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EP-4211119-B1 - 2-AMINOQUINAZOLINES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

EP4211119B1EP 4211119 B1EP4211119 B1EP 4211119B1EP-4211119-B1

Inventors

  • ACTON, JOHN, J., III
  • MORRIELLO, GREGORI, J.
  • YAN, XIN
  • CHAU, Ryan
  • FULLER, Peter, H.
  • GULATI, ANMOL
  • JOHNSON, Rebecca Elizabeth
  • KATTAR, SOLOMON
  • KEYLOR, Mitchell, H.
  • LI, DERUN
  • MARGREY, Kaila, A.

Dates

Publication Date
20260513
Application Date
20210901

Claims (20)

  1. A compound having a structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or CH; X 2 is N or CR 2 ; R 1 is selected from: R 2 is absent or is selected from H, C 1-6 alkyl, and Cl, R 3 is selected from H, Cl, CN, and C 1-6 alkyl; R 4 represents NRR', or an N-linked C 4-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of R d ; each R represents H, or C 1-6 alkyl; R' is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and C 4-10 heterocyclyl, said alkyl, cycloalkyl and heterocyclyl optionally substituted with 1 to 3 groups of R e ; R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylOR, C 1-3 haloalkyl, -(CH 2 ) n C 4 -10heterocyclyl, -(CH 2 ) n C 3-10 cycloalkyl, -(CH 2 ) n C 5-10 heteroaryl, said alkyl, cycloalkyl, heteroaryl, and heterocyclyl optionally substituted with 1 to 3 groups of R c ; R a and R b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-3 haloalkyl, - (CH 2 ) n C 5-10 heteroaryl, and C 3-6 cycloalkyl, provided R a and R b are not the same when R1; or R 5 and R a in (i) and (ii) of R 1 can combine with the nitrogen and carbon atoms to which they are attached, respectively, to form a six membered ring; R c is selected from OR, halogen, (CH 2 ) n CN, C1-3 haloalkyl, C 1-6 alkyl, C 1-6 alkylOR, C1-3 haloalkyl, and C 4-10 heterocyclyl, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of C 1-6 alkyl or CN; R d is selected from oxo, OR, C 1-6 alkyl, C 1-6 alkylOR, CH 2 CF 3 , C 4-10 heterocyclyl, - (CH 2 ) n C 3-10 cycloalkyl, C(O)C 1-6 alkyl, and NRR, said alkyl, heterocyclyl and cycloalkyl optionally substituted with 1 to 3 groups of R e ; R e is selected from OR, C 1-6 alkyl, CN, and fluorine; and Each n is independently 1, 2, 3, or 4.
  2. The compound according to claim 1 wherein X 1 is N, X 2 is CH.
  3. The compound according to claim 1 and 2 wherein R 1 is structural formula (i).
  4. The compound according to claim 1 and 2 wherein R 1 is structural formula (ii).
  5. The compound according to claim 1 and 2 wherein R 1 is structural formula (iii).
  6. The compound according to claim 1 and 2 wherein R 1 is structural formula (iv).
  7. The compound according to claim 1 and 2 wherein R 1 is selected from structural formula (v), and (vi).
  8. The compound according to any one of claims 1 through 7 wherein R 5 of R 1 is selected from the group consisting of CH 3 , CD 3 , CH 2 CH 3 , CH 2 CHF 2 , (CH 2 ) 2 F, CH 2 CF 3 , CHF 2 , (CH 2 ) n C(CH 3 ) 3 , CH 2 C(CH 3 ) 2 OH, CH 2 CH(OH)CH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 CN, (CH 2 ) 2 CN, (CH 2 ) n cyclopropyl, (CH 2 ) n cyclobutyl, (CH 2 ) n cyclopentyl, (CH 2 ) n cyclohexyl, (CH 2 ) n oxetanyl, azetidinyl, piperazinyl, piperidinyl, oxanyl, bicyclopentanyl, dihydropyrrolopyrazolo, azaspiroheptanyl, and tetrahydropyrazolopyridinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, piperazinyl, piperidinyl, oxanyl, bicyclopentanyl, dihydropyrrolopyrazolo, azaspiroheptanyl, and tetrahydropyrazolopyridinyl optionally substituted with 1 to 3 groups of R c .
  9. The compound of any of claims 1 through 8 wherein R 3 is selected from hydrogen chlorine, fluorine, bromine, CN and methyl.
  10. The compound of any one of claims 1 through 9 wherein R 4 is selected from the group consisting of N-linked piperazinyl, oxetanylpiperidinyl, pyrrolidinyl, azetidinyl, diazaspirononanyl, piperidinyl, azabicyclohexanyl, dihydrotriazolopyrazinyl, diazabicycloheptanyl, azabicycloheptanyl, azabicyclooctanyl, pyrrolopyridinyl, oxazolidinonyl, azaspirodecanyl, pyrazolopyridinyl, oxaazaspirodecanonyl, azabicycloheptanonyl, azaspiroheptanyl, diazaspiroheptanyl, piperazinonyl, piperazinyltetrahydrofuranyl, oxazolidinonyl, and azabicycloheptanonyl, said group optionally substituted with 1 to 3 groups of R d selected from C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , oxo, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl optionally substituted with 1 to 3 groups of R e .
  11. The compound according to any one of claims 1 through 9 wherein R 4 is NRR' selected from N(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , NHCH(CH 3 ) 2 , NHCH 2 cyclopropyl, and N(CH 3 )oxetanyl.
  12. The compound according to any one of claims 1 through 11 wherein R a and R b are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, CF 3 , CHF 2 , cyclopropyl, and C(CH 3 ) 2 -triazolyl.
  13. The compound according to claim 12 wherein at least one of R a and R b is hydrogen and the other is selected from the group consisting of chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl.
  14. The compound according to claim 1 represented by structural Formula II: or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from hydrogen, chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl, R 3 is selected from CH 3 , chlorine, fluorine, bromine, hydrogen, and CN, R 4 is selected from the group consisting of wherein R d is selected from C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl optionally substituted with 1 to 3 groups of R e , and R 5 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 F, CH 2 CF 3 , CHF 2 , CH 2 C(CH 3 ) 2 OH, (CH 2 ) n cyclopropyl, (CH 2 ) n oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl, said cyclopropyl, oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl optionally substituted with 1 to 3 groups of R c .
  15. The compound according to claim 1 represented by structural Formula III: or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from hydrogen, chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl, R 3 is selected from CH 3 , chlorine, fluorine bromine, hydrogen, and CN, R 4 is selected from the group consisting of wherein R d is selected from C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl optionally substituted with 1 to 3 groups of R e , and R 5 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 F, CH 2 CF 3 , CHF 2 , CH 2 C(CH 3 ) 2 OH, (CH 2 ) n cyclopropyl, (CH 2 ) n oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl, said cyclopropyl, oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl optionally substituted with 1 to 3 groups of R c .
  16. The compound according to claim 1 represented by structural Formula IV: Z is or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from hydrogen, chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl, R 3 is selected from CH 3 , chlorine, fluorine, bromine, hydrogen, and CN, R 4 is selected from the group consisting of: wherein R d is selected from C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 3 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl optionally substituted with 1 to 3 groups of R e .
  17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
  18. A pharmaceutical composition comprising a compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  19. A compound according to any of claims 1 to 17, or a pharmaceutically acceptable salt thereof for use in therapy.
  20. A compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof for use in treating Parkinson's Disease, abnormal motor symptoms associated with Parkinson's disease, non-motor symptoms associated with Parkinson's disease, Lewy body dementia, L-Dopa induced dyskinesias, Alzheimer's disease, mild cognitive impairment, the transition from mild cognitive impairment to Alzheimer's disease, tauopathy disorders characterized by hyperphosphorylation of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and Parkinson's disease linked to chromosome 17, neuroinflammation associated with of microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury and spinal cord injury, lymphomas, leukemias, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic pupura (ITP), Evans Syndrome, vasculitis, bullous skin disorder, type I diabetes mellitus, Sjorgen's syndrome, Delvic's disease, inflammatory myopathies, and ankylosing spondylitis, renal cancer, breast cancer, lung cancer, prostate cancer, and acute myelogenous leukemia (AML) in subjects expressing the LRRK2 G2019S mutation, papillary renal and thyroid carcinomas in a subject in whom LRRK2 is amplified or overexpressed, Crohn's disease or leprosy.

Description

BACKGROUND OF THE INVENTION Parkinson's disease (PD) is a common neurodegenerative disease caused by progressive loss of mid-brain dopaminergic neurons leading to abnormal motor symptoms such as bradykinesia, rigidity and resting tremor. Many PD patients also experience a variety of non-motor symptoms including cognitive dysfunction, autonomic dysfunction, emotional changes and sleep disruption. The combined motor and non-motor symptoms of Parkinson's disease severely impact patient quality of life. While the majority of PD cases are idiopathic, there are several genetic determinants such as mutations in SNCA, Parkin, PINK1, DJ-1 and LRRK2. Linkage analysis studies have demonstrated that multiple missense mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene lead to an autosomal late onset form of PD. LRRK2 is a 286 kDa cytoplasmic protein containing kinase and GTPase domains as well as multiple protein-protein interaction domains. See for example, Aasly et al., Annals of Neurology, Vol. 57(5), May 2005, pp. 762-765; Adams et al., Brain, Vol. 128, 2005, pp. 2777-85; Gilks et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 415-416, Nichols et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 410-412, and U. Kumari and E. Tan, FEBS journal 276 (2009) pp. 6455-6463. In vitro biochemical studies have demonstrated that LRRK2 proteins harboring the PD associated proteins generally confer increased kinase activity and decreased GTP hydrolysis compared to the wild type protein (Guo et al., Experimental Cell Research, Vol, 313, 2007, pp. 3658-3670) thereby suggesting that small molecule LRRK2 kinase inhibitors may be able to block aberrant LRRK2-dependent signaling in PD. In support of this notion, it has been reported that inhibitors of LRRK2 are protective in models of PD (Lee et al., Nature Medicine, Vol 16, 2010, pp. 998-1000). LRRK2 expression is highest in the same brain regions that are affected by PD. LRRK2 is found in Lewy bodies, a pathological hallmark of PD as well as other neurodegenerative diseases such as Lewy body dementia (Zhu et al., Molecular Neurodegeneration, Vol 30, 2006, pp. 1-17). Further, LRRK2 mRNA levels are increased in the striatum of MPTP-treated marmosets, an experimental model of Parkinson's disease, and the level of increased mRNA correlates with the level of L-Dopa induced dyskinesia suggesting that inhibition of LRRK2 kinase activity may have utility in ameliorating L-Dopa induced dyskinesias. These and other recent studies indicate that a potent, selective and brain penetrant LRRK2 kinase inhibitor could be a therapeutic treatment for PD. (Lee et al., Nat. Med. 2010 Sep;16(9):998-1000; Zhu, et al., Mol. Neurodegeneration 2006 Nov 30; 1: 17; Daher, et al., J Biol Chem. 2015 Aug 7; 290(32):19433-44; Volpicelli-Daley et al., J Neurosci. 2016 Jul 13; 36(28):7415-27). Further LRRK2 inhibitors have been described (Xiao Ding et al, Expert Opinion on Therapetic Patents, 2020, 1-12). LRRK2 mutations have been associated with Alzheimer's-like pathology (Zimprach et al., Neuron. 2004 Nov 18;44(4):601-7) and the LRRK2 R1628P variant has been associated with an increased risk of developing AD (Zhao et al., Neurobiol Aging. 2011 Nov; 32(11):1990-3). Mutations in LRRK2 have also been identified that are clinically associated with the transition from mild cognitive impairment to Alzheimer's disease (see WO2007149798). Together these data suggest that LRRK2 inhibitors may be useful in the treatment of Alzheimer's disease and other dementias and related neurodegenerative disorders. LRRK2 has been reported to phosphorylate tubulin-associated tau and this phosphorylation is enhanced by the kinase activating LRRK2 mutation G2019S (Kawakami et al., PLoS One. 2012; 7(1):e30834; Bailey et al., Acta Neuropathol. 2013 Dec; 126(6):809-27.). Additionally, over expression of LRRK2 in a tau transgenic mouse model resulted in the aggregation of insoluble tau and its phosphorylation at multiple epitopes (Bailey et al., 2013). Hyperphosphorylation of tau has also been observed in LRRK2 R1441G overexpressing transgenic mice (Li et al., Nat Neurosci. 2009 Jul; 12(7):826-8.). Inhibition of LRRK2 kinase activity may therefore be useful in the treatment of tauopathy disorders characterized by hyperphosphorylated of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinson's linked to chromosome 17 (Goedert and Jakes Biochim Biophys Acta. 2005 Jan 3.). A growing body of evidence suggests a role for LRRK2 in immune cell function in the brain with LRRK2 inhibitors demonstrated to attenuate microglial inflammatory responses (Moehle et al., J Neurosci. 2012 Feb 1;32(5):1602-11.). As neuroinflammation is a hallmark of a number of neurodegenerative diseases such PD, AD, MS, HIV-induced dementia, ALS, ischemic stroke, MS, traumatic brain injury and spinal cord injury, LRRK2 kinases inhibitors may have utility in the treatment of neu