3-cyclopropylpyrazole derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor

Abstract

The present invention relates to novel compounds of Formula (I'), wherein P, Q, A, B, m, n, R1, R2, R9, R10, R11 and R12 are defined as in Formula (I'). These compounds may be useful asmuscarinic M4 receptor subtype ("M4-mAChR") positive allosteric modulators which are useful for the treatment or prevention of neurological and psychiatric disorders associated with muscarinic M4 receptor dysfunction and diseases in which the M4 receptor is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases such as for example, cognitive decline, both positive and negative symptoms in schizophrenia as well as other disorders modulated by M4 muscarinic receptors.

Description

[0001] 3-CYCLOPROPYLPYRAZOLE DERIVATIVES AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR

[0002] SUMMARY OF THE INVENTION

[0003] The present invention relates to novel compounds of Formula (I’), wherein P, Q, A, B, m, n, R1, R2, R9, R10, R11and R12are defined as in Formula (I’). These compounds may be useful as muscarinic M4 receptor subtype (“M4-mAChR”) positive allosteric modulators which are useful for the treatment or prevention of neurological and psychiatric disorders associated with muscarinic M4 receptor dysfunction and diseases in which the M4 receptor is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases such as for example, cognitive decline, both positive and negative symptoms in schizophrenia as well as other disorders modulated by M4 muscarinic receptors.

[0004] FIELD OF THE INVENTION

[0005] The invention relates to novel cyclopropyl pyrazolo derivatives which may be useful as muscarinic M4 receptor subtype (“M4-mAChR.”) positive allosteric modulators, salts thereof, pharmaceutical compositions thereof, and uses thereof in the treatment or prevention of neurological and psychiatric disorders such as for example, cognitive decline, schizophrenia (e.g., both positive and negative symptoms in schizophrenia), Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies as well as other disorders modulated by M4 muscarinic receptors. BACKGROUND OF THE INVENTION

[0006] Acetylcholine (ACh) is a key neurotransmitter that modulates neuronal function in the peripheral nervous system (PNS) and central nervous system (CNS). ACh mediates its actions via two families of receptors, termed the ionotropic nicotinic ACh receptors (nAChRs) and the metabotropic muscarinic ACh receptors (mAChRs). mAChRs belong to family A of G-protein-coupled receptors (GPCRs) and consists of five subtypes Ml, M2, M3, M4 and M5 (Bonner et al. (1987) Science 237, 527-32; Bonner et al. (1988) Neuron 1, 403-10). The mAChRs are known to contain one or more allosteric sites which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites. mAChRs in the central nervous system play a critical role in mediating higher cognitive processing and control of dopamine release and are involved in behavior, sensory, motor and autonomic functions. The M4 mAChR is predominantly expressed in the striatum, but also in the hippocampus and cortex (Lebois et al. (2018) Neuropharmacology 136, 362-373). M4 mAChRs are found presy naptically as autoreceptors in glutamatergic synapses on neurons (Levey et al. (1991) J Neurosci 11, 3218-26; Pancani et al. (2014) ACS Chem Neurosci 5,318-24), on cholinergic interneurons (Chis) within the striatum (Paul, S.M. et al. (2022) Am J Psychiatry 179, 611-27). They can also be found post-synaptically on DI -positive medium spiny neurons (MSN) with evidence that M4 activation can directly modulate the response to dopamine (Nair et al. (2015) J Neurosci 35, 14017-30; Nair et al. (2019) Neuropharmacology 146, 74-83).

[0007] Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a reduction of acetylcholine content in the brain, linked to degeneration of cholinergic neurons of the basal forebrain, having repercussions on multiple areas of the brain, including the ones involved in higher processes such as the cortex and hippocampus. Acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of Ach, have been approved in the United States for use in the palliative, but not diseasemodifying, treatment of the cognitive deficits in AD patients. However, use of AChE inhibitors and other cholinergic agents induces adverse effects including cardiovascular effects, gastro-intestinal distress, excessive salivation, and sweating. An alternative approach to pharmacologically target cholinergic hypofunction is through the selective activation of mAChRs. While non-selective agents activating mAChRs, such as xanomeline, have demonstrated clinical efficacy to reduce psychotic behavioral symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer's disease patients (Bodick et al. (1997) Arch Neurol 54, 465-73), their development has been hampered by similar adverse effects, mostly mediated by activation of peripheral M2 and M3 mAChRs. Administration of xanomeline to M4R knock-out animals failed to show antipsychotic effects seen in wild-type control animals, demonstrating the direct link of mAChR M4 subtype to antipsychotic effect (Woolley et al. (2009) J Pharmacol 603, 147-9). A genome wide association study of schizophrenia (11,260 cases and 24,542 controls) identified a single nucleotide polymorphism significantly linked to disease at locus rs7951870, which includes the mAChR M4 gene (Pardinas, et al. (2018) Nat Genet 50, 381-9). These and other evidence suggests mAChR M4 is the most likely subtype for mediating the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognition disorders, and neuropathic pain. Because of this, considerable effort has been focused on developing selective mAChR M4 agonists for treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful because of an inability to develop compounds that are highly selective for the mAChR M4, because of the high conservation of the orthosteric ACh binding site. It is therefore believed that developing compounds that act at allosteric sites on mAChRs which are less highly conserved between mAChR subtypes could circumvent problems associated with targeting the highly conserved orthosteric ACh binding site. Moreover, targeting specifically and selectively the mAChR M4 is believed to result in antipsychotic agents without the adverse effects linked to other mAChR subtypes. Allosteric activators can include allosteric agonists, that act at a site removed from the orthosteric site to directly activate the receptor in the absence of ACh as well as positive allosteric modulators (PAMs), which do not activate the receptor directly but potentiate activation of the receptor by the endogenous orthosteric agonist ACh. Also, it is possible for a single molecule to have both allosteric potentiator and allosteric agonist activity.

[0008] Despite advances in muscarinic acetylcholine receptor research, there is still a scarcity of compounds that are potent, efficacious, and selective activators of the mAChR M4 subtype and effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity and diseases in which the mAChR M4 subtype is involved.

[0009] The hunt for drugs targeting mAChRs has yielded many derivatives, while selective over other GPCRs, lacked intra subtype selectivity, and exhibited side effects hampering their therapeutic use. However, subtype selective compounds, including compounds binding to the allosteric site of mAChRs, have been reported, opening new avenues for therapeutic interventions (Conn et al. (2009) Nat Rev Drug Discov 8:41-54; Conn PJ et al. Trends Pharmacol Sci 30: 148-155).

[0010] While the first generation of M4 selective positive allosteric modulators such as VU0010010 and LY2033298 in ex vivo and in vivo studies provided initial support to the approach (Chan et al. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 10978el0983;

[0011] Shirey et al. (2008) Nat. Chem. Biol. 4, 42-50; Leach et al. (2010) Neuropsychopharmacology 35, 855-869, next generation compounds with better profiles such as VU1052100 and VU0467154 proved invaluable to demonstrate the potential of M4 PAMs for the treatment of schizophrenia (Brady et al. (2008) J. Pharmacol. Exp. Ther. 327, 941-953; Bubser et al. (2014) ACS Chem. Neurosci. 5, 920-942; Byun et al. (2014) Neuropsychopharmacology 39, 1578-1593; Foster et al. (2016) Neuron 91, 1244- 1252.

[0012] Vanderbilt University has published several international patent applications disclosing carboxamido analogs (WO2014 / 035829; WO2015 / 027214), thieno[2,3c]pyridazines derivatives (WO2019 / 113174) and 7,8- dihydro 5H-1,6- naphtyridines analogs (WO2023 / 064587; WO2023 / 141511).

[0013] Merck has disclosed different series of selective M4 PAMs in particular 5-(pyridine- 3-yl)oxazoles (W02019 / 005589) and heteroaryl piperidine ether derivatives (WO2018 / 118734). Emraclidine (CVL-231) from Cerevel is currently in Phase 2 for schizophrenia. This molecule is a 5,7-dihydro-pyrrolo-pyridine which series are described in Pfizer patent applications WO2018 / 002760 and WO2018 / 234953.

[0014] However, improved mAChR M4 positive allosteric modulators are needed for providing therapies to treat mAChR M4 mediated diseases. None of the specifically disclosed compounds are structurally related to the compounds of the present invention.

[0015] SUMMARY OF THE INVENTION

[0016] The invention relates to compounds having muscarinic M4 modulator activity. In its most general compound aspect, the present invention provides a compound according to Formula (I’), a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an N-oxide form thereof, wherein:

[0017] R1is selected from the group of (for example the group consisting of) hydrogen, - (Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl;

[0018] R2is selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl, -(Ci-C6)deuterioalkyl and -(Ci- Ce)haloalkyl (for example -CF3);

[0019] R9, R10, R11and R12are each independently selected from the group of (for example the group consisting of) hydrogen, halogen, deuterium, and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- C6)deuterioalkyl or -(Ci-Ce)haloalkyl;

[0020] P is a heteroaryl or heterocycle; wherein each heteroaryl ring or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl (for example -CF3), -(Co-Ce)alkylene-ORa, -(C3-C7)cycloalkyl, aryl, heteroaryl and heterocycle, or two (A)mtogether form a saturated -(C3-C7) membered ring;

[0021] Q is selected from the group of (for example the group consisting of) -(Ci- Ce)haloalkyl (for example -CF3), -(Co-C6)alkylene-C(=0)-ORaor -(Co-Ce)alkylene- C(=O)-NRbRc, cycloalkyl, aryl, heteroaryl and heterocycle; wherein Ra, Rb and Rcare each independently selected from the group of (for example the group consisting of) hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyl-O-(Ci-Ce)alkyl, and (Ci- Ce)alkyl- (C=O)-(Ci-Ce)alkyl, or Rb and Rc, together with the nitrogen to which they are attached, form a pyrrolopyridine group; wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5; the or each (B)nis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -CD3, -OH, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, - (Ci-C6)deuterioalkyl, -O-(Ci-C6)deuterioalkyl, -N-(Ci-C6)deuterioalkyl, -(Ci- Ce)haloalkyl (for example -CF3), -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co-Ce)alkylene-OR3, -O-(C2-Ce)alkylene- OR3, -NR3(C2-C6)alkylene-OR4, -(Co-C6)alkylene-S-R3, -O-(C2-C6)alkylene-S-R3, - NR3-(C2-C6)alkylene-S-R4, -(Co-C6)alkylene-NR3R4, -O-(C2-C6)alkylene-NR3R4, -NR3- (C2-C6)alkylene-NR4R5, -(Co-C6)alkylene-C(=0)- NR3R4; -(Co-C6)alkylene-S(=0)-R3, - O-(C0-C6)alkylene-S(=O)-R3, -NR3-(C0-C6)alkylene-S(=O)-R4, -(Co-C6)alkylene- S(=O)2-R3, -0-(Co-C6)alkylene-S(=0)2-R3, -NR3-(Co-C6)alkylene-S(=0)2-R4, -0-(Co- C6)alkylene-C(=O)-NR3R4, -NR3-(C0-C6)alkylene-C(=O)-NR4R5, -(Co-C6)alkylene- NR3C(=O)-R4, -O-(C2-C6)alkylene-NR3C(=O)-R4, -NR3-(C2-C6)alkylene-NR4C(=O)- R5, -(C0-C6)alkylene-OC(=O)-R3, -O-(C2-C6)alkylene-OC(=O)-R3, -NR3-(C2- C6)alkylene-OC(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, -0-(Co-C6)alkylene-C(=0)- OR3, -NR3-(C0-C6)alkylene-C(=O)-OR4, -(Co-C6)alkylene-C(=0)-R3, -0-(Co- C6)alkylene-C(=O)-R3and -NR3-(C0-C6)alkylene-C(=O)-R4; R3, R4and R5are each independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl (for example -CF3), -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl, -(Co-C6)alkylene-N-((Ci-Ce)alkyl)2, - (Co-C6)alkylene-NH(Ci-Ce)alkyl, and -(Co-Ce)alkylene-NH2.

[0022] P may be bicyclic, comprising two or more fused heterocyclic or heteroaryl rings, wherein one of the rings is a 5 membered heterocyclic or heteroaryl ring, and wherein P is bonded to the pyrazole core via the 5 membered ring.

[0023] It has now, surprisingly, been found that the compounds of general Formula (F) show potent activity and selectivity on the M4 mACh receptor. The compounds of the invention demonstrate advantageous properties over compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the invention: the potency on the target, the selectivity for the target, the bioavailability, the brain penetration, and the pharmacodynamics.

[0024] Preferably, the compound of Formula (I’) is a compound of Formula (I):

[0025] P may represent an heteroaryl of formula:

[0026] wherein W may be selected from the group of (for example the group consisting of) C- H, C-CH3 and N; and Y may be selected from the group of (for example the group consisting of) O, S and N-CH3.

[0027] R1may be selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl. R2may be selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl and -(Ci-Ce)haloalkyl (for example - CF3).

[0028] The cycloalkyl, aryl, heteroaryl or heterocycle of Q may be represented by formula: wherein p is an integer equal to zero, 1 or 2; and wherein Z1is selected from C=C, C=O, C, N, S or O, and Z2, Z3, Z4, Z5, and Z6are each independently selected from C, N, S or O. Preferably, the compound having the Formula (I’) is a compound of Formula (I): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof, wherein:

[0029] R1is selected from the group of (for example the group consisting of) hydrogen, - (Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl;

[0030] R2is selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl, -(Ci-C6)deuterioalkyl and -(Ci- Ce)haloalkyl (for example -CF3);

[0031] P represents a heteroaryl of formula: wherein W may be selected from the group of (for example the group consisting of) C- H, C-CH3 and N; and Y may be selected from the group of (for example the group consisting of) O, S and N-CH3; wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen, and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl -(Ci-Ce)haloalkyl (for example -CF3), -(Co-C6)alkylene-0-Ra, -(C3-C7)cycloalkyl, aryl, heteroaryl, and heterocycle, or two (A)mtogether form a saturated -(C3-C7) membered ring;

[0032] Q represents a cycloalkyl, aryl, heteroaryl or heterocycle of formula: or, -(Ci-Ce)haloalkyl (for example -CF3), -(Co-C6)alkylene-C(=0)-ORb or -(Co- C6)alkylene-C(=O)-NRbRc; wherein Ra, Rb and Rcare each independently selected from the group of (for example the group consisting of) hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyl-O-(Ci-Ce)alkyl, and (Ci- Ce)alkyl- (C=O)-(Ci-Ce)alkyl, or Rb and Rc, together with the nitrogen to which they are attached, form a pyrrolopyridine group; wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5; wherein p is an integer equal to zero, 1 or 2; wherein Z1is selected from C=C, C=O, C, N, S or O; and Z2, Z3, Z4, Z5and Z6are each independently selected from C, N, S or O; the or each (B)nis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -OH, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- C6)deuterioalkyl, -O-(Ci-C6)deuterioalkyl, -N-(Ci-C6)deuterioalkyl, -(Ci-Ce)haloalkyl (for example -CF3), -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, -(Ci- Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci-Ce)alkylene- heterocycle, -(Co-Ce)alkylene-OR3, -O-(C2-C6)alkylene-OR3, -NR3(C2-Ce)alkylene-OR4, -(Co-C6)alkylene-S-R3, -O-(C2-C6)alkylene-S-R3, -NR3-(C2-C6)alkylene-S-R4, -(Co- Ce)alkylene-NR3R4, -O-(C2-Ce)alkylene-NR3R4, -NR3-(C2-Ce)alkylene-NR4R5and -(Co- C6)alkylene-C(=O)- NR3R4; -(Co-C6)alkylene-S(=0)-R3, -O-(C0-C6)alkylene-S(=O)-R3, -NR3-(Co-C6)alkylene-S(=0)-R4, -(Co-C6)alkylene-S(=0)2-R3, -0-(Co-C6)alkylene- S(=O)2-R3, -NR3-(Co-C6)alkylene-S(=0)2-R4, -O-(C0-C6)alkylene-C(=O)-NR3R4, -NR3- (Co-C6)alkylene-C(=0)-NR4R5, -(C0-C6)alkylene-NR3C(=O)-R4, -O-(C2-C6)alkylene- NR3C(=O)-R4, -NR3-(C2-C6)alkylene-NR4C(=O)-R5, -(C0-C6)alkylene-OC(=O)-R3, -O- (C2-C6)alkylene-OC(=O)-R3, -NR3-(C2-C6)alkylene-OC(=O)-R4, -(Co-C6)alkylene- C(=O)-OR3, -O-(C0-C6)alkylene-C(=O)-OR3, -NR3-(C0-C6)alkylene-C(=O)-OR4, -(Co- C6)alkylene-C(=O)-R3, -O-(C0-C6)alkylene-C(=O)-R3and -NR3-(Co-C6)alkylene- C(=O)-R4;

[0033] R3, R4and R5are each independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-Ce)alkylene- 0-(Co-C6)alkyl, -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl and -(Co-Ce)alkylene-NH2. The pyrrolopyndine group set out above may, for example, be

[0034] Preferably, P represents a heretoaryl of formula: wherein each heteroaryl ring is optionally substituted with m radicals A, wherein W is selected from the group of (for example the group consisting of) C-H, C-CH3 and N, m is an integer equal to 1, 2 or 3 and Y is selected from the group of (for example the group consisting of) O, S and N-CH3.

[0035] Preferably, R1is -(Ci-C3)alkyl, -(Ci-C6)deuterioalkyl or cyclopropyl; and R2is hydrogen, -CF3, -F or -CH3.

[0036] Preferably, P represents a heteroaryl of formula: wherein each heteroaryl ring is optionally substituted with m radicals A, wherein W is selected from the group of (for example the group consisting of) C-H, C-CH3 and N, m is an integer equal to 1, 2 or 3 and Y is selected from the group of (for example the group consisting of) O, S and N-CH3; and R1is -(Ci-C3)alkyl or cyclopropyl; and R2is selected from the group of (for example the group consisting of) hydrogen, -F and -CH3.

[0037] Preferably, the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl and -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle.

[0038] Q may be a cycloalkyl, aryl, heteroaryl or heterocycle of formula: wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5.

[0039] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3, -CD3, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- C6)deuterioalkyl, -O-(Ci-C6)deuterioalkyl, -N-(Ci-C6)deuterioalkyl,-(Ci-C6)haloalkyl, - (C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co- Ce)alkylene-OR3, -NR3(C2-Ce)alkylene-OR4, -(Co-Ce)alkylene-NR3R4and -(Co- C6)alkylene-C(=O)- NR3R4; -(C0-C6)alkylene-NR3C(=O)-R4, -(Co-C6)alkylene-C(=0)- OR3, -NR3-(C0-C6)alkylene-C(=O)-OR4and -NR3-(C0-C6)alkylene-C(=O)-R4;

[0040] R3, R4and R5may each be independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-Ce)alkylene- 0-(Co-C6)alkyl, -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl, and -(Co-Ce)alkylene-NH2.

[0041] Preferably, Q is a aryl, heteroaryl or heterocycle of formula: wherein each aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5.

[0042] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3, -CD3, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-Ce)alkylene- OR3and -(Co-C6)alkylene-C(=0)- NR3R4;

[0043] R3, R4and R5may each be independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-Ce)alkylene- 0-(Co-C6)alkyl, -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl, and -(Co-Ce)alkylene-NH2. The cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mand (B)nmay independently be selected from the group of azetidinyl, dihydrofuranyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R6, R7or R8.

[0044] R6, R7or R8may be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, nitro, -(Ci-Ce)alkyl, -(Co-Ce)alkylene-O-(Co- C6)alkyl, -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl, and - (Co-Ce)alkylene-NH2.

[0045] Preferably, the compounds of Formula (I) are the compounds according to Formula (II): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof, wherein Ai and A2 are each independently selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl and R1is methyl or ethyl and Q, B and n, are as defined in any statement set out above.

[0046] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0047] (III): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof, wherein R1is methyl or ethyl and Q, B and n, are as defined in any statement set out above.

[0048] The compound may exist as stereoisomers, wherein the compound is either a racemic mixture or one or both of the individual stereoisomers.

[0049] The compounds of Formula (I) include a 1,2-di substituted cyclopropane moiety. The hydrogen atoms of the two substituted carbons on the cyclopropyl ring can be in a -cis or -trans relationship, and because of asymmetrical substitution at these carbon atoms each -cis isomer can exist in two stereoisomeric forms and each -trans isomer can exist in two stereoisomeric forms. The structure of Formula (I) is intended to refer to the racemic mixture of the possible -cis and -trans disubstituted cyclopropanes and each of the possible -cis and -trans disubstituted cyclopropanes, unless otherwise specified herein.

[0050] Preferably, the compounds of Formula (I) are the -trans isomers of the 1,2-disubstituted cyclopropane moiety.

[0051] Preferably, the compounds of Formula (I) are the compounds according to Formula (la) or (lb): wherein A, P, R1and R2, Q, B m and n, are as defined in any statement set out above.

[0052] Preferably, the compounds of Formula (I) are the compounds according to Formula (Ila) or (lib) : a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an Af-oxide form thereof, wherein Ai and A2 are each independently selected from H, -(Ci-C2)alkyl and - C3 cycloalkyl, R1is methyl or ethyl and Q, B and n, are as defined in any statement set out above.

[0053] Preferably, the compounds of Formula (I) are the compounds according to Formula a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof, wherein R1is methyl or ethyl and Q, B and n, are as defined in any statement set out above. Particular preferred compounds of the invention are compounds mentioned in the following list (Table A), as well as pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof.

[0054] Table A:

[0055] Further compounds of the invention are compounds mentioned in the following list (Table A-l), as well as pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof.

[0056] Table A-l: (1 R, 2R)-5, 7-d imethy l-2-[ 1 -methy l-3-[2-(1 -methylpyrazol-4-yl)cyclopropyl]pyrazol-5-yl]pyrazolo[1 ,5-a]pyrimidine (1 S, 2S)-5,7-dimethyl-2-[2-methy l-5-[2-(3-py ridy IJcyclopropy l]py razol-3-y l]-[1 ,2,4]triazolo[1 ,5-a]pyrimidine

[0057] The compound may be one or more selected from Table B, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof.

[0058] Table B:

[0059]

[0060]

[0061] The compounds of Formula (I’) may be provided in any form or mixture of isomers thereof. For example the compounds of Formula (I’) may be provided as a racemate or mixture of cis or trans isomers. In an embodiment, the compounds of Formula (I’) are provided as the -trans R,R or -trans S,S isomers of the compounds in Table B.

[0062] Preferably, the compound is one or more selected from the following list (Table C), as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof.

[0063] Table C:

[0064]

[0065] Preferably, the compounds set out in Tables A, B and C are the -trans isomers of the 1,2- disubstituted cyclopropane moiety. Preferably, the compound is one or more selected from the following list (Table D), as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof or an N-oxide form thereof: Table D:

[0066]

[0067] The compounds according to any statement above may exhibit Muscarinic M4 modulator activity.

[0068] The disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as2H and3H; isotopes of carbon, such asnC,13C and14C; isotopes of nitrogen, such as15N; isotopes of oxygen, such as17O and18O; isotopes of phosphorus, such as31P,32P and33P; isotopes of sulfur, such as35S; isotopes of fluorine, such as18F; isotopes of chlorine, such as36C1; and isotopes of iodine, such as125I. The invention includes various isotopically labelled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular,nC,18F,15O and13N or labelled compounds may be particularly desirable for PET studies for examining substrate receptor occupancy. Further, substitution with heavier isotopes, particularly deuterieum (e.g.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of Formula (F), Formula (I) to (III), Formula (la) to (Illa) and Formula (lb) to (Illb). Isotopically-labelled compounds of Formula (I’), Formula (I) to (III), Formula (la) to (Illa) and Formula (lb) to (Illb) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

[0069] In an aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to any statement set out above. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may comprise a therapeutically effective amount of the compound according to any statement set out above.

[0070] In an aspect of the present invention there is provided a method of treating or preventing a condition in a mammal comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any statement set out above. Preferably, the mammal is a human.

[0071] The method may be for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with M4 mACh dysfunction in a mammal. The treatment or prevention may be affected or facilitated by the modulatory effect of a M4 mAChR modulator such as a M4 mAChR positive allosteric modulator. The condition may be one or more of a central nervous system disorder.

[0072] The central nervous system disorder may be psychotic disorder such as schizophrenia, psychosis, acute mania, delusional disorder, schizoaffective disorder, schizophreniform disorder or substance induced psychotic disorder.

[0073] The central nervous system disorder may be selected from the group consisting of: tolerance or dependence, anxiety, depression, inflammatory or neuropathic pain, memory impairment, Alzheimer’s disease, ischemia or drug abuse and addiction.

[0074] The central nervous system disorder may be cognitive disorders: delirium, substance- induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, substance-induced persisting dementia, memory disorders or mild cognitive impairment.

[0075] The central nervous system disorder may be personality disorders: obsessive-compulsive personality disorder.

[0076] The central nervous system disorder may be substance-related disorders: alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence or opioid withdrawal.

[0077] The central nervous system disorder may be movement disorders: Tourette’s syndrome, akinetic-rigid syndrome, levodopa-induced dyskinesia and movement disorders associated with Parkinson’s disease or tardive dyskinesias.

[0078] The central nervous system disorder may be neurodevelopmental disorders, including RETT syndrome, Fragile X syndrome, Huntington’s disease, Angelman’s syndrome, West syndrome.

[0079] The condition may be one or more of a neurological or a psychiatric disorder selected from post-traumatic stress disorder, attention deficit and hyperactivity disorder, attention deficit disorder, sleep disorder, bipolar disorder, bipolar depression, autism, amyotrophic lateral sclerosis, multiple sclerosis, sarcoidosis, progressive supranuclear palsy, pain disorder, inflammatory pain or nociceptive pain, chronic pain and neuropathic pain, comprising administering an effective amount of a compound according to any statement set out above.

[0080] The present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose, for example, about 0.1 to 1000 mg or about 1 mg to about 1000 mg or about 1 mg to about 500 mg. The compositions may be administered by any suitable route. For example orally in the form of capsules, and the like, parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-lotion, rectally in the form of suppositories.

[0081] The pharmaceutical formulations of the invention may be prepared by conventional methods in the art; the nature of the pharmaceutical composition employed will depend on the desired route of administration. The total daily dose may range from about 0.01 - 2000 mg, for example from about 0.05 to 2000 mg to about 0.1 mg to about 1000 mg.

[0082] DEFINITION OF TERMS

[0083] Listed below are definitions of various terms used in the specification and claims to describe the present invention.

[0084] For the avoidance of doubt it is to be understood that in this specification “(Ci-Ce)” means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. “(Co-Ce)” means a carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. In this specification “C” means a carbon atom, "N" means a nitrogen atom, "O" means an oxygen atom and "S" means a sulphur atom.

[0085] In the case where a subscript is the integer 0 (zero) the radical to which the subscript refers, indicates that the radical is absent, i.e. there is a direct bond between the radicals.

[0086] In the case where a subscript is the integer 0 (zero) and the radical to which the subscript refers is alkyl, this indicates the radical is a hydrogen atom.

[0087] In this specification, unless stated otherwise, the term “bond” refers to a saturated covalent bond. When two or more bonds are adjacent to one another, they are assumed to be equal to one bond. For example, a radical -A-B-, wherein both A and B may be a bond, the radical is depicting a single bond.

[0088] In this specification, unless stated otherwise, the term “alkyl” includes both straight and branched chain alkyl radicals and may be methyl, ethyl, / / -propyl, z-propyl, / / -butyl, i- butyl, .s-butyl, Z-butyl, / / -pentyl, / -pentyl, / -pentyl, / / eo-pentyl, / / -hexyl, / -hexyl or t-hexyl.

[0089] In this specification, unless stated otherwise, The term “deuterioalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more hydrogen atoms in the alkyl are the isotope deuterium, i.e.,2H.

[0090] Representative examples of deuterioalkyl include CD3, CH2CD3, and CD2CD3.

[0091] In this specification, unless stated otherwise, the term “alkylene” includes both straight and branched difunctional saturated hydrocarbon radicals and may be methylene (-CH2- ), ethylene (-CH2-CH2-), / / -propylene (-CH2-CH2-CH2-), / -propylene (-CH-(CH3)-CH2- ), / / -butylene (-CH2-CH2-CH2-CH2-), / -butylene (-CH2-CH-(CH3)-CH2-), / -butylene (- CH2-C-(CH3)-CH2-), / / -pentylene (-CH2-CH2-CH2-CH2-CH2-), / -pentylene (-CH2- CH(CH3)-CH2-CH2-), / / eo-pentylene (-CH2-C(CH3)2-CH2-), / / -hexylene (-CH2-CH2- CH2-CH2-CH2-CH2-), / -hexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-) or / / eo-hexylene (- CH2-C(CH3)2-CH2-CH2-).

[0092] In this specification, unless stated otherwise, the term “cycloalkyl” refers to an optionally substituted carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo- fused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l. l]pentanyl, decahydronaphthalene, adamantane, indanyl, fluorenyl and 1,2,3,4-tetrahydronaphthalene and the like. The term “(C3- C7)cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0093] The term “aryl” refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like.

[0094] In this specification, unless stated otherwise, the term “heteroaryl” refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S. Examples of “heteroaryl” may be, but are not limited to benzimidazolyl, benzisothiazolyl benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotri azolyl, benzoxazolyl, furazanyl, furyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, phtalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thionaphthyl, triazinyl and triazolyl.

[0095] In this specification, unless stated otherwise, the term “alkylene-aryl”, “alkyleneheteroaryl” and “alkylene-cycloalkyl” refers respectively to a substituent that is attached via the alkyl radical to an aryl, heteroaryl or cycloalkyl radical, respectively. The term “(Ci-C6)alkylene-aryl” includes aryl-Ci-Ce-alkyl radicals such as benzyl, 1 -phenyl ethyl, 2-phenylethyl, 1 -phenylpropyl, 2-phenylpropyl, 3 -phenylpropyl, 1 -naphthylmethyl and 2-naphthylmethyl. The term “(Ci-C6)alkylene-heteroaryl” includes heteroaryl-Ci-Ce- alkyl radicals, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl, 3 -furylmethyl, 2-thienylmethyl, 3- thienylmethyl, 1 -imidazolylmethyl, 2-imidazolylmethyl, 3 -imidazolylmethyl, 2- oxazolylmethyl, 3-oxazolylmethyl, 2-thiazolylmethyl, 3 -thiazolylmethyl, 2- pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1 -quinolylmethyl and the like.

[0096] In this specification, unless stated otherwise, the term “heterocycle” refers to an optionally substituted, monocyclic, bicyclic or tricyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom selected independently from N, O, P, B and S. Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, by a bridging atom (e.g. O, S, N) or by a bridging group (e.g. alkylene). Examples of heterocyclic moieties include, but are not limited to: azetidinyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, oxazolidinyl, oxazolinyl, oxetanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyranyl, triazolinyl, and the corresponding benzannulated heterocycles (e.g. dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazinyl, dihydrofuropyridinyl, dihydroquinolinyl, dihydrothienopyridinyl, indolinyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, and the like).

[0097] In this specification, unless stated otherwise, the term “halo” or “halogen” may be fluoro, chloro, bromo or iodo.

[0098] In this specification, unless stated otherwise, the term “haloalkyl” means an alkyl radical as defined above, substituted with one or more halo radicals. The term “(Ci- C6)haloalkyl” may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.

[0099] In this specification, unless stated otherwise, the term “cyanoalkyl” means an alkyl radical as defined above, substituted with one or more cyano. In this specification, unless stated otherwise, the term “optionally substituted” refers to radicals further bearing one or more substituents which may be, acyl, (Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(C3- C7)cycloalkyl-(Ci-C6)alkylene, -(Co-C6)alkylene-(C3-C7)spiroalkyl-(Co-C6)alkylene, hydroxy, (Ci-Ce)alkylene-oxy, dimethylamino(Ci-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (Ci-Ce)alkylene-aryl, (Ci-C6)alkylene-heterocycle, (Ci-Ce)alkylene- heteroaryl, halogen, haloalkyl, trifluoromethyl, pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino, amido, amidinyl, oxo, carboxyl, carboxamide, (Ci- Ce)alkylene-oxy carbonyl, carbamate, sulfonamide, ester or sulfonyl.

[0100] In this specification, unless stated otherwise, the term “independently” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0101] In this specification, unless stated otherwise, the term "solvate” refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and a solvent. The solvent is a pharmaceutically acceptable solvent such as water; such solvent may not interfere with the biological activity of the solute.

[0102] In this specification, unless stated otherwise, the term "hydrate” refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and water.

[0103] In this specification, unless stated otherwise, the term "salt” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutically acceptable salts”.

[0104] The pharmaceutically acceptable salts of the invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Such methods can be found e.g. in P. H. Stahl and C. G. Wermuth “ Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002. When both a basic and an acid group are present in the same molecule, the compounds of the invention may also form internal salts, e.g., zwitterionic molecules. In this specification, unless stated otherwise, certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, R-, S-; D- and / .-forms; d- and / -forms; (+) and (-) forms; a- and P-forms; axial and equatorial forms; and combinations thereof, collectively referred to as “isomers” or “isomeric forms”.

[0105] For example, the radical

[0106] The term “isomer” includes compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including, but not limited to, 'H,2H (D), and3H (T); C may be in any isotopic form, including, but not limited to,12C,13C,14C; O may be in any isotopic form, including, but not limited to,16O and18O; and the like. F may be in any isotopic form, including, but not limited to,19F and18F; and the like.

[0107] In this specification, unless stated otherwise, the term "positive allosteric modulator of M4 mAChRs" or "allosteric modulator of M4 mAChRs " refers also to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof.

[0108] PHARMACEUTICAL COMPOSITIONS

[0109] Allosteric modulators of M4 described herein, and the pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The allosteric modulators of M4 will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the compounds of the instant invention can be found in “Remington: The Science and Practice of Pharmacy”, 23rdedition, (2021) Academic Press.

[0110] The amount of allosteric modulators of M4, administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used CNS drugs are well known to the skilled person. The total daily dose usually ranges from about 0.05 - 2000 mg.

[0111] The present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose. The compositions may be administered by any suitable route. For example, orally in the form of capsules and the like, parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, intranasally or transcutaneously in the form of a delivery system like patches.

[0112] For oral administration, the allosteric modulators of M4 thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

[0113] The tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

[0114] For parenteral administration the disclosed allosteric modulators of M4, or salts thereof, can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically- acceptable salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0115] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered for example, by subcutaneously implantation or by intramuscular injection. Thus, for example, the compounds may be formulated as an emulsion in an acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0116] Preferably disclosed allosteric modulators of M4 or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet, or a vial. The quantity of active ingredient in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration which may be by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal.

[0117] METHODS OF SYNTHESIS

[0118] The compounds according to the invention, in particular the compounds according to the Formula (I’), (I) to (III), (la)-(IIIa) and (Ib)-(IIIb), may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Wuts P.G.M., (2014) Greene’s Protective Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I’) or Formula (I) to (III), (la)-(IIIa) and (Ib)-(IIIb).

[0119] The compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or 5-enanti omers. If for instance, a particular enantiomer is required, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as an amino or an acidic functional group such as carboxyl, this resolution may be conveniently performed by fractional crystallization from various solvents as the salts of an optical active acid or by other methods known in the literature (e.g. chiral column chromatography). Resolution of the final product, an intermediate or a starting material may be performed by any suitable method known in the art (Eliel E. L. and Wilen S. H. (1994) Stereochemistry of Organic Compounds, Wiley-Interscience).

[0120] Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A. R. et al. (2008) Comprehensive Heterocyclic Chemistry, Elsevier Science).

[0121] The product from the reaction can be isolated and purified by employing standard techniques, such as extraction, chromatography, recrystallization and distillation.

[0122] The compounds of the invention may be prepared by general route of synthesis as disclosed in the following methods. The schemes in this section are not intended to constrain the scope of the invention in any way.

[0123] In one embodiment of the present invention, compounds of formula (I) may be prepared according to the synthetic sequence illustrated in Scheme 1. Pyrazole compounds 1 may be coupled with pinacol boronic esters 2 in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki-Miyaura coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf), in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to afford compounds of formula (I).

[0124] Scheme 1 X = halogen; A, P, R1and R2, Q, B, m and n are as defined in any statement set out above

[0125] Intermediates g4 may be prepared according to the synthetic sequence illustrated in Scheme 2.

[0126] According to step 1 of Scheme 2, pyrazoles gl may be reacted with hydrazine to afford carbohydrazides g2. According to step 2, compounds g2 may be condensed with bis((methylsulfanyl)methanimidamide) in the presence of sulfuric acid to afford cyclized compounds g3. According to step 3, compounds g3 may be reacted with diones g30 to afford the bicyclic compounds g4.

[0127] Scheme 2

[0128] X = halogen; A1, A2, A3, R1and R2are as defined in any statement set out above

[0129] Compounds I may also be prepared according to the synthetic sequence illustrated in Scheme 2 bis. According to step 1, pyrazoles gl may be coupled with pinacol boronic esters 2 in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki-Miyaura coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf), in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to afford compounds gl’. According to step 2, compounds gl’ may be reacted with hydrazine to afford carbohydrazides g’2. According to step 3, compounds g’2 may be reacted with bis((methylsulfanyl)methanimidamide), sulfuric acid and sodium hydroxide in a cyclocondensation reaction to afford compounds g’3. Finally, in step 4 as in scheme 2, the aminopyrazole intermediate g’3 will be reacted with the dione g30 to afford compounds I.

[0130] Scheme 2 bis

[0131] X = halogen; A1, A2, A3, R1, R2, B, Q and n are as defined in any statement set out above

[0132] Pinacol boronic esters g5, to be used in the preparation of intermediates g4 according to Scheme 4, may be prepared according to the synthetic sequence illustrated in Scheme 3. Corresponding pyrazoles g’5 (for example, bromo-l-methyl-lH-pyrazole) may be coupled with 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane to afford pinacol boronic esters g5.

[0133] Scheme 3

[0134] R1and R2are as defined in any statement set out above Intermediates g4’ may be prepared according to the synthetic sequence illustrated in

[0135] Scheme 4.

[0136] According to step 1 of Scheme 4, pyrazoles g6 may be reacted with compounds g60 to afford bicyclic compounds g7. Compounds g7 may be reacted with phosphoroyl trichloride to afford compounds g8. According to step 3, compounds g8 may be reacted with 2-methylpropan-2-ol to afford methoxy- derivatives g9 in a methoxylation reaction. According to step 4, compounds g9 may be coupled with compounds g5 in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki- Miyaura coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf), in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to afford intermediates g4’.

[0137] Step 3 Step 4

[0138] Scheme 4

[0139] X = halogen; A1, A2, R1and R2are as defined in any statement set out above

[0140] Pinacol boronic esters 2, to be used in the synthesis of compounds [I] according to Scheme 1, may be prepared using either compounds glO, compounds g!3 or compounds g!8 as starting material. Scheme 5 illustrates possible synthesis routes to pinacol boronic esters 2 using glO as starting material.

[0141] According to Route A of Scheme 5, compounds glO may be coupled with vinylboronic acid pinacol ester gll to afford pinacol boronic esters g!2. Cyclopropanation may be performed via any suitable reaction such as a Corey-Chaykovsky reaction, wherein compounds gll are reacted with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride to afford pinacol boronic esters 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0142] According to Route B of Scheme 5, compounds glO may be coupled with tert-butyl acrylate in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki cross coupling reaction, mediated by palladium-complex catalysts such as palladium(II) acetate, in the presence of a base such as triethylamine, in an appropriate solvent such as anhydrous acetonitrile, to afford compounds gl4. Cyclopropanation may be performed via any suitable reaction such as a Corey- Chaykovsky reaction, wherein compounds gl4 are reacted with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride, to afford compounds g!5. According to step 3, esters g!5 may be hydrolysed in acidic conditions to afford the corresponding carboxylic acids g!6. According to step 4, compounds g!6 may be reacted with N-hydroxyphthalimide in the presence of N,N'- dicyclohexylcarbodiimide (DCC) in the presence of triethylamine (TEA), 4- Dimethylaminopyridine (DMAP) and di chloromethane (DCM) to form the corresponding esters g!7. According to step 5, compounds g!7 may be reacted with bis(pinacolato)diboron in the presence of methyl isonicotinate and ethyl acetate at a suitable temperature to afford pinacol boronic esters 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0143] According to Route C of Scheme 5, compounds glO may be coupled with tributyl(vinyl)tin in a Stille reaction, mediated by a Pd(0) catalyst such as tetrakis(triphenyl-phosphine)palladium, in a suitable solvent such as anhydrous THF, to afford corresponding compounds g22. Compounds g22 may then be coupled with tertbutyl diazoacetate in a coupling reaction in the presence of a catalyst such as 5,10,15,20- tetraphenyl-2 l / / ,23 / / -porphine cobalt(II), in a suitable solvent such as anhydrous toluene, to form compounds g!4. To afford pinacol boronic esters 2, the synthesis may be continued according to steps 2 to 5 described above. To then afford the final product [I], the synthesis may be continued according to Scheme 1. According to Route D of Scheme 5, compounds glO may be coupled with ethyl 2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-cyclopropane-l-carboxylate in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki- Miyaura coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf) in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to afford compounds g’15. Esters g’15 may then be hydrolysed, for example by acid hydrolysis with hydrochloric acid in a suitable solvent such as dioxane, to afford carboxylic acids g!6. To afford pinacol boronic esters 2, the synthesis may be continued according to steps 2 to 5 described above. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0144]

[0145] Scheme 5

[0146] X = halogen; Q, B and n are as defined in any statement set out above Scheme 6 illustrates possible synthesis routes to pinacol boronic esters 2 using g!3 as starting material.

[0147] According to Route A of Scheme 6, compounds g!3 may be coupled with bis(pinacolato)diboron g’ll to afford pinacol boronic esters g!2. Cyclopropanation may then be performed via any suitable cyclopropanation reaction such as a Corey- Chaykovsky reaction, wherein compounds g!2 may be reacted with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride to afford pinacol boronic esters 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0148] According to Route B of Scheme 6, compounds g!3 may be reacted with tert-butyl 2- (triphenylphosphoranylidene)acetate in a suitable solvent such as anhydrous toluene to afford esters g!4. Cyclopropanation step 2 may be performed via any suitable cyclopropanation reaction such as a Corey-Chaykovsky reaction, wherein compounds g!4 are reacted with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride to afford compounds g!5. According to step 3, esters g!5 may be hydrolysed in acidic conditions to afford the corresponding carboxylic acids g!6. According to step 4, compounds g!6 may be reacted with N-hydroxyphthalimide in the presence of N,N' -di cyclohexylcarbodiimide (DCC) in the presence of triethylamine (TEA), 4-Dimethylaminopyridine (DMAP) and di chloromethane (DCM) to form the corresponding esters g!7. According to step 5, compounds g!7 may be reacted with bis(pinacolato)diboron in the presence of methyl isonicotinate and ethyl acetate at a suitable temperature to afford pinacol boronic esters 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0149] According to Route C of Scheme 6, compounds g!3 may be condensed with malonic acid in pyridine as solvent and piperidine to afford after decarboxylation by heating the acrylic acids g’14. Compounds g’14 may be acylated by reaction with methoxy(methyl)amine hydrochloride, a suitable base such as N,N- diisopropylethylamine, and 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (step 2A) to obtain the Weinreb amide intermediate. Cyclopropanation step 2B may be performed via any suitable cyclopropanation reaction such as a Corey- Chaykovsky reaction, i.e. reaction with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride to afford corresponding compounds g”15. Hydrolysis may then be performed with any suitable reagent such as a mineral bases like potassium tert-butoxide to afford compounds g!6. To afford pinacol boronic esters 2, the synthesis may be continued according to steps 4 and 5 described above. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0150]

[0151] Scheme 6

[0152] Q, B and n are as defined in any statement set out above Scheme 7 illustrates a possible synthesis route to pinacol boronic esters 2 using compounds gl8 as starting material.

[0153] The Weinreb amide g”15 of Compounds gl8 is synthesized as step 1 by acylation with methoxy(methyl)amine hydrochloride in the presence of a suitable base such as N,N- diisopropylethylamine, and a coupling reagent such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride. Cyclopropanation step 2 may be performed via any suitable cyclopropanation reaction such as a Corey-Chaykovsky reaction, i.e. reaction with a sulfonium halide such as trimethyl sulfoxonium iodide in the presence of a strong base such as sodium hydride to afford corresponding compounds g”15. Hydrolysis step 3 may be performed with any suitable base such as potassium tert-butoxide to afford compounds gl6. To afford pinacol boronic esters 2, the synthesis may be continued according to steps 4 and 5 described above. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0154] Acylation

[0155] Scheme 7

[0156] Q, B and n are as defined in any statement set out above

[0157] Final compounds (I) may be prepared according to the synthetic sequence illustrated in Scheme 8.

[0158] Compound 1 may be coupled with ethyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclopropane-l -carboxylate in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki -Miy aura coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf) in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to afford esters g!3. According to step 2, esters g!3 may be hydrolysed in acidic or basic conditions to afford the corresponding carboxylic acids g!4. According to step 3, compounds g!4 may be reacted with N-hydroxyphthalimide in the presence of N,N'- dicyclohexylcarbodiimide in the presence of triethylamine (TEA), 4- Dimethylaminopyridine (DMAP) and di chloromethane (DCM) to form the corresponding esters g!5. According to step 4, compounds g!5 may be reacted with bis(pinacolato)diboron in the presence of methyl isonicotinate and ethyl acetate at a suitable temperature to afford pinacol boronic esters g!6. According to step 5, compounds g!6 and g5 may be coupled in a suitable reaction known by people skilled in the art of organic synthesis, for example a Suzuki -Miy aura coupling reaction, mediated by palladium-complex catalysts such as PdCh(dppf) in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane / water, to give compounds (I).

[0159] X = halogen; A, P, R1and R2, Q, B, m and n are as defined in any statement set out above EXPERIMENTAL

[0160] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0161] Specifically, the following abbreviations may be used in the examples and throughout the specification.

[0162] All references to brine refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. Most of the reactions were monitored by UPLC-MS (Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer or Waters ACQUITY UPLC I- Class PLUS System with Waters SQ Detector 2) or thin-layer chromatography on 0.25mm Merck silica gel plates (60F-254), visualized with UV light. Flash column chromatography was performed on prepacked silica gel cartridges (50 pM, puriFlash®), Biotage® Sfar KP-Amino D (Duo 50 pM, 28-110 g) and puriFlash® RP-AQ or C18-HP (15 pM, 120-330 g). Preparative TLC was performed on silica gel plates glass-backed, 1000 pM, Analtech.

[0163] Synthesis of intermediates g4:

[0164] R1= Me, Et

[0165] 3-Bromo-l-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyr azole According to Step 1 : 3 -Bromo- 1 -methyl- UT-pyrazole (10.00 g, 62.11 mmol, 1.0 eq.) was dissolved in anhydrous THF (300 ml) in a round-bottom flask equipped with a magnetic stirring bar and cooled to -78 °C. Then, lithium diisopropylamide (2.0 M in THF / heptane / EtPh, 31 mL, 62.11 mmol, 1.0 eq.) was added dropwise keeping the internal temperature below -70 °C. The resulting mixture was stirred at -78 °C for 1 hour and after that 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (23.11 g, 124.22 mmol, 2.0 eq.) was carefully added. Next, the reaction mixture was spontaneously warmed to room temperature and stirred overnight. After the specified time, the reaction mixture was poured into 100 mL of HC1 (10% aq. solution), extracted with ethyl acetate (3^75 mL), dried over MgSCU, filtered and evaporated to dryness. The crude product was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0- 40%) to afford the title compound as a yellow crystals (13.80 g, 74%).

[0166] Synthesis of cores 1 to 7 (intermediates 1):

[0167] Ai = CHF2, H, Me, A2= H, A3= CHF2, H, Me, R1= Me, Et

[0168] Scheme 9

[0169] Table 1

[0170] 2-(3-Bromo-l-ethyl-lH-pyrazol-5-yl)-5,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Core 5)

[0171] 3-Bromo-l -ethyl- IH-pyrazoleS-carbohydrazide

[0172] According to Scheme 9 Step 1 : A 100 mL round bottom flask was charged with methyl 3-bromo-l-ethyl-lH-pyrazole-5-carboxylate (2.0 g, 8.62 mmol), methanol (20 mL) and hydrazine hydrate (862.82 mg, 17.24 mmol). The mixture was stirred for 5 h at 70 °C and then concentrated under reduced pressure to afford 3-bromo-l-ethyl-lH-pyrazole-5- carbohydrazide (2.0 g, 90.0% purity, 89.6% yield) as a yellow solid.

[0173] 3-(3-Bromo-l-ethyl-lH-pyrazol-5-yl)-lH-l, 2, 4-triazol-5-amine

[0174] According to Scheme 9 Step 2: To a solution of 3-bromo-l-ethyl-lH-pyrazole-5- carbohydrazide (2.0 g, 8.62 mmol) in water (20 mL) are added bis((methylsulfanyl)methanimidamide); sulfuric acid (4.79 g, 17.24 mmol) and sodium hydroxide (689.43 mg, 17.24 mmol). The reaction is stirred at 50° C for 24 h. The reaction mixture is filtered and washed with water (5 mL). The solid is dried under reduced pressure at 40° C to give 3-(3-bromo-l-ethyl-lH-pyrazol-5-yl)-lH-l,2,4-triazol- 5-amine (1.0 g, 45.1% yield).

[0175] 2-(3-Bromo-l-ethyl-lH-pyrazol-5-yl)-5, 7-dimethyl-[ 1,2, 4 ]triazolo[ 1, 5 -a] pyrimidine According to Scheme 9 Step 3: To the solution of 3-(3-bromo-l-ethyl-lH-pyrazol-5-yl)- lH-l,2,4-triazol-5-amine (1.0 g, 3.89 mmol) in AcOH (10 mL) was added pentane-2,4- dione (390.36 mg, 3.9 mmol) and the reaction mixture was heated at 100 °C for a night. The solution was cooled to room temperature and diluted with water. The obtained solid was filtered and dried to obtain the product as a white powder (1.0 g, 80% yield). Synthesis of cores 9 (intermediates 1):

[0176] Scheme 10 Ai = CH3, A2= CH3, R1= Me

[0177] Table 2

[0178] 3-Bromo-5-{5, 7-dim ethyl- [ l,3]oxazolo[5,4- / >]pyridin-2-yl}-l-methyl-LH-pyrazole (Core 9)

[0179] 3-Amino-4, 6-dimethyl-l, 2-dihydropyridin-2-one

[0180] According to Scheme 10 Step 1 : In a round bottom flask equipped with a magnetic stirring bar, 4,6-dimethyl-3-nitro-l,2-dihydropyridin-2-one (500 mg, 2.97 mmol, 1.0 eq.) was dissolved in a mixture of anhydrous solvents: methanol (5 mL) and tetrahydrofuran (5 mL). The resulting mixture was degassed and purged with Ar. Then, palladium on carbon (10% wet, 158 mg, 0.14 mmol, 0.05 eq.) was added and the reaction mixture was stirred at room temperature for 24 hours under hydrogen atmosphere. After the specified time, the mixture was filtered through a pad of Celite® Hyflo Supercel, rinsed with methanol and evaporated to dryness to afford the title compound as a yellow solid (420 mg, 99%). The title compound was used as a crude in the next step without additional purification.

[0181] 5, 7 -Dimethyl- [ 1, 3 ]oxazolo[5, 4-b ] pyridine

[0182] According to Scheme 10 Step 2: To a solution of 3-amino-4,6-dimethyl-l,2- dihydropyridin-2-one (420 mg, 2.92 mmol, 1.0 eq.) in hydrochloric acid in methanol (1 mL) was added trimethyl orthoformate (6.4 mL, 58.58 mmol, 20.0 eq.). The resulting mixture was stirred at 120 °C for 48 hours. After that time, reaction mixture was concentrated under vacuum and the crude product was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-20%) to afford the title compound as a yellow solid (160 mg, 35%).

[0183] 2-Bromo-5, 7 -dimethyl- [ 1, 3 ]oxazolo[5, 4-b ]pyridine

[0184] According to Scheme 10 Step 3: 5,7-Dimethyl-[l,3]oxazolo[5,4-Z>]pyridine (110 mg, 0.71 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (2 mL) in a flask with a magnetic stirring bar. The resulting mixture was cooled to -25 °C followed by addition of lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.7 mL, 0.71 mmol, 1.0 eq.). The obtained solution was stirred at 5 °C for 1 hour, then / ' / -bromosuccinimide (125 mg, 0.71 mmol, 1.0 eq.) was subsequently added. The reaction mixture was stirred at 5 °C for additional 4 hours. After the specified time, the resulting mixture was quenched with saturated NH4CI and the aqueous layer was extracted with ethyl acetate (3 / 20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified on FCC (silica gel) eluting with ethyl acetate in hexane (0-15%) to afford the title compound as a white solid (110 mg, 69%).

[0185] 3-Bromo-5-{5, 7-dimethyl-[ 1, 3 ]oxazolo[5, 4-b ]pyridin-2-yl}-l-methyl-lH-pyrazole According to Scheme 10 Step 4: A solution of 2-bromo-5,7-dimethyl-[l,3]oxazolo[5,4- Z>]pyridine (110 mg, 0.48 mmol, 1.0 eq.) and 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (240 mg, 0.53 mmol, 1.1 eq.), potassium phosphate tribasic (308 mg, 1.45 mmol, 3.0 eq.) in the mixture of dioxane (3.9 mL) with water (0.8 mL) was degassed and purged with Ar. Then, XPhos Pd G3 (41 mg, 0.05 mmol, 0.1 eq.) followed by cataCXium A (17 mg, 0.05 mmol, 0.1 eq.) were subsequently added and the reaction mixture was stirred at 80 °C for 1 hour (microwave irradiation). After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated to dryness. The crude product was purified on column chromatography using puriFlash® C18-AQ, 15 pM, 40 g column, eluting with acetonitrile in water (5-100%, acidic method with 0.1% of formic acid in both eluents) to afford the title compound as a white solid (31 mg, 20%).

[0186] Synthesis of cores 10 (intermediates 1):

[0187] Ai = CH3, A2= CH3, R1= Me

[0188] Table 3

[0189] 3-Bromo-5-{5, 7-dim ethyl- [ l,3]thiazolo[5,4- / >]pyridin-2-yl}-l-methyl-LH-pyrazole

[0190] (Core 10)

[0191] 5, 7 -Dimethyl- [ 1, 3 ]thiazolo[5, 4-b ]pyridin-2 -amine According to Scheme 11 Step 1 : In a seal tube equipped with a magnetic stirring bar, 2- chloro-4,6-dimethylpyridin-3-amine (1.00 g, 6.38 mmol, 1.0 eq.) was dissolved in ethanol (50 mL). Then, potassium thiocyanate (3.10 g, 31.92 mmol, 5.0 eq.) was added followed by hydrochloric acid (3.7-4.3 N in dioxane, 82 mL, 52.0 eq.). The resulting mixture was stirred at 100 °C for 12 hours. After that time, the additional portion of potassium thiocyanate (1.24 g, 12.76 mmol, 2.0 eq.) was added and stirring was continued at 100 °C for 12 hours. Next, the reaction mixture was evaporated to dryness and the crude product was purified on FCC (silica gel) eluting with ethyl acetate in hexane (0-100%) to afford the title compound as a white solid (150 mg, 12%).

[0192] 2-Bromo-5, 7 -dimethyl- [ 1, 3 ]thiazolo[ 5, 4-b ]pyridine

[0193] According to Scheme 11 Step 2: Copper(II) bromide (0.22 g, 0.048 mmol, 1.2 eq.) was dissolved in anhydrous acetonitrile (15 mL) in a round bottom flask equipped with a magnetic stirring bar. The resulting solution was cooled to 0 °C and Zc / V-butyl nitrite (0.17 mL, 1.43 mmol, 1.8 eq.) was added followed by 5,7-dimethyl-[l,3]thiazolo[5,4- Z>]pyridin-2-amine (150 mg, 1.0 eq.). The reaction mixture was stirred at room temperature for 4 hours. After the specified time, the mixture was filtered through a pad of Celite® Hyflo Supercel, rinsed with ethyl acetate and evaporated to dryness. The crude product was purified on FCC (silica gel) eluting with ethyl acetate in hexane (0-100%) to afford the title compound as a white solid (95 mg, 49%).

[0194] 3-Bromo-5-{5, 7-dimethyl-[ 1, 3 ]thiazolo[5, 4-b ]pyridin-2-yl}-l-methyl-lH-pyrazole According to Scheme 11 Step 3: A solution of 2-bromo-5,7-dimethyl-[l,3]thiazolo[5,4- Z>]pyridine (95 mg, 0.39 mmol, 1.0 eq.) and 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l / 7-pyrazole (199 mg, 0.43 mmol, 1.1 eq.), potassium phosphate tribasic (249 mg, 1.17 mmol, 3.0 eq.) in the mixture of dioxane (3.5 mL) with water (0.7 mL) was degassed and purged with Ar. Then, XPhos Pd G3 (33 mg, 0.04 mmol, 0.1 eq.) followed by cataCXium A (14 mg, 0.04 mmol, 0.1 eq.) were subsequently added and the reaction mixture was stirred at 100 °C for 1 hour (microwave irradiation). After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated to dryness. The crude product was purified on column chromatography using puriFlash® C18-AQ, 15 pM, 40 g column, eluting with acetonitrile in water (5-100%, acidic method with 0.1% of formic acid in both eluents) to afford the title compound as a white solid (63 mg, 50%).

[0195] Synthesis of cores 11 (intermediates 1):

[0196] Scheme 12

[0197] Ai = CH3, A2= CH3, R = Me, R1= Me

[0198] Table 4

[0199] 3-Bromo- 1 -methyl-5- {3,5,7-trimethyl-3Z / -imidazo[4,5- / >]pyridin-2-yl}- 1 / / -pyrazole (Core 11)

[0200] 4,6-Trimethyl-3-nitropyridin-2-amine

[0201] According to Scheme 12 Step 1 : 2-Chl oro-4, 6-dimethyl-3 -nitro- 1,2-dihydropyri dine (0.48 g, 2.58 mmol, 1.0 eq.) was dissolved in 2-methoxyethanol (3 mL) in a seal tube equipped with a magnetic stirring bar. Then, methylamine (2.0 M in THF, 3.2 mL, 6.45 mmol, 2.5 eq.) was added and the resulting mixture was stirred at 80 °C for 8 hours. After the specified time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-30%) to afford the title compound as a yellow solid (420 mg, 81%).

[0202] 2.4.6-Trimethylpyridine-2, 3-diamine

[0203] According to Scheme 12 Step 2: In a round bottom flask equipped with a magnetic stirring bar, 4,6-trimethyl-3-nitropyridin-2-amine (200 mg, 0.99 mmol, 1.0 eq.) was dissolved in ethanol (4 mL). The resulting mixture was degassed and purged with Ar. Then, palladium on carbon (10% wet, 127 mg, 1.19 mmol, 1.2 eq.) was added and the reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. After the specified time, the mixture was filtered through a pad of Celite® Hyflo Supercel, rinsed with ethanol and evaporated to dryness to afford the title compound as a yellow solid (140 mg, 93%). The title compound was used as a crude in the next step without additional purification.

[0204] 3.5. 7-Trimethyl-3H-imidazo[ 4, 5-b ] pyridine

[0205] According to Scheme 12 Step 3: To a solution of 2, 4, 6-trimethylpyridine-2, 3-diamine (288 mg, 1.89 mmol, 1.0 eq.) in hydrochloric acid in methanol (1 mL) was added trimethyl orthoformate (4.1 mL, 38.08 mmol, 20.0 eq.). The resulting mixture was stirred at 120 °C for 1 hour. After that time, the reaction mixture was concentrated under vacuum and the crude product was purified using FCC (silica gel) eluting with dichloromethane in methanol (0-10%) to afford the title compound as a yellow solid (170 mg, 55%).

[0206] 2-Bromo-3, 5, 7-trimethyl-3H-imidazo[ 4, 5-b ]pyridine

[0207] According to Scheme 12 Step 4: 3,5,7-Trimethyl-37 / -imidazo[4,5- / i]pyridine (0.35 g, 2.19 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (7 mL) in a flask with a magnetic stirring bar. The resulting mixture was cooled to -25 °C followed by addition of lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 2.4 mL, 2.41 mmol, 1.1 eq.). The obtained solution was stirred at 5 °C for 1 hour, then A-bromosuccinimide (0.46 g, 2.63 mmol, 1.2 eq.) was subsequently added. The reaction mixture was stirred at 50 °C overnight. After the specified time, the resulting mixture was quenched with saturated NH4CI and the aqueous layer was extracted with ethyl acetate (3 / 30 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified on FCC (silica gel) eluting with ethyl acetate in hexane (0-15%) to afford the title compound as a yellow solid (225 mg, 30%, 70% content).

[0208] 3-Bromo-l-methyl-5-{3, 5, 7-trimethyl-3H-imidazo[ 4, 5-b ]pyridin-2-yl}-lH-pyr azole According to Scheme 12 Step 5: A solution of 2-bromo-3,5,7-trimethyl-3J / -imidazo[4,5- Z>]pyridine (32 mg, 0.13 mmol, 1.0 eq.) and 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (67 mg, 0.14 mmol, 1.1 eq.), potassium phosphate tribasic (84 mg, 0.39 mmol, 3.0 eq.) in the mixture of dioxane (1.1 mL) with water (0.2 mL) was degassed and purged with Ar. Then, XPhos Pd G3 (11 mg, 0.01 mmol, 0.1 eq.) followed by cataCXium A (5 mg, 0.01 mmol, 0.1 eq.) were subsequently added and the reaction mixture was stirred at 60 °C for 1 hour (microwave irradiation). After that time, reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated to dryness. The crude product was purified on column chromatography using puriFlash® C18-AQ, 15 pM, 40 g column, eluting with acetonitrile in water (5-100%, acidic method with 0.1% of formic acid in both eluents) to afford the title compound as a white solid (15 mg, 8%).

[0209] Synthesis of cores 12 to 14 (intermediates 1):

[0210] Ai = Me, A2= Me, R = H, Me, R1= Me, Et.

[0211] Scheme 13

[0212] Table 5

[0213] 2-(3-Bromo-l-methyl-lH-pyrazol-5-yl)-3,5,7-trimethylpyrazolo[l,5-a]pyrimidine (Core 12)

[0214] 5-Bromo-4-methyl-3-nitro-lH-pyrazole

[0215] According to Scheme 13 Step 1 : Bromine (47.21 g, 299.12 mmol, 15.14 ml, 2.0 equiv) was added toa solution of 4-methyl-3-nitro-lH-pyrazole (19.0 g, 149.56 mmol) in H2O and mixture was stirred overnight at 60°C. The reaction mixture was cold and filtered to give crude 5-bromo-4-methyl-3-nitro-lH-pyrazole (25.0 g, 98.0% purity, 118.93 mmol, 79.5% yield) which was put into the next stage without purification.

[0216] 5-Bromo-4-methyl-lH-pyrazol-3-amine

[0217] According to Scheme 13 Step 2: To a solution of 5-bromo-4-methyl-3-nitro-lH-pyrazole (25.0 g, 121.98 mmol) in EtOH (500 mL) and H2O (50 mL) was added , iron (34.12 g, 609.92 mmol) and ammonium chloride (32.33 g, 609.92 mmol). The resulting solution was heated at 90°C overnight. The reaction mixture was filtered through celite and concentrated under vacuum. Mixture was diluted with H2O and extracted with EtOAc (2*200 ml). The organic layer was washed with brine, and filtered through a Na2SO4. The filtrate was concentrated in vacuo to give the crude 5-bromo-4-methyl-lH-pyrazol-

[0218] 3-amine (10.0 g, 95.0% purity, 53.97 mmol, 44.2% yield).

[0219] 2-Bromo-3, 5, 7-trimethylpyrazolo[ 1, 5 -a] pyrimidine

[0220] According to Scheme 13 Step 3: Pentane-2, 4-dione (3.64 g, 36.38 mmol, 3.76 ml, 1.2 equiv) was added to solution of 3-bromo-4-methyl-lH-pyrazol-5-amine (5.3 g, 30.32 mmol) in acetic acid and mixture was stirred overnight at r.t. Solution was evaporated under vacuum and to give crude 2-bromo-3,5,7-trimethylpyrazolo[l,5-a]pyrimidine (7.0 g, 95.0% purity, 27.7 mmol, 91.4% yield) which was put into the next stage without purification.

[0221] 3-Bromo-l-methyl-5-3, 5, 7-trimethylpyrazolo[ 1, 5 -a Jpyrimidin-2-yl-lH-pyr azole According to Scheme 13 Step 4: A solution of 2-bromo-3,5,7-trimethylpyrazolo[l,5- a]pyrimidine (1.0 g, 4.16 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.31 g, 4.58 mmol), dipotassium carbonate (1.72 g, 12.5 mmol) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (339.09 mg, 416.63 pmol) in dioxane (8 mL) and water (2 mL) was degassed and purget with Ar. The resulting mixture was heated at 80 °C overnight. Then the mixture was cooled to rt. diluted with H2O (10 mL) and extracted with EtOAc (2*20 ml). The organic layer was washed with brine, and filtered through a Na2SO4. The filtrate was concentrated in vacuo to give the crude 3-bromo-l-methyl-5- 3,5,7-trimethylpyrazolo[l,5-a]pyrimidin-2-yl-lH-pyrazole (350.0 mg, 95.0% purity, 1.04 mmol, 24.9% yield) which was purified by FC (SiCL, Hexane-EtOAc).

[0222] Synthesis of cores 15 to 16 (intermediates 1):

[0223] Ai = Me, R = H, Me, R1= Me, Et.

[0224] Scheme 14

[0225] Table 6 3-Bromo-5-5-methoxy-7-methylpyrazolo[l,5-a]pyrimidin-2-yl-l-methyl-lH- pyrazole (Core 15)

[0226] 2 -Bromo- 7-methylpyrazolo[ 1, 5-a ]pyrimidin-5-ol

[0227] According to Scheme 14 Step 1 : 3-Bromo-lH-pyrazol-5-amine (600.0 mg, 3.73 mmol), cesium (I) carbonate (1.82 g, 5.59 mmol) and methyl (2E)-3-methoxybut-2-enoate (872.61 mg, 6.71 mmol) were mixed in DMF and stirred at 110 °C for 48 hrs. Reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution twise. Dried organic extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 2-bromo-7-methylpyrazolo[l,5- a]pyrimidin-5-ol (850.0 mg, 90.0% purity, 90% yield).

[0228] 2-Bromo-5-chloro- 7-methylpyrazolo[ 1, 5-a ] pyrimidine

[0229] According to Scheme 14 Step 2: 2-Bromo-7-methylpyrazolo[l,5-a]pyrimidin-5-ol (850.0 mg, 3.73 mmol) was dissolved in phosphoroyl trichloride (2.83 g, 18.64 mmol, 1.72 ml, 5.0 equiv) and refluxed for 24 hrs. The reaction mixture was evaporated, dissolved in ethyl acetate and washed with sodium bicarbonate twice. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to give 2-bromo- 5-chloro-7-methylpyrazolo[l,5-a]pyrimidine (540.0 mg, 58.8% yield).

[0230] 2-Bromo-5-methoxy- 7-methylpyrazolo[ 1, 5-a pyrimidine

[0231] According to Scheme 14 Step 3: 2-Methylpropan-2-ol (178.4 mg, 2.41 mmol) was dissolved in 5ml of methanol and 2-bromo-5-chloro-7-methylpyrazolo[l,5-a]pyrimidine (540.0 mg, 2.19 mmol) was added. The obtained reaction mixture was stirred for 16 hrs at r.t. When the reaction was completed reaction mixture was evaporated under reduced pressure, dissolved in ethyl acetate washed with aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to give 2-bromo-5-methoxy-7-methylpyrazolo[l,5-a]pyrimidine (450.0 mg, 90.0% purity, 1.67 mmol, 76.4% yield). 3-Bromo-5-5-methoxy-7-methylpyrazolo [ 1, 5-a ]pyrimidin-2-yl- 1 -methyl- IH-pyr azole According to Scheme 14 Step 4: A solution of 2-bromo-5-methoxy-7- methylpyrazolo[l,5-a]pyrimidine (600.0 mg, 85.0% purity, 2.11 mmol), 3-bromo-l- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (663.18 mg, 2.32 mmol), dipotassium carbonate (726.67 mg, 5.27 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (171.54 mg, 210.76 pmol) in dioxane (20 mL) and water (5 ml) was degassed and purget with Ar. The resulting mixture was heated at 80 °C overnight. Then the mixture was cooled to rt. and diluted with H2O (100 ml) and extracted with EtOAc (2*50 ml). The organic layer was washed with brine, and filtered through ISfeSC The filtrate was concentrated in vacuo to give the crude which was purified by FC to give 3-bromo-5-5- methoxy-7-methylpyrazolo[l,5-a]pyrimidin-2-yl-l -methyl- IH-pyrazole (100.0 mg, 99.0% purity, 14.6% yield).

[0232] R1= Me, R1= Me.

[0233] Scheme 15

[0234] Table 7

[0235] 6-(3-Bromo-l-methyl-lH-pyrazol-5-yl)-3-methyl-[l,2,4]triazolo[3,4- b][l,3,4]thiadiazole (Core 17)

[0236] According to Scheme 15 Step 1 : A mixture of pyrazole carboxylic acid (1.0 g, 4.93 mmol) and 4-amino-5-methyl-4H-l,2,4-triazole-3-thiol (640.4 mg, 4.93 mmol) in POCI3 (20 mL) was refluxed for 5 h and condensed under reduced pressure. The residue was poured into ice-water, and the mixture was adjusted to pH 10-11 with 30% sodium hydroxide solution. The solid was collected by filtration, washed with water, and recrystallized with DMF-H20 to afford 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3- methyl-[l,2,4]triazolo[3,4-b][l,3,4]thiadiazole (1.02 g, 69.0% yield) as pink crystals. The compounds shown in Table 3 may be prepared similarly to the compound described above, with appropriate starting materials. Stereochemistry of cPr linker for all examples is defined as trans-rac (apart from isomers separated via chiral-SFC purification).

[0237] EXAMPLE 1: 5-6-Fluoro-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl-l-methyl-3-[2-(l- methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole (Final compound 1-6)

[0238] Scheme 2 bis’ Methyl l-methyl-3-[2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole-5- carboxylate

[0239] According to Scheme 2bis’ Step 1 : To A solution of methyl 3-bromo-l-methyl-lH- pyrazole-5-carboxylate (500.0 mg, 2.29 mmol), l-methyl-4-[2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclopropyl]-lH-pyrazole (1.14 g, 4.59 mmol), di cyclohexyl [2',4',6'-tris(propan-2-yl)-[ 1 , 1 '-biphenyl]-2-yl]phosphane; 2'-amino-[ 1 , 1 '- biphenyl]-2-ylpalladio methanesulfonate (193.88 mg, 229.36 pmol), tripotassium phosphate (1.46 g, 6.88 mmol) and bis(adamantan-l-yl)(butyl)phosphane (82.17 mg, 229.36 pmol) in dioxane (4 mL) and water (1 ml) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was cooled to rt. and diluted with H2O (10 ml) and extracted with EtOAc (2*20 ml). The organic layer was washed with brine, filtered through a Na2SO4. The filtrate was concentrated in vacuo to give the crude which was purified by HPLC (35-35-70% 0-1-5 min H2O / MeOH, flow: 30 ml / min (loading pump 4 ml / min methanol); column: Chromatorex 18 SMB100-5T 100x19 mm 5 um) to provide methyl l-methyl-3-[2-(l -methyl- lH-pyrazol-4- yl)cyclopropyl]-lH-pyrazole-5-carboxylate (40.0 mg, 6.7% yield). l-Methyl-3-[2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole-5-carbohydrazide According to Scheme 2bis’ Step 2: A 25 mL round bottom flask was charged with methyl l-methyl-3-[2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole-5-carboxylate (50.0 mg, 192.09 pmol, methanol (5 mL) and hydrazine hydrate (96.14 mg, 1.92 mmol). The mixture was stirred for 5 h at 70 °C and then concentrated under reduced pressure to afford l-methyl-3-[2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole-5- carbohydrazide (50.0 mg, 97.0% purity, 97% yield) as a yellow solid.

[0240] 3-( 1 -Methyl-3-(2-( 1 -methyl- lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)-lH-l, 2, 4- triazol-5-amine

[0241] According to Scheme 2bis’ Step 3: To a solution of l-methyl-3-[2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl]-lH-pyrazole-5-carbohydrazide (50.0 mg, 192.09 pmol) in water (30 mL) are added bis((methylsulfanyl)methanimidamide); sulfuric acid (106.78 mg, 384.07 pmol) and sodium hydroxide (15.36 mg, 384.07 pmol). The reaction is stirred at 70° C. for 24 h. The reaction mixture evaporated under reduced pressure and purified by HPLC (35-40-90% 0-1.3-5.3 min H2O / MeOH, flow 30 ml / min(loading pump 4 ml / min MeOH); column: Chromatorex 18 SMB 100-ST 100*19 mm 5 um) 3-(l-methyl-

[0242] 3-(2-(l -methyl- lH-pyrazol-4-yl)cy cl opropyl)-lH-pyrazol-5-yl)-lH- 1,2, 4-triazol-5- amine (26.0 mg, 46% yield).

[0243] 5-6-Fluoro-[ 1, 2, 4 ]triazolo[ 1, 5 -a ]pyrimidin-2-yl-l-methyl-3-[2-( 1 -methyl- IH-pyrazol-

[0244] 4-yl) cyclopropyl -lH-pyrazole

[0245] According to Scheme 2bis’ Step 4: To the solution of 3-l-methyl-3-[2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl]-lH-pyrazol-5-yl-lH-l,2,4-triazol-5-amine (26.0 mg, 91.45 pmol) in AcOH (2 ml) was added (2Z)-3-(diethylamino)-2-fluoroprop-2-enal (13.25 mg, 91.33 pmol) and reaction mixture was heated to 100 °C for a night. The solvent was evaporated and the residue was purified by HPLC (5-5-40% 0-1-5 min H2O / MeOH / 0.1%NH4OH, flow: 30 ml / min (loading pump 4 ml / min MeOH); column: XBridge C18 100x19 mm, 5 um) to obtain 5-6-fluoro-[l,2,4]triazolo[l,5-a]pyrimidin-2- yl-l-methyl-3-[2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole (12.8 mg, 37.83 pmol, 41.4% yield).

[0246] EXAMPLE 2: 5-(2-(5-(5,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-l- methyl-lH-pyrazol-3-yl)cyclopropyl)-N-methylpicolinamide (Final compound 1- 29)

[0247] Scheme 1’

[0248] 5-[2-(5-5, 7-Dimethyl-[ 1, 2, 4 ]triazolo[ 1, 5-a lpyrimidin-2-yl-l -methyl- lH-pyrazol-3- yl)cyclopropyl]-2-methoxypyridine

[0249] According to Scheme 1’ Step 1: A solution of 3-bromo-5-5,7-dimethyl- [l,2,4]triazolo[l,5-a]pyrimidin-2-yl-l-methyl-lH-pyrazole (400.0 mg, 1.31 mmol), 2- methoxy-5-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine (719.76 mg, 2.62 mmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T-biphenyl]-2- yl]phosphane; 2'-amino-[l,T-biphenyl]-2-ylpalladio methanesulfonate (110.56 mg, 130.78 pmol), tripotassium phosphate (831.18 mg, 3.92 mmol) and bis(adamantan-l- yl)(butyl)phosphane (46.86 mg, 130.78 pmol) in dioxane (10 mL) and water (2 ml) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was cooled to rt. and diluted with H2O (20 ml) and extracted with EtOAc (2*50 ml). The organic layer was washed with brine, and filtered through a ISfeSC The filtrate was concentrated in vacuo to give crude which was purified by HPLC (5-5-40% 0-1-5 min H2O / MeOH / 0. 1%NH4OH, flow: 30 ml / min (loading pump 4 ml / min MeOH); column: XBridge C18 100x19 mm, 5 um) to provide 5-[2-(5-5,7-dimethyl- [ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl- 1 -methyl- lH-pyrazol-3 -yl)cyclopropyl]-2- methoxypyridine (170.0 mg, 98.0% purity, 33.9% yield).

[0250] EXAMPLE 3: 5-(2-(5-(5,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-l- methyl-lH-pyrazol-3-yl)cyclopropyl)-N-methylpicolinamide (Final compound 1-

[0251] Scheme 16

[0252] 2-(3-(2-(6-Bromopyridin-3-yl)cyclopropyl)-l-methyl-lH-pyrazol-5-yl)-5, 7-dimethyl- [1,2,4 ]triazolo[ 1, 5 -a [pyrimidine

[0253] According to Scheme 16 Step 1 : 5-[2-(5-5,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin- 2-yl-l-methyl-lH-pyrazol-3-yl)cyclopropyl]-2-methoxypyridine (236.0 mg, 628.62 pmol) and phosphoroyl tribromide (892.7 mg, 3.15 mmol) was heated to 110 °C with stirring for 5 h. The r.m. was cooled to r.t. and quenched with crushed ice. Then NaHCCh was added to pH 8 and extracted with EA (3*10 ml). The combined organic layers were dried over Na2SO4 and evaporated. The obtained material was used in the next step. Methyl 5-[2-(5-5, 7-dimethyl-[ 1, 2, 4 ]triazolo[ 1, 5 -a ]pyrimidin-2-yl-l-methyl-lH-pyrazol- 3-yl)cyclopropyl]pyridine-2-carboxylate

[0254] According to Scheme 16 Step 2: [1,1'-

[0255] Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.15 mg, 1.41 pmol) were added to a high pressure reactor charged with a degassed mixture of 2-bromo-5-[2-(5-5,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl-l- methyl-lH-pyrazol-3-yl)cyclopropyl]pyridine (20.0 mg, 47.14 pmol) and triethylamine (5.71 mg, 56.51 pmol) in MeOH. The reactor was flushed with 20 atm. of carbon monoxide, and the mixture was stirred at 110°C for 48 h. After spectral data of an aliquot revealed completion of the reaction, the mixture was concentrated. The residue was dissolved in ethyl acetate (10 mL). The solution was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain methyl 5-[2-(5- 5,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl-l-methyl-lH-pyrazol-3- yl)cyclopropyl]pyridine-2-carboxylate (20.05 mg, 47.0% yield).

[0256] 5-(2-(5-(5, 7-Dimethyl-[ 1, 2, 4 ]triazolo[ 1, 5-a]pyrimidin-2-yl)-l-methyl-lH-pyrazol-3- yl) cyclopropyl) -N-methylpicolinamide

[0257] According to Scheme 16 Step 3: To the solution of methyl 5-[2-(5-5,7-dimethyl- [ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl- 1 -methyl- lH-pyrazol-3 -yl)cyclopropyl]pyridine-2- carboxylate (20.05 mg, 49.7 pmol) in MeOH (1 ml) was added methanamine (15.4 mg, 496.1 pmol, 100.0 pl, 10.0 equiv) and r.m. and heated 50 °C in closed vessel. The solvent was evaporated and residue was purified by HPLC (5-5-40% 0-1-5 min H2O / MeOH / 0.1%NH4OH, flow: 30 ml / min (loading pump 4 ml / min MeOH); column: XBridge C18 100x19 mm, 5 um) to afford 5-(2-(5-(5,7-dimethyl-[l,2,4]triazolo[l,5- a]pyrimidin-2-yl)-l-methyl-lH-pyrazol-3-yl)cyclopropyl)-N-methylpicolinamide (15.0 mg, 37% yield).

[0258] EXAMPLE 4: 5-methoxy-7-methyl-2-(l-methyl-3-(2-( 1-methyl-l II-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)-[l,2,4]triazolo[l,5-a]pyrimidine (Final compound 1-10)

[0259] Scheme 5 Route A’ - Scheme 1

[0260] (E)-l-methyl-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazole According to Scheme 5 Route A’ Step 1 : a mixture of 4-iodo-l-methyl-lH-pyrazole (10.0 g, 48.09 mmol) , 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (8.89 g, 57.7 mmol) , tri-tert-butylphosphonium tetrafluoroborate (1.4 g, 4.81 mmol) , tris(l,5- diphenylpenta-l,4-dien-3-one) dipalladium (2.2 g, 2.4 mmol) , and ethylbi s(propan-2- yl)amine (12.42 g, 96.17 mmol, 16.74 ml, 2.0 equiv) in toluene (100 mL) was degassed and purged with Ar (3x) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs under Ar atmosphere and concentrated under reduced pressure to remove solvent. The residue was purified by CombiFlash to afford l-methyl-4-[(lE)-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)ethenyl]-lH-pyrazole (8.0 g, 95.0% purity, 32.46 mmol, 67.5% yield) as a yellow oil. l-methyl-4-(2-( 4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)cyclopropyl)-lH-pyr azole According to Scheme 5 Route A’ Step 2: diazomethane (4.49 g, 106.75 mmol, 213.51 ml, 5.0 equiv) 0.5M solution in MTBE was added at -50C to the solution of l-methyl-4- [(lE)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethenyl]-lH-pyrazole (5.0 g, 21.35 mmol) and (acetyloxy)palladio acetate (143.44 mg, 640.55 pmol) in THF (100 ml). The r.m. was stirred at -30C for 30 min, heated to r.t. and filtered. The solvent was evaporated to obtain crude l-methyl-4-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclopropyl]-lH-pyrazole (3.65 g, 14.71 mmol, 68.9% yield) which was purified by FCC. To afford the final compound 1-10 the synthesis was continued according to scheme 1 such as example 2.

[0261] EXAMPLE 5: 5,7-dimethyl-2-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)-[l,2,4]triazolo[l,5-a]pyrimidine (Final compound 1-15) gll

[0262] B2

[0263] Scheme 5 Route B’, Scheme 1 tert-butyl (E)-3-(l-methyl-lH-pyrazol-4-yl)acrylate

[0264] According to Scheme 5 routeB’ Step 1 : to a solution of 4-iodo-l -methyl- IH-pyrazole (10.0 g, 48.09 mmol) in N,N-dimethylformamide (100 mL) was added tert-butyl prop-2 - enoate (12.32 g, 96.18 mmol) , triethylamine (9.73 g, 96.18 mmol) , palladium(2+) diacetate (538.44 mg, 2.4 mmol) and triphenylphosphine (1.26 g, 4.81 mmol) . The resulting mixture was heated overnight at 110° C. under nitrogen. The reaction was concentrated, and the resulting residue was purified by flash column chromatography (1 :3 ethyl acetate / petroleum ether) to provide tert-butyl (2E)-3-(l-methyl-lH-pyrazol-4- yl)prop-2-enoate as a light yellow oil (7.6 g, 72%). tert-butyl 2-( I -methyl-lH-pyrazol-4-yl)cyclopropane-l-carboxylate

[0265] According to Scheme 5 routeB’ Step 2: trimethyl sulfoxonium iodide (10.44 g, 47.47 mmol) was added slowly in small portions over a period of 20 min, to a stirred suspension of sodium hydride (1.75 g, 60.0% purity, 43.82 mmol) in dry DMSO (100 mL) at RT. After 1 h, a clear solution was formed and a solution of tert-butyl (2E)-3-(l- methyl-lH-pyrazol-4-yl)prop-2-enoate (7.6 g, 36.52 mmol) in dry DMSO (50 mL) was added slowly dropwise. After 30 min, the reaction mixture was poured into ice water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined extracts were washed with ice water (2 x 100 mL), brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated to dryness to give the crude product, which was purified by LC. Yield = 6.8 g, 84%.

[0266] 2-( I -methyl- lH-pyrazol-4-yl)cyclopropane-l -carboxylic acid

[0267] According to Scheme 5 routeB’ Step 3: a mixture of tert-butyl 2-(l -methyl- IH-pyrazol- 4-yl)cyclopropane-l -carboxylate (6.8 g, 30.59 mmol) and trifluoroacetic acid (34.87 g, 305.94 mmol) in di chloromethane (DCM) (100 mL) was stirred for 24 hours at room temperature, after which LCMS showed complete consumption of starting material. The mixture was concentrated in vacuo and the residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL). The aqueous layer was concentrated to give the desired product as clear colorless oil (4 g, 80 % yield).

[0268] 1, 3-dioxoisoindolin-2-yl 2-( I -methyl- lH-pyrazol-4-yl)cyclopropane-l -carboxylate According to Scheme 5 routeB’ Step 4: to the solution of rac-(lR,2R)-2-(l-methyl-lH- pyrazol-4-yl)cyclopropane-l -carboxylic acid prepared above (2.0 g, 12.04 mmol) and 2- hydroxy-2,3-dihydro-lH-isoindole-l, 3-dione (1.96 g, 12.04 mmol) in dry THF (20 ml) was added N,N' -dicyclohexylmethanediimine (2.98 g, 14.45 mmol) and N,N- dimethylpyridin-4-amine (73.53 mg, 602.26 pmol) at r.t. The reaction mixture was stirred overnight at r.t. Then the solid was filtered, washed with THF (20 ml) and mother liquor was evaporated under reduced pressure to obtain crude l,3-dioxo-2,3-dihydro-lH- isoindol-2-yl 2-(l-methyl-lH-pyrazol-4-yl)cyclopropane-l-carboxylate (2.15 g, 90.0% purity, 6.22 mmol, 51.6% yield) which was used in the next step without further purification. l-methyl-4-(2-( 4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)cyclopropyl)-lH-pyr azole According to Scheme 5 routeB’ Step 5: to the solution of l,3-dioxo-2,3-dihydro-lH- isoindol-2-yl 2-(l -methyl- lH-pyrazol-4-yl)cyclopropane-l -carboxylate (2.15 g, 6.91 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (3.51 g, 13.8 mmol) in dry EA (20 ml) under Ar atmosphere was added methyl pyridine-4-carboxylate (473.65 mg, 3.46 mmol) and r.m. was heated to 80C for a night. The obtained solid was filtered off, solvent was evaporated under reduced pressure to obtain crude product. The residue was purified on CombiFlash to obtain pure 1- methyl-4-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]-lH-pyrazole (1.0 g, 90.0% purity, 3.63 mmol, 52.5% yield)

[0269] 5, 7-dimethyl-2-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5- y I) -[1,2, 4 ]triazolo[ 1, 5 -a [pyrimidine

[0270] According to Scheme 1, a solution of 3-bromo-5-5,7-dimethyl-[l,2,4]triazolo[l,5- a]pyrimidin-2-yl-l-methyl-lH-pyrazole (150.0 mg, 490.16 pmol) , l-methyl-4-[2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]-lH-pyrazole (243.61 mg, 981.62 pmol) , dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T-biphenyl]-2-yl]phosphane; 2'-amino-[l,T-biphenyl]-2-ylpalladio methanesulfonate (41.49 mg, 49.08 pmol) , tripotassium phosphate (311.93 mg, 1.47 mmol) and bis(adamantan-l- yl)(butyl)phosphane (17.58 mg, 49.08 pmol) in dioxane (10 mL) and water (2 ml) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was cooled to rt. and diluted with H2O (20 ml) and extracted with EtOAc (2*50 ml). Organic layer was washed with brine, filtered through a Na2SO4. The filtrate was concentrated in vacuo to give crude which was purified by HPLC to provide the final compound 1-15 5-5,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl-l-methyl-3-[2-(l- methyl- lH-pyrazol-4-yl)cy cl opropyl]-lH-pyrazole (85.0 mg, 243.97 pmol, 49.7% yield) EXAMPLE 6: 2-(3-(2-(l-(difluoromethyl)-lH-pyrazol-4-yl)cyclopropyl)-l-methyl- lH-pyrazol-5-yl)-5,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Final compound 1- 8)

[0271] Acylation Step 2 Step 1 Cyclopropanation Step 3

[0272] H

[0273] Scheme 6 Route C’ - Scheme 1

[0274] (E)-3-( 1 -(difluor omethyl)-lH-pyrazol-4-yl)acrylic acid

[0275] According to Scheme 6 Route C’ Step 1 : To the solution of 5.0 g 1 -(difluoromethyl)- lH-pyrazole-4-carbaldehyde (0.034 mol) in 225 cm3 pyridine, 4.27 g malonic acid (0.041 mol) and 0.874 g piperidine (10.3 mmol) were added. The resulting mixture was heated at 70 °C for 3 days. The solvent was removed in vacuo, and the residue was triturated with H2O. The precipitate was filtered to give the (E)-3-(l-(difluoromethyl)- lH-pyrazol-4-yl)acrylic acid (5.0 g, crude).

[0276] 2-(l-(Difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylcyclopropane-l- carboxamide

[0277] According to Scheme 6 Route C’ Step 2: To a solution of 5.0 g (E)-3-(l- (difluoromethyl)-lH-pyrazol-4-yl)acrylic acid (0.036 mol) in 900 cm3dry CH2CI2, 3.93 g N,O-dimethylhydroxylamine hydrochloride (0.04 mol), 1.64 g DMAP (0.0134 mol), 7.7 g EDC (0.04 mol), and 1.5 cm3 NEt3 (0.01 mol) were added. The resulting mixture was stirred at rt overnight. The organic layer was washed with water (2*50 cm3), 50 cm3 10 % aq. HC1, dried over Na2SO4, and evaporated in vacuo to give the (E)-3-(l- (difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylacrylamide (5.2 g, crude).

[0278] 2-(l-(difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylcyclopropane-l- carboxamide

[0279] According to Scheme 6 Route C’ Step 3: Trimethyl(oxo)-lambda6-sulfanylium iodide (7.42 g, 33.73 mmol) was dissolved in 100 ml THF, and the solution was cooled to 0 °C. Potassium 2-methylpropan-2-olate (3.28 g, 29.24 mmol) was added, and the mixture was stirred for 30 min. (2E)-3-[l-(difluoromethyl)-lH-pyrazol-4-yl]-N-methoxy-N- methylprop-2-enamide (5.2 g, 22.49 mmol) was added, and the reaction mixture was stirred at 40 C overnight, then cooled to rt. The precipitate was filtered off, the filtrate was washed with 50 ml brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by chromatography [hexanes-EtOAc (1 : 1) as eluent, to afford 2-(l- (difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylcyclopropane-l-carboxamide (12.0 g, crude).

[0280] 2-( 1 -(Difluoromethyl)-lH-pyrazol-4-yl)cyclopropane-l -carboxylic acid

[0281] According to Scheme 6 Route C’ Step 4: To a solution of 2-(l -(difluoromethyl)- 1H- pyrazol-4-yl)-N-methoxy-N-methylcyclopropane-l -carboxamide (12.0 g, 0.58 mol) in 200 cm3MeOH, a solution of 4.6 g NaOH (0.115 mol) in 100 cm3H2O was added. The reaction mixture was heated at reflux for 3 h. The MeOH was removed in vacuo, the aqueous phase was washed with CH2Q2 (2*50 cm3), and then acidified with 20 % aq. HC1 to pH = 2. The mixture was cooled to 4 °C, and the precipitate was filtered to give the 2-(l-(difluoromethyl)-lH-pyrazol-4-yl)cyclopropane-l-carboxylic acid (8.0 g, 67% yield).

[0282] To afford the final compound (1-8) the synthesis was continued according to Scheme 5 Route B (Step 4-5) then Scheme 1. Table 8: Compounds prepared according to the Examples.

[0283] The compounds in table 8 are a racemic mixture of the -trans isomers of the 1,2- disubstituted cyclopropane moiety, unless otherwise specified.

[0284] Table 9: Compounds prepared according to the Examples. Table 10: Compounds prepared according to the Examples.

[0285] Table 11: Compounds prepared according to the Examples.

[0286] Physico-Chemical Data

[0287] Melting points: a) Melting point determination was performed on a Buchi B-540 apparatus. b) DSC analysis

[0288] DSC data were collected on Mettler Toledo DSC 822ecalorimeter equipped with a refrigerated cooling system. The sample was placed into aluminium DSC pans covered with a pin-hole punched lid. The sample cell was heated at a rate 10°C / min. over the temperature range 25 to 350°C. A nitrogen purge of 50 mL / min. was maintained over the sample. Melting points are expressed as integers at onset temperature of melting.

[0289] LC-MS

[0290] Equipment: Agilent 1100 Series LC / MSD system with DAD\ELSD and Agilent

[0291] LC\MSD VL (G1956A), SL (G1956B) mass-spectrometer system Reverse phase HPLC was carried out on a Poroshell 120 SB-Cis column (4.6x30mm 2.7 pm) from Agilent, with a flow rate of 1.5 mL / min, at a temperature of 60 °C.

[0292] Mobile phases: Solvent A: water (0.1% formic acid); Solvent B: MeCN (0.1% formic acid).

[0293] The gradient conditions used: 0.01 min - 1% Solvent B, 5.00 min - 100% Solvent B, 5.99 min - 100% Solvent B. Injection volume 5-20 pL. MS Ionization mode: Electrospray ionization (ESI), ES MS detector was used, acquiring both in positive and negative ionization modes, MS Scan range: 83 - 1000 m / z.

[0294] Method 2

[0295] Apparatus:

[0296] Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC -Mass Spectrometer

[0297] Column :Kinetex®2.6 pm XB-C18 (4.6x50mm), 110A, column no. 00B-4496-E0,

[0298] Reagents:

[0299] - Formic acid > 98%, Sigma-Aldrich

[0300] - Acetonitrile for HPLC UV / gradient grade, Baker

[0301] - pQ-water for LCMS

[0302] HPLC conditions:

[0303] -Wavelength range: (190 -350) nm ± 4 nm

[0304] - Flow: l.O ml / min

[0305] - Column temperature: 25 °C

[0306] - Autosampler temperature: 20 °C

[0307] - Analysis time: 6 min

[0308] - Elution: gradient

[0309] Mobile phase A:0.1 % v / v water solution of formic acid Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid Solution for syringe washing: 20% MeOH

[0310] MS conditions:

[0311] - Mass range: 100 -1000 m / z

[0312] - Ionization: alternate

[0313] - Scan speed: 12000 amu / sec

[0314] Method 3

[0315] Apparatus:

[0316] Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC -Mass Spectrometer

[0317] Column :Kinetex®2.6 pm XB-C18 (4.6x50mm), 110A, column no. 00B-4496-E0,

[0318] Reagents:

[0319] - Formic acid > 98%, Sigma-Aldrich

[0320] - Acetonitrile for HPLC UV / gradient grade, Baker

[0321] - pQ-water for LCMS

[0322] HPLC conditions:

[0323] -Wavelength range: (190 -350) nm ± 4 nm

[0324] - Flow: l.O ml / min

[0325] - Column temperature: 25 °C

[0326] - Autosampler temperature: 20 °C

[0327] - Analysis time: 6 min

[0328] - Elution: gradient

[0329] Mobile phase A:0.1 % v / v water solution of formic acid

[0330] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid Solution for syringe washing: 20% MeOH

[0331] MS conditions:

[0332] - Mass range: 100 -1000 m / z

[0333] - Ionization: alternate - Scan speed: 12000 amu / sec

[0334] Method 4

[0335] Apparatus:

[0336] Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC -Mass Spectrometer

[0337] Column :Kinetex®2.6 pm XB-C18 (4.6x50mm), 110A, column no. 00B-4496-E0,

[0338] Reagents:

[0339] - Formic acid > 98%, Sigma-Aldrich

[0340] - Acetonitrile for HPLC UV / gradient grade, Baker

[0341] - pQ-water for LCMS

[0342] HPLC conditions:

[0343] -Wavelength range: (190 -350) nm ± 4 nm

[0344] - Flow: l.O ml / min

[0345] - Column temperature: 25 °C

[0346] - Autosampler temperature: 20 °C

[0347] - Analysis time: 6 min

[0348] - Elution: gradient

[0349] Mobile phase A:0.1 % v / v water solution of formic acid Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid Solution for syringe washing: 20% MeOH

[0350] MS conditions:

[0351] - Mass range: 100 -1000 m / z

[0352] - Ionization: alternate

[0353] - Scan speed: 12000 amu / sec

[0354] NMR:

[0355] 'H-NMR spectra were recorded on Bruker Avance III (600 MHz or 500MHz) spectrometer, equipped with a 5 mm RT BBI probe as well as Varian Unity Plus 400 MHz spectrometer. The samples were recorded at 25 °C using DMSO-tC, CDCI3, pyridine-t / or toluene-t / s as a solvent and TMS as the internal standard. Chemical shifts are expressed in parts per million (ppm, 6 units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).

[0356] Table 12: Physico-chemical data. (RT means retention time in minutes; [MH]+means the protonated mass of the compound (free base); nd = not determined).

[0357] Table 13: Chiral Separation

[0358] Preparative separation was performed with an Agilent 1260 HPLC instrument (Agilent Technologies, Germany) equipped with a G7161 A Preparative Binary Pump, a G7157A Prep Autosampler, a G7115A DAD WR and a G7159B Preparative Fraction Collector.

[0359] The Open Lab CDS software (version C.01.10) was used for instrument control, data acquisition and data handling. RT1 represents the retention time of the first compound which elutes and its Co.No is the first in the rank; RT2 represents the retention time of the second compound which elutes and its Co.No is the second in the rank. For example for Exp. No 1, RT1 corresponds to Co.No 1-10 and RT2 corresponds to Co.No 1-11. *[a]D_ C (g / 100mL)_Solvent is methanol_ X is 589 nM_Temperature is 21°C

[0360] PHARMACOLOGY

[0361] The compounds provided in this invention are positive allosteric modulators of metabotropic acetylcholine (mACh) M4 receptors. The compounds of the present invention do not appear to bind to the mACh recognition site, the orthosteric ligand site, but instead to an allosteric site within the seven transmembrane region of the receptor. In the presence of Ach or an agonist of mACh receptor, the compounds of this invention increase the acetylcholine (Ach) response. The compounds provided in this invention are expected to have their effect at mACh M4 receptors by virtue of their ability to increase the response of such receptors to ACh or ACh agonists, enhancing the response of the receptor. Hence, the present invention relates to a compound for use as a medicine, as well as to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of M4 mACh allosteric modulators, in particular positive M4 mACh allosteric modulators. Some of the compounds of Formula (I’) and (I) have been tested according to the following methods. Because such positive allosteric modulators of M4 mACh receptors, including compounds of Formula (I’) and (I), enhance the response of M4 mACh receptors to ACh, it is an advantage that the present methods utilize endogenous ACh.

[0362] Because positive allosteric modulators of M4 mACh receptors, including compounds of Formula (F) and (I), enhance the response of M4 mACh receptors to agonists, it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with M4 mACh dysfunction by administering an effective amount of a positive allosteric modulator of M4 mACh receptors, including compounds of Formula (F) and (I), in combination with a M4 mACh agonist.

[0363] The compounds of the present invention may be utilized in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (F) and (I) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.

[0364] The behavior of positive allosteric modulators, such as the ones described in Formula (F) and (I), at M4 mACh receptors is shown in the following paragraph, which is suitable for the identification of such compounds.

[0365] Example A

[0366] HEK293 cells stably expressing the Gi-coupled human muscarinic acetylcholine receptors M4 and a chimeric Ga-protein, coupling the receptor response to the calcium pathway, were seeded at a density of 25’000 cells / well in poly-L-omithine coated black 384-well plates (transparent bottom). Cells were incubated overnight in glutamine / glutamate free DMEM medium containing fetal bovine serum (10%), penicillin (100 units / mL), streptomycin (100 pg / mL) and doxycyline (1 pg / ml) at 37°C with 5% CO2 in a humidified atmosphere. 24h after seeding, the medium was aspirated and the cells were loaded with a 3 pM solution of Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After 1 hour at 37°C / 5% CO2, the non-incorporated dye was removed by washing cell plate with PBS and left for 3h (post-washing time) at room temperature in the dark. All assays were performed in a pH 7.4 buffered solution containing 20 mM HEPES, 143 mM NaCl, 6 Mm KC1, 1 mM MgSO4, 1 mM CaCl2, 0.125 mM sulfinpyrazone and 0.1% glucose. Cells were then assayed using a fluorometric imaging plate reader (FLIPR PENTA, Molecular Device, Sunnyvale, CA, USA). Fluorescence (Ex: 470-495 nm / Em: 515-575 nm) was recorded for the duration of the experiment. After 20 seconds of basal fluorescence recording, various concentrations of the compounds of the invention were added to the cells. Changes in fluorescence levels were first monitored for 150 seconds in order to detect any agonist activity of the compounds. Then the cells were stimulated by an EC20 acetylcholine concentration for an additional 150 s in order to measure potentiating activities of the compounds of the invention. EC20 acetylcholine concentration is the concentration giving 20% of the maximal acetylcholine response. All compound concentrations measurements were performed in duplicates. Potencies and efficacy of PAMs were calculated (Dotmatics software, Boston, USA) using a four-parameter curve fit. Potencies were expressed as EC50 values. The compounds of this application have EC50 values usually less than 10 pM.

[0367] The Table 14 below represents the mean EC50 obtained from at least three independent experiments of selected molecules performed in duplicate.

[0368] Table 14: Activity data for selected compounds

[0369] *Table legend:

[0370] NA: Non Active

[0371] (+): 500 nM < EC50 <10 pM (++): 100 nM < EC50 < 500 nM

[0372] (+++): EC50 < 100 nM

[0373] The results shown in Table 14 demonstrate that the compounds described in the present invention are positive allosteric modulators of human Muscarinic M4 receptors.

[0374] Example B

[0375] The effects of compounds on amphetamine-induced locomotor hyperactivity in mice

[0376] The purpose of this study was to evaluate the efficacy of compounds of the present invention to reverse amphetamine-induced locomotor hyperactivity in C57BL / 6 mice, a preclinical model predictive of antipsychotic-like activity (Leite et al. 2008). The locomotor activity was evaluated through the assessment of distance travelled be the animal. Drugs: Racemate Methamphetamine Hydrochloride (CAS:300-42-5) was obtained from Shanghai Yuansi Standard Science and Technology Co. Ltd. Saltcorrection was done to calculate the correct amount of the methamphetamine in milligrams to add to saline in order to obtain 0.178 mg / ml solution, which was dosed at 10 mL / kg body weight of each animal. The compounds of the present invention were formulated in volumes appropriate to the number of animals dosed each day. The suspensions formulated for dosing allowed dosing of animals with a volume of 10 mL / kg body weight for all compounds. The appropriate amount of each compound was mixed with 1% CMC -Na (medium viscosity) and 0.25% Tween 80 in sterile water. Animals: Adult male C57BL / 6 mice weighing 20-24g (Lingchang, Shanghai, China) were used in the study. They were group-housed (4 per cage) in the animal care facility of WuXi AppTec (Nantong) Co., Ltd, with controlled temperature and humidity (targeted at 23±2°C and 50±5%, respectively). The vivarium was maintained on a 12-h light / dark cycle (lights off at 07:00 hours). Food and water were available ad libitum. On the test day, animals were randomly grouped by the body weight. Animals were acclimated in the animal care facility for at least 7 days before experimentation. The regents were prepared fresh on the test day and administrated according to the experiment design. The experiment was performed during the dark phase of the light-dark cycle. Amphetamine- induced locomotor hyperactivity: Mice were transferred to the test room and habituated in the test room for 2 consecutive days. On the day of the experiment animals were habituated for 2 h before being placed in the center of the test box (27.5 x 27.5 x 40 cm) equipped with a video tracking system (TO). Sixty (60) minutes later (T60) animals were dosed with vehicle, haloperidol (0.3 mg / kg, i.p.) or compounds of present invention and returned to test boxes. Thirty (30) minutes later (i.e. T90) animals were treated with vehicle (saline, s.c.) or amphetamine (1.78 mg / kg, s.c.) and returned to test boxes for another 90 min. At the end of the experiment (T180 min) animals were removed from test boxes. FORMULATION EXAMPLES

[0377] Typical examples of formulations of the invention are as follows:

[0378] 1. Tablets

[0379] Active ingredient 5 to 50 mg

[0380] Di-calcium phosphate 20 mg

[0381] Lactose 30 mg

[0382] Talcum 10 mg

[0383] Magnesium stearate 5 mg

[0384] Potato starch ad 200 mg

[0385] In this Example, the active ingredient is any of the compounds according to the present invention.

[0386] 2. Suspension

[0387] An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of the active ingredient of the invention, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 mL. In this Example, the active ingredient is any of the compounds according to the present invention.

[0388] 3. Injectable

[0389] A parenteral composition is prepared by stirring 1.5 % by weight of the active ingredient of the invention in 10% by volume propylene glycol and water. In this Example, the active ingredient is any of the compounds according to the present invention.

[0390] 4. Ointment

[0391] Active ingredient 5 to 1000 mg

[0392] Stearyl alcohol 3 g

[0393] Lanoline 5 g

[0394] White petroleum 15 g Water ad 100 g

[0395] In this Example, the active ingredient is any of the compounds according to the present invention.

[0396] Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the described invention may be varied in many ways by those skilled in the art.

[0397] The invention includes the subject matter described in the following numbered paragraphs:

[0398] 1. A compound having the Formula (I): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an N- oxide form thereof, wherein:

[0399] R1is selected from the group of -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and - (C3-C7)cycloalkyl;

[0400] R2is selected from the group of hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3- C7)cycloalkyl or -(Ci-Ce)haloalkyl;

[0401] P represents a heteroaryl of formula: wherein W is C-H, C-CH3 or N;

[0402] Y is O, S or N-CH3;wherein each heteroaryl ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3; the or each (A)mis independently selected from the group of hydrogen, halogen and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(Co-C6)alkylene-ORa and -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle; Q represents a cycloalkyl, aryl, heteroaryl or heterocycle of formula: or, -(Ci-Ce)haloalkyl, -(Co-C6)alkylene-C(=0)-ORa or -(Co-C6)alkylene-C(=0)- NRbRc; wherein Ra, Rb and Re are each independently selected from the group of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyl-O-(Ci-C6)alkyl, and (Ci-C6)alkyl-(C=O)-(Ci-C6)alkyl, or Rb and Re, together with the nitrogen to which they are attached, form a pyrrolopyridine group; wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5; wherein B1is a radical B; wherein p is an integer equal to zero, 1 or 2; wherein Z1is selected from C=C, C=O, C, N, S or O; and Z2, Z3, Z4Z5and Z6are each independently selected from C, N, S or O; the or each (B)nis independently selected from the group of hydrogen, halogen, - CN, -CD3, -OH, -NH2 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl, -O-(Ci-C6)deuterioalkyl, -N-(Ci- C6)deuterioalkyl, alkyl, , alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci- C6)alkylene-(C3-C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci- C6)alkylene-heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co- C6)alkylene-OR3, -O-(C2-C6)alkylene-OR3, -NR3(C2-C6)alkylene-OR4, -(Co- C6)alkylene-S-R3, -O-(C2-C6)alkylene-S-R3, -NR3-(C2-C6)alkylene-S-R4, -(Co- C6)alkylene-NR3R4, -O-(C2-C6)alkylene-NR3R4, -NR3-(C2-C6)alkylene-NR4R5and -(Co-C6)alkylene-C(=0)- NR3R4; -(Co-C6)alkylene-S(=0)-R3, -0-(Co- C6)alkylene-S(=O)-R3, -NR3-(C0-C6)alkylene-S(=O)-R4, -(Co-C6)alkylene- S(=O)2-R3, -O-(C0-C6)alkylene-S(=O)2-R3, -NR3-(C0-C6)alkylene-S(=O)2-R4, -O- (C0-C6)alkylene-C(=O)-NR3R4, -NR3-(C0-C6)alkylene-C(=O)-NR4R5, -(Co- C6)alkylene-NR3C(=O)-R4, -O-(C2-C6)alkylene-NR3C(=O)-R4, -NR3-(C2- C6)alkylene-NR4C(=O)-R5, -(C0-C6)alkylene-OC(=O)-R3, -O-(C2-C6)alkylene- OC(=O)-R3, -NR3-(C2-C6)alkylene-OC(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, - O-(C0-C6)alkylene-C(=O)-OR3, -NR3-(C0-C6)alkylene-C(=O)-OR4, -(Co- C6)alkylene-C(=O)-R3, -O-(C0-C6)alkylene-C(=O)-R3and -NR3-(Co-C6)alkylene- C(=O)-R4;

[0403] R3, R4and R5are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, - (Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl, -(Co- C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl and -(Co- C6)alkylene-NH2. The compound according to paragraph 1 having the Formula (I) wherein:

[0404] P is represents a heteroaryl of formula: wherein W is C-H, C-CH3 or N; and

[0405] Y is O, S or N-CH3. 3. The compound according to paragraph 1 or 2 having the Formula (I) wherein:

[0406] R1is -(Ci-C3)alkyl, -(Ci-C6)deuterioalkyl or cyclopropyl; and

[0407] R2is hydrogen, -CF3, -F or -CH3;

[0408] 4. The compound according to any one of paragraphs 1 to 3 having the Formula (I) wherein Q is:

[0409] 5. The compound according to any one of paragraphs 1 to 4 having the Formula (I) wherein: the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mand (B)nare independently selected from the group of azetidinyl, dihydrofuranyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R6, R7or R8; wherein R6, R7or R8be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, nitro, -(Ci-Ce)alkyl, - (Co-C6)alkylene-0-(Co-Ce)alkyl and

[0410] -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl, -(Co- Ce)alkylene-NH2.

[0411] 6. The compound according to any one of paragraphs 1 to 5 having the Formula (II): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an N- oxide form thereof, wherein Ai and A2 are each independently selected from H, - (Ci-C2)alkyl and -(C3)cycloalkyl; and R1is methyl or ethyl.

[0412] 7. The compound according to any one of paragraphs 1 to 6 having the Formula (III): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof, wherein R1is methyl or ethyl.

[0413] 8. The compound according to any one of paragraphs 1 to 7, wherein the compound can exist as stereoisomers, and wherein the compound is either a racemic mixture or one or more of the individual stereoisomers.

[0414] 9. The compound according to any one of paragraphs 1 to 8, wherein said compound is one or more selected from Table B, and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof.

[0415] 10. The compound according to any of paragraphs 1 to 5 having the Formula (la) or

[0416] (Ib):

[0417] 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of paragraphs 1 to 10 and a pharmaceutically acceptable carrier and / or excipient.

[0418] 12. A method of treating or preventing a condition in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to paragraphs 1 to 11. 13. The method according to paragraph 12 wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic allosteric modulator, such as a M4 positive allosteric modulator.

[0419] 14. The method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with M4 mACh dysfunction in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any one of paragraphs 1 to 11.

[0420] 15. The method according to paragraph 14, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic M4 positive allosteric modulator.

[0421] 16. The method according to paragraph 12 wherein the condition is one or more of a central nervous system disorder selected from psychotic disorders: Schizophrenia, psychosis, acute mania, Delusional Disorder, Schizoaffective Disorder, Schizophreniform Disorder, Substance-Induced Psychotic Disorder, comprising administering an effective amount of a compound according to paragraphs 1 to 10.

[0422] 17. The method according to paragraph 13 wherein the condition is one or more of a central nervous system disorder selected from cognitive disorders: Delirium, Substance-Induced Persisting Delirium, Dementia, Dementia Due to HIV Disease, Dementia Due to Huntington's Disease, Dementia Due to Parkinson's Disease, Dementia of the Alzheimer's Type, Substance-Induced Persisting Dementia, memory disorders, Mild Cognitive Impairment, comprising administering an effective amount of a compound according to paragraphs 1 to 10.

[0423] 18. The method according to paragraph 13 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of personality disorders: Obsessive-Compulsive Personality Disorder, Schizoid, Schizotypal disorder, comprising administering an effective amount of a compound according to paragraphs 1 to 10.

[0424] 19. The method according to paragraph 12 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of substance- related disorders: Alcohol abuse, Alcohol dependence, Alcohol withdrawal, Alcohol withdrawal delirium, Alcohol-induced psychotic disorder, Amphetamine dependence, Amphetamine withdrawal, Cocaine dependence, Cocaine withdrawal, Nicotine dependence, Nicotine withdrawal, Opioid dependence, Opioid withdrawal, comprising administering an effective amount of a compound according to paragraphs 1 to 10. 0. The method according to paragraph 13 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of movement disorders: Tourette’s syndrome, akinetic-rigid syndrome, levodopa-induced dyskinesia and movement disorders associated with Parkinson’s disease, tardive dyskinesias, comprising administering an effective amount of a compound according to paragraphs 1 to 10. 1. The method according to paragraph 13 wherein the condition is one or more of a neurodevelopmental disorders selected from the group consisting of RETT syndrome, Fragile X syndrome, Huntington’s disease, Angelman’s syndrome, West syndrome comprising administering an effective amount of a compound according to paragraphs 1 to 10. 2. The method of any one of paragraphs 12 to 21, wherein the mammal is a human. 3. Use of a compound according to any one of paragraphs 1 to 10 in the manufacture of a medicament for a treatment or prevention as defined in paragraphs 12 to 22. The use of the compounds of the invention to prepare tracers for imaging muscarinic acetylcholine M4 receptors. The compound according to any one of paragraphs 1 to 10 for use in a method according to any one of paragraphs 12 to 22.

Claims

CLAIMS1. A compound having the Formula (I’):a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an 7V-oxide form thereof, wherein:R1is selected from the group of hydrogen, -(Ci-Ce)alkyl, -(Ci- C6)deuterioalkyl and -(C3-C7)cycloalkyl;R2is selected from the group of hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3- C7)cycloalkyl, -(Ci-C6)deuterioalkyl or -(Ci-Ce)haloalkyl;R9, R10, R11and R12are each independently selected from the group of hydrogen, halogen, deuterium, and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl or -(Ci-Ce)haloalkyl;P is a heteroaryl or heterocycle; wherein each heteroaryl ring or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3; the or each (A)mis independently selected from the group of hydrogen, halogen and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(Co-C6)alkylene-ORa and -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, or two (A)mtogether form a saturated -(C3-C7) membered ring;Q is selected from the group of -(Ci-Ce)haloalkyl, -(Co-C6)alkylene-C(=0)- ORaor -(Co-C6)alkylene-C(=0)-NRbRc, cycloalkyl, aryl, heteroaryl and heterocycle;wherein Ra, Rb and Re are each independently selected from the group of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyl-O-(Ci-C6)alkyl, and (Ci-C6)alkyl-(C=O)-(Ci-C6)alkyl, or Rb and Re, together with the nitrogen to which they are attached, form a pyrrolopyridine group; wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to 1, 2, 3, 4 or 5; the or each (B)nis independently selected from the group of hydrogen, halogen, - CN, -CD3, -OH, -NH2 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl, -O-(Ci-C6)deuterioalkyl, -N-(Ci- C6)deuterioalkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co-Ce)alkylene-OR3, -O-(C2- C6)alkylene-OR3, -NR3(C2-C6)alkylene-OR4, -(Co-C6)alkylene-S-R3, -O-(C2- C6)alkylene-S-R3, -NR3-(C2-C6)alkylene-S-R4, -(Co-C6)alkylene-NR3R4, -O-(C2- Ce)alkylene-NR3R4, -NR3-(C2-Ce)alkylene-NR4R5and -(Co-C6)alkylene-C(=0)- NR3R4; -(Co-C6)alkylene-S(=0)-R3, -O-(C0-C6)alkylene-S(=O)-R3, -NR3-(Co- C6)alkylene-S(=O)-R4, -(Co-C6)alkylene-S(=0)2-R3, -0-(Co-C6)alkylene-S(=0)2- R3, -NR3-(C0-C6)alkylene-S(=O)2-R4, -O-(C0-C6)alkylene-C(=O)-NR3R4, -NR3- (C0-C6)alkylene-C(=O)-NR4R5, -(C0-C6)alkylene-NR3C(=O)-R4, -O-(C2- C6)alkylene-NR3C(=O)-R4, -NR3-(C2-C6)alkylene-NR4C(=O)-R5, -(Co- C6)alkylene-OC(=O)-R3, -O-(C2-C6)alkylene-OC(=O)-R3, -NR3-(C2-C6)alkylene- OC(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, -O-(C0-C6)alkylene-C(=O)-OR3, - NR3-(C0-C6)alkylene-C(=O)-OR4, -(Co-C6)alkylene-C(=0)-R3, -0-(Co- C6)alkylene-C(=O)-R3and -NR3-(C0-C6)alkylene-C(=O)-R4;R3, R4and R5are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, - (Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl, -(Co- C6)alkylene-N-((Ci-C6)alkyl)2, -(C0-C6)alkylene-NH(Ci-C6)alkyl and -(Co- Ce)alkylene-NH2.

2. The compound according to claim 1, having the Formula (I):

3. The compound according to claim 1 or 2 having the Formula (I) or Formula (I’), wherein P is bicyclic, comprising two or more fused heterocyclic or heteroaryl rings, wherein one of the rings is a 5 membered heterocyclic or heteroaryl ring, and wherein P is bonded to the pyrazole core via the 5 membered ring.

4. The compound according to any preceding claim having the Formula (I) or Formula(I’) wherein P is a heteroaryl or heterocycle of formula:wherein W is selected from the group of C-H, C-CH3 and N; and Y is selected from the group of O, S and N-CH3.

5. The compound according to any preceding claim having the Formula (I) or Formula (I’) wherein R1is selected from the group of -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl.- I l l -6. The compound according to any preceding claim having the Formula (I) or Formula (F) wherein R2is selected from the group of hydrogen, halogen, -CN, -(Ci- Ce)alkyl, -(C3-C7)cycloalkyl or -(Ci-C6)haloalkyl.

7. The compound according to any preceding claim having the Formula (I) or Formula(F) wherein the cycloalkyl, aryl, heteroaryl or heterocycle of Q is of formula:wherein p is an integer equal to zero, 1 or 2; and wherein Z1is selected from C=C, C=O, C, N, S or O; and Z2, Z3, Z4, Z5and Z6are each independently selected from C, N, S or O.

8. The compound according to any preceding claim having the Formula (F) orFormula (I) wherein:P is a heteroaryl of formula:and wherein W is selected from the group of C-H, C-CH3 and N; and Y is selected from the group of O, S and N-CH3.

9. The compound according to any preceding claim having the Formula (I’) or Formula (I) wherein:R1is selected from the group of -(Ci-C3)alkyl, -(Ci-C6)deuterioalkyl and cyclopropyl; andR2is selected from the group of hydrogen, -CF3, -F and -CH3.

10. The compound according to any preceding claim having the Formula (F) orFormula (I) wherein Q is a cycloalkyl, aryl, heteroaryl or heterocycle of formula:

11. The compound according to any preceding claim having the Formula (F) orFormula (I) wherein: the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mand (B)nare independently selected from the group of azetidinyl, dihydrofuranyl, furyl,imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R6, R7or R8; wherein R6, R7or R8are independently selected from the group of hydrogen, halogen, -CN, nitro, -(Ci-Ce)alkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl, - (Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci-C6)alkyl, and -(Co- Ce)alkylene-NH2.

12. The compound according to any preceding claim having the Formula (II):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an N- oxide form thereof, wherein Ai and A2 are each independently selected from H, - (Ci-C2)alkyl and -(C3)cycloalkyl; and R1is methyl or ethyl.

13. The compound according to any preceding claim having the Formula (III):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A-oxide form thereof, wherein R1is methyl or ethyl.

14. The compound according to any preceding claim, wherein the compound can exist as stereoisomers, and wherein the compound is either a racemic mixture or one or more of the individual stereoisomers.

15. The compound according to any preceding claim, wherein said compound is one or more selected from Table B, and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an A -oxi de form thereof.

16. The compound according to any preceding claim having the Formula (la) or (lb):

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier and / or excipient.

18. A method of treating or preventing a condition in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to claims 1 to 17.

19. The method according to claim 18 wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic allosteric modulator, such as a M4 positive allosteric modulator.

20. The method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with M4 mACh dysfunction in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any one of claims 1 to 17.

21. The method according to claim 20, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic M4 positive allosteric modulator.

22. The method according to claim 18 wherein the condition is one or more of a central nervous system disorder selected from psychotic disorders: Schizophrenia, psychosis, acute mania, Delusional Disorder, Schizoaffective Disorder, Schizophreniform Disorder, Substance-Induced Psychotic Disorder, comprising administering an effective amount of a compound according to claims 1 to 16.

23. The method according to claim 19 wherein the condition is one or more of a central nervous system disorder selected from cognitive disorders: Delirium, Substance- Induced Persisting Delirium, Dementia, Dementia Due to HIV Disease, Dementia Due to Huntington's Disease, Dementia Due to Parkinson's Disease, Dementia of the Alzheimer's Type, Substance-Induced Persisting Dementia, memory disorders, Mild Cognitive Impairment, comprising administering an effective amount of a compound according to claims 1 to 16.

24. The method according to claim 19 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of personalitydisorders: Obsessive-Compulsive Personality Disorder, Schizoid, Schizotypal disorder, comprising administering an effective amount of a compound according to claims 1 to 16.

25. The method according to claim 18 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of substance-related disorders: Alcohol abuse, Alcohol dependence, Alcohol withdrawal, Alcohol withdrawal delirium, Alcohol-induced psychotic disorder, Amphetamine dependence, Amphetamine withdrawal, Cocaine dependence, Cocaine withdrawal, Nicotine dependence, Nicotine withdrawal, Opioid dependence, Opioid withdrawal, comprising administering an effective amount of a compound according to claims 1 to 16.

26. The method according to claim 19 wherein the condition is one or more of a central nervous system disorder selected from the group consisting of movement disorders: Tourette’s syndrome, akinetic-rigid syndrome, levodopa-induced dyskinesia and movement disorders associated with Parkinson’s disease, tardive dyskinesias, comprising administering an effective amount of a compound according to claims 1 to 16.

27. The method according to claim 19 wherein the condition is one or more of a neurodevelopmental disorders selected from the group consisting of RETT syndrome, Fragile X syndrome, Huntington’s disease, Angelman’s syndrome, West syndrome comprising administering an effective amount of a compound according to claims 1 to 16.

28. The method according to claim 20 wherein the condition is one or more of a neurological or a psychiatric disorder selected from post-traumatic stress disorder, attention deficit and hyperactivity disorder, attention deficit disorder, sleep disorder, bipolar disorder, bipolar depression, autism, amyotrophic lateral sclerosis, multiple sclerosis, sarcoidosis, progressive supranuclear palsy, paindisorder, inflammatory pain or nociceptive pain, chronic pain and neuropathic pain, comprising administering an effective amount of a compound according to claims 1 to 16.

29. The method of any one of claims 18 to 28, wherein the mammal is a human.

30. Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for a treatment or prevention as defined in claims 18 to 29.

31. The use of the compound of any one of claims 1 to 16 to prepare tracers for imaging muscarinic acetylcholine M4 receptors.

32. The compound according to any one of claims 1 to 16 for use in a method according to any one of claims 18 to 29.

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