Search

EP-4735466-A1 - HTRA1 INHIBITORS AND USES THEREOF

EP4735466A1EP 4735466 A1EP4735466 A1EP 4735466A1EP-4735466-A1

Abstract

Disclosed herein are compounds that act as inhibitors of the serine protease HTRA1, compositions comprising the compounds, and uses of the compounds, e.g., in treatment of HTRA1 associated disorders, including age-related macular degeneration.

Inventors

  • SMITH, MARK
  • Mahajan, Vinit B.
  • DENNIS, David G.
  • SUN, Young Joo
  • PARSONS, DYLAN E.

Assignees

  • The Board of Trustees of the Leland Stanford Junior University
  • The United States Government as represented by the Department of Veterans Affairs

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Q N is -X-R N . wherein: X is selected from -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-. and a bond; R N is selected from Ci-Ce alkyl, aryl, and -(CR a R b ) p -Z; p is 1, 2, or 3; R a and R b are each independently selected from hydrogen and C1-C4 alkyd, wherein one R a and one R b , together with the carbon atom to which they are attached, are optionally taken together to form a 3- to 6-membered cycloalkyl; and Z is selected from aryl and heterocyclyl; wherein each R N is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -OH, and -COOH; Q c is selected from -B(OR C1 )2 and -C(O)R C2 , wherein each R C1 is independently selected from hydrogen, Ci-Ce alkyl, and aryl, or two R C1 , together with the atoms to which they are attached, form an optionally substituted ring, and R C2 is selected from C1-C4 alkyl and C1-C4 haloalkyl; R 1 is selected from C3-C8 alkyl, hydroxy-Ci-Ce alky l, C3-C6 cycloalky l, 3- to 6- membered heterocyclyl, and monocyclic heteroaryl; R 2a is hydrogen or Ci-C4-alkyl, and R 2b is selected from Ci-Cs alkyl, aryl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, hydroxy, and -(CH2) m NH-R 2c , wherein m is 1, 2, 3, 4, 5, or 6, R 2c is selected from H and -COO(Ci-C6-alkyl), and the aryl is unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy and C i-C6-alkoxy; or R 2a and R 2b , together with the atoms to which they are attached, form an optionally substituted ring; and R 3 is selected from Ci-Cs alkyl and -(CH2)n-Y, wherein n is 0, 1, 2, or 3, and Y is selected from ary l, heteroaryl, cycloalkyd, and heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycly 1 are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyd, halo, cyano, C1-C4 haloalkyl, hydroxy, amino, and C1-C4 alkoxy, and wherein the aryl or the heteroaryd is optionally substituted with a group that is taken together with R C2 to form an optionally substituted ring.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C3-C4 alkyl and C3-C5 cycloalkyl.
  3. 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
  4. 4. The compound of any one of claims 1-3. or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
  5. 5. The compound of any one of claims 1-4. or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen, and R 2b is selected from C1-C4 alkyl, -Cth-phenyl, -CH2- indolyl, and -(CH2)4NH-R 2c , wherein R 2c is selected from H and -COO(tBu), and the phenyl is unsubstituted or substituted with one substituent selected from hydroxy and Ci-C4-alkoxy.
  6. 6. The compound of any one of claims 1-5. or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen or methyl, and R 2b is selected from:
  7. 7. The compound of any one of claims 1-6. or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen, and R 2b is:
  8. 8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b , together with the atoms to which they are attached, form an optionally substituted five-membered saturated ring.
  9. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from Ci-Ce alkyl, -CH2-phenyl, -CFh-naphthyl, -CFh-indolyl, -CH2-pyridyl, and -Cl b-cyclohexyl. wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, hydroxy, methoxy, cyano, fluoromethyl, difluoromethyl, and trifluoromethyl, and wherein the pyridyl is unsubstituted or substituted with one oxo group.
  10. 10. The compound of any one of claims 1-9. or a pharmaceutically acceptable salt
  11. 10 11. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:
  12. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 3 is:
  13. 13. The compound of any one of claims 1 -12, or a pharmaceutically acceptable salt thereof, wherein R N is selected from C3-C4 alkyl, phenyl, phen l-Ci -Ch-alky I. and heterocyclyl-Ci-Ch-alkyl, wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, methyl, trifluoromethyl, methoxy, and - COOH.
  14. 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R N is selected from:
  15. 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Q N is selected from:
  16. 16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Q c is -B(OR C1 )2, and each R C1 is independently selected from hydrogen, Ci- C4 alkyl, and phenyl, or two R C1 , together with the atoms to which they are attached, form an optionally substituted saturated 5- to 6-membered ring.
  17. 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each R C1 is hydrogen.
  18. 18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Q c is -C(O)R C2 , and R C2 is C1-C4 haloalkyl.
  19. 19. The compound of claim 1, selected from compounds illustrated in FIG. 1, or pharmaceutically acceptable salts thereof.
  20. 20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

HTRA1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/510,797, filed on June 28, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING STATEMENT The contents of the electronic sequence listing titled STDU2_41633_601_SequenceListing.xml (Size: 2,310 bytes; and Date of Creation: June 25, 2024) is incorporated herein by reference in its entirety. FIELD The present disclosure is directed to compounds that act as inhibitors of the serine protease HTRA1, compositions comprising the compounds, and uses of the compounds, e.g., in treatment of HTRA1 associated disorders, including age-related macular degeneration. BACKGROUND Age-related macular degeneration (AMD) is the leading cause of vision loss in people 65 and older, with two different disease forms: dry and wet. There are currently no effective therapeutics for dry- AMD. the more common and earlier form of disease. Genome-wide association studies with AMD patients identified a genetic promoter mutation resulting in overexpression of the serine protease, HTRA1, increasing disease-risk by up to eight-fold (Klein et al. Science 2005, 308 (5720), 385-389.). Increased HTRA1 activity results in abnormal proteolysis of Thrombospondin- 1, which activates a monocyteaccumulation pathway, causing inflammation and retinal pigment epithelial degeneration characteristic of both genetic and age-related dry - AMD. Accordingly, inhibition of HTRA1 may provide a treatment for AMD, including dry AMD, along with other disorders associated with HTRAl. SUMMARY In one aspect, disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: QN is -X-RN, wherein: X is selected from -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-. and a bond; RN is selected from Ci-Ce alkyl, aryl, and -(CRaRb)P-Z; p is 1, 2, or 3; Ra and Rb are each independently selected from hydrogen and C1-C4 alkyl, wherein one Ra and one Rb, together with the carbon atom to which they are attached, are optionally taken together to form a 3- to 6-membered cycloalkyl; and Z is selected from aryl and heterocyclyl; wherein each RN is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -OH, and -COOH; Qc is selected from -B(ORC1)2 and -C(O)RC2, wherein each RC1 is independently selected from hydrogen, Ci-Ce alkyl, and aryl, or two RC1, together with the atoms to which they are attached, form an optionally substituted ring, and RC2 is selected from C1-C4 alkyl and C1-C4 haloalkyl; R1 is selected from C3-C8 alkyl, hydroxy-Ci-Ce alkyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, and monocyclic heteroaryl; R2a is hydrogen or Ci-C4-alkyl, and R2b is selected from Ci-Cs alkyl, aryl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, hydroxy, and -(CH2)mNH-R2c, wherein m is 1, 2. 3, 4, 5, or 6, R2c is selected from H and -COO(Ci-C6-alkyl), and the aryl is unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy and C i-Cg-alkoxy; or R2a and R2b, together with the atoms to which they are attached, form an optionally substituted ring; and R3 is selected from Ci-Cs alkyl and -(CH2)n-Y, wherein n is 0, 1, 2. or 3, and Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, halo, cyano, C1-C4 haloalkyl, hydroxy, amino, and C1-C4 alkoxy, and wherein the ary l or the heteroaryl is optionally substituted with a group that is taken together with RC2 to form an optionally substituted ring. In some embodiments, R1 is selected from C3-C4 alkyl and C3-C5 cycloalkyl. In some embodiments, R1 is selected from: In some embodiments, R1 is selected from: In some embodiments, R2a is hydrogen, and R2b is selected from C1-C4 alkyl, -CH2- phenyl, -CH2-indolyl, and -(CH2)4NH-R2c, wherein R2c is selected from H and -COO(tBu), and the phenyl is unsubstituted or substituted with one substituent selected from hydroxy and Ci-C4-alkoxy. In some embodiments, R2a is hydrogen or methyl, and R2b is selected from: In some embodiments, R2a is hydrogen, and R2b is: In some embodiments, R2a and R2b, together with the atoms to which they are attached, form an optionally substituted five-membered saturated ring. In some embodiments, R3 is selected from Ci-Ce alkyl, -CH2-phenyl, -CH2-naphthyl, - CH2-indolyl, -CH2-pyridyl, and -CH2-cyclohexyl, wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, hydroxy, methoxy, cyano, fluoromethyl, difluoromethyl, and trifluoromethyl, and wherein the pyridyl is unsubstituted or substituted with one oxo group. In some embodiments, R" is selected from: In some embodime