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US-12617795-B2 - Substituted 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines, 5,7-dihydrofuro[3,4-d]pyrimidines, and pyrido[2,3-d]pyrimidines as KCC2 modulators

US12617795B2US 12617795 B2US12617795 B2US 12617795B2US-12617795-B2

Abstract

The invention concerns compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 7 and ring A have any of the meanings hereinbefore defined in the description; process for their preparation; pharmaceutical compositions containing them and their use in treating KCC2 mediated diseases.

Inventors

  • Rebecca Elizabeth Jarvis
  • Roland Werner BÜRLI

Assignees

  • ASTRAZENECA AB

Dates

Publication Date
20260505
Application Date
20210312

Claims (20)

  1. 1 . A compound of Formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkyl, OCH 2 C 6-10 aryl, OC 2-6 alkenyl, OC 2-6 alkynyl, OC 3-7 cycloalkyl, OC 6-10 aryl, C 3-7 cycloalkyl, C 6-10 aryl, thiophenyl, or 6-membered heteroaryl; wherein the C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkyl, OC 2-6 alkenyl, OC 2-6 alkynyl, or C 3-7 cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; wherein the C 6-10 aryl of OCH 2 C 6-10 aryl, OC 6-10 aryl, C 6-10 aryl, or 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 alkyl, OC 1-8 alkyl, and OC 2-8 alkynyl; and wherein each C 1-3 alkyl, OC 1-8 alkyl, and OC 2-8 alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CF 3 , and NHC(O)OC 1-6 alkyl; or any two R 1 substituents, together with the carbon atom to which they are attached, form diazirinyl; R 2 is H, halo, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; is: R 3 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 5- or 6-membered heterocycloalkyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 5- or 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CF 3 , C 1-3 alkyl, C(O)NR 8 R 9 , and NR 8 R 9 ; and wherein each C 1-3 alkyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 4a is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 4b is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 4c is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 4d is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; or R 4c and R 4d , taken together with the carbon atom to which they are attached, form —C(O)—; R 5a is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 5b is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 5c is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 5d is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 6 is H, halo, CN, C 1-3 alkyl, C(O)NR 8 R 9 , C(O)OH, C(O)OC 1-3 alkyl, NH 2 , NHC(O)C 1-3 alkyl, or OC 1-3 alkyl, wherein the C 1-3 alkyl or OC 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; R 7 is NR 10 R 11 , monocyclic 5- to 7-membered heterocycloalkyl, or monocyclic 5- or 6-membered heteroaryl; wherein the 5- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, C 1-6 alkyl, C 1-3 alkylene-NHC(O)C 1-6 alkyl, C 1-3 alkylene-NHC(O)OC 1-6 alkyl, C(O)OH, OC 1-3 alkyl, and C 3-5 cycloalkyl; or wherein the 5- to 7-membered heterocycloalkyl is optionally substituted with 2 substituents on the same ring carbon, which together with the carbon atom to which they are attached, form a monocyclic 5- to 7-membered heterocycloalkyl; wherein the 5- or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, C 1-6 alkyl, C 1-3 alkylene-NHC(O)C 1-6 alkyl, C 1-3 alkylene-NHC(O)OC 1-6 alkyl, C(O)OH, OC 1-3 alkyl, and C 3-5 cycloalkyl; wherein each C 1-6 alkyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CF 3 , and OH; and wherein each OC 1-3 alkyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; each R 8 is independently H or C 1-6 alkyl; each R 9 is independently H or C 1-6 alkyl; R 10 is C 1-6 alkyl; R 11 is C 1-6 alkyl or (CH 2 ) n R 12 , wherein the C 1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F and OC 1-3 alkyl; R 12 is C 3-5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and n is 1, 2, or 3; with the proviso that if R 1 is unsubstituted phenyl and R 7 is morpholinyl, then R 2 is not H.
  2. 2 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C 2-6 alkyl, OC 2-6 alkyl, OCH 2 C 6-10 aryl, OC 3-7 cycloalkyl, OC 6-10 aryl, C 3-7 cycloalkyl, C 6-10 aryl, or thiophenyl; wherein the C 2-6 alkyl, OC 2-6 alkyl, or C 3-7 cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 ; wherein the C 6-10 aryl of OCH 2 C 6-10 aryl, OC 6-10 aryl, or C 6-10 aryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 alkyl, OC 1-8 alkyl, and OC 2-8 alkynyl; and wherein each C 1-3 alkyl, OC 1-3 alkyl, and OC 2-s alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CF 3 , and NHC(O)OC 1-6 alkyl; or any two R 1 substituents, together with the carbon atom to which they are attached, form diazirinyl.
  3. 3 . The compound according to claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is CH 2 CF 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 phenyl, Ocyclopentyl, Ophenyl, cyclobutyl, cyclohexyl, phenyl, or thiophenyl; wherein the Ophenyl is optionally substituted with 1 or 2 F substituents; and wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, CH 3 , O(CH 2 ) 5 CF 3 , O(CH 2 ) 7 CH 3 , OCH 2 C≡CH, O(CH 2 ) 5 C≡CH, O(CH 2 ) 2 NHC(O)OC(CH 3 ) 3 , and O(CH 2 ) 2 —C(N═N)—CH 2 C≡CH.
  4. 4 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is H, F, or CH 3 .
  5. 5 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is:
  6. 6 . The compound according to claim 1 , wherein the compound is of Formula (II): or a pharmaceutically acceptable salt or stereoisomer thereof.
  7. 7 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is CH 2 CH 3 , CH 2 C(O)N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 CH 2 N(CH 3 ) 2 , CH(CH 3 ) 2 , C≡CCH 3 , CH 2 C≡CH, or N-methylpiperidinyl.
  8. 8 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 4a is H; and R 4b is H.
  9. 9 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4c and R 4d , taken together with the carbon atom to which they are attached, form —C(O)—.
  10. 10 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is:
  11. 11 . The compound according to claim 1 , wherein the compound is of Formula (III): or a pharmaceutically acceptable salt or stereoisomer thereof.
  12. 12 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 5a is H; R 5b is H; R 5c is H; and R 5d is H.
  13. 13 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is:
  14. 14 . The compound according to claim 1 , wherein the compound is of Formula (IV): or a pharmaceutically acceptable salt or stereoisomer thereof.
  15. 15 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is H, Br, CN, CH 2 CH 3 , C(O)NH 2 , C(O)OH, C(O)OCH 3 , NH 2 , NHC(O)CH 3 , or OCH 3 .
  16. 16 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl; wherein the thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, C 1-6 alkyl, C 1-3 alkylene-NHC(O)C 1-6 alkyl, C 1-3 alkylene-NHC(O)OC 1-6 alkyl, C(O)OH, OC 1-3 alkyl, and C 3-5 cycloalkyl; or wherein the thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl is optionally substituted with 2 substituents on the same ring carbon, which together with the carbon atom to which they are attached, form a monocyclic 5- to 7-membered heterocycloalkyl; wherein the pyrrolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, C 1-6 alkyl, C 1-3 alkylene-NHC(O)C 1-6 alkyl, C 1-3 alkylene-NHC(O)OC 1-6 alkyl, C(O)OH, OC 1-3 alkyl, and C 3-5 cycloalkyl; wherein each C 1-6 alkyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CF 3 , and OH; and wherein each OC 1-3 alkyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of F and CF 3 .
  17. 17 . The compound according to claim 16 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl; wherein the thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, CH 3 , CH 2 NHC(O)OC(CH 3 ) 3 , CH 2 OH, CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 NHC(O)CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 3 , C(O)OH, OCH 3 , and cyclopropyl; or wherein the thiazolidinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl is optionally substituted with 2 substituents on the same ring carbon, which together with the carbon atom to which they are attached, form a tetrahydropyranyl; and wherein the pyrrolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, CH 3 , CH 2 NHC(O)OC(CH 3 ) 3 , CH 2 OH, CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 NHC(O)CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 3 , C(O)OH, OCH 3 , and cyclopropyl.
  18. 18 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is NR 10 R 11 .
  19. 19 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) each R 8 is independently H; and each R 9 is independently H; or (ii) each R is independently CH 3 ; and each R 9 is independently CH 3 .
  20. 20 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 .

Description

FIELD The specification generally relates to fused amino pyrimidine compounds and pharmaceutically acceptable salts thereof. These compounds and their pharmaceutically acceptable salts selectively modulate KCC2, and the specification therefore also relates to the use of such compounds and salts thereof to treat or prevent KCC2 mediated disease, including neurological disorders. The specification further relates to pharmaceutical compositions comprising such compounds and salts; methods of manufacture of such compounds and salts; and to methods of treating KCC2 mediated disease, including neurological disorders, using such compounds and salts. BACKGROUND KCC2 is an electro-neutral membrane transporter, encoded by the SLC12A5 gene, that plays a key role in inhibitory neurotransmission. KCC2 couples the efflux of K+ and Cl− ions across the membrane of neurons, resulting in the maintenance of a low intracellular chloride concentration. Low intracellular levels of chloride are essential for GABAA receptor-mediated signalling, relying as it does on the ligand gated influx of Cl− ions to hyperpolarise the neuronal membrane, resulting in inhibition of action potential firing. GABAA signalling is the major inhibitory neurotransmitter mechanism in the adult brain and consequently KCC2 has a key role in normal neurodevelopment and various neurological disorders. Decreased activity of KCC2 has been implicated in the pathogenesis of neurological disorders including epilepsy (Galanopoulou et al, Epilepsia 2007; 48:14-18; Huberfield et al, The Journal of Neuroscience (2007) 27, 9866-9873), neuropathic pain (Price et al, Curr Top Med Chem 2005; 5:547-555), Rett's syndrome (Tang et al, 2019, Translational Medicine, 11(503)), autism (Tyzio et al, Science 343, 675-679, Merner et al, Frontiers in cellular neuroscience 9, 2015), mental disorders, spinal cord injury (Boulenguez et al, Nature Medicine 2010, 16, 302-307) and conditions in which there is neuronal hyperexcitability such as ALS (Fuchs et al, Journal of Neuropathology & Experimental Neurology, Volume 69, Issue 10, October 2010, Pages 1057-1070). Increasing the expression level or activity of KCC2 is a therapeutic approach to treat diseases linked to neuronal hyperexcitability. KCC2 is preferentially expressed in neurons, making it an ideal drug target for neurological disorders. The genetic knockdown of KCC2 in mice leads to network hyperexcitability and spontaneous seizure activity (Hubner et al, Neuron 2001:30:515-524; Woo et al, Hippocampus 2002; 12:258-268). Mutations in the KCC2 gene have been found in human patients with epilepsy (Duy et al, Front Cell Neurosci. 2019; 13: 515), reinforcing the link between KCC2 dysfunction and epilepsy and supporting the approach of KCC2 activation as a means to increase Cl− extrusion, restore GABA inhibition and treat disorders such as refractory epilepsy and status epilepticus. Status epilepticus can be caused by nerve agents (de Araujo Furtado et al, 2012, Neuro Toxicology, 33(6), 1476-1490) and activation of KCC2 is a potential therapeutic option. Recently it has been shown that potentiating KCC2 activity by genetic modification of its regulatory sites is sufficient to limit the onset and severity of seizures in mice (Moore et al, Proc Natl Acad Sci USA. 2018 Oct. 2; 115(40): 10166-10171). KCC2 activity is modulated by phosphorylation at a number of regulation sites (Cordshagen et al, Journal of Biological Chemistry 2018, 293, 16984-16993) including phosphorylation at T1007 by STK39 and OSR1. KCC2 cell surface expression is regulated by phosphorylation at S940. Direct modulation of KCC2 by interaction with small molecules has been reported. Delpire et al (Proc Natl Acad Sci USA. 2009 Mar. 31; 106(13): 5383-5388) describe an assay to identify small molecule inhibitors of KCC2 and Zhang et al (Journal of Biomolecular Screening 15(2): 2010) describe an assay used to identify positive modulators of KCC2. There exists a need for new compounds which activate KCC2 and which are therefore useful in the treatment of neurological disorders. SUMMARY Briefly, this specification describes, in part, a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C2-7cycloalkyl; —O—C3-7cycloalkyl; C6-10aryl; —O—(CH2)m—C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from —F and —CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, —C1-3alkyl, —C1-8alkoxy and —C2-8alkynyloxy wherein —C1-3alkyl, —C1-8alkoxy and —C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from —F, —CF3, —NHC(O)O—C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;R2 is selected fr