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EP-4355748-B1 - SUBSTITUTED PYRROLO[2,3-D]PYRIMIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

EP4355748B1EP 4355748 B1EP4355748 B1EP 4355748B1EP-4355748-B1

Inventors

  • BERNARDELLI, PATRICK
  • Deprets, Stéphanie
  • DUBOIS, LAURENT
  • MACOR, JOHN
  • PETIT, Frédéric
  • TERRIER, CORINNE
  • BIANCIOTTO, MARC

Dates

Publication Date
20260513
Application Date
20220614

Claims (15)

  1. A compound of Formula (I) wherein: R1 is selected from the group consisting of an aryl group, an ortho-fused bicyclic heteroaryl group and a heteroaryl group, wherein said ortho-fused bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C 1 -C 3 )-alkyl group; and wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of a) a deuterium atom, b) a fluorine atom, c) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, d) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, wherein the term "cycloalkyl" means a non-aromatic monocyclic ring system of 3 to 6 carbon atoms, e) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, f) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, g) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, h) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, i) an -O-spirocycle group, j) an alkylsulfonylalkyl group, and k) an alkylsulfonyl group; and R2 is selected from the group consisting of an alkyloxylalkyl group and a heterocycloalkyl group, wherein said heterocycloalkyl group represented by R2 is attached via a carbon atom and is unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine; or a pharmaceutically acceptable salt thereof.
  2. The compound of claim 1, wherein (i) R1 is selected from the group consisting of an aryl group, an ortho-fused bicyclic heteroaryl group and a heteroaryl group, wherein said ortho-fused bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C 1 -C 3 )-alkyl group; and wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of a) a deuterium atom, b) a fluorine atom, c) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, d) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom or -(C 1 -C 3 )-alkyl group, e) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, f) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, g) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom or -(C 1 -C 3 )-alkyl group, h) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, i) an -O-spirocycle group, j) an alkylsulfonylalkyl group, and k) an alkylsulfonyl group; or (ii) R1 is selected from the group consisting of a phenyl group and a heteroaryl group, wherein said phenyl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of a) a fluorine atom, b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, f) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, g) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, h) an -O-spirocycle group, i) an alkylsulfonylalkyl group, and j) an alkylsulfonyl group; or a pharmaceutically acceptable salt thereof.
  3. The compound of claim 1, having formula (Ia) wherein: R3 is selected from the group consisting of a hydrogen atom, a -(C 1 -C 3 )-alkyl group and a -(C 1 -C 3 )-alkyloxyl group; m represents 1, 2 or 3; and n represents 0 or 1; or a pharmaceutically acceptable salt thereof.
  4. The compound of claim 1 having formula (Ia) wherein R1 is selected from the group consisting of a phenyl group and a heteroaryl group, wherein said phenyl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of a) a fluorine atom, b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, f) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, g) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, h) an -O-spirocycle group, i) an alkylsulfonylalkyl group, and j) an alkylsulfonyl group; R3 is selected from the group consisting of a hydrogen atom, a -(C 1 -C 3 )-alkyl group and a -(C 1 -C 3 )-alkyloxyl group; m represents 1 or 2; and n represents 0 or 1; or a pharmaceutically acceptable salt thereof.
  5. The compound of any one of claims 1 to 4, having formula (Ib) wherein: R3 is selected from the group consisting of a hydrogen atom, a -(C 1 -C 3 )-alkyl group and a -(C 1 -C 3 )-alkyloxyl group; R4 is selected from the group consisting of a) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, b) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, c) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, and d) an -O-spirocycle group; R5 is selected from the group consisting of a) a hydrogen atom, b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkylsulfonylalkyl group, and f) an alkylsulfonyl group; R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; m represents 1, 2 or 3; and n represents 0 or 1; or a pharmaceutically acceptable salt thereof.
  6. The compound of claim 5, wherein R3 is selected from the group consisting of a -(C 1 -C 3 )-alkyl group and a -(C 1 -C 3 )-alkyloxyl group; R6 is a hydrogen atom; m represents 1 or 2; and n represents 0 or 1; or a pharmaceutically acceptable salt thereof.
  7. The compound of claim 5, wherein (i) R3 is selected from the group consisting of a -(C 1 -C 3 )-alkyl group and a -(C 1 -C 3 )-alkyloxyl group; R4 is selected from the group consisting of a) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, b) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, and c) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group; R5 is selected from the group consisting of a) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, b) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, and c) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group ; R6 is a hydrogen atom; m represents 1; and n represents 1; or (ii) R3 is a -(C 1 -C 3 )-alkyl group; R4 is selected from the group consisting of a) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, and b) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, R5 is an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; R6 is a hydrogen atom; m represents 1; and n represents 1; or a pharmaceutically acceptable salt thereof.
  8. The compound of claim 1, having formula (Ic) wherein: R4 is selected from the group consisting of a) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, b) an -O-cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, c) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, and d) an -O-spirocycle group; R5 is selected from the group consisting of a) a hydrogen atom, b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atom, a hydroxy group or -(C 1 -C 3 )-alkyl group, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkylsulfonylalkyl group, and f) an alkylsulfonyl group; R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; R7 is a -(C 1 -C 3 )-alkyl group; and R8 is a -(C 1 -C 3 )-alkyl group; or a pharmaceutically acceptable salt thereof.
  9. The compound of claim 1, selected from the group consisting of: 2-((1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-methyl-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetan-3-yl]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetan-3-yl]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazol-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
  10. A process for preparing a compound according to claim 1, comprising reacting a compound of formula (11X) with a compound of formula (15X): wherein R1 and R2 are as defined for a compound of formula (I) in claim 1.
  11. A pharmaceutical composition comprising a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  12. A medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
  13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease.
  14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, Lewy body dementia, Pick disease, progressive supranuclear palsy, and frontotemporal dementia.
  15. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is Parkinson' s disease.

Description

Disclosed herein are substituted pyrrolo[2,3-d]pyrimidine compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof. BACKGROUND Parkinson's disease (PD) is an age-dependent neurodegenerative disorder with high unmet medical need, in the context of an aging population. Mutations in several genes segregate PD in families. Among them, seven leucine rich repeat kinase 2 (LRRK2) mutations are linked to autosomal dominant forms of PD. LRRK2 polymorphs were identified as risk factors for sporadic PD in Genome Wide Association Studies (J.H. Kluss, Biochemical Society Transactions 2019). LRRK2 carriers share similar clinical symptoms, disease onset and progression with sporadic patients (H. Tomiyama, Hum. Mov. Disord. 2006) suggesting that LRRK2 signaling pathways may be central to the processes underlying both LRRK2 familial and sporadic late onset PD. All pathogenic LRRK2 mutations, as well as VPS35 D620N mutation which is another target genetically linked to PD, induce increased LRRK2 kinase activity (M. Steger et al., eLife 2016; R, Mir et al., Biochem J. 2018). Beyond familial PD, increased LRRK2 activity or level was reported in human brains from idiopathic PD patients (R. Di Maio et al., Sci. Transl. Med. 2018). These results support the hypothesis that dysregulated LRRK2 kinase activity may contribute to pathogenesis, suggesting the therapeutic potential of LRRK2 kinase inhibitors to block aberrant LRRK2-dependent signaling in both LRRK2 and idiopathic form of PD (A.B. West Exp. Neurol. 2017). Accumulation of synuclein aggregates and loss of dopaminergic neurons are the main hallmarks of PD. Blockade of these phenotypes after LRRK2 kinase inhibitor treatment was demonstrated in numerous reports (E.M. Rocha et al, Neurobiol. Of Disease 2019). These results support the hypothesis that potent, brain penetrant LRRK2 kinase inhibitors have therapeutic potential for the treatment of PD. A growing body of evidence suggests a role of LRRK2 in the regulation of lysosomal activity (J. Schapansky et al, Neurobiol. of Disease 2018). Increased bis(monoacylglycerol)phosphate levels, a marker of lysosomal storage diseases such as Pick's disease, was observed in fluids from LRRK2 gain of function mutations carriers (R.N. Alcalay, Movement Disorders, 2020). Lysosomal glucocerebrosidase (GBA) mutations are the largest risk factor for development of PD (GBA-PD). Decreased glucocerebrosidase activity was reported in neurons from GBA and LRRK2 mutation carriers (D. Ysselstein, Nature com. 2019). Conversely, normalization of glucocerebrosidase activity and level were achieved in vitro and in vivo after treatment with LRRK2 kinase inhibitors, suggesting a potential benefit in patients from lysosomal storage diseases such as GBA-PD (A. Sanyal et al, Mov. Disorders 2020). Immunofluorescence experiments in human brain showed colocalization of LRRK2 with neurofibrillary tangles (J. Miklossy, J Neuropathol. Exp. Neurol. 2006). Moreover, LRRK2 has been reported to phosphorylate tubulin-associated Tau (F. Kawakami et al., PloS One 2012), and Tau hyperphosphorylation was observed in LRRK2 kinase activating mutant transgenic mice (Y. Li et al., Nat. Neurosci. 2009). These data indicate that LRRK2 kinase inhibitor treatment might be useful in treating tauopathy disorders such as Pick's disease, progressive supranuclear palsy and frontotemporal dementia. LRRK2 is expressed in brain glial cells, and attenuation of neuroinflammation was achieved after LRRK2 kinase inhibitor treatment in various in vivo models (M.S. Moehle et al., J. Neurosci. 2012). Neuroinflammation is often observed in neurodegenerative diseases such as Parkinson's disease, Alzheimer disease, multiple sclerosis, HIV-induced dementia and Amyotrophic lateral sclerosis; LRRK2 kinase inhibitors may therefore have utility in the treatment of these pathologies. WO2017106771 discloses compounds having a pyrrolopyrimidine core substituted by a (hetero)arylamine group and by a cyano group. These compounds are capable of inhibiting certain protein kinases, and especially the leucine-rich repeat kinase 2 (LRRK2) protein and can be used to treat disorders including neurodegenerative diseases such as Parkinson's disease. US2020239474 discloses a novel pyrrolo-pyrimidine derivative compound for preventing or treating a protein kinase-related disease. WO2020149715 discloses compounds having a pyrrolopyrimidine core substituted by a (hetero)arylamino group and by a cyano group, which can be advantageously used for treating or preventing protein kinase-related diseases, cancer and degenerative brain diseases. There is a need to provide LRRK2 kinase inhibitors with good efficacy. SUMMARY OF THE INVENTION In accordance with one aspect, disclosed herein are compounds of Formula (I): wherein: R1 is selected from the group consisting of an aryl group, an ortho-fused bicyclic heteroaryl group and a heteroaryl group, where