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 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.

Description

[0001] 3-CYCLOPROPYLPYRAZOLE DERIVATIVES AS POSITIVE ALLOSTERIC

[0002] MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR

[0003] SUMMARY OF THE INVENTION

[0004] The present invention relates to novel compounds of Formula (F), wherein P, Q, A, B, m, n, R1, R2, R9, R10, R11and R12are defined as in Formula (F). 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.

[0005] FIELD OF THE INVENTION

[0006] 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

[0007] 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 presynaptically 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).

[0008] 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.

[0009] 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.

[0010] 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).

[0011] 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, 10978-10983;

[0012] 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.

[0013] 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- naphthyridines analogs (WO2023 / 064587; WO2023 / 141511).

[0014] 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.

[0015] 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.

[0016] SUMMARY OF THE INVENTION

[0017] 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:

[0018] R1is selected from the group of (for example the group consisting of) hydrogen, - (Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl;

[0019] 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);

[0020] 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;

[0021] 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-C6)alkylene-ORa, -(C3-C7)cycloalkyl, aryl, heteroaryl, and heterocycle, or two (A)mtogether form a saturated -(C3-C7) membered ring;

[0022] R is selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)haloalkyl (for example -CF3), -O-(Ci-Ce)alkyl and -O-(C3-C7)cycloalkyl;

[0023] Q is selected from the group of (for example the group consisting of) -(Ci- Ce)haloalkyl (for example -CF3), -(Co-C6)alkylene-C(=0)-ORb or -(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-, -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-Ce)alkylene-OR3, -NR3(C2-Ce)alkylene-OR4, -(Co-C6)alknylene-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(=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;

[0024] 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 and -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co-C6)alkylene-NH(Ci- Ce)alkyl, and -(Co-Ce)alkylene-NH2.

[0025] P may be bicyclic, comprising two or more fused heterocyclic or heteroaryl rings, wherein one of the rings is a 6 membered heterocyclic or heteroaryl ring, and wherein P is bonded to the pyrazole core via the 6 membered ring. P may comprise two fused 6 membered heterocyclic or heteroaryl rings, or a six membered heterocyclic or heteroaryl ring and a 5 membered heterocyclic or heteroaryl ring.

[0026] It has now, surprisingly, been found that the compounds of general Formula (I’) 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.

[0027] Preferably, the compound of Formula (I’) is a compound of Formula (I):

[0028] P may represent an heteroaryl or heterocycle of formula:

[0029] wherein G and J may each be independently C-R or N; and D, E and M may each be independently C or N; and wherein P may be bonded to the pyrazole core via the 6 membered ring.

[0030] R1may be selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl.

[0031] 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).

[0032] The cycloalkyl, aryl, heteroaryl or heterocycle of Q may be represented by formula:

[0033] wherein p may be an integer equal to zero, 1 or 2; and wherein Z1may be selected from C=C, C=O, C, N, S or O; and Z2, Z3, Z4, Z5and Z6may each be independently selected from C, N, S or O.

[0034] 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: R1is selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-C6)deuterioalkyl and -(C3-C7)cycloalkyl;

[0035] R2is selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl or -(Ci-Ce)haloalkyl (for example - CF3); P represents a heteroaryl or or heterocycle of formula: wherein G and J are each independently C-R or N; and D, E and M are each independently C or N; and wherein P is bonded to the pyrazole core via the 6 membered ring; 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;

[0036] R is selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)haloalkyl (for example -CF3), -O-(Ci-Ce)alkyl and -O-(C3-C7)cycloalkyl;

[0037] 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-

[0038] C6)alkylene-C(=0)-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-

[0039] 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-

[0040] 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-(C0-C6)alkylene-S(=O)-R4, -(Co-C6)alkylene-S(=0)2-R3, -0-(Co-C6)alkylene- S(=O)2-R3, -NR3-(C0-C6)alkylene-S(=O)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;

[0041] 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.

[0042] The pyrrolopyridine group set out above may, for example, be:

[0043] P may represent a heteroaryl or heterocycle of formula:

[0044] wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0045] Preferably, P represents a heteroaryl or heterocycle of formula: wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0046] Preferably, P represents a heteroaryl or heterocycle of formula: wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0047] Preferably, P represents a heteroaryl or heterocycle of formula:

[0048] wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0049] Preferably, P represents a heteroaryl or heterocycle of formula: wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0050] P may be a heretoaryl or heterocycle of formula: wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0051] P may be a heretoaryl or heterocycle of formula: wherein each heteroaryl or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3.

[0052] P may be bonded to the pyrazole core via the 6 membered ring.

[0053] Preferably, R1is selected from the group of (for example the group consisting of) -(Ci- Cs)alkyl, -(Ci-C6)deuterioalkyl and -(C3)cycloalkyl; R2is selected from the group of (for example the group consisting of) hydrogen, -CF3, -F and -CH3; and R is selected from the group of (for example the group consisting of) hydrogen, -CF3, -(Ci-C3)alkyl, - (C3)cycloalkyl, -O-(Ci-C3)alkyl and -O-(C3)cycloalkyl.

[0054] Preferably, P represents a heteroaryl or heterocycle of formula: wherein each heteroaryl or or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to 1, 2 or 3; and

[0055] R1is selected from the group of (for example the group consisting of) -(Ci-C3)alkyl, - (Ci-C6)deuterioalkyl and -(C3)cycloalkyl; R2is selected from the group of (for example the group consisting of) hydrogen, -F and -CH3; and R is selected from the group of hydrogen, -CF3, -(Ci-C3)alkyl, -(C3)cycloalkyl, -O-(Ci-C3)alkyl and -O-(C3)cycloalkyl.

[0056] Q may be

[0057] 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; and wherein Bi is a radical B. P may be bonded to the pyrazole core via the 6 membered ring.

[0058] Q may be a cycloalkyl, aryl, heteroaryl or heterocycle of formula:

[0059] 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-R3(Ci-C6)deuterioalkyl)2, -N-R3(CI- C6)deuterioalkyl)2, -(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, -NR3(C2-Ce)alkylene- OR4, -(Co-C6)alkylene-NR3R4, -(Co-C6)alkylene-C(=0)-NR3R4; -(Co-C6)alkylene- NR3C(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, -NR3-(C0-C6)alkylene-C(=O)-OR4, -NR3- (Co-Ce)alkylene-C(=0)-R4and

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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 is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N, and R, Q, B and n, are as defined in any statement set out above.

[0064] Preferably, the compounds of Formula (I) or Formula (II) are the compounds according to 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 -oxi de form thereof, wherein R1is methyl or ethyl and R, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula (IV): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein Ai and A2 are selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl or Ai and A2 together can form a saturated C5 membered ring, R1is methyl or ethyl, G and J independently are C-R or N, and R, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) or Formula (IV) are the compounds according to Formula (V): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl, G is selected from N, C-H and C-CH3 and A2, Q, B and n, are as defined in any statement set out above.

[0065] Preferably, the compounds of Formula (I) are the compounds according to Formula (VI): 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, R1is methyl or ethyl, and R, Q, B and n, are as defined in any statement set out above.

[0066] Preferably, the compounds of Formula (I) or Formula (VI) are the compounds according to Formula (VII): 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 A2, R, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0067] (VIII): 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, A2 and A3 are each independently selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0068] Preferably, the compounds of Formula (I) or Formula (VIII) are the compounds according to Formula (IX): 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, G is selected from N, C-H and C-CH3, and Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula (X):

[0069] 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, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0070] Preferably, the compounds of Formula (I) or Formula (X) are the compounds according to Formula (XI): 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, R and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0071] (XII):

[0072] 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, A2 and A3 are each independently selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0073] Preferably, the compounds of Formula (I) or Formula (XII) are the compounds according to Formula (XIII): 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. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0074] (XIV): 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, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0075] Preferably, the compounds of Formula (I) or Formula (XIV) are the compounds according to Formula (XV): 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 G is selected from N, C-H and C-CH3, and Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0076] (XVI): 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, D is N or C-A3, wherein A3 is selected from H, -(Ci-C2)alkyl and -O-(Ci- C2)alkyl, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0077] Preferably, the compounds of Formula (I) or Formula (XVI) are the compounds according to Formula (XVII): 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, G and n, are as defined in any statement set out above.

[0078] Preferably, the compounds of Formula (I) or Formula (XVI) are the compounds according to Formula (XVIII): (XVIII) 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 A3, Q, B, G, J and n, are as defined in any statement set out above.

[0079] Preferably, the compounds of Formula (I) are the compounds according to Formula (XIX): 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, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0080] Preferably, the compounds of Formula (I) or Formula (XIX) are the compounds according to Formula (XX): 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 G, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) or Formula (XIX) are the compounds according to Formula (XXI): 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, R and n, are as defined in any statement set out above.

[0081] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXII): 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, R1is methyl or ethyl, and Q, B, G, J and n, are as defined in any statement set out above.

[0082] Preferably, the compounds of Formula (I) or Formula (XXII) are the compounds according to Formula (XXIII): (XXIII) 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, G and n, are as defined in any statement set out above.

[0083] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXIV): 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 A2 is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, wherein R1is methyl or ethyl, and Q, B, R and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0084] (XXV): 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 A2 and A3 are independently selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl, R1is methyl or ethyl, and Q, B, G and n, are as defined in any statement set out above.

[0085] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXVI): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl, and Q, B, R and n, are as defined in any statement set out above.

[0086] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXVII): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein A2 is selected from H, methyl, R1is methyl or ethyl, and Q, B, R and n, are as defined in any statement set out above. The compound may exist as stereoisomers, wherein the compound is either a racemic mixture or one or both of the individual stereoisomers.

[0087] 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.

[0088] Preferably, the compounds of Formula (I) are the -trans isomers of the 1,2-disubstituted cyclopropane moiety.

[0089] 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.

[0090] 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 A -oxi de form thereof, wherein Ai is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N, and R, Q, B and n, are as defined in any statement set out above.

[0091] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0092] (Illa) or (Illb): 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 R, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula (IVa) or (IVb): 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 Ai and A2 are selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl or Ai and A2 together form a saturated C5 membered ring, R1is methyl or ethyl, G and J independently are C-R or N, and R, Q, B and n, are as defined in any statement set out above.

[0093] Preferably, the compounds of Formula (I) are the compounds according to Formula (Va) or (Vb): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl, G is selected from N, C-H and C-CH3, and A2, Q, B and n, are as defined in any statement set out above.

[0094] Preferably, the compounds of Formula (I) are the compounds according to Formula (Via) or (VIb): 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 Ai and A2 are each independently selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl, R1is methyl or ethyl and R, Q, B and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula (Vila) or (Vllb): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl, and R, Q, B and n, are as defined in any statement set out above.

[0095] Preferably, the compounds of Formula (I) are the compounds according to Formula (Villa) or (Vlllb): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein Ai, A2 and A3 are each independently selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N and Q, B, R and n, are as defined in any statement set out above.

[0096] Preferably, the compounds of Formula (I) are the compounds according to Formula (IXa) or (IXb):

[0097] 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, G is selected from N, C-H and C-CH3, and Q, B and n, are as defined in any statement set out above.

[0098] Preferably, the compounds of Formula (I) are the compounds according to Formula (Xa) or (Xb): 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, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0099] Preferably, the compounds of Formula (I) are the compounds according to Formula (Xia) or (Xlb):

[0100] 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, R and n, are as defined in any statement set out above.

[0101] Preferably, the compounds of Formula (I) are the compounds according to Formula (Xlla) or (Xllb): 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, A2 and A3 are each independently selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0102] Preferably, the compounds of Formula (I) are the compounds according to Formula (Xllla) or (Xlllb): (Xlllb) 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.

[0103] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0104] (XlVa) or (XlVb): 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, R1is methyl or ethyl, G and J independently are C-R or N and Q, B, R and n, are as defined in any statement set out above.

[0105] Preferably, the compounds of Formula (I) are the compounds according to Formula (XVa) or (XVb):

[0106] 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 G is selected from N, C-H and C-CH3, and Q, B and n, are as defined in any statement set out above.

[0107] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0108] (XVIa) or (XVIb): 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, D is N or C-A3, wherein A3 can be selected from H, -(Ci-C2)alkyl and - O-(Ci-C2)alkyl, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above.

[0109] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0110] (XVIIa) or (XVIIb): 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, G and n, are as defined in any statement set out above.

[0111] Preferably, the compounds of Formula (I) are the compounds according to Formula (XVIIIa) or (XVIIIb): 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 A3, Q, B, G, J and n, are as defined in any statement set out above.

[0112] Preferably, the compounds of Formula (I) are the compounds according to Formula (XIXa) or (XlXb): 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, R1is methyl or ethyl, G and J independently are C-R or N, and Q, B, R and n, are as defined in any statement set out above. Preferably, the compounds of Formula (I) are the compounds according to Formula

[0113] (XXa) or (XXb): 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 G, Q, B and n, are as defined in any statement set out above.

[0114] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXIa) or (XXIb): 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, R and n, are as defined in any statement set out above.

[0115] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXIIa) or (XXIIb): 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, R1is methyl or ethyl, and Q, B, G, J and n, are as defined in any statement set out above.

[0116] Preferably, the compounds of Formula (I) are the compounds according to Formula

[0117] (XXIIIa) or (XXIIIb): 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, G and n, are as defined in any statement set out above.

[0118] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXIVa) or (XXIVb): 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 A2 is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, wherein R1is methyl or ethyl, and Q, B, R and n, are as defined in any statement set out above.

[0119] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXVa) or (XXVb): 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 A2 and A3 are independently selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl, R1is methyl or ethyl, and Q, B, G and n, are as defined in any statement set out above.

[0120] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXVIa) or (XXVIb): 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, R and n, are as defined in any statement set out above.

[0121] Preferably, the compounds of Formula (I) are the compounds according to Formula (XXVIIa) or (XXVIIb): 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 A2 is selected from H, methyl, R1is methyl or ethyl and Q, B, R and n, are as defined in any statement set out above.

[0122] 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.

[0123] Table A: 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.

[0124] Table A-l: Particular preferred compounds of the invention are compounds mentioned in Table B 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.

[0125] Table B:

[0126]

[0127] 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.

[0128] 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.

[0129] Table C:

[0130]

[0131] 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:

[0132]

[0133] Preferably, the compounds set out in Tables A, B, C and D are the -trans isomers of the 1,2-disubstituted cyclopropane moiety. Preferably, the compound is one or more selected from the following list (Table E), 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 E:

[0134]

[0135]

[0136]

[0137] The compounds according to any statement above may exhibit Muscarinic M4 modulator activity. 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.

[0138] 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 (I’), Formula (I) to (XXVII), la to XXVIIa, and lb to XXVIIb. Isotopically-labelled compounds of Formula (I’), Formula (I) to (XXVII), la to XXVIIa, and lb to XXVIIb 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.

[0139] 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.

[0140] 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.

[0141] 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 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.

[0142] The condition may be one or more of a central nervous system disorder.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] The central nervous system disorder may be personality disorders: obsessive-compulsive personality disorder.

[0147] 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.

[0148] 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.

[0149] The central nervous system disorder may be neurodevelopmental disorders including RETT syndrome, Fragile X syndrome, Huntington’s disease, Angelman’s syndrome, West syndrome.

[0150] 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.

[0151] In a further aspect of the present invention there is provided the compounds or compositions as set out in any statement set out above for use as a medicament.

[0152] In a further aspect of the present invention there is provided the compounds or compositions as set out in any statement set out above for use in a method of treatment or prevention as defined in any statement above.

[0153] In a further aspect of the present invention there is provided a use of a compound according to any statement set out above in the manufacture of a medicament for the treatment or prevention of a condition as defined in any statement set out above.

[0154] 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, tablets 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.

[0155] 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 about 0.05 to 2000 mg to about 0.1 mg to about 1000 mg.

[0156] DEFINITION OF TERMS

[0157] Listed below are definitions of various terms used in the specification and claims to describe the present invention. 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] In this specification, a dashed line shown within a ring system denotes a single or double bond. For example, the dashed line in the following ring system denotes either a single bond, in which case the ring would be partially saturated; or a double bond, in which case the ring would be aromatic.

[0162] 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.

[0163] 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.

[0164] Representative examples of deuterioalkyl include CD3, CH2D, CHD2, CH2CD3, and CD2CD3. 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-).

[0165] 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.

[0166] 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.

[0167] 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.

[0168] In this specification, unless stated otherwise, the term “alkylene-aryl”, “alkylene- heteroaryl” 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.

[0169] 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).

[0170] In this specification, unless stated otherwise, the term “halo” or “halogen” may be fluoro, chloro, bromo or iodo.

[0171] 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.

[0172] In this specification, unless stated otherwise, the term “cyanoalkyl” means an alkyl radical as defined above, substituted with one or more cyano.

[0173] 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.

[0174] 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. 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.

[0175] 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.

[0176] 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”.

[0177] 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.

[0178] 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 Z-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”.

[0179] A iHH / ! " 1

[0180] For example, the radical is a tautomer of .

[0181] 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,1H,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.

[0182] 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.

[0183] PHARMACEUTICAL COMPOSITIONS

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] METHODS OF SYNTHESIS

[0194] The compounds according to the invention, in particular the compounds according to the Formula (I’) and Formula (I) to (XXVII), 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’) and Formula (I) to (XXVII).

[0195] 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).

[0196] 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).

[0197] 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).

[0198] The product from the reaction can be isolated and purified by employing standard techniques, such as extraction, chromatography, recrystallization and distillation. 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.

[0199] In one embodiment of the present invention, compounds of formula (I) may be prepared according to the synthetic sequence illustrated in Scheme 1. Pyridazine 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 -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 compounds of formula (I).

[0200] Scheme 1

[0201] X = halogen; A, P, R1and R2, Q, B, m and n are as defined in any statement set out above

[0202] Intermediates g4 (cores 1 to 7) may be prepared according to the synthetic sequence illustrated in Scheme 2.

[0203] According to one route, bicyclic compounds g2 are coupled with pinacol boronic esters g3 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 intermediates g4.

[0204] According to a second route, g2 may be iodinated in the presence of A-iodosuccinimide, in an appropriate solvent such as acetonitrile, at an appropriate temperature, to afford the intermediate g”2. Compounds g”2 may then be coupled with pinacol boronic esters g3 via 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 intermediates g4.

[0205] Scheme 2

[0206] X2= halogen; A1, R, R1and R2are as defined in any statement set out above

[0207] Intermediate g2 may be prepared according to the synthetic sequences illustrated in

[0208] Scheme 3, Scheme 4A and Scheme 4B.

[0209] Scheme 3 refers to the preparation of intermediate g2 using g’l as starting material. Pyridazine compound g’l is reacted with an acyl hydrazide such as acethydrazide to form bicyclic intermediate g’2. To afford halide compounds g2, compounds g’2 may be diazotised and halogenated via a suitable reaction known by people skilled in the art of organic synthesis, for example a a Sandmeyer or Schiemann reaction, via a diazonium salt intermediate. step 1

[0210] Scheme 3

[0211] X1and X2= halogen; A1and R are as defined in any statement set out above

[0212] Schemes 4A and 4B refer to the preparation of compounds g2 using gl as starting material. In Scheme 4A, pyridazine compounds gl are reacted with an acyl hydrazide such as acethydrazide to directly afford compounds g2. Scheme 4A

[0213] X1and X2= halogen; A1and R are as defined in any statement set out above

[0214] In Scheme 4B, bicyclic intermediate g”2 may be prepared by reacting the corresponding gl with Boc-substituted hydrazine with subsequent hydrolysis of the Boc group. Alternatively, compounds g”2 may be prepared by reacting the corresponding gl with hydrazine in an appropriate solvent such as ethanol, at an appropriate temperature. Compounds g”2 may then be reacted with either carboxylic acid - route (i) - or aldehyde - route (ii) - to afford compounds g2 via cyclization. Scheme 4B

[0215] X1and X2= halogen; A1and R are as defined in any statement set out above Pinacol boronic esters g3, to be used in the preparation of intermediates g4 according to Scheme 2, may be prepared according to the synthetic sequence illustrated in Scheme 5. Corresponding pyrazoles g’3 (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 g3.

[0216] Scheme 5

[0217] R1and R2are as defined in any statement set out above

[0218] Pinacol boronic esters 2, to be used in the synthesis of compounds [I] according to Scheme 1, may be prepared using either compounds g5, compounds g8 or compounds g!3 as starting material.

[0219] Scheme 6 illustrates possible synthesis routes to compounds 2 using g5 as starting material.

[0220] According to Route A of Scheme 6, compounds g5 may be coupled with vinylboronic acid pinacol ester g6 to afford pinacol boronic esters g7. Cyclopropanation may be performed via any suitable reaction such as a Corey-Chaykovsky reaction, wherein compounds g7 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 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0221] According to Route B of Scheme 6, compounds g5 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 g9. Cyclopropanation may be performed via any suitable reaction such as a Corey- Chaykovsky reaction, wherein compounds g9 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 glO. According to step 3, esters glO may be hydrolysed in acidic conditions to afford the corresponding carboxylic acids gll. According to step 4, compounds gll may be reacted with N-hydroxyphthalimide in the presence of N,N'- dicyclohexylcarbodiimide (DCC) in the presence of triethylamine (TEA), 4- Dimethylaminopyridine (DMAP) and dichloromethane (DCM) to form the corresponding esters gll. According to step 5, compounds gll 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 1. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0222] According to Route C of Scheme 6, compounds g5 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 gl7. Compounds gl7 may then be coupled with tert-butyl diazoacetate in the presence of a catalyst such as 5,10,15,20-tetraphenyl-21J / ,23J / - porphine cobalt(II), in a suitable solvent such as anhydrous toluene, to form compounds g9. To afford compounds 1, 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.

[0223] According to Route D of Scheme 6, compounds g5 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 compounds g’10. Esters g’10 may then be hydrolysed, for example by acid hydrolysis with hydrochloric acid in a suitable solvent such as dioxane, to afford carboxylic acids gll. To afford compounds 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. - Ill -

[0224] Scheme 6

[0225] X = halogen; Q, B and n are as defined in any statement set out above Scheme 7 illustrates possible synthesis routes to compounds 2 using g8 as starting material.

[0226] According to Route A of Scheme 7, compounds g8 may be coupled with bis(pinacolato)diboron g’6 to afford pinacol boronic esters g7. Cyclopropanation may then be performed via any suitable cyclopropanation reaction such as a Corey- Chaykovsky reaction, wherein compounds g7 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 compounds 2. To then afford the final product [I], the synthesis may be continued according to Scheme 1.

[0227] According to Route B of Scheme 7, compounds g8 may be reacted with tert-butyl 2- (triphenylphosphoranylidene)acetate in a suitable solvent such as anhydrous toluene to afford esters g9. Cyclopropanation step 2 may be performed via any suitable cyclopropanation reaction such as a Corey-Chaykovsky reaction, wherein compounds g9 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 glO. According to step 3, esters glO may be hydrolysed in acidic conditions to afford the corresponding carboxylic acids gll. According to step 4, compounds gll 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 gll. According to step 5, compounds gll 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.

[0228] According to Route C of Scheme 7, compounds g8 may be condensed with malonic acid in pyridine as solvent and piperidine to afford after decarboxylation by heating the acrylic acids g’9. Compounds g’9 may react with methoxy(methyl)amine hydrochloride after activation with 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride in the presence of a suitable base such as N,N-diisopropylethylamine 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”10. Hydrolysis may then be performed with any suitable reagent such as a mineral base like potassium tert- butoxide to afford compounds gll. To afford compounds 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.

[0229]

[0230] Scheme 7

[0231] Q, B and n are as defined in any statement set out above Scheme 8 illustrates a possible synthesis route to intermediate 2 using compounds gl3 as starting material.

[0232] The Weinreb amide g”10 of Compounds gl3 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 1 -(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”10. Hydrolysis step 3 may be performed with any suitable base such as potassium tert-butoxide to afford compounds gll To afford compounds 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.

[0233] Scheme 8

[0234] Q, B and n are as defined in any statement set out above

[0235] Final compounds (I) may be prepared according to the synthetic sequence illustrated in

[0236] Scheme 9. Compounds 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 g23. According to step 2, esters g23 may be hydrolysed in acidic 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 (DCC) 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).

[0237]

[0238] Scheme 9

[0239] X = halogen; A, P, R1and R2, Q, B, m and n are as defined in any statement set out above

[0240] Compounds g22 may be prepared according to the synthetic sequence illustrated in Scheme 10. According to step 1, compounds gl8 and gl9 may be coupled 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 g20. According to step 2, compounds g20 may be reacted with an EtONa-EtOH solution (prepared from sodium and dry EtOH) to afford bicyclic compounds g21. Compounds g21 may then be reacted with phosphoroyl tribromide to afford compounds g22 according to step 3. According to step 4, compounds g22 may be coupled with compounds g23 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 PdC12(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 g24.

[0241] Scheme 10

[0242] Ai, A2, A3, R, R1and R2are as defined in any statement set out above Compounds g29 may be prepared according to the synthetic sequence illustrated in Scheme 11. According to step 1, pyrazoles g25 may be reacted with compounds g40 to afford bicyclic compounds g26. Compounds g26 may be reacted with phosphoroyl trichloride to afford compounds g27. According to step 3, the chloro derivative g27 is reacted with bromotrimethylsilane to afford compounds g28. According to step 4, compounds g28 may be coupled with compounds g3 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 compounds g29.

[0243]

[0244] Scheme 11

[0245] Ai, A2, R, R1and R2are as defined in any statement set out above. Compounds g33 may be prepared according to the synthetic sequence illustrated in Scheme 12. According to step 1, compounds g30 may be condensed with an alpha- halogeno-acetal or an alpha halogeno-ketone-type compound like compounds g300 (for example, 2-bromo-l,l-dimethoxypropane or 2-chlorocyclopentanone) to afford imidazopyridazine compounds g31 after cyclisation. According to step 2, compounds g31 may be reacted with hydrogen iodide and sodium iodide in an iodination reaction to afford compounds g32. According to step 3, compounds g32 and compounds g3 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 afford compounds g33.

[0246]

[0247] Scheme 12

[0248] Ai, A2, R, R1and R2are as defined in any statement set out above Compounds g39 may be prepared according to the synthetic sequence illustrated in Scheme 13. According to step 1, compounds g34 may be reacted with phthalimide, for example in the form of potassium phthalimide or potassium l,3-dioxo-2,3-dihydro-lH- isoindol-2-ide, to afford compounds g35. According to step 2, compounds g35 may be reacted with hydrazine to give amines g36. According to step 3, compounds g36 may be reacted with an acyl chloride or any carboxylic acid in the presence of a coupling reagent like carbonyl di-imidazole or a carbodiimide derivative to give the carboxamido intermediate g37. According to step 4, compounds g37 may be reacted with phosphoroyl trichloride in MeCN solution or other appropriate solvent like toluene to give bicyclic, imidazopyridazine compounds g38. According to step 5, compounds g38 and compounds g3 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 afford compounds g39.

[0249] Scheme 13

[0250] Ai, A2, R, R1and R2are as defined in any statement set out above Alternatively, compounds g39 may be prepared according to the synthetic sequence illustrated in Scheme 21. The reductive amination described in step Ifrom compounds g41 leads to the amino compound g42 which is then subsequently acetylated to afford the compound g43. According to step 3, compound g43 is brominated and cyclized by reaction with phosphoryl tribromide to afford compound g38’. According to step 4, compounds g38’ and compounds g3 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 afford compounds g39.

[0251]

[0252] Ai, A2, R, R1and R2are as defined in any statement set out above

[0253] Compounds g51 may be prepared according to the synthetic sequence illustrated in Scheme 22. According to step 1, the thioamide g45 may be prepared by thionation of the carboxamido compound g44 with phosphorus pentasulfide in an appropriate solvent such as ethanol. Oxy dative cyclization of the carboxythioamide g45 in the presence of hydrogen peroxide proceed in methanol as solvent at room temperature to give the compound g46. The bromination of this amino derivative g46 is conducted following a Sandmeyer reaction according to the step 3 in the presence of ter-butyl nitrite and copper bromide in an appropriate solvent like acetonitrile to afford the compound g48. According to step 4, the compound g50 may be reacted with a boronic acid derivative like g49 in the presence of a palladium catalyst in a Suzuki -Miy aura coupling reaction in the presence of a base to afford the compound g50. According to step 5, compounds g50 and compounds g3 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 afford compounds g51.

[0254] Scheme 22

[0255] Ai, R, R1and R2are as defined in any statement set out above

[0256] The Scheme 23 illustrates possible synthesis routes to compound g58 using g54 as starting material. The compound g54 is prepared by amination of the 2-halogeno pyridine derivative g52.

[0257] According to Route A of Scheme 23, compound g54 is reacted with a reducting mixture of an ammonium chloride solution into water and iron to afford the compound g55. This compound g55 may be condensed with a trimethoxy methane derivative g56 in the presence of para-toluenesulfonic acid to afford the cyclized compound g57 which will be coupled in 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 in step 4 the fcompound g58.

[0258] According to Route B of scheme 23, compound g54 when existing as a bromo derivative (g54’) is firstly coupled in a Suzuki-Miyaura coupling reaction, mediated by palladiumcomplex 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 the intermediate compound g59. Then, the nitro group reduction step 4 is similar to the Route A step 2 leading to the compound g59 which is condensed with a trimethoxy methane derivative g56 according to the reaction conditions described in the Route A step3 to afford the compound g58.

[0259] Scheme 23

[0260] Ai, A2, R, R1and R2are as defined in any statement set out above Compound g63 may be prepared according to the reaction scheme 24. According to step 1, compound g61 may be condensed with a trimethoxy methane derivative g56 in the presence of para-toluenesulfonic acid to afford the cyclized compound g62 which will be coupled in 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 in step 4 the compound g63.

[0261] Scheme 24

[0262] Ai, A2, R1and R2are as defined in any statement set out above

[0263] Compounds g69 may be prepared according to the synthetic sequence illustrated in Scheme 25. The amination step 1 from compounds g64 is performed following the same conditions described in the scheme 23 step 1 to obtain the compound g65. The halogen exchange reaction may be performed with bromotrimethyl silane in an appropriate solvent such as propionitrile according to step 2 to get after heating at 100°C the compound g66. The steps 3, 4 and 5 of the reaction scheme 25 are conducted similarly to the steps 2, 3 and 4 in the Route A of the Scheme 23 to afford the compound g69.

[0264] Scheme 25

[0265] Ai, A2, R, R1and R2are as defined in any statement set out above

[0266] Scheme 26 refers to the preparation of intermediate g72 using g55 as starting material. The diamino pyridine g55 which is described in Scheme 23 is cyclized into the triazine byciclic compound g70 by reaction with a nitrite derivative such as sodium nitrite in aqueous hydrochloric acid media or with 3 -methylbutylnitrite in dimethylformamide. The step 2 of this reaction scheme is an halogen exchange reaction which may be performed with bromotrimethyl silane in an appropriate solvent such as propionitrile according to step 2 to get after heating at 100°C the compound g71 which is subsequently coupled in 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 in step 4 the final compound g72.

[0267] Ai, R, R1and R2are as defined in any statement set out above

[0268] Scheme 27 refers to the preparation of intermediate g74 using g61 as starting material. The reactions steps 1 and 2 are similar to the route of synthesis described in the Scheme 26 steps 1 and 3 when X is a bromo substituent. Alternatively, an halogen exchange reaction such as the synthesis described in the step 2 of Scheme 26 is possible when X is a chloro substituent.

[0269] Scheme 27

[0270] Ai, R, R1and R2are as defined in any statement set out above Compound g77 may be prepared according to the synthetic sequence illustrated in Scheme 28. According to step 1, the ortho-diamino compound g61’ may be reacted with a carbonyl reagent known by people skilled in the art of organic synthesis such as carbonyl-diimidazole in an appropriate solvent such as dioxanne at high temperature to afford the compound g75. This compound may then be alkylated with an halide reagent such as an alkyl bromide or iodide in the presence of a base like dipotassium carbonate in apolar solvent like dimethylformaide to give the compound g76. According to step 3, compounds g76 and compounds g3 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 afford compounds g77.

[0271] Scheme 28

[0272] Ai, A2, R, R1and R2are as defined in any statement set out above

[0273] Compound g82 may be prepared according to the synthetic sequence illustrated in Scheme 29. According to step 1, compound g78 may be coupled in 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 compounds g79. The chlorination of this amino derivative g79 is conducted following a Sandmeyer reaction according to the step 2 in the presence of ter-butyl nitrite and copper chloride in an appropriate solvent like acetonitrile to afford the compound g80. Compound g80 may be condensed with compound g81 by heating in an appropriate solvent like ter-butyl -alcohol to afford compound g82.

[0274] Scheme 29

[0275] Ai, A2, R1and R2are as defined in any statement set out above

[0276] Compound g88 may be prepared according to the synthetic route illustrated in Scheme 30. The carboxy compound g83 is condensed with an hydrazine derivative preferentially under acidic condition such as sulfuric acid in acetonitrile as solvent to afford the hydrazone g84 which may then be cyclised as described is step 3 into the compound g85 under basic condition in an appropriate solvent such as dimethylformamide. The steps 3 may be conducted such as described in the Scheme 25 step 2 and the iodine-exchange reaction of the step 4 is performed with sodium iodide, copper iodide and a base in a solvent such as dioxanne to afford the compound g87 which can be coupled with compound g3 in 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 compounds g88.

[0277] Ai, A2, R, R1and R2are as defined in any statement set out above

[0278] The indazole Compound g91 may be prepared according to the synthetic route illustrated in Scheme 31. The carboxy compound g89 is condensed with an hydrazine derivative in ethanol and subsequently cyclized under basic condition with triethylamine to afford the intermediate g90 which can be coupled with compound g3 in 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 compounds g91.

[0279] Scheme 31

[0280] Ai, A2, A, R1and R2are as defined in any statement set out above

[0281] Scheme 32 refers to the preparation of intermediate g94 using g92 as starting material. The reactions steps 1 consists in the introduction of a tritiate group to the compound g92 with triflic anhydride in the presence of triethylamine as a base or any equivalent and an appropriape solvent like a mixture of methylene chloride and dimethoxy ethane to afford the intermediate g93 which can then be coupled to the compound g3 in a Suzuki-Miyaura coupling reaction 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 g91.

[0282] Scheme 32

[0283] Ai, A2, A3 , R1and R2are as defined in any statement set out above

[0284] Scheme 33 refers to the preparation of intermediate g98 using g95 as starting material. The reactions steps 1 consists in a condensation reaction with for example ethyl 2- oxoacetate in dioxane at high temperature to obtain the compound g96. The step 2 consists in the introduction of a tritiate group or an halogen atom according to the reactions described above in Scheme 31 step 1 or like in Scheme 21 step 3 to afford the intermediate g97 which can then be coupled to the compound g3 in a Suzuki-Miyaura coupling reaction 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 g98.

[0285]

[0286] Scheme 33

[0287] Ai, A2, A3 , R1and R2are as defined in any statement set out above Scheme 34 refers to the preparation of intermediate g!02 using g99 as starting material. The reactions steps 1 consists in a condensation reaction with an amidine derivative such as ethanimidamide in a suitable solvent like tetrahydrofuran to obtain the compound glOO The step 2 consists in the halogen exchange reaction with a reagent like bromotrimethylsilane to afford the intermediate glOl which can then be coupled to the compound g3 in a Suzuki -Miy aura coupling reaction 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!02.

[0288] Scheme 34 Ai, A2, R, R1and R2are as defined in any statement set out above

[0289] EXPERIMENTAL

[0290] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0291] Specifically, the following abbreviations may be used in the examples and throughout the specification.

[0292] 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.

[0293] Examples

[0294] 1. Synthesis of intermediates g4

[0295] R1= Me, Et, R2= Me, H

[0296] Scheme 5’ 3-Bromo-l-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole

[0297] (intermediate g3)

[0298] 3-Bromo-l-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyr azole

[0299] According to Scheme 5’: 3 -Bromo- 1 -methyl- IJT-pyrazole (10.00 g, 62.11 mmol, l.O 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%).

[0300] Synthesis of cores 1 to 7 (intermediates g4)

[0301] Ai = Me, cPr, Ph R = H, Me, iPr, OMe, CF3, R1= Me, Et, iPr, cPr R2= H. Me, F

[0302] Scheme 4A’, 2

[0303] Table 1

[0304] 3-Bromo-5-{3, 8-dim ethyl- [ 1.2.4| triazolo|4.3- / ?| pyridazin-6-ylJ- 1 -methyl- 1 / / - pyrazole (Core 4)

[0305] 6-Chloro-3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4,3-b ]pyridazine

[0306] According to Scheme 4A’ Step 1 : 3,6-Dichloro-4-methylpyridazine (10.00 g, 61.35 mmol, 1.0 eq.) and acethydrazide (20.00 g, 269.94 mmol, 4.4 eq.) were dissolved in n- butanol (300 ml) and the resulting mixture was heated at 140 °C for 48 hours. After that time, the reaction mixture was cooled to room temperature, the precipitated solid was filtered off and the filtrate was concentrated in vacuum. The crude product was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification) and purified using FCC (silica gel) eluting with a mixture of eluents from EtOAc : DCM (50 : 50) to EtOAc: DCM : MeOH (49.5 : 49.5 : 1) to afford the title compound as a beige solid (2.60 g, 23%). The fractions after FCC chromatography were assigned to regioisomers according to 2D NMR (HSQC and NOESY).

[0307] 3-Bromo-5-{3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-l -methyl- IH-pyr azole According to step 2 (as in Scheme 2): A solution of 6-chl oro-3, 8-dimethyl- [l,2,4]triazolo[4,3-Z>]pyridazine (5.50 g, 30.12 mmol, 1.0 eq.), 3-bromo-l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-U / -pyrazole (9.29 g, 93% purity, 30.12 mmol, 1.0 eq.), potassium phosphate tribasic (19.18 g, 90.36 mmol, 3.0 eq.) in the mixture of dioxane (150 mL) with water (30 mL) was degassed, and purged with Ar. Then, XPhos Pd G3 (2.55 g, 3.01 mmol, 0.1 eq.) followed by cataCXium A (1.08 g, 3.01 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 30-35 °C for 1 hour. After the specified time, the mixture was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (3x100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification), then purified on column chromatography using puriFlash® C18-HP 15 pM, 330 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 (2.88 g, 31%).

[0308] The compounds shown in Table 1 may be prepared similarly to the compound described above, with appropriate starting materials.

[0309] Synthesis of core 8 (intermediate g4):

[0310] Scheme 2bis

[0311] 3-Bromo-l-ethyl-4-fluoro-5-3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl-lH-pyr azole According to Scheme 2bis: to a solution of 3-bromo-l-ethyl-5-3-methyl- [l,2,4]triazolo[4,3-b]pyridazin-6-yl-lH-pyrazole (500.0 mg, 1.63 mmol) (Core 3 prepared as for core 1) in acetonitrile (10 mL) l-(chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium; bis(tetrafluoroboranuide) (1.16 g, 3.27 mmol) was added and the resulting solution was stirred at rt for 24 h. After completion of the reaction obtained mixture was concentrated in vacuo and subjected to prep HPLC purification (20-20-70% 0-l-6min H2O / MeOH / 0.1%NH4OH, flow: 30ml / min (loading pump 4ml / min MeOH) target mass 325;343 column: XBridge C18 100x19mm, 5um) to obtain 3-bromo-l-ethyl-4-fluoro-5-3-methyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl-lH-pyrazole (22.0 mg, 92.0% purity, 62.25 pmol, 3.8% yield) as a light yellow amorphous product.

[0312] Synthesis of cores 9 to 10 (intermediates g4):

[0313] Ai = Et, cPr, R = H, R1= Et

[0314] Scheme 4B’ route (i), 2

[0315] Table 2

[0316] 3-Bromo-5-{3-cyclopropyl-[l,2,4]triazolo[4,3-6]pyi'idazin-6-yl}-l-ethyl-lH- pyrazole (Core 10) N '-( 6-bromopyridazin-3-yl) ( tert-butoxy)carbohydrazide

[0317] According to Scheme 4B’ Step 1 : In a seal tube equipped with a magnetic stirring bar, 3,6-dibromopyridazine (5.00 g, 21.01 mmol, 1.0 eq.) and tert-butyl carbazate (2.77 g, 21.01 mmol, 1.0 eq.) were dissolved in ethanol (250 ml). The resulting mixture was stirred at 95 °C for 48 hours. After the specified time, the reaction mixture was evaporated to dryness and the residue was triturated with DCM. The collected filtrates were concentrated in vacuum and purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-50%) to afford the title compound as a white solid (1.60 g, 26%).

[0318] 3-Bromo-6-hydrazinylpyridazine hydrochloride According to Scheme 4B’ Step 2: A-(6-bromopyridazin-3-yl)(terL butoxy)carbohydrazide (1.60 g, 5.53 mmol, 1.0 eq.) was suspended in hydrochloric acid (3.7-4.3 N in dioxane, 28 mL, 20.0 eq.) in a flask with a magnetic stirring bar. The resulting mixture was stirred at room temperature for 6 hours. After that time, the precipitated solid was filtered, rinsed with diethyl ether and evaporated to dryness to afford the title compound as a white solid (1.12 g, 83%). The title compound was used as a crude in the next step without additional purification.

[0319] 6-Chloro-3-cyclopropyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazine

[0320] According to Scheme 4B’ step 3: 3-Bromo-6-hydrazinylpyridazine hydrochloride (0.18 g, 0.75 mmol, 1.0 eq.) was suspended in cyclopropanecarboxylic acid (2.4 mL, 30.15 mmol, 40.0 eq.) in a seal tube equipped with a magnetic stirring bar. The resulting mixture was stirred at 100 °C overnight. After the specified time, the precipitated solid was filtered, rinsed with diethyl ether (2x25 mL) and dried in vacuum to afford the title compound as a white solid (100 mg, 68%). The title compound was used as a crude in the next step without additional purification.

[0321] 3-Bromo-5-{3-cyclopropyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-l -ethyl- IH-pyr azole According to step 4 (as in Scheme 2): A solution of 6-chl oro-3 -cy cl opropyl- [l,2,4]triazolo[4,3-Z>]pyridazine (100 mg, 0.51 mmol, 1.0 eq.) and 3-bromo-l-ethyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (232 mg, 0.77 mmol, 1.5 eq.) potassium phosphate tribasic (327 mg, 1.54 mmol, 3.0 eq.) in the mixture of dioxane (2.5 mL) with water (0.5 mL) was degassed and purged with Ar. Then, XPhos Pd G3 (43 mg, 0.05 mmol, 0.1 eq.) followed by cataCXium A (18 mg, 0.05 mmol, 0.1 eq.) were subsequently added and the reaction mixture was stirred at 80 °C overnight. After that time, the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3x30 mL) The combined organic layers were dried over MgSO4, filtrated and concentrated in vacuum to dryness. The crude product was purified by using preparative TLC (silica gel, ethyl acetate as a eluent) to afford the title compound as a beige solid (60 mg, 63% purity, 22%).

[0322] The compounds shown in Table 2 may be prepared similarly to the compound described above, with appropriate starting materials. Synthesis of cores 11 to 12 (intermediates g4):

[0323] Scheme 4B’ route (ii), 2

[0324] Table 3

[0325] 3-Bromo-l-ethyl-5-[3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl]-lH- pyrazole (Core 11)

[0326] 3-Bromo-6-hydrazinylpyridazine

[0327] According to Scheme 4B’ Step 1 (method 2): A mixture of 3,6-dibromopyridazine (10.0 g, 42.4 mmol) and hydrazine hydrate (2.53 g, 50.46 mmol) in 100 mL of ethanol was refluxed for 1 h. The reaction mixture was evaporated to dryness and the residue was recrystallized from benzene to give 3-bromo-6-hydrazinylpyridazine (5.0 g, 95.0% purity, 59.8% yield) as a yellow solid.

[0328] 3-Bromo-6-[(2E)-2-(2,2,2-trifluoroethylidene)hydrazin-l-yl]pyridazine According to Scheme 4B’, Step 2: To an ethanolic solution (10 mL) of 3-bromo-6- hydrazinylpyridazine (600.06 mg, 3.2 mmol) was added 2,2,2-trifluoroacetaldehyde (373.46 mg, 3.82 mmol). The reaction mixture was refluxed for 30 min. Then, the solvent was evaporated in vacuo to obtain 3-bromo-6-[(2E)-2-(2,2,2- trifluoroethylidene)hydrazin-l-yl]pyridazine (600.5 mg, crude) which was used in the next step without further purifications.

[0329] 6-Bromo-3-(trifluoromethyl)-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazine

[0330] According to Scheme 4B’ Step 3: To a solution of 3-bromo-6-[(2E)-2-(2,2,2- trifluoroethylidene)hydrazin-l-yl]pyridazine (600.5 mg, 2.24 mmol) in dichloromethane (25 ml), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (862.76 mg, 2.68 mmol) was added in small portions and the reaction mixture was stirred for 12 h. Excess solvent was distilled off in vacuo, and the residual mass was triturated with petroleum ether to remove the excess of iodobenzene and a solid product separated, which was purified by FCC to afford 6-bromo-3-(trifhioromethyl)-[l,2,4]triazolo[4,3-b]pyridazine (100.0 mg, 374.52 pmol, 16.8% yield).

[0331] 3-bromo-l-ethyl-5-[ 3-( trifluor ome thy I) -[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl -1H- pyrazole

[0332] According to Step 4 (as in Scheme 2): A solution of 6-bromo-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (110.0 mg, 413.62 pmol), 3-bromo-l-ethyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (248.38 mg, 827.75 pmol), di cyclohexyl [2',4',6'-tris(propan-2-yl)-[ 1 , 1 '-biphenyl]-2-yl]phosphane; 2'-amino-[ 1 , 1 biphenyl]-2-ylpalladio methanesulfonate (34.92 mg, 41.32 pmol) , tripotassium phosphate (262.75 mg, 1.24 mmol) and bis(adamantan-l-yl)(butyl)phosphane (14.79 mg, 41.29 pmol) in dioxane (4 mL) and water (1 ml) was degassed and purged with Ar. The resulting mixture was heated at 60 °C overnight. Then the mixture was cooled to rt. and diluted with EtOAc (20 mL). The solid was filtered, and washed with EtOAc (10 mL) to obtain pure 3-bromo-l-ethyl-5-[3-(trifluoromethyl)-[l,2,4]triazolo[4,3- b]pyridazin-6-yl]-lH-pyrazole (40.0 mg, 26.8% yield).

[0333] The compounds shown in Table 3 may be prepared similarly to the compound described above, with appropriate starting materials. Synthesis of cores 18 to 22 (intermediates g33):

[0334] R = Me, Ai = H, Me, R = H, Me, R1= Me, Et.

[0335] Scheme 12’ (halogeno-ketal condensation)

[0336] Table 4

[0337] 3-bromo-5-3,8-(Hmethylinudazo[l,2-b]pyri(lazin-6-yl-l-methyl-lH-pyrazole (Core 18)

[0338] 6-chloro-3, 8-dimethylimidazo[ 1, 2-b ]pyridazine

[0339] According to Scheme 12’ Step 1 : 6-Chloro-4-methylpyridazin-3-amine (14.0 g, 97.88 mmol) , 2-bromo- 1,1 -dimethoxypropane (39.19 g, 215.35 mmol, 28.82 ml, 2.2 equiv) and 4-m ethylbenzene- 1 -sulfonic acid (1.68 g, 9.79 mmol) acid were mixed in BuOH (150 mL) solution and stirred at 100°C for 2 days. Then solution evaporated in vacuo. The residue was diluted with EtOAc, washed with brine twice, dried over Na2SO4 and concentrated under reduced pressure and to give 6-chl oro-3, 8-dimethylimidazo[ 1,2- b]pyridazine (12.8 g, 70.48 mmol, 72% yield) which was put into the next stage without purification.

[0340] 6-Iodo-3, 8-dimethylimidazo[ 1, 2-b ]pyridazine

[0341] According to Scheme 12’ Step 2: 6-Chloro-3,8-dimethylimidazo[l,2-b]pyridazine (8.5 g, 46.8 mmol) , hydrogen iodide (103.21 g, 58.0% purity, 468.01 mmol, 60.71 ml, 10.0 equiv) and sodium iodide (21.05 g, 140.4 mmol) acid were mixed and stirred at 100°C for 2 days. After returning to room temperature, the reaction medium is poured onto ice, a concentrated sodium carbonate solution is added and the mixture is stirred for 10 minutes. The solution is then extracted with DCM. The organic phase is washed with water, dried over Na2SO4, filtered and concentrated under vacuum. 6-Iodo-3,8- dimethylimidazo[l,2-b]pyridazine (10.7 g, 39.18 mmol, 83.7% yield).

[0342] 3-bromo-5-3, 8-dimethylimidazo[ 1, 2-b ]pyridazin-6-yl-l -methyl- IH-pyrazole

[0343] According to Scheme 12’ Step 3: 6-Iodo-3,8-dimethylimidazo[l,2-b]pyridazine (1.0 g, 3.66 mmol) , 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (1.26 g, 4.39 mmol) , dipotassium carbonate (1.51 g, 10.98 mmol) , bis(adamantan-l-yl)(butyl)phosphane (131.18 mg, 366.15 pmol) and [2'-(methylamino)- [l,l'-biphenyl]-2-yl]palladio methanesulfonate; dicyclohexyl[2',4',6'-tris(propan-2-yl)- [l,l'-biphenyl]-2-yl]phosphane (314.64 mg, 366.15 pmol) in dioxane (25 mL) and water (5 ml) was degassed and purget with Ar. The resulting mixture was heated at 65 °C overnight. Then the mixture was cooled to rt. diluted with H2O (20 ml) and extracted with EtOAc (2*30 ml). The organic layer was washed with brine, and filtered through a Na2SO4. The filtrate was concentrated in vacuo to give crude material, which was purified by FC 3-bromo-5-3,8-dimethylimidazo[l,2-b]pyridazin-6-yl-l-methyl-lH- pyrazole (690.0 mg, 2.25 mmol, 61.6% yield).

[0344] The compounds shown in Table 4 may be prepared similarly to the compound described above, with appropriate starting materials. Synthesis of core 24 (intermediates g33):

[0345] Scheme 12’(halogeno-ketone condensation) ll-(3-bromo-l-methyl-lH-pyrazol-5-yl)-9-methyl-l,7,12- triazatricyclo[6.4.0.0,2,6]dodeca-2(6),7,9,ll-tetraene (Core 24)

[0346] 11 -chlor o-9 -methyl- 1 , 7, 12-triazatricyclo[ 6.4.0.0,2,6]dodeca-2(6), 7,9, 11 -tetraene

[0347] According to Scheme 12’ Step 1 : mixture of 6-chloro-4-methylpyridazin-3-amine (2 g, 14.0 mmol and 2-chlorocyclopentan-l-one (3.3 g, 28.0 mmol) in 1,2-di chloroethane (50 ml) was refluxed for 2 days. To resulting mixture was evaporated in vacuo. Crude product was purified by flash chromatography (hexane-dichloromethane, 100:0 - 0: 100) to give 1.0 g of 1 l-chloro-9-methyl-l,7,12-triazatricyclo[6.4.0.0,2,6]dodeca-2(6),7,9,l 1- tetraene.

[0348] 1 l-iodo-9-methyl-l, 7, 12-triazatricyclo[ 6.4.0.0, 2, 6 ]dodeca-2( 6), 7, 9, 11 -tetraene

[0349] According to Scheme 12’ Step 2: mixture of l l-chloro-9-methyl-l,7,12- triazatricyclo[6.4.0.0,2,6]dodeca-2(6),7,9,l 1-tetraene (1 g, 4.82 mmol), Nal (2.16 g, 14.4 mmol) in 6 ml cone. HI was heated at 100 °C for 2 days. To the resulting mixture was added water and was brought to pH > 8 with solid NaHCCh, then extracted with three portions of CHCh (20 ml). The combined extracts were dried (Na2SC>4) and evaporated in vacuo to give 1.3 g of l l-iodo-9-methyl-l,7,12-triazatricyclo[6.4.0.0,2,6]dodeca- 2(6), 7, 9, 11-tetraene.

[0350] 1 l-(3-bromo-l-methyl-lH-pyrazol-5-yl)-9-methyl-l , 7, 12- triazatricyclo[ 6.4.0.0, 2, 6 ]dodeca-2(6), 7, 9, 11 -tetraene

[0351] According to Scheme 12’ Step 3: the mixture of l l-iodo-9-methyl-l,7,12- triazatricyclo[6.4.0.0,2,6]dodeca-2(6),7,9,l 1-tetraene (1.6 g, 5.35 mmol), 3-bromo-l- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.68 g, 5.88 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (435 mg, 0.53 mmol) and K2CO3 (2.21 g, 16.1 mmol) in 20 ml water-1, 4- di oxane (1 : 10 vol.) was heated at 65 °C for 48 h. Then reaction mixture was diluted with 100 ml EtOAc, organic phase was washed by brine (10 ml), dried (ISfeSCU) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane- EtOAc, 100:0 - 0:100) to give 0.3 g of l l-(3-bromo-l-methyl-lH-pyrazol-5-yl)-9- methyl- 1, 7, 12-tri azatri cyclo[6.4.0.0, 2, 6]dodeca-2(6), 7, 9,11-tetraene.

[0352] Synthesis of core 25 (intermediates g33):

[0353] Scheme 12’bis

[0354] 3-bromo-l-methyl-5-{2,3-dimethylimidazo[l,2-b]pyridazin-6-yl}-lH-pyrazole

[0355] (Core 25)

[0356] 6-chloro-2, 3-dimethylimidazo[ 1, 2-b ]pyridazine According to Scheme 12’ bis Step 1 : the mixture of 6-chl oro-3 -iodo-2- methylimidazo[l,2-Z>]pyridazine (1) (4.0 g, 13.7 mmol), methylboronic acid (1.23 g, 20.5 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (1.11 g, 1.37 mmol) and K2CO3 (5.65 g, 41.0 mmol) in 50 ml water- 1,4-di oxane (1 : 10 vol.) was heated at 65 °C for 48 h. Then the reaction mixture was diluted with 200 ml EtOAc, organic phase was washed by brine (20 ml), dried QSfeSCU) and evaporated in vacuo. Crude product was purified by flash chromatography (hexanedi chloromethane, 100:0 - 0: 100) to give 2.0 g of 6-chl oro-2, 3 -dimethylimidazof 1,2- b]pyridazine.

[0357] 6-iodo-2, 3-dimethylimidazo[ 1, 2-b ]pyridazine

[0358] According to Scheme 12’bis Step 2: mixture of 6-chloro-2,3-dimethylimidazo[l,2- Z>]pyridazine (1.5 g, 11.1 mmol), Nal (6.6 g, 44.2 mmol) in 15 ml cone. HI was heated at 100 °C for 2 days. To the resulting mixture was added water and was brought to pH > 8 with solid NaHCCh, then extracted with three portions of CHCI3 (30 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane-MTBE-methanol, 100:0:0 - 0: 100:0 - 0:50:50) to give 1.0 g of 6-iodo-2, 3 -dimethylimidazof 1,2-Z>]pyridazine (3).

[0359] 3-bromo-l-methyl-5-{2,3-dimethylimidazo[l,2-b]pyridazin-6-yl}-lH-pyrazole

[0360] According to Scheme 12’bis Step 3: the mixture of 6-iodo-2, 3 -dimethylimidazof 1,2- b]pyridazine (0.5 g, 1.83 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-U / -pyrazole (0.58 g, 2.02 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (149 mg, 0.18 mmol) and K2CO3 (0.76 g, 5.49 mmol) in 20 ml water- 1,4-di oxane (1 : 10 vol.) was heated at 65 °C for 48 h. Then reaction mixture was diluted with 100 ml EtOAc, organic phase was wached by brine (10 ml), dried (Na2SO4) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane-EtOAc, 100:0 - 0: 100) to give 0.3 g of 3-bromo-l-methyl-5-{2,3-dimethylimidazo[l,2-Z>]pyridazin-6-yl}-UT- pyrazole.

[0361] Synthesis of core 26 (intermediates g33):

[0362] Scheme 12’ter

[0363] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2,3,8-trimethylimidazo[l,2-b]pyridazine

[0364] (Core26)

[0365] 8-bromo-6-chloro-3-iodo-2-methylimidazo[ 1, 2-b ]pyridazine

[0366] According to Scheme 12’ter Step 1 : mixture of 8-bromo-6-chloro-2-methylimidazo[l,2- b]pyridazine (5.2 g, 21.2 mmol) and N-iodosuccinimide (5.5 g, 24.4 mmol) in di chloromethane was stirred at r.t. for 12 h. Then reaction mixture was concentrated in vacuo and purified by flash chromatography (hexane-EtOAc, 100:0 - 0: 100) to give 7 g of 8-bromo-6-chl oro-3 -iodo-2-methylimidazo[l,2-b]pyridazine. NMRJH (DMSO- e, 400 MHz), 5, ppm: 2.74 (s, 3H, CH3), 7.92 (s, 1H, CH).

[0367] 6-chloro-2, 3, 8-trimethylimidazo[ 1, 2-b ]pyridazine

[0368] According to Scheme 12’ter Step 2: The mixture of 8-bromo-6-chl oro-3 -iodo-2- methylimidazo[l,2-b]pyridazine (7.0 g, 18.9 mmol), methylboronic acid (4.5 g, 75.5 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (1.5 g, 1.9 mmol) and K2CO3 (7.8 g, 56.6 mmol) in 50 ml water- 1,4-di oxane (1 : 10 vol.) was heated at 65 °C for 48 h. Then reaction mixture was diluted with 200 ml EtOAc, organic phase was washed by brine (20 ml), dried (Na2SO4) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane-dichloromethane, 100:0 - 0:100) to give 1.5 g of 6-chloro-2,3,8-trimethylimidazo[l,2-b]pyridazine.

[0369] 6-iodo-2, 3, 8-trimethylimidazo[ 1, 2-b ]pyridazine According to Scheme 12’ter Step 3 : the mixture of 6-chloro-2,3,8-trimethylimidazo[l,2- b]pyridazine (1.5 g, 7.67 mmol), Nal (4.6 g, 30.67 mmol) in 10 ml cone. HI was heated at 100 °C for 2 days. To resulting mixture was added water and was brought to pH > 8 with solid NaHCCE, then extracted with three portions of CHCI3 (30 ml). The combined extracts were dried (Na2SC>4) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane-MTBE-methanol, 100:0:0 - 0: 100:0 - 0:50:50) to give 1.0 g of 6-iodo-2,3,8-trimethylimidazo[l,2-b]pyridazine.

[0370] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2, 3, 8-trimethylimidazo[ 1, 2-b ]pyridazine According to Scheme 12’ter Step 4: the mixture of 6-iodo-2,3,8-trimethylimidazo[l,2- b]pyridazine (1.0 g, 3.48 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.09 g, 3.83 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (283 mg, 0.35 mmol) and K2CO3 (1.44 g, 10.5 mmol) in 40 ml water- 1,4-di oxane (1 : 10 vol.) was heated at 65 °C for 48 h. Then reaction mixture was diluted with 150 ml EtOAc, organic phase was washed by brine (10 ml), dried (Na2SO4) and evaporated in vacuo. Crude product was purified by flash chromatography (hexane-EtOAc, 100:0 - 0: 100) to give 0.7 g of 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2,3,8-trimethylimidazo[l,2- b]pyridazine.

[0371] Synthesis of cores 27 to 29 (intermediates g29):

[0372] Scheme 11’

[0373] Table 5

[0374] 3-Bromo-5-3, 7-dimethylpyrazolo[l, 5-a]pyrinudin-5-yl-l -methyl-LH-pyrazole (Core 27)

[0375] 3, 7-Dimethyl-4H, 5H-pyrazolo[ 1, 5 -a ]pyrimidin-5-one

[0376] According to Scheme 11’ Step 1 : 4-Methyl-lH-pyrazol-5-amine (10.0 g, 103.02 mmol), methyl (2Z)-3-m ethoxyb ut-2-enoate (20.1 g, 154.54 mmol) and cesium (I) carbonate (50.35 g, 154.54 mmol) were mixed in DMF solution and stirred at 100°C for 2 days. The solution was evaporated in vacuo. Water was then added to the residue. The precipitate was filtered, and concentrated under reduced pressure and then crystallized in EtOAc and to give crude 3,7-dimethyl-4H,5H-pyrazolo[l,5-a]pyrimidin-5-one (4.0 g, 90.0% purity, 22.06 mmol, 21.4% yield) which was used in the next stage without purification.

[0377] 5-Chloro-3, 7-dimethylpyrazolo[ 1, 5-a]pyrimidine

[0378] According to Scheme 11’ Step 2: 3,7-Dimethyl-4H,5H-pyrazolo[l,5-a]pyrimidin-5-one (15.0 g, 91.98 mmol) and phosphoroyl trichloride (55.88 g, 367.94 mmol, 33.97 ml, 4.0 equiv) were mixed in MeCN solution and stirred at 80°C for 2 days. Then, the solvent was evaporated, the residue was diluted with ice water, and neutralized to pH 8 with NaHCCh. The mixture was extracted with EtOAc, dried over Na2SO4, and evaporated, and to give crude 5-chloro-3,7-dimethylpyrazolo[l,5-a]pyrimidine (3.0 g, 77.0% purity, 12.72 mmol, 13.8% yield) which was put into the next stage without purification.

[0379] 5-Bromo-3, 7-dimethylpyrazolo[ 1, 5 -a ] pyrimidine

[0380] According to Scheme 11’ Step 3: 5-Chloro-3,7-dimethylpyrazolo[l,5-a]pyrimidine (3.0 g, 16.53 mmol) and bromotrimethylsilane (10.04 g, 66.09 mmol, 8.57 ml, 4.0 equiv) were mixed in EtCN solution and stirred at 100°C for 2 days. Then the mixture was cooled to rt., solution evaporated in vacuo to give crude 5-bromo-3,7-dimethylpyrazolo[l,5- a]pyrimidine (3.7 g, 89.0% purity, 14.57 mmol, 88.1% yield) which was purified by FCC.

[0381] 3-Bromo-5-3, 7-dimethylpyrazolo[ 1, 5-a ]pyrimidin-5-yl- 1 -methyl- IH-pyr azole

[0382] According to Scheme 11’ Step 4: A solution of 5-bromo-3,7-dimethylpyrazolo[l,5- a]pyrimidine (1.0 g, 4.42 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (2.02 g, 7.08 mmol), dipotassium carbonate (1.83 g, 13.27 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (35.99 mg, 44.23 pmol) in dioxane (25 mL) and water (5 ml) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was cooled to rt. diluted with H2O (20 ml) and extracted with EtOAc (2*30 ml). The organic layer was washed with brine, and filtered through a ISfeSC The filtrate was concentrated in vacuo to give crude material, which was purified by FC 3-bromo-5- 3,7-dimethylpyrazolo[l,5-a]pyrimidin-5-yl-l-methyl-lH-pyrazole (400.0 mg, 1.31 mmol, 29.5% yield).

[0383] The compounds shown in Table 5 may be prepared similarly to the compound described above, with appropriate starting materials.

[0384] Synthesis of cores 30 to 34 (intermediates g!4): Ai = H, Me, A2= H, A3= H, Me, R = H, Me, R1= Me, Et.

[0385] Scheme 10’

[0386] 6-(3-Bromo-l-methyl-lH-pyrazol-5-yl)-2,4-dimethyl-l,5-naphthyridine (Core 33)

[0387] Ethyl (E)-3-(3-amino-4, 6-dimethylpyridin-2-yl)acrylate

[0388] According to Scheme 10’ Step 1 : To 2-chloro-4,6-dimethylpyridin-3-amine (10.0 g, 64.08 mmol), ethyl prop-2-enoate (32.06 g, 320.38 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (5.22 g, 6.41 mmol), triethylamine (12.96 g, 128.16 mmol, 17.85 ml, 2.0 equiv), and tetrabutyl azanium bromide (20.58 g, 64.08 mmol) were added in a 250 ml three-necked round bottom flask charged with anhydrous DMF (100 ml). To this palladium(2+) diacetate (717.43 mg, 3.2 mmol) was added, and this was purged with Ar thrice. The reaction was allowed to stir at 120 °C for 12 h. The reaction mixture was poured into 500 mL water and extracted with ethyl acetate twice (200 mL * 2). The organic layers were separated, washed with brine, dried over Na2SO4, and filtered. Excess solvent was removed under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate = 20 / 1-1 / 1 to give the title compound as solid (7.0 g, 49.69% yield).

[0389] 6, 8-Dimethyl-l, 5 -naphthyr idin-2( lH)-one

[0390] According to Scheme 10’ Step 2: A mixture of ethyl (2E)-3-(3-amino-4,6- dimethylpyridin-2-yl)prop-2-enoate (7.0 g, 31.8 mmol) and an EtONa-EtOH solution [prepared from sodium sodium (2.92 g, 63.61 mmol) and dry EtOH (100 ml) was refluxed for 2h. After the removal of the EtOH, the residue was diluted with H2O, and the mixture was extracted with CHCI3. The CHCI3 extract was purified by FCC to give colorless needles.

[0391] 6-Bromo-2, 4-dimethyl-l , 5 -naphthyr idine

[0392] According to Scheme 10’ Step 3: To the solution of 6,8-dimethyl-l,2-dihydro-l,5- naphthyridin-2-one (5.0 g, 28.72 mmol) in dry toluene was added phosphoroyl tribromide (40.75 g, 143.61 mmol) and the reaction mixture was heated under reflux for 5 hours. Then, the solvent was evaporated, the residue was diluted with ice water, and neutralized to pH 8 with NaHCCh. The mixture was extracted with EA, dried over Na2SO4, and evaporated. The crude product was purified by FCC (1.0 g).

[0393] 6-(3-Bromo-l -methyl-lH-pyrazol-5-yl)-2, 4-dimethyl-l, 5 -naphthyr idine

[0394] According to Scheme 10’ Step 4: A solution of 6-bromo-2, 4-dimethyl-l, 5-naphthyridine (800.0 mg, 3.39 mmol), 3-bromo-l-methyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (1.45 g, 5.08 mmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,r-biphenyl]-2- yl]phosphane; 2'-amino-[l,l'-biphenyl]-2-ylpalladio methanesulfonate (286.5 mg, 338.92 pmol), tripotassium phosphate (2.15 g, 10.17 mmol) and bis(adamantan-l- yl)(butyl)phosphane (121.43 mg, 338.92 pmol) in dioxane (20 mL) and water (5 ml) was degassed and purged with Ar. The resulting mixture was heated at 60 °C overnight. Then the mixture was cooled to rt., diluted with H2O (100 ml), and extracted with EtOAc (2*150 ml). The organic layer was washed with brine and filtered through Na2SO4. The filtrate was concentrated in vacuo to give crude which was purified by FCC.

[0395] The compounds shown in Table 6 may be prepared similarly to the compound described above, with appropriate starting materials.

[0396] Synthesis of cores 35 to 36 (intermediates g39):

[0397] Ai = Me, A2= H, R = H, Me, R1= Me, Et.

[0398] Scheme 13’

[0399] Table 7

[0400] 3-Bromo-5-4, 7-dimethylinudazo[l, 5-b]pyridazin-2-yl-l -metbyl-LH-pyrazole

[0401] (Core 35)

[0402] 2-[ ( 6-Chloro-4-methylpyridazin-3-yl)methyl -2, 3-dihydro-lH-isoindole-l, 3-dione

[0403] According to Scheme 13’ Step 1 : To a solution of 6-chl oro-3 -(chi oromethyl)-4- methylpyridazine (2.0 g, 11.36 mmol) in N,N-dimethylformamide (50 mL) was added potassium l,3-dioxo-2,3-dihydro-lH-isoindol-2-ide (2.31 g, 12.5 mmol). After the mixture had been stirred at room temperature for 10 h, water (50 mL) was added, and precipitate appeared. The crude product was collected by filtration and washed with water. After recrystallization from ethanol 2-[(6-chloro-4-methylpyridazin-3-yl)methyl]- 2, 3-dihydro-lH-isoindole-l, 3-dione (2.4 g, 90.0% purity, 7.51 mmol, 66.1% yield) was obtained. l-(6-Chloro-4-methylpyridazin-3-yl)methanamine According to Scheme 13’ Step 2: To a suspension of 2-[(6-chloro-4-methylpyridazin-3- yl)methyl]-2,3-dihydro-lH-isoindole-l, 3-dione (1.61 g, 5.6 mmol) in ethanol (40 mL) was added hydrazine hydrate (420.13 mg, 8.39 mmol, 420.0 pl, 1.5 equiv). The reaction mixture was refluxed for 5 h and then cooled. The precipitated phthalyl hydrazide was filtered and washed with ethanol, and then the combined filtrate was condensed under reduced pressure to give l-(6-chloro-4-methylpyridazin-3-yl)methanamine (500.0 mg, 85.0% purity, 2.7 mmol, 48.2% yield).

[0404] N-[ ( 6-Chloro-4-methylpyridazin-3-yl)methyl acetamide

[0405] According to Scheme 13’ Step 3: To a suspension of l-(6-chloro-4-methylpyridazin-3- yl)methanamine (520.24 mg, 3.3 mmol) in di chloromethane (20 ml) was added triethylamine (500.7 mg, 4.95 mmol, 690.0 pl, 1.5 equiv) thentriethylamine (500.7 mg, 4.95 mmol, 690.0 pl, 1.5 equiv). The reaction mixture was stirred at room temperature for 4 hours then diluted by the addition of dichloromethane (15 ml) and water (15 ml). The aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. N-[(6-chloro-4-methylpyridazin-3-yl)methyl]acetamide (370.0 mg, 95.0% purity, 1.76 mmol, 53.3% yield) was obtained.

[0406] 2-Chloro-4, 7-dimethylimidazo[ 1, 5-b ]pyridazine

[0407] According to Scheme 13’ Step 4: N-[(6-chloro-4-methylpyridazin-3- yl)methyl]acetamide (302.28 mg, 1.51 mmol) and phosphoroyl trichloride (690.9 mg, 4.55 mmol, 420.0 pl, 3.0 equiv) were mixed in MeCN solution and stirred at 80°C for 1 day. Then, the solvent was evaporated, the residue was diluted with ice water, and neutralized to pH 8 with NaHCCh. The mixture was extracted with EtOAc, dried over Na2SO4, and evaporated, and to give 2-chloro-4,7-dimethylimidazo[l,5-b]pyridazine (150.0 mg, 90.0% purity, 743.3 pmol, 49.1% yield) which was put into the next stage without purification.

[0408] 3-Bromo-5-4, 7-dimethylimidazo[ 1, 5-b ]pyridazin-2-yl-l -methyl- IH-pyr azole

[0409] According to Scheme 13’ Step 5: A solution of 2-chl oro-4, 7-dimethylimidazo[ 1,5- b]pyridazine (130.0 mg, 715.77 pmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (225.07 mg, 786.84 pmol), [1,1- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (52.21 mg, 71.53 pmol), tripotassium phosphate (303.07 mg, 1.43 mmol) in dioxane (25 mL) and water (5 ml) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was cooled to rt. diluted with H2O (20 ml) and extracted with EtOAc (2*30 ml). The organic layer was washed with brine, and filtered through a Na2SO4. The filtrate was concentrated in vacuo to give crude material, which was purified by FC 3- bromo-5-4,7-dimethylimidazo[l,5-b]pyridazin-2-yl-l-methyl-lH-pyrazole (110.0 mg, 95.0% purity, 341.32 pmol, 47.7% yield).

[0410] The compounds shown in Table 7 may be prepared similarly to the compound described above, with appropriate starting materials.

[0411] Synthesis of cores 37 (intermediates g39):

[0412] Scheme 21 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-5, 7-dimethylinudazo[l,5-b]pyridazine (Core 37)

[0413] 6-(l -aminoethyl)pyridazin-3-ol

[0414] According to Scheme 21 Step 1 : a mixture of 6-acetyl-2,3-dihydropyridazin-3-one (1.0 g, 7.24 mmol), ammonium acetate (5.58 g, 72.4 mmol) and sodium cyanoborohydride (454.76 mg, 7.22 mmol) in MeOH (13 mL) was stirred for 16 h at room temperature. After completion of the reaction obtained mixture was filtered off and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated to give crude 6-(l- aminoethyl)pyridazin-3-ol (1.0 g, 80.0% purity, 5.75 mmol, 79.4% yield) that was used in the next step without its further purification. N- l-( 6-hydroxypyridazin-3-yl)ethyl ] acetamide

[0415] According to Scheme 21 Step 2: A mixture of 6-(l-aminoethyl)-2,3-dihydropyridazin- 3-one (1.0 g, 80.0% purity, 5.75 mmol) and acetyl acetate (1.47 g, 14.38 mmol) was stirred at 100 °C for 5 h. After completion of the reaction obtained mixture was evaporated under reduced pressure and used in the next step without its further purification.

[0416] 2-Bromo-5, 7-dimethylimidazo[ 1, 5-b ]pyridazine

[0417] According to Scheme 21 Step 3: N-[l-(6-hydroxypyridazin-3-yl)ethyl]acetamide (1.0 g, 5.52 mmol) and phosphoroyl tribromide (7.91 g, 27.89 mmol) were mixed together and stirred at 100 °C for 5 h. After completion of the reaction obtained mixture was quenched with crushed ice, basified to pH = 8 and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered off and evaporated to dryness in vacuo. Isolated crude was purified by prep HPLC (10-60% 0-5 min H20 / Me0H, flow: 30 ml / min (loading pump 4 ml / min MeOH) target mass 226, column: Chromatorex C18 SMB100-5T 100x19 mm 5um) to obtain pure 2-bromo-5,7- dimethylimidazo[l,5-b]pyridazine (23.0 mg, 95% purity, 101.74 pmol, 1.8% yield).

[0418] 3-Bromo-5-5, 7-dimethylimidazo[ 1, 5-b ]pyridazin-2-yl-l-ethyl-lH-pyr azole

[0419] According to Scheme 21 Step 4: A solution of 2-bromo-5,7-dimethylimidazo[l,5- b]pyridazine (23.0 mg, 102.23 pmol), 3-bromo-l-ethyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (45.97 mg, 153.19 pmol), XPhos Pd G3 (8.62 mg, 10.18 pmol), tripotassium phosphate (64.84 mg, 306.05 pmol) and bis(adamantan-l- yl)(butyl)phosphane (3.65 mg, 10.19 pmol) in dioxane (4 mL) and water (1 mL) was degassed and purged with Ar. The resulting mixture was stirred at 60 °C overnight. Then the mixture was cooled to rt, diluted with H2O (10 mL) and extracted with EtOAc (2 x 15 mL). Combined organic layers were washed with brine (15 mL), dried over Na2SC>4, filtered off and concentrated in vacuo to give crude product mixture. Isolated crude was subjected to prep HPLC purification (50-50-100% 0-l-5min H20 / Me0H, flow: 30ml / min (loading pump 4ml / min methanol) target mass 320 column: Chromatorex 18 SMB100-5T 100x19mm 5um) to give 3-Bromo-5-5,7-dimethylimidazo[l,5-b]pyridazin- 2-yl-l-ethyl-lH-pyrazole (15.0 mg, 100% purity, 46.9 pmol, 46% yield).

[0420] Synthesis of core 38 (intermediates g51):

[0421] 5-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3-methylisothiazolo[4,3-b]pyridine (Core 38)

[0422] 3-amino-6-chloropyridine-2-carbothioamide

[0423] According to Scheme 22’ Step 1 : To a solution of a mixture of 3-amino-6- chloropyridine-2-carbonitrile (4.87 g, 31.83 mmol) in EtOH (112.5 mL) was added phosphorus pentasulfide (14.12 g, 63.66 mmol). The reaction mixture was stirred overnight at 75 °C. After completion of the reaction obtained mixture was concentrated in vacuo and triturated with Et2O (75 mL). The precipitated solid was filtered off, washed with Et2O (30 mL) and dried to give 3-amino-6-chloropyridine-2-carbothioamide (3.0 g, 15.99 mmol, 50.2% yield). Isolated crude was used in the next step without its further purification.

[0424] 5-chloro-[ 1, 2 ]thiazolo[ 4, 3-b ]pyridin-3-amine According to Scheme 22’ Step 2: To a solution of 3 -amino-6-chloropyri dine-2- carbothioamide (1.15 g, 6.13 mmol) in methanol (16.95 g, 529.16 mmol, 21.18 ml, 86.32 equiv) was added dropwise 30% aqueous solution of hydrogen peroxide (1.71 g, 50.15 mmol, 1.48 ml, 8.18 equiv) at 0°C. The reaction mixture was stirred overnight at room temperature. After completion of the reaction obtained mixture was concentrated in vacuo and triturated with water (15 ml). The precipitated solid was filtered off, washed with water (10 ml) and dried to give 5-chloro-[l,2]thiazolo[4,3-b]pyridin-3-amine (900.0 mg, 98% purity, 4.85 mmol, 79.1% yield). Isolated product was used in the next step without its further purification.

[0425] 3-bromo-5-chloro-[ 1, 2 ]thiazolo[ 4, 3-b ]pyridine

[0426] According to Scheme 22’ Step 3: To a mixture of 5-chloro-[l,2]thiazolo[4,3-b]pyridin- 3-amine (2.84 g, 15.3 mmol) and copper bromide (2.82 g, 19.89 mmol) in acetonitrile (77.6 g, 1.89 mol, 100.0 ml, 123.64 equiv) tert-butyl nitrite (4.1 g, 39.77 mmol, 4.76 ml, 2.6 equiv) was added dropwise at 0°C. The reaction mixture was allowed to warm up and stir at room temperature overnight. After completion of the reaction obtained mixture was poured into ice-water and extracted with EtOAc (2 x 40 ml). Organic layers were combined together, washed with brine (40 ml), dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give 3-bromo-5-chloro-[l,2]thiazolo[4,3-b]pyridine (2.0 g, 8.02 mmol, 52.4% yield). Isolated product was used in the next step without its further purification.

[0427] 5 -chlor o-3 -methyl- [ 1, 2 ]thiazolo[ 4, 3-b ]pyridine

[0428] According to Scheme 22’ Step 4: To a solution of 3-bromo-5-chloro-[l,2]thiazolo[4,3- b]pyridine (2.5 g, 10.02 mmol), methylboronic acid (1.2 g, 20.04 mmol) and dipotassium carbonate (2.76 g, 20.04 mmol) in 1,4-di oxane (93.06 g, 1.06 mol, 90.0 ml, 105.48 equiv) and water (23.0 g, 1.28 mol, 23.0 ml, 127.46 equiv) ; [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (407.73 mg, 500.96 pmol) was added under argon atmosphere and the reaction mixture was stirred at 80°C for 2 days. After completion of the reaction obtained mixture was diluted with DCM (100 ml), washed with brine (30 ml), dried over Na2SO4, filtered off and evaporated in vacuo. The residue was purified by FCC (Interchim, 80 g SiCh, hexane / EtOAc with EtOAc from 0-100%, flow rate = 60 mL / min, Rv=5.4-9.1 cv) to afford 5-chloro-3-methyl-[l,2]thiazolo[4,3-b]pyridine (600.0 mg, 3.25 mmol, 32.4% yield).

[0429] 5-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3-methylisothiazolo[ 4, 3-b ] pyridine

[0430] According to Scheme 22’ Step 5: To a solution of 5-chloro-3-methyl-[l,2]thiazolo[4,3- b]pyridine (600.0 mg, 3.25 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (687.4 mg, 2.4 mmol) and dipotassium carbonate (662.83 mg, 4.81 mmol) in 1,4-dioxane (22.32 g, 253.49 mmol, 21.59 ml, 105.48 equiv) and water (5.52 g, 306.29 mmol, 5.52 ml, 127.46 equiv) [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (97.79 mg, 120.15 pmol) was added under argon atmosphere and the reaction mixture was stirred at 90°C overnight. After completion of the reaction obtained mixture was diluted with DCM (75 ml), washed with brine (25 ml) dried over Na2SO4, filtered off and evaporated in vacuo. The residue was subjected to prep HPLC purification (33-40-90% 0-1.3-7.3 min H2O / MeOH / 0.1%NH4OH, flow: 30ml / min, loading pump 4ml / min MeOH, target mass 309, column: XBRIDGE BEH 18 SMB100-5T 100x19mm 5um) to afford 5-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3-methylisothiazolo[4,3-b]pyridine (120.0 mg, 388.12 pmol, 16.2% yield).

[0431] Synthesis of cores 39-42 (intermediates g58):

[0432]

[0433] Scheme 23’(ROUTE B)

[0434] Ai = Me, R = Me R1= Me. (X = Cl, Br)

[0435] 3-bromo-5-3,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl-l-methyl-lH-pyrazole (Core 39)

[0436] 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine According to Scheme 23’ Step 1 : To a solution 2,6-dichloro-4-methyl-3-nitropyridine (7.1 g, 34.47 mmol) in THF (150 ml) was added methanamine (1.61 g, 51.71 mmol, 10.22 ml, 1.5 equiv) (20% in MeOH) and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction obtained mixture was diluted with water (150 ml) and extracted with EtOAc (3 x 100 ml). Organic layers were combined together, washed with brine (150 ml), dried over Na2SO4, filtered off and concentrated in vacuo to give the title compound 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine (6.8 g, 70% purity, 23.6 mmol, 68.5% yield). Isolated crude was used in the next step without its further purification.

[0437] 6-bromo-N,4-dimethyl-3-nitropyridin-2-amine

[0438] According to Scheme 23’ Step 2: Bromotrimethylsilane (21.17 g, 139.28 mmol, 18.06 ml, 4.0 equiv) was added to a solution of 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine (7.0 g, 34.82 mmol) in propionitrile (100 ml) and the reaction mixture was stirred overnight at 100°C. After completion of the reaction the resulting solution was evaporated to dryness in vacuo to give crude 6-bromo-N,4-dimethyl-3-nitropyridin-2- amine (4.5 g, 75% purity, 13.72 mmol, 39.4% yield) which was used in the next step without its further purification.

[0439] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-N,4-dimethyl-3-nitropyridin-2-amine

[0440] According to Scheme 23’ Step 3: A mixture of 6-bromo-N,4-dimethyl-3-nitropyridin-2- amine (4.5 g, 18.29 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (5.75 g, 20.12 mmol), potassium carbonate (7.57 g, 54.87 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (1.04 g, 1.28 mmol) in dioxane and H2O (10: 1) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. After completion of the reaction obtained mixture was cooled to rt, diluted with H2O (200 ml) and extracted with EtOAc (3*75 ml). Organic layers were combined together, washed with brine (75 ml), dried over Na2SO4, filtered off and concentrated in vacuo to give crude product material. Isolated crude was purified by FCC (Interchim; 120 + 80g SiO2, CHC13-CH3CN% 0-100, flow rate = 80 mL / min. Rv=3-4; column equilibration CHCI3. Incoming mixture dissolved in CHCI3) to afford 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)- N,4-dimethyl-3-nitropyridin-2-amine (2.3 g, 97% purity, 6.84 mmol, 37.4 % yield).

[0441] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-N2,4-dimethylpyridine-2, 3-diamine

[0442] According to Scheme 23’ Step 4: To a solution 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-

[0443] N,4-dimethyl-3-nitropyridin-2-amine (2.3 g, 7.05 mmol) in EtOH (75 ml) were added a solution ammonium chloride (11.22 g, 211.6 mmol) in water (5 ml) and iron (1.97 g, 35.27 mmol). The resulting mixture was heated up and stirred at 85°C overnight. After completion of the reaction obtained mixture was filtered off, the filtrate was concentrated in vacuo, diluted with H2O (150 ml) and extracted with DCM (3 x 50 ml). Organic layers were combined together, washed with brine (50 ml), dried over Na2SO4, filtered off and concentrated in vacuo to give crude 6-(3 -bromo- 1 -methyl- lH-pyrazol-5-yl)-N2, 4- dimethylpyridine-2,3-diamine (0.4 g, 88% purity, 1.2 mmol, 16.9% yield).

[0444] 3-bromo-5-3, 7-dimethyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl- 1 -methyl- IH-pyr azole

[0445] According to Scheme 23’ Step 5: A mixture of 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)- N2,4-dimethylpyridine-2,3-diamine (399.52 mg, 1.35 mmol), trimethoxymethane (4.3 g, 40.51 mmol, 4.43 ml, 30.0 equiv) and 4-m ethylbenzene- 1 -sulfonic acid (23.2 mg, 134.9 pmol) was stirred at 90 °C overnight. After completion of the reaction obtained mixture was cooled to rt, diluted with H2O (20 ml) and extracted with EtOAc (3 x 20 ml). Combined organic layers were dried over Na2SO4, filtered off and concentrated under reduced pressure to give crude product material. Isolated crude was purified by FCC (Interchim; 12 + 12g SiCh, CHsCN-MeOH %0-100, flow rate = 20 mL / min, Rv=8; column equilibration CHCI3. Incoming mixture dissolved in CHCI3) to afford 3-bromo- 5-3,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl-l-methyl-lH-pyrazole (0.2 g, 92% purity, 0.601 mmol, 44.6% yield).

[0446] Synthesis of core 43-44 (intermediates g63):

[0447] A2= H, Me, (X = Cl, Br)

[0448] Scheme 24’

[0449] Table 9

[0450] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-l,2-(Hmethyl-lH-inudazo[4,5-b]pyrazine (Core 43)

[0451] 6-bromo-l, 2 -dimethyl- lH-imidazo[ 4, 5-b ] pyrazine

[0452] According to Scheme 24’ Step 1 : A mixture of 6-bromo-N2-methylpyrazine-2,3-diamine (3.84 g, 19.01 mmol) and 1,1,1 -trimethoxy ethane (22.83 g, 190.09 mmol, 24.18 ml, 10.0 equiv) was stirred at 100°C for 10 hours. Then the mixture was cooled to room temperature, diluted with H2O (50 ml) and extracted with EtOAc (2 x 20 ml). Organic layers were combined together, washed with brine, dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give 6-bromo-l, 2-dimethyl-lH-imidazo[4,5-b]pyrazine (3.8 g, 89.0% purity, 14.89 mmol, 78.4% yield).

[0453] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-l,2-dimethyl-lH-imidazo[4,5-b]pyrazine

[0454] According to Scheme 24’ Step 2: A solution of 6-bromo-l, 2-dimethyl-lH-imidazo[4, 5- b]pyrazine (2.75 g, 12.17 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (3.48 g, 12.17 mmol), dipotassium carbonate (5.04 g, 36.51 mmol) and l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (696.72 mg, 851.9 pmol) in dioxane (100 mL) and water (25 ml) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. Then the mixture was cooled to room temperature, diluted with H2O (100 ml) and extracted with EtOAc (2 x 50 ml). Organic layers were combined together, washed with brine, dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give 3-bromo-5-l,2-dimethyl-lH-imidazo[4,5-b]pyrazin-6-yl-l-methyl-lH- pyrazole (2.7 g, 91.5% purity, 8.04 mmol, 66.1% yield). Synthesis of core 45-46 (intermediates g69):

[0455] Table 10

[0456] 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-6,8,9-trimethyl-9H-purine (Core 46)

[0457] 2-chloro-N,6-dimethyl-5-nitropyrimidin-4-amine

[0458] According to Scheme 25’ Step 1 : To a solution 2,4-dichloro-6-methyl-5-nitropyrimidine (10.01 g, 48.39 mmol) in THF (150 mL) was added methanamine (2.25 g, 72.58 mmol, 2.87 ml, 1.5 equiv) (20% in MeOH) and the reaction mixture was stirred at rt for 12h.

[0459] After completion of the reaction obtained mixture was diluted with H2O (150 mL) and extracted with EtOAc (3 x 150 mL). Combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to give the title compound 2-chloro-N,6-dimethyl-5-nitropyrimidin-4-amine (9.8 g, 55% purity, 26.62 mmol, 55% yield). Isolated crude was used in the next step without its further purification.

[0460] 2-bromo-N,6-dimethyl-5-nitropyrimidin-4-amine

[0461] According to Scheme 25’ Step 2: Bromotrimethylsilane (29.49 g, 194.04 mmol, 25.16 ml, 4.0 equiv) was added to a solution of 2-chloro-N,6-dimethyl-5-nitropyrimidin-4- amine (9.8 g, 48.51 mmol) in propionitrile (170 mL) and the reaction mixture was stirred at 100°C overnight. Obtained solution was evaporated to dryness in vacuo to give crude 2-bromo-N,6-dimethyl-5-nitropyrimidin-4-amine (12 g, 45% purity, 21.86 mmol, 45% yield) which was used in the next step without its further purification.

[0462] 2-bromo-N4, 6-dimethylpyrimidine-4, 5-diamine

[0463] According to Scheme 25’ Step 3 : To a solution 2-bromo-N,6-dimethyl-5-nitropyrimidin- 4-amine (12.0 g, 48.57 mmol) in EtOH (500 mL) were added a solution of NH4CI (77.24 g, 1.46 mol) in water (200 mL) and iron (13.59 g, 242.88 mmol) and the resulting mixture was stirred at 85°C overnight. After completion of the reaction obtained mixture was filtered off, the precipitate was washed with EtOH (100 mL) and EtOH was concentrated under reduced pressure. Obtained aqueous layer was extracted with DCM (3 x 75 mL), combined organic layers were washed with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to give crude 2-bromo-N4,6-dimethylpyrimidine- 4, 5-diamine (6.1 g, 67% purity, 18.83 mmol, 38.8% yield). Isolated crude was used in the next step without its further purification.

[0464] 2-bromo-6, 8, 9-trimethyl-9H-purine

[0465] According to Scheme 25’ Step 4: A mixture of 2-bromo-N4,6-dimethylpyrimidine-4,5- diamine (6.1 g, 28.1 mmol), 4-methylbenzene-l -sulfonic acid (241.7 mg, 1.41 mmol) and 1,1,1 -trimethoxy ethane (101.23 g, 843.05 mmol, 107.24 ml, 30.0 equiv) was stirred at 85 °C overnight. Then the resulting mixture was cooled to rt, diluted with H2O (200 mL), and extracted with EtOAc (3 x 75 mL). Organic layers were combined together, washed with brine (75 mL), dried over Na2SO4, filtered off and concentrated under reduced pressure. Isolated intermediate product was dissolved in AcOH (100 mL) and stirred at 100°C overnight. Obtained solution was evaporated and dried in vacuo to give crude 2-bromo-6,8,9-trimethyl-9H-purine (6.9 g, 39% purity, 11.17 mmol, 39.7% yield) which was used in the next step without its further purification.

[0466] 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-6, 8, 9-trimethyl-9H-purine

[0467] According to Scheme 25’ Step 5: A mixture of 2-bromo-6,8,9-trimethyl-9H-purine (1.5 g, 6.25 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (2.14 g, 7.5 mmol), potassium carbonate (2.59 g, 18.75 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (356.02 mg, 437.42 pmol) in dioxane and water (10: 1, 40 mL) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. After completion of the reaction obtained mixture was cooled to rt, diluted with H2O (120 mL) and extracted with EtOAc (3 x 60 mL). Organic layers were combined together, washed with brine (60 mL), dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give crude product material. Isolated crude was purified by FCC to afford 2-(3-bromo-l- methyl-lH-pyrazol-5-yl)-6,8,9-trimethyl-9H-purine (0.3 g, 95% purity, 0.887 mmol, 14.3% yield).

[0468] Scheme 26’

[0469] 3-Bromo-5-3,7-dimethyl-3H-[l,2,3]triazolo[4,5-b]pyridin-5-yl-l-methyl-lH- pyrazole (Core 47)

[0470] 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine According to Scheme 26’ Step 1 : To a solution 2,6-dichloro-4-methyl-3-nitropyridine (20.0 g, 97.1 mmol) in THF (400 mL) was added methanamine (4.52 g, 145.65 mmol, 28.8 ml, 1.5 equiv) (20% in MeOH) and the reaction mixture was stirred at rt for 12h. After completion of the reaction obtained mixture was diluted with water (400 mL) and extracted with EtOAc (3 x 200 mL). Combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to afford the title compound 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine (17.9 g, 63% purity, 56.1 mmol, 57.6% yield) as yellow crystals. Isolated crude was used in the next step without its further purification.

[0471] 6-chloro-N2, 4-dimethylpyridine-2, 3-diamine

[0472] According to Scheme 26’ Step 2: To a solution 6-chloro-N,4-dimethyl-3-nitropyridin-2- amine (10.0 g, 49.74 mmol) in EtOH (500 mL) were added a solution of NH4CI (79.09 g, 1.49 mol) in water (200 mL) and iron (13.91 g, 248.71 mmol) . The resulting mixture was heated up and stirred at 85°C overnight. After completion of the reaction obtained mixture was filtered off, the precipitate was washed with EtOH (100 mL) and EtOH was concentrated under reduced pressure. Obtained aqueous layer was extracted with DCM (3 x 75 mL), combined organic layers were washed with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to give crude 6-chloro-N2,4- dimethylpyridine-2, 3-diamine (10.2 g, 68.0% purity, 40.42 mmol, 81.2% yield). Isolated crude was used in the next step without its further purification.

[0473] 5-chloro-3, 7-dimethyl-3H-[ 1, 2, 3 ]triazolo[ 4, 5-b ] pyridine

[0474] According to Scheme 26’ Step 3: 6-Chloro-N2,4-dimethylpyridine-2, 3-diamine (10.2 g, 59.63 mmol) was dissolved in aqueous HCI (2N) and cooled to 0°C. Then sodium nitrite (4.11 g, 59.63 mmol) was added and the temperature rised to 10°C. The reaction mixture was cooled down and stirred at 0°C for 2h. After completion of the reaction obtained mixture was basified with aqueous NaOH (2N) and extracted with DCM (3 x 50 mL). Combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered off and evaporated in vacuo to give crude 5-chloro-3,7-dimethyl-3H-[l,2,3]triazolo[4,5- b]pyridine (10.85 g, 100% purity, 59.42 mmol, 99% yield). 5-bromo-3, 7-dimethyl-3H-[ 1, 2, 3 ]triazolo[ 4, 5-b ] pyridine

[0475] According to Scheme 26’ Step 4: Bromotrimethylsilane (36.23 g, 238.39 mmol, 30.91 ml, 4.0 equiv) was added to a solution of 5-chloro-3,7-dimethyl-3H-[l,2,3]triazolo[4,5- b]pyridine (10.85 g, 59.6 mmol) in propionitrile (100 mL) and the reaction mixture was stirred at 100°C overnight. The resulting solution was evaporated to dryness in vacuo to give crude 5-bromo-3,7-dimethyl-3H-[l,2,3]triazolo[4,5-b]pyridine (13.1 g, 86% purity, 49.63 mmol, 83.3% yield) which was put into the next step without purification.

[0476] 3-bromo-5-3, 7-dimethyl-3H-[ 1, 2, 3 ]triazolo[ 4, 5-b ]pyr idin-5-yl-l -methyl- IH-pyrazole According to Scheme 26’ Step 5: A solution of 5-bromo-3,7-dimethyl-3H- [l,2,3]triazolo[4,5-b]pyridine (3.3 g, 14.53 mmol), 3-bromo-l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (4.57 g, 15.99 mmol), potassium carbonate (6.01 g, 43.6 mmol)and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (828.02 mg, 1.02 mmol) in dioxane and water (10: 1, 150 mL) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. After completion of the reaction obtained mixture was cooled to rt, diluted with H2O (150 mL) and extracted with EtOAc (3 x 100 ml). Organic layers were combined together, washed with brine (100 mL), dried over Na2SO4, filtered off and concentrated in vacuo to give crude product material. Isolated crude was purified by FCC (Interchim; 120+120 g SiO2, CHCI3- CH3CN % 0-100, flow rate = 80 mL / min. Rv=3; column equilibration CHCI3. Incoming mixture dissolved in CHCI3) to give 3-bromo-5-3,7-dimethyl-3H-[l,2,3]triazolo[4,5- b]pyridin-5-yl-l -methyl- IH-pyrazole (1.8 g, 92% purity, 5.39 mmol, 37.1% yield).

[0477] Synthesis of core 48 (intermediates g74):

[0478] Scheme 27’ 3-bromo-l-methyl-5-l-methyl-lH-[l,2,3]triazolo[4,5-b]pyrazin-6-yl-lH-pyrazole

[0479] (Core 48)

[0480] 6-bromo-l -methyl- 1H~[ 1,2,3 ]triazolo[ 4, 5-b ] pyrazine

[0481] According to Scheme 27’ Step 1 : To a stirred cooled solution of 6-Bromo-N2- methylpyrazine-2,3-diamine (3.0 g, 14.85 mmol) in DMF (40 mL) was added 3- methylbutyl nitrite (2.61 g, 22.28 mmol, 2.99 ml, 1.5 equiv) dropwise at 0°C. After that, the reaction mixture was stirred at 70°C overnight. After completion of the reaction the resulting solution was concentrated in vacuo, diluted with EtOAc (30 mL) and water (30mL). Organic layer was separated and water layer was washed with EtOAc (3 x 15 mL). Organic layers were combined together, washed with brine (3 x 25 mL), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to give 6-bromo-l-methyl-lH- [l,2,3]triazolo[4,5-b]pyrazine (1.4 g, 82.0% purity, 5.36 mmol, 36.1% yield). Isolated crude was used in the next step without its further purification.

[0482] 3-bromo-l-methyl-5-l -methyl- lH-[ 1, 2, 3 ]triazolo[ 4, 5-b ]pyrazin-6-yl-lH-pyr azole According to Scheme 27’ Step 2: A solution 6-bromo-l-methyl-lH-[l,2,3]triazolo[4,5- b]pyrazine (320.0 mg, 1.5 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (472.87 mg, 1.65 mmol), dipotassium carbonate (621.78 mg, 4.51 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (85.62 mg, 105.2 pmol) in dioxane and water (10: 1, 30 mL) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. Then the mixture was cooled to rt, diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). Organic layers were combined together, washed with brine (30 mL), dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give 3-bromo-l-methyl-5-l- methyl-lH-[l,2,3]triazolo[4,5-b]pyrazin-6-yl-lH-pyrazole (440 mg, 50.6% purity, 756.99 pmol, 50.4% yield). Isolated crude was used in the next step without its further purification.

[0483] Synthesis of core 49 (intermediates g77):

[0484] Scheme 28’

[0485] 5-(3-bromo-l-methyl-lH-pyrazol-5-yl)-l,3-dimethyl-l,3-dihydro-2H-imidazo[4,5- bjpyr azin -2-one (Core 49)

[0486] 5-bromo-lH, 2H, 3H-imidazo[ 4, 5-b ]pyrazin-2-one

[0487] According to Scheme 28’ Step 1 : A mixture of 5-bromopyrazine-2, 3 -diamine (1.6 g, 8.51 mmol) and l-(lH-imidazole-l-carbonyl)-lH-imidazole (1.79 g, 11.06 mmol) in dioxane (40 ml) was stirred at 100°C for 10 hours. Then the mixture was cooled to room temperature, concentrated in vacuo, diluted with H2O (50 ml) and filtered off. The precipitated solid was dried to give 5-bromo-lH,2H,3H-imidazo[4,5-b]pyrazin-2-one (1.5 g, 100% purity, 6.98 mmol, 82% yield) was obtained.

[0488] 5-bromo-l, 3-dimethyl-lH, 2H, 3H-imidazo[ 4, 5-b ]pyrazin-2-one

[0489] According to Scheme 28’ Step 2: A solution of 5-bromo-lH,2H,3H-imidazo[4,5- b]pyrazin-2-one (702.42 mg, 3.28 mmol), iodomethane (1.07 g, 7.55 mmol, 470.0 pl, 2.3 equiv) and dipotassium carbonate (1.81 g, 13.13 mmol) in DMF (40 mL) was stirred at 70 °C overnight. Then the mixture was cooled to room temperature, diluted with H2O (100 ml) and extracted with EtOAc (2 x 30 ml). Organic layers were combined together, washed with brine (30 ml), dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give the crude which was purified by FC (SiO2, hexane / EtOAc, 1 : 1, Rf = 0.57) to give 5-bromo-l, 3-dimethyl-lH,2H,3H-imidazo[4,5-b]pyrazin-2-one (665.0 mg, 75.0% purity, 2.05 mmol, 62.5% yield). 5-(3-bromo-l -methyl- lH-pyrazol-5-yl)-l, 3 -dimethyl- 1 , 3-dihydro-2H-imidazo[ 4, 5- b ]pyr azin-2 -one

[0490] According to Scheme 28’ Step 3: A solution of 5-bromo-l,3-dimethyl-lH,2H,3H- imidazo[4,5-b]pyrazin-2-one (500.0 mg, 2.06 mmol), 3-bromo-l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (647.52 mg, 2.26 mmol), dipotassium carbonate (851.42 mg, 6.17 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (83.74 mg, 102.89 pmol) in dioxane (50 mL) and water (12 ml) was degassed and purged with Ar. The resulting mixture was stirred at 80 °C overnight. Then the mixture was cooled to room temperature, diluted with H2O (50 ml) and extracted with EtOAc (2 x 30 ml). Organic layers were combined together, washed with brine (30 ml), dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give 5-(3-bromo-l-methyl-lH-pyrazol-5-yl)-l,3-dimethyl- lH,2H,3H-imidazo[4,5-b]pyrazin-2-one (410.0 mg, 76.0% purity, 964.26 pmol, 46.9% yield).

[0491] Synthesis of core 50-51 (intermediates g82):

[0492] Table 11

[0493] 3-bromo-5-{6,7-dimethylimidazo[l,2-b][ l,2,4]triazin-2-yl}-l-methyl-LH-pyrazole (Core 50)

[0494] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3-amino-l, 2, 4-triazine

[0495] According to Scheme 29’ Step 1 : A mixture of 6-bromo-l,2,4-triazin-3-amine (15 g, 86.2 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (25.9 g, 90.5mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (1.4 g, 1.73 mmol) and K2CO3 (35.7 g, 258.7 mmol) in H2O and 1,4-dioxane (1 : 10 vol., 100 mL) was stirred at 80 °C for 12 h. Then the reaction mixture was concentrated in vacuo, diluted with EtOAc (400 mL) and washed with H2O (3 x 130 mL). Organic layers were combined together, washed with brine (130 mL), dried over Na2SO4, filtered off and evaporated in vacuo to give 6-(3 -bromo- 1-methyl- 7J / -pyrazol-5-yl)-3-amino-l, 2, 4-triazine (12 g, 70% purity, 32.94 mmol, 38.2% yield). Isolated product was used in the next step without its further purification.

[0496] 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)-3-chloro-l, 2, 4-triazine

[0497] According to Scheme 29’ Step 2: A mixture of 6-(3-bromo-l-methyl-177-pyrazol-5-yl)- 3 -amino- 1,2, 4-triazine (12 g, 47.3 mmol), CuCl (6.5 g, 66.1 mmol) and tert-butyl nitrite (9.1 ml, 75.6 mmol) in ACN (100 mL) was heated at 70 °C for 4 h. Then the reaction mixture was diluted with EtOAc (300 mL), filtered through a thin layer of Na2SO4 and evaporated in vacuo. Isolated crude product was purified by FCC (hexane-EtOAc, 100:0 - 0: 100) to give 6-(3-bromo-l-methyl-177-pyrazol-5-yl)-3-chloro-l, 2, 4-triazine (7.5 g, 60% purity, 16.39 mmol, 34.7% yield). Isolated product was used in the next step without any additional purification.

[0498] 3-bromo-5-{6, 7-dimethylimidazo[ 1, 2-b ][ 1, 2, 4 ]triazin-2-yl}-l -methyl- IH-pyrazole According to Scheme 29’ Step 3: A mixture of 6-(3-bromo-l-methyl-lH-pyrazol-5-yl)- 3 -chi oro-1, 2, 4-triazine (3 g, 10.9 mmol) and l-(2-methyl-l,3-dioxolan-2-yl)ethan-l- amine (1.72 g, 13.11 mmol) in tert-butyl alcohol (20 mL) was heated at 100°C for 48 h. Then the reaction mixture was concentrated in vacuo. Obtained residue was purified by FCC (hexane-EtOAc, 100:0 - 0: 100) to give 3-bromo-5-{6,7-dimethylimidazo[l,2- b][l,2,4]triazin-2-yl}-l-methyl-lH-pyrazole (0.6 g, 100% purity, 1.95 mmol, 17.9 yield).

[0499] Synthesis of core 52-53 (intermediates g88):

[0500] Table 12

[0501] 3-bromo-5-l,4-dimethyl-lH-pyrazolo[3,4-b]pyridin-6-yl-l-methyl-lH-pyrazole

[0502] (Core 52)

[0503] 2, 6-dichloro-4-methyl-3-[ (Z)-(2-methylhydrazin-l-ylidene)methyl pyridine According to Scheme 30’ Step 1 : A mixture of 2,6-Dichloro-4-methylpyridine-3- carbaldehyde (6.5 g, 34.4 mmol), methylhydrazine; sulfuric acid (6.44 g, 44.72 mmol), ethylbis(propan-2-yl)amine (10.66 g, 82.56 mmol, 14.37 ml, 2.4 equiv) and magnesium(2+) sulfate (10.31 g, 86.0 mmol) in ACN (200 mL) was stirred at 80°C for 12 h. After that obtained mixture was cooled to rt and filtered off. The filtrate was evaporated to dryness in vacuo to obtain 2,6-dichloro-4-methyl-3-[(Z)-(2- methylhydrazin-l-ylidene)methyl]pyridine (4.8 g, 98.2% purity, 21.61 mmol, 62.8% yield).

[0504] 6-chloro-l, 4-dimethyl-lH-pyrazolo[ 3, 4-b ] pyridine

[0505] According to Scheme 30’ Step 2: A solution of 2,6-dichloro-4-methyl-3-[(Z)-(2- methylhydrazin-l-ylidene)methyl]pyridine (4.8 g, 22.01 mmol) and cesium carbonate (21.51 g, 66.02 mmol) in DMF (250 mL) was heated at 100°C for. Then the reaction mixture was cooled to rt, the solvent was evaporated under reduced pressure and obtained residue was purified by FCC (Interchim; 80 + 40g SiCh, Hex-THF % 0-100, flow rate = 60 mL / min. Rv=5; column equilibration hexane. Incoming mixture dissolved in CHCh) to obtain 6-chloro-l, 4-dimethyl-lH-pyrazolo[3,4-b]pyridine (900.0 mg, 98.2% purity, 4.87 mmol, 22.1% yield).

[0506] 6-bromo-l, 4-dimethyl-lH-pyrazolo[ 3, 4-b ] pyridine

[0507] According to Scheme 30’ Step 3: A solution of 6-chloro-l, 4-dimethyl-lH-pyrazolo[3, 4- b]pyridine (350.0 mg, 1.93 mmol) and bromotrimethylsilane (1.47 g, 9.67 mmol) in ACN (50 mL) was stirred at 80°C for 24 h. Then the reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure to obtain crude 6-bromo-l, 4-dimethyl- lH-pyrazolo[3,4-b]pyridine (570.0 mg, 85.9% purity, 2.17 mmol, crude). Isolated crude was used in the next step without its further purification.

[0508] 6-iodo-l, 4-dimethyl-lH-pyrazolo[ 3, 4-b ] pyridine

[0509] According to Scheme 30’ Step 4: A solution of 6-bromo-l, 4-dimethyl-lH-pyrazolo[3, 4- b]pyridine (530.0 mg, 2.36 mmol), sodium iodide (705.9 mg, 4.71 mmol), copper(I) iodide (44.7 mg, 235.47 pmol) and methyl[2-(methylamino)ethyl]amine (20.74 mg, 235.47 pmol) in 1,4-di oxane (50 mL) was stirred at 100°C for 24 h under Ar. After completion of the reaction obtained mixture was cooled to rt and the solvent was evaporated under reduced pressure. Concentrated residue was subjected to prep HPLC purification (35-35-55% 0-1-5 min H2O / ACN, flow: 30ml / min, loading pump 4ml / min ACN, target mass 273, column: Chromatorex 18 SMB100-5T 100x19mm 5um) to obtain 6-iodo-l,4-dimethyl-lH-pyrazolo[3,4-b]pyridine (47.0 mg, 99.0% purity, 170.39 pmol, 7.2% yield).

[0510] 3-bromo-5-l, 4-dimethyl-lH-pyrazolo[ 3, 4-b ]pyr idin-6-yl-l -methyl- IH-pyr azole

[0511] According to Scheme 30’ Step 5: A solution of 6-iodo-l,4-dimethyl-lH-pyrazolo[3,4- b]pyridine (47.0 mg, 172.11 pmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (54.16 mg, 189.34 pmol), bis(adamantan-l- yl)(butyl)phosphane (6.17 mg, 17.21 pmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,l'- biphenyl]-2-yl]phosphane; 2'-amino-[l, l'-biphenyl]-2-ylpalladio methanesulfonate (14.55 mg, 17.21 pmol) and tripotassium nonahydrate phosphate (193.34 mg, 516.39 pmol) in 1,4-dioxane (10 mL) and H2O (0.5 mL) was stirred at 70°C for 48 h under Ar. After that the reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. Obtained residue substance was subjected to prep HPLC purification (40-65% 0-5min H2O / ACN, flow: 30ml / min, loading pump 4 ml / min ACN, target mass 306.17, column: Chromatorex 18 SMB100-5T 100x19mm 5um) to obtain 3-bromo-5- l,4-dimethyl-lH-pyrazolo[3,4-b]pyridin-6-yl-l-methyl-lH-pyrazole (24.0 mg, 87.7% purity, 68.75 pmol, 39.9% yield).

[0512] Synthesis of core 54-55 (intermediates g91):

[0513] A = CH, N

[0514] Scheme 31’ able 13

[0515] 3-bromo-5-l,3-dimethyl-lH-pyrazolo[4,3-b]pyridin-5-yl-l-methyl-lH-pyrazole (Core 55)

[0516] 5-bromo-l, 3-dimethyl-lH-pyrazolo[ 4, 3-b ] pyridine

[0517] According to Scheme 31’ Step 1: To a solution of l-(6-bromo-3-fluoropyridin-2- yl)ethan-l-one (500.0 mg, 2.3 mmol) in ethanol (10 mL) were added a 40% water solution of methylhydrazine (212.26 mg, 4.61 mmol, 610.0 pl, 2.0 equiv) and tri ethylamine (466.08 mg, 4.61 mmol). The resulting solution was stirred at 100°C for 16 h. After completion of the reaction obtained mixture was concentrated in vacuo and the residue was diluted with water (20 ml). The product was extracted with ethyl acetate (3x30 ml). Combined organic layers were dried over Na2SO4, filtered off and evaporated in vacuo to give 5-bromo-l, 3-dimethyl-lH-pyrazolo[4,3-b]pyridine (0.3 g, 1.33 mmol, 60% yield). Isolated product was used in the next step without its further purification. s

[0518] 3-bromo-5-l, 3-dimethyl-lH-pyrazolo[ 4, 3-b ]pyridin-5-yl-l-methyl-lH-pyrazole

[0519] According to Scheme 31’ Step 2: A suspension of 5-bromo-l, 3-dimethyl-lH- pyrazolo[4,3-b]pyridine (250.0 mg, 72.0% purity, 800.03 pmol), 3-bromo-l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (228.91 mg, 800.23 pmol), dipotassium carbonate (331.09 mg, 2.4 mmol), bis(adamantan-l-yl)(butyl)phosphane (28.67 mg, 80.02 pmol) and dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T-biphenyl]-2- yl]phosphane; 2'-amino-[l,T-biphenyl]-2-ylpalladio methanesulfonate (33.82 mg, 40.01 pmol) in a degassed mixture of dioxane and water (2:1, 15 ml) was stirred under Ar at 90°C overnight. After cooling to ambient temperature the mixture was diluted with EtOAc (75 ml). Organic layer was separated, washed with water (3 x 30) and brine (30 ml), dried over Na2SO4, filtered off and concentrated in vacuo to afford 3-bromo-5-l,3- dimethyl-lH-pyrazolo[4,3-b]pyridin-5-yl-l-methyl-lH-pyrazole (0.2 g, 82% purity, 0.536 mmol, 81.6 % yield). Isolated product was used in the next step without its further purification.

[0520] Synthesis of core 56 (intermediates g94):

[0521] Scheme 32’

[0522] 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-8-methylpyrido[3,4-b]pyrazine (Core 56) 8-Methylpyrido [ 3, 4-b ]pyrazin-2-yl trifluoromethanesulfonate

[0523] According to Scheme 32’ Step 1: To a stirred solution of 8-methylpyrido[3,4-b]pyrazin- 2-ol (0.3 g, 1.86 mmol) in DCM (10 mL) at -20 °C were added tri ethylamine (0.245 g, 2.42 mmol) and TfzO (0.577 g, 2.05 mmol) dropwise under argon atmosphere. The resulting solution was stirred at the same temperature for 15 minutes. After 15 minutes DCM was evaporated under reduced pressure at 0°C. Crude 8-methylpyrido[3,4- b]pyrazin-2-yl trifluoromethanesulfonate was used immediately in the next step without its further purification.

[0524] 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-8-methylpyrido[ 3, 4-b ] pyrazine

[0525] According to Scheme 32’ Step 2: DME (20 mL) was added to the 8-methylpyrido[3,4- b]pyrazin-2-yl trifluoromethanesulfonate and the reaction mixture was allowed to warm up to 60 °C. Then K2CO3 (0.77 g, 5.58 mmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.531 g, 1.86 mmol) and Pd(dppf)C12*CH2C12 (0.151 g, 0.19 mmol) were added and the resulting mixture was stirred at 60°C for 2 hours under argon atmosphere. After completion of the reaction obtained mixture was concentrated in vacuo and subjected to prep HPLC purification (25-25-45% 0-1-5 min H2O / ACN, flow: 30ml / min (loading pump 4ml / min ACN) target mass 304;306 column: Chromatorex 18 SMB100-5T 100x19mm 5um) to afford 2-(3-bromo-l-methyl-lH- pyrazol-5-yl)-8-methylpyrido[3,4-b]pyrazine (23.4 mg, 96% purity, 73.89 pmol, 3.98% yield).

[0526] Synthesis of core 57 (intermediates g98):

[0527] Scheme 33’

[0528] 3-bromo-5-6,8-dimethylpyrido[2,3-b]pyrazin-2-yl-l-methyl-lH-pyrazole (core 57)

[0529] 6, 8-dimethylpyrido[2, 3-b ]pyrazin-2-ol

[0530] According to Scheme 33’ Step 1 : A mixture of 4,6-Dimethylpyridine-2,3-diamine (800.0 mg, 5.84 mmol) and ethyl 2-oxoacetate (892.84 mg, 8.75 mmol, 1.73 ml, 1.5 equiv) in dioxane (15 mL) was stirred at 120 °C for 1 h. Then the reaction solution was cooled to rt and diluted with diethyl ether (80 mL). The precipitated solid was filtered off to produce the 6,8-dimethylpyrido[2,3-b]pyrazin-2-ol (432.0 mg, 89.0% purity, 2.19 mmol, 37.6% yield) as a dark beige solid. Isolated crude was used in the next step without further purification.

[0531] 6, 8-Dimethylpyrido[2, 3-b ]pyrazin-2-yl trifluoromethane sulfonate According to Scheme 33’ Step 2: To a stirred solution of 6,8-dimethylpyrido[2,3- b]pyrazin-2-ol (432.0 mg, 2.47 mmol) in DCM (5 mL) were added triethylamine (299.36 mg, 2.96 mmol, 410.0 pl, 1.2 equiv) and trifluoromethanesulfonyl trifluoromethanesulfonate (765.03 mg, 2.71 mmol, 460.0 pl, 1.1 equiv) dropwise at -10 °C. The resulting reaction mixture was stirred at -10 °C for 20 min. After that the solvent was evaporated and obtained crude product was used in the next step without it isolation and purification.

[0532] 3-bromo-5-6, 8-dimethylpyrido[2, 3-b ]pyr azin-2 -yl-1 -methyl- IH-pyr azole

[0533] According to Scheme 33’ Step 3: To a stirred solution of 6,8-dimethylpyrido[2,3- b]pyrazin-2-yl trifluoromethanesulfonate (750.0 mg, 2.44 mmol) in glyme (10 mL) were added potassium carbonate (1.01 g, 7.33 mmol), 3-bromo-l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (628.7 mg, 2.2 mmol) and Pd(dppf)C12*CH2C12 (198.76 mg, 244.21 pmol) under argon atmosphere. The resulting reaction mixture was stirred at 60 °C for Ih (LCMS control). After completion of the reaction obtained mixture was filtered off and concentrated under reduced pressure. Crude product was purified by prep HPLC (40-40-90% 0-l-6min H2O / MeOH, flow: 30ml / min (loading pump 4ml / min MeOH) target mass 318 column: XBridge C18 100x19mm, 5um) to afford 3-bromo-5-6,8-dimethylpyrido[2,3-b]pyrazin-2-yl-l- methyl-lH-pyrazole (58.3 mg, 97.52% purity, 178.69 pmol, 7.3% yield).

[0534] Synthesis of core 58 (intermediates g):

[0535] Scheme 34’ 3-Bromo-5-2,4-dimethylpyrido[3,2-d]pyrimidin-6-yl-l-methyl-lH-pyrazole (core 58)

[0536] 6-Chloro-2, 4-dimethylpyrido[ 3, 2 -d] pyrimidine

[0537] According to Scheme 34’ Step 1 : A vial containing 1 -(6-chl oro-3 -fluoropyridin-2- yl)ethan-l-one (150.0 mg, 867.03 pmol) was charged with ethanimidamide hydrochloride (122.37 mg, 1.3 mmol), tripotassium phosphate (735.2 mg, 3.47 mmol) and THF (10 mL). The vial was sealed and heated at 80°C for 16 h. The resulting mixture was cooled to rt and concentrated in vacuo. Water (15 mL) was added to the concentrated residue and obtained precipitate was filtered off, washed with water (5 mL) and dried to afford 6-chloro-2,4-dimethylpyrido[3,2-d]pyrimidine (0.12 g, 99% purity, 71.4% yield).

[0538] 6-Bromo-2, 4-dimethylpyrido[ 3, 2-d]pyrimidine

[0539] According to Scheme 34’ Step 2: To a vial containing 6-chl oro-2, 4-dimethylpyrido[3, 2- d]pyrimidine (120.0 mg, 619.73 pmol) in acetonitrile (5 mL) bromotrimethylsilane (661.26 mg, 4.35 mmol, 560.0 pl, 7.0 equiv) was added at rt. The vial was sealed and stirred at 80°C for 16 h. After the reaction completion (LCMS control) the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (40 mL) and water (40 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). Organic layers were combined together, washed with brine (30 mL), dried over Na2SO4, filtered off and concentrated under reduced pressure to afford 6-bromo-2,4-dimethylpyrido[3,2-d]pyrimidine (0.15 g, 44% purity, 44.6% yield). Isolated crude was used in the next step without further purification.

[0540] 3-Bromo-5-2, 4-dimethylpyrido[ 3, 2 -d]pyrimidin-6-yl-l -methyl- IH-pyrazole

[0541] According to Scheme 34’ Step 3: A suspension of 6-bromo-2,4-dimethylpyrido[3,2- d]pyrimidine (150.0 mg, 630.03 pmol), 3-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (179.81 mg, 628.59 pmol), potassium carbonate (260.07 mg, 1.89 mmol, 260.0 pl, 3.0 equiv) and Pd(dppf)C12*CH2C12 (51.16 mg, 62.86 pmol) in a degassed mixture of dioxane and water (2:1, 15 mL) was stirred at 95°C overnight under Ar. After the reaction completion (LCMS control) the resulting mixture was cooled to rt, partitioned between ethyl acetate (25 mL) and water (15 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over ISfeSCU, filtered off and concentrated under reduced pressure. Isolated residue was subjected to prep HPLC purification (22-22-62% 0-1.5-6min H2O / ACN, flow: 30ml / min (loading pump 4ml / min ACN) target mass 318 column: Chromatorex 18 SMB100-5T 100x19mm 5um) to afford 3-bromo-5-2,4-dimethylpyrido[3,2-d]pyrimidin-6-yl-l-methyl-lH- pyrazole (46 mg, 100% purity, 23% yield).

[0542] Stereochemistry of cPr linker for all examples is defined as trans-rac (apart from isomers separated via chiral-SFC purification).

[0543] EXAMPLE 1: 5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-^]pyi'idazin-6-yl}-3-[2-(l-ethyl- l / / -pyrazol-4-yl)cyclopropyl|-l-niethyl-l / / -pyrazole (Final compound 1-53) Scheme 7 Route B’ - Scheme 1

[0544] Tert-butyl (2E)-3-( I -ethyl- lH-pyrazol-4-yl)pr op-2 -enoate

[0545] According to Step 1 : To a seal tube equipped with a stir bar, 1 -ethyl- lrt-pyrazole-4- carbaldehyde (10.00 g, 80.55 mmol, 1.0 eq.) was added and dissolved in anhydrous toluene (150 mL). Then, tert-butyl 2-(triphenylphosphoranylidene)acetate (45.5 g, 120.82 mmol, 1.5 eq.) was added and the reaction mixture was stirred at 80 °C overnight. After the specified time, the solvent was evaporated. The semi-solid residue was triturated with diethyl ether and the filtrate was evaporated. The crude was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification) and purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-30%) to afford the title compound as a yellow oil (11.86 g, 66%).

[0546] Tert-butyl 2-( I -ethyl-lH-pyrazol-4-yl)cyclopropane-l -carboxylate

[0547] According to Step 2: At first, sodium hydride (60% dispersion in mineral oil, 1.29 g, 32.39 mmol, 1.2 eq.) was placed in a round-bottomed flask, then triturated with anhydrous hexane (2x25 mL) and decanted. Residual solid was suspended in anhydrous DMSO (120 mL) and trimethyl sulfoxonium iodide (7.12 g, 32.39 mmol, 1.2 eq.) was added portionwise while stirring at room temperature. The reaction mixture was stirred at room temperature for 1 - 1.5 h (until a clear solution was formed). After the specified time, a solution of tert-butyl (2£)-3-(l -ethyl- U / -pyrazol-4-yl)prop-2-enoate (6.00 g, 26.99 mmol, 1.0 eq.) in anhydrous DMSO (40 mL) was added dropwise. After addition, the reaction mixture was heated at 50 °C overnight. After the complete conversion of the starting material (monitored by NMR measurements), the reaction mixture was quenched with ice (100 g) and extracted with diethyl ether (3x100 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford the title compound as a yellow oil (4.83 g, 70%). The title compound was used as a crude in the next step without additional purification.

[0548] 2-( 1 -Ethyl- lH-pyrazol-4-yl)cyclopropane-l -carboxylic acid hydrochloride According to Step 3: Tert-butyl 2-(l -ethyl -1 rt-pyrazol -4-yl )cyclopropane-l -carboxyl ate (4.83 g, 19.00 mmol, 1.0 eq.) was suspended in hydrochloric acid (3.7-4.3 N in dioxane, 38 mL, 8.0 eq.) in a flask with a magnetic stirring bar. The obtained a clear solution was stirred at room temperature overnight. After that time, a solid precipitated out and 20 mL of DCM with 40 mL of hexane were added to enhance the product precipitation. The solid was filtered, rinsed with hexane and dried on rotary evaporator to afford the title compound as a beige solid (4.25 g, quant). The title compound was used as a crude in the next step without additional purification.

[0549] 1, 3-Dioxo-2, 3-dihydro-l H-isoindol-2-yl-2-( 1 -ethyl- lH-pyrazol-4-yl) cyclopropane- 1- carboxylate

[0550] According to Step 4: To a suspension of 2-(l-ethyl-17 / -pyrazol-4-yl)cyclopropane-l- carboxylic acid hydrochloride (4.25 g, 19.41 mmol, 1.0 eq.) in anhydrous DCM (100 mL) was added triethylamine (13.5 mL, 97.09 mmol, 5.0 eq.). The resulting mixture was stirred at room temperature for 5 min (to create a clear solution). Next, 4- dimethylaminopyridine (237 mg, 1.94 mmol, 0.1 eq.) was added followed by N,N'- dicyclohexylcarbodiimide (4.40 g, 21.36 mmol, 1.1 eq.) and the obtained solution was stirred for additional 5 min. After the specified time, A-hydroxyphthalimide (3.48 g, 21.36 mmol, 1.1 eq.) was added and the reaction mixture was stirred at room temperature overnight. After the complete conversion of A-hydroxyphthalimide, the white precipitate of urea was filtered off and the solution was concentrated. The crude product was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification), then purified by column chromatography on silica gel eluting with ethyl acetate in hexane (0-20%) to afford the title compound as a yellow oil (3.88 g, 61%). l-Ethyl-4-[ 2-( 4, 4, 5, 5-tetramethyl-l, 3, 2 -dioxaborolan-2-yl) cyclopropyl -lH-pyrazole According to Step 5: To a seal tube equipped with a magnetic stirring bar, l,3-dioxo-2,3- dihydro-U / -isoindol-2-yl-2-(l-ethyl-U / -pyrazol-4-yl)cyclopropane-l-carboxylate (2.00 g, 6.14 mmol, 1.0 eq.) was added followed by bis(pinacolato)diboron (3.12 g, 12.29 mmol, 2.0 eq.) and dissolved in anhydrous ethyl acetate (40 mL). The resulting mixture was degassed and purged with Ar, then methyl isonicotinate (421 mg, 3.07 mmol, 0.5 eq.) was added as a solution in anhydrous ethyl acetate (1 mL). The reaction mixture was stirred at 80 °C overnight. After that time, the mixture was cooled to room temperature and evaporated to dryness. The crude product was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification), then purified by column chromatography using Biotage® Sfar KP -Amino D - Duo 50 pM, 50 g column eluting with acetone in hexane (0-10%) to afford the title compound as a slightly yellow oil (1.15 g, 70%).

[0551] 5-{3, 8-Dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-3-[ 2-(l -ethyl- IH-pyr azoleyl) cyclopropyl] -1 -methyl- IH-pyr azole

[0552] According to step 6 (as in Scheme 1): A solution of 3-bromo-5-{3,8-dimethyl- [l,2,4]triazolo[4,3-Z>]pyridazin-6-yl}-l-methyl-177-pyrazole (0.54 g, 1.72 mmol, 1.0 eq.), l-ethyl-4-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]-UT- pyrazole (0.58 g, 2.23 mmol, 1.3 eq.), potassium phosphate tribasic (1.28 g, 6.03 mmol, 3.5 eq.) in the mixture of dioxane (14 mL) and water (3 mL) was degassed, and purged with Ar. Then, XPhos Pd G3 (145 mg, 0.17 mmol, 0.1 eq.) followed by cataCXium A (62 mg, 0.17 mmol, 0.1 eq.) were subsequently added and the reaction mixture was stirred at 100 °C overnight. After the specified time, the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3^50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified on column chromatography using puriFlash® RP-AQ, 15 pM, 120 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 beige solid (0.43 g, 67%). UPLC- MS: RT = 3.98 min; MS m / z [M+H]+: = 363.2 Found 363.2.

[0553] EXAMPLE 2: Methyl A-{5-[2-(l-methyl-5-{3-methyl-[l,2,4]triazolo[4,3- / >]pyridazin-6-yl}-lH-pyrazol-3-yl)cyclopropyl]pyridin-2-yl}carbamate (Final compound 1-29)

[0554] Scheme 6 Route B’

[0555] Tert-butyl (2E)-3-( 6-acetamidopyridin-3-yl)prop-2-enoate

[0556] According to Scheme 6 Route B’ step 1 : To a suspension of 2-acetamido-5- bromopyridine (1.00 g, 4.65 mmol, 1.0 eq.) in anhydrous acetonitrile (20 mL), tri ethylamine (3.2 mL, 23.25 mmol, 5.0 eq.) was added. Then, / c / 7-butyl acrylate (3.4 mL, 23.25 mmol, 5.0 eq.) followed by tri-o-tolylphosphine (0.56 g, 1.86 mmol, 0.4 eq.) were added and the reaction mixture was degassed, and purged with Ar. Next, palladium(II) acetate (210 mg, 0.93 mmol, 0.2 eq.) was added and the resulting mixture was stirred at 80 °C overnight. After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with ethyl acetate and evaporated to dryness. The crude was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-50%) to afford the title compound as a green solid (0.66 g, 54%).

[0557] To afford the final compound (1-29) the synthesis was continued according to Scheme 6 Route B (Steps 2-5) to afford the intermediate 2 and then to Scheme 1.

[0558] EXAMPLE 3: 3,8-dimethyl-6-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1-64) ste 3

[0559] Scheme 6 Route A’ (steps 1-2) - Scheme 1

[0560] (E)-l-methyl-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazole

[0561] A mixture of 4-iodo-l-methyl-lH-pyrazole (20.0 g, 96.18 mmol), 2-ethenyl-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (17.79 g, 115.41 mmol), tri s( 1,5 -diphenylpenta- 1,4- dien-3-one) dipalladium (4.4 g, 4.81 mmol), DIPEA (24.85 g, 192.36 mmol), and tetrafluoroboranuide; tri-tert-butylphosphanium (2.79 g, 9.62 mmol) in toluene (300 mL) was degassed and purged with Ar (3x) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs under an Ar atmosphere and concentrated under reduced pressure to remove solvent. The residue was purified by silica gel column chromatography using a 0-8% EtOAc / petroleum ether gradient eluent to afford the title compound (15 g) as a red oil. 'H NMR (400 MHz, CDC13) 5 (ppm) 8 7.58 - 7.48 (m, 1 H), 7.35 (s, 1 H), 7.21 - 7.16 (m, 1 H), 5.73 (d, J=18.5 Hz, 1 H), 3.81 (s, 3 H), 1.22 (s, 12 H).

[0562] MS-ESI (m / z) calcd for C12H20BN2O2 [M+H]+: 235.2. Found 235.1. l-methyl-4-(2-( 4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)cyclopropyl)-lH-pyr azole Diazomethane (4.49 g, 106.75 mmol, 213.51 ml, 5.0 equiv) 0.5M solution in MTBE was added at -50 °C 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 -30 °C for 30 min, heated to r.t. and filtered. The solvent was evaporated to obtain crude which was purified using FCC (SiO2, Hexane - MtBE as a solvent mixture) affording 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).

[0563] MS-ESI (m / z) calcd for C13H21BN2O2 [M+H]+: 249.2. Found 249.2.

[0564] 5-3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl-l-methyl-3-[ 2-( 1 -methyl- 1H- pyrazol-4-yl) cyclopropyl ]-lH-pyrazole

[0565] A solution of 3-bromo-5-3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl-l-methyl- IH-pyrazole (2.1 g, 6.8 mmol), l-methyl-4-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cyclopropyl]-lH-pyrazole (2.37 g, 9.3 mmol), potassium phosphate tribasic (5.1 g, 23.9 mmol) in the mixture of dioxane (53 mL) and water (11 mL) was degassed, and purged with Ar. Then, XPhos Pd G3 (578 mg, 0.68 mmol, 0.1 equiv.) followed by cataCXium A (245 mg, 0.68 mmol, 0.1 equiv.) were subsequently added and the reaction mixture was stirred at 100 °C overnight. Then the mixture was cooled to room temperature and diluted with H2O (20 ml) and extracted with EtOAc (3x50 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 on column chromatography using Puriflash RP-AQ, 15 pm, 120 g column, eluting with acetonitrile in water (5-100%, acidic method with 0.1% of formic acid in both eluents). Yield - 1.31 g (54%), a beige solid as 5-3, 8-dimethyl-[l, 2, 4]triazolo[4,3-b]pyridazin-6-yl-l-methyl-3-[2-(l -methyl- lH-pyrazol-4-yl)cyclopropyl]-lH-pyrazole (final compound 1-64).

[0566] MS-ESI (m / z) calcd [M+H]+: 349.2. Found 349.2.

[0567] The compound 1-64 was submitted to chiral purification according to the conditions described in the Table 24 to give 3,8-dimethyl-6-(l-methyl-3-((lR,2R)-2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1-67) and 3,8-dimethyl-6-(l-methyl-3-((lS,2S)-2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1- 68). EXAMPLE 4: A^V-Dimethyl-5-[2-(l-methyl-5-{3-methyl-[l,2,4]triazolo[4,3- / >]pyridazin-6-yl}-LH-pyrazol-3-yl)cyclopropyl]pyridin-2-amine (Final compound 1-31)

[0568] Scheme 14

[0569] In a round-bottom flask equipped with a magnetic stirring bar, A-methyl-5-[2-(l-methyl- 5-{3-methyl-[l,2,4]triazolo[4,3-Z>]pyridazin-6-yl}-lJH-pyrazol-3-yl)cyclopropyl]- pyridin-2-amine (Final compound 1-28) (10 mg, 0.13 mmol, 5.0 eq.) was dissolved in ethanol (0.2 mL). Next, acetic acid (8 pL, 0.13 mmol, 5.0 eq.) was added and the resulting mixture was stirred at room temperature for 5 hours. After the specified time, cyanoborohydride (polymer supported, 17 mg, 0.03 mmol, 1.2 eq.) was added and the reaction mixture was continued at room temperature overnight. After the complete conversion of starting material (monitored by UPLC-MS), the reaction mixture was filtered, evaporated to dryness and purified by preparative HPLC (under basic conditions) to afford the title compound as a light yellow solid (2 mg, 19%).

[0570] UPLC-MS: RT = 1.94 min; MS m / z ES+= 375 [M+H]+; 'H NMR (300 MHz, DMSO-tL) 57.45 (d, J= 9.7 Hz, 1H), 7.16 (s, 1H), 6.94 (d, J = 9.8 Hz, 1H), 6.56 (s, 1H), 6.09 (s, 1H), 5.85 (d, J = 9.0 Hz, 1H), 3.45 (s, 3H), 2.26 (s, 6H), 2.05 (s, 3H), 1.37 (d, J= 18.5 Hz, 2H), 0.66 (s, 2H).

[0571] EXAMPLE 5: Methyl A-{5-[2-(5-{3,8-dimethyl-[l,2,4]triazolo[4,3-6]pyridazin-6- yl}-l-methyl-LH-pyrazol-3-yl)-cyclopropyl]pyridin-2-yl}carbamate (Final compound 1-46)

[0572] Scheme 15

[0573] 5-[2-(5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl}-l-methyl-lH-pyrazol-3- yl) cyclopropyl ]-pyridin-2 -amine

[0574] A-{5-[2-(5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-Z>]pyridazin-6-yl}-l-methyl-17 / -pyrazol-

[0575] 3 -yl)cyclopropyl]pyridin-2-yl} acetamide (11 mg, 0.24 mmol, 1.0 eq.) (prepared as Scheme 6 for Final compound 1-29) was dissolved in methanol (0.33 mL) and water (0.11 mL) in a round-bottom flask at room temperature. Then, sodium hydroxide (20 mg, 0.25 mmol, 3.3 eq.) was added and the resulting mixture was stirred at 80 °C for

[0576] 1 hour. After the specified time, the reaction mixture was cooled to room temperature and evaporated to dryness to afford the title compound as an off-white solid (9.2 mg, 73%). The title compound was used as a crude in the next step without additional purification to afford 5-[2-(l-methyl-5-(3-methyl-[l,2,4]triazolo[4,3-Z>]pyridazine-6-yl)- 17 / -pyrazol-3-yl)cyclopropyl]pyridin-2-amine, the final compound (1-39), analogous synthesis on 7V-(5-[2-(l-methyl-5-{3-methyl-[l,2,4]triazolo[4,3-Z>]pyridazin-6-yl)-lJT- pyrazol-3-yl)cyclopropyl]pyridin-2-yl} acetamide (final compound 1-29) was done and the crude was purified by preparative HPLC. Methyl N-{5-[2-(5-{3, 8-dimethyl-[ 1, 2, 4 ]triazolo[4, 3-b ]pyridazin-6-yl}-l -methyl- 1H- pyrazol-3-yl)-cyclopropyl]pyridin-2-yl}carbamate

[0577] 5-[2-(5-{3,8-Dimethyl-[l, 2, 4]triazolo[4,3-Z>]pyridazin-6-yl}-l -methyl- U / -pyrazol-3- yl)cyclopropyl]-pyridin-2-amine (9.2 mg, 0.17 mmol, 1.0 eq.) was dissolved in anhydrous DCM (3.7 mL) and tri ethylamine (0.04 mL, 0.26 mmol, 1.5 eq.) was added. The resulting mixture was cooled to 0 °C followed by addition of methyl chloroformate (0.02 mL, 0.26 mmol, 1.5 eq.). The obtained suspension was stirred at room temperature for 1 hour and then concentrated in vacuum to dryness. The crude product was purified by preparative HPLC (under basic conditions) to afford the title compound as a white solid (2.3 mg, 31%).

[0578] UPLC-MS: RT = 3.53 min; MS m / z ES+= 419 [M+H]+; *HNMR (300 MHz, Methanol- dd) 5 8.14 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.62 - 7.43 (m, 2H), 6.88 (s, 1H), 4.23 (s, 3H), 3.76 (s, 3H), 2.83 (s, 3H), 2.71 (d, J = 1.3 Hz, 3H), 2.26 (ddd, J= 18.6, 9.1, 5.0 Hz, 2H), 1.50 (ddt, J= 24.9, 9.0, 5.3 Hz, 2H).

[0579] EXAMPLE 6: 5-[2-(5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-6]pyridazin-6-yl}-l- methyl-lH-pyrazol-3-yl)cyclopropyl]-V-ethylpyridin-2-amine (Final compound 1- 50)

[0580] Scheme 16

[0581] In a round-bottom flask equipped with a magnetic stirring bar, 5-[2-(5-{3,8-dimethyl- [ 1 ,2,4]triazolo[4,3 -Z>]pyridazin-6-yl } - 1 -methyl- 177-pyrazol -3 -yl)cyclopropyl]-pyridin- 2-amine, as prepared in example 5 (stepl) (100 mg, 0.28 mmol, 1.0 eq.) was dissolved in ethanol (1.9 mL) and acetic acid (2.3 mL, 2.39 mmol, 8.3 eq.) was added. Then, acetaldehyde solution (40% wt. in H2O, 0.08 mL, 0.63 mmol, 2.2 eq.) was added at room temperature followed by addition of cyanoborohydride (polymer supported, 159 mg, 0.31 mmol, 1.1 eq.) and the resulting mixture was stirred for 2 hours. After the complete conversion of starting material, the reaction mixture was evaporated to dryness and purified by preparative HPLC (under basic conditions) to afford the title compound as a beige solid (60 mg, 55%).

[0582] UPLC-MS: RT = 2.97 min; MS m / z ES+= 389 [M+H]+; *HNMR (300 MHz, Methanol- dd) 5 7.84 (d, J = 2.4 Hz, 1H), 7.58 (t, J= 1.3 Hz, 1H), 7.29 (dd, J = 8.7, 2.5 Hz, 1H), 6.87 (s, 1H), 6.52 (d, J= 8.7 Hz, 1H), 4.24 (s, 3H), 3.31 - 3.25 (m, 2H), 2.84 (s, 3H), 2.73 (d, .7= 1.3 Hz, 3H), 2.24 - 2.10 (m, 2H), 1.48 - 1.39 (m, 1H), 1.38 - 1.33 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).

[0583] EXAMPLE 7: 5-[2-(5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-6]pyridazin-6-yl}-l- methyl-lH-pyrazol-3-yl)cyclopropyl]-3-methyl-l,2,4-thiadiazole (Final compound 1-2)

[0584] Scheme 6 Route C’

[0585] 5 -Ethenyl- 3 -me thy I- 1, 2, 4-thiadiazole

[0586] According to Scheme 6 Route C’ Step 1 A solution of 5-bromo-3-methyl-l,2,4- thiadiazole (2.50 g, 13.26 mmol, 1.0 eq.), potassium carbonate (3.66 g, 26.53 mmol, 2.0 eq.), tributyl(vinyl)tin (4.3 mL, 14.59 mmol, 1.1 eq.) in anhydrous THF (75 mL) was degassed and purged with Ar. Next, tetrakis(triphenyl-phosphine)palladium (0.77 g, 0.66 mmol, 0.05 eq.) was added and the resulting mixture was heated at 90 °C overnight. After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated. The crude was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-10%) to afford the title compound as a yellow oil (0.66 g, 39%).

[0587] Tert-butyl 2-( 3-methyl-l, 2, 4-thiadiazol-5-yl)cyclopropane-l -carboxylate

[0588] According to Scheme 6 Route C’ Step 2: To a seal tube equipped with a magnetic stirring bar, 5-ethenyl-3-methyl-l,2,4-thiadiazole (0.66 g, 5.23 mmol, 1.0 eq.) was added followed by tert-butyl diazoacetate

[0589] (0.8 mL, 5.75 mmol, 1.1 eq.) and both reagents were dissolved in anhydrous toluene (13 mL). The resulting mixture was degassed and purged with Ar, then 5,10,15,20- tetraphenyl-21J / ,23J / -porphine cobalt(II) (70 mg, 0.10 mmol, 0.02 eq.) was added. The reaction mixture was stirred at 80 °C overnight. After the specified 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 was purified using FCC (silica gel) eluting with ethyl acetate in hexane (0-10%) to afford the title compound as a dark red oil (0.80 g, 64%).

[0590] To afford the Final compound (1-2) the synthesis was continued according to Scheme 6 Route B (Steps 2-5), then Scheme 1.

[0591] EXAMPLE 8: 5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-6]pyridazin-6-yl}-3-(2-

[0592] {imidazo[ 1 , 2-a]pyridin-6-yl} cyclopropyl)- 1 -methyl- IH-pyrazole (Final compound 1-1)

[0593] Ethyl 2-{imidazo[ 1, 2-a]pyridin-6-yl}cyclopropane-l -carboxylate

[0594] According to Scheme 6 Route D’ Step 1 : In a seal tube equipped with a magnetic stir bar, 6-bromoimidazo[l,2-a]pyridine (2.00 g, 10.15 mmol, 1.0 eq.), ethyl 2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-cyclopropane-l-carboxylate (3.44 g, 12.18 mmol, 1.2 eq.) (synthesized according to the literature: Adv. Synth. Catal. 10.1002 / adsc.201900879) followed by potassium phosphate tribasic (10.77 g, 50.75 mmol, 5.0 eq.) were dissolved in dioxane (70 mL) and water (14 mL). The resulting mixture was degassed and purged with Ar, then XPhos Pd G3 (859 mg, 1.01 mmol, 0.1 eq.) with cataCXium A (364 mg, 1.01 mmol, 0.1 eq.) were added, and the reaction mixture was stirred at 100 °C overnight. After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with ethyl acetate and evaporated to dryness. The crude product was purified on column chromatography using Puriflash RP-AQ, 15 pm, 120 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 slightly yellow oil (0.80 g, 34%).

[0595] 2- {! midazo / 1 ,2-a / pyridin-6-yll cyclopropane- 1 -car boxylic acid hydrochloride

[0596] According to Scheme 6 Route D’ Step 2: Ethyl 2-{imidazo[l,2-a]pyridin-6- yl} cyclopropane- 1 -carboxylate (0.8 g, 3.47 mmol, 1.0 eq.) was suspended in hydrochloric acid (3.7-4.3 N in dioxane, 6.9 mL, 8.0 eq.) in a flask with a magnetic stirring bar. The obtained a clear solution was stirred at 60 °C overnight. After that time, the reaction mixture was cooled to room temperature and the precipitated solid was filtered, rinsed with hexane, and dried on rotary evaporator to afford the title compound as a beige solid (0.70 g, 84%). The title compound was used as a crude in the next step without additional purification.

[0597] To afford the Final compound (1-1) the synthesis was continued according to Scheme 6 Route B (Steps 4-6), then Scheme 1.

[0598] EXAMPLE 9: 5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-^]pyi'idazin-6-yl}-l-methyl-3-[2- (trifluoro-methyl)cydopropylJ-lH-pyrazole (Final compound 1-49)

[0599] Scheme 8’

[0600] (2E)-4, 4, 4-Trifluoro-N-methoxy-N-methylbut-2-enamide

[0601] According to Scheme 8’ Acylation step 1 : Methoxy(methyl)amine hydrochloride (1.81 g, 18.56 mmol, 1.3 eq.) was suspended in anhydrous DCM (30 mL) in a flask with a magnetic stirring bar. Then, 7V,7V-diisopropylethylamine (7.6 mL, 42.83 mmol, 3.0 eq.) was slowly added to prepare a solution of free-base of used starting reagent. In other flask equipped with a magnetic stirring bar, 4,4,4-trifluorocrotonic acid (2.00 g, 14.27 mmol, 1.0 eq.) was dissolved in anhydrous DCM (50 mL) and cooled to -15 °C. Next, a previously prepared a free-base solution of methoxy(methyl)amine hydrochloride was carefully transferred to a flask equipped with a mixture of 4,4,4-trifluorocrotonic acid stirred at -15 °C followed by addition of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (3.28 g, 17.13 mmol, 1.2 eq.). The obtained reaction mixture was allowed to warm to room temperature and stirred overnight. After the specified time, the reaction mixture was quenched by addition of water (20 mL) and extracted with DCM. The combined organic layers were dried over Na2SO4 and carefully evaporated (due to the assumed a high volatility of the compound). The crude was purified using FCC (silica gel) eluting with DCM in hexane (0-50%) to afford the title compound as a colourless oil (0.89 g, 34%).

[0602] N-Methoxy-N-methyl-2-(trifluoromethyl)cyclopropane-l-carboxamide

[0603] According to Scheme 8’ cyclopropanation step 2: At first, a sodium hydride (60% dispersion in mineral oil, 232 mg, 5.83 mmol, 1.2 eq.) was placed in a round-bottom flask and suspended in anhydrous DMSO (20 mL). Then, trimethyl sulfoxonium iodide (1.28 g, 5.83 mmol, 1.2 eq.) was added portionwise while stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour (until a clear solution was formed). After the specified time, a solution of (2E)-4,4,4-trifluoro-A-methoxy-7V- methylbut-2-enamide (0.89 g, 4.86 mmol, 1.0 eq.) in anhydrous DMSO (20 mL) was added dropwise. After addition, the reaction mixture was stirred at 50 °C overnight. After the complete conversion of the starting material (monitored by NMR measurements), the reaction mixture was quenched with a mixture of cold water and ice (50 mL), then extracted with diethyl ether (3x 100 mL). The combined organic layers were dried over Na2SO4 and carefully evaporated (due to the assumed a high volatility of the compound) to afford the title compound as a slightly yellow oil (0.70 g, 66%). The title compound was used as a crude in the next step without additional purification.

[0604] 2-(T dfluoromethyl)cyclopropane-l -carboxylic acid

[0605] According to Scheme 8’ Hydolysis step 3: A-Methoxy-A-methyl-2-

[0606] (trifluoromethyl)cyclopropane-l -carboxamide (0.70 g, 3.19 mmol, 1.0. eq.) was placed in a flask with a magnetic stirring bar and potassium Zc / V-butoxide (1.0 M in THF, 16 mL, 15.97 mmol, 5.0 eq.) was added. Then, water (0.1 mL) was added and the obtained suspension was stirred at room temperature overnight. After the specified time, the reaction mixture was quenched by addition of ice and cold water (until it became a homogeneous mixture) and acidified with aq. 1 M HC1 to pH = 4. Next, the aqueous layer was extracted with ethyl acetate (3x 15 mL) and the combined organic layers were dried over Na2SO4, then carefully evaporated (due to the assumed volatility of the compound) to afford the title compound as an orange oil (0.63 g, 90%, 70% purity).

[0607] To afford the Final compound (1-49) the synthesis was continued according to Scheme 6 Route B (Steps 4-6), then Scheme 1.

[0608] EXAMPLE 10: 5-[2-( l-Ethyl-5-{3-methyl-[ 1,2,4 Jtriazolo [4,3-6]py ridazin-6-yl}-l H- pyrazol-3-yl)cyclopropyl]-l,3-thiazole (Final compound 1-13)

[0609] Ethyl 2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropane-l -carboxylate

[0610] (trans-rac) was synthesized according to the literature: Adv. Synth. Catal. 10.1002 / adsc.201900879. In a two-neck round-bottom flask with a magnetic stir bar, vinylboronic acid pinacol ester (2.00 g, 12.98 mmol, 1.0 eq.) was dissolved in anhydrous DCM (52 mL). The resulting solution was degassed and purged with Ar, then palladium(II) acetate (58 mg, 0.25 mmol, 0.02 eq.) was added. Next, a solution of ethyl diazoacetate (3.4 mL, 32.46 mmol, 2.5 eq.) in anhydrous DCM (10 mL) was prepared in other a round-bottom flask and carefully added to a mixture of vinylboronic acid pinacol ester at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 hour, then filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated in vacuum to afford the title compound as a slightly yellow oil (3.50 g, 60% purity, 67%). The title compound was used as a crude in the next step without additional purification.

[0611] Ethyl 2-( I -ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-lH-pyrazol-3- yl)cyclopropane-l -carboxylate

[0612] According to Scheme 9’ Step 1 : In a sealed tube equipped with a magnetic stirring bar, ethyl 2-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)cyclopropane-l -carboxylate (2.93 g, 7.32 mmol, 2.0 eq.) and 3-bromo-l-ethyl-5-{3-methyl-[l,2,4]triazolo[4,3- Z>]pyridazin-6-yl}-17 / -pyrazole (1.50 g, 3.66 mmol, 1.0 eq.) were dissolved in dioxane (53 mL) and water (8 mL) followed by addition of potassium phosphate tribasic (2.33 g, 10.98 mmol, 3.0 eq.). The resulting mixture was degassed and purged with Ar, then XPhos Pd G3 (310 mg, 0.36 mmol, 0.1 eq.) with cataCXium A (131 mg, 0.36 mmol, 0.1 eq.) were added. The reaction mixture was stirred at 100 °C for 3 hours, then cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated. The crude product was purified on column chromatography using puriFlash® RP-AQ, 15 pM, 120 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 beige solid (210 mg, 17%).

[0613] 2-( I -Ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-lH-pyrazol-3- yl)cyclopropane-l -carboxylic acid hydrochloride

[0614] According to Scheme 9’ Step 2: Ethyl 2-(l-ethyl-5-{3-methyl-[l,2,4]triazolo[4,3- Z>]pyridazin-6-yl}-17 / -pyrazol-3-yl)cyclopropane-l-carboxylate (210 mg, 0.61 mmol, 1.0 eq.) was suspended in hydrochloric acid (3.7-4.3 N in dioxane, 1.3 mL, 8.0 eq.) in a flask with a magnetic stirring bar. The obtained a clear solution was stirred at 60 °C overnight. After that time, the reaction mixture was cooled to room temperature and the precipitated solid was filtered, rinsed with hexane, and dried on rotary evaporator to afford the title compound as a white solid (188 mg, 90%). The title compound was used as a crude in the next step without additional purification.

[0615] 1.3-Dioxo-2, 3-dihydro-l H-isoindol-2-yl-2-( 1 -ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3- b]pyridazin-6-yl}-lH-pyrazol-3-yl)cyclopropane-l-carboxylate

[0616] According to Scheme 9’ Step 3: To a suspension of 2-(l-ethyl-5-{3-methyl- [1, 2, 4]triazolo[4,3-Z>]pyridazin-6-yl}-lJ / -pyrazol-3-yl)cyclopropane-l -carboxylic acid hydrochloride (188 mg, 0.54 mmol, 1.0 eq.) in anhydrous DCM (4 mL) triethylamine (0.16 mL, 1.14 mmol, 2.0 eq.) was added. The resulting mixture was stirred at room temperature for 5 min (to create a clear solution). Next, 4-dimethylaminopyridine (7 mg, 0.06 mmol, 0.1 eq.) was added followed by A,A'-dicyclohexyl-carbodiimide (129 mg, 0.62 mmol, 1.1 eq.) and the obtained solution was stirred for additional 5 min. After the specified time, A-hydroxyphthalimide (102 mg, 0.62 mmol, 1.1 eq.) was added and the reaction mixture was stirred at room temperature overnight. After the complete conversion of A-hydroxyphthalimide, the white precipitate of urea was filtered off and the solution was concentrated. The crude product was adsorbed on Celite® Hyflo Supercel (used as a pre-column for purification), then purified by column chromatography on silica gel eluting with acetone in hexane (0-90%) to afford the title compound as a beige solid (170 mg, 58%). l-Ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-3-[2-( 4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxa-borolan-2-yl) cyclopropyl -lH-pyrazole

[0617] According to Scheme 9’ Step 4: To a seal tube equipped with a magnetic stirring bar,

[0618] 1.3-dioxo-2,3-dihydro-lJ / -isoindol-2-yl-2-(l-ethyl-5-{3-methyl-[l,2,4]triazolo[4,3- Z>]pyridazin-6-yl}-17 / -pyrazol-3-yl)cyclopropane-l-carboxylate (170 mg, 0.33 mmol, 1.0 eq.) was added followed by bis(pinacolato)diboron (169 mg, 0.66 mmol, 2.0 eq.) and dissolved in anhydrous ethyl acetate (3 mL). The resulting mixture was degassed and purged with Ar, then methyl isonicotinate (23 mg, 0.16 mmol, 0.5 eq.) was added as a solution in anhydrous ethyl acetate (0.5 mL). The reaction mixture was stirred at 80 °C for 1 hour. After that time, the mixture was cooled to room temperature and evaporated to dryness. The crude product was adsorbed on Celite® Hyflo Supercel (used as a precolumn for purification), then purified by column chromatography using Biotage® Sfar KP-Amino D - Duo 50 pm, 25 g column (acetone in hexane, 0-10% as eluent) to afford the title compound as a slightly yellow oil (90 mg, 50% purity, 34%).

[0619] 5-[ 2-(l -Ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl}-lH-pyrazol-3- yl) cyclopropyl -l, 3-thiazole

[0620] According to Scheme 9’ Step 5: A solution of l-ethyl-5-{3-methyl-[l,2,4]triazolo[4,3- Z>]pyridazin-6-yl}-3-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]-UT- pyrazole (90 mg, 0.24 mmol, 50% purity, 1.0 eq.), 5-bromo-l, 3-thiazole (40 mg, 0.24 mmol, 1.0 eq.), potassium phosphate tribasic (155 mg, 0.73 mmol, 3.0 eq.) in the mixture of dioxane (1.4 mL) with water (0.2 mL) was degassed and purged with Ar. Then, XPhos Pd G3 (21 mg, 0.02 mmol, 0.1 equiv.) followed by cataCXium A (9 mg, 0.02 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 100 °C for 2 hours. After the specified time, the reaction mixture was evaporated to dryness and purified by preparative HPLC (under basic conditions) to afford the title compound as a brown solid (7 mg, 8%).

[0621] EXAMPLE 11:

[0622] 2-methyl-5-(2-(l-methyl-5-(3-methyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-lH- pyrazol-3-yl)cyclopropyl)thiazole (Final compound 1-216)

[0623]

[0624] Scheme 7 Route A’ - Scheme 1

[0625] (E)-2-methyl-5-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)thiazole

[0626] According to Scheme 7 Route A’ Step 1 : Under Ar atmosphere, an oven-dried 2-dram vial with a magnetic stir bar was charged with 2,2,6,6-tetramethylpiperidine (3.2 g, 22.63 mmol) and dry THF (50 mL) and n-butyllithium (1.45 g, 22.63 mmol, 9.06 ml) was added dropwise at -20 °C and stirred for 30 min. Then a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-l,3,2- dioxaborolan-2-yl)methyl]-l,3,2-dioxaborolane (6.07 g, 31.86 mmol) in THF (30 mL) was added at -30 °C. The reaction vial was allowed to stir for 15 minutes at 0°C. Then the reaction vial was cooled to -78 °C, and a solution of2-methylthiazole-5-carbaldehyde (3.0 g, 18.86 mmol) in THF (30 mL) was added. The reaction vial was allowed to stir at -78 °C for an additional 4 hours. Upon completion, the under reduced reaction mixture was concentrated. The (E)-2- methyl-5-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)thiazole was isolated by SiCL chromatography (Hexane -EtO Ac).

[0627] 2-methyl-5-(2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropyl) thiazole

[0628] According to Scheme 7 Route A’ Step 2: A Diazomethane (886.2 mg, 21.09 mmol) 0.5M solution in MTBE was added at -50 °C to the solution of 2-[(lE)-2-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan -2 -yl)ethenyl]- 1,3 -thiazole (1.06 g, 4.22 mmol) and (acetyloxy)palladio acetate (28.33 mg, 126.53 pmol) in THF (100 ml). The r.m. was stirred at -30 °C for 30 min, heated to r.t. and filtered. The solvent was evaporated to obtain crude vSic2-methyl-5-(2-(4.4.5.5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)thiazole (201.0 mg, 90.0% purity, 716 pmol, 18.8% yield) which was purified by FCC (SiCE, Hexane-EtOAc) to afford the final compound (1-216)

[0629] The compound 1-216 was submitted to chiral purification according to the conditions described in the Table 24 to give 2-methyl-5-((l S,2S)-2-(l-methyl-5-(3-methyl- [l,2,4]triazolo[4,3-b]pyridazin-6-yl)-lH-pyrazol-3-yl)cyclopropyl)thiazole (Final compound 1-239) and 2-methyl-5-((lR,2R)-2-(l-methyl-5-(3-methyl- [l,2,4]triazolo[4,3-b]pyridazin-6-yl)-lH-pyrazol-3-yl)cyclopropyl)thiazole (Final compound 1-240).

[0630] EXAMPLE 12: 6-(3-(2-(l-(Difluoromethyl)-lH-pyrazol-4-yl)cyclopropyl)-l- methyl-lH-pyrazol-5-yl)-3-methyl-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1-62)

[0631] Scheme 7 Route C’ - Scheme 1

[0632] (E)-3-(l -(difluoromethyl)- lH-pyrazol-4-yl)acrylic acid

[0633] According to Scheme 7 Route C’ Step 1: To the solution of 5.0 g 1 -(difluoromethyl)- 1H- pyrazole-4-carbaldehyde (0.034 mol) in 225 cm3pyridine, 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). (E)-3-(l-(difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylacrylamide

[0634] According to Scheme 7 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 cm3NEts (0.01 mol) were added. The resulting mixture was stirred at rt overnight. The organic layer was washed with water (2x50 cm3), 50 cm310 % 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).

[0635] 2-(l-(difluoromethyl)-lH-pyrazol-4-yl)-N-methoxy-N-methylcyclopropane-l- carboxamide

[0636] According to Scheme 7 Route C’ Step 3: Trimethyl-sulfonium 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).

[0637] 2-( 1 -(Difluoromethyl)-lH-pyrazol-4-yl)cyclopropane-l -carboxylic acid

[0638] According to Scheme 7 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). To afford the final compound (1-62) the synthesis was continued according to Scheme 6 Route B (Step 4-5) then Scheme 1.

[0639] EXAMPLE 13: 6-(3-(2-(5-Fluoropyridin-3-yl)cyclopropyl)-l-methyl-lH-pyrazol-5- yl)-3-methyl-7,8-dihydro-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1-97)

[0640] Scheme 17

[0641] 3-Fluoro-5-[ 2-(l -methyl-5-3-methyl- 7H, 8H-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl-lH- pyrazol-3-yl)cyclopropyl]pyridine

[0642] According to Scheme 17 Step 1: To the solution of 3-fluoro-5-[2-(l-methyl-5-3-methyl- [l,2,4]triazolo[4,3-b]pyridazin-6-yl-lH-pyrazol-3-yl)cyclopropyl]pyridine Final cpd (1-60) (32.02 mg, 91.7 pmol) in AcOH (1 ml) was added zinc (59.94 mg, 937.6 pmol). The resulting mixture was stirred for 12 h at 20° C. Then, the solid was filtered off, solvent was evaporated and purified by HPLC (10-10-35% 0-1-6 min H2O / MeCN / 0.1%NH4OH, flow: 30 mL / min (loading pump 4 mL / min acetonitrile); column: XBridge BEH C18 5 um 130 A) to obtain pure 3-fhioro-5-[2-(l-methyl-5-3- methyl-7H,8H-[l,2,4]triazolo[4,3-b]pyridazin-6-yl-lH-pyrazol-3- yl)cyclopropyl]pyridine (20 mg, 35% yield) as white solid.

[0643] LCMS(ESI): [M+H]+m / z: calcd 352.2; found 352.2; Rt = 1.093 min.

[0644] EXAMPLE 14: rac-\-(2-Methoxyethyl)-4-|( / / 2 / ?)-2-(l-methyl-5-3-methyl-

[0645] [l,2,4]triazolo[4,3-b]pyridazin-6-yl-7Z / -pyrazol-3-yl)cyclopropyl]pyridin-2-amine (Final compound 1-186)

[0646] Scheme 6 Route A’ (steps 1-2) - Scheme 1

[0647] 2-fluoro-4-[ (lE)-2-(4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)ethenyl Jpyridine

[0648] According to Scheme 6 Route A’ Step 1 : A solution of 4-bromo-2-fluoropyridine (5.0 g, 28.58 mmol), 2-ethenyl-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (5.29 g, 34.3 mmol), tetrafluoroboranuide; tri-tert-butylphosphanium (829.38 mg, 2.86 mmol), tris(l,5- diphenylpenta-l,4-dien-3-one) dipalladium (1.31 g, 1.43 mmol) in toluene (210.49 g, 2.29 mol, 242.78 ml, 80.0 equiv) was degassed and purged with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was evaporated under vacuum, diluted with H2O (100 ml) and extracted with EtOAc (2*50 ml). The organic layer was washed with brine, and filtered through Na2SO4. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give 2-fluoro-4-[(lE)-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)ethenyl]pyridine (3.7 g, 95.0% purity, 49.4% yield).

[0649] 2-fluoro-4-[2-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)cyclopropyl pyridine

[0650] According to Scheme 6 Route A’ Step 2: 2-Fluoro-4-[(lE)-2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)ethenyl]pyridine (3.7 g, 14.85 mmol) was dissolved in THF solution of diazomethane and stirred at r.t. for 24 h. After reaction was completed reaction mixture was evaporated to give crude 2-fluoro-4-[2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)cyclopropyl]pyridine (3.7 g, 95.0% purity, 89.9% yield) which was used without any further purification.

[0651] N-( 2-Methoxyethyl)-4-[ 2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) cyclopropyl ]pyridin-2 -amine

[0652] According to Scheme 6 Route A’ Step 3: 2-Fluoro-4-[2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)cyclopropyl]pyridine (700.0 mg, 2.66 mmol) and 2-methoxyethan-l- amine (2.0 g, 26.62 mmol) were mixed in 15 ml of dioxane and were stirred in autoclave at 130 °C. After reaction was completed reaction mixture was evaporated under vacuum and product was purificated by HPLC to give N-(2-methoxyethyl)-4-[2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]pyridin-2-amine (158.0 mg, 95.0% purity, 17.7% yield).

[0653] To afford the final compound (1-186) the synthesis was continued according to Scheme 1 described in Example 1.

[0654] Scheme 18

[0655] EXAMPLE 15: l-Ethyl-5-{3-methyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl}-3-[2- 15 / / .6 / / .7 / / -pyrrolo|3.4-b|pyridine-6-c:irbonylJcyclopropyl|-l / / -pyr:izole (Final compound 1-79) l-Ethyl-5-{3-methyl-[ 1, 2, 4 ]triazolo[4, 3-b ]pyridazin-6-yl}-3-[2-{5H, 6H, 7H- pyrrolo[ 3, 4-b ]pyridine-6-carbonyl}cyclopropyl ]-lH-pyrazole

[0656] According to Scheme 18 Step 1 : In a round-bottom flask with a magnetic stir bar, 2-(l- ethyl-5-{3-methyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl}-lH-pyrazol-3-yl)cyclopropane- 1-carboxylic acid hydro-chloride gl4 (Example 10) (0.055 g, 0.158 mmol, 1.0 eq) was dissolved in anhydrous DMF (2 mL). Next, triethylamine (0.111 ml, 0.792 mmol, 5.0 eq) was added. The mixture was cooled in ice bath then, HATU (0.09 g, 0.238 mmol, 1.5 eq) was added. The mixture was stirred for 10 minutes at room temperature and 6,7-dihydro- 5H-pyrrolo[3,4-b]pyridine (0.095 g, 0.792 mmol, 5.0 eq) was added. The mixture was allowed to warm to RT while overnight stirring. After that time the reaction mixture was evaporated and was purified by preparative HPLC (under acidic conditions) to afford the title compound as a light brown solid (10 mg, 14%).

[0657] UPLC-MS: RT = 2.64 min; MS m / z ES+= 415 [M+H]+; 'HNMR (300 MHz, DMSO-d6) 5 8.52 - 8.47 (m, 1H), 8.42 (d, J = 9.7 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.69 (dd, J = 9.8, 1.2 Hz, 1H), 7.35 (dd, J = 7.7, 5.0 Hz, 1H), 7.08 (s, 1H), 5.05 (p, J = 14.8 Hz, 2H), 4.70 (d, J = 17.6 Hz, 2H), 4.56 (q, J = 7.2 Hz, 2H), 3.87 (d, J = 1.7 Hz, 1H), 2.75 (s, 3H), 2.44 - 2.38 (m, 1H), 2.31 - 2.23 (m, 1H), 1.44 (d, J = 7.0 Hz, 3H), 1.38 (d, J = 6.6 Hz, 1H).

[0658] Scheme 19

[0659] EXAMPLE 16: 5-[2-(5-{3,8-Dimethyl-[l,2,4]triazolo[4,3-6]pyridazin-6-yl}-l- methyl-lH-pyrazol-3-yl)cyclopropyl]-l,2-dihydropyridin-2-one (Final compound 1-127)

[0660] According to Scheme 19 Step 1 : 2-Chloro-5-[2-(5-{3,8-dimethyl-[l,2,4]triazolo[4,3- Z>]pyridazin-6-yl}-l -methyl- 17 / -pyrazol-3-yl)cyclopropyl]pyri dine (70 mg, 0.17 mmol, 1.0 eq.) prepared according to Example 2 following Scheme 6B, was dissolved in acetic acid (1.4 mL) and sodium acetate (29 mg, 0.35 mmol, 2.0 eq.) was added. The resulting mixture was stirred at 120 °C for 48 hours, then continued at 150 °C for additional 24 hours. After the specified time, the solvent was evaporated and the crude was purified by preparative HPLC (under acidic conditions) to afford the title compound as a white solid (20 mg, 31%).

[0661] UPLC-MS: RT = 2.14 min; MS m / z ES+= 362 [M+H]+; 'H NMR (300 MHz, Methanol-^) 5 7.57 (d, J= 1.3 Hz, 1H), 7.54 (dd, J= 9.4, 2.7 Hz, 1H), 7.34 (d, J= 2.6 Hz, 1H), 6.88 (s, 1H), 6.63 - 6.53 (m, 1H), 4.24 (s, 3H), 2.84 (s, 3H), 2.73 (d, J = 1.3 Hz, 3H), 2.25 - 2.10 (m, 2H), 1.50 - 1.42 (m, 1H), 1.43 - 1.31 (m, 1H).

[0662] Scheme 20

[0663] EXAMPLE 17: 2-[2-( l-Ethyl-5-{3-methyl-[ 1,2,4 Jtriazolo [4,3-6]py ridazin-6-yl}-l H- pyrazol-3-yl)cyclopropyl]pyrimidine (Final compound 1-107)

[0664] 2-Ethenylpyrimidine

[0665] According to Scheme 20 Step 1 : A solution of 2-chloropyrimidine (2.00 g, 17.46 mmol, 1.0 eq.), cesium carbonate (14.22 g, 43.65 mmol, 2.5 eq.), potassium vinyltrifluoroborate (2.57 g, 19.20 mmol, 1.1 eq.) in THF (60 mL) and water (6 mL) was degassed and purged with Ar. Next, bis(triphenylphosphine)palladium(II) dichloride (1.22 g, 1.74 mmol, 0.1 eq.) was added and the resulting mixture was stirred at 90 °C overnight. After that time, the reaction mixture was cooled to room temperature, filtered through a pad of Celite® Hyflo Supercel, rinsed with DCM and evaporated. The crude was purified using FCC (silica gel) eluting with DCM to afford the title compound as a yellow oil (0.88 g, 47%). Due to the assumed volatility of the compound, product was carefully evaporated after purification and used in the next step as a solution in DCM.

[0666] To afford the Final compound (1-107) the synthesis was continued according to Scheme 6 Route C such as Example 7 (Step 2-5), then Scheme 1.

[0667] EXAMPLE 18: 5-[2-[5-(3,7-dimethylpyrazolo[l,5-a]pyrimidin-5-yl)-l-methyl- pyrazol-3-yl]cyclopropyl]-3-methyl-l,2,4-thiadiazole (Final compound 2-51)

[0668] 2-(5-3, 7-dimethylpyrazolo[ 1, 5-a]pyrimidin-5-yl-l-methyl-lH-pyrazol-3- yl)cyclopropane-l-carbonitrile

[0669] According to Scheme 33 Step 1 : A solution of 3-bromo-5-3,7- dimethylpyrazolo[l,5-a]pyrimidin-5-yl-l-methyl-lH-pyrazole (Core 27) 200.0 mg, 653.25 pmol), 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropane-l- carbonitrile (252.6 mg, 1.31 mmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T- biphenyl]-2-yl]phosphane; 2'-amino-[l, l'-biphenyl]-2-ylpalladio methanesulfonate (55.28 mg, 65.4 pmol), tripotassium phosphate (415.63 mg, 1.96 mmol) and bis(adamantan-l-yl)(butyl)phosphane (23.43 mg, 65.4 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 2-(5-3,7-dimethylpyrazolo[l,5-a]pyrimidin-5-yl-l-methyl-lH- pyrazol-3-yl)cyclopropane-l -carbonitrile (130.0 mg, 444.69 pmol, 68.1% yield). LCMS: 293.2 [M+H]+ 2-(5-3, 7-dimethylpyrazolo[ 1, 5-a lpyrimidin-5-yl- 1 -methyl- lH-pyrazol-3- yl)cyclopropane-l-carbothioamide

[0670] According to Scheme 33 Step 2: To the solution of 2-(5-3,7-dimethylpyrazolo[l,5- a]pyrimidin-5-yl-l-methyl-lH-pyrazol-3-yl)cyclopropane-l -carbonitrile (130.51 mg, 446.43 pmol) in dry pyridine (5 ml) was added JtS Py (5 ml) and r.m. was stirred in the capped flask at 60°C for a night. The solvent was evaporated under reduced pressure and crude was purified by HPLC to obtain 2-(5-3,7-dimethylpyrazolo[l,5-a]pyrimidin-5-yl- l-methyl-lH-pyrazol-3-yl)cyclopropane-l-carbothioamide (91.0 mg, 278.78 pmol, 67.4% yield). LCMS: 327.2 [M+H]+

[0671] (E)-N-( 1 -(dimethylamino)ethylidene)-2-(5-(3, 7-dimethylpyrazolo[ 1, 5-a]pyrimidin-5- yl)-l-methyl-lH-pyrazol-3-yl)cyclopropane-l -carbothioamide

[0672] According to Scheme 33 Step 3: A solution of rac-(lR,2R)-2-(5-3,7- dimethylpyrazolof 1 , 5-a]pyrimidin-5-yl- 1 -methyl- lH-pyrazol-3 -yl)cyclopropane- 1 - carbothioamide (91.38 mg, 279.94 pmol) in CH2CI2 (5 mL) was treated with (1,1- dimethoxyethyl)dimethylamine (89.28 mg, 670.71 pmol, 100.0 pl, 2.4 equiv) for 16 h. The mixture was evaporated under reduced pressure and used in the next step without further purification. LCMS: 396.2 [M+H]+

[0673] 5-[ 2-[5-(3, 7-dimethylpyrazolo[ 1, 5-a ]pyrimidin-5-yl)-l-methyl-pyrazol-3- yl]cyclopropyl]-3-methyl-l,2,4-thiadiazole (Final compound 2-51)

[0674] According to Scheme 33 Step 4: A solution of (E)-N-(l-(dimethylamino)ethylidene)-2- (5-(3,7-dimethylpyrazolo[l,5-a]pyrimidin-5-yl)-l -methyl- lH-pyrazol-3- yl)cyclopropane-l -carbothioamide (100.33 mg, 253.66 pmol) in EtOH (5 mL) was treated with pyridine (40.1 mg, 507.3 pmol, 40.0 pl, 2.0 equiv) and (aminooxy)sulfonic acid (34.39 mg, 304.39 pmol) in MeOH (2 mL) for 2 h. The solvent was evaporated and the residue was purified by HPLC.

[0675] UPLC-MS: RT = 3.83 min; MS m / z ES+= 366.0 [M+H]+; 'HNMR (500 MHz, dmso) 5 8.10 (s, 1H), 7.39 - 7.10 (m, 1H), 6.93 (d, J = 1.6 Hz, 1H), 4.22 (d, J = 1.6 Hz, 3H), 3.02 - 2.96 (m, 1H), 2.71 (d, J = 1.0 Hz, 3H), 2.62 (ddd, J = 8.8, 6.4, 4.2 Hz, 1H), 2.51 (d, J = 1.6 Hz, 3H), 2.31 (s, 3H), 1.80 - 1.70 (m, 2H).

[0676] Scheme 34 (from step 2 Scheme 6 Route A’ (steps l-2)-Schemel as in Example 14)

[0677] EXAMPLE 19: 2-((5-((lR,2R)-2-(5-(3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin- 6-yl)-l-methyl-lH-pyrazol-3-yl)cyclopropyl)pyridin-2-yl)amino)cyclopentan-l-ol (Final compound 1-242) rac-( 1R, 2R)-2-[ (5-bromopyridin-2-yl)amino ] cyclopentan- l-ol

[0678] According to Scheme 34 Step 1 : 5-Bromo-2-fluoropyridine (1.0 g, 5.72 mmol) and rac- (lR,2R)-2-aminocyclopentan-l-ol (2.89 g, 28.57 mmol) were mixed in 50 ml of dioxane and were stirred in autoclave at 130 °C. After reaction was completed reaction mixture was evaporated under vacuum and product was purified by FC to rac-(lR,2R)-2-[(5- bromopyridin-2-yl)amino]cy cl opentan- l-ol (1.1 g, 98.0% purity, 4.19 mmol, 80.9% yield). rac-( 1R, 2R)-2-(5-[ ( lE)-2-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)ethenyl]pyridin-2-ylamino)cyclopentan-l-ol

[0679] According to Scheme 34 Step 2: a solution of rac-(lR,2R)-2-[(5-bromopyridin-2- yl)amino]cyclopentan-l-ol (2.0 g, 7.81 mmol), 2-ethenyl-4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolane (1.44 g, 9.37 mmol, 1.59 ml, 1.2 equiv), tris(l,5-diphenylpenta-l,4-dien- 3-one) dipalladium (357.04 mg, 390.58 pmol); ethylbis(propan-2-yl)amine (2.52 g, 19.53 mmol), toluene (50.34 g, 546.82 mmol) in tetrafluoroboranuide; tri-tert- butylphosphanium (226.69 mg, 781.17 pmol) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was evaporated under vacuum, diluted with H2O (100 ml) and extracted with EtOAc (2*50 ml). The organic layer was washed with brine, and filtered through Na2SO4. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give rac-(lR,2R)-2-(5-[(lE)-2- (4, 4, 5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)ethenyl]pyridin-2-ylamino)cyclopentan-l- ol (2.0 g, 95.0% purity, 5.75 mmol, 79.4% yield). rac-( 1R, 2R)-2-(5-[2-(4, 4, 5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropyl]pyridin- 2 -ylamino) cyclopentan- l-ol

[0680] According to Scheme 34 Step 3: a diazomethane (5.09 g, 121.16 mmol) was added at - 50 °C to the solution rac-(lR,2R)-2-(5-[(lE)-2-(4, 4, 5,5-tetramethyl-l, 3, 2-dioxaborolan- 2 -yl)ethenyl]pyridin-2-ylamino)cy cl opentan- l-ol (2.0 g, 6.06 mmol) and palladium(2+) diacetate (54.26 mg, 242.32 pmol) in THF (100 ml). The r.m. was stirred at -30 °C for 30 min, heated to r.t. and filtered. The solvent was evaporated to obtain crude rac- (lR,2R)-2-(5-[2-(4, 4, 5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropyl]pyridin-2- ylamino)cy cl opentan- l-ol (1.5 g, 77.0% purity, 3.36 mmol, 59.5% yield) which was purified by FC (SiCL, Hexane-EtOAc). rac-( 1R, 2R)-2-((5-( ( 1R, 2R)-2-(5-(3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl)-l- methyl-lH-pyrazol-3-yl)cyclopropyl)pyridin-2-yl)amino)cyclopentan-l-ol

[0681] According to Scheme 34 Step 4: A solution of rac-(lR,2R)-2-(5-[2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclopropyl]pyridin-2-ylamino)cyclopentan-l-ol (5) (202.59 mg, 588.48 pmol), 3-bromo-5-3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl-l- methyl-lH-pyrazole (150.0 mg, 490.16 pmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)- [1,1 '-biphenyl]-2-yl]phosphane; 2'-amino-[ 1 , 1 '-biphenyl]-2-ylpalladio methanesulfonate (41.45 mg, 49.04 pmol), tripotassium phosphate (311.67 mg, 1.47 mmol) and bis(adamantan-l-yl)(butyl)phosphane (17.57 mg, 49.04 pmol) in dioxane (4 mL) and water (1 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 which was purified by

[0682] HPLC to rac-(lR,2R)-2-((5-((lR,2R)-2-(5-(3,8-dimethyl-[l,2,4]triazolo[4,3- b]pyridazin-6-yl)-l-methyl-lH-pyrazol-3-yl)cyclopropyl)pyridin-2- yl)amino)cyclopentan-l-ol (final compound 1-242) (4.7 mg, 10.57 pmol, 2.2% yield).

[0683] Scheme 35 -Scheme7 RouteA’ - Scheme 1 EXAMPLE 20: 2-[2-[5-(3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-l- methyl-pyrazol-3-yl]cyclopropyl]-5-methoxy-l,3,4-thiadiazole (Final compound 1- 231)

[0684] [ (methoxymethane thioyl) amino ] amine According to Scheme 35 Step 1 : to potassium [methyl hydroxy(carbonothioyl)]sulfanide (20.5 g, 140.48 mmol) in a round-bottom flask was added water (13.67 g, 758.83 mmol, 13.67 ml, 5.40151 equiv). The flask was cooled to 0 °C in an ice bath, and hydrazine hydrate (6.97 g, 139.27 mmol, 6.97 ml, 0.9913474 equiv) was then added dropwise to the reaction mixture. The mixture was warmed back to 20 °C and stirred upon completion of the addition. Solids precipitated within 15 min of stirring. The resulting slurry was allowed to continue to stir for 2 h at rt and then cooled to 0 °C. The pH of the heterogeneous solution was adjusted to 7 using AcOH (dropwise addition), and then the solids were isolated by filtration. The light yellow solid was dried under reduced pressure for 24 h to afford [(methoxymethanethioyl)amino]amine (10.0 g, 94.21 mmol, 67.1% yield). ethyl 5-methoxy-l, 3, 4-thiadiazole-2-carboxylate

[0685] According to Scheme 35 Step 2: to a solution of [(methoxymethanethioyl)amino]amine (9.1 g, 85.83 mmol) in 1,4-dioxane (66.56 g, 755.94 mmol, 64.37 ml, 8.8072209 equiv) at 5 °C ethyl 2-chloro-2-oxoacetate (3) (12.26 g, 90.12 mmol, 10.03 ml, 1.05 equiv) was added dropwise and stirred at 75 °C for 30 min. Then solution was evaporated in vacuo. The residue was added to a sulfuric acid (109.95 g, 1.12 mol, 60.08 ml, 13.0757338 equiv) at 0..10°C and stirred at the same temperature for 2 h. Then mixture poured into ice and extracted with DCM twice, washed with brine, dried over Na2SO4 and evaporated in vacuo to obtain ethyl 5-methoxy-l, 3, 4- thiadiazole-2-carboxylate (9.0 g, 47.82 mmol, 55.7% yield).

[0686] (5-methoxy-l, 3, 4-thiadiazol-2-yl)methanol

[0687] According to Scheme 35 Step 3: a solution of ethyl 5-methoxy-l, 3,4- thiadiazole-2-carboxylate (13.3 g, 70.74 mmol) in methanol (152.04 g, 4.75 mol, 190.06 ml, 67.1176452 equiv) was cooled to 0°C and then sodium boranuide (8.07 g, 212.2 mmol) was added slowly. The reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixture was quenched with ice and adjusted to slightly acidic pH with acetic acid, extracted with ethyl acetate, the organic layer was washed with brine solution, the organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to obtain (5-methoxy-l,3,4-thiadiazol-2-yl)methanol (6.5 g, 44.47 mmol, 62.9% yield).

[0688] 5-methoxy-l , 3, 4-thiadiazole-2-carbaldehyde According to Scheme 35 Step 4: to a stirred solution of (5-methoxy-l,3,4- thiadiazol-2-yl)methanol (6.8 g, 46.57 mmol) in dichloromethane (360.11 g, 4.29 mol, 271.78 ml, 92.1087345 equiv) , l,l-bis(acetyloxy)-3-oxo-3H-5,2-benziodaoxol-l-yl acetate (23.69 g, 55.88 mmol) was added at 0 °C and the resulting mixture was stirred at rt for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHCCh solution and extracted with DCM. The combined organic layer wasdried over Na2SO4 and concentrated. The resulting crude product was purified by flash chromatography (Hex-MTBE), affording 5 -methoxy- 1,3, 4-thiadiazole-2- carbaldehyde.

[0689] To afford the final compound (1-231) the synthesis was continued according to Scheme7 RouteA’ and Schemel as described in Examples 11 and 1.

[0690] Scheme 36 -Scheme7 RouteA’ - Scheme 1

[0691] EXAMPLE 21: 2-(5-{3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl}-l-methyl- lH-pyrazol-3-yl)cyclopropyl]-5-methoxy-l, 3-thiazole (Final compound 1-235)

[0692] 5-methoxy-l , 3-thiazole

[0693] According to Scheme 36 Step 1 : to the solution of methanol (3.94 g, 122.95 mmol, 4.92 ml, 2.0 equiv) in dry THF (100 ml) was added sodium hydride (4.92 g, 60.0% purity, 122.95 mmol) at 0C and r.m. stirred until gas had been evolved. Then 5-bromo- 1, 3-thiazole (10.01 g, 61.47 mmol) was added and r.m. was heated to reflux for a night. The solid was filtered, solvent was evaporated under reduced pressure to obtain crude 5- methoxy-1, 3-thiazole 90.0% purity 7 g.

[0694] 5-methoxy-l , 3-lhiazole-2-carbaldehyde According to Scheme 36 Step 2: to the solution 5-methoxy-l,3-thiazole (5.56 g, 48.34 mmol) in THF (lOml / g) at -78°C was added n-butyllithium (4.03 g, 62.85 mmol, 25.14 ml, 1.3 equiv). Upon addition colour immediately changed to dark red. Mixture was stirred at -78°C for 45 minutes, then N,N-dimethylformamide (17.66 g, 241.72 mmol) was added dropwise. Mixture was stirred 30 minutes more at -78°C, then 30 minutes at -10°C, quenched with ice-cold 3% aqueous hydrochloric acid and extracted with ethyl acetate (3*50ml). Combined organic layer was washed with brine solution (2*30 ml), dried with anhydrous sodium sulfate (15 g), filtered and evaporated under reduced pressure (15 Torr) to obtain 5.88g of pure (96.63% GCMS) 5 -methoxy- 1,3- thiazole-2-carbaldehyde as brown solid.

[0695] To afford the final compound (1-235) the synthesis was continued according to Scheme7 RouteA’ and Schemel as described in Examples 11 and 1.

[0696] Scheme 37 -Scheme 6 Route B - Schemel

[0697] EXAMPLE 22: rac-4-(2-(5-(3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-l- methyl-lH-pyrazol-3-yl)cyclopropyl)-l-((lR,2R)-2-hydroxycyclohexyl)pyridin- 2(lH)-one (Final compound 1-236) rac-4-bromo-l-[ (1R, 2R)-2-hydroxycyclohexyl ]-l, 2-dihydropyridin-2-one

[0698] According to Scheme 37 Step 1 : a mixture of 4-bromopyridin-2-ol (6.56 g, 37.93 mmol), 7-oxabicyclo[4.1.0]heptane (18.6 g, 189.65 mmol, 19.17 ml, 5.0 equiv) and dipotassium carbonate (21.8 g, 60.0% purity, 94.82 mmol) was heated at 120 °C for 4 h. The reaction mixture was cooled to rt and concentrated to dryness under reduced pressure. The remaining residue was triturated with H2O and EtOAc, precipitate was filtered, washed with H2O and EtOAc and dried on air to affod rac-4-bromo-l-[(lR,2R)- 2-hydroxycyclohexyl]-l,2-dihydropyridin-2-one (6.0 g, 22.05 mmol, 63.8% yield). LCMS: RT 1.02; 274.2 [M+H]+

[0699] To afford the final compound (1-236) the synthesis was continued according to Scheme 6 Route B and Scheme 1 as described in Examples 2 and 1.

[0700] EXAMPLE 23 : rac-5-(2-(5-(3,8-dimethyl- [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl)- 1- methyl-lH-pyrazol-3-yl)cyclopropyl)-N-((lR,2R)-2 hydroxycyclohexyl)picolinamide (Final compound 1-232) methyl 5-[(lE)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)ethenyl ]pyridine-2-carboxylate

[0701] According to Scheme 38 Step 1 : A solution of methyl 5-bromopyridine-2- carboxylate (3.0 g, 13.96 mmol), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.58 g, 16.75 mmol), tetrafluoroboranuide; tri-tert-butylphosphanium (404.98 mg, 1.4 mmol), tris(l,5-diphenylpenta-l,4-dien-3-one) dipalladium (637.85 mg, 697.77 pmol) in toluene (89.93 g, 976.88 mmol, 103.73 ml, 70.0 equiv) was degassed and purget with Ar. The resulting mixture was heated at 100 °C overnight. Then the mixture was evaporated under vacuum, diluted with H2O (100 ml) and extracted with EtOAc (2*50 ml). The organic layer was washed with brine, and filtered through Na2SO4. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give methyl 5-[(lE)- 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethenyl]pyridine-2-carboxylate (2.5 g, 8.65 mmol, 62% yield). LCMS: 290.0 [M+H]+ ; RT = 1.21. methyl 5-[ 2-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2- yl)cyclopropyl]pyridine-2-carboxylate

[0702] According to Scheme 38 Step 2: A diazomethane (7.27 g, 172.91 mmol) was added at -50 °C to the solution methyl 5-[(lE)-2-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)ethenyl]pyridine-2-carboxylate (2.5 g, 8.65 mmol) and palladium(2+) diacetate (77.44 mg, 345.82 pmol) in THF (100 ml). The r.m. was stirred at -30 °C for 30 min, heated to r.t. and filtered. The solvent was evaporated to obtain crude methyl 5- [2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropyl]pyridine-2-carboxylate (2.5 g, 8.25 mmol, 95.4% yield) which was purified by FCC (SiCh, Hexane-EtOAc) to give methyl 5-[2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclopropyl]pyridine-2- carboxylate (2.5 g, 8.25 mmol, 95.4% yield). LCMS: 304.2 [M+H]+ ; RT = 1.38. rac-N-( R, 2R)-2-hydroxycyclohexyl)-5-(2-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)cyclopropyl)picolinamide

[0703] According to Scheme 38 Step 3: methyl 5-[2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)cyclopropyl]pyridine-2-carboxylate (1.13 g, 3.73 mmol) and rac- (lR,2R)-2-aminocyclohexan-l-ol (858.19 mg, 7.46 mmol) were mixed in 15 ml of methanol and were stirred in autoclave at 100 °C. After reaction was completed reaction mixture was evaporated under vacuum and product was purified by HPLC to give rac- N-( (1R, 2R)-2-hydroxycyclohexyl)-5-(2-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2- yl)cyclopropyl)picolinamide (500.0 mg, 1.29 mmol, 39.7% yield). LCMS: 387.2 [M+H]+ ; RT = 1.41. rac-5-(2-(5-(3, 8-dimethyl-[ 1,2, 4 ]triazolo[4, 3-b ]pyridazin-6-yl)- 1 -methyl- 1H- pyrazol-3-yl)cyclopropyl)-N-((lR,2R)-2-hydroxycyclohexyl)picolinamide

[0704] According to Scheme 38 Step 4: a solution of N-[(lRS&,2RS&)-2- hydroxycyclohexyl]-5-[(lRS,2RS)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclopropyl]pyridine-2-carboxamide (390.13 mg, 1.01 mmol), 3-bromo-5-3,8- dimethyl-[l, 2, 4]triazolo[4,3-b]pyridazin-6-yl-l -methyl- IH-pyrazole (237.74 mg,

[0705] 776.87 pmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,l'-biphenyl]-2-yl]phosphane; 2'- amino-[l,l'-biphenyl]-2-ylpalladio methanesulfonate (65.67 mg, 77.69 pmol) and bis(adamantan-l-yl)(butyl)phosphane (27.83 mg, 77.69 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 Na2SO4. The filtrate was concentrated in vacuo to give the crude which was purified by FC to give rac-5-(2-(5-(3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-l- methyl- lH-pyrazol-3-yl)cy cl opropyl)-N-((lR,2R)-2-hydroxycy cl ohexyl)picolinamide

[0706] (Final compound 1-232) (44.9 mg, 92.28 pmol, 11.9% yield). LCMS: 487.2 [M+H]+; RT = 3.30.

[0707]

[0708] Scheme 39 - Scheme 6 A - Scheme 1

[0709] EXAMPLE 24: 6-(3-(2-(3-chloro-l-(methyl-d3)-lH-pyrazol-4-yl)cyclopropyl)-l- methyl-lH-pyrazol-5-yl)-3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazine (Final compound 1-252 and 1-253) l-(methyl-d3)-3-nitro-lH-pyrazole

[0710] According to Scheme 39 Step 1 : sodium hydride (2.23 g, 92.9 mmol) was added portionwise to a solution of 5-nitro-lH-pyrazole (10.0 g, 88.48 mmol) in anhydrous THF (100 mL). The resulting mixture was stirred for 30 min at room temperature, cooled to 0°C, and treated with (d3)methyl methanesulfonate (10.0 g, 88.48 mmol). Then the reaction mixture was stirred overnight at ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered off and concentrated under reduced pressure to obtain l-(methyl-d3)-3- nitro-lH-pyrazole (10.0 g, 90.0% purity, 69.17 mmol, 78.2% yield), that was used in the next step without its further purification. l-(methyl-d3)-lH-pyrazol-3-amine

[0711] According to Scheme 39 Step 2: a mixture of l-(methyl-d3)-3-nitro-lH-pyrazole (10.0 g, 76.85 mmol) and palladium on activated charcoal (813.92 mg, 7.69 mmol) in methanol (100 mL) was stirred at room temperature for 24 hours under a pressure of hydrogen ( 1 atm?). After completion of the reaction obtained mixture was filtered off, the filtrate was evaporated to dryness in vacuo to obtain l-(methyl-d3)-lH-pyrazol-3- amine (8.0 g, 95.0% purity, 75.9 mmol, 98.8% yield) which was used in the next step.

[0712] 3-chloro-l-(methyl-d3)-lH-pyrazole

[0713] According to Scheme 39 Step 3: to a solution of l-(methyl-d3)-lH-pyrazol-3- amine

[0714] (5.0 g, 49.96 mmol) in concentrated HC1 (30 mL) was added a solution of sodium nitrite (3.79 g, 54.95 mmol) in H2O (10.0 mL) over a 10 min period at 0 °C. The reaction solution was stirred for 0.5 hour at 0 °C, and then a solution of copper (I) chloride (4.89 g, 49.96 mmol) in concentrated HC1 (10 mL) was added dropwise. The mixture was stirred at room temperature overnight, and extracted with DCM (80 mL x 3), and the combined organic phase was washed with sat. aq. NaHCCL (50 mLx 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 3-chloro-l- (methyl-d3)-lH-pyrazole (4.0 g, 95.0% purity, 31.78 mmol, 63.6% yield) which was used in the next step.

[0715] 3-chloro-4-iodo-l-(methyl-d3)-lH-pyrazole

[0716] According to Scheme 39 Step 4: 1 -Iodopyrrolidine-2, 5-dione (9.18 g, 40.82 mmol) was dissolved in CH3CN (100 mL) and 3-chloro-l-(methyl-d3)-lH-pyrazole (4.0 g, 33.45 mmol) was added. The reaction mixture was stirred at 80°C for 24 hours. After completion of the reaction obtained mixture was concentrated in vacuo, mixed with water (100 mL) and CHCh (50 mL) and stirred for 15 minutes. Unreacted N-Iodosuccinimide was quenched with Na2S20s sat. aq. solution until a colorless solution was obtained. The organic layer was separated from the aqueous layer. The aqueous layer was washed with CHCh (50 mL x 3). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered off and evaporated under reduced pressure. The residue was purified by FCC (Interchim; 120g + 40g SiCh, CHCh-MTBE % 0-15-100, flow rate = 40 mL / min, column equilibration CHCh. Incoming matter dissolved in CHCh) to obtain pure 3-chloro-4-iodo-l-(methyl-d3)-lH-pyrazole (4.6 g, 100% purity, 18.74 mmol, 56% yield).

[0717] (E)-3-chloro-l-(methyl-d3)-4-( 2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)vinyl)-lH-pyrazole

[0718] According to Scheme 39 Step 5: a mixture of 3-chloro-4-iodo-l-(methyl-d3)-lH- pyrazole (4.3 g, 17.52 mmol) , 2-ethenyl-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (3.24 g, 21.03 mmol) , tetrafluoroboranuide; tri-tert-butylphosphanium (508.55 mg, 1.75 mmol), tris(l,5-diphenylpenta-l,4-dien-3-one) dipalladium (800.97 mg, 876.21 pmol) , and ethylbis(propan-2-yl)amine (4.53 g, 35.05 mmol, 6.1 ml, 2.0 equiv) in toluene (80 mL) was degassed and purged with Ar (3x) at 20 °C. Then the reaction mixture was stirred at 90 °C for 12 hrs under Ar atmosphere. After completion of the reaction obtained mixture was concentrated under reduced pressure to remove solvent. The residue was purified by FCC (Interchim; 120+80g SiCh, Hexane-MTBE% 0-100, flow rate = 80 mL / min, Rv=10-12. Column equilibration Hexane. Incoming mixture dissolved in CHCh) to afford (E)-3-chloro-l-(methyl-d3)-4-(2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)vinyl)-lH-pyrazole (4.0 g, 90.0% purity, 13.26 mmol, 75.6% yield) which was used in the next step.

[0719] 3-chloro-l-(methyl-d3)-4-(2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) cyclopropyl) -IH-pyrazole

[0720] According to Scheme 39 Step 6: diazomethane (3.1 g, 73.65 mmol, 1, 5.0 equiv) 0.5M solution in MTBE was added at -50 °C to the solution (E)-3-chloro-l-(methyl-d3)- 4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazole (4.0 g, 14.73 mmol) and palladium(2+) diacetate (164.93 mg, 736.54 pmol) in THF (100 ml). The reaction mixture was stirred at -30 °C for 30 min, heated to r.t. and filtered off. The solvent was evaporated to obtain crude rel-3-chloro-l-(methyl-d3)-4-(2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)-lH-pyrazole (2.0 g, 7.0 mmol, 47.5% yield) which was purified by FCC (Interchim; 120 g SiCh, petroleum ether / THF from 0-95%, flow rate = 35 mL / min) to give 3-chloro-l-(methyl-d3)-4-(2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)-lH-pyrazole ( 3 g, 95% purity, 9.98 mmol, 68% yield).

[0721] 6-(3-(2-(3-chloro-l-(methyl-d3)-lH-pyrazol-4-yl)cyclopropyl)-l-methyl-lH- pyrazol-5-yl)-3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazine

[0722] According to Scheme 39 Step 6: a solution of 3-bromo-5-3,8-dimethyl-

[0723] [1.2.4]triazolo[4,3-b]pyridazin-6-yl-l-methyl-lH-pyrazole (300.0 mg, 980.32 pmol), 3- chloro-l-(methyl-d3)-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)- IH-pyrazole (559.54 mg, 1.96 mmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T- biphenyl]-2-yl]phosphane; 2'-amino-[l, l'-biphenyl]-2-ylpalladio methanesulfonate (82.81 mg, 97.96 pmol), tripotassium phosphate (622.57 mg, 2.94 mmol) and bis(adamantan-l-yl)(butyl)phosphane (35.1 mg, 97.96 pmol) in dioxane (12 mL) and water (3 ml) was degassed and purged with Ar. The resulting mixture was stirred at 100 °C overnight. After completion of the reaction obtained mixture was cooled to room temperature, diluted with H2O (20 ml) and extracted with EtOAc (2 x 50 ml). Organic layer was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo to give crude product mixture. Isolated crude was purified by prep HPLC (20-20-40% 0- l-5min H2O / ACN, flow: 30ml / min, loading pump 4ml / min ACN), target mass 385.83, column: Chromatorex 18 SMB100-5T 100x19mm 5um) to provide 6-(3-(2-(3-chloro-l- (methyl-d3)-lH-pyrazol-4-yl)cyclopropyl)-l-methyl-lH-pyrazol-5-yl)-3,8-dimethyl-

[0724] [1.2.4]triazolo[4,3-b]pyridazine (96.0 mg, 100% purity, 248.79 pmol, 25.4% yield).

[0725] The racemic mixture was then submitted to chiral chromatography according to the conditions described in Table 24 to afford the final compounds 1-252 and 1.253.

[0726] Scheme 40 - Scheme 6 A - Scheme 1

[0727] EXAMPLE 25: 5-(2-(5-(3,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-l- methyl-lH-pyrazol-3-yl)cyclopropyl)-2-(methyl-d3)thiazole (Final compound 1-256 and 1-257)

[0728] 2-(methyl-d3 ) thiazole

[0729] According to Scheme 40 Step 1 : to a solution of 1,3-thiazole (10.0 g, 117.65 mmol) in THF (100 mL) was added a solution of n-butyllithium (8.29 g, 129.42 mmol, 51.77 ml, 1.1 equiv) dropwise at -78 °C over a period of 10 min under Ar. During that time the temperature was maintained below -60 °C. Then iodomethane-d3 (22.17 g, 152.95 mmol, 9.52 ml, 1.3 equiv) was added at -60 °C and the resulting mixture was allowed to warm up and stir at 0 °C for next 2h. After completion of the reaction obtained mixture was quenched with sat. aq. NH4CI solution (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered off and concentrated under reduced pressure to give a crude mixture of the title compound. Isolated crude was distilled at atmospheric pressure to obtain 2-(methyl-d3)thiazole (6.0 g, 70.0% purity, 41.11 mmol, 34.9% yield) which was used in the next step.

[0730] 5-bromo-2-( methyl-d3 ) thiazole

[0731] According to Scheme 40 Step 2: a solution of 2-(methyl-d3)thiazole (1.7 g, 16.64 mmol) and 1 -bromopyrrolidine-2, 5-dione (3.53 g, 19.97 mmol) in DMF (20 ml) was stirred at room temperature for 8h. After completion of the reaction obtained mixture was quenched with water (20 mL) and extracted with Et2O (3 x 20 mL). Organic layers were combined together, dried over Na2SO4, filtered off and concentrated under reduced pressure to give 5-bromo-2-(methyl-d3)thiazole (1.7 g, 90.0% purity, 8.45 mmol, 50.8% yield) which was used in the next step.

[0732] (E)-2-(methyl-d3)-5-(2-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)vinyl)thiazole

[0733] According to Scheme 40 Step 3 : a mixture of 5-bromo-2-(methyl-d3)thiazole (1.7 g, 9.45 mmol), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.75 g, 11.34 mmol), tetrafluoroboranuide; tri-tert-butylphosphanium (274.24 mg, 945.03 pmol), tris(l,5- diphenylpenta-l,4-dien-3-one) dipalladium (431.94 mg, 472.52 pmol) and ethylbis(propan-2-yl)amine (2.44 g, 18.9 mmol, 3.29 ml, 2.0 equiv) in toluene (40 mL) was degassed and purged with Ar (3x times) at 20 °C. Then the reaction mixture was stirred at 90°C for 12h under Ar atmosphere and concentrated under reduced pressure to remove the solvent. The residue was purified by FCC (Interchim; 40 g SiCh, petroleum ether / THF from 0-95%, flow rate = 27 mL / min) to afford (E)-2-(methyl-d3)-5-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)thiazole (600.0 mg, 100% purity, 2.36 mmol, 25% yield) which was used in the next step.

[0734] 2-(methyl-d3)-5-(2-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)cyclopropyl)thiazole According to Scheme 40 Step 4: diazomethane (495.9 mg, 11.8 mmol) 0.5M solution in MTBE was added at -50°C to the solution of (E)-2-(methyl-d3)-5-(2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)thiazole (600.0 mg, 2.36 mmol) and palladium(2+) diacetate (26.43 mg, 118.01 pmol) in THF (20 ml). The reaction mixture was stirred at -30°C for 30 min and then was allowed to warm up to ambient temperature. The resulting mixture was filtered off and the solvent was evaporated to obtain crude product mixture (0.6 g, 76% by LCMS). Isolated crude was purified by FCC to give 2- (methyl-d3)-5-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)thiazole (200.0 mg, 95.0% purity, 708.43 pmol, 30% yield).

[0735] 5-(2-(5-( 3, 8-dimethyl-[ 1, 2, 4 ]triazolo[ 4, 3-b ]pyridazin-6-yl)-l-methyl-lH- pyrazol-3-yl)cyclopropyl)-2-(methyl-d3)thiazole

[0736] According to Scheme 40 Step 5: a solution of 3-bromo-5-3,8-dimethyl- [l,2,4]triazolo[4,3-b]pyridazin-6-yl-l-methyl-lH-pyrazole (100.0 mg, 326.77 pmol), 2- (methyl-d3)-5-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)thiazole (174.69 mg, 651.34 pmol), dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,T-biphenyl]-2- yl]phosphane; 2'-amino-[l,l'-biphenyl]-2-ylpalladio methanesulfonate (27.53 mg, 32.57 pmol), tripotassium phosphate (206.97 mg, 977.0 pmol) and bis(adamantan-l- yl)(butyl)phosphane (11.67 mg, 32.57 pmol) in dioxane (4 mL) and water (1 ml) was degassed and purged with Ar. The resulting mixture was stirred at 100 °C overnight. Then obtained mixture was cooled to ambient temperature, diluted with H2O (20 ml) and extracted with EtOAc (2 x 50 ml). Organic layers were combined together, washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo to give crude product mixture. Isolated crude was purified by prep HPLC (40-40-75% 0-1-5 min H2O / MeOH / 0.1%NH4OH, flow: 30ml / min, loading pump 4ml / min MeOH, column: XBridge C18 100x19mm, 5um, target mass 369) to provide 5-(2-(5-(3,8-dimethyl- [ 1 ,2,4]triazolo[4,3 -b]pyridazin-6-yl)- 1 -methyl- lH-pyrazol-3 -yl)cy clopropyl)-2- (methyl-d3)thiazole (82.0 mg, 100% purity, 222.54 pmol, 68.3% yield).

[0737] The racemic mixture was then submitted to chiral chromatography according to the conditions described in Table 24 to afford the final compounds 1-256 and 1.257.

[0738] Scheme 41 EXAMPLE 26: 3,7-dimethyl-5-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)oxazolo[4,5-b]pyridin-2(3H)-one (Final compound 6-5)

[0739] 3-methoxy-4-methyl-6-( 1 -methyl-3-(2-( 1 -methyl-lH-pyrazol-4-yl)cyclopropyl)-lH- pyrazol-5-yl)-2 -nitropyridine

[0740] According to Scheme 41 step 1 : A suspension of 6-(3-bromo-l-methyl-lH-pyrazol-5- yl)-3-methoxy-4-methyl-2-nitropyridine (350.0 mg, 1.07 mmol), l-methyl-4-(2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)-lH-pyrazole (265.42 mg, 1.07 mmol), dipotassium carbonate (442.5 mg, 3.21 mmol), bis(adamantan-l- yl)(butyl)phosphane (38.32 mg, 106.95 pmol) and dicyclohexyl[2',4',6'-tris(propan-2- yl)-[ 1 , 1 '-biphenyl]-2-yl]phosphane; 2'-amino-[ 1 , 1 '-biphenyl]-2-ylpalladio methanesulfonate (45.2 mg, 53.48 pmol) in a degassed mixture of dioxane and water (2: 1, 15 ml) was stirred under Ar at 90°C overnight. After completion of the reaction obtained mixture was cooled to room temperature and diluted with EtOAc (50 ml). The organic layer was separated, washed with water (3 x 20 ml) and brine (20 ml), dried over Na2SO4, filtered off and concentrated in vacuo to give crude product mixture. Isolated crude was purified by FCC (Interchim, 80 g SiCh, hexane / EtOAc with EtOAc from 0-100%, flow rate = 60 mL / min, Rv=39-42 cv) to afford 3 -methoxy -4-methyl-6-(l- methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)-2-nitropyridine (0.2 g, 91% purity, 0.543 mmol, 50.76% yield).

[0741] 3-methoxy-4-methyl-6-( 1 -methyl-3-(2-( 1 -methyl-lH-pyrazol-4-yl)cyclopropyl)-lH- pyrazol-5-yl)pyridin-2-amine

[0742] According to Scheme 41 step 2: 3-methoxy-4-methyl-6-(l-methyl-3-(2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)-2-nitropyridine (150.0 mg, 407.18 pmol) was dissolved in methanol (35 mL), then carbon (24.47 mg, 2.04 mmol), iron(3+) trichloride hexahydrate (10.97 mg, 40.78 pmol) and hydrazine hydrate (61.23 mg, 1.22 mmol, 60.0 pl, 3.0 equiv) were added subsequently. The reaction mixture was stirred under reflux for 3 h. After completion of the reaction obtained mixture was filtered off and the filtrate was concentrated in vacuo. Obtained residue was partitioned between EtOAc (75 ml) and water (30 ml). Organic layer was separated, washed with water (3 x 25 ml) and brine (25 ml), dried over Na2SO4, filtered off and concentrated in vacuo to give crude 3-methoxy-4-methyl-6-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)pyridin-2-amine (0.12 g, 88.9% yield). Isolated crude was used in the next step without its further purification.

[0743] 2-amino-4-methyl-6-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH- pyrazol-5-yl)pyridin-3-ol

[0744] According to Scheme 41 step 3: 3-methoxy-4-methyl-6-(l-methyl-3-(2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)pyridin-2-amine (120.0 mg, 354.6 pmol) was dissolved in HBr (48% aqueous solution, 1.42 g, 17.73 mmol, 2.08 ml, 50.0 equiv) and stirred at 110 °C for 5 h. After completion of the reaction obtained solution was neutralized with saturated NaHCCE aqueous solution (20 ml) and extracted with EtOAc (3 x 20 ml). Combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to give 2-amino-4-methyl-6-(l- methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)pyridin-3-ol (0.1 g, 85% purity, 87% yield). Isolated material was used in the next step without its further purification.

[0745] 7-methyl-5-( 1 -methyl-3-(2-( 1 -methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5- yl) oxazolo[ 4, 5-b ]pyridin-2 ( 3H) -one

[0746] According to Scheme 41 step 4: To an ice-cooled solution of 2-amino-4-methyl-6-(l- methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)pyridin-3-ol (100.0 mg, 308.28 pmol) and triethylamine (71.69 mg, 708.95 pmol, 100.0 pl, 2.3 equiv) in CH2Q2 (50 ml) was added dropwise a solution of ditrichloromethyl carbonate (36.22 mg, 123.3 pmol) in DCM (10 ml). The resulting mixture was stirred at room temperature for 2 h, then diluted with DCM (50 ml) and washed with water (50 ml). Organic layer was separated, washed with brine (50 ml), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to give 7-methyl-5-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4- yl)cyclopropyl)-lH-pyrazol-5-yl)oxazolo[4,5-b]pyridin-2(3H)-one (0.1 g, 84% purity, 92.5% yield). Isolated crude was used in the next step without its further purification.

[0747] 3, 7-dimethyl-5-(l-methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5- yl) oxazolo[ 4, 5-b ]pyridin-2 ( 3H) -one

[0748] According to Scheme 41 step 5: A mixture of 7-methyl-5-(l-methyl-3-(2-(l-methyl-lH- pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)oxazolo[4,5-b]pyridin-2(3H)-one (150.0 mg, 428.11 pmol), dipotassium carbonate (88.56 mg, 642.15 pmol) and iodomethane (91.14 mg, 642.15 pmol, 40.0 pl, 1.5 equiv) in DMF (10 ml) was stirred at room temperature for 16 hours. After completion of the reaction obtained mixture was concentrated in vacuo, diluted with water (50 ml) and extracted with EtOAc (3 x 30 ml). Organic layers were combined together, washed with brine (30 ml), dried over Na2SO4, filtered off and evaporated to dryness in vacuo to give crude product mixture. Isolated crude was purified by prep HPLC to afford 3,7-dimethyl-5-(l-methyl-3-(2-(l-methyl- lH-pyrazol-4-yl)cyclopropyl)-lH-pyrazol-5-yl)oxazolo[4,5-b]pyridin-2(3H)-one (75 mg, 100% purity, 206.04 pmol, 48.1% yield) as orange gum.

[0749] LCMS(ESI): [M+H]+m / z: calcd 364.18; found 365.2; Rt = 3.296 min Table 14: Compounds prepared according to the Examples.

[0750] The compounds in table 14 are a racemic mixture of the -trans isomers of the 1,2- disubstituted cyclopropane moiety, unless otherwise specified.

[0751] Table 15: Compounds prepared according to the Examples.

[0752] Table 16: Compounds prepared according to the Examples.

[0753] Table 17: Compounds prepared according to the Examples. Table 18: Compounds prepared according to the Examples.

[0754] Table 19: Compounds prepared according to the Examples.

[0755] Table 20: Compounds prepared according to the Examples.

[0756] Table 21: Compounds prepared according to the Examples.

[0757] Table 22: Compounds prepared according to the Examples.

[0758] Table 22A: Compounds prepared according to the Examples.

[0759] Physico-Chemical Data

[0760] Melting points: a) Melting point determination was performed on a Buchi B-540 apparatus. b) DSC analysis

[0761] 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.

[0762] Preparative HPLC purification:

[0763] Purifications were run on Agilent 1290 Infinity II series preparative HPLC system (1290 Infinity II Binary pump, 1260 Infinity II Diode Array Detector, LC / MSD mass detector), Waters SunFire (Cis, 19 x 100 mm, 5 pm) or Waters XBridge (Cis, 19 x 100 mm, 5 pm) columns using H2O + 0,1 % formic acid or H2O + 0,1 % ammonia (25% ammonia in water) and MeCN as eluents. Gradients used covered the range from 10% MeCN to 100 % MeCN. NMR:

[0764] 'H-NMR spectra were recorded on Bruker DPX 300 MHz equipped with a RT 5 mm BBI probe, Bruker AV400 MHz equipped with a RT 5 mm BBO probe, Bruker DRX 500 MHz equipped with a RT 5 mm SEI and TXI probes, 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, CDCh, pyridine-t / or toluene-t / . 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).

[0765] UPLC-MS / LC-MS:

[0766] (RT means retention time in minutes; [MH]+means the protonated mass of the compound (free base); nd = not determined).

[0767] Apparatus and general conditions (unless other specification):

[0768] Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC -Mass Spectrometer

[0769] Column: cf methods

[0770] HPLC conditions:

[0771] - Wavelength range: (190 -340) nm ± 4 nm

[0772] - Flow: l.O ml / min

[0773] - Column temperature: 25 °C

[0774] - Autosampler temperature: 20 °C

[0775] - Solution for syringe washing: 20% MeOH

[0776] MS conditions:

[0777] - Mass range: 100 -1000 m / z

[0778] - Ionization: alternate

[0779] - Scan speed: 12000 amu / sec

[0780] Method 1

[0781] Column: Gemini -NX 3 pm (4.6x50mm), 110A, column no. OOB-4453-EO

[0782] Reagents:

[0783] - Ammonium Hydroxide solution 28-30%, Sigma-Aldrich

[0784] - Acetonitrile for HPLC UV / gradient grade, Baker

[0785] - pQ-water for LCMS

[0786] - Analysis time: 9 min Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NHs basis)

[0787] Mobile phase D: acetonitrile

[0788] Elution: gradient:

[0789] Method 2

[0790] (Same as method 1)

[0791] Elution: gradient:

[0792] Method 3

[0793] Column:Kinetex®2.6 pm XB-C18 (4.6x50mm), 110A, column no. 00B-4496-E0, Reagents:

[0794] - Formic acid > 98%, Sigma-Aldrich

[0795] - Acetonitrile for HPLC UV / gradient grade, Baker

[0796] - pQ-water for LCMS

[0797] HPLC conditions:

[0798] - Same as method 1 excepted analysis time: 6 min

[0799] Mobile phase A:0.1 % v / v water solution of formic acid

[0800] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0801] - Elution: gradient

[0802] Method 4

[0803] Column: same as method 3

[0804] Reagents:

[0805] - Ammonium Hydroxide solution 28-30%, Sigma-Aldrich

[0806] - Acetonitrile for HPLC UV / gradient grade, Baker

[0807] - pQ-water for LCMS

[0808] HPLC conditions:

[0809] - Analysis time: 7 min

[0810] - Elution: gradient

[0811] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NH3 basis)

[0812] Mobile phase D: acetonitrile

[0813] Method 5

[0814] Column: same as method 3

[0815] Reagents: same as method 3

[0816] HPLC conditions:

[0817] - Analysis time: 7 min

[0818] - Elution: gradient

[0819] Mobile phase A:0.1 % v / v water solution of formic acid

[0820] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0821] Method 6

[0822] Column: same as method 3

[0823] Reagents: same as method 3

[0824] HPLC conditions: same as method 3

[0825] Elution: gradient

[0826] Mobile phase A:0.1 % v / v water solution of formic acid

[0827] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[0828] Method 7

[0829] Column: same as method 3

[0830] Reagents: same as method 3

[0831] HPLC conditions: same as method 3

[0832] Elution: gradient

[0833] Mobile phase A:0.1 % v / v water solution of formic acid

[0834] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[0835] Method 8 Columns: same as method 3

[0836] Reagents: same as method 3

[0837] HPLC conditions: same as method 3

[0838] Elution: gradient

[0839] Mobile phase A:0.1 % v / v water solution of formic acid

[0840] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0841] Method 9

[0842] Columns: same as method 3

[0843] Reagents: same as method 3

[0844] HPLC conditions: same as method 3

[0845] Mobile phase A:0.1 % v / v water solution of formic acid

[0846] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0847] Method 10

[0848] Column: same as method 3

[0849] Reagents: same as method 4

[0850] HPLC conditions: same as method 3

[0851] - Elution: gradient Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NH3basis)

[0852] Mobile phase D: acetonitrile

[0853] Method 11

[0854] Column: Gemini -NX 3 pm (4.6x50mm), 110A, column no. OOB-4453-EO

[0855] Reagents: same as method 1

[0856] HPLC conditions: same as method 1

[0857] Elution: gradient

[0858] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NIL basis)

[0859] Mobile phase D: acetonitrile

[0860] Method 12

[0861] Column :ACQUITY UPLC BEH C8 1.7 pm (2.1x150mm), 130 A, column no. 186003377

[0862] Reagents: same as method 3

[0863] HPLC conditions:

[0864] - Wavelength range: (190 -340) nm ± 4 nm

[0865] - Flow: 0.5 ml / min

[0866] - Column temperature: 55 °C

[0867] - Autosampler temperature: 20°C

[0868] - Analysis time: 10 min

[0869] - Elution: gradient

[0870] Mobile phase A: 0.1% v / v water solution of formic acid Mobile phase B: 0.1% v / v acetonitrile solution of formic acid

[0871] Method 13

[0872] Column: same as method 11

[0873] Reagents: same as method 1

[0874] HPLC conditions: same as method 1

[0875] Elution: gradient

[0876] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NHs basis)

[0877] Mobile phase D: acetonitrile

[0878] Method 14

[0879] Apparatus: same as method 3

[0880] Reagents: same as method 3

[0881] HPLC conditions: same as method 3

[0882] Elution: gradient

[0883] Mobile phase A:0.1 % v / v water solution of formic acid

[0884] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0885] Method 15

[0886] Column: same as method 11

[0887] Reagents: same as method 1

[0888] HPLC conditions: Column: same as method 11

[0889] Reagents: same as method 1

[0890] Elution: gradient

[0891] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NIL basis)

[0892] Mobile phase D: acetonitrile

[0893] Method 16

[0894] Column: same as method 3

[0895] Reagents: same as method 3

[0896] HPLC conditions: same as method 4

[0897] Elution: gradient

[0898] Mobile phase A:0.1 % v / v water solution of formic acid

[0899] Mobile phase B:0. 1 % v / v acetonitrile solution of formic acid

[0900] Method 17

[0901] Column: same as method 11

[0902] Reagents: same as method 1

[0903] HPLC conditions: same as method 11

[0904] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NIL basis)

[0905] Mobile phase D: acetonitrile

[0906] Method 18

[0907] Column: same as method 11

[0908] Reagents: same as method 1

[0909] HPLC conditions: same as method 11

[0910] - Analysis time: 12 min

[0911] - Elution: gradient

[0912] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NIL basis)

[0913] Mobile phase D: acetonitrile

[0914] Method 19

[0915] Column: same as method 11

[0916] Reagents: same as method 1

[0917] HPLC conditions: same as method 11 Elution: gradient

[0918] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NHs basis)

[0919] Mobile phase D: acetonitrile

[0920] Method 20

[0921] Column: same as method 3

[0922] Reagents: same as method 3

[0923] HPLC conditions: same as method 3

[0924] Elution: gradient

[0925] Mobile phase A: 0.1 % v / v water solution of formic acid

[0926] Mobile phase B: 0.1 % v / v acetonitrile solution of formic acid

[0927] Method 21

[0928] Column: same as method 11

[0929] Reagents: same as method 1

[0930] HPLC conditions: same as method 11

[0931] Elution: gradient

[0932] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NHs basis)

[0933] Mobile phase D: acetonitrile

[0934] Method 22

[0935] Column: same as method 11

[0936] Reagents: same as method 3

[0937] HPLC conditions: same as method 18

[0938] Elution: gradient

[0939] Mobile phase A: 0.1 % v / v water solution of formic acid

[0940] Mobile phase B: 0.1 % v / v acetonitrile solution of formic acid

[0941] Method 23

[0942] Column: same as method 11

[0943] Reagents: same as method 1

[0944] HPLC conditions: same as method 1

[0945] Elution: gradient

[0946] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NHs basis)

[0947] Mobile phase D: acetonitrile

[0948] Method 24 (SFC chiral purification)

[0949] Apparatus:

[0950] Prep SFC 150 AP

[0951] Column: LuxCelullose 1, 21.2 x 250 mm, 5 pm

[0952] Reagents:

[0953] - Acetonitrile for HPLC UV / gradient grade, Baker

[0954] - Methanol grade for liquid chromatography, Supelco,

[0955] - Ammonium Hydroxide solution 28-30%, Sigma-Aldrich

[0956] SFC conditions:

[0957] - Wavelength: (210 - 800) nm ± 4 nm

[0958] Total Flow: 61 ml / min

[0959] Column temperature: 40 °C

[0960] ABPR: 100 bar

[0961] Elution: isocratic

[0962] Total method duration time : 9 min

[0963] Mobile phase details:

[0964] - Mobile Phase A: 58%, CO2

[0965] - Mobile Phase B: 42%, Methanol / Acetonitrile (1: 1)

[0966] - Additive: Ammonium Hydroxide 1.0 %

[0967] MS conditions:

[0968] - Mass range: 110 - 1000 m / z

[0969] - Ionization: Positive

[0970] - Sampling Frequency: 2 Hz

[0971] The sample was dissolved in a mixture of MeOH and ACN

[0972] Method 25

[0973] Column: same as method 3

[0974] Reagents: same as method 3

[0975] HPLC conditions: same as method 3

[0976] Elution: gradient

[0977] Mobile phase A:0.1 % v / v water solution of formic acid

[0978] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[0979] Method 26

[0980] Column: same as method 3

[0981] Reagents: same as method 3

[0982] HPLC conditions: same as method 3

[0983] Elution: gradient

[0984] Mobile phase A:0.1 % v / v water solution of formic acid

[0985] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[0986] Solution for syringe washing: 20% MeOH

[0987] Method 27

[0988] Column: same as method 3

[0989] Reagents: same as method 3

[0990] HPLC conditions: same as method 3

[0991] Elution: gradient

[0992] Mobile phase A:0.1 % v / v water solution of formic acid

[0993] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[0994] Solution for syringe washing: 20% MeOH

[0995] Method 28

[0996] Column: same as method 3

[0997] Reagents: same as method 3

[0998] HPLC conditions: same as method 3

[0999] Elution: gradient

[1000] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NFF basis)

[1001] Mobile phase D: acetonitrile

[1002] Solution for syringe washing: 20% MeOH

[1003] Method 29

[1004] Column: same as method 3

[1005] Reagents: same as method 3

[1006] HPLC conditions: same as method 3

[1007] Elution: gradient

[1008] Mobile phase C: 0.05% water solution of ammonium hydroxide (28.0-30.0% NFF basis)

[1009] Mobile phase D: acetonitrile

[1010] Solution for syringe washing: 20% MeOH - Til -

[1011] Method 30

[1012] Column: same as method 3

[1013] Reagents: same as method 3

[1014] HPLC conditions: same as method 3

[1015] Elution: gradient

[1016] Mobile phase A:0.1 % v / v water solution of formic acid

[1017] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[1018] Solution for syringe washing: 20% MeOH

[1019] Method 31

[1020] Column: same as method 3

[1021] Reagents: same as method 3

[1022] HPLC conditions: same as method 3

[1023] Elution: gradient

[1024] Mobile phase A:0.1 % v / v water solution of formic acid

[1025] Mobile phase B:0.1 % v / v acetonitrile solution of formic acid

[1026] Solution for syringe washing: 20% MeOH

[1027] Method 32 Equipment: Agilent 1100 Series LC / MSD system with DAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass-spectrometer system

[1028] Column: Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm

[1029] Column Temperature: 60°C

[1030] Mobile phase: A - water (0.1% formic acid), B - acetonitrile (0.1% formic acid)

[1031] Flow rate: 3 ml / min

[1032] Gradient: 0.01 min - 1% B, 1.5 min - 100% B, 1.73 min - 100% B

[1033] MS Ionization mode: Electrospray ionization (ESI)

[1034] MS Scan range: 83 - 600 m / z

[1035] UV detection: 215 nm, 254nm, 280 nm

[1036] Method 33

[1037] Column: Phenomenex Kinetex EVO C18 - 4.6x50 mm, 2.6 pm

[1038] Column Temperature: 60°C

[1039] Mobile phase: A - water (0.1% formic acid), B - acetonitrile (0.1% formic acid)

[1040] Flow rate: 3 ml / min

[1041] Gradient: 0.01 min - 1% B, 5.00 min - 100% B, 5.52 min - 100% B

[1042] MS Ionization mode: Electrospray ionization (ESI)

[1043] MS Scan range: 83 - 1000 m / z

[1044] UV detection: 215 nm, 254nm, 280 nm

[1045] Method 34

[1046] Column: Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm

[1047] Column Temperature: 60°C

[1048] Mobile phase: A - water (0.1% formic acid), B - acetonitrile (0.1% formic acid)

[1049] Flow rate: 1.5 ml / min

[1050] Gradient: 0.01 min - 1% B, 5.00 min - 100% B, 5.99 min - 100% B

[1051] MS Ionization mode: Electrospray ionization (ESI)

[1052] MS Scan range: 83 - lOOOm / z

[1053] UV detection: 215 nm, 254nm, 280 nm

[1054] Method 35

[1055] Column: Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm

[1056] Column Temperature: 60°C

[1057] Mobile phase: A - water (0.1% formic acid), B - acetonitrile (0.1% formic acid)

[1058] Flow rate: 3 ml / min

[1059] Gradient: 0.01 min - 1% B, 1.50 min - 100% B, 2.2 min - 100% B

[1060] MS Ionization mode: Electrospray ionization (ESI)

[1061] MS Scan range: 83 - lOOOm / z

[1062] UV detection: 215 nm, 254nm, 280 nm

[1063] Method 36

[1064] Column: Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm

[1065] Column Temperature: 60°C

[1066] Mobile phase: A - water , B - acetonitrile

[1067] Flow rate: 3 ml / min

[1068] Gradient: 0.01 min - 1% B, 1.5 min - 100% B, 1.73 min - 100% B

[1069] MS Ionization mode: Electrospray ionization (ESI)

[1070] MS Scan range: 83 - lOOOm / z

[1071] UV detection: 215 nm, 254nm, 280 nm

[1072] Method 37 Column: GEMINI NX-C 18 4,6x50 mm 5 Micron

[1073] Column Temperature: 25°C

[1074] Mobile phase: A - lOmM NH4OAc in water, pH = 10, B - acetonitrile

[1075] Flow rate: 2.3 ml / min

[1076] Gradient: 0.01 min - 1% B, 1.5 min - 100% B, 2.2 min - 100% B

[1077] MS Ionization mode: Electrospray ionization (ESI)

[1078] MS Scan range: 83 - lOOOm / z

[1079] UV detection: 215 nm, 254nm, 280 nm

[1080] Method 38

[1081] LCMS UPLC

[1082] Column: 4.6x50mm ZORBAX SB-C18 1.8Micron

[1083] Temperature: 50°C

[1084] Mobile phase: Solvent A: CH3CN+H2O+ FA 0.1% (900: 100:2)

[1085] Solvent B: H2O+FA 0.1% (1000:2)

[1086] Flow rate: 3 ml / min

[1087] Gradient:

[1088] Time A(%) B(%)

[1089] 0,00 3,0 97,0

[1090] 0,01 3,0 97,0

[1091] 4,00 100,0 0,0

[1092] 4.60 100,0 0,0

[1093] 4.61 3,0 97,0

[1094] 4,7 3,0 97,0

[1095] MS Ionization mode: Electrospray ionization (ESI)

[1096] MS Scan range: 83 - 1000 m / z

[1097] UV detection: 215 nm, 254nm, 280 nm

[1098] UV detection: 215 nm, 254nm, 280 nm

[1099] Table 23: Physico-chemical data. (RT means retention time in minutes; [MH]+means the protonated mass of the compound (free base); nd = not determined).

[1100] Table 24: Chiral Separation 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.

[1101] The Open Lab CDS software (version C.01.10) was used for instrument control, data acquisition and data handling.

[1102] 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 2-6 and RT2 corresponds to Co.No 2-7.

[1103]

[1104] PHARMACOLOGY

[1105] 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.

[1106] Because such positive allosteric modulators of M4 mACh receptors, including compounds of Formula (F) and (I), enhance the response of M4 mACh receptors to ACh, it is an advantage that the present methods utilize endogenous ACh.

[1107] 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 (I’) and (I), in combination with a M4 mACh agonist.

[1108] 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.

[1109] The behavior of positive allosteric modulators, such as the ones described in Formula I, at M4 mACh receptors is shown in the following paragraph, which is suitable for the identification of such compounds.

[1110] Example A

[1111] 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 10% decomplemented foetal bovine serum, Penicillin / Streptomycin (100 units / mLPenicillin, 100 pg / mL Streptomycin), 40 pg / ml Hygromycin and 1 pg / ml Puromycin) 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 15 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 180 seconds to detect any agonist activity of the compounds. Then the cells were stimulated by an EC20 acetylcholine concentration for an additional 180 s in 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.

[1112] The compounds of this application have EC50 values usually less than 10 pM.

[1113] Tables 25, 26 and 27 below represent the mean EC50 obtained from at least three independent experiments of selected molecules performed in duplicate.

[1114] Table 25: Activity data for selected compounds

[1115] Table 26: Activity data for selected compounds

[1116] Table 27: Activity data for selected compounds *Table legend:

[1117] NA: Non Active

[1118] (+): 500 nM < ECso <10 pM

[1119] (++): 100 nM < EC50 < 500 nM

[1120] (+++): EC50 < 100 nM

[1121] The results shown in Table 25 demonstrate that the compounds described in the present invention are positive allosteric modulators of human Muscarinic M4 receptors.

[1122] Example B

[1123] The effects of compounds on amphetamine-induced locomotor hyperactivity in mice

[1124] 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.

[1125] Table 28: In vivo activity data for selected compounds FORMULATION EXAMPLES

[1126] Typical examples of formulations of the invention are as follows:

[1127] 1. Tablets

[1128] Active ingredient 5 to 50 mg

[1129] Di-calcium phosphate 20 mg

[1130] Lactose 30 mg

[1131] Talcum 10 mg

[1132] Magnesium stearate 5 mg

[1133] Potato starch ad 200 mg

[1134] In this Example, the active ingredient is any of the compounds according to the present invention.

[1135] 2. Suspension

[1136] 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.

[1137] 3. Injectable

[1138] 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.

[1139] 4. Ointment

[1140] Active ingredient 5 to 1000 mg

[1141] Stearyl alcohol 3 g

[1142] Lanoline 5 g

[1143] White petroleum 15 g Water ad 100 g

[1144] In this Example, the active ingredient is any of the compounds according to the present invention.

[1145] 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.

[1146] The invention includes the subject matter described in the following numbered paragraphs:

[1147] 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 A-oxide form thereof, wherein:

[1148] R1is selected from the group of -(Ci-C6)alkyl, -(Ci-C6)deuterioalkyl and - (Cs-Cvjcycloalkyl;

[1149] R2is selected from the group of hydrogen, halogen, -CN, -CF3, -(Ci- Cejalkyl, -(Cs-Cvjcycloalkyl or -(Ci-Ce)haloalkyl;

[1150] P represents a heteroaryl or or heterocycle of formula: wherein each heteroaryl or 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-0-Ra, -(C3-C7)cycloalkyl, aryl, heteroaryl, and heterocycle; R is selected from the group of hydrogen, halogen, -CN, -(Ci-Ce)alkyl, - (C3-C7)cycloalkyl, -(Ci-Ce)haloalkyl, -O-(Ci-Ce)alkyl and -O-(C3-C7)cycloalkyl;

[1151] Q represents a cycloalkyl, aryl, heteroaryl or heterocycle of formula: or, -(Ci-C6)haloalkyl, -(C0-C6)alkylene-C(=O)-ORbor -(Co-C6)alkylene-C(=0)-

[1152] NRbRc; wherein Ra, Rb and Re are each independently selected from the group of hydrogen,

[1153] (Ci-C6)alkyl, (Ci-C6)alkyl-O-(Ci-C6)alkyl, and (Ci-C6)alkyl- (C=O)-(Ci-

[1154] Ce)alkyl, or Rb and Re, together with the nitrogen to which they are attached, form a pyrrol opyri dine 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 Bi is 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, Z4, Z5and Z6are each independently selected from C, N, S or O; the or each (B)nis independently selected from the group of hydrogen, halogen, - CN, -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; -(C0-C6)alkylene-S(=O)-R3, -O-(C0-C6)alkylene-S(=O)-R3, -NR3-(Co- C6)alkylene-S(=O)-R4, -(Co-C6)alkylene-S(=0)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- (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, -(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;

[1155] 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- Ce)alkylene-NH2. The compound according to paragraph 1 having the Formula (I) wherein:

[1156] P is a heteroaryl or heterocycle of formula: The compound according to paragraph 1 having the Formula (I) wherein:

[1157] P is a heteroaryl or heterocycle of formula: The compound according to any preceding paragraph having the Formula (I) wherein:

[1158] R1is -(Ci-C3)alkyl, -(Ci-C4)deuterioalkyl or -(C3)cycloalkyl;

[1159] R2is hydrogen, -F, -CF3 or -CH3; and

[1160] R is selected from the group of hydrogen, -CF3, -(Ci-C3)alkyl, -(C3)cycloalkyl, -O- (Ci-C3)alkyl and -O-(C3)cycloalkyl. The compound according to any preceding paragraph having the Formula (I) wherein Q is: or -CF3. The compound according to any preceding paragraph 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 R8are independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, nitro, -(Ci-Ce)alkyl, - (Co-C6)alkylene-0-(Co-C6)alkyl, -(Co-C6)alkylene-N-((Ci-C6)alkyl)2, -(Co- Ce)alkylene-NH(Ci-C6)alkyl and -(Co-Ce)alkylene-NH2. 7. The compound according to any preceding paragraph having the Formula

[1161] (XXVIII): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof or an V-oxide form thereof, wherein Ai is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl and R1is methyl or ethyl.

[1162] 8. The compound according to any preceding paragraph 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 V-oxide form thereof, wherein R1is methyl or ethyl. 9. The compound according to any of paragraphs 1 to 6 having the Formula (XXIX): 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 Ai is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl and R1is methyl or ethyl. The compound according to any of paragraphs 1 to 6 or 9 having the Formula

[1163] (XXX): 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. The compound according to any of paragraphs 1 to 6 having the Formula (XXXI): 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 Ai is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl and R1is methyl or ethyl. The compound according to any of paragraphs 1 to 6 or 11 having the Formula

[1164] (XXXII): (XXXII) 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. The compound according to any of paragraphs 1 to 6 having the Formula (VIII): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein Ai, A2 and A3 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl. The compound according to any of paragraphs 1 to 6 or 13 having the Formula

[1165] (IX): 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.

[1166] 15. The compound according to paragraphs 1 to 14, wherein the compound can exist as stereoisomers, and wherein the compound is either a racemic mixture or one or more of the individual stereoisomers.

[1167] 16. The compound according to paragraphs 1 to 15, 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.

[1168] 17. The compound according to paragraphs 1 to 16, wherein said compound is one or more selected from Table D, 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:

[1169] 18. The compound according to any of paragraphs 1 to 6 having the Formula (la) or

[1170] (lb):

[1171] 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of paragraphs 1 to 18 and a pharmaceutically acceptable carrier and / or excipient. 20. 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 19.

[1172] 21. The method according to paragraph 20 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.

[1173] 22. 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 19.

[1174] 23. The method according to paragraph 22, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic M4 positive allosteric modulator.

[1175] 24. The method according to paragraph 20 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 18.

[1176] 25. The method according to paragraph 20 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 18.

[1177] 26. The method according to paragraph 20 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 18.

[1178] 27. The method according to paragraph 20 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, Opioi...

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 A -oxi de 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 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-0-Ra, -(C3-C7)cycloalkyl, aryl, heteroaryl, and heterocycle, or two (A)mtogether form a saturated -(C3-C7) membered ring;R is selected from the group of hydrogen, halogen, -CN, -(Ci-Ce)alkyl, -(C3- C7)cycloalkyl, -(Ci-Ce)haloalkyl, -O-(Ci-Ce)alkyl and -O-(C3-C7)cycloalkyl;Q is selected from the group of -(Ci-Ce)haloalkyl, -(Co-C6)alkylene-C(=0)- ORb or -(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- Ce)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, -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, -(Co-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 6 membered heterocyclic or heteroaryl ring, and wherein P is bonded to the pyrazole core via the 6 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 G and J are each independently C-R or N; and D, E and M are each independently C or N; and wherein P is bonded to the pyrazole core via the 6 membered ring.

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

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 (I) or Formula(F) wherein P is a heteroaryl or heterocycle of formula:

9. The compound according to any preceding claim having the Formula (I) or Formula (F) wherein P is a heteroaryl or heterocycle of formula:

10. The compound according to any of claims 1 to 8 having the Formula (I) or Formula (F) wherein P is a heteroaryl or heterocycle of formula:

11. The compound according to any preceding claim having the Formula (I) or Formula (F) wherein: R1is selected from the group of -(Ci-C3)alkyl, -(Ci-C4)deuterioalkyl and - (C3)cycloalkyl;R2is selected from the group of hydrogen, -F, -CF3 and -CH3; andR is selected from the group of hydrogen, -CF3, -(Ci-C3)alkyl, -(C3)cycloalkyl, -O- (Ci-C3)alkyl and -O-(C3)cycloalkyl.

12. The compound according to any preceding claim having the Formula (I) or Formula (F) wherein Q is:

13. The compound according to any preceding claim having the Formula (I) or Formula (F) 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.

14. The compound according to any of claims 1 to 7, or 11 to 13 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 Af-oxide form thereof, wherein Ai is selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, and G and J independently are C-R or N.

15. The compound according to any of claims 1 to 7, or 11 to 14 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 Af-oxide form thereof, wherein R1is methyl or ethyl.

16. The compound according to any of claims 1 to 7 or 11 to 13 having the Formulaa pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an Af-oxideform thereof, wherein Ai and A2 are selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl or Ai and A2 together form a saturated C5 membered ring, R1is methyl or ethyl, and G and J independently are C-R or N.

17. The compound according to any of claims 1 to 7, 11 to 12, or 16 having the Formula(V):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, and G is selected from N, C-H and C- CH3.

18. The compound according to any of claims 1 to 7, or 11 to 13 having the Formula(VI):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 Ai and A2 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, and R1is methyl or ethyl.

19. The compound according to any of claims 1 to 7, 11 to 13, or 18 having the Formula(VII):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.

20. The compound according to any of claims 1 to 7, or 11 to 13 having the Formula(VIII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein Ai, A2 and A3 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl and G and J independently are C-R or N.

21. The compound according to any of claims 1 to 7, 11 to 13, or 20 having the Formula(IX):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 R1is methyl or ethyl and G is selected from N, C-H and C- CH3.

22. The compound according to any of claims 1 to 7, or 11 to 13 having the Formula (X):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 G and J independently are C-R or N.

23. The compound according to any of claims 1 to 7, 11 to 13, or 22 having the Formula (XI):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.

24. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(XII):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, A2 and A3 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, and G and J independently are C-R or N.

25. The compound according to any of claims 1 to 7, 11 to 13, or 24 having the Formula(XIII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl.

26. The compound according to any of claims 1 to 7, or 11 to 13 having the Formula(XIV):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein Ai and A2 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, and G and J independently are C-R or N.

27. The compound according to any of claims 1 to 7, 11 to 13, or 26 having the Formula(XV):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 R1is methyl or ethyl and G is selected from N, C-H and C- CH3.

28. The compound according to any of claims 1 to 7, or 11 to 13 having the Formula(XVI):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, D is N or C-A3, wherein A3 is selected from H, -(Ci- C2)alkyl and -O-(Ci-C2)alkyl, R1is methyl or ethyl, and G and J independently are C-R or N.

29. The compound according to any of claims 1 to 7, 11 to 12, or 28 having the Formula(XVII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl.

30. The compound according to any of claims 1 to 7, 11 to 13, or 28 having the Formula(XVIII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl.

31. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula (XIX):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxideform thereof, wherein Ai and A2 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, R1is methyl or ethyl, and G and J independently are C-R or N.

32. The compound according to any of claims 1 to 7, 11 to 24, or 31 having the Formula(XX):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.

33. The compound according to any of claims 1 to 7, 11 to 13, or 31 having the Formula(XXI):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.

34. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(XXII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an / Vox ide form thereof, wherein Ai and A2 are each independently selected from H, -(Ci- C2)alkyl and -(C3)cycloalkyl, and R1is methyl or ethyl.

35. The compound according to any of claims 1 to 7, 11 to 13, or 34 having the Formula (XXIII):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.

36. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(XXIV):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein A2 is selected from H, -(Ci-C2)alkyl and - (C3)cycloalkyl, wherein R1is methyl or ethyl.

37. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula (XXV):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein A2 and A3 are independently selected from H, -(Ci-C2)alkyl and -(C3)cycloalkyl, and R1is methyl or ethyl.

38. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(XXVI):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein R1is methyl or ethyl.

39. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(XXVII):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a solvate form thereof, a hydrate form thereof, or an V-oxide form thereof, wherein A2 is selected from H, methyl and R1is methyl or ethyl.

40. The compound according to claims 1 to 39, wherein the compound can exist as stereoisomers, and wherein the compound is either a racemic mixture or one or more of the individual stereoisomers.

41. The compound according to claims 1 to 40, 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 V-oxide form thereof.

42. The compound according to claims 1 to 41, wherein said compound is one or more selected from Table D, 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.

43. The compound according to any of claims 1 to 7 or 11 to 13 having the Formula(la) or (lb):

44. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier and / or excipient.

45. 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 44.

46. The method according to claim 45 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.

47. A 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 suchtreatment or prevention, an effective amount of a compound / composition according to any one of claims 1 to 44.

48. The method according to claim 47, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a Muscarinic M4 positive allosteric modulator.

49. The method according to claim 47 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 43.

50. The method according to claim 47 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 43.

51. The method according to claim 47 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 claims 1 to 43.

52. The method according to claim 47 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, Alcoholwithdrawal 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 43.

53. The method according to claim 45 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 43.

54. The method according to claim 45 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 43.

55. The method according to claim 45 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, pain disorder, inflammatory pain or nociceptive pain, chronic pain and neuropathic pain, comprising administering an effective amount of a compound according to claims 1 to 43.

56. The method of any one of claims 45 to 55, wherein the mammal is a human.

57. Use of a compound according to any one of claims 1 to 43 in the manufacture of a medicament for a treatment or prevention as defined in claims 45 to 55.

58. The use of a compound according to any one of claims 1 to 43 to prepare tracers for imaging muscarinic acetylcholine M4 receptors.

59. The compound according to any one of claims 1 to 43 for use in a method according to any one of claims 45 to 55.

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