Novel mitofusin inhibitors
AssigneeAlbert Einstein College of Medicine
InventorsEvripidis Gavathiotis, Emmanouil Zacharloudakis
Life of this patent
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Abstract
Disclosed herein are mitofusin inhibitors which are capable of inducing mitochondrial fission, decreasing mitochondrial respiration, TCA metabolism, and inducing mitochondrial outer membrane permeabilization that leads to caspase activation and DNA damage signaling. Also disclosed are methods of treating diseases or conditions associated with imbalanced mitochondrial dynamics.
Claims20
A compound of formula I or a pharmaceutically acceptable salt thereof,
- wherein
- M is selected from hydrogen, deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, COOH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6alkyleneOC1-6alkyl, OC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneOC1-6alkyl, SC1-6alkyleneSC1-6alkyl, OC1-6alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6alkylene-CN, SC1-6alkylene-CN, OC1-6alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, and C1-6alkylOSO2, or Ar,
- Ar is a phenyl, naphthyl, 5-10-membered heteroaryl or 4-8 membered heterocyclyl, wherein the phenyl, naphthyl, heteroaryl or heterocycyl is optionally substituted with one more substituents selected from the group consisting of deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, COOH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6 alkyleneOC1-6alkyl, OC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneOC1-6alkyl, SC1-6 alkyleneSC1-6alkyl, OC1-6alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6 alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6alkylene-CN, SC1-6alkylene-CN, OC1-6alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, and C1-6alkylOSO2;
- X is halogen;
- L is C1-3alkylene optionally substituted with an oxo (═O), SO, SO2 or OC(═O);
- R1 is hydrogen, C1-6alkyl or C(O)C1-4alkyl,
- R2 and R3 are independently selected from the group consisting of hydrogen, OC1-6alkyl, SC1-6alkyl, C1-4alkyl, CN, halogen, C1-6alkylene-CN, OC1-6alkylene-CN, haloC1-6alkyl, SC1-6alkylene-CN, C2-6alkynyl, C2-6alkenyl, and C1-6alkylSO2 (sulfone);
- R4, R5, and R6 are independently selected from the group consisting of hydrogen, deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6alkyleneOC1-6alkyl, OC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneOC1-6alkyl, SC1-6alkyleneSC1-6alkyl, OC1-6alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6 alkylene-CN, SC1-6alkylene-CN, OC1-6alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, C1-6alkylOSO2;
- R7 is selected from the group consisting of hydrogen, deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6alkyleneOC1-6 alkyl, OC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneOC1-6alkyl, SC1-6alkyleneSC1-6alkyl, OC1-6alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6alkylene-CN, SC1-6alkylene-CN, OC1-6alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, C1-6alkylOSO2, phenyl, naphthyl, 5-10-membered heteroaryl or 4-8 membered heterocyclyl, wherein the phenyl, naphthyl, heteroaryl or heterocycyl is optionally substituted with one more substituents selected from the group consisting of deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, COOH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6alkyleneOC1-6alkyl, OC1-6 alkyleneO-haloC1-6alkyl, SC1-6alkyleneOC1-6alkyl, SC1-6alkyleneSC1-6alkyl, OC1-6 alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6alkylene-CN, SC1-6alkylene-CN, OC1-6 alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, and C1-6alkylOSO2
- optionally, two adjacent substituents of R2, R3, R4, R5, and R6 link up to form, together with the phenyl they are attached to, a bicyclic ring, wherein the bicyclic ring is optionally substituted with one more substituents selected from the group consisting of deuterium, OC1-6alkyl, SC1-6alkyl, CN, OH, SH, COOH, halogen, NO2, N(Rm)2, C(O)ORm, C(O)N(Rm)2, C(O)C1-6alkyl, haloC1-6alkyl, haloC1-6alkyleneO, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, C3-6cycloalkyl, C(═NC1-6alkyl)C1-6alkyl, OC(O)N(Rm)2, C(O)SRm, OC1-6alkyleneOC1-6alkyl, OC1-6alkyleneO-haloC1-6alkyl, SC1-6 alkyleneOC1-6alkyl, SC1-6alkyleneSC1-6alkyl, OC1-6alkyleneSC1-6alkyl, SC1-6alkyleneO-haloC1-6alkyl, SC1-6alkyleneS-haloC1-6alkyl, OC1-6alkyleneS-haloC1-6alkyl, C1-6alkylene-CN, OC1-6alkylene-CN, SC1-6alkylene-CN, OC1-6alkylene-N(Rm)2, C2-6alkynyl, C2-6alkenyl, SO2N(Rm)2, NRmSO2C1-6alkyl, C1-6alkylSO2 (sulfone), S(O)OH, C1-6alkylS(O) (sulfoxide), nitroso, and C1-6alkylOSO2
- alternatively, L, NR1, and R2, together with the phenyl attached to NR1, form an optionally substituted bicyclic ring,
- and
- Rm in each instance is independently hydrogen or C1-6alkyl or halo-C1-6alkyl.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1,
- Wherein R1 is hydrogen or methyl.
- The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-2, wherein X is fluorine or chlorine.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein R2 and R3 are independently selected from the group consisting of C1-4alkyl, CN, halo-C1-4alkyl and halogen.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein at least one of R2, R3, R4, R5, and R6 is halo-C1-4alkyl or halogen.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein L is CH2, CHCH3, CO, or SO2.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein R2 and R3 are independently C1-3alkyl or halo-C1-4alkyl.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein L is CO.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein L is SO2.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein wherein L and NR1, together with the phenyl attached to NR1, form a bicyclic ring.
The compound of formula (I) or the pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein Ar is phenyl optionally substituted with one or more substituents selected from the group consisting of C1-4alkyl OC1-4alkyl, CN, halogen, N(Rm)2, C(O)ORm, and C(O)N(Rm).
The method of claim 20, wherein the disease is selected from the group consisting of Leukemia, Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphoblastic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Lymphoma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Lung cancer, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Melanoma, Prostate cancer, Brain Tumors, Breast Cancer, Bladder Cancer, Colorectal Cancer, Head and Neck Cancer, Ovarian Cancer, Pancreatic Cancer, Hepatocellular (Liver) Cancer, Renal Cell (Kidney) Cancer, Skin Cancer, Ewing Sarcoma, Rhabdomyosarcoma, Osteosarcoma, Soft tissue sarcoma, obesity, mitochondrial disorder, diabetes, insulin resistance, sarcopenia, acute liver failure, liver fibrosis, nonalcoholic steatohepatitis, hepatosteatosis, alcoholic fatty liver, kidney fibrosis, chronic kidney disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, lewy body disease, parkinson's disease, spinal muscular atrophy, frontotemporal dementia, prion diseases, mitochondrial encephalopathy, age-related macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa.
Dependencies are inferred from the claim text.