WO2022140528A1 - Inhibiteurs deutérés du récepteur du facteur 1 de stimulation des colonies (csp-1r) - Google Patents

Inhibiteurs deutérés du récepteur du facteur 1 de stimulation des colonies (csp-1r) Download PDF

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WO2022140528A1
WO2022140528A1 PCT/US2021/064831 US2021064831W WO2022140528A1 WO 2022140528 A1 WO2022140528 A1 WO 2022140528A1 US 2021064831 W US2021064831 W US 2021064831W WO 2022140528 A1 WO2022140528 A1 WO 2022140528A1
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alkyl
compound
methyl
cycloalkyl
heteroaryl
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PCT/US2021/064831
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English (en)
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John L. Kane
Nellwyn A. HAGAN
Maria A. FITZGERALD
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Genzyme Corporation
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Priority to JP2023538678A priority Critical patent/JP2024500919A/ja
Priority to EP21844906.4A priority patent/EP4267573A1/fr
Priority to CN202180085787.4A priority patent/CN116848110A/zh
Priority to US17/669,950 priority patent/US11530216B2/en
Publication of WO2022140528A1 publication Critical patent/WO2022140528A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • ADME absorption, distribution, metabolism and/or excretion
  • Aldehyde oxidase is a cytosolic molybdenum-containing enzyme involved in the biotransformation of numerous drugs.
  • the challenge represented by AO-mediated metabolism is driven by several overlapping factors, including the complex biology of the enzyme and the widespread use of structural motifs that are AO substrates (e.g., azaheterocycles and amides.) See, e.g., Manevski, N. et al, Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery, J. Med. Chem. 2019, 62, 10955-10994.
  • differences in AO-mediated metabolism not only between species, but also between individuals, contribute to variability in exposure and complicate human dose selection.
  • CSF-1R inhibitor compounds as set forth in WO 2017/015267 that are substituted with deuterium can have improved ADME properties.
  • CSF-1R inhibitor compounds substituted with deuterium at specific positions have improved ADME properties, in particular, significant resistance to AO degradation, thus potentially improving the drug efficacy and the exposure of the drug in vivo.
  • Disclosed herein are deuterated Colony Stimulating Factor-1 Receptor inhibitors (“CSF-1R inhibitors”) that are resistant to enzymatic degradation in vivo.
  • the CSF-1R inhibitors of this disclosure are small molecule compounds that are capable of penetrating the blood-brain barrier to reach the central nervous system (CNS.) Because these compounds are advantageously able to penetrate the blood-brain barrier (a highly desirable property in neurological indications), the compounds need to be able to exhibit sufficient absorption, metabolism, distribution, and excretion (ADME) properties in order to ensure proper dosing. Metabolism issues can include rapid metabolism as well as metabolic degradation, both of which can lead to toxicities and/or suboptimal dosing of the active agent.
  • This disclosure relates to deuterated CSF-1R inhibitors and to the use of deuterated CSF-1R inhibitors and pharmaceutical compositions to treat disease, comprising CSF-1R inhibitors that have a surprising reduction of AO degradation and high efficacy as CSF-1R inhibitors to treat disease.
  • Such compounds include compounds of Formula (I): and/or or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof, wherein: the dashed lines represent optional double bonds;
  • X 1 is C, N, or CR 7 ;
  • X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently selected from N, NR 7 , or CR 7 ;
  • X 8 and X 9 are each independently selected from N or C; wherein each R 7 is independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkylnyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, C(O)-, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl-, COOH-(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-, R 8 -(C 1 -C 10
  • T 1 , T 2 , and T 3 is each independently selected from are each independently selected from N or CR 10 , wherein each R 10 is independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkylnyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, C(O)-, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl-, COOH-(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-,
  • Y 1 is O, NR 12 , or CR 12 R 13 , wherein R 12 is absent or R 12 and R 13 are each independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl, COOH-(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl
  • R 5 is absent or selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C3)alkynylamine, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-O-, (C 2 -C 9 )heterocycloalkyl-O-, (C 6 -C 14 )aryl-O-, (C 2 -C 9 )heteroaryl-O-, HO-, halo, and H 2
  • R 6 is selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkylnyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, C(O)-, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl-, COOH-(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-, R 14 -(C 1 -C 10 )alkyl-, R 14 -(C 3 -C 10 )cycl
  • Z 1 is selected from H, halo, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkoxy-, or H 2 N-;
  • Y 2 is O, S, NR 17 , or CR 17 R 18 , and wherein R 17 is absent or R 17 and R 18 are each independently selected from H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl, COOH-(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alky
  • the disclosure relates to compounds of Formula (I): and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof, wherein: the dashed lines represent optional double bonds;
  • X 1 is C, N, or CR 7 ;
  • X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from N, NR 7 , or CR 7 ;
  • X 8 , and X 9 are each independently selected from N or C; wherein each R 7 is independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl,(C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O-,(C 1 -C 10 )alkoxy-,
  • Y 1 is O, NR 12 , or CR 12 R 13 ; wherein R 12 is absent or R 12 and R 13 are each independently selected from H, D, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, HO-, halo, and H 2 N-;
  • R 1 and R 2 are each independently selected from H, D, (C 1 -C 10 )alkyl, HO-, halo, and H 2 N;
  • R 5 is absent or selected from H, D, (C 1 -C 10 )alkyl, HO-, halo, and H 2 N-;
  • R 6 is selected from D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, R 14 -(C 3 -C 10 )cycloalkyl, R 14 -(C 6 -C 14 )aryl, R 14 -(C 2 -C 9 )heteroaryl, and R 14 -(C 1 -C 10 )alkylamine; wherein R 14 is each independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine
  • Z 1 is selected from H, halo, and (C 1 -C 10 )alkyl
  • Y 2 is O, NR 17 , or CR 17 R 18 ; wherein R 17 is absent or R 17 and R 18 are each independently selected from H, (C 1 -C 10 )alkyl, HO-, halo, and H 2 N-; wherein at least one of R 7 , R 1 , or R 2 is D.
  • the disclosure relates to compounds of Formula (I’): and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof, wherein: the dashed lines represent optional double bonds;
  • A is selected from H and D;
  • X 3 is CR 3 wherein R 3 is selected from H and D;
  • X 4 is CR 4 wherein R 4 is selected from H, D, and R 7 ;
  • X 5 is CR 5 wherein R 5 is selected from H and D, wherein at least one of A, R 3 , R 4 , and R 5 is D.
  • This disclosure also relates to pharmaceutical formulations comprising deuterated CSF-1R inhibitors and to the use, for treating disease, of deuterated CSF-1R inhibitors and pharmaceutical compositions comprising CSF-1R inhibitors. Further disclosed herein is the use of deuterated CSF-1R inhibitors and pharmaceutical compositions comprising deuterated CSF-1R inhibitors that are aldehyde oxidase degradation -resistant, for treating immune-mediated diseases, including multiple sclerosis, lupus nephritis, and rheumatoid arthritis, and neurological diseases, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Huntington’s disease.
  • ALS amyotrophic lateral sclerosis
  • MSA multiple system atrophy
  • PSP progressive supranuclear palsy
  • Huntington’s disease Huntington’s disease.
  • deuterium modification With deuterium modification, one attempts to slow the CYP -mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to materially affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • the variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).
  • the compounds of the disclosure are CSF-1R inhibitor compounds as set forth in WO 2017/015267 that are substituted with deuterium and have improved ADME properties, and are in particular, highly resistant to AO degradation, thus potentially improving the drug efficacy and the exposure of the drug in vivo.
  • the disclosure relates to a method of treating a disease or disorder mediated by colony stimulating factor-1 receptors (CSF-1R) or a disease or disorder in which CSF-1R is implicated in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound according to Formula (I) or Formula (I’), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • CSF-1R colony stimulating factor-1 receptors
  • the disease or disorder is a neurological and immune mediated disease, including Multiple Sclerosis, ALS, MSA, PSP, Huntington’s disease, lupus, lupus nephritis, and rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula (I) or Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • a neurological and immune mediated disease including Multiple Sclerosis, ALS, MSA, PSP, Huntington’s disease, lupus, lupus nephritis, and rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula (I) or Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • compositions comprising a compound according to Formula (I) or Formula (F).
  • FIGS. 1A and IB shows the impact of an exemplary CSF-1R inhibitory compound (Compound 24) on MCP-1 chemokine production following CSF-1 stimulation.
  • the mean (FIG 1A) and standard deviation (FIG IB) are shown.
  • FIGS. 2A and 2B show the impact of an exemplary deuterated CSF-1R inhibitory compound (Compound 6) on MCP-1 chemokine production following CSF-1.
  • the mean (FIG 2A) and standard deviation (FIG 2B) are shown.
  • FIGS. 3A and 3B show IC 50 curves for the experiment of Figure 1.
  • FIGS. 4A and 4B show IC 50 curves for the experiment of Figure 2.
  • FIGS. 5A-5C show the CSF-1R inhibitors Compound 6 (FIG. 5A) and the
  • FIGS. 6A-6C show that CSF-1 stimulation significantly increases the Iba1 + area, and treatment with the CSF-1R inhibitors Compound 6 (FIG. 6 A) and control PLX3397 (FIG. 6C) significantly abrogated this effect in a concentration dependent manner. Results for Compound 49 are shown in FIG 6B.
  • FIGS. 7A-7C show that CSF-1 stimulation increases the number of cells within the culture (as evidence by DAPI + cells), and that CSF-1R inhibitors Compound 6 (FIG. 7A) and control PLX3397 (FIG. 7C) reduce this number in a concentration dependent manner. Results for Compound 49 are shown in FIG 7B.
  • FIGS 8A-8B show cell viability following pre-treatment with DMSO (control) or Compound 6 and CSF-1 stimulation in wild type (FIG 8 A) or SOD1 (FIG 8B) cells.
  • FIGS 9A-9B show cell viability following treatment with DMSO (control) or Compound 6 and LPS stimulation in wild type (FIG 9A) or SOD1 (FIG 9B) cells.
  • FIGS 10A-10B show MCP-1 production following treatment with DMSO (control) or Compound 6 and CSF-1 stimulation in wild type (FIG 10A) or SOD1 (FIG 10B) cells.
  • FIGS 11A-11B show IL-12p40 production following treatment with DMSO (control) or Compound 6 and LPS stimulation in wild type (FIG 11 A) or SOD1 (FIG 11B) cells.
  • FIG. 12A shows an in vitro metabolic profile of Compound 24 following incubation in human cryopreserved hepatocytes in the absence of AO inhibitor hydralazine.
  • FIG. 12B shows an in vitro metabolic profile of Compound 24 following incubation in human cryopreserved hepatocytes in the presence of AO inhibitor hydralazine.
  • FIG. 13 shows proposed metabolic pathways of Compound 24 in cryopreserved human hepatocyctes in the absence and presence of AO inhibitor hydralazine.
  • FIG. 14A shows an in vitro metabolic profile of Compound 6 following incubation in human cryopreserved hepatocytes in the absence of AO inhibitor hydralazine.
  • FIG. 14B shows an in vitro metabolic profile of Compound 6 following incubation in human cryopreserved hepatocytes in the presence of AO inhibitor hydralazine.
  • FIG. 15 shows proposed metabolic pathways of Compound 6 in cryopreserved human hepatocyctes in the absence and presence of AO inhibitor hydralazine.
  • FIG. 16 shows cell viability following CSF1R inhibitor treatment and CSF1 stimulation.
  • FIG. 17 shows the blocking effect of Compound 6 on CSF1 -induced MCP-1 production in this experiment.
  • FIGS. 18A-18B compares MCP1 production of Compound 6 (FIG. 18A) with Compound 24 (FIG. 18B), showing similar effect on MCP1.
  • FIGS. 19A-19B show that both CSF1R inhibitors (Compound 6 and Compound 24) significantly mean disease scores.
  • the deuterated CSF1R inhibitor, Compound 6, ameliorated paralytic symptoms to a surprisingly greater extent than nondeuterated Compound 24.
  • FIG. 20 shows an XRPD pattern of Compound 6 Form A.
  • FIG. 21 shows a PLM image of Compound 6 Form A.
  • FIG. 22 shows a TGA (top pattern)/DSC (bottom pattern) overlay of
  • FIG. 23 shows HPLC of Compound 6 Form A.
  • This disclosure relates to colony stimulating factor- 1 receptor inhibitors
  • CSF-1R inhibitors that are small molecules capable of penetrating the blood-brain barrier to reach the central nervous system (CNS).
  • CNS central nervous system
  • This disclosure also relates to pharmaceutical formulations comprising CSF-1R inhibitors and to the use of CSF-1R inhibitors and pharmaceutical compositions comprising CSF-1R inhibitors to treat disease.
  • diseases include immune-mediated diseases, including multiple sclerosis, lupus nephritis, rheumatoid arthritis, and neurological diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
  • ALS amyotrophic lateral sclerosis
  • Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the CNS that causes intermittent relapses and progressive neurological deterioration.
  • Activated microglial cells and macrophages contribute to CNS damage and play a significant role in disease progression and neurodegeneration in multiple sclerosis.
  • These activated innate immune cells can participate in antigen presentation and produce inflammatory and neurotoxic mediators that are destructive to neurons and oligodendrocytes.
  • CSF-1R is a receptor-tyrosine kinase expressed on macrophages, monocytes, and microglial cells and represents a potential target for therapeutic modulation of effector function.
  • the CSF-1R inhibitors described herein are particularly useful in the treatment of multiple sclerosis, and have demonstrated the following in preclinical in vitro and in vivo studies: a reduction of inflammatory cytokines/chemokines, inhibition of the expansion and activation of macrophages/microglial cells while not negatively affecting their phagocytic activity, an inhibition of CNS infiltration in multiple in vivo disease models, and a therapeutic benefit in mouse disease models.
  • CSF-1R antagonism provide neuroprotection in multiple sclerosis by reducing inflammation, demyelination, and axonal loss.
  • CSF-1R signaling has also been found to be upregulated in ALS and it may be as well in, e.g., PSP and MSA, and it has been noted in the literature that CSF-1R inhibition appears to be efficacious in preclinical models of ALS, MSA and PSP. See, e.g., Gowing, G. et al., Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase, Exp Neurol. 2009 Dec; 220(2):267-75; Martinez-Muriana, A.
  • M-CSF Macrophage colony stimulating factor
  • CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves, Sci Rep. 2016 May 13; 6:25663; Neal, M.L. et al., Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.
  • CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1; 142(10):3243-3264; Lodder, C. et al., CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia. Acta Neuropathol Commun. 2021 Jun 8; 9(1): 108.
  • the disclosure relates to compounds of Formula (I): and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof, wherein: the dashed lines represent optional double bonds;
  • X 1 is C, N, or CR 7 ;
  • X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from N, NR 7 , or CR 7 ;
  • X 8 , and X 9 are each independently selected from N or C wherein each R 7 is independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl,(C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O-,(C 1 -C 10 )alkoxy-,
  • T 1 , T 2 , and T 3 are each independently selected from N or CR 10 , wherein each R 10 is independently selected from H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O-, COOH-(C 1 -C 10 )alkyl-, COOH-(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-, R 10A -(C 1 -C 10 )alkyl-, R 10A -(C 1 -C 10 )alkylamine, R 10A -((C 1 -C 10 )alkyl) 2 amine, R 1OA -(C 2 -C
  • Y 1 is O, NR 12 , or CR 12 R 13 ; wherein R 12 is absent or R 12 and R 13 are each independently selected from H, D, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, HO-, halo, and H 2 N-;
  • R 1 and R 2 are each independently selected from H, D, (C 1 -C 10 )alkyl, HO-, halo, and H 2 N;
  • R 5 is absent or selected from H, D, (C 1 -C 10 )alkyl, HO-, halo, and H 2 N-; and R 6 is selected from D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, R 14 -(C 3 -C 10 )cycloalkyl, R 14 -(C 6 -C 14 )aryl, R 14 -(C 2 -C 9 )heteroaryl, and R 14 -(C 1 -C 10 )alkylamine; wherein R 14 is each independently selected from the group consisting of H, D, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heteroaryl
  • Z 1 is selected from H, halo, and (C 1 -C 10 )alkyl
  • Y 2 is O, NR 17 , or CR 17 R 18 ; wherein R 17 is absent or R 17 and R 18 are each independently selected from H, (C 1 -C 10 )alkyl, HO-, halo, or H 2 N-; wherein at least one of R 7 , R 1 , or R 2 is D.
  • the compounds according to Formula (I) are such that X 1 is N. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 2 is N. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 3 is CR 7 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 4 is CR 7 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 5 is CR 7 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 6 is N.
  • the compounds according to Formula (I) are such that X 7 is CR 7 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 8 is C. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 9 is C. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that X 1 is N; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; and X 9 is C.
  • the compounds according to Formula (I) are such that T 1 is CR 10 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that T 2 is CR 10 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that T 3 is CR 10 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that at least two of T 1 , T 2 , and T 3 are each independently CR 10 . In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that T 1 , T 2 , and T 3 are each independently CR 10 .
  • the compounds according to Formula (I) are such that each R 10 is independently selected from H, (C 1 -C 10 )alkyl, (C 3 - C 10 )cycloalkyl, (C 1 -C 10 )alkoxy, and halo. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that each R 10 is independently selected from H, (C 1 -C 10 )alkyl, and halo. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that each R 10 is independently selected from H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, and halo.
  • the compounds according to Formula (I) are such that each R 10 is independently selected from H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, and halo. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that each R 10 is independently selected from H and halo.
  • the compounds according to Formula (I) are such that Y 1 is O. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that Y 2 is O. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that Y1 and Y2 are each O.
  • the compounds according to Formula (I) are such that Z 1 is selected from H, halo, and (C 1 -C 10 )alkyl. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that Z 1 is (C 1 -C 10 )alkyl. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that Z 1 is halo. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that Z 1 is H.
  • the compounds according to Formula (I) are such that R 1 and R 2 are each independently selected from H and D. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that R 1 and R 2 are both H. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that R 1 and R 2 are both D. In at least one embodiment of the disclosure, the compounds according to Formula (I) are such that one of R 1 and R 2 is H and the other is D.
  • the compounds according to Formula (I) are such that R 6 is selected from (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heteroaryl, R 14 -(C 6 -C 14 )aryl, R 14 -(C 2 -C 9 )heteroaryl, and R 14 -(C 1 -C 10 )alkylamine; wherein R 14 is each independently selected from H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkoxy-, HO-, F 2 HC-O-, F 3 C-C(O)-, F 3 C-, and F 2 HC-; and wherein each (C 3 -C 10 )cycloalkyl, or (C 2 - C 9 )heterocycloalkyl are further optionally substituted by one to four groups selected from (C 1 -C 10 )cycloalkyl, (C 2
  • the compounds according to Formula (I) are such that R 6 is selected from (C 3 -C 10 )cycloalkyl, and (C 2 -C 9 )heteroaryl; and wherein each (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl are further optionally substituted by one to two groups selected from (C 1 -C 10 )alkyl, HO-, halo, or H 2 N-.
  • the disclosure relates to compounds of Formula (F): and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof, wherein: the dashed lines represent optional double bonds;
  • A is selected from H and D;
  • X 3 is CR 3 wherein R 3 is selected from H and D;
  • X 4 is CR 4 wherein R 4 is selected from H, D, and R 7 ;
  • X 5 is CR 5 wherein R 5 is selected from H and D, wherein at least one of A, R 3 , R 4 , and R 5 is D.
  • the compounds according to Formula (I’) are such that R 1 and R 2 are each independently selected from H and D.
  • the compounds according to Formula (F) are such that R 6 is selected from (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heteroaryl, R 14 -(C 6 -C 14 )aryl, R 14 -(C 2 - C 9 )heteroaryl, and R 14 -(C 1 -C 10 )alkylamine; wherein R 14 is each independently selected from H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkoxy-, HO-, F 2 HC-O-, F 3 C-C(O)-, F 3 C-, and F 2 HC-; and wherein each (C 1 -C 10 )alkyl, (C 6
  • the compound is selected from 3- (((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the compound is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d .
  • compositions comprising a pharmaceutically acceptable excipient and a compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof.
  • Another aspect of the disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound of Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises a compound of Formula (F) and/or a pharmaceutically acceptable salt thereof.
  • compositions comprising a pharmaceutically acceptable excipient and a compound of Table A, and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises a compound of Table A and/or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises 3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3- methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d Form A.
  • Another aspect of the disclosure is a method of treating a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a therapeutically effective amount of a compound of Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a therapeutically effective amount of a compound of Table A, and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the pharmaceutical composition comprises 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3- yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d Form A.
  • Another aspect of the disclosure is a method of treating a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Table A, and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a therapeutically effective amount of a pharmaceutical composition
  • a pharmaceutical composition comprising 3-(((2S,3S)-8- methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)- 3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable salts thereof as described herein.
  • the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d Form A and/or pharmaceutically acceptable salts thereof as described herein.
  • the present disclosure provides a compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use as a medicament.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use as a medicament is a compound of Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use as a medicament is a compound of Table A, and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use as a medicament is a compound selected from 3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the compound comprises 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound comprises 3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo[4,5-b]pyridine-2-d Form A and/or pharmaceutically acceptable salts thereof as described herein.
  • the present disclosure provides a compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use in the treatment of a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use in the treatment of a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof is a compound of Formula (F), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use in the treatment of a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof is a compound of Table A, and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound of Formula (I), and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof as described herein for use in the treatment of a disease or disorder, such as neurological and immune mediated diseases, in a subject in need thereof is a compound selected from 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3- yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof.
  • the compound comprises 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d and/or stereoisomers, optical isomers, racemic and diastereomeric mixtures, and/or pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable salts thereof as described herein.
  • the compound comprises 3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo[4,5-b]pyridine-2-d Form A and/or pharmaceutically acceptable salts thereof as described herein.
  • the neurological and immune mediated diseases include multiple sclerosis, ALS, MSA, PSP, Huntington’s disease, lupus, lupus nephritis, and rheumatoid arthritis.
  • amino means a functional group having a nitrogen atom and 1 to 2 hydrogen atoms. “Amino” generally may be used herein to describe a primary, secondary, or tertiary amine, and those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in this disclosure.
  • amine or “amine group” or “ammonia group” means a functional group containing a nitrogen atom derived from ammonia (NH3).
  • the amine groups are preferably primary amines, meaning the nitrogen is bonded to two hydrogen atoms and one substituent group comprising a substituted or unsubstituted alkyl or aryl group or an aliphatic or aromatic group.
  • the amine groups may be secondary amines meaning, the nitrogen is bonded to one hydrogen atom and two substituent groups comprising a substituted or unsubstituted alkyl or aryl groups or an aliphatic or aromatic group, as defined below.
  • the amine groups may be tertiary amines meaning the nitrogen is bonded to three substituent groups comprising a substituted or unsubstituted alkyl or aryl groups or an aliphatic or aromatic group.
  • the amine groups may also be quaternary amines meaning the designated amine group is bonded to a fourth group, resulting in a positively charged ammonium group.
  • any or all of the amines in this disclosure may be in the free amine form (that is, as -NH 2 for a primary amine) or in a protonated form with a pharmaceutically acceptable anion (that is, as -NH3 + Y" for a primary amine, where Y" is the pharmaceutically acceptable anion).
  • amide group means a functional group comprising a carbonyl group linked to a nitrogen.
  • alkane means a saturated hydrocarbon, bonded by single bonds. Alkanes can be linear or branched. “Cycloalkanes” are saturated hydrocarbons rings bonded by single bonds.
  • (C 1 -C 10 )alkyl means a saturated straight chained or branched or cyclic hydrocarbon consisting essentially of 1 to 10 carbon atoms and a corresponding number of hydrogen atoms. Typically, straight chain or branched groups have from one to ten carbons, or more typically one to five carbons. Exemplary (C 1 -C 10 )alkyl groups include methyl (represented by -CH 3 ), ethyl (represented by -CH 2 -CH 3 ), n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C 1 -C 10 )alkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.
  • (C 2 -C 9 )heteroalkyl means a saturated straight chained or branched or cyclic hydrocarbon consisting essentially of 2 to 10 atoms, wherein 2 to 9 of the atoms are carbon and the remaining atom(s) is selected from the group consisting of nitrogen, sulfur, and oxygen.
  • Exemplary (C 2 -C 9 )heteroalkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.
  • (C 3 -C 10 )cycloalkyl means a nonaromatic saturated hydrocarbon group, forming at least one ring consisting essential of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms.
  • (C 3 -C 10 )cycloalkyl groups can be monocyclic or multicyclic. Individual rings of multicyclic cycloalkyl groups can have different connectivities, for example, fused, bridged, spiro, etc., in addition to covalent bond substitution.
  • Exemplary (C 3 -C 10 )cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo-octanyl, octahydro-pentalenyl, spiro-decanyl, cyclopropyl substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc.
  • Other (C 3 -C 10 )cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.
  • (C 2 -C 9 )heterocycloalkyl means a nonaromatic group having 3 to 10 atoms that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) is selected from the group consisting of nitrogen, sulfur, and oxygen.
  • (C 2 -C 9 )heterocycloalkyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heterocycloalkyl groups can have different connectivities, for example, fused, bridged, spiro, etc., in addition to covalent bond substitution.
  • Exemplary (C 2 -C 9 )heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin- 3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetra
  • the (C 2 - C 9 )heterocycloalkyl group is typically attached to the main structure via a carbon atom or a nitrogen atom.
  • Other (C 2 -C 9 )heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.
  • the term “aliphatic group” or “aliphatic” means a non-aromatic group consisting of carbon and hydrogen, and may optionally include one or more double and/or triple bonds. In other words, an aliphatic group is any group consisting of carbon and hydrogen which contains no aromatic functionality.
  • An aliphatic group may be straight chained, branched or cyclic and typically contains between about one and about 24 carbon atoms.
  • aryl group may be used interchangeably with “aryl,” “aryl ring,” “aromatic,” “aromatic group,” and “aromatic ring.”
  • Aryl groups include carbocyclic aromatic groups, typically with six to fourteen ring carbon atoms.
  • Aryl groups also include heteroaryl groups, which typically have five to fourteen ring atoms with one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • (C 6 -C 14 )aryl means an aromatic functional group having 6 to 14 carbon atoms that form at least one ring.
  • (C 2 -C 9 )heteroaryl means an aromatic functional group having 5 to 10 atoms that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) is selected from the group consisting of nitrogen, sulfur, and oxygen.
  • (C 2 -C 9 )heteroaryl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heteroaryl groups can have different connectivities, for example, fused, etc., in addition to covalent bond substitution.
  • Exemplary (C 2 -C 9 )heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5
  • the (C 2 -C 9 )heteroaryl group is typically attached to the main structure via a carbon atom, however, those of skill in the art will realize when certain other atoms, for example, hetero ring atoms, can be attached to the main structure.
  • Other (C 2 -C 9 )heteroaryl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.
  • alkynyl means a functional group containing triple bonded carbons, represented by (C 2 -C 10 )alkynyl-.
  • alkylamine means an (C 1 -C 10 )alkyl containing a primary, secondary, or tertiary amine group in place of one hydrogen atom, represented by (C 1 -C 10 )alkyl amine and ((C 1 -C 10 )alkyl) 2 amine.
  • alkynylamine means a (C 2 -C 10 ) group containing triple bonded carbons and an amine group, represented by (C 2 -C 10 )alkynylamine.
  • alkoxy means a (C 1 -C 10 )alkyl bound to an oxygen, represented by (C 1 -C 10 )alkyl-O- or (C 1 -C 10 )alkoxy-.
  • alkoxyalkyl means a (C 1 -C 10 )alkyl bound to an oxygen bound to another (C 1 -C 10 )alkyl, represented by (C 1 -C 10 )alkyl-O-(C 1 -C 10 )alkyl- or (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-.
  • alkyl ester means a (C 1 -C 10 )alkyl containing an ester group in place of one hydrogen atom, represented by-0(O)C-(C 1 -C 10 )alkyl.
  • alkyl acid means an (C 1 -C 10 )alkyl containing a carboxylic acid group in place of one hydrogen atom, represented by (C 1 -C 10 )alkyl-COOH.
  • aliphatic acid means an acid of nonaromatic hydrocarbons, represented by (C 1 -C 10 )alkyl-COOH and (C 3 -C 10 )cycloalkyl-COOH.
  • dicarbonyl refers to an organic molecule containing two or more adjacent carbonyl groups.
  • halo or “Hal” means a fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At) ion.
  • i- refers to iso.
  • methoxy means a (Ci)alkyl containing an oxygen in place of one hydrogen atom, represented by -(O)CH 3 .
  • n- refers to normal.
  • polyol means an alcohol containing multiple hydroxyl (-OH) groups.
  • Steps refers to both enantiomers and diastereomers.
  • Substituted means the substitution of a carbon in alkyl, heterocyclic or aryl groups with one or more non-carbon substituents.
  • Non-carbon substituents are selected from nitrogen, oxygen and sulfur.
  • a 3 to 10-member ring means a closed ring; the 3 to 10-member ring may be acyclic, aromatic or heterocyclic.
  • pharmaceutically acceptable anion means an anion that is suitable for pharmaceutical use.
  • Pharmaceutically acceptable anions include halides, carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate, persulfate, phosphate, sulfite, acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate.
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • Presently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g., by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of the base compounds are those which can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 -naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,
  • base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed to ensure completeness of reaction and maximum product yields of the desired solid salt.
  • Bases which can be used to prepare the pharmaceutically acceptable base addition salts of the base compounds are those which can form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine- (meglumine), lower alkanolammonium and other such bases of organic amines.
  • pharmacologically acceptable cations such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine- (meglumine), lower alkanolammonium and other such bases of organic amines.
  • Stereoisomers e.g., cis- and trans- isomers
  • optical isomers of a presently disclosed compound e.g., R and S enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of this disclosure.
  • the compounds, salts, prodrugs, hydrates, and solvates presently disclosed can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of this disclosure.
  • Atropisomers are also within the scope of this disclosure. Atropisomers refer to compounds that can be separated into rotationally restricted isomers.
  • compositions comprising at least one presently disclosed compound and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro, ed. 1985.)
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable carrier.
  • compositions can be used in an animal or human.
  • a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g., intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds presently disclosed may also be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.
  • the pharmaceutical composition may take the form of, for example, a tablet or capsule prepared by conventional means with a pharmaceutically acceptable excipient(s) such as a binding agent (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolate); and/or wetting agent (e.g., sodium lauryl sulphate).
  • a pharmaceutically acceptable excipient(s) such as a binding agent (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricant (e.g., magnesium stearate, tal
  • Liquid preparations for oral administration may take the form of a, for example, solution, syrup or suspension, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g., almond oil, oily esters or ethyl alcohol); and/or preservative (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid.)
  • a suspending agent e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicle e.g., almond oil, oily esters
  • a proposed dose of a presently disclosed compound for oral, parenteral or buccal administration to the average adult human for the treatment or prevention of a CSF- IR-related disease state is about 0.1 mg to about 2000 mg. In certain embodiments, the proposed dose is from about 0.1 mg to about 200 mg of the active ingredient per unit dose. Irrespective of the amount of the proposed dose, administration of the compound can occur, for example, 1 to 4 times per day.
  • compositions and methods of treatment or prevention comprising administering prodrugs of at least one presently disclosed compound are also within the scope of this disclosure.
  • Non-limiting examples of suitable CSF-1R inhibitors according to Formula (I) and Formula (I’) are presented in the Examples below. It is understood that any or all of the amines of the structures presented in inhibitors according to Formula (I) and Formula (F) are presented in the Examples below may be in the free amine form or in a protonated form with a pharmaceutically acceptable anion.
  • Preferred pharmaceutically acceptable anions include halides, carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate, persulfate, phosphate, sulfite, acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate.
  • Most preferred pharmaceutically acceptable anions include chloride, carbonate, and bicarbonate. It is also understood that any or all of the CSF-1R inhibitors according to Formula (I) and Formula (I’) may be the racemate or an enantiomer of the racemate.
  • Example 1-1 Preparation of (+/-)-methyl (trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate
  • Example 1-2 Preparation of (+/-)-((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol
  • the mixture was quenched by the addition of water (0.12 mL), IN sodium hydroxide solution (0.12 mL), and water (0.38 mL). The resulting mixture was stirred at 0 °C for 10 minutes, and then magnesium sulfate (ca. 5 g) was added. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (50 mL).
  • Example 1-3 Preparation of (+/-)-5-bromo-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1.4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine
  • Example 1-4 Preparation of (+/-)-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2.3-dihydrobenzo [b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine-5-d
  • the vessel was sealed, and the contents were degassed under vacuum/backfilled with N 2 (x 3).
  • the mixture was heated to 100 °C and was allowed to stir. After 2 h, LC/MS analysis revealed that the reaction was complete.
  • the mixture was cooled to room temperature and was concentrated to provide a brown oil.
  • Example 2-1 Preparation of 2-bromo-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo[4,5-b] pyridine-5-d
  • Example 2-2 Preparation of (+/-)-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine-2,5-d2
  • the vessel was sealed, and the contents were degassed under vacuum/backfilled with N 2 (x 3).
  • the mixture was heated to 100 °C and was stirred. After 2 h, LC/MS analysis revealed that the reaction was complete.
  • the mixture was cooled to room temperature and was concentrated to provide a brown oil.
  • Example 3 Synthesis of (+/-)-3-(((trans)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[6][ 1 ,4]dioxin-6-yl)methyl-d2)-3H-imidazo[4,5- 6] pyridine (Compound 3)
  • Example 3-1 Preparation of (+/-)-((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methan-d2-ol
  • the mixture was quenched by the addition of water (0.50 mL), IN sodium hydroxide solution (0.50 mL), and water (1.5 mL). The resulting mixture was stirred at 0 °C for 15 min, and then magnesium sulfate (ca. 10 g) was added. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated to provide
  • Example 3-2 Preparation of (+/-)-5-((trans)-6-(azidomethyl-d2)-8- methoxy-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-2-methoxypyridine
  • Example 3-3 Preparation of (+/-)-((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methan-d2-amine
  • Example 3-4 Preparation of (+/-)-N-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-3- nitropyridin-2-amine
  • Example 3-5 Preparation of (+/-)-A 2 -(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl- d2)pyridine-2,3-diamine
  • Example 3-6 Preparation of (+/-)-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-3H- imidazo [4,5-b] pyridine
  • Example 4 Synthesis of (+/-)-3-(((trans)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-3H-imidazo[4,5- b]pyridine-2-d (Compound 4)
  • Example 4-1 Preparation of (+/-)-2-bromo-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-3H- imidazo [4,5-b] pyridine
  • Example 4-2 Preparation of (+/-)-3-(((trans)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-3H- imidazo [4,5-b] pyridine-2-d
  • the vessel was sealed, and the contents were degassed under vacuum/backfilled with N 2 (x 3).
  • the mixture was heated to 100 °C in a heating block. After 2 h, LC/MS analysis revealed that the reaction was complete.
  • the mixture was cooled to room temperature and was concentrated to provide a brown oil. Chromatographic purification (CombiFlash, 80 g SiO 2 gold column, 20-70% 3: 1 ethyl acetate :ethanol/heptane elute) afforded an impure brown oil.
  • Example 5 Synthesis of 3-(((2R,3R)-8-methoxy-2-(6-methoxypyridin-3- yl)-3-methyl-2,3-dihydrobenzo [b][1,4] dioxin-6-yl )met hyl )-3H-iniidazo [4,5-b] pyridine-2- d (Compound 5)
  • Example 5-1 Preparation and separation of 3-(((2R,3R)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine and 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
  • (+/-)-3-(((trans)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine was accomplished in five steps from (+/-)-((trans)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methanol (Example 1-2) according to the procedures described in Example 3-2 through Example 3-6.
  • the racemic product ( ⁇ 95:5 trans: cis) was subjected to chiral SFC separation (Whelk-01 21 x 250mm column, flow rate 70 mL/min, 50% ethanol in CO 2 /0.1% diethylamine elute, compound (2.24 g) dissolved in 60 mL methanol/15 mL dichloromethane, 1.8 mL of solution per injection) to provide three fractions.
  • the first fraction contained a small amount of one of the cis-enantiomers.
  • the second fraction contained 3-(((2R,3R)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
  • Example 5-2 Preparation of 2-bromo-3-(((2R,3R)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine
  • Example 5-3 Preparation of 3-(((2R,3R)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)niethyl)-3H-imidazo[4,5-b]pyridine-
  • Example 6 Synthesis of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)- 3-methyl-2,3-dihydrobenzo [b][1,4] d iox in-6-yl)methyl)-3H-imidazo [4,5-b] pyridine-2-d (Compound 6) Method A:
  • Example 6-1 Preparation of 2-bromo-3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine
  • Example 6-2 Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)niethyl)-3H-imidazo[4,5-b]pyridine-
  • Example 7 Synthesis of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)- 3-methyl-2,3-dihydrobenzo [b][1,4] dioxin-6-yI)melthy)-3H-imidazo [4,5-b] pyridine-2-d (Compound 6)
  • Example 8 Large-Scale Synthesis of 3-(((2S,3S)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H- imidazo [4,5-b] pyridine-2-d (Compound 6)
  • the resulting slurry was solvent exchanged with 2-methyl THF (2 x 250 mL) at below 60 °C to 3.0 to 4.0 volumes. After charging 800 mL(16 vol) of 2-methyl THF, the mixture was warmed to 60 to 65 °C and charged with 50 mL of MeOD and 67 mL (1.0 eq) of a 20% potassium tertiary butoxide solution in THF at 60-65 °C. The reaction mixture was maintained for 3h at 60-65 °C. The reaction was cooled to 20-30 °C, and quenched with 1000 mL (20 vol.) of an aqueous 10% ammonium chloride solution.
  • the organic layer was diluted with ethyl acetate and washed with water (3 x 250 mL) and 25% brine solution (250 mL). The organic layer was distilled to 3.0 to 4.0 volumes at 60 °C under vacuum. The mixture was chased with toluene (2 x 250 mL) below 60 °C to 3.0 to 4.0 volumes, chased with heptane (2 x 250 mL) at below 60 °C to 3.0 to 4.0 volumes. The resulting slurry was solvent exchanged with 2-methyl THF (2 x 250 mL) at below 60 °C to 3.0 to 4.0 volumes.
  • the mixture was charged with 1050 mL (21 vol) of 2-methyl THF and reaction mass warm up to 60-65 °C to get a clear solution.
  • the pale- yellow clear solution that was obtained contained 80-85% D Compound 6 by 1H NMR.
  • the solution was charged with 100 mL of MeOD and 13.4 mL (0.2 eq) of 20 % potassium tertiary butoxide solution in THF at 60-65 °C.
  • the reaction was maintained for 3 h at 60-65 °C.
  • the reaction was cooled to 20-30 °C, and quenched with 500 mL (10 vol.) of 10% ammonium chloride solution.
  • the organic layer was further washed with water (3 x 250 mL).
  • the organic layer was distilled to 7.5 to 8.0 volumes at 60 °C under vacuum.
  • the resulting slurry was refluxed at 65-70°C to get a clear solution.
  • the mixture was cooled to 60-65 °C over a period of 20 min and seeded 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][ 1 ,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine- 2-d (0.025 g).
  • the mixture was slowly cooled to 25 to 30 °C over a period of 2-3h and further cooled to 0-5 °C over a period of 2-3 h and stirred for 1-2 h.
  • the solids were filtered and washed with 50 mL (1.0 vol) of per-chilled 2-methyl THF.
  • Example 9 Additional large-scale synthesis advantageously stereoselective for Compound 6
  • Example 9-1 Preparation of 2-(5-((3H-imidazo[4,5-b]pyridin-3- yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)-1-(6-methoxypyridin-3-yl)propan-1-one
  • the reactor was purged with nitrogen and charged with hydrogen to 70 psi. After stirring at 70 psi hydrogen pressure at 22 °C for 5 h, HPLC analysis showed the complete consumption of the starting material. Hydrogenolysis was carried out by charging Pd/C (4.8 g, 34 wt%, 5% Pd on active carbon, 50% wet) into the reactor. The Parr reactor was purged with nitrogen and charged with hydrogen to 70 psi. After stirring at 70 psi hydrogen pressure at 22 °C for 48 h, HPLC analysis showed the reaction was essentially completed. The reaction mixture was filtered through a celite pad, washed with isopropanol and methanol. The filtrate was concentrated to a clear yellow oil.
  • Example 9-3 Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl)methyl)-3H-imidazo [4,5-b] pyridine
  • Tri n-butyl phosphine (11.99 ml; 48.60 mmol; 2.10 eq.) was added dropwise over 10 min with a slight exotherm. The resulting brown solution was stirred at 45-50 °C for 1.5 h.
  • sodium hydroxide solution (15 wt%, 40 mL, 6.5 eq.) and the mixture was stirred at 45 °C for 0.5-1 h.
  • the reaction was cooled to room temperature. The layers were separated. The aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to a wet-solid.
  • Example 9-4 Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin- 3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine- 2-d
  • the suspension was washed with aqueous 10% w/w ammonium chloride (400 mL).
  • the organic layer was separated, diluted with ethyl acetate (200 mL) and washed with water (3 x 100 mL) followed by 1/2 saturated sodium chloride solution (100 mL).
  • the organic layer was dried (sodium sulfate), filtered and concentrated to a solid.
  • the solid was dried by azeotroping with toluene (2 x 100 mL).
  • Samples were dispersed on a microscope slide as slurries or if dry, samples were dispersed with silicone oil and examined under transmitted polarized light.
  • HEK293 cells overexpressing human cFMS were cultured in RPMI media in T225 flasks and split twice a week. For the experiment, the cells were trypsinized, counted and diluted with serum-free Megacell media (Sigma Cat# M3817) to 600,000 cells/ml (30,000 cells/well).
  • test compounds were prepared by the Echo 555 (LABCYTE) using Echo LDV Plates, Cat# LP- 0200; and 500 nl of each compound concentration was added to 96-well BD Biocoat poly-d- lysine plate (BD Cat#356640) in DMSO (0.5% final). 50 ⁇ L/well MegaCell serum-free media was then added to cover compounds before adding cells at 50 ⁇ L/well cells (30,000/well). The plates were spun down for 1 minute at 1000 rpm and then incubated on benchtop for 15-30 minutes; the plates were moved to a CO 2 incubator at 37°C for overnight incubation.
  • White 96-well Perkin Elmer OptiPlates (Cat# 6005509) were pre-coated with 50 ng/well (100 ⁇ L/well) anti-cFMS/CSF-lR (C-20) (Santa Cruz Cat# sc-692) in PBS, sealed with a foil seal, spun down at 1000 rpm for one minute and incubated overnight at 4°C.
  • OptiPlates plates were blocked with 200 ul/well 1% BSA in 1x PBST (PBS with 0.1% Triton-X) at room temperature for 2 - 3 hours.
  • 100 ⁇ L/well 2x hCSFl (final 150ng/ml) R&D Systems, Cat# 216-MC-025/CF) (or media as a negative control) was added to the HEK293/hFMS cells (BD culture plates) incubated overnight with compounds.
  • % response with CSF1 treatment
  • 0 % response without CSF1 control columns were used to calculate percent inhibition of tested compounds and a Z' prime value. Plates were incubated at 37°C for 10 minutes.
  • Media/hCSFl was aspirated off and cells were lysed with 100 ul/well pre-chilled lysis buffer made up with lysis buffer (Cell Signaling Cat# 9803), protease/phosphatase inhibitors (Pierce Cat#78444), and PMSF (Sigma Cat#93482). Plates were shaken for 60 seconds; then, spun at 3200 rpm for 5 minutes at 4°C and kept on ice. 90 ul of the lysate was transferred to the pre-coated/blocked OptiPlates. The plates were then spun at 1000 rpm for 60 seconds and incubated overnight at 4°C sealed.
  • IC 50 values for phosphor c-FMS are provided for selected CSF-1R inhibitors in Table B, below.
  • Compound 24 was prepared in accordance with the procedure outlined in Example 1-92 of WO2017/015267.
  • Both test compounds were prepared in diluted stock solution (10 mM) with culture media to get a 100 ⁇ M working solution and treated at 3.125 nM, 6.25 nM, 12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM or 400 nM.
  • BV2 mouse microglia were suspended at a concentration of 5 x 10 5 cells/mL and 100 ⁇ L of this cell suspension was added to each well of a 96-well plate. Microglia cells were allowed to rest overnight at 37°C, 5% CO 2 . The following day, the media was removed and cells were treated with either dimethyl sulfoxide (DMSO), Compound 24, or Compound 6 for 30 minutes at 37°C, 5% CO 2 . Cells were then stimulated with 100 ng/mL recombinant mouse M-CSF for 24 hours. After stimulation, the culture supernatant was removed from each well and aliquoted into two different 96-well plates for subsequent ELISA assays.
  • DMSO dimethyl sulfoxide
  • mouse MCP-1 conjugate 100 ⁇ L of mouse MCP-1 conjugate was added to each well, covered with a new strip of adhesive tape, and incubated at room temperature for 2 hours. After incubation, the plate was washed as described above. Substrate Solution was then added to each well and incubated for 30 minutes at room temperature in the dark. After incubation, the acid stop solution was added to each well, and the plate was read on the ELISA plate reader at 450nm.
  • BV2 murine microglia were plated at 50,000 cells per well and rested overnight. Cells were pre-treated with DMSO, Compound 24, or Compound 6 for 30 minutes, and then subjected to CSF-1 stimulation. Cell culture supernatants from this experiment were processed in an MCP1 ELISA to determine whether stimulation/treatment impacted chemokine production. As seen in Figures 1A-1B and Figures 2A-2B, CSF-1 stimulation induced a significant increase in the release of MCP-1 (CCL2 - chemokine) and both small molecule CSF-1R inhibitors significantly reduced MCP-1 production in a concentration dependent manner. Percent inhibition was calculated based upon unstimulated and stimulated controls and IC 50 curves were generated. As seen in Figures 3A-3B and 4A- 4B, both compounds exhibit a similar IC 50 value for this assay between 28.8 nM - 36.5 nM.
  • Compound 49 was prepared in accordance with the procedure outlined in Example 1-5 of WO2017/015267.
  • test compounds were prepared in diluted stock solution (10 mM) with culture media to get a 100 ⁇ M working solution and treated at 3.125 nM, 6.25 nM, 12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM or 400 nM.
  • Substrate Solution was then added to each well and incubated for 30 minutes at room temperature in the dark. After incubation, the acid stop solution was added to each well, and the plate was read on the FlexStation3 Multi-Mode Microplate Reader (Molecular Devices, cat # Flex3) with SoftMax Pro Software at 450nm.
  • CSF-1 stimulation induced a significant increase in the release of MCP-1 (CCL2 - chemokine.
  • CSF-1-induced MCP-1 production was not robust in the plate for treated with Compound 49 ( Figure 5B), so an IC 50 value for this compound could not be generated.
  • MCP-1 secretion was assessed after 24 hours utilizing R&D MCP-1 Elisa Kit. Each data point represents a single well while graphical columns represent the mean and standard deviation of six wells.
  • Ibal + area was quantified following a microglial stimulation assay.
  • CSF-1 stimulation significantly increases the Ibal + area and treatment with CSF-1R inhibitors significantly abrogated this effect in a concentration dependent manner.
  • Statistical significance was determined by a one-way ANOVA and p values are indicated by * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001, and **** p ⁇ 0.0001.
  • DAPI + -labeled nuclei were quantified with following a microglial stimulation assay.
  • CSF-1 stimulation increases the number of cells within the culture and CSF-1R inhibitors reducing this number in a concentration dependent manner.
  • Statistical significance was determined by a one- way ANOVA and p values are indicated by * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001, and **** p ⁇ 0.0001.
  • Lipopolysaccharide from Escherichia coli O55:B5 (Sigma, cat# L6529-lmg, lot#059M4103V) - Made 0.2 mg LPS/mL PBS stock and treated microglia with 10 ng/mL.
  • Cell viability was determined using Promega’s Cell Titer Gio Luminescent Cell Viability Assay.
  • the assay reagent was first allowed to equilibrate to room temperature for 30 minutes. After culture supernatants were removed, 100 ⁇ L fresh room temperature media was added to each well. Subsequently, 100 ⁇ L of assay reagent was added to each well. The assay plate was then shaken for two minutes and left to rest for 10 minutes. 100 ⁇ L was transferred from each well to a white plate and luminescence was read immediately on the FlexStation3 plate reader.
  • mice MCP- 1 conjugate were added to each well, covered with a new strip of adhesive tape, and incubated at room temperature for 2 hours. After incubation, the plate was washed as described above. Substrate Solution was then added to each well and incubated for 30 minutes at room temperature in the dark. After incubation, the acid stop solution was added to each well, and the plate was read on the ELISA plate reader at 450nm.
  • mice IL-12p40 conjugate were added to each well, covered with a new strip of adhesive tape, and incubated at room temperature for 2 hours. After incubation, the plate was washed as described above. Substrate Solution was then added to each well and incubated for 30 minutes at room temperature in the dark. After incubation, the acid stop solution was added to each well, and the plate was read on the ELISA plate reader at 450nm.
  • CSF-1R inhibitor treatment had no toxic effect on microglia at the concentrations assessed.
  • Graphical columns represent the mean and standard deviation of six wells.
  • CSF-1R inhibition had no deleterious effect on cell viability.
  • Graphical columns represent the mean and standard deviation of six wells. No significant differences were observed in wild-type versus SOD1 microglia cell viability in response to CSF-1 or LPS stimulation.
  • Example 13 Caco-2 Permeability and Efflux Assay to compare Compound 6 to Compound 24.
  • Caco-2 permeability and efflux assays were performed in cell-based permeability model using Caco-2/TC7 cells.
  • Caco-2/TC7 cells were seeded on to Millipore Millicell 96 and for efflux assays, 24-well plates were used. The plates with cells were ready to use between 21-25 days of culturing. Both permeability and efflux assays were performed using the TEC AN automated liquid handling platform.
  • test compounds were prepared at 20 ⁇ M test concentrations in permeability assay buffer (10mM HEPES in HBSS buffer, pH 6.5) containing 0.5% BSA.
  • Basolateral permeability buffer (pH 7.4) contains 5% BSA.
  • test compounds were prepared at 1 ⁇ M test concentrations in permeability assay buffer (10mM HEPES in HBSS buffer, pH 7.4) containing 0.5% BSA.
  • the basolateral permeability buffer (pH 7.4) contained 0.5% BSA.
  • the permeability assay was initiated by adding 20 ⁇ M test solution to apical side of plate containing Caco-2/TC7 cells.
  • 1 ⁇ M test compound was added to an apical compartment for apical to basolateral (A to B) permeability determination.
  • Basolateral to apical (B to A) permeability determination the test compound was added to the basolateral side.
  • the objective of this assay method was to determine the inhibitory potential of test articles, in vitro, against specific cytochrome P450 (CYP) enzymes, using human liver microsomes (HLMs).
  • the test compounds were diluted from pure DMSO stocks to a final test concentration range of 10 ⁇ M - 0.07 ⁇ M in a 0.5% DMSO solution.
  • the compounds were co-incubated at 37°C with 0.22mg/mL human liver microsomes (HLMs), 50mM phosphate buffer, 1.33mM NADPH, 3.33mM glucose-6-phosphate, 3.33mM magnesium hexahydrate, 0.4 units/mL glucose-6-phosphate dehydrogenase, and appropriate concentrations of individual chemical probes for 10-30 minutes.
  • Incubations were performed in 0.5 million hepatocytes cells/mL at 1 ⁇ M concentration of test compound in duplicate with rat, human, dog, monkey, or mouse hepatocytes, and the concentration-time course of test compound depletion was determined after withdrawing samples from the incubation at assay time points followed by liquid chromatography with tandem mass spectrometry analysis. An organic solvent was used to terminate incubations.
  • This method provides a benchmarking tool for an in vitro - in vivo correlation of intrinsic clearance using commercial drugs known to be metabolized by AO.
  • Example 14 Metabolite profiles of Compound 24 in human cryopreserved hepatocytes in the absence and presence of the aldehyde oxidase inhibitor hydralazine
  • the metabolite profiles of Compound 24 were investigated in vitro in human cryopreserved hepatocytes in the absence and presence of the aldehyde oxidase (AO) inhibitor hydralazine. A total of nine metabolites were identified and quantified by LC-MS following incubation of Compound 24 in human cryopreserved hepatocytes for 2 hours.
  • AO aldehyde oxidase
  • H10 was proposed to be derived from hydroxylation at the 2C position of the
  • H4a was proposed to be derived from hydration at the 3H-imidazole[4,5-b]pyridine moiety and glucuronide at the 2C position of the 3H-imidazole[4,5-b]pyridine moiety of Compound 24.
  • Hi la was proposed to be derived from glucuronidation of the 3H-imidazole[4,5-b]pyridine moiety of H10.
  • H7 was proposed to be derived from the O-demethylation at 2-methoxyl-pyrindine moiety of Compound 24.
  • H6 was proposed to be glucuronide conjugate of Compound 24.
  • the proposed major metabolic pathways included AO-mediated hydroxylation followed by glucuronidation and a combination of hydration and glucuronidation.
  • Other observed metabolic pathways included non-AO mediated hydroxylation followed by glucuronidation, direct glucuronidation, demethylation followed by glucuronidation, and combinations of oxidative deamination followed by oxidation.
  • Compound 24 was prepared in accordance with the procedure outlined in Example 1-92 of WO2017/015267.
  • Metabolite identification was performed on UPLC (Thermo Vanquish) coupled with UV (Thermo Vanquish) and mass spectrometry (MS) detection (Thermo Orbitrap ID-X).
  • the mass peak areas were used for metabolite profiling, due to low sample concentrations.
  • the percentage of metabolite or unchanged parent was calculated based on the total integrated MS peak areas of Compound 24 and its identified metabolites on the assumption of equal mass spectral response for equivalent molar concentration of the metabolites or parent compound.
  • Metabolites having a peak area that accounts for equal to or more than 0.1% of the toral integrated MS peaks areas are reported in Table 1 below.
  • the metabolites are characterized based on their accurate masses (tolerance ⁇ 5 ppm), mass fragmentation patterns, and comparison with other in vitro studies.
  • Table 1 Metabolite profiles of Compound 24 following incubation in human cryopreserved hepatocytes for 2 hours in the absence and presence of hydralazine
  • H10 was the most abundant metabolite detected and accounted for 20.3% of the total integrated MS peak areas of Compound 24 and its identified metabolites. Metabolite H4a accounted for 4.5% of the total integrated MS peak areas of Compound 24 and its identified metabolites. Each of other metabolites identified were ⁇ 2% of the total integrated MS peak areas of Compound 24 and its identified metabolites.
  • H10 was proposed to be derived from hydroxylation at 2C position of 3H- imidazole[4,5-b]pyridine moiety of Compound 24.
  • H4a was proposed to be derived from hydration at 3H-imidazole[4,5-b]pyridine moiety and glucuronide at 2C position of 3H- imidazole[4,5-b]pyridine moiety of Compound 24.
  • Hl la was proposed to be derived from glucuronidation of 3H-imidazole[4,5-b]pyridine moiety of H10.
  • H7 was proposed to be derived from O-demethylation at 2-methoxyl-pyrindine moiety of Compound 24.
  • H6 was proposed to be glucuronide conjugate of Compound 24.
  • the proposed major metabolic pathways include AO-mediated hydroxylation followed by glucuronidation and combination of hydration and glucuronidation.
  • Other observed metabolic pathways included non-AO mediated hydroxylation followed by glucuronidation, direct glucuronidation, demethylation followed by glucuronidation, and combination of oxidative deamination followed by oxidation.
  • Example 15 Metabolite profiles of Compound 6 in human cryopreserved hepatocytes in the absence and presence of aldehyde oxidase inhibitor hydralazine
  • the metabolite profiles of Compound 6 were investigated in vitro in human cryopreserved hepatocytes in the absence and presence of aldehyde oxidase (AO) inhibitor hydralazine. A total of nine metabolites were identified and quantified by LC-MS following incubation of Compound 6 in human cryopreserved hepatocytes for 2 hours.
  • AO aldehyde oxidase
  • H10 was proposed to be derived from hydroxylation at the 2C position of the
  • H4a was proposed to be derived from hydration at the 3H-imidazole[4,5-b]pyridine moiety and glucuronide at the 2C position of the 3H-imidazole[4,5-b]pyridine moiety of Compound 6.
  • Hl la was proposed to be derived from glucuronidation of the 3H-imidazole[4,5-b]pyridine moiety of H10.
  • H7 was proposed to be derived from O-demethylation at the 2-methoxyl-pyrindine moiety of Compound 6.
  • H6 was proposed to be a glucuronide conjugate of Compound 6.
  • the proposed major metabolic pathways included AO-mediated hydroxylation followed by glucuronidation and a combination of hydration and glucuronidation.
  • Other observed metabolic pathways included non-AO mediated hydroxylation followed by glucuronidation, direct glucuronidation, demethylation followed by glucuronidation, and combinations of oxidative deamination followed by oxidation. Incubation conditions
  • Metabolite identification was performed on UPLC (Thermo Vanquish) coupled with UV (Thermo Vanquish) and mass spectrometry (MS) detection (Thermo Orbitrap ID-X).
  • the mass peak areas are used for metabolite profiling, due to low sample concentrations.
  • the percentage of metabolite or unchanged parent was calculated based on the total integrated MS peak areas of Compound 6 and its identified metabolites on the assumption of equal mass spectral response for equivalent molar concentration of the metabolites or parent compound.
  • Metabolites having a peak area that accounts for equal to or more than 0.1% of the toral integrated MS peaks areas are reported in Table 2 below.
  • Table 2 Metabolite profiles of Compound 6 following incubation in human cryopreserved hepatocytes for 2 hours in the absence and presence of hydralazine
  • H10 and H4a were the major metabolites detected and accounted for 6.6% and 4.6% of the total integrated MS peak areas of Compound 6 and its identified metabolites, respectively. Each of other metabolites identified were ⁇ 1% of the total integrated MS peak areas of Compound 6 and its identified metabolites.
  • H10 was proposed to be derived from hydroxylation at the 2C position of the
  • H4a was proposed to be derived from hydration at the 3H-imidazole[4,5-b]pyridine moiety and glucuronide at the 2C position of the 3H-imidazole[4,5-b]pyridine moiety of Compound 6.
  • Hl la was proposed to be derived from glucuronidation of the 3H-imidazole[4,5-b]pyridine moiety of H10.
  • H7 was proposed to be derived from (9-demethylation at the 2-methoxyl-pyrindine moiety of Compound 6.
  • H6 was proposed to be a glucuronide conjugate of Compound 6.
  • the proposed major metabolic pathways include AO-mediated hydroxylation followed by glucuronidation and a combination of hydration and glucuronidation.
  • Other observed metabolic pathways included non- AO mediated hydroxylation followed by glucuronidation, direct glucuronidation, demethylation followed by glucuronidation, and combinations of oxidative deamination followed by oxidation.
  • Example 16 in vitro Microglia Stimulation Study
  • iCell microglia human iPSC derived microglia
  • FujiFilm catalog# Cl 110, lot# 105458. These cells were thawed and maintained in iCell Microglia Complete Media according the manufacture instructions.
  • iCell microglia were resuspended at a concentration of 5 x 10 5 cells/mL and 100 ⁇ L of this cell suspension was added to the inner 60 wells of a 96-well plate. iCell microglia were allowed to rest overnight at 37°C, 5% CO 2 .
  • CellTiter Glo 2.0 Viability Assay [00279] Cell viability was determined using the CellTiter Gio 2.0 Luminescent Cell Viability Assay (Promega, cat# G9242). The assay reagent was first allowed to equilibrate to room temperature for 30 minutes. After culture supernatants were removed, 100 ⁇ L fresh room temperature media was added to each well. Subsequently, 100 ⁇ L of assay reagent was added to each well. The assay plate was then shaken for two minutes and left to rest for 10 minutes. 100 ⁇ L was transferred from each well to a white plate and luminescence was read immediately on the FlexStation3 Multi-Mode Microplate Reader (Molecular Devices, cat # Flex3) with SoftMax Pro Software.
  • iCell microglia human iPSC derived microglia
  • iCell microglia human iPSC derived microglia
  • Media containing growth factors was removed and then the cells were allowed to rest overnight again.
  • cells were pre-treated with DMSO or Compound 6 or Compound 24for 30 minutes, and then subjected to CSF1 stimulation.
  • Cell viability was assessed utilizing Promega’ s Cell Titer Gio Assay Kit.
  • Cell culture supernatants from this experiment were processed in a MCP1 ELISA to determine whether stimulation/treatment impacted chemokine production.
  • Figure 16 depicts cell viability following CSF1R inhibitor treatment and CSF1 stimulation as described above. iCell human microglia were plated at 50,000 cells/well and rested overnight following growth factor starvation. Cells were pre-treated with DMSO or RA16100017 for 30 minutes and then subjected to CSF1 stimulation. Cell viability was assessed after 24 hours utilizing Promega’s Cell Titer Glo 2.0 Assay Kit. CSF1 stimulation induced an increase in cell viability and the CSF1R inhibitor had no impact on this effect. Each data point represents a single well while graphical columns represent the mean and standard deviation of six wells.
  • FIG. 17 shows the blocking effect of Compound 6 on CSF1 -induced MCP-1 production in this experiment.
  • iCell human microglia were plated at 50,000 cells/well and rested overnight following growth factor starvation. Cells were pre-treated with DMSO or RA16100017 for 30 minutes and then subjected to CSF1 stimulation. MCP-1 secretion was assessed after 24 hours utilizing R&D MCP1 Elisa Kit.
  • the CSF1R inhibitor treatment significantly reduced MCP1 production in a concentration dependent manner (Ordinary one-way ANOVA). Each data point represents a single well while graphical columns represent the mean and standard deviation of six wells.
  • EAE Experimental autoimmune encephalomyelitis
  • MOG myelin oligodendrocyte glycoprotein
  • MOG35-55 peptide New England Peptides, lot# BU01787) - 250 ⁇ g/mouse in 4 mg/mL complete Freund’s adjuvant (CFA; Chondrex Inc, Cat# 7009, lot# 190446) Bordetella pertussis toxin (PTX, Sigma, cat# P7208-50UG, lot# MKCL 1350) - 280 ng/mouse in 200 ⁇ L PBS
  • MOG peptide & CFA subcutaneous injection to 2 sites in the hind flank (100 ⁇ L/site).
  • Bordetella pertussis toxin i.v. injection of 280 ng/mouse in 200 ⁇ L PBS on Day 0 and 2.
  • CSF1R inhibitor oral gavage every 12 hours
  • mice were clinically assessed daily for signs of paralytic disease and weighed intermittently to document weight loss. At study termination, 1/2 brain was fixed for histology and brain/liver/plasma were collected for exposure. Spinal cord and whole blood was collected for flow cytometry. Additional plasma aliquots were saved for follow up analysis.
  • mice Female C57BL/6J mice were immunized with an emulsion of MOG35-55 peptide (250 ⁇ g/mouse) in complete Freund’s adjuvant (CFA). The emulsion was delivered by two subcutaneous injections to the hind flank in a volume of 100 ⁇ L per injection site. Bordetella pertussis toxin (PTX) was administered via tail vein injection on Day 0 and Day 2 at a dose of 280 ng/animal in 200 ⁇ L of PBS.
  • CFA complete Freund’s adjuvant
  • mice were monitored daily for paralytic symptoms and scored for their clinical presentation using a progressive scoring system (Score 0: no disease; Score 1 : flaccid tail; Score 2: hindlimb weakness; Score 3: hindlimb paralysis; Score 4: Front limb weakness or partial paralysis; Score 5: death).
  • Score 0 no disease
  • Score 1 flaccid tail
  • Score 2 hindlimb weakness
  • Score 3 hindlimb paralysis
  • Score 4 Front limb weakness or partial paralysis
  • Score 5 death

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Abstract

La divulgation concerne des composés deutérés de la formule, qui sont utiles en tant qu'inhibiteurs du récepteur du facteur 1 de stimulation des colonies (inhibiteurs de CSF-1R).
PCT/US2021/064831 2020-12-23 2021-12-22 Inhibiteurs deutérés du récepteur du facteur 1 de stimulation des colonies (csp-1r) WO2022140528A1 (fr)

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JP2023538678A JP2024500919A (ja) 2020-12-23 2021-12-22 重水素化コロニー刺激因子－１受容体（ｃｓｆ－１ｒ）阻害剤
EP21844906.4A EP4267573A1 (fr) 2020-12-23 2021-12-22 Inhibiteurs deutérés du récepteur du facteur 1 de stimulation des colonies (csp-1r)
CN202180085787.4A CN116848110A (zh) 2020-12-23 2021-12-22 氘代集落刺激因子-1受体（csf-1r）抑制剂
US17/669,950 US11530216B2 (en) 2020-12-23 2022-02-11 Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors

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WO2023249989A1 (fr) * 2022-06-22 2023-12-28 Genzyme Corporation Formes solides d'inhibiteurs du récepteur du facteur-1 de stimulation des colonies deutérées (csf-1r)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023249989A1 (fr) * 2022-06-22 2023-12-28 Genzyme Corporation Formes solides d'inhibiteurs du récepteur du facteur-1 de stimulation des colonies deutérées (csf-1r)

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