HN HN HN . NH NH HO . HN N H2N HO " OH HN N NH OH N₂H NH N₂H HO HN HN . HO N HN HN . HN . CN - 1055 - N₂H WO 2025/0493 N₂H HN N₂H N₂H N₂H HN HO . HO . HO . HN . F F HN . HN N HN HO . N₂H HO . PCT / US2024 / 0436 HN N N₂H HO HN . CI HN N OH HN - 1056 - N₂H N₂H HN HO HO O N HN HN WO 2025/0493 N₂H HO HN N HO HN N N₂H HN ' F N₂H N₂H N₂H HO HN HN N HN .OH HO HO HO . PCT / US2024 / 0436 N N₂H F F .OH N HN HN HN NH - 1057 - NH2 WO 2025/0493 -OH PCT / US2024 / 0436 OH N HN ' HN HN HN . HN . NH .OH HN HN NH OH IZ .N . NH OH HN HN . NH OH N N HN HN HN NH N OH N₂H HN N HN NH .OH HN HN . NH - 1058 - ﮎﺎﻣ NH OH N HN .OH N HN HN . NH F WO 2025/0493 N₂H N₂H HN HN OH PCT / US2024 / 0436 .OH N HN HN HN . NH OH NH HN . OH HN HN HN . HN 、 NH OH HN N HN NH HO .OH - 1059 - N₂H HN HN N₂H ' N₂H NH HO .OH OH HN NH2 WO 2025/0493 N₂H HN N₂H HN HN N₂H HN NH HO .OH N OH N HN NH OH N N- OH HN . PCT / US2024 / 0436 OH CFHN CF - 1060 - N₂H N₂H HN HN ₂HN HO OH .OH N HN HN . CN OH HN HN . NH2 WO 2025/0493 OH PCT / US2024 / 0436 N .OH HN N HN . HN & HN .OH ` ₂HN OH .OH NH OH N N HN HN . NH OH N N HN HN HN . OH N .OH NH OH N N HN HN HN . NH - 1061 - NH NH HN ✓ + WO 2025/0493 .OH PCT / US2024 / 0436 OH N N HN F HN HN . CI HN . -F F NH OH HN & NH HN . OH HN N HN . ₂HN HN NH OH .OH HN ₂HN HN HN HN N HN . .OH ﻞﻫ ﻭ ﻢﻄﺤﻧﺓ - 1062 - NH .OH N HN HN HO NH2 WO 2025/0493 .OH PCT / US2024 / 0436 .OH N N HN ' HN . OH HN NH OH NH HN .OH N N OH HN HN HN . HN . NHNH .NH OH N HN HN . OH NH OH N ﺱﻮﻳﺪﻳ HN & ₂HN HN . OH N HN HN . ₂HN F ד ד F - 1063 - NH-NH OH N HN HN NH2 WO 2025/0493 -OH OH HN N NH PCT / US2024 / 0436 OH N HN HO . HN . OH N HN HN . NH OH ₂HN HN . LOH HN HN . HN HN HO . HN . NH OH N HN HN NH - 1064 - NH NH .OH HN . OH HN HN . NH2 WO 2025/0493 OH NH OH PCT / US2024 / 0436 .OH N N HN HN HN . HN NH NH .OH HN N NH .OH ₂HN .OH N HN HN . NH F. N₂H .OH N N HN F HN F HN HN . NH OH N HN OH NH NH OH N HN HN . NH - 1065 - CN OH NH2 WO 2025/0493 .OH N HN HN S PCT / US2024 / 0436 .OH N HN HN OH N₂H ₂HN .OH .OH N N HN HN HN . NH F N₂H CI HO HN N HN N₂H .OH HN N F CI N₂H NH OH COH HN -F F .OH N N HN HN HN . HN ₂HN - 1066 - N₂H WO 2025/0493 OH HN N NH HN .OH N HN HN PCT / US2024 / 0436 OH S N HN NH OH NH .OH N HN HN . OH NHNH .OH S N HN NH HO .OH .NH CN N HN HN NH OH - 1067 - N₂H WO 2025/0493 F .OH N HN HN N₂H S F .OH PCT / US2024 / 0436 .OH N HN OH OH NH .NH OH N N HN HN HN HO HN NH OH NH .OH N N HN O HN ' HN HN N₂H - 1068 - NH2 WO 2025/0493 ' N ' ZI H HN ₂HN ﻢﺤﻣﺩ ` NH .OH N PCT / US2024 / 0436 .OH N O HN ' HN HN . ' N ' .OH .OH N HN NH .OH N HN HN . NH NH .OH N N HN HN HN . HN HN NH - 1069 - ₂HN WO 2025/0493 S OH N HN NH PCT / US2024 / 0436 OH HN . HN N OH N HN HN NH HN NH N₂H HN . .OH N HN HN .NH .OH N OH NH - 1070 - N₂H LL .OH S HN N₂H N ZI H N .CI .NH WO 2025/0493 HN .OH N N₂H N ZI NH .OH ZI PCT / US2024 / 0436 .OH HN N NH HN OH N N O HN ' HN HN HN N H ' S ' NH OH NH .OH N N HN HN HN . ' N ' ZI HN NH - 1071 - NH2 WO 2025/0493 .OH PCT / US2024 / 0436 OH N N HN HN HN . HN ZI ' N ' 54 . ..... ZI NH .OH NH .OH N N HN HN HN HN ' N ' ZI NH .OH N HN N₂H ZI ' N ' NH OH N HN NH HN . N .HCI ` ₂HN A compound of formula ( II ) , or a pharmaceutically acceptable salt thereof : - 1072 - WO 2025/0493 wherein : ring B C RA B2 B ( ³BR ) m( RB2 ) m( RD ) a ( II ) ; PCT / US2024 / 0436 Band ring are each independently selected from aryl , heteroaryl , cycloalkyl , ring heterocycloalkyl , partially unsaturated cycloalkyl , or partially unsaturated heterocycloalkyl ; C D ring is optionally substituted aryl , heteroaryl , cycloalkyl , or heterocycloalkyl ; is aryl , heteroaryl , cycloalkyl , or heterocycloalkyl ; J represents –HN– , -CH2- , -C ( O ) - , -O- , -S- , -S ( O ) - , -SO2- , -N ( alkyl ) - , -CH ( alkyl ) — , -CH ( CF3 ) - , -CH ( aryl ) - , -C ( alkyl ) 2- , -CH ( cycloalkyl ) - , ✗ , or is absent ; ﻭ K represents -C ( O ) — , —0— , –HN– , —2HC— , —S— , S— ( O ) - , -SO2- , -N ( alkyl ) — , –2HCHN— , -CH ( alkyl ) - , -CH ( cycloalkyl ) - , or is absent ; wherein at least one of J and K is absent , or is -C ( O ) - , -CH2- , -CH ( alkyl ) - , or – CH ( aryl ) - ; Y represents -H , 2HN₂HC- , -C ( = NH ) ( NH2 ) , C– ( O ) NH2 , -NH2 , -CN , halo , -CH2C ( O ) OH , -C ( O ) OH , -S ( O ) 2NH2 , NC₂HC— , -NHBoc , 3HCHN₂HC- , HC– ( CH3 ) NH2 , HCHN₂HC- = NOH , HO₂HC- , amino - substituted cycloalkyl , or optionally substituted alkyl , alkenyl , aryl , arylalkyl , arylalkenyl , heteroaryl , or heteroarylalkyl ; V is -C ( O ) RE or H ; RE is -OH , -NH - OH , -O ( alkyl ) , C ( O ) ( haloalkyl ) , or N- ' N ' ﻢﮩﻴﻨﮨ RA represents H , alkyl , alkoxy , halo , -NHBoc , tosyl , hydroxyalkyl , aminoalkyl , or alkoxyalkyl ; - 1073 - WO 2025/0493 B PCT / US2024 / 0436 RB2 and ³BR each , independently for each occurrence , represent halo , -C ( O ) OH , C– ( O ) NH2 , C– ( O ) NH ( alkyl ) , C– ( O ) NH ( aminoalkyl ) , oxo , cyano , hydroxy , or optionally substituted alkyl , alkoxy , haloalkyl , hydroxyalkyl , cycloalkyl , heterocycloalkyl , aryl , or heteroaryl ; RD , independently for each occurrence , represents hydroxy , halo , -CN , C– ( O ) OH , C– ( O ) NH ( alkyl ) , C– ( O ) NH ( cycloalkyl ) , -CH2C ( O ) ( alkyl ) , C2HC— ( O ) ¹³RO , - CH2C ( O ) NHRD1 , -O [ ( CH2 ) xO ] y ( alkyl ) , O– ( CH2 ) xCOOH , ( hydroxy ) alkoxy , ( halo ) alkoxy , ( alkoxy ) alkoxy , arylalkoxy , ( cycloalkyl ) alkoxy , or optionally substituted alkyl , alkenyl , aryl , arylalkyl , arylalkenyl , heteroaryl , heteroarylalkyl , alkoxy , hydroxyalkyl , or haloalkyl ; RDI , independently for each occurrence , represents H , alkyl , cycloalkyl , ( cycloalkyl ) alkyl , heterocycloalkyl , ( heterocycloalkyl ) alkyl , aryl , arylalkyl , heteroaryl , or heteroarylalkyl ; q , m1 , and m2 are each integers independently selected from 0-3 ; the sum of m1 and m2 is 3 or less ; and x and y are each integers independently selected from 1-10 . 55 . The compound of claim 54 , wherein B- ( ³BR ) m ( RB2 ) mstructure : B2 B ( ³BR ) m( RB2 ) m2 has the following B2 B( ³BR ) 56 . The compound of claim 55 , wherein ( RB2 ) m2 has a structure selected from the group consisting of : - 1074 - WO 2025/0493 N- RB 57 . ( ³BR ) m m , HN- - ( ³³R ) m m , and The compound of claim 54 , wherein B( ³BR ) mstructure : ( RB2 ) m ﻡﺓ PCT / US2024 / 0436 ( ³BR ) B2 B ( ³BR ) m( RB2 ) ²m has the following B2 B ( ³BR ) m58 . The compound of claim 57 , wherein ( RB2 ) mhas a structure selected from the group consisting of : ` ( ³BR ) m1 , ( ³BR ) m1 , and , V ( ³BR ) m 59 . The compound of any one of claims 54-58 , wherein RB2 and RB3 each , independently for each occurrence , represent halo or alkyl . 60 . The compound of any one of claims 54-59 , wherein V is -C ( O ) RE . 61 . The compound of claim 60 , wherein RE is -OH or -O ( methyl ) . 62 . The compound of claim 60 , wherein RE is -OH . - 1075 - WO 2025/049326 PCT / US2024 / 0436 63 . halo . The compound of any one of claims 54-62 , wherein RA represents H , alkyl , alkoxy , or 64 . The compound of claim 63 , wherein RA represents alkoxy . 65. The compound of any one of claims 54-64 , wherein -J - K- is selected from the group consisting of -C ( O ) -NH- , -C ( O ) -N ( CH3 ) - , -C ( O ) -NHCH2- , -CH2 - O- , and -CH2 - –HN . 66. The compound of claim 65 , wherein -J - K- is -C ( O ) –HN- . C . The compound of any one of claims 54-66 , wherein ring substituted thiophenyl . is optionally D . The compound of any one of claims 54-67 , wherein ring is phenyl . 69. The compound of any one of claims 54-67 , wherein ring indolyl , or isoquinolinyl . D is benzoimidazolyl , D . The compound of any one of claims 54-69 , wherein ring is represented by : NH ³N -NH or Y. , 71 . The compound of claim 70 , wherein Y is -NH2 . D . The compound of any one of claims 54-69 , wherein ring is represented by www ( RD ) a - 1076 - WO 2025/049326 PCT / US2024 / 0436 73. The compound of claim 72 , wherein Y is selected from the group consisting of 2HN₂HC— , C– ( = NH ) ( NH2 ) , and C– ( O ) NH2 . 74 . The compound of claim 73 , wherein Y is -CH2NH2 . 75 . The compound of claim 73 , wherein Y is -C ( = NH ) ( NH2 ) . 76 . The compound of any one of claims 54-75 , wherein q is 0 . 77 . The compound of claim 54 , or a pharmaceutically acceptable salt thereof , selected from the following table : HN OMe .OH S NH HN HN NH N₂H NH HN N₂H NH OH OH - 1077 - HN NH HN N₂H NH HN ' N₂H ' N ' OH OH OH WO 2025/0493 HN N₂H HN N₂H H2N HN HN HN HN HO . NH NH .OH OH OH HN N₂H N₂H HN HN .S . HN - 1078 - H2N HN -NH HO . HO PCT / US2024 / 0436 .OH .OH .F WO 2025/0493 HN ₂HN N₂H N₂H HO OH S HN NH .S . NH NH OH OH N HN NH N₂H N₂H N₂H PCT / US2024 / 0436 OH .OH S. NH HN- NH OH · S . NH NH OH CI 78 . A pharmaceutical composition , comprising a compound of any one of claims 1-77 , or a pharmaceutically acceptable salt thereof ; and a pharmaceutically acceptable carrier . - 1079 - WO 2025/049326 PCT / US2024 / 0436 79 . 80 . 81 . 82 . 83 . 84 . 85 . 86 . 87 . A method of treating or preventing a disease or condition characterized by aberrant kallikrein activity , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-77 , or a pharmaceutically acceptable salt thereof . The method of claim 79 , wherein the disease or condition is characterized by aberrant kallikrein - related peptidase 5 ( KLK5 ) activity . The method of claim 79 or 80 , wherein the disease or condition is a skin disease . The method of any one of claims 79-81 , wherein the disease or condition is Netherton Syndrome . The method of claim 81 , wherein the skin disease is eczema , atopic eczema , atopic dermatitis , ichthyosiform ( scaly ) erythroderma ( IE ) , rosacea , or a skin infection . The method of claim 79 or 80 , wherein the disease or condition is selected from the group consisting of rhinitis , conjunctivitis , angioedema , eosinophilia , eosinophilic esophagitis , growth delay , failure to thrive , trichorrhexis invaginata ( TI ) , respiratory tract infections , systemic infections , and gastrointestinal disorders . The method of claim 79 or 80 , wherein the disease or condition is selected from the group consisting of hypersensitivity of the immune system ( atopy ) , hyper IgE syndrome , allergies ( including allergies to food and airborne agents ) , asthma , allergic asthma , and chronic inflammation . The method of claim 79 or 80 , wherein the disease or condition is cancer . The method of claim 86 , wherein the cancer is selected from the group consisting of ovarian cancer , breast cancer , prostate cancer , bladder cancer , cervical cancer , glioblastoma multiforme , and neuroblastoma . - 1080 -
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