Fused pyrimidine compounds as KCC2 modulators

Abstract

The present invention relates to fused pyrimidine compounds as modulators of KCC2. The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R7 and ring A have any of the meanings as defined in the specification; a preparation process thereof; pharmaceutical compositions comprising them and their use in the treatment of KCC2 mediated diseases. # imgabs0 #

Description

[0001] This application is a divisional application of an application filed on March 12, 2021, with application number 202180020856.3, and invention name “Fused pyrimidine compounds as KCC2 regulators”.

[0002] field

[0003] The present specification generally relates to fused aminopyrimidine compounds and pharmaceutically acceptable salts thereof. These compounds and pharmaceutically acceptable salts thereof selectively regulate KCC2, and therefore the present specification also relates to the use of such compounds and salts thereof for treating or preventing KCC2-mediated diseases including neurological disorders. The present specification also relates to pharmaceutical compositions comprising such compounds and salts; methods for manufacturing such compounds and salts; and methods for using such compounds and salts to treat KCC2-mediated diseases including neurological disorders.

[0004] background

[0005] KCC2 is an electroneutral membrane transporter encoded by the SLC12A5 gene that plays a key role in inhibitory neurotransmission. + Ions and Cl - Ions flow out across the neuron membrane, resulting in low intracellular chloride concentrations. Low intracellular levels of chloride have a significant effect on GABA A Receptor-mediated signaling is essential and depends on ligand-gated Cl - The influx of ions hyperpolarizes the neuronal membrane, resulting in inhibition of action potential firing.

[0006] GABA ASignaling is the major inhibitory neurotransmitter mechanism in the adult brain, and thus KCC2 has a critical role in normal neurodevelopment and various neurological disorders. Reduced KCC2 activity has been associated with 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 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), psychiatric 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, Vol. 69, No. 10, October 2010, pp. 1057-1070).

[0007] Increasing the expression level or activity of KCC2 is a therapeutic approach for treating diseases associated with neuronal hyperexcitability. KCC2 is preferentially expressed in neurons, making it an ideal drug target for neurological disorders.

[0008] Genetic knockout of KCC2 in mice results in network hyperexcitability and spontaneous seizure activity (Hubner et al., Neuron 2001:30:515-524; Woo et al., Hippocampus 2002;12:258-268).

[0009] Mutations in the KCC2 gene have been found in human patients with epilepsy (Duy et al., Front Cell Neurosci. 2019; 13:515), strengthening the link between KCC2 dysfunction and epilepsy and supporting KCC2 activation as a means of increasing Cl - A means of extrusion, restoring GABA inhibition and treating disorders such as refractory epilepsy and status epilepticus.

[0010] Status epilepticus can be induced by nerve agents (de Araujo Furtado et al., 2012, NeuroToxicology, 33(6), 1476-1490), and activation of KCC2 is a potential therapeutic option.

[0011] It has recently been shown that enhancing KCC2 activity by genetically modifying its regulatory sites is sufficient to limit the onset and severity of epileptic seizures in mice (Moore et al., Proc Natl Acad Sci USA. 2018 Oct 2;115(40):10166-10171).

[0012] KCC2 activity is regulated by phosphorylation at many regulatory sites (Cordshagen et al., Journal of Biological Chemistry 2018, 293, 16984-16993), including phosphorylation by STK39 and OSR1 at T1007. KCC2 cell surface expression is regulated by phosphorylation at S940.

[0013] Direct regulation 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) described an assay for identifying small molecule inhibitors of KCC2, and Zhang et al. (Journal of Biomolecular Screening 15(2):2010) described an assay for identifying positive regulators of KCC2.

[0014] There is a need for new compounds that activate KCC2 and therefore can be used to treat neurological disorders.

[0015] Overview

[0016] Briefly, this specification describes, in part, compounds of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC 1-6 A substituent of an alkyl group is substituted, or two substituents together with the carbon to which they are attached form a diazirinyl group;

[0020] R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0021] A is selected from

[0022] or its N-oxide;

[0023] R 3 Selected from -H; -C 1-6 Alkyl; -C 2-6 Alkenyl; -C 2-6 Alkynyl; C 3-7 Cycloalkyl; and 5-membered or 6-membered heterocycloalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 selected from -F, -CF3, -C 1-3 Alkyl group substituted, the -C 1-3 The alkyl group is optionally substituted by 1 or 2 groups selected from -F, -CF3, -C(O)NR 8 R 9 and-NR 8 R 9 Substituents are substituted;

[0024] R 4a and R 4b each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0025] R4c and R 4d are each independently selected from -H and -C optionally substituted with 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; or R 4c and R 4d Together with the carbon to which they are attached, they represent a carbonyl group;

[0026] R 5a , R 5b , R 5c and R 5d are each independently selected from -H and -C optionally substituted with 1, 2 or 3 substituents selected from -F and CF3 1-3 alkyl;

[0027] R 6 -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 ; -C(O)OH and -NHC(O)-C 1-3 alkyl;

[0028] R 7 Selected from NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents, said two substituents together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; and wherein when R 7 is morpholinyl and R 1 When R is an unsubstituted phenyl group, 2 Not -H;

[0029] R8 and R 9 are each independently selected from -H and -C 1-6 alkyl;

[0030] R 10 Yes-C 1-6 alkyl;

[0031] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; and -(CH2) n R 12 ;

[0032] R 12 is a 5-membered or 6-membered heteroaryl, a 3-membered to 5-membered cycloalkyl or a 3-membered to 6-membered heterocycloalkyl;

[0033] m is 0 or 1; and

[0034] n is 1, 2, or 3.

[0035] This specification also describes, in part, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable diluent or carrier.

[0036] This specification also describes, in part, a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.

[0037] This specification also describes, in part, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a neurological disorder.

[0038] This specification also describes, in part, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a neurological disorder.

[0039] This specification also describes, in part, a method for treating a neurological disorder in a warm-blooded animal in need of such treatment, the method comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0040] Further aspects of the present disclosure will be apparent to those skilled in the art from reading this specification.

[0041] Description of Illustrative Embodiments

[0042] Many embodiments are described in detail throughout the specification and will be apparent to readers skilled in the art. This specification should not be construed as limited to any particular embodiment described herein.

[0043] In an embodiment, a compound of formula (I) is provided:

[0044]

[0045] or a pharmaceutically acceptable salt thereof, wherein:

[0046] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group;

[0047] R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0048] A is selected from:

[0049] or its N-oxide;

[0050] R 3 Selected from -H; -C 1-6 Alkyl; -C 2-6 Alkenyl; -C 2-6 Alkynyl; -C 3-7 Cycloalkyl; and 5-membered or 6-membered heterocycloalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 selected from -F, -CF3, -C 1-3 Alkyl group substituted, the -C1-3 The alkyl group is optionally substituted by 1 or 2 groups selected from -F, -CF3, -C(O)NR 8 R 9 and-NR 8 R 9 Substituents are substituted;

[0051] R 4a and R 4b each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0052] R 4c and R 4d are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkyl; or R 4c and R 4d Together with the carbon to which they are attached, they represent a carbonyl group;

[0053] R 5a , R 5b , R 5c and R 5d are each independently selected from -H and -C optionally substituted with 1, 2 or 3 substituents selected from -F and CF3 1-3 alkyl;

[0054] R 6 -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 ; -C(O)OH and -NHC(O)-C 1-3 alkyl;

[0055] R 7 Selected from NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents, said two substituents together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; and wherein when R 7 is morpholinyl and R 1 When R is an unsubstituted phenyl group, 2 Not -H;

[0056] R 8 and R 9 are each independently selected from -H and -C 1-6 alkyl;

[0057] R 10 Yes-C 1-6 alkyl;

[0058] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; and -(CH2) n R 12 ;

[0059] R 12 is a 5-membered or 6-membered heteroaryl, a 3-membered to 5-membered cycloalkyl or a 3-membered to 6-membered heterocycloalkyl;

[0060] m is 0 or 1; and

[0061] n is 1, 2, or 3.

[0062] In the context of this specification, unless otherwise stated, the term "alkyl" includes both straight-chain alkyl groups and branched-chain alkyl groups. p-q Alkyl and other terms with the prefix C p-q (where p and q are integers) indicates the range of carbon atoms present in the group, for example C 1-3 The alkyl group includes a C1 alkyl group (methyl group), a C2 alkyl group (ethyl group) and a C3 alkyl group (propyl group such as n-propyl group and isopropyl group).

[0063] The term "C p-q "Alkoxy" includes -OC p-q Alkyl groups and -C in which the O atom is within the alkyl chain p-q Alkyl groups, such as -CH2-O-CH 3。

[0064] The term "C p-q"Alkenyl" includes both straight chain and branched chain alkyl groups containing at least two carbon atoms and at least one carbon-carbon double bond.

[0065] The term "C p-q "Alkenyloxy" includes -OC p-q Alkenyl groups and -C p-q Alkenyl group.

[0066] The term "C p-q "Alkynyl" includes both straight chain and branched chain alkyl groups containing at least two carbon atoms and at least one carbon-carbon triple bond.

[0067] The term "C p-q "Alkynyloxy" includes -OC p-q Alkynyl groups and -C in which the O atom is within the alkynyl chain p-q Alkynyl group.

[0068] C p-q Cycloalkyl refers to a cyclic non-aromatic group of pq carbon atoms and no heteroatoms. For example, a 3- to 7-membered cycloalkyl refers to a ring containing 3 to 7 carbon atoms. Suitable C 3-7 Cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0069] Aryl is a 6- to 10-membered monocyclic or bicyclic aromatic ring containing no heteroatoms. Aryl includes phenyl.

[0070] Heterocycloalkyl is a monocyclic saturated or partially unsaturated non-aromatic ring, having, for example, 3 to 7 members, such as 3 to 6 members, 5 to 7 members, such as 5 or 6 members, wherein at least one member of the ring and up to 4 members, particularly 1, 2 or 3 members are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms, which are in a stable combination known to those skilled in the art. Heterocycloalkyl ring nitrogen atom and sulfur atom are optionally oxidized. Suitable heterocycloalkyl rings include morpholinyl, thiazolidinyl, homomorpholine, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and tetrahydrofuranyl. In one embodiment, when R 7 When R is heterocycloalkyl, two substituents optionally on the same ring carbon are taken together with the carbon to which they are attached to form a 5- to 7-membered heterocycloalkyl ring, thereby creating a spirocyclic ring system. For example, in one embodiment, R 7 It is morpholinyl and two substituents on the same ring carbon together form tetrahydropyran.

[0071] Heteroaryl is a polyunsaturated, monocyclic 5- or 6-membered aromatic ring containing at least one and up to 3 heteroatoms, particularly 1 or 2 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms. The heteroaryl ring nitrogen atom and the sulphur atom are optionally oxidized. Suitable heteroaryl rings include pyridyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazinyl, oxazolyl, thienyl and thiazolyl.

[0072] The term "halogen" is fluorine, chlorine or bromine.

[0073] The use of a dashed line "------" in Ring A of Formula (I) indicates the fusion of the pyrimidine rings.

[0074] Where the term "optionally" is used, it is intended that the subsequent feature may or may not occur. Thus, the use of the term "optionally" includes instances where the feature is present, and also includes instances where the feature is not present. For example, a group "optionally substituted with 1, 2, or 3 -F substituents" includes groups with and without -F substituents.

[0075] The term "substituted" means that one or more hydrogens (e.g., 1 or 2 hydrogens, or alternatively 1 hydrogen) on a specified group are replaced by a specified substituent (e.g., 1, 2 or 3 substituents, or alternatively 1 or 2 substituents, or alternatively 1 substituent) provided that any atom with a substituent maintains an allowed valence. Substituent combinations only encompass stable compounds and stable synthetic intermediates. "Stable" means that a related compound or intermediate is robust enough to be isolated and has utility as a synthetic intermediate or as an agent with potential therapeutic utility. If a group is not described as "substituted" or "optionally substituted", the group will be considered to be unsubstituted (i.e., none of the hydrogens on the specified group have been replaced).

[0076] The term "pharmaceutically acceptable" is used to specify that an object (e.g., salt, dosage form, or excipient) is suitable for use in a patient. An exemplary list of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl and C. G. Wermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.

[0077] Suitable pharmaceutically acceptable salts of the compounds of formula (I) are, for example, salts which are formed in vivo in a human or animal after administration of the compounds of formula (I) to said human or animal.

[0078] Additional embodiments provide any of the embodiments defined herein (e.g., the embodiments described above), with the proviso that one or more specific embodiments (e.g., one, two or three specific embodiments) selected from the group consisting of the following embodiments are individually excluded: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113 and 114.

[0079] The following embodiments of Part A can be applied to the description of the compounds of Formula (I) provided herein:

[0080] A is selected from:

[0081] or an N-oxide thereof.

[0082] In one embodiment, A is

[0083] In one embodiment, A is

[0084] In one embodiment, A is

[0085] In one embodiment, A is

[0086] In one embodiment, A is

[0087] In an embodiment, a compound of formula (II) is provided:

[0088]

[0089] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4a, R 4b and R 7 As defined for formula (I).

[0090] In one embodiment, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R 1 , R 2 , R 3 , R 4a , R 4b and R 7 As defined for formula (I), and when R 7 When morpholinyl, any of the following:

[0091] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; heteroaryl is optionally substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC 1-6 The alkyl group is substituted with a substituent, or the two substituents together with the carbon to which they are attached form a diazirine group; and the aryl group is substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC 1-6 alkyl, or the two substituents, together with the carbon to which they are attached, form a diazirine group; and R 2-H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkyl; or

[0092] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and heteroaryl is optionally substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC 1-6 alkyl, or the two substituents, together with the carbon to which they are attached, form a diazirine group; and R 2 -C selected from -halogen and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl.

[0093] In an embodiment, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0094] R 1 Selected from: -C 2-6 Alkyl; -C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; optionally 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted phenyl, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC1-6 alkyl, or the two substituents together with the carbon to which they are attached form a diazirine; -O-phenyl optionally substituted with 1 or 2 -halogen substituents; -O-CH2-phenyl; and thienyl; wherein -C 2-6 Alkyl and -C 2-6 The alkoxy group is optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;

[0095] R 2 is selected from -H, -F and -CH3;

[0096] R 3 Selected from -C 2-4 Alkynyl and optionally -NR 8 R 9 Replaced-C 1-3 alkyl;

[0097] R 4a and R 4b Both are -H;

[0098] R 7 Selected from -NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1 or 2 substituents selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-3 Alkyl; -C 1-3 Alkoxy; Cyclopropyl; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl;

[0099] R 8 and R 9 Each independently selected from -C 1-6 alkyl;

[0100] R 10 Selected from -C 1-3 alkyl;

[0101] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-3 Alkyl; and -(CH2) n R12 ;

[0102] R 12 is selected from 5-membered or 6-membered heteroaryl, 3-membered to 5-membered cycloalkyl or 3-membered to 6-membered heterocycloalkyl;

[0103] n is 1 or 2.

[0104] In one embodiment, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0105] R 1 Selected from: -C 2-6 Alkyl; -C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy substituents substituted phenyl, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -NHC(O)OC 1-6 alkyl, or the two substituents together with the carbon to which they are attached form a diazirine; -O-phenyl optionally substituted with 1 or 2 -halogen substituents; -O-CH2-phenyl; and thienyl; wherein -C 2-6 Alkyl and -C 2-6 The alkoxy group is optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and R 2 is selected from -H, -F and -CH3; or

[0106] R 1 Selected from -C 2-6 Alkyl; -C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; unsubstituted phenyl; -O-phenyl optionally substituted with 1 or 2 halogen substituents; -O-CH2-phenyl; and thienyl; wherein -C 2-6 Alkyl and -C 2-6 The alkoxy group is optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and R 2 Selected from -F and -CH3;

[0107] R 3 Selected from -C 2-4 Alkynyl and optionally -NR 8 R 9 Replaced-C1-3 alkyl;

[0108] R 4a and R 4b Both are -H;

[0109] R 7 Selected from -NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1 or 2 substituents selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-3 Alkyl; -C 1-3 Alkoxy; Cyclopropyl; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl;

[0110] R 8 and R 9 Each independently selected from -C 1-6 alkyl;

[0111] R 10 Selected from -C 1-3 alkyl;

[0112] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-3 Alkyl; and -(CH2) n R 12 ;

[0113] R 12 is selected from 5-membered or 6-membered heteroaryl, 3-membered to 5-membered cycloalkyl or 3-membered to 6-membered heterocycloalkyl; and

[0114] n is 1 or 2.

[0115] In one embodiment, a compound of formula (III) is provided:

[0116]

[0117] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5a , R 5b , R5c , R 5d and R 7 As defined for formula (I).

[0118] In one embodiment, a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0119] R 1 Selected from C 3-7 Cycloalkyl and C 6-10 Aryl, wherein the aryl group is optionally substituted by -C 2-8 Alkoxy substituents, wherein the alkoxy is optionally substituted with 1 or 2 -CF3 substituents;

[0120] R 2 Yes - H;

[0121] R 5a , R 5b , R 5c and R 5d Each is -H;

[0122] R 7 Selected from -NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents, said two substituents together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; and wherein when R 7 is morpholinyl and R 1 When R is an unsubstituted phenyl group, 2 Not -H.

[0123] In one embodiment, a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0124] R 1 Selected from C 3-7 Cycloalkyl and C 6-10 Aryl, wherein the aryl group is optionally substituted by -C2-8 Alkoxy substituents, wherein the alkoxy is optionally substituted with 1 or 2 -CF3 substituents;

[0125] R 2 Yes - H;

[0126] R 5a , R 5b , R 5c and R 5d Each is -H;

[0127] R 7 is selected from 5- to 7-membered monocyclic heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl, wherein heterocycloalkyl and heteroaryl are optionally selected from -C 1-3 Alkyl and cyclopropyl substituents are substituted, the -C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 substituents selected from -F and -OH.

[0128] In one embodiment, a compound of formula (IV) is provided:

[0129]

[0130] or its N-oxide or pharmaceutically acceptable salt, wherein R 1 , R 2 , R 6 and R 7 As defined for formula (I).

[0131] In one embodiment, a compound of formula (IV) or an N-oxide or a pharmaceutically acceptable salt thereof is provided, wherein:

[0132] R 1 is selected from C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 3-7 Cycloalkyl;

[0133] R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0134] R 6 Selected from: -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9; -C(O)OH and -NHC(O)-C 1-3 alkyl;

[0135] R 7 Selected from -NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl;

[0136] R 8 and R 9 are each independently selected from -H and -C 1-6 alkyl;

[0137] R 10 Yes-C 1-6 alkyl;

[0138] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; and -(CH2) n R 12 ;

[0139] R 12 is a 5-membered or 6-membered heteroaryl, a 3-membered to 5-membered cycloalkyl or a 3-membered to 6-membered heterocycloalkyl;

[0140] n is 1, 2, or 3.

[0141] In one embodiment, a compound of formula (IV) or an N-oxide or a pharmaceutically acceptable salt thereof is provided, wherein:

[0142] R 1 is selected from C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 3-7 Cycloalkyl;

[0143] R2 Yes - H;

[0144] R 6 Selected from: -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 ; -C(O)OH and -NHC(O)-C 1-3 alkyl;

[0145] R 7 is selected from a 5- to 7-membered monocyclic heterocycloalkyl group optionally substituted by 1, 2 or 3 groups selected from: -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl, and C 3-5 Cycloalkyl;

[0146] R 8 and R 9 are each independently selected from -H and -C 1-6 alkyl.

[0147] Part R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6a , R 6b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m, and n may be applied alone or in combination to the description of the compounds of Formula (I) provided herein. 1 , R 2 , R 3 , R 4a , R 4b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m, and n may be applied alone or in combination to the description of the compounds of formula (II) provided herein.1 , R 2 , R 5a , R 5b , R 5c , R 5d , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m, and n may be applied alone or in combination to the description of the compounds of formula (III) provided herein. 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m, m, and n may be applied alone or in combination to the description of the compounds of Formula (IV) provided herein.

[0148] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0149] In one embodiment, R 1 Selected from C 2-6 Alkyl; C2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -O-(CH2) m -C 6-10 Aryl and heteroaryl are optionally substituted by 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 alkyl, or the two substituents, together with the carbon to which they are attached, form a diazirine; and C 6-10 Aryl is substituted by 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0150] In one embodiment, R 1 Selected from C 2-6 Alkyl; C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 Aryl; and thienyl, wherein alkyl, alkoxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein aryl is optionally substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0151] In one embodiment, R 1 Selected from: C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 2-6 Alkyl; C 2-4 Alkoxy; C 4-6 Cycloalkyl; -OC 4-6 Cycloalkyl; phenyl; -O-(CH2) m -phenyl; and thienyl; wherein the phenyl group is optionally substituted by 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0152] In one embodiment, R 1 Selected from: C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 2-6 Alkyl; C 2-4 Alkoxy; C 4-6 Cycloalkyl; -OC 4-6 Cycloalkyl; phenyl; -O-(CH2) m -phenyl; and thienyl; wherein -O-(CH2) m -phenyl is optionally substituted by 1 or 2 selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6The phenyl group is substituted with a substituent selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0153] In one embodiment, R 1 Selected from: -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thienyl; phenyl; -O-phenyl; -O-CH2-phenyl; wherein phenyl is optionally substituted by 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7.

[0154] In one embodiment, R 1 selected from: -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thienyl; substituted by 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7 substituted phenyl; -O-phenyl; -O-CH2-phenyl; wherein -O-phenyl and -O-CH2-phenyl are optionally substituted by 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7.

[0155] In one embodiment, R 1 In another embodiment, R 1is phenyl substituted by -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3, and -O-(CH2)7. In another embodiment, R 1 It is phenyl.

[0156] R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 In one embodiment, R 2 is -H. In another embodiment, R 2 In one embodiment, R 2 In another embodiment, R 2 Yes-C 1-3 In one embodiment, R 2 It's methyl.

[0157] R 3 Selected from -H; -C 1-6 Alkyl; -C 2-6 Alkenyl; -C 2-6 Alkynyl; -C 3-7 Cycloalkyl; and 5-membered or 6-membered heterocycloalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 selected from -C 1-3 Alkyl groups, for example 1 or 2 selected from -C 1-3 Alkyl group substituted, the -C 1-3 The alkyl group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -C(O)NR 8 R 9 and-NR 8 R 9 substituted by a substituent.

[0158] In one embodiment, R 3 Selected from -H; -C 2-4 Alkynyl; optionally substituted by -C(O)NR 8 R 9 or -NR 8 R 9 Replaced-C 1-3 and optionally C 1-3 Alkyl-substituted 5-membered or 6-membered heterocycloalkyl.

[0159] In one embodiment, R 3 Selected from -H; -C 2-4Alkynyl; optionally substituted by -C(O)NR 8 R 9 or -NR 8 R 9 Replaced-C 1-3 and optionally C 1-3 Alkyl-substituted 5- or 6-membered nitrogen-containing heterocycloalkyl group.

[0160] In one embodiment, R 3 Selected from -H; -C 2-4 Alkynyl; optionally substituted by -C(O)NR 8 R 9 or -NR 8 R 9 Replaced-C 1-3 and optionally C 1-3 Alkyl substituted piperidinyl.

[0161] In one embodiment, R 3 is selected from methyl, ethyl, isopropyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C≡CH, -CH2C(O)N(CH3)2 and N-methylpiperidine. In one embodiment, R 3 Selected from ethyl, isopropyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C≡CH, -CH2C(O)N(CH3)2 and N-methylpiperidine.

[0162] In one embodiment, R 3 Selected from -C 2-4 Alkynyl and optionally -NR 8 R 9 Replaced-C 1-3 alkyl;

[0163] In one embodiment, R 3 Selected from ethyl, isopropyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2 and -CH2C≡CH.

[0164] In one embodiment, R 3 It is isopropyl.

[0165] R 4a and R 4b each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 In one embodiment, R 4a is methyl and R 4b is -H. In one embodiment, R 4a and R4b Both are -H.

[0166] R 4c and R 4d each independently selected from -H and C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkyl; or R 4c and R 4d Together with the carbon to which they are attached, represent a carbonyl group. 4c and R 4d Together with the carbon to which they are attached, represent a carbonyl group. 4c and R 4d each independently selected from -H and C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 In another embodiment, R 4c and R 4d Both are -H or together with the carbon to which they are attached represent a carbonyl group. In yet another embodiment, R 4c and R 4d Both are -H.

[0167] R 5a , R 5b , R 5c and R 5d each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 In one embodiment, R 5a , R 5b , R 5c and R 5d each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 In one embodiment, R 5a , R 5b , R 5c and R 5d are each independently selected from -H and -C 1-3 In one embodiment, R 5a is methyl and R 5b , R 5c and R 5d Each is -H. In one embodiment, R 5a , R 5b and R 5c Each is -H and R 5d In one embodiment, R 5a , R 5b , R 5cand R 5d Each represents -H.

[0168] R 6 -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 ; -C(O)OH and -NHC(O)-C 1-3 In one embodiment, R 6 Selected from -H; -Br; -NH2; -CN; methoxy; ethyl; -C(O)OCH3; -C(O)NH2; -C(O)OH; and -NHC(O)CH3.

[0169] R 7 Selected from -NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 (e.g., 1 or 2) groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0170] In one embodiment, R 7 Selected from: NR 10 R 11; a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 (e.g., 1 or 2) groups selected from the following: -CN; -C optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0171] In one embodiment, R 7 Selected from: NR 10 R 11 ; a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 (e.g., 1 or 2) groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3 and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted on the same ring carbon with two substituents that, together with the carbon atoms to which they are attached, form a 6-membered monocyclic heterocycloalkyl.

[0172] In one embodiment, R 7 Selected from: NR 10 R 11 , where R 10 is selected from methyl, ethyl or propyl and R 11 Selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) p R 12; a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1 or 2 groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3 and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted on the same ring carbon by two substituents which, together with the carbon atoms to which they are attached, form a tetrahydropyranyl.

[0173] In one embodiment, R 7 Selected from NR 10 R 11 , where R 10 is selected from methyl, ethyl or propyl and R 11 Selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 .

[0174] In one embodiment, R 7 Selected from NR 10 R 11 , where R 10 is selected from methyl, ethyl or propyl; R 11 Selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 ; n is 1 or 2; and R 12 is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

[0175] In one embodiment, R 7 is selected from a 5- to 7-membered monocyclic heterocycloalkyl group optionally substituted by 1, 2 or 3 (e.g., 1 or 2) groups selected from: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl and C 3-5Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0176] In one embodiment, R 7 is selected from: a 5- to 7-membered monocyclic heterocycloalkyl group selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; wherein the heterocycloalkyl group is optionally substituted with 1 or 2 groups selected from the following: -CN; -C optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -CH2NHC(O)CH3; -CH2NHC(O)OC(CH3)3; and C 3-5 Cycloalkyl; or heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl.

[0177] In one embodiment, R 7 is a 5- to 7-membered monocyclic heterocycloalkyl group optionally substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, cyclopropyl, -CH2CH2OH, -CH2OH, -C(O)OH, -CH2CF3, and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl group is optionally substituted with two substituents on the same ring carbon which, together with the carbon atoms to which they are attached, form a tetrahydropyran.

[0178] In one embodiment, R 7 is morpholinyl optionally substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, cyclopropyl, -CH2CH2OH, -CH2OH, -C(O)OH, -CH2CF3, and -CH2NHC(O)OC(CH3)3; or optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form tetrahydropyran (i.e., R 7 to become a spirocyclic group).

[0179] In one embodiment, R 7 It is 2-methylmorpholin-4-yl.

[0180] R 8 Selected from -H and -C 1-6 In one embodiment, R 8 Selected from -H and -C 1-3 In one embodiment, R 8is -H. In one embodiment, R 8 Yes-C 1-3 In one embodiment, R 8 It's methyl.

[0181] R 9 Selected from -H and -C 1-6 In one embodiment, R 9 Selected from -H and -C 1-3 In one embodiment, R 9 is -H. In one embodiment, R 9 Yes-C 1-3 In one embodiment, R 9 It's methyl.

[0182] R 10 Yes-C 1-6 In one embodiment, R 10 Yes-C 1-3 In one embodiment, R 10 In another embodiment, R 10 In another embodiment, R 10 It is propyl.

[0183] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; or -(CH2) n R 12 In one embodiment, R 11 Selected from: -C optionally substituted by 1 or 2 substituents selected from -F and ethoxy 1-6 In one embodiment, R 11 Selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 In one embodiment, R 11 Selected from -(CH2) n R 12 .

[0184] R 12 is selected from 5-membered or 6-membered heteroaryl, 3-membered to 5-membered cycloalkyl or 3-membered to 6-membered heterocycloalkyl. 12 is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

[0185] m is 0 or 1. In one embodiment, m is 0. In another embodiment, m is 1.

[0186] n is 1, 2, or 3. In one embodiment, n is 1 or 2. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0187] In an embodiment, the compound of formula (I) is selected from:

[0188] 2-(Diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0189] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0190] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0191] 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0192] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0193] 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0194] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0195] 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0196] 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0197] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0198] 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0199] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0200] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0201] 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0202] 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0203] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0204] tert-Butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate;

[0205] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0206] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0207] 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0208] 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0209] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(1,2-oxazol-3-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0210] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(1,2,4-oxadiazol-3-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0211] 4-[(4-cyclohexylphenyl)amino]-2-(1,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0212] 4-[(4-cyclohexylphenyl)amino]-2-(1,9-dioxa-4-azaspiro[5.5]undec-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0213] 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0214] 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0215] 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0216] 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0217] 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0218] 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0219] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0220] 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0221] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0222] 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0223] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0224] (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid;

[0225] N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide;

[0226] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0227] 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile;

[0228] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0229] 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0230] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0231] 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0232] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0233] 4-[(4-cyclohexylphenyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0234] 4-[(4-cyclohexylphenyl)amino]-2-(1,3-oxazol-5-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0235] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0236] 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0237] 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0238] 2-(2-cyclopropylmorpholin-4-yl)-4-({4′-[(hept-6-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0239] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4′-(heptyloxy)[1,1′-biphenyl]-4-yl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0240] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diaziren-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0241] 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0242] 4-{[4-(Butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0243] 4-{[4-(Benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0244] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0245] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0246] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0247] 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0248] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0249] 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0250] 4-{[4-(Cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0251] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0252] tert-Butyl {2-[(4′-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate;

[0253] 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0254] 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0255] tert-Butyl {2-[(4′-{[2-(morpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate;

[0256] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0257] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-({4′-[(prop-2-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0258] 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0259] 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0260] 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0261] 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0262] 2-(Morpholin-4-yl)-4-{[4-(prop-2-yl)phenyl]amino}-6-(prop-2-yn-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0263] 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0264] 4-[(4-cyclohexylphenyl)amino]-2-(1H-imidazol-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0265] 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2'-methyl[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0266] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0267] 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0268] 2-(Morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0269] 4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0270] 4-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0271] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0272] 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0273] 4-[(2-methyl[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0274] 4-[(4'-chloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0275] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0276] N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0277] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0278] 2-(2-cyclopropylmorpholin-4-yl)-N-[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0279] 2-[(2R)-2-methylmorpholin-4-yl]-N-{4′-[(6,6,6-trifluorohexyl)oxy][1,1′-biphenyl]-4-yl}-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0280] N-(4-cyclohexylphenyl)-2-(2-methylpyridin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0281] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0282] 6-Bromo-N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0283] N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0284] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-8-oxo-8λ 5-pyrido[2,3-d]pyrimidin-4-amine;

[0285] N-(4-cyclohexylphenyl)-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0286] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile;

[0287] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester;

[0288] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid;

[0289] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxamide;

[0290] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)pyrido[2,3-d]pyrimidine-6-carboxamide;

[0291] N-(4-cyclohexylphenyl)-6-methoxy-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0292] N-{4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-6-yl}acetamide;

[0293] N4-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-4,6-diamine;

[0294] N-(4-cyclohexylphenyl)-2-(morpholin-4-yl)-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0295] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0296] 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide;

[0297] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0298] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0299] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0300] and pharmaceutically acceptable salts thereof.

[0301] Where the term "optionally" is used, it is intended that the subsequent feature may or may not occur. Thus, the use of the term "optionally" includes instances where the feature is present, and also includes instances where the feature is not present. For example, a group that is "optionally substituted with a methoxy group" includes groups with and without the methoxy substituent.

[0302] The term "substituted" means that one or more hydrogens (e.g., 1 or 2 hydrogens, or alternatively 1 hydrogen) on a specified group are replaced by a specified substituent (e.g., 1 or 2 substituents, or alternatively 1 substituent), provided that any atom with a substituent maintains an allowed valence. Substituent combinations only encompass stable compounds and stable synthetic intermediates. "Stable" means that a related compound or intermediate is robust enough to be isolated and has utility as a synthetic intermediate or as an agent with potential therapeutic utility. If a group is not described as "substituted" or "optionally substituted", the group will be considered unsubstituted (i.e., none of the hydrogens on the specified group are replaced).

[0303] The term "pharmaceutically acceptable" is used to specify that an object (e.g., salt, dosage form, diluent, or carrier) is suitable for use in a patient. An exemplary list of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P. H. Stahl and C. G. Wermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.

[0304] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid addition salts. Acid addition salts of compounds of formula (I) may be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to the skilled person.

[0305] The compounds described in this specification can form base addition salts. Base addition salts of compounds of formula (I) can be formed by contacting the compounds with a suitable inorganic base or organic base under conditions known to the skilled person.

[0306] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0307] In one embodiment, a compound of formula (I) is provided.

[0308] In one embodiment, a pharmaceutically acceptable salt of a compound of formula (I) is provided.

[0309] The compounds and salts described in this specification may exist in solvated and unsolvated forms. For example, the solvated form may be a hydrated form, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or an optional amount thereof. The present invention encompasses all such solvated and unsolvated forms of the compounds of formula (I), particularly to the extent that such forms have KCC2 modulating activity, as measured, for example, using the test described herein.

[0310] The atoms of the compounds and salts described in this specification may exist as their isotopes. All compounds of formula (I) in which atoms are replaced by one or more of their isotopes (e.g., in which one or more carbon atoms are 11 C or 13 C carbon isotope, or one or more of the hydrogen atoms is 2 H or 3 H isotope, or one or more nitrogen atoms are 15 N isotope or one or more of the oxygen atoms is 17 O or 18 O isotopes of compounds of formula (I)) are encompassed herein.

[0311] The compound of the present application can exist in one or more geometric forms, optical forms, enantiomeric forms and diastereomeric forms, including but not limited to cis-form and trans-form, E-form and Z-form and R-form, S-form and meso-form. Unless otherwise indicated, the reference to a particular compound includes all such isomeric forms, including racemic mixtures and other mixtures thereof. Where appropriate, such isomers can be separated from their mixtures by applying or adjusting known methods (such as chromatography techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by applying or adjusting known methods. In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (such as, racemates) by using, for example, chiral chromatography. In other embodiments, a single stereoisomer is obtained by directly synthesizing from, for example, chiral starting materials.

[0312] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is a single optical isomer in an enantiomeric excess (%ee) of ≥95%, ≥98% or ≥99%. In one embodiment, a single optical isomer is present in an enantiomeric excess (%ee) of ≥99%.

[0313] In one embodiment there is provided an N-oxide of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0314] A compound of formula (I), wherein R 7 Yes - NR 10 R 11 (i.e., R 7 Attached to an aliphatic N atom), can be prepared, for example, by reaction of a compound of formula (V) or a salt thereof with an amine:

[0315]

[0316]

[0317] Where R 1 , R 2 and A is as defined in any of the embodiments herein. The reaction is conveniently carried out in a suitable solvent and at a suitable temperature, for example diisopropylethylamine in dimethylsulfoxide at a temperature of 20°C to 100°C, or TsOH in butanol at 80°C.

[0318] When R 7 When attached via a carbon atom, compounds of formula (I) can be prepared by reaction of compounds of formula (V) with boronic acids or esters of formula (VI), wherein R 7As defined in any embodiment herein, and each R is the same or different and represents -H, an aliphatic chain, or wherein two R groups together with boron and two oxygen atoms form a ring. The reaction is conveniently carried out with a suitable base in the presence of a palladium catalyst and a solvent at a suitable temperature. For example, cesium carbonate or sodium carbonate and a palladium catalyst such as Pd(PPh3)4 in aqueous dioxane at a temperature in the range of 80°C-100°C.

[0319]

[0320] When R 7 When linked via an aromatic N atom, the compound of formula (I) can be linked to R 7 For example, by treating the generated imidazolium anion with a suitable base (such as sodium hydride) in a suitable solvent (such as dimethylformamide) and reacting it with a compound of formula (V).

[0321] The compound of formula (V) can be prepared from a compound of formula (VII) or a salt thereof and a compound of formula (VIII) or a salt thereof in a suitable solvent in the presence of a base (e.g., diisopropylethylamine in tert-butyl alcohol or dimethyl sulfoxide) and at a suitable temperature (e.g., 20° C. to 100° C.), wherein A in the compound of formula (VII) or a salt thereof is as defined in any embodiment herein, and R in the compound of formula (VIII) or a salt thereof is 1 and R 2 As defined in any embodiment herein.

[0322]

[0323]

[0324] The compound of formula (I) can also be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) and an amine R 7 The stepwise addition reaction of is prepared in one pot. The reaction is conveniently carried out in the presence of a base (eg, diisopropylethylamine) in a suitable solvent (dimethyl sulfoxide) at a suitable temperature (eg, a temperature of 20°C to 100°C).

[0325] Compounds of formula (VII) can be prepared, for example, from compounds of formula (IX). Suitable conditions for this transformation are heating in POCl3 at a temperature of about 80°C in the presence of an amine base such as diethylaniline.

[0326]

[0327] Compounds of formula (IX) can, for example, be prepared from compounds of formula (X) by reaction with propan-2-amine and formaldehyde in a suitable solvent (eg ethanol) at a suitable temperature (eg a temperature of 0°C to 80°C).

[0328]

[0329] The compound of formula (I), when R 5a and R 5b When both are H, it can also be prepared by reacting a compound of formula (XI) or a salt thereof with a suitable amine such as N,N-dimethylpropane-1,3-diamine. In the compound of formula (XI) or a salt thereof, R 1 , R 2 and R 7 As defined in any of the embodiments herein. Suitable conditions for the reaction are HCl in ethanol at a temperature of about 190°C in a sealed tube.

[0330]

[0331] It will be appreciated that some of the various ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications before or after the above-mentioned method, and are therefore included in the method aspects of the present invention. For example, compounds of formula (I) can be converted into compounds of other formula (I) by conventional functional group modifications. Such reactions and modifications include, for example, introducing substituents by means of aromatic substitution reactions, CH activation reactions, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the chemical field. Specific examples of aromatic substitution reactions include the introduction of halogen groups.

[0332] It will also be understood that in some of the reactions mentioned herein, it may be necessary / desirable to protect any sensitive groups in the compounds. The situations in which protection is necessary or desirable and the appropriate methods for protection are known to those skilled in the art. Conventional protecting groups can be used according to standard practice (illustrated in TW Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Therefore, if the reactant contains a group such as an amino, carboxyl or hydroxyl group, it may be desirable to protect the group in some of the reactions mentioned herein.

[0333] Compounds of formula (I), formula (II), formula (III) and formula (IV), as well as any intermediates used to prepare these compounds, can be prepared by methods analogous to those shown in the Examples section.

[0334] Compounds may also be selected based on additional biological or physical properties, which can be measured by techniques known in the art and which can be used to evaluate or select compounds for therapeutic or prophylactic applications.

[0335] Due to their KCC2 activating activity, the compounds of Formula (I) and their pharmaceutically acceptable salts are expected to be useful in therapy, for example, treating diseases or medical conditions mediated at least in part by KCC2, including neurological disorders such as epilepsy, pain, autism spectrum disorders, cognition, anxiety and amyotrophic lateral sclerosis.

[0336] Certain compounds described herein may be selective for other targets including P2X3.

[0337] The term "therapy" is intended to have the ordinary meaning of treating a disease so as to fully or partially alleviate one, some or all of the symptoms of the disease, or to correct or compensate for the underlying pathology. The term "treatment" also includes "prevention", unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0338] The term "prevention" is intended to have its ordinary meaning and includes: primary prevention to prevent the development of disease; and secondary prevention, whereby the disease has already developed and the patient is temporarily or permanently protected from an exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0339] The term "treatment" is used synonymously with "therapy." Similarly, the term "treatment" may be viewed as "applying treatment," wherein "treatment" is as defined herein.

[0340] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0341] In one embodiment, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[0342] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating a disease mediated by KCC2. In one embodiment, the disease mediated by KCC2 is a neurological disorder.

[0343] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating epilepsy. In one embodiment, epilepsy is selected from the group consisting of treating refractory epilepsy, status epilepticus, status epilepticus resistant to benzodiazepines (e.g., lorazepam or diazepam), status epilepticus caused by neurological agents or organophosphorus compounds (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, Jeavons syndrome, and myoclonic absence epilepsy.

[0344] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating pain. In one embodiment, the pain is selected from the group consisting of widespread pain, local pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neuropathic pain, central and peripheral neuropathy, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia, causalgia, allodynia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, pain caused by burns, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with fibromyalgia, pain associated with IBS, and pain associated with cancer.

[0345] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating an autism spectrum disorder. In one embodiment, the autism spectrum disorder is selected from autism, Asperger syndrome, childhood disintegrative disorder and Rett syndrome.

[0346] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a cognitive disorder. In one embodiment, the cognitive disorder is selected from the group consisting of amnesia, dementia and delirium.

[0347] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating anxiety.

[0348] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a motor neuron disease. In one embodiment, the motor neuron disease is amyotrophic lateral sclerosis.

[0349] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or disorder mediated by KCC2. In one embodiment, the disease or disorder mediated by KCC2 is epilepsy. In another embodiment, the disease or disorder mediated by KCC2 is pain. In another embodiment, the disease or disorder mediated by KCC2 is autism spectrum disorder. In another embodiment, the disease or disorder mediated by KCC2 is cognitive disorder. In another embodiment, the disease or disorder mediated by KCC2 is anxiety. In another embodiment, the disease or disorder mediated by KCC2 is amyotrophic lateral sclerosis.

[0350] The term "therapeutically effective amount" refers to an amount of a compound of formula (I) as described in any embodiment herein that is effective in providing "treatment" or "treating" a disease or disorder in a subject. In the case of a neurological disorder, a therapeutically effective amount may cause any observable or measurable change in a subject as described above in the definitions of "therapy", "treatment" and "prevention". As will be appreciated by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and co-use with other agents. For example, in the case of a combination therapy, the amount of the compound of formula (I) or a pharmaceutically acceptable salt described in this specification and the amount of other pharmaceutically active agents are combined to effectively treat the targeted disorder in an animal patient. In this case, if the amount of the combination is sufficient to reduce the symptoms of a disease or disorder in response to KCC2 activation as described above, the amount of the combination is a "therapeutically effective amount". Typically, such an amount can be determined by those skilled in the art, for example, starting from the dosage range described in this specification for the compound of formula (I) or its pharmaceutically acceptable salt and the approved or otherwise published dosage range of other pharmaceutically active compounds.

[0351] "Subject" includes, for example, humans.

[0352] In one embodiment, a method of treating a neurological disease or disorder selected from epilepsy, pain, autism spectrum disorder, cognition, anxiety and amyotrophic lateral sclerosis in a subject in need of such treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0353] In one embodiment, a method of treating epilepsy in a subject in need of such treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, a method of treating pain in a subject in need of such treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0354] In one embodiment, a method of treating an autism spectrum disorder in a subject in need of such treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0355] In one embodiment, a method of treating a cognitive disorder in a subject in need of such treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0356] In one embodiment, a method of treating anxiety in a subject in need of such treatment is provided, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0357] In one embodiment, a method of treating amyotrophic lateral sclerosis in a subject in need of such treatment is provided, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0358] In any embodiment referring to epilepsy in a general sense, the epilepsy can be selected from the group consisting of: refractory epilepsy, status epilepticus, status epilepticus resistant to benzodiazepines (e.g., lorazepam or diazepam), status epilepticus caused by neuroleptic agents or organophosphorus compounds (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, Jeavons syndrome, and myoclonic absence epilepsy.

[0359] In any embodiments referring to epilepsy in a general sense, the following embodiments may apply:

[0360] In one embodiment, the epilepsy is treatment of refractory epilepsy.

[0361] In one embodiment, the epilepsy is status epilepticus.

[0362] In one embodiment, the epilepsy is status epilepticus that is resistant to benzodiazepines (eg, lorazepam or diazepam).

[0363] In one embodiment, the epilepsy is status epilepticus induced by a neurological agent or an organophosphorus compound such as soman.

[0364] In one embodiment, the epilepsy is Dravet syndrome.

[0365] In one embodiment, the epilepsy is Lennox-Gastaut syndrome.

[0366] In one embodiment, the epilepsy is Doose syndrome.

[0367] In one embodiment, the epilepsy is Jeavons syndrome.

[0368] In one embodiment, the epilepsy is myoclonic absence epilepsy.

[0369] In any of the embodiments referring to pain in a general sense, the pain can be selected from the group consisting of widespread pain, localized pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neurogenic pain, central and peripheral neuropathy, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia to touch, causalgia, allodynia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, pain caused by burns, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with fibromyalgia, pain associated with IBS, and pain associated with cancer.

[0370] In any embodiments referring to pain in a general sense, the following embodiments may apply:

[0371] In one embodiment, the pain is widespread pain.

[0372] In one embodiment, the pain is local pain.

[0373] In one embodiment, the pain is nociceptive pain.

[0374] In one embodiment, the pain is central pain.

[0375] In one embodiment, the pain is central and peripheral neuropathic pain.

[0376] In one embodiment, the pain is diabetic neuropathic pain.

[0377] In one embodiment, the pain is central and peripheral neuropathic pain.

[0378] In one embodiment, the pain is central and peripheral neuropathic pain.

[0379] In one embodiment, the pain is lower back pain.

[0380] In one embodiment, the pain is postoperative pain.

[0381] In one embodiment, the pain is visceral pain.

[0382] In one embodiment, the pain is pelvic pain.

[0383] In one embodiment, the pain is pain to touch.

[0384] In one embodiment, the pain is anesthesia.

[0385] In one embodiment, the pain is burning pain.

[0386] In one embodiment, the pain is allodynia.

[0387] In one embodiment, the pain is fibromyalgia.

[0388] In one embodiment, the pain is hyperalgesia.

[0389] In one embodiment, the pain is hyperesthesia.

[0390] In one embodiment, the pain is hyperalgesia.

[0391] In one embodiment, the pain is ischemic pain.

[0392] In one embodiment, the pain is sciatica pain.

[0393] In one embodiment, the pain is pain caused by burns.

[0394] In one embodiment, the pain is pain associated with multiple sclerosis.

[0395] In one embodiment, the pain is pain associated with arthritis.

[0396] In one embodiment, the pain is pain associated with pancreatitis.

[0397] In one embodiment, the pain is pain associated with psoriasis.

[0398] In one embodiment, the pain is pain associated with fibromyalgia.

[0399] In one embodiment, the pain is pain associated with IBS.

[0400] In one embodiment, the pain is cancer-related pain.

[0401] In any of the embodiments referring generally to an autism spectrum disorder, the autism spectrum disorder may be selected from the group consisting of autism, Asperger's syndrome, childhood disintegrative disorder, and Rett syndrome.

[0402] In any of the embodiments referring generally to autism spectrum disorders, the following embodiments may apply:

[0403] In one embodiment, the autism spectrum disorder is autism.

[0404] In one embodiment, the autism spectrum disorder is Asperger's syndrome.

[0405] In one embodiment, the autism spectrum disorder is childhood disintegrative disorder.

[0406] In one embodiment, the autism spectrum disorder is Rett syndrome.

[0407] In any of the embodiments referring generally to a cognitive disorder, the cognitive disorder may be selected from the group consisting of amnesia, dementia, and delirium.

[0408] In any of the embodiments referring generally to anxiety, the anxiety may be selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and post-traumatic stress disorder.

[0409] In any of the embodiments referring generally to a motor neuron disease, the motor neuron disease may be amyotrophic lateral sclerosis.

[0410] The compounds of formula (I) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients.

[0411] Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0412] The excipient selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can be used as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, adhesives, disintegrants, lubricants, glidants, thickeners and coating agents. As will be appreciated by those skilled in the art, certain pharmaceutically acceptable excipients can play more than one role and can act as substitutes, depending on how much the excipient is present in the composition and what other excipients are present in the composition.

[0413] The pharmaceutical composition may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as finely divided powders or liquid aerosols), for administration by insufflation (e.g., as finely divided powders), or for parenteral administration (e.g., as sterile aqueous or oily solutions or suspensions for intravenous, subcutaneous or intramuscular administration), or as suppositories for rectal administration. The composition may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0414] The compound of formula (I) will usually be administered at 2.5-5000 mg / m 2 Unit doses in the range of about 0.05-100 mg / kg per animal body area or about are administered to warm-blooded animals, and this generally provides a therapeutically effective dose. Unit dosage forms, such as tablets or capsules, will generally contain, for example, 0.1-250 mg of active ingredient. The daily dose will necessarily vary depending on the host being treated, the particular route of administration, any co-administered treatment, and the severity of the disease being treated.

[0415] The pharmaceutical compositions described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.

[0416] Thus, in one embodiment, there is provided a pharmaceutical composition for use in therapy, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0417] In one embodiment, a pharmaceutical composition for use in treating a disease or condition in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0418] In one embodiment, a pharmaceutical composition for use in treating epilepsy is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0419] In one embodiment, a pharmaceutical composition for use in treating epilepsy in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0420] In one embodiment, a pharmaceutical composition for use in the treatment of refractory epilepsy, status epilepticus, status epilepticus resistant to benzodiazepines (e.g., lorazepam or diazepam), status epilepticus caused by neurological agents or organophosphorus compounds (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, Jeavons syndrome, and myoclonic absence epilepsy is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0421] In one embodiment, a pharmaceutical composition for use in treating pain is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0422] In one embodiment, a pharmaceutical composition for use in the treatment of pain in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0423] In one embodiment, a pharmaceutical composition is provided for use in treating widespread pain, local pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neurogenic pain, central and peripheral neuropathy, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia to pain, causalgia, allodynia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, pain caused by burns, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with IBS, and pain associated with cancer, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0424] In one embodiment, a pharmaceutical composition for use in treating autism spectrum disorders is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0425] In one embodiment, a pharmaceutical composition for use in treating an autism spectrum disorder in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0426] In one embodiment, a pharmaceutical composition for use in treating autism, Asperger's syndrome, childhood disintegrative disorder or Rett syndrome is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0427] In one embodiment, a pharmaceutical composition for use in treating cognitive disorders is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0428] In one embodiment, a pharmaceutical composition for use in treating a cognitive disorder in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0429] In one embodiment, a pharmaceutical composition for use in treating amnesia, dementia or delirium is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0430] In one embodiment, a pharmaceutical composition for use in treating anxiety is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0431] In one embodiment, a pharmaceutical composition for use in the treatment of anxiety in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0432] In one embodiment, a pharmaceutical composition for use in treating generalized anxiety disorder, panic disorder, obsessive compulsive disorder, or post-traumatic stress disorder is provided.

[0433] In one embodiment, a pharmaceutical composition for use in treating amyotrophic lateral sclerosis is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0434] In one embodiment, a pharmaceutical composition for use in treating amyotrophic lateral sclerosis in which KCC2 activation is beneficial is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0435] In one embodiment, a pharmaceutical composition for use in treating amyotrophic lateral sclerosis is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Example

[0436] Various embodiments of the present specification are illustrated by the following examples. The present specification should not be construed as being limited to the examples.

[0437] General experimental details

[0438] Unless otherwise stated:

[0439] (i) Unless otherwise stated, all syntheses were carried out at ambient temperature, i.e. in the range of 17°C to 25°C and under an atmosphere of an inert gas such as nitrogen;

[0440] (ii) evaporation by rotary evaporation or in vacuo using a Genevac apparatus or Biotage v10 evaporator and work-up procedures after removal of residual solids by filtration;

[0441] (iii) flash column chromatography on Merck Kieselgel silica (Art. 9385) or on reverse phase silica (Fluka silica gel 90C18) or on a Silicycle column (40-63 μm silica, 4 g to 330 g weight) or on a Graceresolv column (4 g-120 g) or on a RediSep Rf 1.5 flash column or on a RediSep Rf High Efficiency Gold flash column (150 g-415 g weight) or on a RediSep Rf Gold C18 reverse phase column (20-40 μm silica) either manually or automatically using an Isco CombiFlash Companion system or similar system;

[0442] (iv) Preparative HPLC conditions A: Xselect CSH OBD column 30 x 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm.

[0443] Preparative HPLC conditions B: XBridge Preparative OBD C18 column 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm.

[0444] Preparative HPLC conditions C: XBridge preparative OBD C18 column 30×150 mm, 5 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm.

[0445] Preparative HPLC conditions D: XBridge preparative OBD C18 column 30×150 mm, 5 μm; mobile phase A: water (10 mL NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm.

[0446] (v) the yield, where it exists, is not necessarily the maximum achievable;

[0447] (vi) Unless otherwise stated, 1H NMR spectra were obtained using a Bruker 300 MHz, 400 MHz or 500 MHz spectrometer at 25°C; chemical shifts are expressed in parts per million (ppm, delta units) and are referenced to the residual mono 1H isotope of the solvent (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in Hertz (Hz). Splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and brs (broad singlet).

[0448] (vii) Typically, the final product of formula (I) is also characterized by mass spectrometry after liquid chromatography (LCMS or UPLC); typically reverse phase C18 silica is used with a flow rate of 1 mL / min and detection is performed by electrospray mass spectrometry and UV absorbance recording wavelength range 220 nm to 320 nm. Analytical UPLC is performed on CSH C18 reverse phase silica using a Waters XSelect CSH C18 column with dimensions 2.1×50 mm and a particle size of 1.7 microns. Gradient analysis is performed using a mixture of decreasing polarity as the eluent, such as a mixture of decreasing polarity of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B. A typical 2-minute analytical UPLC method will use a solvent gradient over 1.3 minutes, at about 1 mL per minute, from a mixture of 97:3 solvent A and solvent B, respectively, to a mixture of 3:97 solvent A and solvent B. Unless otherwise stated, the reported molecular ions correspond to [M+H] + ; For molecules with multiple isotopic patterns (Br, Cl, etc.), unless otherwise stated, the reported values ​​are those obtained for the lowest isotopic mass;

[0449] (viii) where the reaction involves the use of microwaves, one of the following microwave reactors is used: BiotageInitiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator, or CEM Explorer;

[0450] (ix) assessing intermediate purity by thin layer chromatography, mass spectrometry, LCMS, UPLC / MS, HPLC and / or NMR analysis;

[0451] (x) Where compounds are presented as individual stereoisomers, it will be understood that the absolute stereochemistry has not been determined and reference to each individual stereoisomer also encompasses reference to alternate stereoisomers and racemic forms;

[0452] (xi) The following abbreviations have been used:

[0453] abbreviation:

[0454]

[0455]

[0456] Synthesis of intermediates

[0457] Intermediate 1: 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0458]

[0459] Intermediate 1, Step 1: 2,4-Dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0460]

[0461] At 0 ° C, propan-2-amine (136mL, 1601.57mmol) was added dropwise to 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (50g, 320.31mmol) and formaldehyde solution (120mL, 1601.57mmol) in ethanol (800mL). The resulting solution was stirred at 80 ° C for 16h. The reaction mixture was cooled in an ice bath, and the white solid was collected by filtration and washed with ethanol to give a rough intermediate (45g) as a solid. 2-Methoxyethanol (250mL) and 12N HCl (25mL, 822.86mmol) were added to the above rough intermediate (45g). The reaction mixture was refluxed for 16 h, cooled in an ice bath, and the solid was collected by filtration and washed with ethanol to give 2,4-dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (35.0 g, 52.2%) as a solid. 1 H NMR (400MHz, DMSO-d6) δ 11.81 (s, 1H), 11.26 (s, 1H), 4.27 (p, J = 6.7Hz, 1H), 4.14 (s, 2H), 1.20 (d, J = 6.7Hz, 6H).

[0462] Intermediate 1, Step 2: 2,4-Dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0463]

[0464] At 0 ℃ under nitrogen in the time period of 20 minutes, N, N- diethylaniline (67.1mL, 418.25mmol) is added dropwise to 2,4- dihydroxy -6- isopropyl -5,6- dihydro -7H- pyrrolo [3,4-d] pyrimidin -7- one (35g, 167.30mmol) in POCl (300mL). The resulting solution is stirred at 80 ℃ for 2.5 hours, and then concentrated under reduced pressure, wherein toluene is co-evaporated to remove any trace of phosphorus oxychloride. The residue is poured onto crushed ice, and 30% NH OH is used at 0 ℃, the pH of the mixture is adjusted to pH 6 and extracted with EtOAc (3x 400mL). The organic layers are merged and washed with brine (200mL). The organic layer is dried over Na SO , filtered and evaporated to provide a dark oil. The crude product was purified by flash silica gel chromatography with an elution gradient of 25% to 30% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to afford 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (23.40 g, 56.8%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ4.58 (s, 2H), 4.45 (p, J = 6.7Hz, 1H), 1.27 (d, J = 6.8Hz, 6H). ES+m / z[M+H] + :246,HPLC t R =0.92min (99.0%).

[0465] Intermediate 2: 2,4-dichloro-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0466]

[0467] 2,4-Dichloro-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one was prepared using the method described for Intermediate 1. 1 H NMR (300MHz, CD3OD) δ1.31 (t, J=7.3, 7.3Hz, 3H), 3.73 (q, J=7.3, 7.3, 7.3Hz, 2H), 4.63 (s, 2H). ES+m / z[M+H] + :232,HPLC t R =1.10min (99.0%).

[0468] Intermediate 3: 2-Chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0469]

[0470] DIEA (3.55 mL, 20.32 mmol) was added to 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (5.0 g, 20.32 mmol) and 4-cyclohexylaniline (3.56 g, 20.32 mmol) in tBuOH (100 mL) at room temperature. The resulting solution was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature. The precipitate was collected by filtration, washed with water (100 mL) and Et2O (50 mL) and dried under vacuum to provide 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (7.00 g, 90%) as a white solid, which was used without further purification. 1 H NMR (400MHz, DMSO) δ1.25(m,8H),1.32-1.47(m,4H),1.72(d,J=12.7Hz,1H),1.81(d,J=9.6 Hz,4H),4.37(s,2H),4.36-4.47(m,1H),7.23-7.31(m,2H),7.56-7.62(m,2H),9.93(s,1H). ES+m / z[M+H] + :385,HPLC t R =1.32min (98.0%).

[0471] Intermediate 4: 2-Chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0472]

[0473] 2-Chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one was prepared using the method described for Intermediate 3. 1 H NMR(400MHz,DMSO)δ1.22(d,J=6.8Hz,6H),1.25(d,J=6.7Hz,6H),2.82-2.97(m,1H) ,4.36(s,2H),4.36-4.47(m,1H),7.25-7.32(m,2H),7.56-7.63(m,2H),9.94(s,1H). ES+m / z[M+H] + :345,HPLC t R=0.98min (84.3%).

[0474] Intermediate 5: 4′-(hept-6-yn-1-yloxy)-[1,1′-biphenyl]-4-amine

[0475]

[0476] Intermediate 5, Step 1: tert-Butyl (4'-hydroxy-[1,1'-biphenyl]-4-yl)carbamate

[0477]

[0478] Di-tert-butyl dicarbonate (0.860 g, 3.94 mmol) was added to 4′-amino-[1,1′-biphenyl]-4-ol (0.73 g, 3.94 mmol), DIEA (2.065 mL, 11.82 mmol) in DMF (10 mL) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with DCM (50 mL), then washed with water (3×50 mL) and saturated brine (50 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 20% MeOH in DCM. The pure fractions were evaporated to dryness to provide tert-butyl (4′-hydroxy-[1,1′-biphenyl]-4-yl)carbamate (0.462 g, 41.1%) as a yellow solid. 1 HNMR (300MHz, DMSO) δ1.46(s,9H),6.74-6.83(m,2H),7.36-7.51(m,6H),9.35(s,1H),9.44(s,1H). ES + m / z[M-tBu] + :230,HPLC t R =1.33min (97.0%).

[0479] Intermediate 5, Step 2: tert-butyl (4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-yl)carbamate

[0480]

[0481] Methanesulfonic acid hept-6-alkyne-1-ester (160mg, 0.84mmol) was added to (4'-hydroxy-[1,1'-biphenyl]-4-yl) tert-butyl carbamate (200mg, 0.70mmol) and K2CO3 (194mg, 1.40mmol) in DMF (2mL). The resulting mixture was stirred at 60°C for 14h. The reaction mixture was diluted with water, extracted with DCM, and the organic layer was dried over Na2SO4, filtered and evaporated to provide a yellow liquid. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. The pure fraction was evaporated to dryness to provide tert-butyl (4'-(hept-6-alkyne-1-yloxy)-[1,1'-biphenyl]-4-yl) carbamate (300mg, 113%) as a yellow solid. 1 H NMR(300MHz,DMSO)δ1.47(s,9H),1.45-1.55(m,4H),1.68-1.74(m,3H),2.14-2.22(m,1H),2. 75(t,J=2.7Hz,1H),3.97(t,J=6.4Hz,2H),6.91-7.01(m,2H),7.45-7.56(m,6H),9.37(s,1H). ES + m / z[M-tBu] + :324,HPLCt R =1.56min (97.0%).

[0482] Intermediate 5, Step 3: 4′-(hept-6-yn-1-yloxy)-[1,1′-biphenyl]-4-amine

[0483]

[0484] Tert-butyl (4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-yl)carbamate (300 mg, 0.79 mmol) was added to HCl in 1,4-dioxane (10 mL). The resulting mixture was stirred at room temperature for 2 h. The solid was dried under vacuum and 4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-amine (290 mg, 116%) was provided as a yellow solid. ES+m / z[M+H] + :280,HPLC t R =1.17min (95.4%).

[0485] Intermediate 6: 4′-(Heptyloxy)-[1,1′-biphenyl]-4-amine

[0486]

[0487] Intermediate 6, Step 1: 1-Bromo-4-(heptyloxy)benzene

[0488]

[0489] At room temperature, 4-bromophenol (1.932g, 11.17mmol) was added to 1-bromoheptane (2g, 11.17mmol) and K2CO3 (1.543g, 11.17mmol) in MeCN (30mL). The resulting mixture was stirred at 80°C for 16h. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 10% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to provide 1-bromo-4-(heptyloxy)benzene (2.80g, 92%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ0.89-0.97(m,3H),1.27-1.37(m,4H),1.33-1.42(m,2H),1.39-1.5 1(m,2H),1.74-1.85(m,2H),3.94(t,J=6.6Hz,2H),6.76-6.83(m,2H),7.34-7.43(m,2H).

[0490] Intermediate 6, Step 2: 4′-(Heptyloxy)-[1,1′-biphenyl]-4-amine

[0491]

[0492] Pd(PPh3)4 (0.426 g, 0.37 mmol) was added to 1-bromo-4-(heptyloxy)benzene (1 g, 3.69 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.808 g, 3.69 mmol) and K2CO3 (1.529 g, 11.06 mmol) in 1,4-dioxane (15 mL) and water (3 mL) at room temperature under nitrogen. The resulting mixture was stirred at 90 °C for 16 h. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to provide 4'-(heptyloxy)-[1,1'-biphenyl]-4-amine (0.302 g, 28.9%) as a yellow solid. 1H NMR (300MHz, DMSO) δ0.80-0.88(m,2H),1.24-1.30(m,8H),1.62-1.77(m,3H),3.94(t,J=6.5Hz,2H),5 .10(s,2H),6.58(d,J=8.5Hz,2H),6.90(d,J=8.8Hz,2H),7.25(d,J=8.5Hz,2H),7.40(d,J=8.8Hz,2H). ES + m / z[M+H] + :284,HPLC t R =1.18min (97.2%).

[0493] Intermediate 7: 4′-(2-(3-(but-3-yn-1-yl)-3H-diazirine-3-yl)ethoxy)-[1,1′-biphenyl]-4-amine

[0494]

[0495] Intermediate 7, Step 1: tert-Butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazain-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate

[0496]

[0497] 3-(but-3-alkynes-1-yl)-3-(2-iodoethyl)-3H-diazirine (300mg, 1.21mmol) is added to (4'-hydroxy-[1,1'-biphenyl]-4-yl) tert-butyl carbamate (414mg, 1.45mmol) and K2CO3 (334mg, 2.42mmol) in DMF (2mL). The resulting mixture is stirred at room temperature for 14h. The reaction mixture is diluted with water. The water layers are merged and washed with EtOAc (3×50mL). The solvent is removed under reduced pressure to give a crude product. The crude product is purified by flash silica gel chromatography, and the elution gradient is 0% to 9.8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazinin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate as a yellow solid (110 mg, 22%). 1H NMR (400MHz, DMSO) δ1.49(s,9H),1.68(t,J=7.4Hz,2H),1.90(t,J=6.1Hz,2H),2.03-2.09(m,2H),2.85(t,J= 2.6Hz, 1H), 3.86 (t, J = 6.1Hz, 2H), 6.94-7.02 (m, 2H), 7.49-7.53 (m, 4H), 7.56 (d, J = 2.9Hz, 2H), 9.40 (s, 1H). ES + m / z[M-tBu] + :350,HPLC t R =1.17min (89.1%).

[0498] Intermediate 7, Step 2: 4′-(2-(3-(But-3-yn-1-yl)-3H-diazain-3-yl)ethoxy)-[1,1′-biphenyl]-4-amine

[0499]

[0500] Tert-butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazirine-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate (110 mg, 0.27 mmol) was added to 4M HCl / dioxane (2 mL). The resulting mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure to give the crude product 4'-(2-(3-(but-3-yn-1-yl)-3H-diazirine-3-yl)ethoxy)-[1,1'-biphenyl]-4-amine (100 mg, 121%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.68(t,J=7.4Hz,2H),1.91(t,J=6.1Hz,2H),2.01-2.10(m,2H),2.86(t,J=2.7Hz,1H) ,3.87(t,J=6.0Hz,2H),6.99-7.06(m,2H),7.33(d,J=3.7Hz,2H),7.59-7.62(m,2H),7.67(d,J=2.1Hz,2H). ES+m / z[M+H] + :306,HPLC t R = 1.16 min (58.2%). The product was used without further purification.

[0501] Intermediate 8: tert-Butyl (2-((4'-amino-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate

[0502]

[0503] Pd(PPh3)4 (0.731 g, 0.63 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline (2.77 g, 12.65 mmol), tert-butyl (2-(4-bromophenoxy)ethyl)carbamate (4 g, 12.65 mmol) and Cs2CO3 (8.24 g, 25.30 mmol) in 1,4-dioxane (50 mL), water (10 mL) at room temperature under nitrogen. The resulting mixture was stirred at 80 ° C for 16 hours. The crude product was purified by flash silica gel chromatography with an elution gradient of 40% to 55% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (2-((4'-amino-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate (3.57 g, 86%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.40(s,9H),3.31(p,J=5.2,5.8Hz,2H),3.97(t,J=5.9Hz,2H),5.12(s,2H),6 .58-6.68(m,2H),6.89-6.97(m,2H),7.00(t,J=5.7Hz,1H),7.23-7.34(m,2H),7.40-7.48(m,2H). ES+m / z[M+H] + :329,HPLC t R =1.08min (95.0%).

[0504] Intermediate 9: 2-Chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0505]

[0506] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.890 g, 4.06 mmol) was added to 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1 g, 4.06 mmol) and DIEA (1.419 mL, 8.13 mmol) in DMSO (10 mL) at 25 °C and stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×50 mL), and the organic layer was dried over Na2SO4, filtered and evaporated to provide a yellow residue. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1.070 g, 61%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ1.24 (d, J = 6.7Hz, 6H), 1.37 (s, 12H), 4.25 (s, 2H), 4.63 (p, J=6.8Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.85 (d, J=8.1Hz, 2H), 7.97 (s, 1H). ES+m / z[M+H] + :429,HPLC t R =1.38min(71%).

[0507] Intermediate 10: 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0508]

[0509] Pd(PPh3)4 (256 mg, 0.22 mmol) was added to 2-chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (950 mg, 2.22 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (698 mg, 3.32 mmol) and Na2CO3 (470 mg, 4.43 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at 80°C for 3 hours. The solvent was removed by distillation under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (650 mg, 61.6%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ1.29(s,12H),1.38(s,6H),2.77(s,2H),3.78(t,J=5.4Hz,1H),3.94(t,J=5.5Hz,2H),4.2 2(q,J=2.8Hz,1H),4.42(d,J=3.0Hz,2H),4.63-4.77(m,1H),6.55(s,1H),7.55-7.60(m,2H),7.82-7.89(m,2H). ES+m / z[M+H] + :477,HPLC t R =1.21min (76.4%).

[0510] Intermediate 11: 6-isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0511]

[0512] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.890 g, 4.06 mmol) was added to 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1 g, 4.06 mmol) and DIEA (1.419 mL, 8.13 mmol) in DMSO (6 mL) at 25 °C. After stirring at room temperature for 16 hours, morpholine (0.708 g, 8.13 mmol) was added. The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3×50 mL), and the organic layer was dried over Na2SO4, filtered and evaporated to provide a yellow residue. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 8% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1.477 g, 76%) as a yellow solid. 1 HNMR (400MHz, DMSO) δ1.24 (d, J = 6.7Hz, 6H), 1.29 (s, 12H), 3.64-3.70 (m, 9H), 4.29 (s, 2H), 7.63-7.70 (m, 2H), 7.74-7.81 (m, 2H), 9.41 (s, 1H). ES+m / z[M+H] + :480,HPLC t R =1.30min(70.9%).

[0513] Intermediate 12: 1-Bromo-4-(prop-2-yn-1-yloxy)benzene

[0514]

[0515] At room temperature, 3-bromoprop-1-yne (0.825 g, 6.94 mmol) was added to 4-bromophenol (1.0 g, 5.78 mmol) and K2CO3 (1.598 g, 11.56 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 6% EtOAc in petroleum ether. The pure fraction was evaporated to dryness to provide 1-bromo-4-(prop-2-yne-1-yloxy)benzene (0.598 g, 49.0%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ2.55 (t, J = 2.4Hz, 1H), 4.70 (d, J = 2.4Hz, 2H), 6.85-6.93 (m, 2H), 7.38-7.47 (m, 2H).

[0516] Intermediate 13: 3-(2-(4-bromophenoxy)ethyl)-3-(but-3-yn-1-yl)-3H-diazirine

[0517]

[0518] 3-(but-3-yne-1-yl)-3-(iodoethyl)-3H-diazirine (300mg, 1.28mmol) is added to K2CO3(531mg, 3.85mmol) and 4-bromophenol (244mg, 1.41mmol) in MeCN (3mL). The resulting solution is stirred at room temperature for 1 hour. The reaction mixture is filtered through diatomaceous earth. The solvent is removed under reduced pressure. The crude product is purified by flash silica gel chromatography with an elution gradient of 0% to 10% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to provide 3-(2-(4-bromophenoxy)ethyl)-3-(but-3-yne-1-yl)-3H-diazirine (100mg, 26.6%) as a brown oil. 1 H NMR (300MHz, CDCl3) δ1.75(t,J=7.4Hz,2H),1.91(t,J=6.2Hz,2H),2.01(t,J=2.6Hz, 1H),2.05-2.13(m,2H),3.81(t,J=6.2Hz,2H),6.74-6.86(m,2H),7.34-7.45(m,2H). ES+m / z[M+H] + : Massless, HPLC t R=1.30min (99.0%).

[0519] Intermediate 14: tert-butyl (2-(4-bromophenoxy)ethyl)carbamate

[0520]

[0521] At room temperature, K2CO3 (3.00 g, 21.68 mmol) was added to 4-bromophenol (2.5 g, 14.45 mmol) and tert-butyl (2-bromoethyl)carbamate (3.89 g, 17.34 mmol) in DMF (30 mL). The resulting mixture was stirred at 60 ° C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined and washed with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide a colorless oil. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to provide tert-butyl (2-(4-bromophenoxy)ethyl)carbamate (4.37 g, 96%) as a white solid. 1 H NMR (400MHz, CDCl3) δ1.47 (s, 9H), 3.54 (q, J = 5.3Hz, 2H), 4.00 (t, J = 5.2Hz, 2H), 4.98 (s, 1H), 6.72-6.83 (m, 2H), 7.37-7.41 (m, 2H). ES+m / z[M-tBu] + :260,HPLC t R =1.46min (92%).

[0522] Intermediate 15: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one

[0523]

[0524] At room temperature, DIEA (0.598 mL, 3.42 mmol) was added to 2,4-dichlorofurano[3,4-d]pyrimidin-7(5H)-one (234 mg, 1.14 mmol) and 4-cyclohexylaniline (200 mg, 1.14 mmol) in DMSO (2 mL). The resulting mixture was stirred at room temperature for 16 h. (R)-2-methylmorpholine (115 mg, 1.14 mmol) was added to the above mixture. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered with water and ethyl acetate and evaporated to provide (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furano[3,4-d]pyrimidin-7(5H)-one (412 mg, 88%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.16(d,J=6.1Hz,3H),1.31-1.46(m,5H),1.77-1.82(m,5H),2.60-2.71(m,1H),2.99(t,J=11.4Hz,1H),3.43-3.55 (m,3H),3.91(d,J=10.8Hz,1H),4.40(dd,J=13.2,30.2Hz,2H),5.23(s,2H),7.23(d,J=8.3Hz,2H),7.62(d,J=8.2Hz,2H),9.53(s,1H). ES+m / z[M+H] + :409,HPLC t R =1.50min(81.4%).

[0525] Intermediate 16: (R)-4-((4-cyclobutylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one

[0526]

[0527] (R)-4-((4-cyclobutylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one was prepared from 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one using a method analogous to that described for Intermediate 15. 1H NMR (400MHz, DMSO) δ1.16 (d, J = 6.2Hz, 3H), 1.75-1.87 (m, 1H), 1.88-2.04 (m, 1H) ),2.01-2.16(m,2H),2.22-2.34(m,2H),2.65(dd,J=10.4,13.1Hz,1H),2.92-3. 04(m,1H),3.47-3.51(m,3H),3.86-3.94(m,1H),4.36(d,J=13.1Hz,1H),(d,J= 13.1Hz, H), 5.22 (s, 2H), 7.22-7.27 (m, 2H), 7.63 (d, J = 8.4Hz, 2H), 9.53 (s, 1H). ES+m / z[M+H] + :381,HPLC t R =1.58min (90.7%).

[0528] Intermediate 17: 4-((4-isopropylphenyl)amino)-2-morpholinofurano[3,4-d]pyrimidin-7(5H)-one

[0529]

[0530] Prepared using a method analogous to that described for Intermediate 15: 4-((4-isopropylphenyl)amino)-2-morpholinofurano[3,4-d]pyrimidin-7(5H)-one. 1 H NMR (400MHz, DMSO) δ1.21 (d, J = 6.9 Hz, 6H), 2.88 (p, J = 6.9 Hz, 1H), 3.63-3.75 (m, 8H), 5.23 (s, 2H), 7.21-7.29 (m, 2H), 7.61-7.67 (m, 2H), 9.51 (s, 1H). ES+m / z[M+H] + :355,HPLC t R =1.46min (97.3%).

[0531] Synthesis of Examples

[0532] Example 1: 2-(Diethylamino)-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0533]

[0534] DIEA (0.152 mL, 0.87 mmol) was added to diethylamine (63.6 mg, 0.87 mmol) and 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.29 mmol) in DMSO (5 mL). The resulting mixture was stirred at 100 °C for 4 hours. The crude product was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide 2-(diethylamino)-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (70.0 mg, 63%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.14(t,J=6.9Hz,6H),1.22(m,12H),2.79-2.92(m,1H),3.60(q, J=7.0Hz,4H),4.24(s,2H),4.36-4.48(m,1H),7.20(d,2H),7.75(d,2H),9.03(s,1H). m / z(ES+),[M+H] + :382; HPLC t R =1.73min.

[0535] Example 2: 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0536]

[0537] 2-Cyclopropylmorpholine (49.6 mg, 0.39 mmol) was added to 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol) and DIEA (0.091 mL, 0.52 mmol) in DMSO (2 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. The crude product was purified by preparative HPLC condition D. The fractions containing the desired compound were evaporated to dryness to provide 4-((4-cyclohexylphenyl)amino-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (60.0 mg, 48.6%) as a white solid. 1H NMR (400MHz, DMSO) δ0.22-0.37(m,2H),0.44-0.55(m,2H),0.84-0.96(m,1H),1.23(d,J=6. 8Hz,7H),1.30-1.47(m,4H),1.75(dd,J=35.9,10.9Hz,5H),2.47(s,1H),2.70-2.86(m,2H), 2.98(td,J=12.5,11.8,3.4Hz,1H),3.40(td,1H),3.90(dd,1H),4.25(s,2H),4.33(d,J=13. 1Hz, 1H), 4.37-4.47 (m, 1H), 4.52 (d, J = 12.5Hz, 1H), 7.19 (d, 2H), 7.63 (d, 2H), 9.19 (s, 1H). m / z(ES+),[M+H] + :476; HPLC t R =2.37min (99.8%).

[0538] The enantiomers of 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one were separated using preparative chiral-HPLC: column: (R,R) WHELK-01, 5 / 100 Kromasil, 2.11 cm x 25 cm (5 μm); mobile phase A: Hex (8 mM NH3.MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; 40% B over 20 min; detection at 254 / 220 nm; isomer 1, t R 1 = 13.818 min; Isomer 2, t R 2 = 16.895 min. The data for Isomer 1 (Example 15) and Isomer 2 (Example 14) are shown in Table 1.

[0539] The examples in Table 1 were prepared in a similar manner to Examples 1 and 2 from Intermediate 3 and Intermediate 4.

[0540] Table 1:

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552] Example 40: 6-isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0553]

[0554] Pd(PPh3)4(67.0mg, 0.06mmol) was added to 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (200mg, 0.58mmol), pyridin-4-ylboronic acid (86mg, 0.70mmol) and Cs2CO3(378mg, 1.16mmol) in 1,4-dioxane (5mL), water (1mL) at room temperature under nitrogen. The resulting solution was stirred at 100°C for 3 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 3% to 5% DCM in MeOH. The pure fractions were evaporated to dryness to provide the product as a yellow solid. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to afford 6-isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 44.5%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.27 (dd, J=15.8, 6.8Hz, 12H), 2.85-2.99 (m, 1H), 4.44-4.5 3(m,3H),7.34(dd,2H),7.81(dd,2H),8.23(dd,2H),8.77(dd,2H),9.70(s,1H). m / z(ES+),[M+H] + :388; HPLC t R =1.358min (98.8%).

[0555] Example 41: 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)pyridinecarbonitrile

[0556]

[0557] Pd(PPh3)4 (30.0 mg, 0.03 mmol) was added to Cs2CO3 (169 mg, 0.52 mmol), 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol) and 2-cyanopyridin-4-ylboronic acid (90 mg, 0.39 mmol) in 1,4-dioxane (2 mL), water (0.400 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100 ° C for 6 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)pyridinecarbonitrile as a crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to afford 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)pyridinecarbonitrile (20.10 mg, 17%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.29(d,J=6.7Hz,7H),1.36-1.51(m,4H),1.73(d,J=11.9Hz,1H),1.83(s,4H),4.42-4.54(m,3H) ,7.31(d,J=8.1Hz,2H),7.74(d,J=8.1Hz,2H),8.49(d,J=5.7Hz,1H),8.62(s,1H),8.95(d,J=5.1Hz,1H),9.80(s,1H). m / z(ES+)[M+H] + :453; HPLC t R =2.976min (99.3%).

[0558] The examples in Table 2 were prepared from Intermediate 3 and Intermediate 4 and the appropriate boric acid ester or acid according to the procedures of Example 40 and Example 41.

[0559] Table 2:

[0560]

[0561]

[0562]

[0563]

[0564] Example 51: (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0565]

[0566] At room temperature, 4-(4-fluorophenoxy)aniline (83 mg, 0.41 mmol) was added to 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.41 mmol) and DIEA (0.213 mL, 1.22 mmol) in DMSO (2 mL). The resulting mixture was stirred at 40 ° C for 16 hours. At room temperature, (R)-2-methylmorpholine (41.1 mg, 0.41 mmol) was added to the reaction. The resulting mixture was stirred at 100 ° C for 16 hours. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (63.0 mg, 32.5%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.15(d,J=6.2Hz,3H),1.24(d,J=6.7Hz,6H),2.61(dd,J=13.1,10.4Hz,1H),2.88-3.00(m,1H),3.44-3.54(m,2H), 3.89(d,J=9.3Hz,1H),4.26(s,2H),4.31-4.46(m,3H),6.99-7.11(m,4H),7.18-7.29(m,2H),7.74(dd,J=9.2,3.0Hz,2H),9.30(s,1H). m / z(ES+),[M+H] + :478; HPLC t R =1.946min (98%).

[0567] The examples in Table 3 were prepared from Intermediate 1 or Intermediate 2 according to procedures similar to those described above and the appropriate amine, which was either commercially available or described in the Intermediates section.

[0568] Table 3:

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] Example 69: tert-Butyl (2-((4′-((6-isopropyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-4-yl)oxy)ethyl)carbamate

[0577]

[0578] Pd(dppf)Cl2 (15.26 mg, 0.02 mmol) was added to Cs2CO3 (136 mg, 0.42 mmol), tert-butyl (2-(4-bromophenoxy)ethyl)carbamate (99 mg, 0.31 mmol) and 6-isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.21 mmol) in dioxane (5 mL) and water (1.000 mL) at 25°C under air. The resulting mixture was stirred at 100°C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 8% MeOH in DCM to give a yellow oil. The oily product was purified by preparative HPLC condition C. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (2-((4'-((6-isopropyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate as a grey solid (56.5 mg, 46.0%).1 H NMR (400MHz, DMSO) δ1.25(d,J=6.8Hz,6H),1.40(s,9H),3.13(d,J=5.8Hz,2H),3.70(dd,J=12.4,4.4Hz,8H),4.00(t,J =5.8Hz,2H),4.30(s,2H),4.29-4.43(m,1H),6.96-7.09(m,3H),7.62(t,J=8.6Hz,4H),7.77-7.85(m,2H),9.34(s,1H). m / z(ES+),[M+H] + :589; HPLC t R =1.79min (99.4%).

[0579] The examples in Table 4 were prepared from intermediate 11 and the appropriate bromide according to the procedure of Example 69.

[0580] Table 4:

[0581]

[0582]

[0583] Example 72: (R)-4-((4-cyclohexylphenyl)amino)-6-(3-(dimethylamino)propyl)-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0584]

[0585] HCl (0.191 mL, 2.20 mmol) was added to N1, N1-dimethylpropane-1,3-diamine (75 mg, 0.73 mmol) and (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furano[3,4-d]pyrimidin-7(5H)-one (100 mg, 0.24 mmol) in 2-(2-methoxyethoxy)ethanol (2 mL). The resulting mixture was stirred at 190 ° C for 4 hours. The reaction mixture was diluted with water (100 mL), extracted with DCM (3×200 mL), and washed with water (100 mL) and saturated brine (100 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-((4-cyclohexylphenyl)amino)-6-(3-(dimethylamino)propyl)-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (21.0 mg, 14%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.16(d,J=6.2Hz,3H),1.23(d,J=10.9Hz,1H),1.32-1.47(m,4H),1.71(d,J= 12.7Hz,1H),1.79(d,J=9.9Hz,4H),1.92-2.02(m,2H),2.47(s,1H),2.53-2.68(m,1H),2.78(d,6 H),2.95(td,J=12.6,12.1,3.4Hz,1H),3.01-3.11(m,2H),3.42-3.55(m,2H),3.61(t,J=12.9Hz, 2H),3.90(dd,1H),4.33(s,3H),4.43(s,1H),7.20(d,2H),7.63(d,2H),9.28(s,1H),9.43(s,1H). m / z(ES+),[M+H] + :493; HPLC t R =1.614min (95%).

[0586] The examples in Table 5 were prepared by procedures similar to those used in Example 72 using Intermediate 15, Intermediate 16 or Intermediate 17.

[0587] Table 5:

[0588]

[0589]

[0590]

[0591] Example 78: 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0592]

[0593] Palladium on carbon (73.8 mg, 0.07 mmol) was added to 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (300 mg, 0.69 mmol) in MeOH (10 mL) at room temperature under hydrogen. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through celite. The crude product was purified by preparative HPLC condition C. The fractions containing the desired compound were evaporated to dryness to provide 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (68.0 mg, 22%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.25(d,J=6.7Hz,7H),1.32-1.48(m,4H),1.71(d,J=12.6Hz,1H),1.75-1.91(m,8H),2.46(d,J=10.7Hz,1H),2.92-3 .04(m,1H),3.40-3.51(m,2H),3.90-3.99(m,2H),4.35(s,2H),4.44(p,J=6.7Hz,1H),7.18-7.26(m,2H),7.71-7.79(m,2H),9.42(s,1H). ES + m / z[M+H] + :435,HPLCt R =1.855min (99.8%).

[0594] Example 79: 4-((4-cyclohexylphenyl)amino)-2-(1H-imidazol-1-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0595]

[0596] NaH (31.2 mg, 0.78 mmol) was added to 1H-imidazole (53 mg, 0.78 mmol) and 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol) in DMF (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 14 hours. The crude product was purified by preparative HPLC column: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution, detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to afford 4-((4-cyclohexylphenyl)amino)-2-(1H-imidazol-1-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (10.0 mg, 9%) as a white solid. 1 HNMR(DMSO-d6,400MHz)δ1.28(d,J=6.8Hz,7H),1.31-1.51(m,4H),1.72(d,J=12.5Hz,1H),1.83(d,J=9.0Hz,4H),2.51(s,1H),4.41-4. 52(m,3H),7.13(d,J=1.2Hz,1H),7.28-7.36(m,2H),7.65-7.72(m,2H),7.86(t,J=1.4,1.4Hz,1H),8.47(d,J=1.1Hz,1H),9.91(s,1H). ES + m / z[M+H] + :417,HPLC t R =1.655min (99.3%).

[0597] Example 80: 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0598]

[0599] Pd(dppf)Cl2 (30.7 mg, 0.04 mmol) was added to 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (200 mg, 0.42 mmol), 1-bromo-2-toluene (108 mg, 0.63 mmol) and Cs2CO3 (274 mg, 0.84 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100°C for 2 hours. The solvent was removed by distillation under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to provide a yellow oil. The crude product was purified by preparative HPLC condition A. The fractions containing the desired compound were evaporated to dryness to provide 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (25.0 mg, 13%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ1.28(d,J=6.7Hz,6H),2.29(s,3H),2.62(s,2H),3.83(t,J=5.4,5.4Hz,2H),4.32(q,J=2.8,2.8,2 .8Hz,2H),4.38-4.58(m,3H),7.19(d,J=2.8Hz,1H),7.20-7.34(m,4H),7.34-7.42(m,2H),7.90-7.97(m,2H),9.59(s,1H). ES + m / z[M+H] + :441,HPLC t R =1.796min (98.6%).

[0600] Example 81: 4-((4′-(2-(3-(But-3-yn-1-yl)-3H-diazain-3-yl)ethoxy)-[1,1′-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0601]

[0602] Example 81, Step 1: 2-(3,6-dihydro-2H-pyran-4-yl)-4-((4'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0603]

[0604] Pd(dppf)Cl2 (100 mg, 0.14 mmol) was added to 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (650 mg, 1.36 mmol), 4-bromophenol (283 mg, 1.64 mmol) and Cs2CO3 (889 mg, 2.73 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100° C. under nitrogen for 2.5 hours. The crude product was purified by flash silica gel chromatography with a gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-(3,6-dihydro-2H-pyran-4-yl)-4-((4′-hydroxy-[1,1′-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (210 mg, 35%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.28(d,J=6.7Hz,6H),2.62(s,2H),3.84(t,J=5.4Hz,2H),3.94(s,2H),4.33(d,J=2.8Hz,2H),4.44(m,1H),6. 84(d,J=8.7Hz,2H),7.19(d,J=2.7Hz,1H),7.49-7.56(m,2H),7.62(d,J=8.7Hz,2H),7.87-7.93(m,2H),9.50(s,1H),9.54(s,1H). ES + m / z[M+H] + :443; HPLC t R =1.175min (95.4%).

[0605] Example 81, Step 2: 4-((4′-(2-(3-(But-3-yn-1-yl)-3H-diazinin-3-yl)ethoxy)-[1,1′-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0606]

[0607] 3-(But-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (188 mg, 0.76 mmol) was added to K2CO3 (105 mg, 0.76 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4-((4'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (168 mg, 0.38 mmol) in DMF (2 mL) at room temperature under air. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to provide a crude product. The crude product was purified by preparative HPLC column: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase A: water (10 mM ammonium formate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution, detection at 254 / 220 nm. The fractions containing the desired compound were evaporated to dryness to provide 4-((4'-(2-(3-(but-3-yn-1-yl)-3H-diazirine-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (6.2 mg, 2.9%) as a yellow solid. 1 H NMR (400MHz, MeOD) δ1.38(d,J=6.7Hz,6H),1.73(t,J=7.5Hz,2H),1.91(t,J=6.0Hz,2H),2.05-2.15(m,2H),2.30(t,J=2.7Hz,1H),2.73(s,2H), 3.86-3.96(m,4H),4.34-4.47(m,4H),4.53-4.66(m,1H),6.98(d,J=8.7 Hz, 2H), 7.27 (s, 1H), 7.57 (dd, J = 8.6, 7.0Hz, 4H), 7.87 (d, J = 8.5Hz, 2H). ES +m / z[M+H] + :563,HPLC t R =3.053min (95.9%).

[0608] Example 82: 2-(3,6-dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0609]

[0610] Example 82, Step 1: 2-Chloro-4-((2-fluoro-[1,1′-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0611]

[0612] DIEA (0.426 mL, 2.44 mmol) was added to 2-fluoro-[1,1′-biphenyl]-4-amine (228 mg, 1.22 mmol) and 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (300 mg, 1.22 mmol) in DMSO (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The crude product was purified by C18-flash chromatography with an elution gradient of 90% to 100% MeOH in water (0.1% formic acid). The pure fractions were evaporated to dryness to provide 2-chloro-4-((2-fluoro-[1,1′-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (150 mg, 31.0%) as a white solid. m / z(ES+),[M+H] + =397; HPLC t R =1.402min.

[0613] Example 82, Step 2: 2-(3,6-dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0614]

[0615] Pd(PPh3)4 (43.7 mg, 0.04 mmol) was added to 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.45 mmol), 2-chloro-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (150 mg, 0.38 mmol) and Cs2CO3 (246 mg, 0.76 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature under nitrogen. The resulting mixture was stirred at 80°C for 3 hours. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to provide a yellow solid. The crude product was purified by preparative HPLC: XSelect CSH PrepC18 OBD column, 5 μm, 50 mm diameter, 150 mm length, using a mixture of water (containing 0.1% formic acid) and acetonitrile of decreasing polarity as eluent. The fractions containing the desired compound were evaporated to dryness to provide 2-(3,6-dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (20.0 mg, 12%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.28(d,J=6.7Hz,6H),2.64(s,2H),3.85(t,J=5.4Hz,2H),4.34(d,J=3.0Hz,2H),4.47(d,J=6.1Hz,3H),7.20(s,1H), 7.34-7.43(m,1H),7.48(dd,J=8.4,6.9Hz,2H),7.53-7.62(m,3H),7.73(dd,J=8.6,2.1Hz,1H),8.02(dd,J=14.0,2.1Hz,1H),9.79(s,1H). ES + m / z[M+H] + :445,HPLC t R =2.977min (98.6%).

[0616] The examples in Table 6 were prepared by procedures similar to those described above.

[0617] Table 6:

[0618]

[0619]

[0620]

[0621] Example 90: (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

[0622]

[0623] At room temperature, 4-cyclohexylaniline (0.918 g, 5.24 mmol) was added to 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (1 g, 5.24 mmol) and DIEA (2.74 mL, 15.71 mmol) in DMSO (15 mL). The resulting mixture was stirred at 50 °C for 7 hours. (R)-2-methylmorpholine (0.635 g, 6.28 mmol) was added to the above mixture and stirred at 100 °C for 16 hours. The reaction mixture was purified by C18-flash chromatography with an elution gradient of 10% to 85% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (0.932 g, 45.1%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.13(d,J=6.1Hz,3H),1.18-1.25(m,1H),1.27-1.44(m,4H),1.70(d,J=12.7Hz, 1H),1.78(d,J=9.7Hz,4H),2.42-2.46(m,1H),2.57(dd,J=13.0,10.3Hz,1H),2.90(td,J=12.4,3.5H z,1H),3.37-3.56(m,2H),3.86(dd,J=11.3,3.2Hz,1H),4.30(d,J=13.2Hz,1H),4.38(d,J=12.6Hz,1 H), 4.68 (t, J = 2.3Hz, 2H), 4.87 (t, J = 2.4Hz, 2H), 7.12-7.19 (m, 2H), 7.52-7.60 (m, 2H), 8.76 (s, 1H). ES + m / z[M+H] + :395,HPLC t R =1.78min (99.6%).

[0624] Example 91: N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

[0625]

[0626] At room temperature, DIEA (0.069 mL, 0.39 mmol) was added to 2,4-dichloro-5,7-dihydrofurano[3,4-d]pyrimidine (50 mg, 0.26 mmol) and 4-cyclobutylaniline (38.5 mg, 0.26 mmol) in DMSO (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (2×25 mL), and the organic layer was dried over Na2SO4, filtered and evaporated to provide a crude intermediate. At 25 ° C under nitrogen, Pd (PPh 3) 4 (30.2 mg, 0.03 mmol) was added to Cs 2 CO 3 (171 mg, 0.52 mmol), (3,6-dihydro-2H-pyran-4-yl) boronic acid (50.2 mg, 0.39 mmol) and the crude intermediate in 1,4-dioxane (2.0 mL) and water (0.4 mL). The resulting mixture was stirred at 90 ° C for 3 hours. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (2 × 50 mL), and the organic layer was dried over Na 2 SO 4, filtered and evaporated to provide a crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to afford N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (40.0 mg, 43.7%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ1.75-1.87(m,1H),1.88-2.02(m,1H),2.02-2.16(m, 2H),2.28(qt,J=7.8,2.4Hz,2H),2.55(s,2H),3.49(p,J=8.8Hz,1H),3.80(t ,J=5.4Hz,2H),4.29(q,J=2.8Hz,2H),4.85(t,J=2.5Hz,2H),5.01(t,J=2.5H z,2H),7.06-7.12(m,1H),7.17-7.25(m,2H),7.65-7.73(m,2H),9.03(s,1H). ES + m / z[M+H] + :350,HPLC t R =1.72min (98.4%).

[0627] The compounds in Table 7 were prepared in a manner analogous to Example 91 and above using the appropriate intermediates.

[0628] Table 7:

[0629]

[0630]

[0631]

[0632] Example 99: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine 8-oxide

[0633]

[0634] At room temperature under nitrogen, m-CPBA (222 mg, 1.29 mmol) was added to (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4-amine (130 mg, 0.32 mmol) in CHCl3 (3 mL). The resulting mixture was stirred at 60 ° C for 5 hours. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 6% MeOH in DCM. The pure fractions were evaporated to provide a yellow liquid. The crude product was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine 8-oxide (11.0 mg, 8%) as a yellow solid. 1 H NMR(400MHz,MeOD)δ1.15-1.39(m,5H),1.44-1.57(m,4H),1.80(d,J=12.6Hz,1H),1.90(d, J=8.3Hz,4H),2.56(s,1H),2.76(dd,J=13.4,10.3Hz,1H),3.11(d,J=11.3Hz,1H),3.60(s, 2H),3.97(d,J=11.0Hz,1H),4.61(s,1H),4.88-5.10(m,1H),7.14(dd,J=8.2,6.3Hz,1H),7 .28(d,J=8.5Hz,2H),7.61(d,J=8.4Hz,2H),8.33-8.39(m,1H),8.59(dd,J=6.4,1.3Hz,1H). ES + m / z[M+H] +:420,HPLC t R =1.73min (99.4%).

[0635] Example 100: (R)-N-(4-cyclohexylphenyl)-6-ethyl-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine

[0636]

[0637] Diethylzinc (0.118 mL, 0.41 mmol) was added to (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.41 mmol), Pd(dppf)Cl2 (303 mg, 0.41 mmol) in dioxane (2 mL) at room temperature under nitrogen. The resulting solution was stirred at 70 ° C for 5 hours. The reaction mixture was added to a silica gel column and eluted with 0%-10% MeOH in DCM to give a crude product as a yellow solid. The crude product was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide (R)-N-(4-cyclohexylphenyl)-6-ethyl-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (50.0 mg, 28%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ1.16 (d, J=6.2Hz, 3H), 1.21-1.29 (m, 2H), 1.26-1.49 (m, 6H), 1.71 (d, J= 12.4Hz,1H),1.81(d,J=8.8Hz,4H),2.43-2.50(m,1H),2.60-2.76(m,3H),2.92-3.04(m,1H),3. 43-3.56(m,2H),3.90(dd,J=11.5,3.0Hz,1H),4.47(d,J=13.0Hz,1H),4.56(d,J=13.1Hz,1H),7 .21-7.28(m,2H),7.66-7.73(m,2H),8.55(d,J=2.4Hz,1H),8.64(d,J=2.3Hz,1H),9.65(s,1H). ES + m / z[M+H] + :432,HPLC t R =1.70min (99.9%).

[0638] Example 101: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carbonitrile

[0639]

[0640] At room temperature under nitrogen, copper cyanide (111 mg, 1.24 mmol) was added to (R)-6-bromo-N-(4-cyclohexyl-phenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4-amine (200 mg, 0.41 mmol) in DMF (2 mL). The resulting mixture was stirred at 150 ° C for 6 hours. The reaction mixture was added to a silica gel column and eluted with 0%-10% MeOH in DCM to give a crude product as a yellow solid. The crude product was purified by preparative HPLC condition A. The fraction containing the desired compound was evaporated to dryness to provide (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carbonitrile (80 mg, 45.0%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ1.07-1.30(m,4H),1.30-1.61(m,4H),1.72(d,J=12.4Hz,1H) ,1.81(d,J=9.3Hz,4H),2.34-2.52(m,1H),2.73-2.87(m,1H),3.05-3.17(m,1H), 3.37-3.66(m,2H),3.90-3.98(m,1H),4.32-4.77(m,2H),7.29(d,J=8.6Hz,2H),7 .67(d,J=8.3Hz,2H),9.04(d,J=2.2Hz,1H),9.22(d,J=2.3Hz,1H),10.07(s,1H). ES + m / z[M+H] + :429,HPLC t R =3.35min (98.3%).

[0641] Example 102: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester

[0642]

[0643] Palladium acetate (0.023 g, 0.10 mmol) was added to DIEA (1.086 mL, 6.22 mmol), (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (1.0 g, 2.07 mmol) in MeOH (5.0 mL) and toluene (5.00 mL) at room temperature under carbon monoxide (60 atm). The resulting solution was stirred at 100 °C for 36 hours. The reaction mixture was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. Pure fractions were evaporated to dryness to provide a yellow solid.

[0644] The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to afford (R)-methyl 4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylate (25.0 mg, 42%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.08-1.30(m,4H),1.31-1.50(m,4H),1.65-1.88(m,5H),2.49-2.51(m,1H),2.70-2.77(m,1H),3.01-3.07(m,1H),3.44-3 .56(m,2H),3.92(s,4H),4.38-4.79(m,2H),7.22-7.29(m,2H),7.65-7 .74(m,2H),9.14(d,J=2.3Hz,1H),9.33(d,J=2.3Hz,1H),10.14(s,1H). ES + m / z[M+H] + :462,HPLC t R =1.74min (99.8%).

[0645] Example 103: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid

[0646]

[0647] (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester (150 mg, 0.32 mmol) was added to 1N HCl (2 mL) at room temperature under nitrogen. The resulting solution was stirred at 60 ° C for 16 hours. The crude product was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid (20.00 mg, 34.4%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.16 (d, J = 6.2Hz, 3H), 1.22-1.27 (m, 1H), 1.34-1.49 (m, 4H), 1. 64-1.89(m,5H),2.49-2.51(m,1H),2.69-2.74(m,1H),3.02-3.10(m,1H),3.44-3.5 4(m,2H),3.92(d,J=9.8Hz,1H),4.48-4.66(m,2H),7.25(d,J=8.5Hz,2H),7.67-7.7 4(m,2H),9.13(d,J=2.2Hz,1H),9.32(d,J=2.3Hz,1H),10.11(s,1H),13.16(s,1H). ES + m / z[M+H] + :448,HPLC t R =1.74min (98.1%).

[0648] Example 104: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide

[0649]

[0650] (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester (150 mg, 0.32 mmol) was added to NH3 in MeOH (4 mL) at room temperature under nitrogen. The resulting solution was stirred at 60 ° C for 16 hours. The crude reaction was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide (20.0 mg, 35%) as a yellow solid. 1H NMR (400MHz, DMSO) δ1.10-1.27(m,4H),1.31-1.49(m,4H),1.76(dd,J=10.9,3 7.6Hz,5H),2.33-2.50(m,1H),2.72(d,J=11.7Hz,1H),3.01-3.06(m,1H),3.4 2-3.59(m,2H),3.93(s,1H),4.53(s,2H),7.25(d,J=8.5Hz,2H),7.55(s,1H), 7.71(d,J=8.5Hz,2H),8.04(s,1H),9.19(dd,J=2.3,23.8Hz,2H),9.98(s,1H). ES + m / z[M+H] + :447,HPLC t R =1.42min (99.5%).

[0651] Example 105: 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide

[0652]

[0653] The title compound was prepared using the procedure described above for (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide. 1 H NMR(300MHz,DMSO)δ0.28(d,J=20.5Hz,2H),0.49(d,J=8.3Hz,2H),0.89(s,1H),1.30(d,J=47.9Hz,5H),1 .70(d,J=12.7Hz,1H),1.79(d,J=7.9Hz,4H),2.43-2.49(m,1H),2.71(s,1H),2.85-2.93(m,1H),3.02-3. 09(m,1H),3.31-3.45(m,1H),3.91(d,J=11.4Hz,1H),4.48(s,1H),4.64(s,1H),7.22(d,J=8.4Hz,2H),7. 52(s,1H),7.68(d,J=8.2Hz,2H),8.01(s,1H),9.13(d,J=2.2Hz,1H),9.18(d,J=2.3Hz,1H),9.97(s,1H). ES + m / z[M+H] + :473,HPLC t R =1.66min (99.4%).

[0654] Example 106: (R)-N-(4-cyclohexylphenyl)-6-methoxy-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine

[0655]

[0656] Quinoline-6-ol (60.2 mg, 0.41 mmol) was added to (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4-amine (200 mg, 0.41 mmol), cuprous (I) iodide (3.95 mg, 0.02 mmol) and tripotassium phosphate (176 mg, 0.83 mmol) in MeOH (6 mL) at room temperature under argon. The resulting mixture was stirred at 110 ° C for 24 hours. The reaction mixture was evaporated to dryness. The crude product was purified by C18-flash chromatography with an elution gradient of 50% to 100% MeOH in water (0.1% NH4HCO3). The pure fraction was evaporated to dryness to provide a yellow liquid. The yellow liquid obtained was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to afford (R)-N-(4-cyclohexylphenyl)-6-methoxy-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (10.0 mg, 5.5%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.16(d,J=6.2Hz,3H),1.25(d,J=9.7Hz,1H),1.31-1.50(m,4H),1.72(d,J =12.5Hz,1H),1.81(d,J=8.6Hz,4H),2.32-2.49(m,1H),2.62(dd,J=13.1,10.4Hz,1H),2.90-3. 01(m,1H),3.43-3.54(m,2H),3.91(s,4H),4.43(d,J=13.2Hz,1H),4.51(d,J=12.9Hz,1H),7.26 (d,J=8.6Hz,2H),7.65-7.72(m,2H),8.24(d,J=3.1Hz,1H),8.55(d,J=3.0Hz,1H),9.60(s,1H). ES + m / z[M+H] + :434,HPLCt R =1.89min (99.6%).

[0657] Example 107: (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide

[0658]

[0659] The 3rd generation Brettphos Pd catalyst (96 mg, 0.10 mmol) was added to Cs2CO3 (675 mg, 2.07 mmol), acetamide (184 mg, 3.11 mmol) and (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100 °C for 5 hours. The crude product was purified by flash silica gel chromatography, elution gradient was 0% to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide (275 mg) as a yellow solid. The obtained crude product (275 mg) was purified by preparative HPLC column: XBridge preparative OBD C18 column, 19 x 250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution, detection at 254 / 220 nm. The fractions containing the desired compound were evaporated to dryness to provide (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide (25 mg, 5%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ1.15(d,J=6.2Hz,3H),1.20-1.49(m,5H),1.76(dd,J=38.0,10.7Hz,5H ),2.10(s,3H),2.49-2.51(m,1H),2.64(dd,J=13.3,10.4Hz,1H),2.91-3.02(m,1H),3.48(d d,J=12.0,9.3Hz,2H),3.85-3.93(m,1H),4.49(dd,J=33.9,13.2Hz,2H),7.19-7.26(m,2H), 7.63-7.71(m,2H),8.68(d,J=2.6Hz,1H),8.84(d,J=2.7Hz,1H),9.76(s,1H),10.14(s,1H). ES +m / z[M+H] + :461,HPLC t R =1.59min (97.7%).

[0660] Example 108: (R)-N4-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4,6-diamine

[0661]

[0662] (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide (100 mg, 0.22 mmol) was added to 1N aqueous HCl (1 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. The crude product was purified by preparative HPLC condition B. The fractions containing the desired compound were evaporated to dryness to provide (R)-N4-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4,6-diamine (35.0 mg, 38.5%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ1.15(d,J=6.2Hz,3H),1.24(s,1H),1.30-1.49(m,4H),1.71(d,J=12.6Hz, 1H),1.80(d,J=9.6Hz,4H),2.46-2.51(m,1H),2.57(dd,J=13.0,10.3Hz,1H),2.85-2.97(m,1H ),3.43-3.56(m,2H),3.89(dd,J=11.3,3.1Hz,1H),4.37(d,J=13.0Hz,1H),4.46(d,J=12.9Hz, 1H), 5.25 (s, 2H), 7.21 (d, J = 8.5Hz, 2H), 7.67-7.74 (m, 3H), 8.34 (d, J = 2.8Hz, 1H), 9.42 (s, 1H). ES + m / z[M+H] + :419,HPLCt R =2.30min (99.8%).

[0663] Example 109: N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0664]

[0665] Borane-THF complex (3 mL, 3.00 mmol) was added dropwise to 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-morpholino-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (120 mg, 0.28 mmol) in THF (3 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with MeOH (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC condition A. The fractions containing the desired compound were evaporated to dryness to provide N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine formate (37.0 mg, 29.8%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.10(d,J=6.2Hz,6H),1.19-1.30(m,1H),1.31-1.44(m,4H),1.70(d,J=12.8Hz,1H),1.78(d,J=10.0Hz,4H),2.41-2.4 6(m,1H),2.72(q,J=6.2Hz,1H),3.57-3.69(m,10H),3.75(d,J=2.2Hz,2H),7.11-7.17(m,2H),7.55-7.63(m,2H),8.20(s,1H),8.56(s,1H). ES+m / z[M+H] + :422,HPLC t R =2.30min (98.2%).

[0666] Example 110: (R)-N-(4-cyclohexylphenyl)-6-isopropyl-2-(2-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0667]

[0668] (R)-N-(4-cyclohexylphenyl)-6-isopropyl-2-(2-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine formate was prepared using the method described for N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine. 1H NMR (400MHz, DMSO) δ1.12 (dd, J=6.2, 16.1Hz, 9H), 1.19-1.29 (m, 1H), 1.35-1.40 (m, 4H ),1.70(d,J=12.8Hz,1H),1.78(d,J=9.8Hz,4H),2.65-2.76(m,1H),2.87(t,J=12.2Hz, 1H),3.41-3.56(m,3H),3.70(d,J=35.7Hz,5H),3.87(d,J=11.3Hz,1H),4.32(dd,J=12. 9, 32.2Hz, 2H), 7.14 (d, J = 8.3Hz, 2H), 7.59 (d, J = 8.3Hz, 2H), 8.23 ​​(s, 1H), 8.56 (s, 1H). ES+m / z[M+H] + :436,HPLC t R =1.47min (99.0%).

[0669] Example 111: 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide

[0670]

[0671] Example 111, Step 1: tert-Butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0672]

[0673] 4-Cyclohexylaniline (3.02 g, 17.23 mmol) was added to DIEA (3.61 mL, 20.68 mmol) and tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5 g, 17.23 mmol) in DMSO (25 mL). The resulting mixture was stirred at 65 ° C for 16 hours. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 20% MeOH in DCM. Pure fractions were evaporated to dryness to provide tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (7.78 g, 105%). 1H NMR (400MHz, DMSO) δ1.20-1.26(m,1H),1.26-1.41(m,4H),1.47(d,J=4.7Hz,9H),1.71(d,J=12.9Hz,1H),1.80(d,J=9 .8Hz,4H),2.50-2.51(m,1H),4.39-4.49(m,4H),7.22(d,J=8.3Hz,2H),7.52(t,J=8.1Hz,2H),9.49(d,J=12.3Hz,1H). ES+m / z[M+H] + :429,HPLC t R =1.71min (96.7%).

[0674] Example 111, Step 2: tert-Butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0675]

[0676] Pd(PPh3)4 (1.347 g, 1.17 mmol) was added to Cs2CO3 (7.60 g, 23.31 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.69 g, 12.82 mmol) and 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (5 g, 11.66 mmol) in water (10 mL) and 1,4-dioxane (50 mL). The resulting mixture was stirred at 80 °C for 14 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed with water (2×100 mL) and saturated brine (75 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.62 g, 119%) as a white solid. ES+m / z[M+H] + :477,HPLC t R =1.42min (92.7%).

[0677] Example 111, Step 3: N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0678]

[0679] Tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.622 g, 13.89 mmol) was added to HCl in 1,4-dioxane (4M, 20 mL). The resulting mixture was stirred at room temperature for 4 hours.

[0680] The mixture was filtered to afford N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride (3.69 g, 64%) as a white solid. 1 H NMR (400MHz, DMSO) δ1.14-1.29(m,1H),1.32-1.43(m,4H),1.70(d,J=12.6Hz,1 H),1.79(d,J=9.3Hz,4H),2.38-2.49(m,1H),2.49-2.56(m,3H),3.36(s,1H),3 .78(t,J=5.5Hz,2H),4.27(q,J=2.8Hz,2H),4.42(d,J=10.2Hz,2H),4.51(s,2H ),7.05(s,1H),7.16(d,J=8.2Hz,2H),7.65-7.73(m,2H),8.96(d,J=7.0Hz,1H). ES+m / z[M+H] + :377,HPLC t R =1.18min (95.1%).

[0681] Example 111, Step 4: 2-(4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-N,N-dimethylacetamide

[0682]

[0683] 2-Bromo-N,N-dimethylacetamide (88 mg, 0.53 mmol) was added to N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine (200 mg, 0.53 mmol) and DIEA (0.278 mL, 1.59 mmol) in DMF (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC: column XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution, detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to afford 2-(4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-N,N-dimethylacetamide formate (13.0 mg, 5%) as a pale yellow solid. 1 H NMR (400MHz, DMSO) δ1.19-1.27(m,1H),1.32-1.47(m,4H),1.71(d,J=12.6Hz,1H ),1.79(d,J=9.8Hz,4H),2.49-2.50(m,2H),2.85(s,3H),3.01(s,3H),3.63(s,2H ),3.80(t,J=5.4Hz,2H),3.94(s,2H),4.00(d,J=2.7Hz,2H),4.28(d,J=3.0Hz,2 H),7.04(s,1H),7.13-7.20(m,2H),7.65-7.72(m,2H),8.29(s,1H),8.78(s,1H). ES+m / z[M+H] + :462,HPLC t R =2.34min (96.0%).

[0684] Example 112: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0685]

[0686] Example 112, Step 1: tert-Butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0687]

[0688] 2-Cyclopropylmorpholine (178 mg, 1.40 mmol) was added to tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (600 mg, 1.40 mmol) and DIEA (0.489 mL, 2.80 mmol) in DMSO (3 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. The crude product was purified by C18-flash chromatography with an elution gradient of 80% to 100% MeOH in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (625 mg, 86%) as a white solid. 1 H NMR(400MHz,MeOD)δ0.29(dd,J=4.6,9.6Hz,1H),0.35-0.44(m,1H),0.49-0.63(m,2H),0.84-0.96(m,1H),1.31(d,J=7.9Hz,2 H),1.37-1.50(m,4H),1.54(s,9H),1.77(d,J=12.7Hz,1H),1.87(d,J=8.7Hz,4H),2.49(s,1H),2.73(ddd,J=2.3,8.1,10.4Hz, 1H),2.83(dd,J=10.4,12.9Hz,1H),3.00(ddd,J=3.5,11.7,13.3Hz,1H),3.52(td,J=2.8,11.6Hz,1H),3.90-3.98(m,1H),4.30 -4.39(m,3H),4.41(t,J=2.2Hz,1H),4.46(d,J=2.2Hz,1H),4.51-4.59(m,1H),7.15(dd,J=1.9,8.6Hz,2H),7.49-7.56(m,2H). ES+m / z[M+H] + :520,HPLC t R =1.79min (97.8%).

[0689] Example 112, Step 2: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0690]

[0691] Tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (615 mg, 1.18 mmol) was added to HCl in 1,4-dioxane (8 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through EA to provide N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-4-amine hydrochloride (510 mg, 103%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ0.24-0.28(m,1H),0.28-0.37(m,1H),0.43-0.53(m,2H),0.82-0.95(m,1H),1.22- 1.27(m,1H),1.30-1.47(m,4H),1.67-1.75(m,1H),1.79(d,J=9.2Hz,4H),2.76(t,J=9.7Hz,1H),2.90( dd,J=10.4,13.1Hz,1H),3.07(t,J=12.1Hz,1H),3.42(td,J=2.7,11.6Hz,1H),3.57(s,1H),3.91(dd,J =3.1,11.4Hz,1H),4.23-4.52(m,6H),7.18-7.24(m,2H),7.54-7.61(m,2H),9.72(s,1H),10.14(s,2H). ES+m / z[M+H] + :420,HPLC t R =1.14min (99.8%).

[0692] Example 112, Step 3: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine

[0693]

[0694] At room temperature, AcOH (0.126mL, 2.19mmol) is added to N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-4-amine hydrochloride (100mg, 0.22mmol), 1-methylpiperidin-4-one (74.4mg, 0.66mmol) and DIEA (0.115mL, 0.66mmol) in DCM (3mL). The resulting mixture is stirred at room temperature for 30min. At room temperature, sodium triacetoxyborohydride (139mg, 0.66mmol) is added to the above mixture. The resulting mixture is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure. The crude product is dissolved in MeOH (5mL). The crude product was purified by C18-flash chromatography with an elution gradient of 90% to 100% MeOH in water (0.1% NH4HCO3). The pure fractions were evaporated to dryness to provide the product as a white solid. The obtained product was purified by preparative HPLC: Kinetex EVO C18 column, 30×150, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution, detection at 254 / 220 nm. The fractions containing the desired compound were evaporated to dryness to provide N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine (32.5 mg, 28.7%) as a white solid. 1 H NMR (400MHz, DMSO) δ0.19-0.37(m,2H),0.45-0.52(m,2H),0.87(s,1H),1.23(s,1H),1.27-1.53( m,6H),1.63-1.86(m,7H),1.95(t,J=10.9Hz,2H),2.15(s,3H),2.38(m,2H),2.69-2.76(m,4H),2 .84-2.94(m,1H),3.33-3.43(m,1H),3.64(s,2H),3.73(s,2H),3.87(d,J=11.9Hz,1H),4.24(d,J =13.0Hz, 1H), 4.44 (d, J = 10.1Hz, 1H), 7.13 (d, J = 8.4Hz, 2H), 7.57 (d, J = 8.5Hz, 2H), 8.56 (s, 1H). ES+m / z[M+H] + :517,HPLC t R =1.05min (97.4%).

[0695] Bioassay

[0696] The thallium transport FLIPR-based assay was used to measure the ability of compounds to activate KCC2. + KCC2 activity was assessed by influx. The assay protocol was based on that described by Delpire et al. (Proc Natl Acad Sci USA. 2009 Mar 31; 106(13):5383-5388) and Zhang et al. (Journal of Biomolecular Screening 15(2):2010).

[0697] Preparation of HEK cells expressing KCC2

[0698] KCC2 was synthesized and codon optimized by GeneArt based on the Uniprot sequence Q9H2X9. The final sequence was subcloned into pcDNA3.1.

[0699] HEK293 cells were grown in 10-layer cell stacks at 37°C, 5% CO2, in DMEM, 10% fetal bovine serum and 2mM glutamine. The cells were detached by removing the media and washing the cell stack with 100ml of PBS. The PBS was removed, and 100ml of 1x TrypLE was added and the cell stack was returned to 37°C for 5min. The detached cells were then counted in a Vi cell counter and spun at 1250rpm in a Solval Legend centrifuge for 10min. The cells were diluted in Maxcyte electroporation buffer at 4x final concentration and spun as before. The cell pellet was centrifuged at 1×10 8 Cells were resuspended per ml and electroporated in a Maxcyte Cl 2.2 bag via the HEK293 program on a Maxcyte STX machine with 200 μg / ml of plasmid DNA. The cells were then allowed to recover for 30 min before being added to 500 ml of PBS and then counted again on Vi cells. The cells were then frozen in a planer controlled rate freezer in 90% complete medium, 10% DMSO.

[0700] Procedure for KCC2 Thallium Assay

[0701] Unless otherwise stated, all reagents were dispensed using the Mulitdrop Combi. All FluXOR Invitrogen appropriate buffer compositions are mentioned in the table below.

[0702] 3.33×10 5HEK293 KCC2 cells were harvested at a density of 1 cell / ml in complete medium (DMEM, Sigma, D6546, 10% fetal bovine serum and 1% glutamine) and 30 μL per well were inoculated into 384-well PDL-coated black transparent plates (Corning, 354663). Cells were allowed to settle for 20 min at room temperature, then incubated for 48 h at 37 ° C, 5% CO2. After incubation, three cleaning steps were performed in HBSS (Sigma, H6648) using a Biotek cell washer, wherein the final suction left 20 μL HBSS residual volume in each well. Then, 20 μL of thallium loading dyes were further added per well (1 h, room temperature, protected from light). 5 μL of test compounds (100 μM maximum concentration, 1:2 dilution, 12-point curve) were added using FLIPR TETRA, and incubated for 90 min in the dark at room temperature. After compound incubation, the thallium flux response is read on the FLIPR TETRA (e.g., 515-575 nm), initiated by dispensing 5 μL of stimulation buffer into each well by the FLIPR TETRA. Recordings are taken every 1 second for 120 seconds. The thallium flux at 120 seconds is used to determine the EC 50 .

[0703] Reagents used for KCC2 assay:

[0704] Assay buffer

[0705] For 100mL

[0706]

[0707] Adjust pH to 7.4 using NaOH

[0708] Loading buffer

[0709] For 10mL

[0710]

[0711]

[0712] Loading buffer must be kept fresh on the day of the assay.

[0713] Compound buffer: Assay buffer with 1 μL of bumetanide per 10 ml.

[0714] Stimulation buffer

[0715] For 10mL

[0716] Materials / Reagents More Information source FluxOR Chloride-Free Buffer (Component E) 1.5ml Life Tech(F10017) Deionized water 6ml Medium preparation <![CDATA[K + (K2SO4) solution (component F)]]> 2ml Life Tech(F10017) <![CDATA[Tl+(Tl2SO4) solution (Component G)]]> 0.5ml Life Tech(F10017) Bumetanide (100 mM in DMSO) 1μl Sigma(D129)

[0717] Activity of the Examples in the KCC2 Thallium Assay.

[0718] All compounds showed E max >140% DMSO signal.

[0719]

[0720] The present invention also provides the following items:

[0721] 1. A compound of formula (I):

[0722]

[0723] R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group;

[0724] R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0725] A is selected from:

[0726] or its N-oxide;

[0727] R 3 Selected from -H; -C 1-6 Alkyl; -C 2-6 Alkenyl; -C2-6 Alkynyl; -C 3-7 Cycloalkyl; and 5-membered or 6-membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 selected from -F, -CF3, -C 1-3 Alkyl group substituted, the -C 1-3 The alkyl group is optionally substituted by 1 or 2 groups selected from -F, -CF3, -C(O)NR 8 R 9 and-NR 8 R 9 Substituents are substituted;

[0728] R 4a and R 4b each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl;

[0729] R 4c and R 4d are each independently selected from -H and -C optionally substituted with 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; or R 4c and R 4d Together with the carbon to which they are attached, they represent a carbonyl group;

[0730] R 5a , R 5b , R 5c and R 5d are each independently selected from -H and -C optionally substituted with 1, 2 or 3 substituents selected from -F and CF3 1-3 alkyl;

[0731] R 6 -H; -halogen; -NH2; -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 ; -C(O)OH and -NHC(O)-C 1-3 alkyl;

[0732] R 7 Selected from NR 10 R 11; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 or the heterocycloalkyl is optionally substituted on the same ring carbon by two substituents, the two substituents together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; and wherein when R 7 is morpholinyl and R 1 When R is an unsubstituted phenyl group, 2 Not -H;

[0733] R 8 and R 9 are each independently selected from -H and -C 1-6 alkyl;

[0734] R 10 Yes-C 1-6 alkyl;

[0735] R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; and -(CH2) n R 12 ;

[0736] R 12 is a 5-membered or 6-membered heteroaryl, a 3-membered to 5-membered cycloalkyl or a 3-membered to 6-membered heterocycloalkyl;

[0737] m is 0 or 1; and

[0738] n is 1, 2, or 3.

[0739] 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein A is And R 3 , R 4a , R 4b , R 4c and R 4d As defined in item 1.

[0740] 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein A is And R 5a , R 5b , R 5c and R 5d As defined in item 1.

[0741] 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein A is or its N-oxide, and R 6 As defined in item 1.

[0742] 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 1 Selected from C 2-6 Alkyl; C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 Aryl; and thienyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein the aryl is optionally substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

[0743] 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 1 Selected from: -CH2CF3; -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; phenyl optionally substituted by 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7; -O-phenyl optionally substituted by -F; -O-CH2-phenyl and thienyl.

[0744] 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 2 It is -H, -F or methyl.

[0745] 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 2 and 5 to 7, wherein R 3 It is ethyl, isopropyl, propynyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C(O)N(CH3)2 or N-methylpiperidine.

[0746] 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 2 and 5 to 8, wherein R 4a and R 4b Both are -H.

[0747] 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 2 and 5 to 9, wherein R 4d and R 4c Together with the carbon to which they are attached they represent a carbonyl group.

[0748] 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1, 3 and 5 to 7, wherein R 5a , R 5b , R 5c and R 5d Each is -H.

[0749] 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1, 4 and 5 to 7, wherein R 6 Selected from -H, -Br, -NH2, -CN, methoxy, ethyl, -C(O)OCH3, -C(O)NH2, -C(O)OH and -NHC(O)CH3.

[0750] 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 7 is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 or the heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atoms to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0751] 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 7 is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3 and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atoms to which they are attached, form a tetrahydropyranyl.

[0752] 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12, wherein R 7 YesNR 10 R 11 .

[0753] 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1, 2, 4 to 10 and 12 to 15, wherein R 8 and R 9 Both are -H or both are methyl.

[0754] 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12, 15 and 16, wherein R 10 Selected from methyl, ethyl and propyl.

[0755] 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12 and 15 to 17, wherein R 11 Selected from ethyl, -CH2CHF2, propyl, -(CH2)2O(CH2)2 and -(CH2) n R 12 .

[0756] 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12 and 15 to 18, wherein R 12 is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

[0757] 20. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0758]

[0759] Where R 1 , R 2 , R 3 , R 4a , R 4b and R 7 As defined in formula (I) in item 1.

[0760] 21. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0761]

[0762] Where R 1 , R 2 , R 5a , R 5b , R 5c , R 5d and R 7 As defined in item 1.

[0763] 22. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IV) or an N-oxide or a pharmaceutically acceptable salt thereof:

[0764]

[0765] Where R 1 , R 2 , R 6 and R 7 As defined in formula (I) in item 1.

[0766] 23. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1, wherein the compound of formula (I) is selected from the group consisting of:

[0767] 2-(Diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0768] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0769] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0770] 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0771] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0772] 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0773] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0774] 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0775] 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0776] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0777] 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0778] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0779] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0780] 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0781] 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0782] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0783] tert-Butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate;

[0784] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0785] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0786] 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0787] 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0788] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(1,2-oxazol-3-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0789] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(1,2,4-oxadiazol-3-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0790] 4-[(4-cyclohexylphenyl)amino]-2-(1,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0791] 4-[(4-cyclohexylphenyl)amino]-2-(1,9-dioxa-4-azaspiro[5.5]undec-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0792] 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0793] 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0794] 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0795] 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0796] 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0797] 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0798] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0799] 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0800] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0801] 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0802] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0803] (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid;

[0804] N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide;

[0805] 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0806] 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile;

[0807] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0808] 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0809] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0810] 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0811] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0812] 4-[(4-cyclohexylphenyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0813] 4-[(4-cyclohexylphenyl)amino]-2-(1,3-oxazol-5-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0814] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0815] 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0816] 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0817] 2-(2-cyclopropylmorpholin-4-yl)-4-({4′-[(hept-6-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0818] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4′-(heptyloxy)[1,1′-biphenyl]-4-yl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0819] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazinin-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0820] 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0821] 4-{[4-(Butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0822] 4-{[4-(Benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0823] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0824] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0825] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0826] 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0827] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0828] 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0829] 4-{[4-(Cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0830] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0831] tert-Butyl {2-[(4′-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate;

[0832] 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0833] 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0834] tert-Butyl {2-[(4′-{[2-(morpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate;

[0835] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0836] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-({4′-[(prop-2-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0837] 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0838] 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0839] 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0840] 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0841] 2-(Morpholin-4-yl)-4-{[4-(prop-2-yl)phenyl]amino}-6-(prop-2-yn-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0842] 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0843] 4-[(4-cyclohexylphenyl)amino]-2-(1H-imidazol-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0844] 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2'-methyl[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0845] 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0846] 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0847] 2-(Morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0848] 4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0849] 4-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0850] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0851] 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0852] 4-[(2-methyl[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0853] 4-[(4'-chloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0854] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0855] N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0856] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0857] 2-(2-cyclopropylmorpholin-4-yl)-N-[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0858] 2-[(2R)-2-methylmorpholin-4-yl]-N-{4′-[(6,6,6-trifluorohexyl)oxy][1,1′-biphenyl]-4-yl}-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0859] N-(4-cyclohexylphenyl)-2-(2-methylpyridin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;

[0860] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0861] 6-Bromo-N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0862] N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0863] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-8-oxo-8λ 5 -pyrido[2,3-d]pyrimidin-4-amine;

[0864] N-(4-cyclohexylphenyl)-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0865] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile;

[0866] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester;

[0867] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid;

[0868] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxamide;

[0869] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)pyrido[2,3-d]pyrimidine-6-carboxamide;

[0870] N-(4-cyclohexylphenyl)-6-methoxy-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;

[0871] N-{4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-6-yl}acetamide;

[0872] N4-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-4,6-diamine;

[0873] N-(4-cyclohexylphenyl)-2-(morpholin-4-yl)-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0874] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0875] 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide;

[0876] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;

[0877] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; and

[0878] 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one.

[0879] 24. A pharmaceutical composition comprising a compound of formula (I) according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0880] 25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 23 for use in therapy.

[0881] 26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 23 for use in the treatment of a neurological disorder.

[0882] 27. The compound for use according to item 26, wherein the neurological disorder is selected from epilepsy, pain, autism spectrum disorder, cognition, anxiety and amyotrophic lateral sclerosis.

[0883] 28. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of items 1 to 23 for the manufacture of a medicament for treating a neurological disorder.

[0884] 29. A method of treating a neurological disorder in a warm-blooded animal in need of such treatment, the method comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy; C 2-6 Alkenyloxy; C 2-6 Alkynyloxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thienyl; 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 -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group; R 2 -H; -halogen; and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl; A is R 3 Selected from -H; -C 1-6 Alkyl; -C 2-6 Alkenyl; -C 2-6 Alkynyl; -C 3-7 Cycloalkyl; and 5-membered or 6-membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 selected from -F, -CF3, -C 1-3 Alkyl group substituted, the -C 1-3 The alkyl group is optionally substituted by 1 or 2 groups selected from -F, -CF3, -C(O)NR 8 R 9 and-NR 8 R 9 Substituents are substituted; R 4a and R 4b each independently selected from -H and -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 alkyl; R 4c and R 4d Together with the carbon to which they are attached, they represent a carbonyl group; R 7 Selected from NR 10 R 11 ; 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 or the heterocycloalkyl is optionally substituted on the same ring carbon by two substituents, the two substituents together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; and wherein when R 7 is morpholinyl and R 1 When R is an unsubstituted phenyl group, 2 Not -H; R 8 and R 9 are each independently selected from -H and -C 1-6 alkyl; R 10 Yes-C 1-6 alkyl; R 11 Selected from: Optionally 1 or 2 selected from -F and -C 1-3 Alkoxy substituents substituted -C 1-6 Alkyl; and -(CH2) n R 12 ; R 12 is a 5-membered or 6-membered heteroaryl, a 3-membered to 5-membered cycloalkyl or a 3-membered to 6-membered heterocycloalkyl; m is 0 or 1; and n is 1, 2, or 3.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from C 2-6 Alkyl; C 2-6 Alkoxy; C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 Aryl; and thienyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein the aryl is optionally substituted with 1 or 2 substituents selected from -halogen, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The substituents of the alkynyloxy group are substituted, wherein -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 The alkynyloxy group is optionally substituted by 1, 2 or 3 groups selected from -F, -CF3 and -NHC(O)OC 1-6 The substituents of the alkyl group are substituted, or the two substituents together with the carbon to which they are attached form a diazirine group.

3. A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: -CH2CF3; -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; phenyl optionally substituted by 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7; -O-phenyl optionally substituted by -F; -O-CH2-phenyl and thienyl.

4. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -H, -F or methyl.

5. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 3 It is ethyl, isopropyl, propynyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C(O)N(CH3)2 or N-methylpiperidine.

6. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Both are -H.

7. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 7 is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted by 1, 2 or 3 groups selected from the following: -CN; -C optionally substituted by 1, 2 or 3 substituents selected from -F, -CF3 and -OH 1-6 Alkyl; -C optionally substituted by 1, 2 or 3 substituents selected from -F and -CF3 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl; -C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; and C 3-5 or the heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

8. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 7 is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridyl, dihydropyranyl, imidazolyl, oxazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3 and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted on the same ring carbon with two substituents which, together with the carbon atoms to which they are attached, form a tetrahydropyranyl.

9. A compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 7 YesNR 10 R 11 .

10. A compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Both are -H or both are methyl.

11. A compound of formula (I) according to any one of claims 1 to 6 and 9 to 10, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from methyl, ethyl and propyl.

12. A compound of formula (I) according to any one of claims 1 to 6 and 9 to 11, or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from ethyl, -CH2CHF2, propyl, -(CH2)2O(CH2)2 and -(CH2) n R 12 .

13. A compound of formula (I) according to any one of claims 1 to 6 and 9 to 12, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is selected from the group consisting of: 2-(Diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(1,2-oxazol-3-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(1,2,4-oxadiazol-3-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,9-dioxa-4-azaspiro[5.5]undec-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid; N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide; 6-(Propan-2-yl)-4-{[4-(Propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,3-oxazol-5-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-({4′-[(hept-6-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4′-(heptyloxy)[1,1′-biphenyl]-4-yl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazinin-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(Butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(Benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(Cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {2-[(4′-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate; 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {2-[(4′-{[2-(morpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1′-biphenyl]-4-yl)oxy]ethyl}carbamate; 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-({4′-[(prop-2-yn-1-yl)oxy][1,1′-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(Morpholin-4-yl)-4-{[4-(prop-2-yl)phenyl]amino}-6-(prop-2-yn-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1H-imidazol-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2'-methyl[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(But-3-yn-1-yl)-3H-diazain-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(Morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-methyl[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-chloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; and 2-(Morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one.

15. A pharmaceutical composition comprising a compound of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

16. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for treatment.

17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for treating a neurological disorder.

18. Use according to claim 17, wherein the neurological disorder is selected from epilepsy, pain, autism spectrum disorders, cognition, anxiety and amyotrophic lateral sclerosis.

19. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment of a neurological disorder in a warm-blooded animal in need of such treatment.

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