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CA-3156303-C - 5-FLUORONICOTINAMIDE DERIVATIVES AND USES THEREOF

CA3156303CCA 3156303 CCA3156303 CCA 3156303CCA-3156303-C

Abstract

Provided herein is a compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein R¹, Y, X, and n are defined herein. Also provided herein are compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt thereof, e.g., in the treatment of heart disease.

Inventors

  • Mohammad A. Mandegar
  • Frederick SEIDL
  • David Sperandio
  • Tien WIDJAJA
  • Xiaodong Wang
  • Snahel Patel
  • Ulhas Bhatt
  • Pingyu Ding
  • Martin HOLAN
  • John Lee
  • Yihong Li
  • Julio Medina
  • Alok NERURKAR

Assignees

  • TENAYA THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20201002
Priority Date
20191003

Claims (20)

  1. 138 What is claimed: 1. A compound of Formula (I), or pharmaceutically acceptable salt thereof: (I); wherein n is 0 or 1; X is NR4 or CR4R4'; Y is a bond, CR2R3 or S(O)2; R1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R2 and R3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –(CH2)–carbocyclyl, –(CH2)–heterocyclyl, –(CH2)–aryl, and –(CH2)–heteroaryl; or R1 and R2 taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; and R4 is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, –(CH2)–carbocyclyl, and –(CH2)–heterocyclyl; R4' is selected from the group consisting of H, alkyl, –CO2–alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –(CH2)–carbocyclyl, –(CH2)–heterocyclyl, –(CH2)–aryl, and –(CH2)–heteroaryl; or R4 and R4' taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, –OCH3, –CO2CH3, –C(O)NH(OH), –CH3, morpholine, and –C(O)N-cyclopropyl .
  2. 2. The compound of claim 1, wherein n is 1.
  3. 3. The compound of claim 1, wherein n is 0. 139
  4. 4. The compound of any one of claims 1 to 3, wherein X is NR4.
  5. 5. The compound of any one of claims 1 to 4, wherein Y is CR2R3.
  6. 6. The compound of any one of claims 1 to 5, wherein R1 is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine.
  7. 7. The compound of any one of claims 1 to 5, wherein R1 is phenyl.
  8. 8. The compound of any one of claims 1 to 7, wherein R2 and R3 are independently selected from the group consisting of H, F, C1-6 alkyl, C3-6 cycloalkyl, –(CH2)–C3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and –(CH2)–(4- to 6-membered heterocyclyl).
  9. 9. The compound of any one of claims 1 to 7, wherein R2 and R3 taken together with the carbon atom to which they are attached form a cyclopropyl.
  10. 10. The compound of any one of claims 1 to 9, wherein R4 is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, –(CH2)–carbocyclyl, and –(CH2)– heterocyclyl.
  11. 11. The compound of any one of claims 1 to 10, wherein R4 and R4' are each H.
  12. 12. A compound, wherein the compound is: , , , , , , 140 , , , , , , , , , , , , 141 , , , , , , , , , , , , , , , , , , , 142 , , , , , , , , , , , , , , , , , 143 , , , , , , , , , , , , , , , , or a pharmaceutically acceptable salt thereof.
  13. 13. The compound of claim 1, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, –OCH3, –CO2CH3, and –CH3. 144
  14. 14. The compound of claim 1, wherein the compound is a compound of Formula (IIa): (IIa); wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from N and CR5; wherein R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, and -O-alkyl.
  15. 15. The compound of claim 14, wherein the compound is a compound of Formula (IIb): (IIb); wherein R6, R7 R8, R9, and R10 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –CO2H, –CO2–alkyl, -O-alkyl, - O-haloalkyl, -O-aryl, -O-heteroaryl, –SO2–alkyl, and –CN.
  16. 16. The compound of claim 15, wherein R6, R7 R8, R9, and R10 are independently selected from the group consisting of H and halogen.
  17. 17. The compound of claim 14, wherein the compound is a compound of Formula (IIc): (IIc); wherein R6, R7 R8, and R9 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –CO2H, –CO2–alkyl, -O-alkyl, -Ohaloalkyl, -O-aryl, -O-heteroaryl, –SO2–alkyl, and –CN.
  18. 18. A compound, wherein the compound is: 145 , , , , , , , , , , , , 146 , , , , , , , , , , or a pharmaceutically acceptable salt thereof.
  19. 19. A compound of Formula (I), or pharmaceutically acceptable salt thereof: (I); wherein n is 0; X is O; 147 Y is CR2R3; R1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R2 and R3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –(CH2)–carbocyclyl, –(CH2)–heterocyclyl, –(CH2)–aryl, and –(CH2)–heteroaryl, or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; and R4 and R4' are independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –(CH2)–carbocyclyl, –(CH2)–heterocyclyl, –(CH2)–aryl, and –(CH2)–heteroaryl; or R4 and R4' taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; and wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, –OCH3, –CO2CH3, and –CH3.
  20. 20. A compound, wherein the compound is: , , , , , or a pharmaceutically acceptable salt thereof.

Description

1 5-FLUORONICOTINAMIDE DERIVATIVES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S Provisional Application Serial No. 62/910,278, filed October 3, 2019. BACKGROUND [0002] Histone deacetylase (HDAC) are a class of enzymes with deacetylase activity with a broad range of genomic and non-genomic substrates. There are eleven zinc-dependent HDAC enzymes classified based on sequence identity and catalytic activity. [0003] Histone deacetylase inhibitors have been described and used in various therapeutic applications, including oncology, neurodegeneration, autoimmune disease, chemotherapyinduced peripheral neuropathy and cardiac indications. However, many HDAC inhibitors are non-specific (i.e., they inhibit the activity of more than one HDAC with more or less the same affinity). When administered to humans, these so-called pan-HDAC inhibitors (e.g., SAHA and Panabinostat) exhibit significant adverse effects such as fatigue, nausea, diarrhea and thrombocytopenia. Thus, there is a need for HDAC inhibitors that selectively target a particular HDAC, such as HDAC6. SUMMARY [0004] The present disclosure is directed to compounds that selectively inhibit HDAC6 activity and uses thereof in treating various diseases and disorders. For example, the present disclosure provides small molecules and compositions as well as therapeutic compositions and uses of specific small molecule compounds. [0005] In one aspect, the present disclosure provides a compound of Formula (I) or pharmaceutically acceptable salt thereof: (I); wherein: n is 0 or 1; WO 2021/067859 PCT /0S2020/054134 Xis O NR4 or CR4R4'· ' ' ' R1 is selected from the group consisting ofH, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R2 and R3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, - (CH2)-aryl, and -(CH2)-heteroaryl; or R1 and R2 taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; and R 4 and R 4 ' are each independently selected from the group consisting of H, alkyl, -CO2-alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, - (CH2)-aryl, and -(CH2)-heteroaryl; or R4 and R4 ' taken together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl; wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, -OCH3, -C02CH3, -C(O)NH(OH), -CH3, morpholine, and -C(O)N-cyclopropyl . [0006] In some embodiments, the present disclosure provides a compound of Formula (Ia) or pharmaceutically acceptable salt thereof: 3z4 ~~ ,.OH z~ 'z5 I N z2, Jl. ,,.X ✓,; H 'z1 y n N (Ia); wherein: n, X, and Y are as defined above for Formula (I); and Z1, Z2, Z3, Z4 and Z5 are independently selected from N and CR5; 2 WO 2021/067859 PCT /0S2020/054134 wherein R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -CO2H, -CO2-alkyl, -O-alkyl, -Ohaloalkyl, -O-aryl, -O-heteroaryl, -SO2-alkyl, and -CN. [0007] In some embodiments, the present disclosure provides a compound of Formula (lb) or pharmaceutically acceptable salt thereof: Rg 0 Rs*"I " R10 X F~~,OH y/ WN) R7 R6 (lb); wherein: n, X, and Y are as defined above for Formula (I); and R6, R7 Rs, R9, and R10 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -CO2H, -CO2-alkyl, -O-alkyl, -Ohaloalkyl, -O-aryl, -O-heteroaryl, -SO2-alkyl, and -CN. [0008] In some embodiments, the present disclosure provides a compound of Formula (le) or pharmaceutically acceptable salt thereof: Rs 0 R~Rg ~"-::::: N,.OH ~ .. Jl X I /4 H R6 N y,,, n N (le); wherein: n, X, and Y are as defined above for Formula (I); and R6, R7 Rs, R9, and R10 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -CO2H, -CO2-alkyl, -O-alkyl, -Ohaloalkyl, -O-aryl, -O-heteroaryl, -SO2-alkyl, and -CN. [0009] In another aspect, the present disclosure provides a compound of Formula (II) or pharmaceutically acceptable salt thereof: 3 WO 2021/067859 PCT/0S2020/054134 wherein: n is O or I; Xis NR4 or CR4R4'· ' R1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R2 and R3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, - (CH2)-aryl, and -(CH2)-heteroaryl, or R2 and R3 taken together with the carbon atom to which they are attached form a carbocy