Search

EP-4734979-A2 - TMEM175 AGONISTS, COMPOSITIONS, AND METHODS OF USE

EP4734979A2EP 4734979 A2EP4734979 A2EP 4734979A2EP-4734979-A2

Abstract

The present disclosure relates to compounds of the Formula I or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Also provided are compositions comprising said compounds and methods of use for treating certain diseases or disorders, including, for example, neurodegenerative diseases and lysosomal storage diseases.

Inventors

  • IYENGAR, RAJESH R.
  • LEE, THOMAS WAI-HO
  • SCHMIDT, DARBY R.

Assignees

  • Caraway Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. CLAIMS 1. A compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Z 1 is C 1-6 alkyl or C 1-4 alkylene-aryl, substituted with one or two halogen, or ; Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 is absent, CR 5 or N; X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N; and when X 2 or X 3 to which ring A is attached is CR 5 , R 5 of the CR 5 to which X 2 or X 3 is attached is absent; X 6 is absent or is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X7 is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 8 is selected from the group consisting of C and N; R 1 is H or C 1-4 alkyl; R 2 is C 1-4 alkyl or H, wherein the C 1-4 alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy; or R 1 and R 2 , together with the carbon atom to which R 1 and R 2 are attached, form C 3-4 cycloalkylene;
  2. R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl; R 4 is H or C 1-6 alkyl; R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that when Z 1 is and when X 6 is CH, X 7 is N or CH, X 8 is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X 6 is absent, X 7 is C(=O), X 8 is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X 6 is CH wherein the H of CH is optionally substituted by methyl, X 7 is N, X 8 is C, ring B is phenyl, and ring A is attached to X 2 , ring B is substituted with 1- 4 R 3 ; when X 6 is CH, X7 is N or CH, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not N-bound 6-membered heterocyclyl; and when X 6 is CH, X7 is N, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not triazole. 2. A compound of Formula II: Formula II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N; and when X 2 or X 3 to which ring A is attached is CR 5 , R 5 of the CR 5 to which X 2 or X 3 is attached is absent; X 6 is absent or is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X7 is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 8 is selected from the group consisting of C and N; R 1 is H or C 1-4 alkyl; R 2 is C 1-4 alkyl or H, wherein the C 1-4 alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy; or R 1 and R 2 , together with the carbon atom to which R 1 and R 2 are attached, form C 3-4 cycloalkylene; R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl; R 4 is H or C 1-6 alkyl; R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that: when X 6 is CH, X 7 is N or CH, X 8 is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X 6 is absent, X7 is C(=O), X 8 is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X 6 is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X 8 is C, ring B is phenyl, and ring A is attached to X 2 , ring B is substituted with 1- 4 R 3 ; when X 6 is CH, X 7 is N or CH, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not N-bound 6-membered heterocyclyl; and when X 6 is CH, X 7 is N, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not triazole. 3. A compound of Formula II-A: Formula II-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 4 , and X 5 are N; X 6 is absent or is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X7 is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 8 is selected from the group consisting of C and N; R 1 is H or C 1-4 alkyl;
  3. R 2 is C 1-4 alkyl or H, wherein the C 1-4 alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy; or R 1 and R 2 , together with the carbon atom to which R 1 and R 2 are attached, form C 3 -4cycloalkylene; R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl; R 4 is H or C 1-6 alkyl; R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3 -6 cycloalkyl, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0. Formula II-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N; and when X 2 or X 3 to which ring A is attached is CR 5 , the R 5 of CR 5 to which X 2 or X 3 is attached is absent; X 6 and X7 are each independently selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 8 is selected from the group consisting of C and N; R 1 is H or C 1-4 alkyl; R 2 is C 1-4 alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy; R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl; R 4 is H; R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3 -6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that: when X 6 is CH, X7 is N or CH, X 8 is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X 6 is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X 8 is C, ring B is phenyl, and ring A is attached to X 2 , ring B is substituted with 1- 4 R 3 ; when X 6 is CH, X 7 is N or CH, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not N-bound 6-membered heterocyclyl; and when X 6 is CH, X 7 is N, X 8 is C, ring B is phenyl, q is 0, X 1 , X 2 , X 4 , and X 5 are CH, and X 3 is C, ring A is not triazole. 5. A compound of Formula II-C: Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl,
  4. 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 4 , and X 5 are N; X 6 and X 7 are each independently selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 8 is selected from the group consisting of C and N; R 1 is H or C 1-4 alkyl; R 2 is C 1-4 alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy; R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl; R 4 is H; R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3 -6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0.
  5. 6. The compound of any one of claims 1, 2 and 4, wherein X 1 , X 3 , X 4 , and X 5 are CR 5 or N and X 2 is C.
  6. 7. The compound of any one of claims 1, 2 and 4, wherein X 1 , X 2 , X 4 , and X 5 are CR 5 or N and X 3 is C.
  7. 8. The compound of any one of claims 1-5 and 7, wherein X 1 , X 2 , X 4 , and X 5 are CR 5 .
  8. 9. The compound of any one of claims 1-5and 7, wherein one of X 1 , X 2 , X 4 , and X 5 is N.
  9. 10. The compound of any one of claims 1-5, wherein the compound is a compound of Formula II-H: Formula II-H or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  10. 11. The compound of any one of claims 1-5, wherein the compound is a compound of Formula II-J: Formula II-J or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  11. 12. The compound of any one of claims 1-11, wherein the bicyclic ring containing X 6 , X7, X 8 , and ring B is selected from the group consisting of: wherein the bicyclic ring is substituted with 0-4 R 3 .
  12. 13. The compound of any one of claims 1-12, wherein the bicyclic ring containing X 6 , X 7 , X 8 , and ring B is selected from the group consisting of: wherein the bicyclic ring is substituted with 0-4 R 3 .
  13. 14. The compound of any one of claims 1-13, wherein the bicyclic ring containing X 6 , X7, X 8 , and ring B is selected from the group consisting of: wherein the bicyclic ring is substituted with 0-4 R 3 .
  14. 15. The compound of any one of claims 1-14, wherein q is an integer 0-2.
  15. 16. The compound of any one of claims 1-15, wherein q is 0.
  16. 17. The compound of any one of claims 1-15, wherein q is 1.
  17. 18. The compound of any one of claims 1-15, wherein q is 2.
  18. 19. The compound of any one of claims 1-18, wherein R 1 is H or C1-2 alkyl.
  19. 20. The compound of any one of claims 1-19, wherein R 1 is H or methyl.
  20. 21. The compound of any one of claims 1-20, wherein R 1 is H.

Description

TMEM175 AGONISTS, COMPOSITIONS, AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63/524,082, filed June 29, 2023, and 63/524,085, filed June 29, 2023, the contents of each of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD [0002] The present disclosure relates to compounds and compositions which activate TMEM175 and are useful for the treatment or prevention of a variety of diseases and disorders, such as neurodegenerative diseases and lysosomal storage diseases. BACKGROUND [0003] Lysosome dysfunction is a key component in a variety of diseases and disorders such as neurodegenerative diseases and lysosomal storage diseases (e.g., Parkinson’s Disease (PD)) (Robak, L. A. et al., Brain J. Neurol.2017, Vol.140, pp.3191–3203; Nguyen, M. et al., Trends Neurosci.2019, Vol.42, pp.140–149). For example, mutations in the lysosomal TMEM175 gene are prevalent and significant risk factors for PD (Jinn, S. et al., Hum. Mol. Genet.2019, Vol.28, pp.3244-54; Krohn, L. et al., Ann. Neurol.2019, Vol.87, pp.139- 153). TMEM175 encodes a lysosomal potassium and proton ion channel with unique structure, biophysical properties and pharmacology (see, e.g., Cang, C., et al., Cell 2015, Vol. 162, pp.1101–1112). The 12-transmembrane span architecture and lack of canonical ion selectivity filter in this channel, as well as its higher permeability to cesium ions relative to potassium ions and its ability to permeate protons make TMEM175 distinct from any known ion channel (Brunner, J. D. et al., bioRxiv 2018). [0004] The TMEM175 M393T allele is present in 14% of the general population and 25% of PD patients (Paul, K. C., et al., JAMA Neurol.2018, Vol.75, pp.360–366). This mutation significantly alters age-of-onset in PD with a risk factor of 1.2 years per allele and provides the second greatest genetic risk factor for age of onset in the idiopathic population following GBA (Lill, C. M. et al., Mov. Disord. Off. J. Mov. Disord. Soc.2015, Vol.30, pp.847–850; Iwaki, H. et al., Neurol. Genet.2019, Vol.5, e348). The M393T allele also showed a significant correlation with reduced glucocerebrosidase (GCase) activity in PD patients. M393T heterozygotes showed a 6.2% decrease in GCase activity compared to wild-type carriers, while homozygotes showed a 12.4% decrease (Krohn, L. et al.2019). These values were corrected for GBA or LRRK2 mutations, emphasizing the deleterious effect of the M393T allele on enzyme activity. Additional studies have identified the M393T mutation as a risk factor for certain diseases and disorders including REM sleep disorder (Krohn, L. et al., Nat. Commun.2022, Vol.13, 7496), dementia with Lewy Bodies (Guo, P. et al., BMC Med. 2022, Vol.20, 214), and amyotrophic lateral sclerosis (Wightman, D. P. et al., Neurobiol. Aging 2023, Vol.127, pp.99–112). Beyond M393T, 15 less common loss of function mutations in TMEM175 have also been associated with onset of Parkinson’s Disease, some of them highly penetrant (Palomba, N. P. et al., Mol. Neurobiol.2023, Vol.60, pp.2150– 2173). Functional data indicated that the majority of these loss of function mutations, including M393T, led to decreased ion current through the channel. Interestingly, a putative protective allele (Q65P) has also been identified (Jinn, S. et al.2019). Molecular dynamics simulations suggest that the Q65P mutation affects TMEM175 channel structure and conductance (Krohn, L. et al.2019). [0005] Multiple studies have demonstrated that loss of TMEM175 via genetic knock-out in cell lines and animals led to lysosome dysfunction, including pH destabilization (via direct conduction of protons through the channel), reduced enzyme activity, and impaired autophagy (Cang, C. et al.2015; Jinn, S. et al., Proc. Natl. Acad. Sci. U. S. A.2017, Vol.114, pp.2389–2394). Impaired mitochondrial respiration was also observed. Introduction of the M393T mutation via CRISPR in SH-SY5Y cells led to an intermediate effect, indicating that this allele is a partial loss of function (Jinn, S. et al.2019). The M393T mutation did not alter lysosomal localization of TMEM175 (Krohn, L. et al.2019), suggesting the mutation disrupts protein function rather than assembly or trafficking. In iPSC-derived human neurons, TMEM175 knock-down led to increased phosphorylated alpha-synuclein (p-a-syn) accumulation following exposure to alpha-synuclein pre-formed fibrils (a-syn PFF) (Jinn, S. et al.2017). These results were confirmed in cultured rat primary neurons (Jinn, S. et al. 2019). TMEM175+/- heterozygous neurons displayed an intermediate phenotype, reinforcing the gene dosing effect observed in human genetic studies. In normal neurons, overexpression of wild-type TMEM175 was able to reduce p-a-syn inclusions resulting from exposure to a- syn PFF, but overexpression of TMEM175-M393T was not (Jinn, S. et al.2019). [0006] Accordingly, there is a need to develop novel co