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US-20260124204-A1 - METALLOENZYME INHIBITOR COMPOUNDS

US20260124204A1US 20260124204 A1US20260124204 A1US 20260124204A1US-20260124204-A1

Abstract

Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.

Inventors

  • Christopher M. Yates

Assignees

  • EIKONIZO THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20250609

Claims (20)

  1. 1 - 69 . (canceled)
  2. 70 . A compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein: A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, wherein A is optionally substituted with 1-3 independent substituents R 5 ; X is NR 4 ; R 1 and R 2 together with the atoms to which they are attached form a cycloalkyl ring; R 3 is haloalkyl; R 4 is hydrogen or alkyl; each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, —NR a R b , —NHSO 2 R c , —(CH 2 ) n NR a R b , —(CH 2 ) n C(O)NR a R b , —(CH 2 ) n NR d SO 2 R d , —S(O)R d , —S(O) 2 R d , —CO 2 R e , —COR f , —(CR e R f ) n OR f , —OR f , or aryl substituted with 0-3 independent halogen, —NR a R b , —NHSO 2 R c , —(CH 2 ) n NR a R b , —(CH 2 ) n C(O)NR a R b , —(CH 2 ) n NR d SO 2 R d , —S(O)R d , —S(O) 2 R d , —CO 2 R e , —COR f , —(CR e R f ) n OR f , or —OR f ; or two occurrences of R 5 , together with the atoms to which they are attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each occurrence of R a , R b , R c , R d , R e , and R f is, independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring; or 2 instances of R d together with the atoms to which they are attached form a heterocycloalkyl ring.
  3. 71 . The compound of claim 70 , wherein R 1 and R 2 together with the atoms to which they are attached form a cyclopropyl ring.
  4. 72 . The compound of claim 71 , wherein R 3 is —CF 3 , —CHF 2 , or —CH 2 F.
  5. 73 . The compound of claim 72 , wherein each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or —OR f ; and R f is haloalkyl or alkyl.
  6. 74 . The compound of claim 73 , wherein R 4 is hydrogen or methyl.
  7. 75 . The compound of claim 74 , wherein A is heteroaryl.
  8. 76 . The compound of claim 75 , wherein A is pyridyl.
  9. 77 . The compound of claim 76 , wherein A is wherein p is 0, 1, 2, or 3.
  10. 78 . The compound of claim 76 , wherein A is
  11. 79 . The compound of claim 74 , wherein A is phenyl.
  12. 80 . The compound of claim 79 , wherein A is wherein p is 0, 1, 2, or 3
  13. 81 . The compound of claim 80 , wherein p is 0.
  14. 82 . The compound of claim 79 , wherein A is
  15. 83 . The compound of claim 70 , wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  16. 84 . The compound of claim 70 , wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  17. 85 . The compound of claim 70 , wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  18. 86 . A compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein: A is phenyl or pyridyl, wherein A is optionally substituted with 1-3 independent substituents R 5 ; X is NR 4 ; R 1 and R 2 together with the atoms to which they are attached form a cyclopropyl ring; R 3 is —CF 3 , —CHF 2 , or —CH 2 F; R 4 is hydrogen or methyl; each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or —OR f ; and each occurrence of R f is, independently, hydrogen, alkyl, or haloalkyl.
  19. 87 . The compound of claim 86 , wherein R 3 is —CHF 2 .
  20. 88 . The compound of claim 86 , wherein each occurrence of R 5 is, independently, fluoro, cyano, methyl, haloalkyl, or —OR f ; and R f is methyl, —CF 3 , —CHF 2 , or —CH 2 F.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a Continuation application of and claims priority under 35 U.S.C. § 120 to U.S. application Ser. No. 18/443,509, filed Feb. 16, 2024, which is a Continuation application of and claims priority under 35 U.S.C. § 120 to U.S. application Ser. No. 17/336,444, filed Jun. 2, 2021, which is a Continuation application of and claims priority under 35 U.S.C. § 120 to U.S. application Ser. No. 16/518,279, filed Jul. 22, 2019, which is a Continuation application of and claims priority under 35 U.S.C. § 120 to U.S. application Ser. No. 15/917,555, filed Mar. 9, 2018, now issued U.S. Pat. No. 10,357,493, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. No. 62/469,565, filed Mar. 10, 2017, and U.S. Provisional Patent Application Ser. No. 62/513,145, filed May 31, 2017. The entirety of each is incorporated herein by reference. BACKGROUND Living organisms have developed tightly regulated processes that specifically import metals, transport them to intracellular storage sites and ultimately transport them to sites of use. One of the most useful functions of metals such as zinc and iron in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme active site and utilize the metal as a part of the catalytic process. More than one-third of all characterized enzymes are metalloenzymes. The function of metalloenzymes is highly dependent on the presence of the metal ion in the active site of the enzyme. It is well recognized that agents which bind to and inactivate the active site metal ion dramatically decrease the activity of the enzyme. Nature employs this same strategy to decrease the activity of certain metalloenzymes during periods in which the enzymatic activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteases) binds to the zinc ion in the active site of various matrix metalloprotease enzymes and thereby arrests the enzymatic activity. The pharmaceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungals fluconazole and voriconazole contain a 1-(1,2,4-triazole) group that binds to the heme iron present in the active site of the target enzyme lanosterol demethylase and thereby inactivates the enzyme. Another example includes the zinc-binding hydroxamic acid group that has been incorporated into most published inhibitors of matrix metalloproteinases and histone deacetylases. Another example is the zinc-binding carboxylic acid group that has been incorporated into most published angiotensin-converting enzyme inhibitors. In the design of clinically safe and effective metalloenzyme inhibitors, use of appropriate metal-binding groups for any particular target and clinical indication is desirable. If a weakly binding metal-binding group is utilized, potency may be ineffective. On the other hand, if a very tightly binding metal-binding group is utilized, non-selectivity for the target enzyme versus related metalloenzymes may result. The lack of effective selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes. One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently-available azole antifungal agents such as fluconazole and voriconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized 1-(1,2,4-triazole) to iron in the active site of CYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint pain that has been observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to inhibition of off-target metalloenzymes due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active sites. Therefore, the search for metal-binding groups that can achieve a better balance of potency and selectivity remains an important goal and would be significant in the realization of therapeutic agents and methods to address currently unmet needs in treating and preventing diseases, disorders and symptoms thereof. Post-translational lysine acetylation of proteins is a critical process in regulating many cellular functions. This modification is a dynamic process controlled by two enzyme families: histone acetyltransferases (HAT) and histone deacetylases (HDAC). HDACs are responsible for the deacetylation of lysine residues on a variety of substrates including histone and non-histone (e.g. (t-tubulin) proteins. There are 18 mammalian HDAC enzymes which are divided into four classes based on sequence identity and catalytic activity. Class I, II, and IV HDAC enzymes are Zn2+ dependent metalloenzymes whereas the sirtuins, HDAC class III, are nicotinomide adenine dinucleotide (NAD