Octahydroisoquinolinyl derivatives

Abstract

The present invention relates to an octahydroisoquinolinyl derivative of formula (I): [Formula 1] JPEG2023551173000113.jpg45166 It is a positive allosteric modulator of D1 and is therefore useful as a pharmaceutical for the treatment of diseases involving the D1 receptor.

Description

[Technical Field]

[0001] The present invention relates to octahydroisoquinolinyl derivatives and their use in therapy. In particular, the present invention relates to pharmacologically active fused octahydroisoquinolinyl derivatives and analogs thereof. More particularly, the present invention relates to substituted 3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinol-2-yl derivatives and analogs thereof.

[0002] The compounds according to the invention are D1 positive allosteric modulators and are therefore useful as pharmaceuticals for the treatment of diseases in which the D1 receptor plays a role. [Background technology]

[0003] The monoamine dopamine regulates motor function, reward mechanisms, cognitive processes, and other physiological functions via two GPCR families. Specifically, dopamine acts on neurons primarily via D1-like receptors, including dopamine D1 and D5, which couple to Gs G proteins to stimulate cAMP production, and D2-like receptors, including D2, D3, and D4, which couple to Gi / q G proteins to inhibit cAMP production. These receptors are widely expressed in various brain regions. In particular, D1 receptors are involved in many physiological and behavioral processes. For example, D1 receptors are involved in synaptic plasticity, cognitive function, goal-directed motor function, and reward processes. Due to their role in several physiological / neurological processes, D1 receptors have been implicated in a variety of disorders, including cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction sleep disorders, apathy, traumatic spinal cord injury, and neuropathic pain. Summary of the Invention [Problem to be solved by the invention]

[0004] Developing orally bioavailable small molecules targeting the D1 receptor has proven challenging. D1 agonists developed to date generally feature a catechol moiety, limiting their clinical use to invasive treatments. Furthermore, the high homology of ligand-binding sites between dopamine receptor subtypes (e.g., dopamine D1 and D5) makes it difficult to achieve sufficient selectivity. Furthermore, D1 agonists are associated with potentially limiting side effects, including but not limited to dyskinesia and hypotension.

[0005] Therefore, there is a need to design new drugs that can modulate D1 receptors.

[0006] Identifying allosteric modulators of GPCRs has attracted considerable interest as a tool for understanding receptor mechanisms and as potential therapeutic agents. GPCRs are the largest family of cell surface receptors, and many commercially available drugs directly activate or block signaling pathways mediated by these receptors. However, for some GPCRs (e.g., peptide receptors), the ligand-binding sites are highly homologous across subtypes (e.g., dopamine D1 and D5, or D2 and D3), making the development of small molecules and achieving sufficient selectivity difficult. Therefore, much of the drug research has shifted to identifying small molecules that target sites distinct from those of the orthosteric natural agonists. Ligands bound to these sites induce conformational changes in the GPCR, thereby allosterically modulating receptor function. Allosteric ligands possess diverse activities, including the ability to enhance (positive allosteric modulators, PAMs) or attenuate (negative allosteric modulators, NAMs) the effects of endogenous ligands by affecting affinity and / or potency. In addition to subtype selectivity, allosteric modulators may exhibit other potential advantages from a drug discovery perspective, such as the absence of direct or intrinsic effects, the potentiation of effects only where and when endogenous transmitters are released, a reduced tendency to cause desensitization resulting from constant exposure to agonists, and a reduced tendency to induce target-related side effects.

[0007] The compounds according to the invention potentiate the effects of D1 agonists or endogenous ligands on the D1 receptor via an allosteric mechanism and are therefore D1 positive allosteric modulators (D1 PAMs).

[0008] The compounds of the present invention, which are D1 PAMs, are therefore useful for the treatment and / or prevention of diseases and disorders in which D1 receptors play a role, including cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury, or neuropathic pain.

[0009] International patent application WO2014 / 193781A1 discloses certain 3,4-dihydroisoquinolin-2(1H)-yl derivatives useful for the treatment of cognitive impairment associated with Parkinson's disease or schizophrenia.

[0010] International patent application WO2016 / 055479 discloses substituted 3,4-dihydroisoquinolin-2(1H)-yl derivatives and analogues thereof that are useful for the treatment of diseases in which the D1 receptor plays a role.

[0011] However, there remains a need for the development of potent D1-positive allosteric modulators that have favorable pharmacokinetic and pharmacodynamic properties and that reduce the side effects traditionally associated with treatment with selective D1 agonists, such as hypotension and dyskinesia. [Means for solving the problem]

[0012] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] where: Z represents CH2 or NH; R 4 is hydroxy, halogen and C 1‐6 C optionally substituted with one or more substituents selected from alkyl 1‐6 Alkyl; or hydroxy and C 1‐6 C optionally substituted with one or more substituents selected from alkyl 1‐6 Alkyne; or halogen, cyano, C 1‐6 Alkyl and C 1‐6 C optionally substituted by one or more substituents selected from alkoxy 5‐8 is heteroaryl; R 5 is hydrogen or C optionally substituted by one or more substituents selected from hydroxy and halogen 1‐6 represents alkyl; and G is (G a ), (G b ) and (G c represents an aromatic group selected from the group consisting of: [ka] where: asterisk( * ) represents the point of attachment of G to the rest of the molecule; X represents CH, C-F or N; R 1 is hydrogen; or C optionally substituted by one or more substituents selected from hydroxy and halogen 1‐6 Alkyl or C 1‐6 represents alkoxy; R 2 and R 3 independently represent halogen or cyano; X 1 represents CH or N; R a is hydrogen or C 1‐6 represents alkyl; and R b is C 1‐6 represents alkyl or halogen.

[0013] None of the prior art available to date discloses or suggests the precise structural class of substituted octahydrohydroisoquinolinyl derivatives as provided by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein, the term "C 1‐6 "Alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched and may contain 1 to 6 carbon atoms in the chain. Suitable alkyl groups which may be present on compounds used in the present invention include straight and branched C 1‐4 Exemplary C alkyl groups include: 1‐6 Alkyl groups include methyl, ethyl, propyl and butyl.

[0015] The term “C 1‐6 "Alkoxy" refers to a group of the formula -O-R, where R is an optionally substituted "C 1‐6 Alkoxy groups suitable according to the present invention include methoxy.

[0016] The term "heteroaryl," as used herein, refers to an aromatic carbocyclic group of 5 to 14 carbon atoms having a single ring or multiple condensed rings, wherein one or more of the carbon atoms is replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen.

[0017] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group may be unsubstituted or substituted with one or more substituents. Typically, such groups will be unsubstituted or substituted with one or two substituents. Suitable substituents for each specific group of compound formula (I) are further described hereinafter.

[0018] Formula (I) and the formulae depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof unless otherwise stated or indicated.

[0019] Stereoisomers of the compounds of formula (I) include optical isomers such as cis and trans isomers, R and S enantiomers, diastereomers, geometric isomers, rotamers, atropisomers, and conformational isomers of the compounds of formula (I) (including compounds exhibiting more than one type of isomerism); and mixtures thereof (such as racemates and diastereomeric pairs).

[0020] The compounds of formula (I) contain asymmetric carbon atoms. The carbon-carbon bonds of the compounds of formula (I) are represented herein by solid lines. [ka] solid wedge [ka] or dotted wedge [ka] It is depicted using The use of a solid line to represent a bond to an asymmetric carbon atom means that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of a solid or dotted wedge to represent a bond to an asymmetric carbon atom indicates that only the depicted stereoisomer is intended to be included. Compounds of Formula (I) may contain two or more asymmetric carbon atoms. In such compounds, the use of a solid line to represent a bond to an asymmetric carbon atom means that all possible stereoisomers are included.

[0021] Examples of stereoisomers according to the present invention include compounds represented by formula (IA) and (IA-a), as depicted below. [ka] where G, R 4 , R 5 and Z are as defined above for compounds of formula (I).

[0022] Some compounds of formula (I) may exist in tautomeric forms. Although not explicitly shown in the formula above, such forms are intended to be included within the scope of the present invention. Examples of tautomers include keto (CHC=O)⇔enol (CH=CHOH) tautomers or amide (NHC=O)⇔hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or shown.

[0023] It will also be understood that the individual atoms present in formula (I) or in the formulae depicted below may in fact be present in the form of any of their naturally occurring isotopes, with the most abundant isotope being preferred. Thus, by way of example, the individual hydrogen atoms present in formula (I) or in the formulae depicted below may be: 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H or 2 H. Similarly, by way of example, each carbon atom present in formula (I) or in the formulae depicted below can be present as: 12 C. 13 C or 14 C atoms, preferably 12 It may also exist as C.

[0024] Specific embodiments of the compound of formula (I) according to the present invention will be described below.

[0025] In one embodiment, Z represents CH. In another embodiment, Z represents N.

[0026] In one embodiment, G is (G a In a second embodiment, G represents (Gb In a third embodiment, G represents (G c )

[0027] In a first embodiment, X represents CH. In a second embodiment, X represents N. In a third embodiment, X represents C—F.

[0028] In the first embodiment, R 1 represents hydrogen.

[0029] In a second embodiment, R 1 is C optionally substituted with one or more substituents selected from hydroxy and halogen 1‐6 In a first aspect according to this embodiment, R 1 is a C substituted with one or more hydroxy 1‐6 R according to this embodiment represents alkyl. 1 Examples of R are hydroxymethyl, hydroxyethyl, and hydroxypropyl. In a second aspect according to this embodiment, R 1 is C substituted by one or more hydroxy and by one or more halogens 1‐6 R according to this embodiment represents alkyl. 1 Examples of R are (difluoro)(hydroxy)ethyl and (difluoro)(hydroxy)propyl. 1 is a C optionally substituted with one or more substituents selected from halogens 1‐6 Represents alkyl.

[0030] In a third embodiment, R 1 is C optionally substituted with one or more substituents selected from hydroxy and halogen 1‐6 In a first aspect according to this embodiment, R 1 is C 1‐6 R according to this embodiment represents alkoxy. 1 Examples of R are methoxy and deuterated methoxy (CD3O-). In a second aspect according to this embodiment, R 1 is C substituted with one or more halogens1‐6 R according to this embodiment represents alkoxy. 1 An example of is difluoromethoxy.

[0031] In general, R 1 is hydrogen, C substituted by one or more hydroxy 1‐6 C substituted with alkyl, one or more hydroxy and one or more halogen 1‐6 Alkyl, C 1‐6 Alkoxy or C substituted with one or more halogens 1‐6 represents alkoxy.

[0032] Preferably, R 1 is a C substituted with one or more hydroxy 1‐6 C substituted with alkyl, one or more hydroxy and one or more halogen 1‐6 Alkyl, C 1‐6 Alkoxy or C substituted with one or more halogens 1‐6 represents alkoxy.

[0033] Typically, R 1 represents hydrogen, hydroxymethyl, hydroxyethyl, (hydroxy)propyl, (hydroxy)(difluoro)ethyl, (hydroxy)(difluoro)propyl, methoxy, deuterated methoxy, or difluoromethoxy.

[0034] Ideally, R 1 represents hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2,2-difluoro-1-hydroxyethyl, 1,1-difluoro-2-hydroxypropan-2-yl, methoxy, deuterated methoxy, or difluoromethoxy.

[0035] For example, R 1 represents hydrogen, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2,2-difluoro-1-hydroxyethyl, 1,1-difluoro-2-hydroxypropan-2-yl, methoxy, deuterated methoxy or difluoromethoxy.

[0036] Selectively, R 1 denotes hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2,2-difluoro-1-hydroxyethyl, 1,1-difluoro-2-hydroxypropan-2-yl, methoxy, deuterated methoxy, or difluoromethoxy.

[0037] In the first embodiment, R 2 represents a halogen. In a first aspect of this embodiment, R 2 represents chloro. In a second aspect of this embodiment, R 2 represents bromo. In a third aspect of this embodiment, R 2 represents fluoro. In a second embodiment, R 2 represents cyano.

[0038] For example, R 2 represents chloro or cyano.

[0039] In the first embodiment, R 3 represents a halogen. In a first aspect of this embodiment, R 3 represents chloro. In a second aspect of this embodiment, R 3 represents bromo. In a third aspect of this embodiment, R 3 represents fluoro. In a second embodiment, R 3 represents cyano.

[0040] For example, R 3 represents chloro or cyano.

[0041] In one embodiment, X 1 represents CH. In another embodiment, X 1 represents N.

[0042] In one embodiment, R a represents hydrogen. In a second embodiment, R a is C 1‐6 R according to this embodiment represents alkyl. a An example of is methyl.

[0043] In one embodiment, R b is C 1‐6 R according to this embodiment represents alkyl. b An example of R is methyl. b represents halogen, especially chloro.

[0044] In the first embodiment, R 4 is hydroxy, halogen and C 1‐6 C optionally substituted with one or more substituents selected from alkyl 1‐6 In a first aspect of this embodiment, R 4 is C 1‐6 In a second aspect of this embodiment, R 4 is C substituted by one or more hydroxy and by one or more halogens 1‐6 R according to this embodiment represents alkyl. 4 Examples of R are (trifluoro)(hydroxy)ethyl, (difluoro)(hydroxy)ethyl, (difluoro)(hydroxy)propyl, and (trifluoro)(hydroxy)propyl. In a third aspect of this embodiment, R 4 is one or more C 1‐6 C substituted with alkyl and one or more hydroxy 1‐6 R according to this embodiment represents alkyl. 4 An example of is (hydroxy)(methyl)butyl.

[0045] In a second embodiment, R 4 is hydroxy and C 1‐4 C optionally substituted with one or more substituents selected from alkyl 1‐6 In a first aspect of this embodiment, R 4 is C 1‐6 In a second aspect of this embodiment, R represents an alkyne. 4 is one or more hydroxy and one or more C 1‐6 Alkyl-substituted C 1‐6 R according to this embodiment represents an alkyne.4 An example of is (hydroxy)(methyl)butynyl. In a third embodiment, R 4 is trifluoromethyl, halogen, cyano, C 1‐6 Alkyl or C 1‐6 C optionally substituted with alkoxy 5‐8 In one aspect of this embodiment, R represents heteroaryl. 4 is C 5‐8 R according to this embodiment represents heteroaryl. 4 An example of is 2H-triazol-4-yl.

[0046] In general, R 4 is a C substituted with one or more hydroxyl and one or more halogens 1‐6 Alkyl, one or more C 1‐6 C substituted with alkyl and one or more hydroxy 1‐6 Alkyl, one or more hydroxy and one or more C 1‐6 C substituted with alkyl 1‐6 Alkyne, or C 5‐8 represents a heteroaryl.

[0047] Preferably, R 4 is a C substituted with one or more hydroxyl and one or more halogens 1‐6 Alkyl, one or more C 1‐6 C substituted with alkyl and one or more hydroxy 1‐6 Alkyl, or one or more hydroxy and one or more C 1‐6 Alkyl-substituted C 1‐6 Represents an alkyne.

[0048] Typically, R 4 represents (trifluoro)(hydroxy)ethyl, (difluoro)(hydroxy)ethyl, (difluoro)(hydroxy)propyl, (trifluoro)(hydroxy)propyl, (hydroxy)(methyl)butyl, (hydroxy)(methyl)butynyl or 2H-triazol-4-yl.

[0049] In certain embodiments, R 4 represents (trifluoro)(hydroxy)ethyl, (difluoro)(hydroxy)ethyl, (difluoro)(hydroxy)propyl, (trifluoro)(hydroxy)propyl, (hydroxy)(methyl)butyl or (hydroxy)(methyl)butynyl.

[0050] For example, R 4 represents 2,2,2-trifluoro-1-hydroxyethyl, 2,2-difluoro-1-hydroxyethyl, 1,1-difluoro-2-hydroxypropan-2-yl, 1,1,1-trifluoro-2-hydroxypropan-2-yl, 3-hydroxy-3-methylbutyl, hydroxy-3-methylbut-1-ynyl or 2H-triazol-4-yl.

[0051] In further particular embodiments, R 4 represents 2,2,2-trifluoro-1-hydroxyethyl, 2,2-difluoro-1-hydroxyethyl, 1,1-difluoro-2-hydroxypropan-2-yl, 1,1,1-trifluoro-2-hydroxypropan-2-yl, 3-hydroxy-3-methylbutyl or hydroxy-3-methylbut-1-ynyl.

[0052] In the first embodiment, R 5 represents hydrogen. In a second embodiment, R 5 is C optionally substituted with one or more substituents selected from hydroxy and halogen 1‐6 In a first aspect of this embodiment, R 5 is C 1‐6 In a second aspect of this embodiment, R 5 is a C substituted with hydroxy 1‐6 R according to this embodiment represents alkyl. 5 An example of is (hydroxy)methyl.

[0053] In general, R 5 is hydrogen or C substituted by hydroxy 1‐6 Represents alkyl.

[0054] Typically, R 5 represents hydrogen or (hydroxy)methyl.

[0055] Ideally, R 5 represents hydrogen.

[0056] In certain embodiments, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (IB): [ka] where G, R 4 , and R 5 is as defined above.

[0057] A particular subgroup of compounds of formula (IB) according to the invention is represented by formula (IB-a): [ka] where G, R 4 and R 5 is as defined above.

[0058] In a particular embodiment, the present invention relates to a particular subgroup of compounds of formula (IB-a), represented by formula (IB-aa): [ka] where: R 6 and R 7 are independently hydrogen or C 1‐6 represents alkyl, which may be optionally substituted with one or more halogens; and G and R 5 is as defined above.

[0059] In certain embodiments, R 6 is hydrogen or C 1‐6 represents alkyl, and R 7 is C 1‐6 alkyl, which may be optionally substituted with one or more halogens.

[0060] In the first embodiment, R 6 represents hydrogen. In a second embodiment, R 6 is C 1‐6 In one aspect of this embodiment, R 6 represents methyl. In a third embodiment, R 6 is C substituted with one or more halogens 1‐6 In a first aspect of this embodiment, R 6 represents fluoromethyl. In a second aspect of this embodiment, R 6 represents difluoromethyl. In a third aspect of this embodiment, R 6 represents trifluoromethyl.

[0061] In general, R 6 is hydrogen, C 1‐6 C substituted with alkyl or one or more halogens 1‐6 Represents alkyl.

[0062] Preferably, R 6 is hydrogen or C 1‐6 Represents alkyl.

[0063] For example, R 6 represents hydrogen or methyl.

[0064] In the first embodiment, R 7 represents hydrogen. In a second embodiment, R 7 is C 1‐6 In one aspect of this embodiment, R 6 represents methyl. In a third embodiment, R 7 is C substituted with one or more halogens 1‐6In a first aspect of this embodiment, R 7 In a second aspect of this embodiment, R 7 represents difluoromethyl. In a third aspect of this embodiment, R 7 represents trifluoromethyl.

[0065] In general, R 7 is hydrogen, C 1‐6 C substituted with alkyl or one or more halogens 1‐6 Represents alkyl.

[0066] Preferably, R 7 is C substituted with one or more halogens 1‐6 Represents alkyl.

[0067] For example, R 7 represents trifluoromethyl or difluoromethyl.

[0068] In a specific embodiment, the present invention relates to a compound of formula (IB-aa) as defined above, wherein: G is (G c ) represents; X represents C-H or N; R 1 is one or more hydroxy or C 1‐6 Alkoxy-substituted C 1‐6 Represents alkyl; R 2 and R 3 independently represent halogen or cyano; R 5 represents hydrogen; R 6 is hydrogen or C 1‐6 represents alkyl; and R 7 is C substituted with one or more halogens 1‐6 Represents alkyl.

[0069] Illustratively, the present invention relates to a compound of formula (IB-aa) as shown above, wherein: G is (G c ) represents; X represents C-H or N; R 1 represents 1-hydroxyethyl, methoxy or deuterated methoxy; R 2 and R 3 independently represent chloro or cyano; R 5 represents hydrogen; R 6 represents hydrogen or methyl; and R 7 represents trifluoromethyl or difluoromethyl.

[0070] R 6 and R 7 The compound represented by formula (IB-aa) in which R 6 and R 7 It will be apparent to those skilled in the art that the carbon bearing the group can exist in two stereoisomeric forms having either (R) or (S) absolute stereochemical configuration.

[0071] In certain embodiments, the hydroxy, R 6 and R 7 The carbon bearing the has the absolute stereochemical configuration (S).

[0072] Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying Examples, their individual stereoisomers, and their pharmaceutically acceptable salts and solvates.

[0073] Thus, in a particular embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of: 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-6-methoxybenzonitrile; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-2-methoxypyridin-4-yl)ethanone; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-(trideuteriomethoxy)benzonitrile; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indol-4-yl)ethenone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[2,6-dichloro-3-(difluoromethoxy)phenyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aR,5R,8aS)-5-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; 1-[(1S,4aR,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; (1S,4aR,5R,8aS)-N-(2,6-dichlorophenyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxamide; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aS,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2H-triazol-4-yl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile; 1-[(1S,3R,4aR,5R,8aS)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; and 1-[(1S,3R,4aS,5S,8aR)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone.

[0074] The present invention also provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy.

[0075] In another aspect, the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases and / or disorders in which D1 receptors play a role.

[0076] In another aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease drug addiction, sleep disorders, apathy, traumatic spinal cord injury and neuropathic pain.

[0077] In a particular embodiment of this aspect, the invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0078] Thus, in one particular aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of Parkinson's disease and other movement disorders.

[0079] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament useful for the treatment and / or prevention of diseases and / or disorders in which D1 receptors play a role.

[0080] In another further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury and neuropathic pain.

[0081] In a particular embodiment of this aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0082] In one particular aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of Parkinson's disease and other movement disorders.

[0083] The present invention also provides a method for the treatment and / or prevention of disorders in which the administration of a D1 positive allosteric modulator is indicated, said method comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0084] In another aspect, the present invention provides a method for the treatment and / or prophylaxis of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0085] In a particular embodiment of this aspect, the invention provides a method for the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0086] In one particular aspect, the present invention provides a method for the treatment of Parkinson's disease and other movement disorders, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0087] Activity in any of the above therapeutic indications or disorders can, of course, be determined by conducting appropriate clinical trials in a manner known to those skilled in the relevant art for the particular indication and / or in clinical trial design in general.

[0088] When used in medicine, the salt of the compound of formula (I) will be a pharmaceutically acceptable salt. However, other salts may also be useful in preparing the compounds used in the present invention or their pharmaceutically acceptable salts. The standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include, for example, acid addition salts that can be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0089] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents or with water.

[0090] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The technical term "co-crystal" is used to describe a situation in which neutral molecular components exist in a crystalline compound in a defined stoichiometric ratio. By preparing pharmaceutical co-crystals, the crystalline form of an active pharmaceutical ingredient can be modified, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0091] The compounds according to the present invention may exist in different polymorphic forms, and although not explicitly stated in the above formula, all such forms are intended to be included within the scope of the invention.

[0092] The present invention also includes within its scope prodrug forms of the compounds of formula (I) and its various subscopes and subgroups.

[0093] To treat a disease, the compounds of formula (I) or their pharmaceutically acceptable salts may be employed in an effective daily amount and administered in the form of a pharmaceutical composition.

[0094] Accordingly, another embodiment of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0095] To prepare pharmaceutical compositions according to the present invention, one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to those skilled in the art.

[0096] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, or nasal.

[0097] Pharmaceutical compositions containing compounds according to the invention can be administered, for example, orally, parenterally, ie, intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or intranasally.

[0098] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may be in the form of, for example, tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gums, or the like.

[0099] For this purpose, the active ingredient can be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain binders such as microcrystalline cellulose, tragacanth gum or gelatin, disintegrating agents such as alginic acid, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or coloring agents or flavoring agents such as peppermint or methyl salicylate.

[0100] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are generally in conventional forms such as aqueous or oily solutions or suspensions contained in ampoules, disposable syringes, glass or plastic vials, or infusion containers.

[0101] In addition to the active ingredient, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, saline, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent, an antibacterial agent such as benzyl alcohol, an antioxidant such as ascorbic acid or sodium bisulfite, a chelating agent such as ethylenediaminetetraacetic acid, a buffer such as acetate, citrate or phosphate, an agent for adjusting osmotic pressure such as sodium chloride or dextrose, and the like.

[0102] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0103] The amount of active ingredient in a pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the patient's sex, age, weight, and condition, as well as the method of administration. Thus, the amount of the compound of formula (I) in a composition for oral administration is at least 0.5% by weight and can be up to 80% by weight, relative to the total weight of the composition.

[0104] It has also been found in accordance with the present invention that the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically active ingredients.

[0105] In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight, relative to the total weight of the composition. For preferred parenteral compositions, the dosage unit is in the range of 0.5 mg to 3000 mg of compound of formula (I).

[0106] The daily dosage of the compound of formula (I) can fall within a wide range of dosage units, generally in the range of 0.5 to 3000 mg. However, it should be understood that the specific dosage can be adapted to a particular case according to the individual requirements, at the discretion of the physician.

[0107] It will be apparent to one skilled in the art that there may be a variety of synthetic routes to the compounds according to the invention. The following processes are intended to illustrate some of these synthetic routes, but should not be construed in any way as limiting the methods for making the compounds according to the invention.

[0108] Compounds of formula (I) where Z=NH may be prepared by a process comprising the reaction of an intermediate of formula (II-U) with an intermediate of formula (III). [ka] where G, R 4 and R 5 is as defined above.

[0109] The reaction is conveniently carried out in the presence of a base such as triethylamine, in a suitable solvent such as dichloromethane, at room temperature.

[0110] Compounds of formula (I) where Z=CH2 can be prepared by a process comprising the reaction of an intermediate of formula (II) with an intermediate of formula (III): [ka] where G, R 4 and R 5 is as defined above.

[0111] The reaction is conveniently carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate in a suitable solvent such as dimethylformamide, together with a catalytic amount of 4-methylmorpholine.

[0112] Alternatively, the reaction can be carried out in the presence of a classical coupling agent such as a benzotriazolyl derivative (e.g., BOP), a uronium derivative (e.g., HBTU, COMU (registered trademark), etc.), or other reagents known to those skilled in the art, in a solvent such as N,N-dimethylformamide, dichloromethane, etc., in the presence of a base such as triethylamine, diisopropylethylamine, etc.

[0113] R 5 represents hydrogen, and R 4 is substituted with a hydroxy group 1‐6 Represents alkyl, i.e., R 4 =‐C(OH)R 6 R 7 Compounds of formula (I), which are: can be prepared by a process comprising reaction of intermediate (Ia): [ka] where G and Z are as defined above, and R 6is as defined below.

[0114] R 6 represents hydrogen, and R 7 When represents difluoromethyl or trifluoromethyl, the reaction is conveniently carried out in the presence of difluoro- or trifluoromethyl-trimethylsilane in the presence of caesium fluoride in a suitable solvent such as DMF.

[0115] R 6 represents difluoromethyl or trifluoromethyl, R 7 When represents methyl, the reaction may be carried out using a methylmagnesium halide, such as methylmagnesium chloride, in a suitable solvent, such as THF, according to methods known to those skilled in the art.

[0116] R 6 Intermediates of formula (Ia) in which represents hydrogen can be prepared by functional group transformation of intermediates of formula (Ib) [ka] Here, G and Z have the same definitions as above.

[0117] This reaction can be carried out according to a two-step sequence comprising (i) a Wittig reaction of a phosphorus ylide prepared from a phosphonium salt, preferably (methoxymethyl)triphenylphosphonium chloride, with a base such as n-butyllithium or sodium tert-butoxide in tetrahydrofuran at −78° C., followed by (ii) acidic hydrolysis of the enol ether intermediate with an acid solution such as hydrochloric acid at room temperature.

[0118] R 6 wherein R represents difluoromethyl or trifluoromethyl, 4 Ga-C(OH)R 6 R 7 represents R 7represents hydrogen. This reaction can be carried out using an oxidizing agent such as Dess-Martin periodinane, or other reagents known to those skilled in the art.

[0119] R 5 represents hydrogen, and R 4 is the formula -(CH2)2C(R t R u )OH hydroxy group substituted C 1‐6 Compounds of formula (I) representing alkyl can be prepared by a process comprising the reduction of intermediate (Ic): [ka] where G and Z have the same definitions as above, and R t and R u =C1-C3 alkyl.

[0120] This reaction can conveniently be carried out under hydrogen pressure in a suitable solvent such as ethanol at room temperature in the presence of a catalytic amount of Pd / C or other catalyst known to those skilled in the art.

[0121] Intermediate (Ic) can be prepared by reacting intermediate (Id) with the compound of formula R t R u It can be prepared by reaction of C=O with a ketone, [ka] where G, Z, R t and R u has the same definition as above. This reaction can be carried out by deprotonation with a strong base, for example n-butyllithium, in a suitable solvent such as THF at −78° C., followed by the addition of the appropriate ketone R t R u This can be achieved by hydroxyalkylation at C=O.

[0122] The intermediate of formula (Id) is R 6=H in a suitable solvent such as methanol using 1-diazo-1-dimethoxyphosphoryl-propan-2-one in the presence of a base such as potassium carbonate at room temperature (Seyferth-Gilbert homologation with Ohira-Bestmann reagent), or by any method known to those skilled in the art.

[0123] R 5 represents hydrogen, and R 4 C 5‐8 represents heteroaryl, i.e., R 4 Some compounds of formula (I) where = 2,3,4-triazolyl can be prepared by reaction of intermediate (Id) with an azide reagent such as sodium azide or trimethylsilyl azide, or according to any method known to one skilled in the art.

[0124] G is (G c ), X represents N, and R 1 is the formula C(OH)R w R z C substituted by a hydroxy group of 1‐6 Compounds of formula (I) representing alkyl can be prepared by a process comprising the reaction of intermediate (Ie): [ka] where Z, R 2 , R 3 , R 4 and R 5 has the same definition as above for compounds of formula (I), and R w is defined here below.

[0125] R w represents methyl, and R z When represents hydrogen, the reaction is conveniently carried out in a suitable solvent such as methanol using a reducing agent such as sodium borohydride at 0° C., or according to any method known to those skilled in the art.

[0126] Rw represents methyl, and R z When represents methyl, the reaction is conveniently carried out using methyllithium in a suitable solvent such as THF at 0° C., or according to any method known to those skilled in the art.

[0127] R w represents hydrogen or methyl, R z When represents difluoromethyl or trifluoromethyl, the reaction is conveniently carried out in the presence of difluoro- or trifluoromethyl-trimethylsilane in the presence of caesium fluoride in a suitable solvent such as DMF.

[0128] R w represents hydrogen, the intermediate of formula (Ie) is 1 represents CH2OH, Z, R 2 , R 3 , R 4 and R 5 where R has the same definition as above, can be prepared by oxidizing a compound of formula (I). This reaction can be conveniently carried out using an oxidizing agent such as manganese dioxide in a suitable solvent such as 1,4-dioxane at 70°C, or by other methods known to those skilled in the art.

[0129] R w Intermediates of formula (Ie) in which represents methyl may be conveniently prepared by acidic hydrolysis of intermediates of formula (If): [ka] where Z, R 2 , R 3 , R 4 and R 5 has the same definition as above, and R y is C 1‐3 The reaction may be conveniently carried out using an acid such as hydrochloric acid in a suitable solvent such as THF at room temperature.

[0130] The intermediate of formula (If) in which Z represents CH2 may be prepared by a process comprising the reaction of an intermediate of formula (IIf) with an intermediate of formula (III): [ka] where R y , R 2 , R 3 , R 4 and R 5 is as defined above.

[0131] The reaction is conveniently carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate in a suitable solvent such as dimethylformamide, together with a catalytic amount of 4-methylmorpholine.

[0132] Alternatively, the reaction can be carried out in the presence of a classical coupling agent such as a benzotriazolyl derivative (e.g., BOP) or a uronium derivative (e.g., HBTU, COMU (registered trademark)), or a reagent known to those skilled in the art, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as N,N-dimethylformamide or dichloromethane.

[0133] R 5 Compounds of formula (I) in which Z represents C1-C6 alkyl substituted by a hydroxy group, in particular CH2-OH, can be prepared by a process comprising the reaction of an intermediate of formula (II) in which Z represents CH2 or an intermediate of formula (II-U) in which Z represents NH, with an intermediate of formula (III-S) as defined above, [ka] where X and R 2 , R 3 and R 4 is as defined above.

[0134] When Z represents CH2, the reaction is conveniently carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate in a suitable solvent such as dimethylformamide with a catalytic amount of 4-methylmorpholine.

[0135] Alternatively, the reaction may be carried out in the presence of a classical coupling agent such as a benzotriazolyl derivative (e.g., BOP), a uronium derivative (e.g., HBTU, COMU®), or other reagent known to those skilled in the art, in a solvent such as N,N-dimethylformamide, dichloromethane, or the like, in the presence of a base such as triethylamine, diisopropylethylamine.

[0136] When Z represents NH, the reaction is conveniently carried out in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, at room temperature. The hydroxyl group may first be protected with a suitable protecting group, such as tert-butyldimethylsilyl, or other group known to those skilled in the art, and deprotected after the coupling reaction by any method known to those skilled in the art.

[0137] The intermediate of formula (III-S) can be prepared by ring-opening the intermediate of formula XII: [ka] where R 4 is defined as above. The reaction is conveniently carried out using a base such as sodium hydroxide in a suitable solvent such as ethanol at 80°C.

[0138] The intermediate of formula (Ib) can be prepared according to a process comprising reacting an intermediate of formula (II), where Z represents CH, or an intermediate of formula (II-U), where Z represents NH, with an intermediate of formula (IV), as defined above, under conditions similar to those described for the coupling of an intermediate of formula (II) with an intermediate of formula (III). [ka]

[0139] The intermediate of formula (IV) can be prepared by deprotecting the intermediate of formula (V): [ka] where P is a protecting group, such as a tert-butoxycarbonyl (Boc) group or benzyloxycarbonyl (Cbz). The reaction is conveniently carried out in the presence of an acid, such as trifluoroacetic acid or hydrochloric acid, or according to any method known to those skilled in the art.

[0140] The intermediate of formula (V) can be prepared by oxidizing the intermediate of formula (VI). [ka]

[0141] This reaction can be carried out using an oxidizing agent such as sodium hypochlorite in an acidic medium at low temperature, or with other oxidizing agents known to those skilled in the art.

[0142] The intermediate of formula (VI) can be prepared by reduction of a phenolic intermediate of formula (VII). [ka]

[0143] This reaction can be carried out by hydrogenation in the presence of a metal catalyst, such as rhodium on activated carbon, in a polar solvent, such as isopropanol, at a temperature in the range of 80-110°C, or according to any conditions known to one skilled in the art.

[0144] The intermediate of formula (VI) can be prepared by hydroxylation of the intermediate of formula (VIII): [ka] where Y is a halogen such as bromine.

[0145] This reaction can be carried out using a metal hydroxide, such as potassium hydroxide, in the presence of a palladium catalyst, such as t-BuXPhos-palladium, in a polar solvent such as 1,4-dioxane / water at a temperature in the range of 75-90°C, or according to conditions known to those skilled in the art.

[0146] The intermediate of formula (VIII) may be prepared by a process comprising reaction of an intermediate of formula (IX): [ka] where Y is as defined above.

[0147] The reaction is conveniently carried out in the presence of a suitable reducing agent, for example sodium borohydride, in a suitable solvent, for example ethanol, at reduced temperature, according to methods known to those skilled in the art.

[0148] The intermediate of formula (VIII) may be prepared by a process comprising reaction of an intermediate of formula (X): [ka] where Y is as defined above.

[0149] The reaction is conveniently carried out in the presence of a transition metal salt, for example iron chloride, in a suitable solvent, for example dichloromethane, in the presence of oxalyl chloride at low temperature.

[0150] The intermediate of formula (X) can be prepared by a process comprising the reaction of commercially available intermediate (XI): [ka] where Y is as defined above.

[0151] R 4 is a hydroxy group, i.e., C(OH)R 6 R 7 C replaced by 1‐6 The intermediate of formula (XII) representing an alkyl group can be prepared by reducing the intermediate of formula (XIII). [ka]

[0152] R 6 represents hydrogen, and R 7 When represents difluoromethyl or trifluoromethyl, the reaction is conveniently carried out in the presence of difluoro- or trifluoromethyl-trimethylsilane in the presence of caesium fluoride in a suitable solvent such as DMF.

[0153] R 6 represents difluoromethyl or trifluoromethyl, R 7 When represents methyl, the reaction may be carried out using a methylmagnesium halide, such as methylmagnesium chloride, in a suitable solvent, such as THF, according to methods known to those skilled in the art.

[0154] R 6 Intermediates of formula (XIII) in which represents hydrogen can be prepared by functional group transformation of intermediates of formula (XIV) [ka]

[0155] This reaction can be carried out according to a two-step sequence comprising (i) a Wittig reaction with a phosphorus ylide prepared from a phosphonium salt, preferably (methoxymethyl)triphenylphosphonium chloride, and sodium tert-butoxide in tetrahydrofuran at −78° C., followed by (ii) acidic hydrolysis of the enol ether intermediate with an acid solution such as hydrochloric acid at room temperature.

[0156] R 6The intermediate of formula (XIII) is R 4 Ga-C(OH)R 6 R 7 represents R 7 represents hydrogen. This reaction can be conveniently carried out using Dess-Martin periodinane or by any oxidizing agent known to those skilled in the art.

[0157] The intermediate of formula (XIV) can be prepared by oxidizing the intermediate of formula (XV): [ka]

[0158] This reaction may be carried out at room temperature using an oxidizing agent such as Dess-Martin periodinane, or other oxidizing agents known to those skilled in the art.

[0159] The intermediate of formula (XV) can be prepared by reduction of a phenolic intermediate of formula (XVI): [ka]

[0160] This reaction can be carried out by hydrogenation in the presence of a metal catalyst, such as rhodium on activated carbon, in a polar solvent, such as isopropanol, at a temperature in the range of 80-110°C, or according to any conditions known to one skilled in the art.

[0161] The intermediate of formula (XVI) can be prepared by hydroxylation of the intermediate of formula (XVII): [ka] where Y is a halogen such as bromine.

[0162] This reaction can be carried out using a metal hydroxide, such as potassium hydroxide, in the presence of a palladium catalyst, such as t-BuXPhos-palladium, in a polar solvent such as 1,4-dioxane / water at a temperature in the range of 80-100°C, or according to conditions known to those skilled in the art.

[0163] The intermediate of formula (XVII) may be prepared by a process comprising reaction of an intermediate of formula (XVIII). [ka] Here, Y represents a halogen, i.e., bromine.

[0164] This reaction can be carried out using a coupling agent such as carbonyldiimidazole (CDI) in a suitable solvent such as DCM or DMF in the presence of a base such as diisopropylethylamine at room temperature, or according to any method known to one skilled in the art.

[0165] The intermediate of formula (XVIII) can be prepared by deprotecting the intermediate of formula (XIX): [ka] where Y represents a halogen, i.e., bromine, and P represents a protecting group such as tert-butyldimethylsilyl. This reaction can be carried out at room temperature in a polar solvent such as 2-propanol, in the presence of an acid such as hydrochloric acid, or according to any method known to those skilled in the art.

[0166] Intermediates of formula (XIX) may be prepared by a process comprising reaction of an intermediate of formula (XX), wherein Y and P are as defined above. [ka]

[0167] The reaction is conveniently carried out in the presence of methylmagnesium chloride in a suitable solvent such as tetrahydrofuran at low temperature.

[0168] Intermediate (XX) can be prepared by a two-step process involving reaction of an intermediate of formula (XXI): [ka] where Y is as defined above and P represents hydrogen or tert-butyl-dimethylsilyl.

[0169] In a first step, intermediate (XXII) in which P represents hydrogen is reacted with tert-butyldimethylsilyl chloride in the presence of a suitable base, for example 4-dimethylamino-pyridine, at room temperature to give intermediate (XXI) in which P represents tert-butyldimethylsilyl.

[0170] In a second step, intermediate (XXI), in which P represents tert-butyl-dimethylsilyl, is reacted with N-chlorosuccinimide (NCS) in a suitable solvent, such as THF, to produce intermediate (XX).

[0171] Intermediate (XXII), in which P represents hydrogen, can be prepared by a process involving an intermediate of formula (XXIII), in which Y is as defined above. [ka]

[0172] The reaction is conveniently carried out in the presence of a strong base, such as sodium hydroxide, in a suitable solvent, such as a mixture of ethanol and water, at elevated temperature.

[0173] The intermediate of formula (XXIII) can be prepared by a process comprising reaction of intermediate (XXIV): [ka] where Y is as defined above.

[0174] The reaction is conveniently carried out in the presence of trimethylsilyl triflate and paraformaldehyde in a suitable solvent such as dichloromethane.

[0175] Intermediate (XXIV) can be prepared in a two-step process involving commercially available intermediate (XXV): [ka] where Y is as defined above.

[0176] The reactions are conveniently carried out according to methods described in the accompanying examples or methods known to those skilled in the art.

[0177] The intermediate of formula (III) may alternatively be prepared by a process comprising reaction of an intermediate of formula (IIIa): [ka] Here, Y represents a halogen, for example, bromo.

[0178] Some intermediates of formula (III) can be prepared by reacting intermediates of formula (IIIa) with intermediates of formula R in the presence of a transition metal complex, typically a palladium complex, and a base, according to methods known to those skilled in the art. 4 -Y 1 (where Y 1 represents hydrogen, halogen or a boronic acid derivative), the reaction is conveniently carried out in a suitable solvent at elevated temperature.

[0179] The following describes some of these conditions for specific groups: (i)R 4 C 1‐6In the case where alkyl represents, the reaction could be carried out by first reacting intermediate (IIIa) with a vinylboronic acid / boronic ester in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base, followed by reduction under hydrogen pressure in the presence of a transition metal catalyst such as Pd / C in a suitable solvent such as ethanol under conditions known to those skilled in the art. (ii)R 4 C 5‐8 When heteroaryl is represented, the reaction can be carried out by reacting intermediate (IIIa) with a heteroaryl boronic acid / boronic ester in the presence of a transition metal catalyst, such as tetrakis(triphenylphosphine)palladium(0), and a base, under conditions known to those skilled in the art.

[0180] The intermediate of formula (IIIa) can be prepared by hydrogenating the intermediate of formula (VIII) in the presence of a catalyst such as rhodium on charcoal in a suitable solvent such as methanol, or by any method known to those skilled in the art. Prior to the hydrogenation step, those skilled in the art may consider first protecting the amine with a protecting group such as tert-butoxycarbonyl (Boc), followed by deprotection according to any method that would be known to those skilled in the art.

[0181] R 4 is a hydroxy group, i.e., C(OH)R 6 R 7 C replaced by 1‐6 The intermediate of formula (III) representing alkyl can be prepared by deprotection of intermediate (IIIb), [ka] where P is a protecting group, such as a tert-butoxycarbonyl (Boc) group or a benzyloxycarbonyl (Cbz) group. The reaction is conveniently carried out in the presence of an acid, such as trifluoroacetic acid or hydrochloric acid, or according to any method known to those skilled in the art.

[0182] The intermediate of formula (IIIb) can be prepared by reducing the intermediate of formula (IIIc): [ka] where P is as defined above and R 6 is defined as follows:

[0183] R 6 represents hydrogen, and R 7 When represents difluoromethyl or trifluoromethyl, the reaction is conveniently carried out in the presence of difluoro- or trifluoromethyl-trimethylsilane in the presence of caesium fluoride in a suitable solvent such as DMF.

[0184] R 6 represents difluoromethyl or trifluoromethyl, R 7 When represents methyl, the reaction may be carried out using a methylmagnesium halide, such as methylmagnesium chloride, in a suitable solvent, such as THF, according to methods known to those skilled in the art.

[0185] R 6 The intermediate of formula (IIIc), in which P represents hydrogen, can be prepared by functional group transformation of the intermediate of formula V, in which P has the same definition as above. This reaction can be carried out according to a two-step sequence comprising: (i) a Wittig reaction with a phosphorus ylide prepared from a phosphonium salt, preferably (methoxymethyl)triphenylphosphonium chloride, and n-butyllithium in tetrahydrofuran at −78° C., followed by (ii) acidic hydrolysis of the enol ether intermediate with an acid solution such as hydrochloric acid at room temperature.

[0186] R 6 wherein R represents difluoromethyl or trifluoromethyl, 4 Ga-C(OH)R 6 R 7 represents R 7represents hydrogen. This reaction can be carried out using any oxidizing agent known to those skilled in the art.

[0187] Alternatively, some intermediates of formula (III) may be formed by adding X, R 1 , R 2 , R 3 and R 4 as defined above. This reaction can be carried out by hydrolysis under basic conditions using a metal hydroxide, such as lithium hydroxide, in an aqueous medium at elevated temperature, or according to any conditions known to those skilled in the art.

[0188] G is (G c The intermediate of formula (II) representing [ka] where: R 9 is cyano or -COOR c represents; R c is C 1‐6 represents alkyl; and X, R 1 , R 2 and R 3 is as defined above.

[0189] R 9 ga-COOR c represents the reaction is conveniently carried out in the presence of a suitable base, for example lithium hydroxide, in a suitable solvent, for example water, according to methods known to those skilled in the art.

[0190] R 9 When represents cyano, the reaction is conveniently carried out in the presence of a strong acid, for example sulphuric acid, or a strong base, for example sodium hydroxide, in a suitable solvent, for example a polar solvent such as water or ethanol, at elevated temperature.

[0191] The intermediate of formula (IIa) can be prepared by a process comprising decarboxylation of an intermediate of formula (IIb): [ka] where X and R 1 , R 2 , R 3 , R c and R 9 is as defined above.

[0192] R 9 ga-COOR c represents R c When is as defined above, the decarboxylation is conveniently carried out in the presence of lithium chloride in a suitable solvent, for example a mixture of water and dimethylsulfoxide, at elevated temperature.

[0193] R 9 When represents cyano, decarboxylation is conveniently carried out in the presence of a suitable acid, for example trifluoroacetic acid, in a suitable solvent, for example dichloromethane, at elevated temperature.

[0194] Alternatively, the intermediates of formula (IIa) and (IIb) can be an intermediate of formula (IIc) [ka] where Y 1 represents halogen, such as fluoro, bromo or iodo; X, R 1 , R 2 , R 3 is as defined above; and the formula CHR d R 9 Compounds of; where: R d are hydrogen or MY; or -COOR c represents; M is a metal, for example zinc; and R c , R 9 and Y is as defined above It can be prepared by a process comprising reacting

[0195] R d When represents hydrogen, the reaction is conveniently carried out in the presence of a suitable base, for example lithium hydroxide, in a suitable solvent, for example water, according to methods known to those skilled in the art.

[0196] R d ga-COOR c represents the reaction is conveniently carried out in the presence of an inorganic base such as caesium carbonate in a suitable solvent such as dimethylformamide at elevated temperature.

[0197] R d When represents MY, the reaction is conveniently carried out in the presence of a transition metal catalyst complex such as tri[(tert-butyl)phosphine]Pd(II) in a suitable solvent such as THF at elevated temperature.

[0198] Or, if G is (G c Intermediates of formula (II) representing ) can be prepared by a process comprising carboxylation of an intermediate of formula (IId). [ka] where R e represents methyl, and X, R 1 , R 2 and R 3 is as defined above. The reaction is conveniently carried out using a base such as potassium tert-butoxide and dimethyl carbonate in a suitable solvent such as DMF at room temperature.

[0199] G is (G c The intermediate of formula (IIf) representing [ka] where W represents 1-ethoxyvinyl and R9 HA-COOR c represents R c is C 1‐6 represents alkyl, and X and R 2 and R 3 is as defined above. The reaction is conveniently carried out in the presence of a suitable base, for example lithium hydroxide, in a suitable solvent, for example water, according to methods known to those skilled in the art.

[0200] The intermediate of formula (IIg) can be prepared from the intermediate of formula (IIh) by a coupling reaction: [ka] where Y 2 represents halogen, and X, R 9 , R c , R 2 and R 3 is as defined above. The reaction can be carried out by Still-type coupling of a stannyl reagent such as tributyl(1-ethoxyvinyl)tin in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) at elevated temperature in a suitable solvent such as toluene, or by any alternative method known to those skilled in the art.

[0201] G is (G a ) or (G b ) (respectively, the intermediates of formula (II) (G a ) or II-(G b ) is represented as: [ka] where R a is hydrogen or C 1‐6 represents alkyl, i.e., methyl, and R b is C 1‐6 represents alkyl or halogen, i.e., chlorine, i.e., fluorine, and X 1 represents N or CH, and X, R 3 and R 9 is defined above) is the same as G (Gc The intermediates of formula (II) may be prepared according to the methods described above for the intermediates of formula (II)

[0202] Alternatively, R b represents halogen, i.e., chlorine, in formula II-(G a ) intermediate is R b represents hydrogen; a This reaction can be conveniently carried out using a chlorinating agent such as N-chlorosuccinimide in a suitable solvent such as dichloromethane at room temperature, or by any method known to those skilled in the art.

[0203] Or X 1 represents N and R b represents hydrogen, and R 3 represents halogen, i.e., chlorine, in formula II-(G a ) is an intermediate of formula II-(G aa ) by reaction of the intermediate [ka] where R 3 represents amino, and R a , X, X 1 and R 9 is as defined above.

[0204] The reaction is conveniently carried out by adding concentrated hydrochloric acid and sodium nitrite, followed by hydrochloric acid and copper(II) chloride, and is conveniently carried out at low temperatures.

[0205] Formula II-(G aa ) intermediate is R 3 Formula II-(G aa ) can be prepared by reducing the intermediate of formula (II). This reaction is conveniently carried out by Pd / C catalyzed hydrogenation under high pressure in a suitable solvent such as methanol.

[0206] R 3Intermediate II-(G) represents nitro aa ) is represented by the formula (II-G ab ) [ka] where R a , X, X 1 is as defined above, and R 3 is nitro.

[0207] This reaction is X 3 represents halogen, i.e., chlorine, and R 9 Formula X, where 3 -CH2-R 9 is conveniently carried out using a reagent of the formula (I) in a suitable solvent such as THF in the presence of a base such as potassium tert-butoxide at low temperature.

[0208] Alternatively, R b represents halogen, i.e., chlorine, in formula II-(G b ) is an intermediate of formula II-(G d ) [ka] where X 1 represents N, X, R 3 and R 9 is as defined above. This reaction can be carried out using phosphorus oxychloride in the presence of N,N-dimethylaniline at a temperature ranging from 90 to 120° C., or by any alternative method known to those skilled in the art.

[0209] Formula II-(G d The intermediate of formula (II-G e ) [ka] where X 1represents NH2, and X, R 3 and R 9 is as defined above. This reaction can be carried out using a coupling agent such as carbonyldiimidazole in a suitable solvent such as THF at room temperature.

[0210] Formula (IId), (IIe), II-(G a ), II‐(G ab ), and II‐(G e Intermediates of formula (I) are commercially available or can be prepared by processes involving a series of reactions known to those skilled in the art.

[0211] Where any of the above-described processes for the preparation of compounds or intermediates according to the invention gives rise to a mixture of products, the desired products may be separated therefrom at an appropriate stage by conventional methods such as, for example, preparative HPLC; or normal phase column chromatography, employing, for example, silica and / or alumina in combination with a suitable solvent system.

[0212] If the above-described process for preparing the compounds according to the present invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of the compound of formula (I) or intermediate (II) or (III), this can be prepared from the corresponding mixture of enantiomers using any suitable conventional procedure for separating enantiomers. Thus, for example, diastereomeric derivatives, e.g., salts, can be prepared by reacting a mixture of enantiomers, e.g., a racemate of formula (I), with a suitable chiral compound, e.g., a chiral base. The diastereomers can then be separated by any convenient means, e.g., crystallization, and the desired enantiomer can be recovered, e.g., by treatment with an acid if the diastereomer is a salt. In another separation process, the racemate of formula (I) can be separated using chiral HPLC or chiral SFC.

[0213] Furthermore, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the above processes. Alternatively, a specific enantiomer can be obtained by enantiospecific enzymatic biotransformation, e.g., ester hydrolysis using an esterase, followed by purification of the enantiomerically pure hydrolyzed acid from the unreacted ester antipodes. Chromatography, recrystallization, and other conventional separation procedures can also be used on intermediates or final products where it is desired to obtain a specific geometric isomer of the present invention. Alternatively, the undesired enantiomer can be racemized to the desired enantiomer in the presence of an acid or base according to methods known to those skilled in the art or as described in the accompanying examples.

[0214] In any of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by conventional protecting groups, for example, as described in Protective Groups in Organic Chemistry, ed. J.F.W.M. Comie, Plenum Press, 1973; and T.W. Greene & P.G.M. Buts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0215] The compounds of formula (I) according to the present invention do not directly activate dopamine D1 receptors, but rather potentiate the effects of D1 agonists or dopamine, the endogenous ligand of D1 receptors, via an allosteric mechanism, and therefore can be said to be D1 positive allosteric modulators (D1 PAMs).

[0216] D1 agonists, including dopamine, directly activate dopamine D1 receptors.

[0217] The assays are designed to measure the effect of compounds according to the invention in the absence ("activation assay") and in the presence of dopamine ("potentiation assay").

[0218] The activation assay measures stimulation of cyclic adenosine monophosphate (cAMP) production in a homogeneous time-resolved fluorescence (HTRF) assay, with 100% activation defined as the maximal increase in cAMP with increasing concentrations of the endogenous agonist, dopamine.

[0219] When tested, compounds of formula (I) according to the invention lack significant direct agonist-like effects in that they produce less than 20% activation (compared to the dopamine maximal response) when present at a concentration of 10 μM.

[0220] The potentiation assay measures the ability of compounds to increase the levels of cAMP produced by a low-threshold concentration of dopamine. The concentration of dopamine used ([EC 20 ]) is designed to stimulate 20% of the maximal response (100%) seen with increasing concentrations of dopamine. To measure this potentiation, the [EC 20 The mixture is incubated with increasing concentrations of a compound with the formula [Chemical structure: ], the potentiation is measured as an increase in cAMP production, and the concentration of compound that produces 50% of the potentiation of cAMP levels is determined.

[0221] When tested in the cAMP HTRF assay, compounds of formula (I) according to the present invention generally exhibit a pEC 50 The values ​​of β-D1 were greater than about 5.5, ideally greater than about 6.5, and suitably greater than about 7.0, indicating that they were D1 positive allosteric modulators. Specific values ​​are reported in Table A of the Examples.

[0222] GABA AReceptor inhibition is known to be closely related to seizures and epilepsy, so the development of compounds that act as D1 positive allosteric modulators while minimizing such effects is highly desirable.

[0223] GABA as described herein A Thus, when tested in a receptor inhibition assay, compounds of formula (I) according to the present invention inhibit the GABA receptor activity by about 20% or less, ideally about 10% or less, suitably about 5% or less, when measured at a concentration of 10 μM of the compound of formula (I), as further shown in Table B of the Examples. A It is desirable to show the percentage of receptor inhibition.

[0224] A potential problem encountered in developing compounds for therapeutic use is the ability of certain compounds to inhibit CYP450 enzymes. Inhibition of such enzymes can affect the exposure of such compounds or other compounds that may be administered to a patient together, thereby altering their respective safety or efficacy. Therefore, it is desirable to develop compounds that minimize the potential for such inhibition.

[0225] The CYP450 inhibitory ability of compounds of formula (I) according to the invention has been tested by measuring the potential reduction in CYP450 activity in human hepatocytes incubated with increasing concentrations of compounds according to the invention.

[0226] When tested in a CYP3A4 inhibition assay at a concentration of 20 μM according to the protocol described in this patent application, the compounds of formula (I) according to the present invention generally exhibit an inhibition rate of less than about 80%, preferably about 70% or less, ideally about 60% or less, ideally about 40% or less, and preferably about 20% or less, as further shown in Table C of the Examples. [Example]

[0227] Experimental section Abbreviations / Recurring Reagents Ac: Acetyl ACN: acetonitrile Brine: saturated aqueous sodium chloride solution nBu: n-butyl tBu: tert-butyl tBuXPhos palladacycle: [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) chloride CDI: carbonyldiimidazole dba: dibenzylidene acetonate DCM: dichloromethane DEA: Diethylamine DHP: 3,4-dihydropyran DIPEA: N,N-diisopropylethyamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EC 20 / 50 : Concentration that produces 20% / 50% of the maximum response Erel: Relative Effectiveness ES + : Electrospray positive ionization Et: Ethyl EtOH: ethanol Et2O: Diethyl ether EtOAc: ethyl acetate h: time HBTU: [Benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylammonium hexafluorophosphate HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC: High-Performance Liquid Chromatography HTRF: Homogeneous time-resolved fluorescence IPAC: Isopropyl acetate LC: liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry LDA: lithium diisopropylamide Me: Methyl MeOH: Methanol min.:minutes NCS: N-chlorosuccinimide NMR: nuclear magnetic resonance iPr: Isopropyl iPrOH: Isopropanol p-TSA: p-toluenesulfonic acid rt: room temperature RT: retention time SFC: Supercritical Fluid Chromatography SPE: solid phase extraction TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: Trimethylsilyl UPLC: Ultra-high performance liquid chromatography Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. cAMP: cyclic adenosine monophosphate

[0228] IUPAC names were generated using Biovia Draw Version 19.1 (2019) or Ver. 20.1 (2020).

[0229] Analysis method All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere using dry solvents and glassware. Experiments requiring microwave irradiation were performed using a Biotage Initiator Sixty microwave oven, with the operating software upgraded to version 2.0. Experiments were performed to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercially available solvents and reagents were usually used without further purification; anhydrous solvents were also used when appropriate (typically Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions were generally followed by thin-layer chromatography, HPLC, or mass spectrometry.

[0230] HPLC analysis was performed on a Shimadzu HPLC system equipped with an LC-2010 CHT module and an SPD-M20A photodiode array detector (210-400 nm) using a YMC Triart C-18 (150 x 4.6) mm 3µ column. Gradient elution was performed with 5 mM ammonium formate in water + 0.1% ammonia (phase A), acetonitrile + 5% solvent A + 0.1% ammonia (phase B), with a gradient of 5-95% B at 8.0 min hold, 13.0 min hold, and 5% B at 15.0 min hold, 18.0 min hold. HPLC flow rate.

[0231] It will be apparent to one skilled in the art that different analytical conditions will result in different retention times (RT) for the LC data.

[0232] Mass spectrometry measurements in LCMS mode were performed using various methods and instruments: -Basic LCMS method 1: LC-MS analysis was performed using a Shimadzu 2010EV single quadrupole mass spectrometer. This spectrometer was equipped with an ESI source, an LC-20AD binary gradient pump, and an SPD-M20A photodiode array detector (210–400 nm). Data were acquired in both positive and negative modes using MS full scans from m / z 70 to 1200. Reversed-phase analysis was performed using a Waters XBridge C 18 (30 × 2.1) mm 2.5 μm column. Gradient elution was performed with 5 mM ammonium formate + 0.1% NH4OH in H2O (solvent A) or ACN + 5% solvent A + 0.1% NH4OH (solvent B). The gradient elution was performed in 4.0 min, from 5 to 95% B, held to 5.0 min, and then at 5.1 min to 5% B, held to 6.5 min. The HPLC flow rate was 1.0 mL / min, and the injection volume was 5 μL.

[0233] -Basic LCMS method 2: LCMS analysis was performed using a QDA Waters simplified quadrupole mass spectrometer. The spectrometer was equipped with a UPLC Acquity Classic with an ESI source and a diode array detector (210–400 nm). Data were acquired in positive / negative mode with a base elution, with a full MS scan from m / z 70 to 800. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm) column at 45 °C with a base elution. Gradient elution was performed with H2O / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / H2O / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Full flow rate on MS. [Table 1]

[0234] -Acid LCMS method 1: LCMS analysis was performed using a QDA Waters simplified quadrupole mass spectrometer. The spectrometer was equipped with an ESI source and a UPLC Acquity with a diode array detector (200–400 nm). Data were acquired as a full MS scan from m / z 70 to 800 in positive / negative mode with acidic elution. Reversed-phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 50 mm) column at 45 °C with acidic elution. Gradient elution was performed with HO / ACN / TFA (95 / 5 / 0.05%) (solvent A) and ACN (solvent B). [Table 2]

[0235] Some reaction mixtures can be processed using Isolute® separation phase cartridges (Biotage), acidic columns, catch-and-release SPE (solid phase extraction) cartridges. Crude materials can be purified by normal phase chromatography, preparative TLC, (acidic or basic) reverse phase chromatography, chiral separation trituration, or recrystallization.

[0236] Normal phase chromatography was performed using a silica gel column (100:200 mesh silica gel or cartridges for normal phase column chromatography systems such as Biotage® Isolera™ Four or Teledyne Isco CombiNormal phase column®).

[0237] Preparative reverse phase chromatography is performed as follows: -Basic LCMS preparative: LCMS purification (basic mode, LCMS preparative) using an SQD Waters single quadrupole mass spectrometer was used. The spectrometer was equipped with an ESI source, a Waters 2525 binary pump coupled to a 2767 sample manager, and a diode array detector (210-400 nm). Data were acquired with a full MS scan from m / z 100 to 850 in positive and negative modes with basic elution.

[0238] LC parameters: Reversed-phase separation was performed at room temperature using a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm). Gradient elution was performed with solvent A1 (H2O + NH4HCO3 10 mM + 50 μL / L NH4OH) and solvent B1 (100% ACN) (pH 8.5). HPLC flow rate: 35 mL / min–45 mL / min, injection volume: 990 μL. The split ratio was ±1 / 6000 relative to the MS. [Table 3]

[0239] -Acidic LCMS preparative: LCMS purification was performed using an SQD Waters single quadrupole mass spectrometer (acid mode, LCMS preparative). The spectrometer was equipped with an ESI source, a Waters 2525 binary pump coupled to a 2767 sample manager, and a diode array detector (210-400 nm). Data were acquired as a full MS scan from m / z 100 to 850 in positive mode with acid elution.

[0240] LC parameters: Reversed phase separation is performed at room temperature using a Waters Sunfire ODB MS C18 column (5 μm, 30×50 mm). Solvent A2 (Water / TFA: 99.5% + 0.5% TFA) and Solvent B2Gradient elution was performed with ACN / TFA: 99.5% + 0.5% (pH 2). The HPLC flow rate was 35 mL / min to 45 mL / min, and the injection volume was 990 μL. The split ratio was set to ±1 / 6000 relative to the MS. [Table 4]

[0241] Before submission for final analysis and biological testing, the product was typically dried under vacuum.

[0242] NMR spectra were recorded on different instruments: - BRUKER AVANCEIII 400 MHz-Ultrashield NMR Spectrometer equipped with a Windows 7 Professional workstation running Topspin 3.2 software and a 5 mm Double Resonance Broadband Probe (PABBI) 1 H / 19 F‐BB Z‐GRD Z82021 / 0075) or 1mm Triple Resonance Probe (PATXI 1 H / D‐ 13 C / 15 NZ-GRD Z868301 / 004) was installed.

[0243] - Varian MR 400MHz NMR spectrometer running Linux 3.2 software, Red Hat Enterprise Linux 5.1 operating system, and 5mm inverse 1 H / 13 A Varian VNMR 400MHz NMR equipped with a C probehead was run on Linux 3.2 software, the operating system Red Hat Enterprise Linux 6.3, and a 5mm inverse 1 H / 13 C / 19 Equipped with an F triple probe head.

[0244] Chemical shifts are referenced to signals from residual protons in the deuterated solvent (DMSO-d6, MeOH-d4, or CDCl3). Chemical shifts are expressed in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). Spin multiplicities are indicated as broad (br), singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m).

[0245] All final products were analyzed by LCMS in both basic and acidic modes as follows: -Basic LCMS method 3: LCMS analysis was performed using a QDA Waters simplified quadrupole mass spectrometer. The spectrometer was equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210–400 nm). Data were acquired in positive / negative mode with a basic elution, with a full MS scan from m / z 70 to 800. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 100 mm) column at 45 °C with a basic elution. Gradient elution was performed with H2O / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / H2O / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Full flow on the MS. [Table 5]

[0246] -Acid LCMS method 2: LCMS analysis was performed using a QDA Waters simplified quadrupole mass spectrometer. The spectrometer was equipped with a UPLC Acquity Hclass with an ESI source and a diode array detector (210–400 nm). Data were acquired as a full MS scan from m / z 70 to 800 in positive / negative mode with acidic elution. Reversed-phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 100 mm) column at 45 °C with acidic elution. Gradient elution was performed with HO / ACN / TFA (95 / 5 / 0.05%) (solvent A) and ACN (solvent B). [Table 6]

[0247] Synthetic Intermediates A. Synthesis of intermediates of formula (II) Synthesis of 2-(2-chloro-6-cyano-3-methoxyphenyl)acetic acid a3. [ka]

[0248] A.1.1. Synthesis of 3-chloro-2-iodo-4-methoxybenzonitrile a1 To a solution of 3-chloro-4-methoxybenzonitrile (commercially available, 12.0 g, 71.8 mmol) in THF (150 mL) was added LDA (51.0 mL, 165 mmol) at −78 °C, and the reaction mixture was stirred for 45 min at the same temperature. I2 (27.0 g, 108 mmol) was added at −78 °C, and the reaction mixture was stirred at the same temperature for 3 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (200 mL), extracted with EtOAc (2 × 200 mL), and washed with H2O (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude residue was purified by normal-phase column chromatography (elution: 10% EtOAc in hexane) to give 10.5 g of 3-chloro-2-iodo-4-methoxybenzonitrile a1 as a pink solid.

[0249] Yield: 50%. 1 H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J = 8.58 Hz, 1H), 7.33 (d, J = 8.11 Hz, 1H), 3.94 (s, 3H).

[0250] A.1.2. Synthesis of ethyl 2-(2-chloro-6-cyano-3-methoxyphenyl)acetate a2 To a solution of 3-chloro-2-iodo-4-methoxybenzonitrile a1 (10.0 g, 34.1 mmol) in THF (150 mL) was added Pd(OAc) (0.76 g, 3.41 mmol) and (tBu)P.HBF (1.97 g, 6.82 mmol), followed by additional ethoxycarbonylmethylzinc bromide (11.8 g, 51.1 mmol). The reaction mixture was heated at 60 °C for 8 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was filtered through a pad of Celite®, and the filtrate was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (3 x 150 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by normal phase column chromatography (elution: 0 to 12% EtOAc in hexanes) to give 6.86 g of ethyl 2-(2-chloro-6-cyano-3-methoxyphenyl)acetate a2 as a pale yellow solid.

[0251] Yield: 79%. 1 H NMR (400 MHz, DMSO-d6): δ 7.88 (d, J = 8.80 Hz, 1H), 7.29 (d, J = 8.80 Hz, 1H), 4.13 (q, J = 7.34 Hz, 2H), 4.00 (s, 2H), 3.96 (s, 3H), 1.19 (t, J = 7.09 Hz, 3H).

[0252] A.1.3. Synthesis of 2-(2-chloro-6-cyano-3-methoxyphenyl)acetic acid a3 To a solution of ethyl 2-(2-chloro-6-cyano-3-methoxyphenyl)acetate a2 (2.20 g, 8.69 mmol) in THF (5 mL) and HO (5 mL) was added LiOH (0.62 g, 26.0 mmol). The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was acidified to pH 2 with a 2 N aqueous solution of HCl and extracted with EtOAc (50 mL). The organic layer was washed with HO (2 × 50 mL), dried over anhydrous NaSO, and concentrated in vacuo to give 1.60 g of 2-(2-chloro-6-cyano-3-methoxyphenyl)acetic acid a3 as an off-white solid, which was used in the next step without further purification.

[0253] Yield (crude): 84%. HPLC (basic mode): 99% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.86 (brs, 1H), 7.86 (d, J = 8.80 Hz, 1H), 7.27 (d, J = 8.80 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 2H).

[0254] A.2. Synthesis of 2-(6-chloro-2-cyano-3-methoxyphenyl)acetic acid a9 [ka]

[0255] A.2.1. Synthesis of 5-chloro-2-methoxybenzaldehyde a4 To a solution of 5-chloro-2-hydroxy-benzaldehyde (commercially available, 15.0 g, 96.1 mmol) in acetone (150 mL) was added K2CO3 (16.4 g, 119 mmol), followed by dropwise addition of MeI (14.7 mL, 240 mmol), and the reaction mixture was heated to reflux for 5 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was extracted with EtOAc (3 × 300 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by normal phase column chromatography (elution: 8% EtOAc in hexane) to give 15.0 g of 5-chloro-2-methoxybenzaldehyde a4 as a white solid.

[0256] Yield: 92%. 1 H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 7.71 (dd, J = 8.8, 2.45 Hz, 1H), 7.62 (d, J = 2.45 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H).

[0257] A.2.2. Synthesis of (NE)-N-[(5-chloro-2-methoxyphenyl)methylidene]hydroxylamine a5 To a solution of 5-chloro-2-methoxybenzaldehyde a4 (15.0 g, 88.2 mmol) in EtOH (150 mL) was added NH2OH·HCl (9.13 g, 132 mmol). The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with HO (200 mL) and extracted with EtOAc (3 × 250 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 15.1 g of (NE)-N-[(5-chloro-2-methoxyphenyl)methylidene]hydroxylamine a5 as a brown liquid, which was used in the next step without further purification.

[0258] Yield (crude): 92%. 1 H NMR (400 MHz, DMSO-d6): δ 11.45 (d, J = 1.96 Hz, 1H), 8.23 ​​(d, J = 1.96 Hz, 1H), 7.59 (d, J = 2.45 Hz, 1H), 7.35 - 7.46 (m, 1H), 7.04 - 7.17 (m, 1H), 3.83 (s, 3H).

[0259] A.2.3. Synthesis of 5-chloro-2-methoxybenzonitrile a6 A stirred solution of (NE)-N-[(5-chloro-2-methoxyphenyl)methylidene]hydroxylamine a5 (15.0 g, 81.0 mmol) in AcO (100 mL) was heated at 100 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude residue was purified by normal-phase column chromatography (elution: 15% EtOAc in hexane) to give 7.68 g of 5-chloro-2-methoxybenzonitrile a6 as an off-white solid.

[0260] Yield: 57%. 1 H NMR (400 MHz, DMSO-d6): δ 7.86 - 7.98 (m, 1H), 7.67 - 7.77 (m, 1H), 7.27 (dd, J = 8.56, 4.16 Hz, 1H), 3.91 (s, 3H).

[0261] A.2.4. Synthesis of 3-chloro-2-iodo-6-methoxybenzonitrile a7 To a solution of 5-chloro-2-methoxybenzonitrile a6 (4.00 g, 23.9 mmol) in THF (50 mL) was added LDA (26.3 mL, 52.6 mmol) at −78 °C. The reaction mixture was stirred at the same temperature for 45 min, and then I2 (7.29 g, 28.7 mmol) was added. The reaction mixture was stirred at −78 °C for 45 min. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (40 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was washed with H2O (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude residue was purified by normal-phase column chromatography (elution: 20% EtOAc in hexane) to give 2.6 g of 3-chloro-2-iodo-6-methoxybenzonitrile a7 as an off-white solid.

[0262] Yield: 37%. 1 H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J = 9.29 Hz, 1H), 7.31 (d, J = 9.29 Hz, 1H), 3.87 - 3.95 (s, 3H).

[0263] A.2.5. Synthesis of ethyl 2-(6-chloro-2-cyano-3-methoxyphenyl)acetate a8 To a solution of 3-chloro-2-iodo-6-methoxybenzonitrile a7 (5.00 g, 17.0 mmol) in THF (120 mL) was added ethoxycarbonylmethylzinc bromide (51.0 mL, 25.5 mmol), followed by Pd(tBuP) (0.43 g, 0.85 mmol). The reaction mixture was heated at 50 °C for 6 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 250 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by normal-phase column chromatography (elution: 20% EtOAc in hexanes) to give 2.10 g of ethyl 2-(6-chloro-2-cyano-3-methoxyphenyl)acetate a8 as a brown solid.

[0264] Yield: 9%. 1 H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 8.80 Hz, 1H), 7.24 (d, J = 8.80 Hz, 1H), 4.12 (q, J = 6.85 Hz, 2H), 3.93 (brs, 3H), 3.91 (brs, 2H), 1.18 (t, J = 7.09 Hz, 3H).

[0265] A.2.6. Synthesis of 2-(6-chloro-2-cyano-3-methoxyphenyl)acetic acid a9 To a solution of ethyl 2-(6-chloro-2-cyano-3-methoxyphenyl)acetate a8 (2.00 g, 7.90 mmol) in THF (15 mL) and HO (15 mL) was added LiOH (0.57 g, 23.7 mmol). The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with HO (25 mL), acidified to pH 2 with a 6 N aqueous solution of HCl, and extracted with EtOAc (200 mL). The organic layer was washed with HO (200 mL), dried over anhydrous NaSO, and concentrated in vacuo. The resulting crude residue was purified by normal-phase column chromatography (elution: 4% MeOH in DCM) to afford 1.10 g of 2-(6-chloro-2-cyano-3-methoxyphenyl)acetic acid a9 as an off-white solid.

[0266] Yield: 62%. HPLC (basic mode): 98% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.91 (s, 1H), 7.77 (d, J = 8.80 Hz, 1H), 7.23 (d, J = 9.29 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 2H).

[0267] A.3. Synthesis of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetic acid a15. [ka]

[0268] A.3.1. Synthesis of 2-methoxypyridin-4-amine a10 To a solution of NaOMe (672 mL, 3.11 mol) at rt, 2-chloropyridin-4-amine (commercially available, 50.0 g, 389 mmol) was added, and the reaction mixture was heated in an autoclave at 160 °C for 8 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo, and the resulting residue was then diluted with ice-cold HO (1 L). This compound was extracted with a solution of 5% MeOH in DCM. The organic layer was dried over NaSO and concentrated in vacuo. The crude residue was diluted with EtOAc (1 L), and the organic layer was then washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 15.0 g of 2-methoxypyridin-4-amine a10 as a pale yellow sticky substance, which was used in the next step without further purification.

[0269] Yield (crude): 31%. Basic LCMS Method 1 (ES + ): 125 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 7.60-7.64 (m, 1H), 6.16 (dd, J = 5.61, 2.02 Hz, 1H), 5.88 (brs, 2H), 5.80 (d, J = 1.80 Hz, 1H), 3.68-3.73 (s, 3H).

[0270] A.3.2. Synthesis of 3,5-dichloro-2-methoxy-pyridin-4-amine a11 To a solution of 2-methoxypyridin-4-amine a10 (30.0 g, 242 mmol) in ACN (1 L) at rt, NCS (129 g, 967 mmol) was added portionwise, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with 20% aqueous potassium carbonate solution (500 mL). The compound was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 50% EtOAc in hexane) to give 35.1 g of 3,5-dichloro-2-methoxy-pyridin-4-amine a11.

[0271] Yield: 75%. Basic LCMS Method 1 (ES + ): 194 / 196 / 198 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 7.70-7.91 (s, 1H), 6.50 (s, 2H), 3.80-3.97 (s, 3H).

[0272] A.3.3. Synthesis of 3,5-dichloro-4-iodo-2-methoxy-pyridine a12 To a solution of CuI (59.0 g, 311 mmol) in ACN (1 L) was added tBuONO (93.0 mL, 777 mmol) dropwise at 50 °C. The reaction mixture was heated at 80 °C for 30 min. A solution of 3,5-dichloro-2-methoxy-pyridin-4-amine a11 (30.0 g, 155 mmol) in ACN (500 mL) was added portionwise (nitrogen gas evolution was observed), and the reaction mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo, and the crude residue was diluted with EtOAc (100 mL) and hexane (2 L). The resulting suspension was passed through a short silica pad, and the filtrate was concentrated in vacuo to give 34.9 g of 3,5-dichloro-4-iodo-2-methoxy-pyridine a12 as a pale yellow solid.

[0273] Yield: 74%. Basic LCMS Method 1 (ES + ): 305 (M+2) + . 1 H NMR (400 MHz, DMSO-d6): δ 8.19-8.34 (s, 1H), 3.87-4.00 (s, 3H).

[0274] A.3.4. Synthesis of tert-butyl 2-cyano-2-(3,5-dichloro-2-methoxypyridin-4-yl)acetate a13 To a solution of 3,5-dichloro-4-iodo-2-methoxy-pyridine a12 (10.0 g, 32.9 mmol), tert-butyl 2-cyanoacetate (9.40 mL, 65.8 mmol), and cesium carbonate (42.9 g, 132 mmol) in DMF (160 mL) was added CuI (0.63 g, 3.29 mmol), and the reaction mixture was stirred at 100 °C for 3 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was poured into ice-cold water and neutralized with 6 N aqueous HCl. The compound was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 20% EtOAc in hexane) to give 6.70 g of tert-butyl 2-cyano-2-(3,5-dichloro-2-methoxypyridin-4-yl)acetate a13.

[0275] Yield: 64%. 1 H NMR (400 MHz, DMSO-d6): δ 8.39-8.53 (s, 1H), 6.32 (s, 1H), 3.92-4.07 (s, 3H), 1.42 (s, 9H).

[0276] A.3.5. Synthesis of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetonitrile a14 To a solution of tert-butyl 2-cyano-2-(3,5-dichloro-2-methoxypyridin-4-yl)acetate a13 (20.0 g, 63.0 mmol) in DCM (500 mL) was added TFA (80 mL) at rt, and the reaction mixture was refluxed for 2 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo, and the crude residue was neutralized with a saturated aqueous solution of sodium bicarbonate. The compound was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 13.5 g of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetonitrile a14 as a yellow solid, which was used in the next step without further purification.

[0277] Yield (crude): 98%. 1 H NMR (400 MHz, DMSO-d6): δ 8.31-8.47 (s, 1H), 4.19-4.30 (m, 2H), 3.86-4.06 (s, 3H).

[0278] A.3.6. Synthesis of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetic acid a15 To a solution of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetonitrile a14 (13.5 g, 62.0 mmol) in EtOH (300 mL) was added 10 N aqueous NaOH (93.5 mL, 933 mmol), and the reaction mixture was refluxed for 12 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with HO, and then NHCl (60 g) was added. The solvent was removed in vacuo, and the aqueous layer was acidified to pH 5 with a 6 N aqueous solution of HCl. The compound was extracted with a 5% solution of MeOH in DCM. The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 5% MeOH in DCM). The crude residue was further washed with a solution of 50% DCM in hexanes, filtered and dried to give 5 g of 2-(3,5-dichloro-2-methoxy-4-pyridyl)acetic acid a15 as an off-white solid.

[0279] Yield: 34%. Basic LCMS Method 1 (ES + ): 237 / 239 / 241 (M+H) + . 1 H NMR (400 MHz, CD3OD): δ 8.03-8.18 (s, 1H), 3.99 (d, J = 3.02 Hz, 3H), 3.26-3.42 (s, 2H).

[0280] A.4. Synthesis of 2-[2-chloro-6-cyano-3-(trideuteriomethoxy)phenyl]acetic acid a21 [ka]

[0281] A.4.1. Synthesis of 2-(3-chloro-4-fluorophenyl)-1,3-dioxolane a16 To a solution of 3-chloro-4-fluorobenzaldehyde (10.0 g, 63.3 mmol) in toluene (150 mL) was added ethylene glycol (5.88 g, 95.0 mmol) and p-TSA (1.20 g, 6.33 mmol). The reaction mixture was heated to reflux for 18 h while removing HO using a Dean-Stark apparatus. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with HO (150 mL) and extracted with EtOAc (2 × 150 mL). The organic layer was washed with HO (50 mL), brine (50 mL), dried over anhydrous NaSO, and concentrated in vacuo. The resulting crude residue was purified by normal-phase column chromatography (elution: 5% EtOAc in hexane) to give 9.00 g of 2-(3-chloro-4-fluorophenyl)-1,3-dioxolane a16 as a colorless liquid.

[0282] Yield: 70%. 1H NMR (400 MHz, DMSO-d6): δ 7.59 (dd, J = 7.21, 1.59 Hz, 1H), 7.40 - 7.43 (m, 2H), 5.72 (s, 1H), 4.01 - 4.04 (m, 2H), 3.91 - 3.95 (m, 2H).

[0283] A.4.2. Synthesis of 2-(3-chloro-4-fluoro-2-methylphenyl)-1,3-dioxolane a17 To a solution of 2-(3-chloro-4-fluorophenyl)-1,3-dioxolane a16 (7.00 g, 34.6 mmol) in THF (140 mL) was added nBuLi (3.32 g, 51.9 mmol) dropwise at −78 °C, and the reaction mixture was stirred at the same temperature for 1 h. MeI (24.6 g, 173 mmol) was added at −78 °C, and the reaction mixture was stirred at the same temperature for 1 h, followed by RT for 30 min. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (70 mL) at −78 °C. The reaction mixture was extracted with Et2O (2 × 100 mL). The organic layer was washed with HO (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude residue was purified by normal phase column chromatography (elution: 4% EtOAc in hexane) to give 7.00 g of a 7:3 mixture of 2-(3-chloro-4-fluoro-2-methylphenyl)-1,3-dioxolane a17 and its regioisomer 2-(3-chloro-4-fluoro-5-methylphenyl)-1,3-dioxolane a17b.

[0284] Yield: 93%. Basic LCMS Method 1 (ES + ): 217 / 219 (M+H) + , 89% purity. 1H NMR (major isomer a17, 400 MHz, DMSO-d6): δ 7.48 (m, 1H), 7.27 (m, 1H), 5.94 (s, 1H), 4.02 - 4.07 (m, 2H), 3.96 - 3.99 (m, 2H), 2.40 (s, 3H).

[0285] A.4.3. Synthesis of 3-chloro-4-fluoro-2-methylbenzaldehyde a18. To a 7:3 mixture of 2-(3-chloro-4-fluoro-2-methylphenyl)-1,3-dioxolane a17 and its regioisomer 2-(3-chloro-4-fluoro-5-methylphenyl)-1,3-dioxolane a17b (8.80 g, 40.7 mmol) in THF (100 mL) was added 1N aqueous HCl (100 mL), and the reaction mixture was heated to reflux for 4 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was basified with saturated aqueous NaHCO to pH 8 and extracted with EtO (3 × 100 mL). The organic layer was washed with HO (150 mL), brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The resulting crude residue was purified by normal phase column chromatography (elution: 4% EtOAc in hexanes) to give 5.80 g of a 7:3 mixture of 3-chloro-4-fluoro-2-methylbenzaldehyde a18 and its regioisomer 3-chloro-4-fluoro-5-methylbenzaldehyde a18b.

[0286] Yield: 83%. 1 H NMR (major isomer a18, 400 MHz, DMSO-d6): δ 10.20 (s, 1H), 7.84-7.92 (m, 1H), 7.48 (t, J = 8.56 Hz, 1H), 2.68 (s, 3H).

[0287] A.4.4. Synthesis of 3-chloro-4-fluoro-2-methylbenzonitrile a19. To a solution of a 7:3 mixture of 3-chloro-4-fluoro-2-methylbenzaldehyde a18 and its regioisomer 3-chloro-4-fluoro-5-methylbenzaldehyde a18b (6.80 g, 39.5 mmol) in THF (70 mL) and NH4OH (680 mL), I2 (10.8 g, 39.5 mmol) was added and stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of Na2SO3 (300 mL) and extracted with Et2O (3 × 250 mL). The organic layer was washed with HO (200 mL), brine (250 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude residue was purified by normal phase column chromatography (elution: 2% EtOAc in hexanes) to give 6.00 g of a 7:3 mixture of 3-chloro-4-fluoro-2-methylbenzonitrile a19 and its regioisomer 3-chloro-4-fluoro-5-methylbenzonitrile a19b.

[0288] Yield: 89%. 1 H NMR (major isomer a19, 400 MHz, DMSO-d6): δ 7.90 (dd, J = 8.56, 5.14 Hz, 1H), 7.50 (t, J = 8.56 Hz, 1H), 2.56 (s, 3H).

[0289] A.4.5. Synthesis of 2-(2-chloro-6-cyano-3-fluorophenyl)acetic acid a20. To a solution of KOtBu (0.36 g, 3.25 mmol) in THF (10 mL) was added LDA (0.35 g, 3.25 mmol) at −78 °C and stirred at the same temperature for 10 min. A solution of a 7:3 mixture of 3-chloro-4-fluoro-2-methylbenzonitrile a19 and its regioisomer 3-chloro-4-fluoro-5-methylbenzonitrile a19b (0.50 g, 2.95 mmol) in THF (2 mL) was added at −78 °C. The reaction mixture was stirred at −78 °C for 30 min. CO was purged into the reaction mixture for 15 min. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with H2O (10 mL) and extracted with Et2O (2 × 15 mL). The aqueous layer was acidified to pH 3 with a 3N aqueous solution of HCl and extracted with Et2O (3 × 15 mL). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 40% EtOAc in hexanes) to give 0.13 g of 2-(2-chloro-6-cyano-3-fluorophenyl)acetic acid a20 as an off-white solid.

[0290] Yield: 24%. Basic LCMS Method 1 (ES + ): 214 / 216 (M+H) + , 95% purity. 1 H NMR (400 MHz, DMSO-d6): δ 13.05 (brs, 1H), 7.99 (dd, J = 8.58, 5.25 Hz, 1H), 7.63 (t, J = 8.82 Hz, 1H), 3.99 (s, 2H).

[0291] A.4.6. Synthesis of 2-[2-chloro-6-cyano-3-(trideuteriomethoxy)phenyl]acetic acid a21. To a solution of 2-(2-chloro-6-cyano-3-fluorophenyl)acetic acid a20 (1.07 g, 5.00 mmol) in CD3OD (13.3 g, 366 mmol) was added sodium hydride (1.00 g, 25.0 mmol) slowly at 0 °C. The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The crude residue was dissolved in MeOH (50 mL), and the mixture was heated at 60 °C for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was triturated with heptane and filtered. The solid was dissolved in MeOH (10 mL), and then Na (575 mg, 25.0 mmol) was added. The reaction mixture was heated at 60° C. overnight, then diluted with EtOAc (150 mL) and washed successively with a 1N aqueous solution of HCl (50 mL) and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give 1.14 g of 2-[2-chloro-6-cyano-3-(trideuteriomethoxy)phenyl]acetic acid a21, which was used in the next step without further purification.

[0292] Yield (crude): quantitative Basic LCMS Method 2 (ES + ): 183 / 185 (M+H) + . 1 H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.10 (s, 2H).

[0293] A.5. Synthesis of 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetic acid a28 [ka]

[0294] A.5.1. Synthesis of 3,5-dichloro-4-methyl-pyridine a22 A 2 M solution of LDA in THF (1.86 L, 3.72 mol) and THF (5 L) were charged to a reactor under nitrogen. 3,5-Dichloro-4-methyl-pyridine (commercially available, 500 g, 3.38 mol) was added at -20 °C, and the mixture was stirred at -10 °C for 30 min. The reaction was cooled to -70 °C, and MeI (815 g, 5.74 mol) was added. The mixture was warmed to rt and stirred for 4 h. This overall procedure was carried out in parallel with four batches of the same size worked together. The mixture was cooled to 0 °C, quenched with water (5 L), and stirred for 10 min. The aqueous layer was extracted with ethyl acetate (2 × 3 L), and the organic layer was washed twice with brine (10 L), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOH (4 L) at −70° C. to give 1.50 kg of 3,5-dichloro-4-methyl-pyridine a22 as a yellow solid. Yield: 68%

[0295] A.5.2. Synthesis of methyl 2-(3,5-dichloro-4-pyridyl)acetate a23 3,5-Dichloro-4-methyl-pyridine 22 (375 g, 2.31 mol) and DMF (1.87 L) were placed in a reactor, and the mixture was cooled to 15 °C. Potassium tert-butoxide (779 g, 6.94 mol) was added under nitrogen at 10–15 °C, and the mixture was stirred at 15 °C for 30 min. Dimethyl carbonate (730 g, 8.10 mol) was added at 10–15 °C, and the mixture was stirred at 30 °C for 4 h. This overall procedure was carried out in parallel with four batches of the same size that were run together. The mixture was cooled to 0 °C, and the reaction was quenched with H2O (10 L) and stirred for 10 min. The reaction mixture was filtered. The filter cake was washed twice with EtOAc (2 L). The aqueous layer was extracted twice with EtOAc (3 L), and the organic layer was washed twice with brine (5 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 1.30 kg of methyl 2-(3,5-dichloro-4-pyridyl)acetate a23 as a dark brown liquid, which was used in the next step without further purification. Yield: 64%

[0296] A.5.3. Synthesis of methyl 2-(3,5-dichloro-1-oxide-pyridin-1-ium-4-yl)acetate a24 Methyl 2-(3,5-dichloro-4-pyridyl)acetate a23 (650 g, 2.95 mol) and DCM (3.25 L) were charged to a reactor. m-CPBA (1.27 kg, 5.91 mol, 80% purity) was added under nitrogen at 0 °C, and the mixture was stirred at rt for 5 h. This entire procedure was carried out in parallel with four batches of the same size working together. The mixture was cooled to 0 °C, and the reaction was quenched with water (4 L) and stirred for 10 min. The reaction mixture was filtered. The filter cake was washed twice with DCM (3 L). The aqueous layer was extracted twice with DCM (2 L), and the organic layer was washed three times with a saturated aqueous solution of NaSO (15 L) and twice with brine (10 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 5-50% EtOAc in petroleum ether) to give 900 g of methyl 2-(3,5-dichloro-1-oxide-pyridin-1-ium-4-yl)acetate a24 as a yellow solid. Yield: 64%

[0297] A.5.4. Synthesis of methyl 2-(2-bromo-3,5-dichloro-4-pyridyl)acetate a25 Methyl 2-(3,5-dichloro-1-oxide-pyridin-1-ium-4-yl)acetate a24 (900 g, 3.81 mol) and ACN (8 L) were charged to a reactor at rt. Phosphorus oxybromide (1.09 kg, 3.81 mol) was added under nitrogen at 0 °C, and the mixture was stirred at rt for 12 h. This entire procedure was carried out in parallel with another batch (1.64 mol scale), and the two batches were worked together. The mixture was cooled to 0 °C, and the reaction was quenched with HO (3 L) and stirred for 10 min. The aqueous layer was extracted twice with EtOAc (2 L). The organic layer was washed twice with brine (5 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 2-50% EtOAc in petroleum ether) to give 503 g of methyl 2-(2-bromo-3,5-dichloro-4-pyridyl)acetate a25 as an off-white solid.

[0298] Yield: 43% 1 H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 4.07 (s, 2H), 3.75 (s, 3H)

[0299] A.5.5. Synthesis of methyl 3,5-dichloro-4-(2-methoxy-2-oxo-ethyl)pyridine-2-carboxylate a26 To a solution of methyl 2-(2-bromo-3,5-dichloro-4-pyridyl)acetate a25 (3.00 g, 103 mmol) in MeOH (60 mL) was added DIPEA (2.42 mL, 14.6 mmol) and 1,4-bis(diphenylphosphino)butane-palladium(II) chloride (91.0 mg, 0.15 mmol). The reactor was flushed with nitrogen three times and then pressurized with 5 bar of CO (three flushes), and the mixture was heated at 80 °C for 3 h. The reaction mixture was filtered through a pad of Celite® at rt, and the solvent was removed under reduced pressure. The crude residue was purified by normal phase column chromatography (elution: 50% EtOAc in hexane). The solvent was removed under vacuum to give 1.84 g of 3,5-dichloro-4-(2-methoxy-2-oxo-ethyl)pyridine-2-carboxylic acid a26 as a yellow liquid.

[0300] Yield: 66% Basic LCMS Method 2 (ES + ): 278 / 280 / 282 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 4.12 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H).

[0301] A.5.6. Synthesis of methyl 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetate a27 To a solution of methyl 3,5-dichloro-4-(2-methoxy-2-oxo-ethyl)pyridine-2-carboxylate a26 (305 mg, 1.09 mmol) in THF (10 mL) was added sodium borohydride (124 mg, 3.29 mmol) at rt, and the reaction mixture was allowed to stir at rt for 18 h. The reaction mixture was filtered, and the solvent was removed in vacuo. The crude residue was purified by normal phase column chromatography (elution: 0 to 10% MeOH in DCM) to give 139 mg of methyl 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetate a27 as a solid.

[0302] Yield: 50% Basic LCMS Method 2 (ES + ): 250 / 252 / 254 1 H NMR (400 MHz, CDCl): δ 8.51 (s, 1H), 4.78 (s, 2H), 4.04 (s, 2H), 3.74 (s, 3H). No OH protons observed.

[0303] A.5.7. Synthesis of 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetic acid a28. To a solution of methyl 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetate a27 (98.1 g, 392 mmol) in a mixture of THF (1.1 L) and HO (110 mL) was added LiOH·HO (25.2 g, 589 mmol). The resulting mixture was stirred at rt for 18 h and then concentrated in vacuo. The crude residue was azeotropically evaporated with toluene (3 × 250 mL) to afford 92.6 g of 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetic acid a28 as a free-flowing off-white powder, which was used in the next step without further purification.

[0304] Yield (crude): quantitative 1H NMR (400 MHz, DMSO-d): δ 8.54 (s, 1H), 4.62 (s, 2H), 2.46 (s, 2H). Two OH protons were not observed.

[0305] A.6. Synthesis of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid a33 [ka]

[0306] A.6.1. Synthesis of 1-methyl-5-nitro-indazole a29 5-Nitro-1H-indazole (commercially available, 3.00 kg, 18.4 mol) and DMF (30 L) were charged into a 50 L three-neck round-bottom flask at 15-30 °C. KOH (2.06 kg, 36.7 mol) was added to the reactor in one portion at 0-5 °C. The mixture was stirred at 0-50 °C for 1 h. MeI (2.87 kg, 20.2 mol) was then added at 0-5 °C, and the mixture was stirred at 15-30 °C for 3 h. The reaction mixture was added to HO (30 L) at 0-10 °C, and the mixture was stirred for 10 min and then filtered. The filter cake was washed with HO (5 L) and dried. This overall procedure was carried out in parallel for four batches of the same size. The solids obtained from the four batches were combined to give 10.0 kg of 1-methyl-5-nitro-indazole a29 as a brown solid, which was used in the next step without further purification.

[0307] Yield: 57% (75% purity) 1 H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.21 (d, J = 9.17 Hz, 1 H), 8.13 (s, 1 H), 7.39 (d, J = 9.17 Hz, 1 H), 4.08 (s, 3 H).

[0308] A.6.2. Synthesis of tert-butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate a30 tBuOK (4.43 kg, 39.5 mol) and THF (30 L) were charged to a 50 L three-necked round-bottom flask, and the mixture was cooled to −45 / −35 °C with stirring under nitrogen. 1-Methyl-5-nitro-indazole a29 (3.50 kg, 19.7 mol) was then added portionwise at −45 / −35 °C. t-Butyl 2-chloroacetate (3.57 kg, 23.7 mol) was added dropwise at the same temperature, and the mixture was stirred for 1 h. The mixture was warmed to 15–30 °C and stirred for 5 h. The reaction was quenched by the addition of a saturated aqueous solution of NH4Cl (9 L) and H2O (2 L). The aqueous layer was extracted with EtOAc (2 × 5 L). The organic layers were combined, washed with brine (2 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc (5 L). This overall procedure was carried out in parallel on two batches of equal size. The solids from the two batches were combined and dried together to give 5.30 kg of tert-butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate as a yellow solid a30.

[0309] Yield: 45% 1 H NMR (400 MHz, CDCl3): δ 8.18-8.20 (m, 2H), 7.37 (d, J = 9.21 Hz, 1 H), 4.27 (s, 2 H), 4.14 (s, 3 H), 1.44 (s, 9 H).

[0310] A.6.3. Synthesis of tert-butyl 2-(5-amino-1-methyl-indazol-4-yl)acetate a31 tert-Butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate a30 (7.30 kg, 25.0 mol) and MeOH (76.0 L) were charged to a reactor. After purging with argon, Pd / C (50%, 760 g, 7.00 mmol) was added. H2 was added three times, and the mixture was stirred under an H2 atmosphere (50 psi) at 50 °C for 3 h. The reaction mixture was filtered, and the solid was washed with MeOH (5 L). The mixture was concentrated to give 6.50 kg of tert-butyl 2-(5-amino-1-methyl-indazol-4-yl)acetate a31 as a brown oil, which was used in the next step without further purification.

[0311] Yield: 95% 1 H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.27 (d, J = 8.80 Hz, 1 H), 6.91 (d, J = 8.80 Hz, 1 H), 4.60 (s, 2 H), 3.93 (s, 3 H), 3.68 (s, 2H), 1.38 (s, 9 H).

[0312] A.6.4. Synthesis of 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid a32 tert-Butyl 2-(5-amino-1-methyl-indazol-4-yl)acetate a31 (2.00 kg, 7.65 mol) and 12N concentrated aqueous HCl (10 L, 120 mol) were charged into a 50 L three-necked round-bottom flask, and the mixture was cooled to -10 / -5 °C and stirred. A solution of sodium nitrite (686 g, 9.95 mol) in HO (5 L) was added dropwise at -10 / -5 °C and stirred for 30 min. CuCl (833 g, 8.42 mol) and 12N concentrated aqueous HCl (10.0 L, 120 mol) were charged into a 20 L three-necked round-bottom flask, and the mixture was stirred at -10 / -5 °C for 30 min before being added to another reactor. The mixture was stirred at -10 / -5 °C for 1 h and then at 10-30 °C for 16 h. The reaction mixture was filtered, and the solid was washed with HO. This overall procedure was carried out in three batches of equal size in parallel. The solids from the three batches were combined and dried to give 4.00 kg of 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid a32 as a yellow solid, which was used in the next step without further purification. Yield (crude): 71% (purity 92%)

[0313] A.6.5. Synthesis of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid a33 2-(5-Chloro-1-methyl-indazol-4-yl)acetic acid A32 (1.30 kg, 5.79 mol) and DMF (6.50 L) were charged to a 50 L three-neck round-bottom flask at rt. NCS (772 g, 5.79 mol) was added portionwise at rt, and the mixture was stirred at rt for 2 h. The reaction mixture was poured into HO (25 L) and filtered. The crude residue was triturated with isopropyl ether: EtOAc (3:1) (7 L) for 2 h at rt, and the resulting solid was then filtered and dried under vacuum. This overall procedure was carried out in three equal-sized batches in parallel. The solids obtained from the three batches were combined to give 2.10 kg of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid A33.

[0314] Yield: 45% 1H NMR (400 MHz, CDCl3): δ 12.67 (s, 1 H), 7.68 (d, J = 9.05 Hz, 1 H), 7.53 (d, J = 9.05 Hz, 1 H), 4.20 (s, 2 H), 4.02 (s, 3 H).

[0315] A.7. Synthesis of 2-(3,5-dichloro-1-methyl-1H-indol-4-yl)acetic acid a39b. [ka]

[0316] A.7.1. Synthesis of 1-(benzenesulfonyl)-4-nitro-indole a34. To a solution of commercially available 4-nitro-1H-indole (25.0 g, 154 mmol) in ACN (250 mL) was added DIPEA (29.5 mL, 170 mmol) at rt. The reaction was cooled to 0 °C and benzenesulfonyl chloride (23.0 mL, 185 mmol) was added. The reaction was heated at 80 °C for 3 h. Upon completion, the reaction was quenched with a saturated aqueous solution of NaHCO and extracted with EtOAc. The organic layer was washed with HO, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 34.9 g of 1-(benzenesulfonyl)-4-nitro-indole a34, which was used in the next step without further purification.

[0317] Yield (crude): 97% 1 H NMR (400 MHz, DMSO-d6): δ 8.47 - 8.39 (m, 1H), 8.26 - 8.17 (m, 2H), 8.12 - 8.04 (m, 2H), 7.78 - 7.68 (m, 1H), 7.67 - 7.54 (m, 3H), 7.38 - 7.26 (m, 1H).

[0318] A.7.2. Synthesis of 1-(benzenesulfonyl)indol-4-amine a35. To a stirred solution of 1-(benzenesulfonyl)-4-nitro-indole a34 (25.0 g, 82.8 mmol) in MeOH (250 mL) was added Fe (69.5 g, 1.24 mol) and NH4Cl (67.0 g, 1.24 mol), and the reaction mixture was heated under reflux for 15 h. Upon completion, the reaction was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes) to afford 7.00 g of 1-(benzenesulfonyl)indole-4-amine a35.

[0319] Yield: 31% Basic LCMS Method 1 (ES + ): 273 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 7.95 - 7.85 (m, 2H), 7.72 - 7.49 (m, 4H), 7.14 - 6.91 (m, 3H), 6.35 (d, J= 7.7 Hz, 1H), 5.55 (s, 2H).

[0320] A.7.3. Synthesis of 1-(benzenesulfonyl)-5-chloro-indol-4-amine a36. To a stirred solution of 1-(benzenesulfonyl)indole-4-amine a35 (35.4 g, 130 mmol) in DCM (300 mL) at 0 °C was added a solution of NCS (17.3 g, 130 mmol) in DCM (100 mL). The mixture was stirred at the same temperature for 1 h and then at rt for 1 h. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with DCM. The organic layer was washed with HO, dried over anhydrous NaSO, filtered, and concentrated under vacuum. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes) to give 14.8 g of 1-(benzenesulfonyl)-5-chloro-indole-4-amine a36.

[0321] Yield: 37% 1H NMR (400 MHz, DMSO-d6): δ 7.95 - 7.87 (m, 2H), 7.76 - 7.54 (m, 4H), 7.09 (dd, J = 17.3, 3.3 Hz, 3H), 5.82 (s, 2H).

[0322] A.7.4. Synthesis of 1-(benzenesulfonyl)-5-chloro-4-iodo-indole a37. To a solution of 1-(benzenesulfonyl)-5-chloro-indole-4-amine a36 (13.8 g, 45.1 mmol) in 12 N aqueous HCl (414 mL) at 0 °C, a solution of NaNO (7.77 g, 113 mmol) in HO (70 mL) was added dropwise. The mixture was stirred at the same temperature for 30 min. Next, a solution of KI (74.84 g, 450.9 mmol) in HO (137 mL) was added dropwise at 0 °C, and the mixture was stirred at the same temperature for 3 h. Upon completion, the reaction was extracted with EtOAc. The organic layer was washed with HO, dried over NaSO, filtered, and concentrated under vacuum. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexane) to give 17.2 g of 1-(benzenesulfonyl)-5-chloro-4-iodo-indole a37.

[0323] Yield: 92% 1 H NMR (400 MHz, DMSO-d6): δ 8.05 - 7.85 (m, 4H), 7.77 - 7.67 (m, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 3.7 Hz, 1H).

[0324] A.7.5. Synthesis of ethyl 2-[1-(benzenesulfonyl)-5-chloro-indol-4-yl]acetate a38. To a stirred solution of activated Zn (12.2 g, 188 mmol) in dry THF (75 mL) was added chlorotrimethylsilane (2.39 mL, 18.8 mmol). The mixture was stirred at rt for 15 min, and then ethyl bromoacetate (8.30 mL, 75.4 mmol) was added dropwise at rt. 1-(Benzenesulfonyl)-5-chloro-4-iodo-indole a37 (5.00 g, 12.0 mmol) was dissolved in THF (50 mL) and purged with argon for 15 min. Pd(t-BuP) (608 mg, 1.19 mmol) was added, followed by the above Reformatsky reagent. The reaction was heated at 65 °C for 16 h. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic layer was washed with HO, dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes) to give 3.34 g of ethyl 2-[1-(benzenesulfonyl)-5-chloroindol-4-yl]acetate a38.

[0325] Yield: 74% Basic LCMS Method 1 (ES + ): 378 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 8.00 (dd, J = 7.8, 1.6 Hz, 2H), 7.94 - 7.85 (m, 2H), 7.71 (t, J= 7.4 Hz, 1H), 7.60 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 3.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.02 (s, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0326] A.7.6. Synthesis of 2-(5-chloro-1H-indol-4-yl)acetic acid a39. To a stirred solution of ethyl 2-[1-(benzenesulfonyl)-5-chloro-indol-4-yl]acetate a38 (4.55 g, 12.1 mmol) in EtOH (40 mL) was added a 3N aqueous solution of NaOH (20 mL). The mixture was heated to reflux for 8 h, and upon completion, the reaction was evaporated under reduced pressure. The crude residue was diluted with H2O, acidified to pH 2 with a 1N aqueous solution of HCl, and extracted with EtOAc. The organic layer was washed with H2O, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2.50 g of 2-(5-chloro-1H-indol-4-yl)acetic acid a39, which was used in the next step without further purification.

[0327] Yield (crude): 99% 1 H NMR (400 MHz, DMSO-d6): δ 12.31 (s, 1H), 11.27 (s, 1H), 7.38-7.40 (m, 1H), 7.32 (dd, J = 8.6, 0.9 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.50-6.52 (m, 1H), 3.91 (s, 2H).

[0328] A.7.7. Synthesis of 2-(5-chloro-1-methyl-1H-indol-4-yl)acetic acid a39a. To a suspension of NaH (800 mg, 33.3 mmol) in THF (20 mL) was added a solution of 2-(5-chloro-1H-indol-4-yl)acetic acid a39 (1.40 g, 6.69 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 30 min. A solution of MeI (1.42 mL, 22.0 mmol) in THF (5 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with ice and washed with EtOAc (2 × 250 mL). The aqueous layer was acidified with a 6 N aqueous solution of HCl and extracted with DCM (2 × 300 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1.35 g of 2-(5-chloro-1-methyl-1H-indol-4-yl)acetic acid a39a as an off-white solid, which was used in the next step without further purification.

[0329] Yield (crude): 90% Basic LCMS Method 1 (ES + ): 224 (M+H) + , 85% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.27 - 12.41 (m, 1H), 7.35 - 7.43 (m, 2H), 7.17 (d, J = 8.80 Hz, 1H), 6.48 - 6.54 (m, 1H), 3.91 (s, 2H), 3.79 (s, 3H).

[0330] A.7.8. Synthesis of 2-(3,5-dichloro-1-methyl-1H-indol-4-yl)acetic acid a39b. To a solution of 2-(5-chloro-1-methyl-1H-indol-4-yl)acetic acid a39a (1.30 g, 5.82 mmol) in DCM (30 mL) was added NCS (0.78 g, 5.82 mmol) at 0 °C, and the reaction mixture was stirred at rt for 3 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with HO (150 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 2.5% MeOH in DCM) to give 950 mg of 2-(3,5-dichloro-1-methyl-1H-indol-4-yl)acetic acid a39b as an off-white solid.

[0331] Yield: 64% HPLC purity: 91% 1 H NMR (400 MHz, DMSO-d6): δ 12.42 (brs, 1H), 7.55 - 7.60 (m, 1H), 7.45 (d, J = 8.80 Hz, 1H), 7.25 (d, J = 8.80 Hz, 1H), 4.21 (s, 2H), 3.65 (s, 3H).

[0332] A.8. Synthesis of 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetic acid a45. [ka]

[0333] A.8.1. Synthesis of 2,4-dichloro-1-methoxybenzene a40. To a solution of 2,4-dichlorophenol (commercially available, 30.0 g, 184 mmol) in acetone (300 mL) was added KCO (31.7 g, 230 mmol) at room temperature, followed by MeI (28.6 mL, 460 mmol). The reaction mixture was heated to reflux for 2 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with HO (200 mL) and extracted with EtO (3 × 100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 32.0 g of 2,4-dichloro-1-methoxybenzene a40 as a colorless liquid, which was used in the next step without further purification.

[0334] Yield (crude): 99% 1 H NMR (400 MHz, DMSO-d6): δ 7.56 (brs, 1H), 7.38 (d, J= 8.31 Hz, 1H), 7.17 (d, J = 8.80 Hz, 1H), 3.85 (s, 3H).

[0335] A.8.2. Synthesis of 1,3-dichloro-4-methoxy-2-methylbenzene a41. To a solution of 2,4-dichloro-1-methoxybenzene a40 (21.0 g, 121 mmol) in dry THF (200 mL) was added n-BuLi (74.3 mL, 119 mmol) dropwise at −78 °C and stirred at the same temperature for 1 h. MeI (6.61 mL, 131 mmol) was added dropwise at −78 °C and the reaction mixture was stirred at the same temperature for 1 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated solution of NaHCO3 (200 mL) at −78 °C and concentrated in vacuo. The crude residue was extracted with EtOAc (3 × 200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 0 to 3% EtOAc in hexanes) to give 21.0 g of 1,3-dichloro-4-methoxy-2-methylbenzene a41 as a colorless liquid.

[0336] Yield: 92% 1 H NMR (400 MHz, DMSO-d6): δ 7.40 (d, J = 8.80 Hz, 1H), 7.04 (d, J = 8.80 Hz, 1H), 3.85 (s, 3H), 2.40 (s, 3H).

[0337] A.8.3. Synthesis of methyl 2-(2,6-dichloro-3-methoxyphenyl)acetate a42. To a solution of 1,3-dichloro-4-methoxy-2-methylbenzene a41 (21.0 g, 109 mmol) in dry THF (200 mL), LDA (65.9 mL, 131 mmol) was added dropwise at −78 °C and stirred at the same temperature for 1 h. Dimethyl carbonate (11.0 mL, 131 mmol) was added dropwise at −78 °C, and the reaction mixture was stirred at the same temperature for 1 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH₄Cl (150 mL) at −78 °C and concentrated in vacuo. The crude residue was extracted with EtOAc (3 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 0-4% EtOAc in hexanes) to give 15.0 g of 2-(2,6-dichloro-3-methoxyphenyl)acetic acid a42 as a colorless liquid.

[0338] Yield: 55% 1 H NMR (400 MHz, DMSO-d6): δ 7.46 (d, J = 9.29 Hz, 1H), 7.15 (d, J = 8.80 Hz, 1H), 3.98 (s, 2H), 3.87 (s, 3H), 3.64 (s, 3H).

[0339] A.8.4. Synthesis of methyl 2-(2,6-dichloro-3-hydroxyphenyl)acetate a43. To a solution of methyl 2-(2,6-dichloro-3-methoxyphenyl)acetate a42 (10.0 g, 40.1 mmol) in DCM (100 mL) was added BBr3 (9.65 mL, 100 mmol) dropwise at -15 °C and stirred for 15 min at the same temperature. The reaction mixture was stirred at 0 °C for 90 min. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was poured onto ice-cold MeOH (100 mL), quenched with H2O (100 mL), and concentrated in vacuo. The crude residue was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 20% EtOAc in hexanes) to give 9.50 g of methyl 2-(2,6-dichloro-3-hydroxyphenyl)acetate a41 as a white solid.

[0340] Yield: 91% 1 H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 7.27 (d, J= 8.80 Hz, 1H), 6.94 (d, J = 8.80 Hz, 1H), 3.94 (s, 2H), 3.63 (s, 3H)

[0341] A.8.5. Synthesis of methyl 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetate a44. To a solution of methyl 2-(2,6-dichloro-3-hydroxyphenyl)acetate a43 (5.00 g, 21.2 mmol) in ACN (50 mL) was added dropwise a solution of KOH (23.8 g, 425 mmol) in HO (50 mL) at 0 °C. 1-[[Bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (commercially available, 7.57 mL, 42.5 mmol) was added dropwise and stirred at 0 °C for 30 min. The reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was acidified with a 12 N aqueous concentrated solution of HCl (30 mL) and concentrated in vacuo. The crude residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 4% EtOAc in hexanes) to give 4.50 g of 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetate a44 as a white solid.

[0342] Yield: 74% 1 H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 9.29 Hz, 1H), 7.37 (d, J = 9.29 Hz, 1H), 7.32 (t, J = 74 Hz, 1H), 4.02 (s, 2H), 3.64 (s, 3H)

[0343] A.8.6. Synthesis of 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetic acid a45. To a solution of methyl 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetate a44 (3.50 g, 12.2 mmol) in MeOH (20 mL) and THF (20 mL) was added a solution of LiOH (1.41 g, 58.9 mmol) in HO (10 mL) dropwise at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with NH4Cl (3.12 g) and concentrated in vacuo. The crude residue was diluted with HO (50 mL), acidified to pH 3 with a 6N aqueous solution of HCl (20 mL), and extracted with EtOAc (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 0 to 20% EtOAc in hexanes) to give 3.30 g of 2-(2,6-dichloro-3-(difluoromethoxy)phenyl)acetic acid a45 as a white solid.

[0344] Yield: 77% HPLC purity: 96% 1 H NMR (400 MHz, DMSO-d6): δ 7.57 (d, J = 8.80 Hz, 1H), 7.36 (d, J = 8.80 Hz, 1H), 7.32 (t, J = 74 Hz, 1H), 3.93 (s, 2H)

[0345] A.9. Synthesis of 2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a55. [ka]

[0346] A.9.1. Synthesis of diethyl 2-(3,6-dichloropyridin-2-yl)malonate a46. To a solution of 2,3,6-trichloropyridine (commercially available, 10.0 g, 54.8 mmol) and diethyl malonate (16.7 mL, 110 mmol) in DMF (100 mL) was added CsCO (35.7 g, 110 mmol), and the reaction mixture was heated at 80 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to rt, diluted with HO (500 mL), and extracted with EtOAc (3 × 200 mL). The organic layer was washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 4% EtOAc in hexanes) to afford 16.7 g of diethyl 2-(3,6-dichloropyridin-2-yl)malonate a46 as a light brown liquid.

[0347] Yield: quantitative Basic LCMS Method 1 (ES + ): 306 (M+H) + , 64% purity. 1 H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 5.29 (s, 1H), 4.14-4.27 (m, 4H), 1.18 (t, J = 6.8 Hz, 6H).

[0348] A.9.2. Synthesis of ethyl 2-(3,6-dichloropyridin-2-yl)acetate a47. To a solution of diethyl 2-(3,6-dichloropyridin-2-yl)malonate a46 (15.7 g, 51.3 mmol) in DMSO (50 mL) and HO (50 mL) was added LiCl (21.7 g, 513 mmol), and the reaction mixture was heated to 120 °C for 24 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to rt and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 4% EtOAc in hexanes) to give 4.90 g of ethyl 2-(3,6-dichloropyridin-2-yl)acetate a47 as a colorless liquid.

[0349] Yield: 41% Basic LCMS Method 1 (ES + ): 235 (M+H) + , 96% purity. 1 H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95 (s, 2H), 1.16 (t, J = 7.2 Hz, 3H).

[0350] A.9.3. Synthesis of 2-(3,6-dichloropyridin-2-yl)acetic acid a48. To a solution of ethyl 2-(3,6-dichloropyridin-2-yl)acetate a47 (4.90 g, 20.9 mmol) in MeOH (25 mL), THF (25 mL), and HO (10 mL) was added LiOH (0.75 g, 31.4 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under vacuum at 30 °C. The crude residue was diluted with HO (100 mL), acidified to pH 2 with a 6 N solution of HCl, and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under vacuum at 30 °C. The crude residue was purified by washing with EtO (50 mL) and drying to give 4.31 g of 2-(3,6-dichloropyridin-2-yl)acetic acid a48 as an off-white solid, which was used in the next step without further purification.

[0351] Yield (crude): quantitative Basic LCMS Method 1 (ES + ): 205.9 (M+H) + , 92% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.75 (brs, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.87 (s, 2H).

[0352] A.9.4. Synthesis of tert-butyl 2-(3,6-dichloropyridin-2-yl)acetate a49. To a solution of 2-(3,6-dichloropyridin-2-yl)acetic acid a48 (4.30 g, 20.9 mmol) in t-BuOH (50 mL) was added (Boc)2O (7.19 mL, 31.3 mmol), followed by DMAP (260 mg, 2.09 mmol) at rt, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with HO (100 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 5% EtOAc in hexanes) to give 4.94 g of tert-butyl 2-(3,6-dichloropyridin-2-yl)acetate a49 as a pale yellow liquid.

[0353] Yield: 90% Basic LCMS Method 1 (ES + ): 205.9 (M-tBu+H) + , 94% purity. 1 H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 3.86 (s, 2H), 1.40 (s, 9H)

[0354] A.9.5. Synthesis of tert-butyl 2-(3-chloro-6-hydrazineylpyridin-2-yl)acetate a50. To a solution of tert-butyl 2-(3,6-dichloropyridin-2-yl)acetate A49 (4.90 g, 18.7 mmol) in 1,4-dioxane (50 mL) was added hydrazine monohydrate (1.81 mL, 37.4 mmol), and the reaction mixture was heated at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 5% MeOH in DCM) to give 1.21 g of tert-butyl 2-(3-chloro-6-hydrazineylpyridin-2-yl)acetate A50 as a pale yellow viscous liquid.

[0355] Yield: 25% Basic LCMS Method 1 (ES + ): 258 (M+H) + , 90% purity. 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (brs, 1H), 7.48 (d, J = 8.8Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 4.15 (brs, 2H), 3.61 (s, 2H).

[0356] A.9.6. Synthesis of tert-butyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate a51. To a solution of tert-butyl 2-(3-chloro-6-hydrazineylpyridin-2-yl)acetate A50 (3.94 g, 15.3 mmol) in THF (50 mL) was added CDI (2.97 g, 18.3 mmol) in portions at rt, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was purified by washing with EtO (50 mL), and the precipitate was dried in vacuo to give 2.61 g of tert-butyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate A51 as an off-white solid.

[0357] Yield: 60% Basic LCMS Method 1 (ES + ): 228 (M-tBu+H) + , 99% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.58 (brs, 1H), 7.12 - 7.18 (m, 2H), 4.28 (s, 2H), 1.37 (s, 9H).

[0358] A.9.7. Synthesis of 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a52. To a solution of tert-butyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate a51 (1.20 g, 4.23 mmol) in DCM (12 mL) was added TFA (3.14 mL, 42.3 mmol) at 0 °C, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was purified by washing with EtO (3 × 50 mL) and dried in vacuo to give 0.99 g of 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a52 as the TFA salt as an off-white solid, which was used in the next step without further purification.

[0359] Yield: 69% HPLC purity: 98% Basic LCMS Method 1 (ES + ): 228 (M+H) + , 99% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.78 (brs, 1H), 12.60 (s, 1H), 7.13-7.18 (m, 2H), 4.31 (s, 2H).

[0360] A.9.8. Synthesis of ethyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate hydrochloride a53. To a solution of 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a52 (2.43 g, 7.11 mmol) in EtOH (50 mL) was added SOCl2 (1.56 mL, 21.3 mmol) at 0 °C, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was purified by washing with Et2O (50 mL) and dried under vacuum to give 2.00 g of ethyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate hydrochloride a53 as an off-white solid.

[0361] Yield: 96% HPLC purity: 98% Basic LCMS Method 1 (ES + ): 256 (M+H) + , 98% purity. 1 H NMR (400 MHz, DMSO-d6): δ 12.63 (brs, 1H), 7.14-7.21 (m, 2H), 5.45 (brs, 1H), 4.36 (s, 2H), 4.11 (q, J= 6.8 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H).

[0362] A.9.9. Synthesis of ethyl 2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate a54. To a solution of ethyl 2-(6-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate hydrochloride a53 (1.20 g, 4.11 mmol) in POCl3 (10 mL, 109 mmol) was added N,N-dimethylaniline (0.10 mL, 0.82 mmol), and the reaction mixture was heated in a sealed tube at 100 °C for 36 h. Upon completion, the reaction mixture was cooled to rt and concentrated in vacuo. The crude residue was diluted in the cold with ice HO (100 mL), basified with saturated aqueous NaHCO3 (20 mL) to pH 8, and extracted with EtOAc (3 × 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 5% MeOH in DCM for 30 min, then 2% MeOH in DCM) to give 0.98 g of ethyl 2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate a54 as a pale yellow solid.

[0363] Yield: 87% Basic LCMS Method 1 (ES + ): 274 (M+H) + , 93.9% purity. 1 H NMR (400 MHz, DMSO-d6): δ 7.86 (d, J = 10.0 Hz, 1H), 7.55 (d, J = 9.6 Hz, 1H), 4.58 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.6 Hz. 3H).

[0364] A.9.10. Synthesis of 2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a55. To a solution of ethyl 2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetate a54 (0.98 g, 3.58 mmol) in MeOH (5 mL), THF (10 mL), and HO (1 mL) was added LiOH (0.13 g, 5.36 mmol) at 0 °C, and the reaction mixture was stirred at rt for 3 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under vacuum at 30 °C. The crude residue was diluted with HO (50 mL), acidified to pH 2 with a 6 N aqueous solution of HCl, filtered, washed with EtO (100 mL), and dried under vacuum to give 709 mg of 2-(3,6-dichloro[1,2,4]triazolo[4,3-a]pyridin-5-yl)acetic acid a55 as an off-white solid, which was used in the next step without further purification.

[0365] Yield (crude): 81% HPLC purity: 95.6% Basic LCMS Method 1 (ES + ): 246 (M+H) + , 98% purity. 1 H NMR (400 MHz, DMSO-d6): δ 13.32 (brs, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.55 (d, J = 9.6 Hz, 1H), 4.51 (s, 2H).

[0366] A.10. Synthesis of 2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)acetic acid a65. [ka]

[0367] A.10.1. Synthesis of 7-fluoro-4-nitro-1H-indazole a56. To a solution of 7-fluoro-1H-indazole (commercially available, 10.0 g, 73.5 mmol) in concentrated HSO (100 mL) was added KNO (7.43 g, 73.5 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 4 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was poured onto ice-cold H2O (500 mL), filtered, and dried. The crude residue was purified by normal-phase column chromatography (elution: 8% EtOAc in hexanes for 30 min, then 10% EtOAc in hexanes for 30 min, and 8% EtOAc in hexanes) to give 2.60 g of 7-fluoro-4-nitro-1H-indazole a56 as an off-white solid.

[0368] Yield: 20% 1 H NMR (400 MHz, DMSO-d6): δ 14.58 (brs, 1H), 8.64 (brs, 1H), 8.21 (dd, J = 4.8, 3.6 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H).

[0369] A.10.2. Synthesis of 7-fluoro-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a57. To a solution of 7-fluoro-4-nitro-1H-indazole a56 (4.80 g, 26.5 mmol) in DCM (50 mL) was added DHP (4.85 mL, 53.0 mmol) and p-TSA (0.39 g, 2.04 mmol) at rt, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (200 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 10% EtOAc in hexanes for 30 min, then 5% EtOAc in hexanes) to give 6.97 g of 7-fluoro-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a57 ​​as an off-white solid.

[0370] Yield: 99% 1 H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.24 (dd, J= 8.4, 3.6 Hz, 1H), 7.55 (t, J = 9.6 Hz, 1H), 5.94-5.96 (m, 1H), 3.87-3.95 (m, 1H), 3.65-3.75 (m, 1H), 2.35-2.48 (m, 1H), 2.05-2.13 (m, 2H), 1.70-1.85 (m, 1H), 1.56-1.60 (m, 2H).

[0371] A.10.3. Synthesis of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a58. To a solution of 7-fluoro-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a57 ​​(6.90 g, 26.0 mmol) in MeOH (200 mL) and EtOAc (200 mL) was added Pd / C (2.00 g, 18.8 mmol), and the reaction mixture was stirred at rt under H2 (balloon pressure) for 16 h. Reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 20% EtOAc in hexanes for 30 min, then 10% EtOAc in hexanes) to afford 6.10 g of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a58 as a brown semi-solid.

[0372] Yield: 76% Basic LCMS Method 1 (ES + ): 151.85 (M+H) + , 85% purity. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J = 1.5 Hz, 1H) 6.89 (dd, J = 12.2, 8.3 Hz, 1H), 6.06 (dd, J = 8.3, 2.4 Hz, 1H), 5.71 (dd, J = 10.3, 1.71 Hz, 1H), 5.68 (s, 2H), 3.88-3.91 (m, 1H), 3.57-3.66 (m, 1H), 2.36-2.45 (m, 1H), 1.97-2.08 (m, 2H), 1.66-1.78 (m, 1H), 1.51-1.55 (m, 2H).

[0373] A.10.4. Synthesis of 5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a59. To a solution of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a58 (5.80 g, 24.7 mmol) in DCM (60 mL) was added NCS (3.29 g, 24.7 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (250 mL) and extracted with DCM (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 20% EtOAc in hexanes for 30 min, then 10% EtOAc in hexanes) to give 2.20 g of 5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a59 as a brown semi-solid.

[0374] Yield: 33% Basic LCMS Method 1 (ES + ): 185.85 (M+H) + , 92% purity. 1H NMR (400 MHz, DMSO-d6): δ 8.33 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 11.2 Hz, 1H), 5.95 (s, 2H), 5.70-5.72 (m, 1H), 3.89 (d, J = 11.7 Hz, 1H), 3.56-3.68 (m, 1H), 2.32-2.43 (m, 1H), 2.00-2.02 (m, 2H), 1.66-1.78 (m, 1H), 1.52-1.54 (m, 2H).

[0375] A.10.5. Synthesis of 5-chloro-7-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a60. A stirred mixture of CuI (3.11 g, 16.3 mmol) in MeCN (25 mL) was heated at 50 °C, followed by the dropwise addition of tBuONO (4.85 mL, 40.8 mmol) at 50 °C, and the reaction mixture was stirred at the same temperature for 30 min. A solution of 5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine a59 (2.20 g, 8.16 mmol) in MeCN (5 mL) was added, and the reaction mixture was heated at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was basified with a saturated aqueous solution of NaHCO (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes for 30 min, then 4% EtOAc in hexanes) to give 1.47 g of 5-chloro-7-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a60 as a white solid.

[0376] Yield: 47% 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.65 (d, J = 11.6 Hz, 1H), 5.79-5.81 (m, 1H), 3.87-3.90 (m, 1H), 3.62-3.68 (m, 1H), 2.30-2.40 (m, 1H), 2.00-2.10 (m, 2H), 1.65-1.80 (m, 1H), 1.50-1.60 (m, 2H).

[0377] A.10.6. Synthesis of 5-chloro-7-fluoro-4-iodo-1H-indazole a61. To a solution of 5-chloro-7-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a60 (200 mg, 0.53 mmol) in DCM (5 mL) was added TFA (500 μL, 6.73 mmol) at 0 °C, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was basified with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This reaction was repeated with 870 mg of a60, and the crude residues from both reactions were combined and purified by normal phase column chromatography (elution: 20% EtOAc in hexanes for 30 min, then 10% EtOAc in hexanes) to give 640 mg of 5-chloro-7-fluoro-4-iodo-1H-indazole a61 as an off-white solid.

[0378] Yield: 77% 1 H NMR (400 MHz, DMSO-d6): δ 14.18 (brs, 1H), 8.00 (s, 1H), 7.56 (d, J = 10.8 Hz, 1H).

[0379] A.10.7. Synthesis of 3,5-dichloro-7-fluoro-4-iodo-1H-indazole a62. To a solution of 5-chloro-7-fluoro-4-iodo-1H-indazole a61 (640 mg, 2.16 mmol) in MeCN (10 mL) was added NCS (580 mg, 4.32 mmol), and the reaction mixture was heated at 70 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was diluted with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 10% EtOAc in hexanes for 30 min, then 6% EtOAc in hexanes) to afford 360 mg of 3,5-dichloro-7-fluoro-4-iodo-1H-indazole a62 as an off-white solid.

[0380] Yield: 46% Basic LCMS Method 1 (ES + ): 331.5 (M+H) + , 92% purity. 1 H NMR (400 MHz, DMSO-d6): δ 14.34 (brs, 1H), 7.67 (d, J = 10.4 Hz, 1H).

[0381] A.10.8. Synthesis of 3,5-dichloro-7-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a63. To a solution of 3,5-dichloro-7-fluoro-4-iodo-1H-indazole a62 (350 mg, 1.06 mmol) in DCM (10 mL) was added DHP (190 μL, 2.12 mmol) and p-TSA (20.0 mg, 0.11 mmol) at 0 °C, and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes for 30 min, then 5% EtOAc in hexanes) to give 440 mg of 3,5-dichloro-7-fluoro-4-iodo-1-(tetrahydro-2Hpyran-2-yl)-1H-indazole a63 as an off-white solid.

[0382] Yield: 84% 1 H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J = 11.6 Hz, 1H), 5.79-5.80 (m, 1H), 3.86-3.89 (m, 1H), 3.61-3.67 (m, 1H), 2.10-2.32 (m, 1H), 1.95-2.10 (m, 2H), 1.63-1.80 (m, 1H), 1.44-1.48 (m, 2H).

[0383] A.10.9. Synthesis of ethyl 2-(3,5-dichloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate a64. Synthesis of Reformatsky reagent: To a solution of Zn (3.00 g, 45.9 mmol) in THF (30 mL) under an argon atmosphere, TMSCl (600 μL, 4.73 mmol) was added and the reaction mixture was stirred at rt for 15 min. Ethyl 2-bromoacetate (3.30 mL, 0.61 mmol) was added dropwise and the reaction mixture was stirred at rt for 15 min.

[0384] A mixture of 3,5-dichloro-7-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole a63 (960 mg, 2.31 mmol) and Pd(tBuP)2 (120 mg, 0.23 mmol) was purged with argon for 5 minutes, after which THF (5 mL) was added. The above Reformatsky reagent (0.6 M, 12 mL, 6.93 mmol) was added, and the reaction mixture was heated in a sealed tube at 65 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes for 30 min, then 6% EtOAc in hexanes) to give ethyl 2-(3,5-dichloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate a64 as 680 mg of a light brown solid.

[0385] Yield: 79% Basic LCMS Method 1 (ES + ): 291 (M+H) + , 93% purity. 1 H NMR (400 MHz, DMSO-d6): δ 7.66 (d, J = 11.6 Hz, 1H), 5.77-5.80 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.86-3.89 (m, 1H), 3.60-3.67 (m, 1H), 2.26-2.30 (m, 1H), 1.99-2.05 (m, 2H), 1.62-1.75 (m, 1H), 1.45-1.55 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H).

[0386] A.10.10. Synthesis of 2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)acetic acid a65. A stirred solution of ethyl 2-(3,5-dichloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate a64 (100 mg, 0.27 mmol) in 6 N aqueous hydrochloric acid (2.00 mL, 12.0 mmol) was heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo. The crude residue was basified with a saturated aqueous solution of NaHCO (50 mL) and extracted with EtOAc (2 × 50 mL). The aqueous layer was acidified to pH 2 with a 6 N aqueous solution of HCl and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. This reaction was repeated with 580 mg of a64, and the crude residues from both reactions were combined, dissolved in EtOAc (10 mL), and concentrated in vacuo. The resulting solid was washed with pentane (10 mL) and dried to give 305 mg of 2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)acetic acid a65 as an off-white solid.

[0387] Yield: 64% HPLC purity: 97% Basic LCMS Method 1 (ES + ): 261 (M+H) + , 97% purity. 1 H NMR (400 MHz, DMSO-d6): δ 14.17 (brs, 1H), 12.68 (brs, 1H), 7.54 (d, J = 10.4 Hz, 1H), 4.16 (s, 2H).

[0388] A.11. Synthesis of 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67 [ka]

[0389] A.11.1. Synthesis of methyl 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetate a66 To a solution of methyl 2-(2-bromo-3,5-dichloro-4-pyridyl)acetate a25 (11.9 g, 40.0 mmol) in toluene (60 mL) was added tributyl(1-ethoxyvinyl)tin (14.6 mL, 42.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.86 g, 1.59 mmol) at rt. The reaction mixture was then heated at 120 °C under nitrogen and with stirring overnight. The reaction mixture was cooled to rt. Toluene (250 mL) was added, and the organic layer was washed with saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 5% EtOAc in hexane) to give 8.20 g of methyl 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetate a66.

[0390] Yield: 64% 1 H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 4.57 - 4.46 (m, 2H), 4.05 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H)

[0391] A.11.2. Synthesis of 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67 To a solution of methyl 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetate a66 (8.21 g, 28.3 mmol) in THF (80 mL) was added LiOH·HO (1.82 g, 42.5 mmol) dissolved in HO (15 mL) dropwise, and the reaction mixture was stirred at rt overnight. The reaction mixture was evaporated in vacuo to give 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67 (8.10 g) as a white solid, which was used in the next step without further purification.

[0392] Yield (crude): quantitative Basic LCMS Method 2 (ES+ ): 276 / 278 / 280 (M+H) + .

[0393] B. Synthesis of intermediates of formula (III) B.1. Synthesis of tert-butyl (1S)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(S) and tert-butyl (1R)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(R). [ka]

[0394] B.1.1. Synthesis of 7-bromo-10b-methyl-5,6-dihydro-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione b1 To a solution of N-[2-(2-bromophenyl)ethyl]acetamide (commercially available, 106 g, 439 mmol) in DCM (1.50 L) at 0 °C was added oxalyl chloride (72.0 mL, 792 mmol) dropwise. The mixture was stirred at 0 °C for 2 h, then warmed to rt and stirred for 3 h. The reaction mixture was then cooled to 0 °C, and ferric chloride (86.0 g, 530.2 mmol) was added in two portions. The reaction mixture was warmed to rt, stirred at rt overnight, diluted with DCM (2.50 L), and quenched at 0 °C with a 12 M concentrated solution of ammonia (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give 108 g of 7-bromo-10b-methyl-5,6-dihydro-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione b1 as a brown solid, which was used in the next step without further purification.

[0395] Yield (crude): 83%. Basic LCMS Method 2 (ES + ): 296 / 298 (M+H) + .

[0396] B.1.2. Synthesis of 5-bromo-1-methyl-3,4-dihydroisoquinoline b2 To a suspension of 7-bromo-10b-methyl-5,6-dihydro-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione b1 (108 g, 365 mmol) in MeOH (1.50 L) was added sulfuric acid (75.0 mL) dropwise at rt. The reaction mixture was stirred at 65 °C overnight and then quenched at 0 °C with a 15 M concentrated solution of ammonia (300 mL). The mixture was concentrated in vacuo, and H2O (300 mL) was added. The aqueous layer was extracted six times with DCM (1.00 L). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 86.4 g of 5-bromo-1-methyl-3,4-dihydroisoquinoline b2 as a brown solid, which was used in the next step without further purification.

[0397] Yield (crude): 95%. HPLC (basic mode): RT 4.75 min, 87% purity.

[0398] B.1.3. Synthesis of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline b3 To a solution of 5-bromo-1-methyl-3,4-dihydroisoquinoline b2 (86.4 g, 347 mmol) in EtOH (2.00 L) was added sodium borohydride (13.2 g, 349 mmol) in small portions (13 * 1 g) was added. The mixture was stirred at 0 °C for 2 h, then a 5 N aqueous solution of HCl (250 mL) was added at 0 °C. The reaction mixture was stirred at rt overnight, then EtOH was concentrated in vacuo. DCM (1 L) was added, and the mixture was quenched with a 6 M concentrated solution of ammonia (400 mL) at 0 °C. The organic layer was extracted twice with DCM (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 83.0 g of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline b3 as a brown solid, which was used in the next step without further purification.

[0399] Yield (crude): 85%. HPLC (basic mode): RT 4.53 min, 80% purity.

[0400] B.1.4. Synthesis of tert-butyl (1S)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(S) and tert-butyl (1R)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(R) To a solution of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline b3 (78.0 g, 276 mmol) in DCM (1 L) was added TEA (160 mL, 1.14 mol) at 0 °C. Then, a solution of di-tert-butyl dicarbonate (65.0 g, 295 mmol) in DCM (250 mL) was added dropwise at 0 °C. The reaction mixture was stirred at rt overnight and quenched with water (100 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was triturated twice with a mixture of MeOH and hexane (1:2, 450 mL) to give 63.0 g of racemic tert-butyl 5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid b4 (yield: 70%, HPLC (basic mode): RT 6.59 min, purity 98%) as a white solid.

[0401] Chiral separation of racemic tert-butyl 5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4 (SFC, Whelko 01(R,R), 50x227mm, 360mL / min, 220nm, 25°C, elution: EtOH 20%-CO2 80%) gave: - 25.1 g of tert-butyl (1S)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(S) as a solid. Yield: 40%. HPLC (basic mode): RT 6.59 min, 91% purity. Chiral analysis (LC, Whelko‐01(R,R), 250 *4.6 mm, 1 mL / min, 220 nm, 30 °C, elution: iPrOH / heptane / DEA 50 / 50 / 0.1) RT 4.86 min, 98% ee.

[0402] - 29.3 g of tert-butyl (1R)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(R) as a solid. Yield: 46%. HPLC (basic mode): RT 6.59 min, 98% purity. Chiral analysis (LC, Whelko‐01(R,R), 250 * 4.6 mm, 1 mL / min, 220 nm, 30°C, elution: iPrOH / heptane / DEA 50 / 50 / 0.1), RT 5.62 min, 92% ee.

[0403] B.2. Synthesis of 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b11 [ka]

[0404] B.2.1. Synthesis of tert-butyl (1S)-5-hydroxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b5 To a solution of tert-butyl (1S)-5-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b4-(S) (24.9 g, 76.5 mmol) in 1,4-dioxane (80 mL) was added tBuXPhos palladacycle (750 mg, 1.09 mmol). Then, a solution of KOH (11.6 g, 176 mmol) in water (20 mL) was added, and the reaction mixture was stirred at 85 °C for 2 h. The reaction mixture was quenched with a 1N aqueous solution of HCl (400 mL) at rt and extracted with EtOAc (400 mL). The organic layer was washed twice with HO (250 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 20% EtOAc in hexanes) to give 16.6 g of tert-butyl (1S)-5-hydroxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b5 as a white solid.

[0405] Yield: 76% Basic LCMS Method 2 (ES + ): 208 (M-tBu+H) + , 164 (M-Boc+H) + .

[0406] B.2.2. Synthesis of tert-butyl (1S)-5-hydroxy-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b6 To a solution of tert-butyl (1S)-5-hydroxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate b5 (2.00 g, 7.60 mmol) in isopropanol (20 mL) was added rhodium on activated carbon (Johnson-Matthey type 20C, 234 mg, 0.11 mmol). The reaction mixture was flushed with nitrogen and then with H2. The reaction mixture was heated at 100 °C under 8 bar of H2 pressure for 72 h. The reaction mixture was cooled to rt, filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give 2.37 g of tert-butyl (1S)-5-hydroxy-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b6, which was used in the next step without further purification.

[0407] Yield (crude): quantitative Basic LCMS Method 2 (ES + ): 214 (M+H) + .

[0408] B.2.3. Synthesis of tert-butyl (1S)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7 To a solution of tert-butyl (1S)-5-hydroxy-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b6 (68.0 g, 203 mmol) in acetic acid (280 mL, 4.89 mol) was added a 0.87 M aqueous solution of sodium hypochlorite (1.00 L, 870 mmol) at 0 °C. The reaction mixture was stirred at 10 °C during the addition and then overnight at rt. The reaction mixture was extracted twice with DCM (250 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 69.0 g of tert-butyl (1S)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7, which was used in the next step without further purification.

[0409] Yield (crude): 96%. Basic LCMS Method 2 (ES + ): 212 (M+H) + .

[0410] B.2.4. Synthesis of (1S)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one hydrochloride b8 To a solution of tert-butyl (1S)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7 (3.12 g, 11.7 mmol) in iPrOH (6.00 mL) was added dropwise a 5N aqueous solution of HCl in iPrOH (6.00 mL) at rt. The reaction mixture was stirred at rt overnight. The resulting solid was filtered and washed once with the mother liquor phase and twice with fresh iPrOH (6.00 mL). The mother liquor phase was concentrated under vacuum to give 2.17 g of (1S)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one hydrochloride b8 as a brown oil, which was used in the next step without further purification.

[0411] Yield (crude): 64%. Basic LCMS Method 2 (ES + ): 168 (M+H) + .

[0412] B.2.5. Method A (Peptide Coupling) Synthesis of 2-[2-[(1S,4aR,8aS)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b9 To a solution of 2-(2-chloro-6-cyano-3-methoxyphenyl)acetic acid a3 (4.43 g, 17.3 mmol) and (1S)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one hydrochloride b8 (4.00 g, 19.6 mmol) in DMF (10 mL) was added HBTU (8.19 g, 21.6 mmol), followed by EtN (8.30 mL, 59.5 mmol) at 0 °C. The reaction mixture was stirred overnight at rt, poured into EtOAc (300 mL), and then washed twice with 1 N aqueous HCl (150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was triturated with EtOAc (20 mL), and the resulting precipitate was filtered. The mother liquor was sonicated, and a second precipitate was filtered. Both precipitates were combined and dried under vacuum to give 4.21 g of 2-[2-[(1S,4aR,8aS)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b9 as the pure desired isomer.

[0413] Yield: 57% Basic LCMS Method 3 (ES + ): 375 / 377 (M+H) + , 99% purity Acid LCMS method 2 (ES + ): 375 / 377 (M+H) + , 99% purity

[0414] B.2.6. Synthesis of 2-[2-[(1S,4aR,8aS)-5-(methoxymethylidene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b10 To a solution of (methoxymethyl)triphenylphosphonium chloride (7.68 g, 22.4 mmol) in THF (100 mL) was added dropwise a 2.5 M solution of n-BuLi (8.10 mL, 20.2 mmol) in hexane at -78 °C. The reaction mixture was slowly warmed to 0 °C and stirred at 0 °C for 15 min. The reaction mixture was then cooled to -78 °C, and 2-[2-[(1S,4aR,8aS)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b9 (4.20 g, 11.2 mmol) was added portionwise. The reaction mixture was slowly warmed to rt and stirred at rt for 2 h before being diluted with EtO (500 mL). The mixture was washed with water (250 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: EtOAc / hexanes) to give 4.10 g of 2-[2-[(1S,4aR,8aS)-5-(methoxymethylidene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b10.

[0415] Yield: 91% Basic LCMS Method 2 (ES + ): 403 / 405 (M+H) + .

[0416] B.2.7. Synthesis of 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b11 To a solution of 2-[2-[(1S,4aR,8aS)-5-(methoxymethylidene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b10 (4.00 g, 9.93 mmol) in THF (200 mL) was added 1N aqueous HCl (50 mL) dropwise at rt. The reaction mixture was stirred at rt for 48 h. EtOAc (150 mL) was added, and the mixture was washed successively with HO (50 mL), saturated aqueous NaHCO (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 3.86 g of 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl-3-chloro-4-methoxybenzonitrile b11, which was used in the next step without further purification.

[0417] Yield (crude): quantitative Basic LCMS Method 2 (ES + ): 389 / 391 (M+H) + .

[0418] B.3. Synthesis of (1S,4aR,8aS)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one b8-peak 2 [ka]

[0419] B.3.1. Synthesis of tert-butyl (1S,4aS,8aR)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7-peak1 and tert-butyl (1S,4aR,8aS)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7-peak2 Chiral separation of 5.50 g of tert-butyl (1S)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7 (LC, YMC Chiralart cellulose-sc, 4.6 * 250 mm, 1 mL / min, 220 nm, 30°C, elution: iPrOH / hexane / NH3 10 / 90 / 0.1) gave: - 2.31 g of tert-butyl (1S,4aS,8aR)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7-peak1 as an undesired mixture of cis and trans isomers. Yield: 42%. Basic LCMS Method 1 (ES + ): 168 (M+H) + , 90% purity. 1 H NMR (400 MHz, CDCl3): δ 4.21 - 4.31 (m, 1H), 4.08-4.12 (m, 1H), 2.84-2.92 (m, 1H), 2.72-2.78 (m, 1H), 2.42-2.54 (m, 1H), 2.24-2.30 (m, 1H), 2.04-2.12 (m, 1H), 1.79 - 1.96 (m, 3H), 1.60 - 1.67 (m, 3H), 1.47 (s, 9H),1.17 (m, J=6.85 Hz, 3H) Chiral analysis (LC, IC, 150*4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: iPrOH / heptane / DEA 10 / 90 / 0.1) RT 5.93 min, 72% de + RT 6.33 min, 28% de.

[0420] - 2.16 g of tert-butyl (1S,4aR,8aS)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7-peak 2 as the pure desired isomer. Yield: 39% Basic LCMS Method 1 (ES+ ): 168 (M+H) + , 100% purity. 1 H NMR (400 MHz, CDCl3): δ 4.40-4.48 (s, 1H), 4.19-4.29 (m, 1H), 4.03-4.16 (m, 1H), 3.96-4.02 (m, 1H), 2.69-2.90 (m, 1H), 2.40-2.49 (m, 1H), 2.21-2.38 (m, 2H), 2.04-2.12 (m, 1H), 1.65 - 1.92 (m, 4H), 1.45 (s, 9H), 1.12 (d, J=6.85 Hz, 3H). Chiral analysis (LC, IC, 150*4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: iPrOH / heptane / DEA 10 / 90 / 0.1) RT 7.80 min, 95% de.

[0421] B.3.2. Synthesis of (1S,4aR,8aS)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one b8-peak 2 To a solution of tert-butyl (1S)-1-methyl-5-oxo-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b7 (1.00 g, 3.74 mmol) in MeOH (50 mL) was added dropwise a 12 M solution of HCl in MeOH (15.0 mL) at rt. The reaction mixture was then allowed to stir at rt for 4 h overnight and concentrated in vacuo to give 625 mg of (1S)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one hydrochloride b8-peak 2, which was used in the next step without further purification.

[0422] Yield (crude): quantitative. Basic LCMS Method 2 (ES + ): 168 (M+H) + .

[0423] B.4. Synthesis of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2-difluoroethanol hydrochloride b18-(S) [ka]

[0424] B.4.1. Synthesis of (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinoline b12 To a solution of 2-[2-[(1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxy-benzonitrile b10 (21.5 g, 53.4 mmol) in 1,4-dioxane (200 mL) was added lithium hydroxide monohydrate (32.0 g, 750 mmol) dissolved in water (500 mL) at rt. The reaction mixture was heated at 130 °C for 4 days. The reaction mixture was cooled to rt and extracted with DCM (4 x 250 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 11.0 g of (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinoline b12 as a solid, which was used in the next step without further purification.

[0425] Yield (crude): 100% Acic LCMS Method 1 (ES + ): 196 (M+H) + .

[0426] B.4.2. Synthesis of benzyl (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b13 To a solution of (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinoline b12 (11.0 g, 53.5 mmol) in DCM (200 mL), N-(benzyloxycarbonyloxy)succinimide (16.4 g, 64.5 mmol) was added and the reaction mixture was stirred for 5 min. DIPEA (30.0 mL, 180 mmol) was then added dropwise, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (250 mL), and the organic layer was washed with HO (2 x 250 mL). The organic phase was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10% EtOAc in hexanes) to give 14.0 g of benzyl (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b13.

[0427] Yield: 79% Acid LCMS method 1 (ES + ): 330 (M+H) + .

[0428] B.4.3. Synthesis of benzyl (1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b14 To a solution of benzyl (1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinoline-2-carboxylate b13 (14.0 g, 42.5 mmol) in THF (560 mL) was added dropwise 1N aqueous HCl (85 mL) at rt, and the reaction mixture was stirred at rt overnight. EtOAc (200 mL) was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under high vacuum to give 13.0 g of benzyl (1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b14, which was used in the next step without further purification.

[0429] Yield: 96% Acic LCMS Method 1 (ES + ): 316 (M+H) + .

[0430] B.4.4. Synthesis of benzyl (1S,4aR,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b15 To a solution of benzyl (1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b14 (3.40 g, 11.0 mmol) in DMF (50 mL) was added cesium fluoride (3.27 g, 21.3 mmol), and the reaction mixture was cooled to 0 °C. Difluoromethyl)trimethylsilane (3.08 mL, 21.3 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 15 min and warmed to rt for 6 h. 37% aqueous HCl (1.80 mL, 22.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at rt overnight. EtOAc (250 mL) was added to the reaction mixture. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and then brine (100 mL). The aqueous layer was extracted again with EtOAc (250 mL). The combined organic layers were finally washed with water (250 mL), dried over MgSO, filtered, and concentrated under high vacuum to give 4.46 g of benzyl (1S,4aR,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8a-octahydro-1H-isoquinoline-2-carboxylate b15, which was used in the next step without further purification.

[0431] Yield (crude): 100% Acic LCMS Method 1 (ES + ): 368 (M+H) +

[0432] B.4.5. Synthesis of benzyl (1S,4aR,5R,8aS)-5-(2,2-difluoroacetyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b16 To a solution of benzyl (1S,4aR,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b15 (4.46 g, 10.9 mmol) in DCM (100 mL) was added Dess-Martin Periodinane (6.20 g, 14.0 mmol) in portions at 0 °C, and the reaction mixture was stirred at rt overnight. DCM (100 mL) was added, followed by saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted with DCM (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2 × 100 mL) and finally with water (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 5% to 60% EtOAc in hexanes) to give 3.10 g of benzyl (1S,4aR,5R,8aS)-5-(2,2-difluoroacetyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b16.

[0433] Yield: 77% Acic LCMS Method 1 (ES + ): 366 (M+H) + .

[0434] B.4.6. Synthesis of benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17-(S) and benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17-(R) To a solution of benzyl (1S,4aR,5R,8aS)-5-(2,2-difluoroacetyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b16 (1.55 g, 4.24 mmol) in 2-MeTHF (30.0 mL) was added lithium borohydride (120 mg, 5.23 mmol) at 0 °C, and the reaction mixture was stirred overnight. The reaction mixture was quenched with HO (5 mL) and stirred for 1 h. After that, a 1N aqueous solution of HCl (5 mL) was added dropwise, and the reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed once with HO. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 1.50 g of benzyl (1S,4aR,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17.

[0435] Yield: 93% Acic LCMS Method 1 (ES + ): 368 (M+H) + .

[0436] Chiral separation of racemic b17 (SFC, Chiralpak AD Daicel®, 20 μm, 279×50 mm, 360 mL / min, 220 nm, 30° C., elution: EtOH 20%-CO2 80%) gave: -910mg benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17-(S) Yield: 63% Acic LCMS Method 1 (ES + ): 368 (M+H) + , 100% purity.

[0437] Chiral analysis (LC, Chiralpak AD Daicel (registered trademark), 3 μm, 150 * 4.6mm, 1.5mL / min, 220nm, 30℃, elution: MeOH / DEA 100 / 0.1): RT 1.72 min, 100% de. - 335 mg of benzyl (1S,4aR,5R,8aS)-5-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17-(R) Yield: 23% Acetic LCMS method 1 (ES + ):368(M+H) + ,100% purity

[0438] Chiral analysis (LC, Chiralpak AD Daicel (registered trademark), 3μm, 150x4.6mm, 1.5mL / min, 220nm, 30℃, elution: MeOH / DEA 100 / 0.1): RT 3.92 min, 100% de. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 150 x 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: MeOH / DEA 100 / 0.1): RT 3.92 min, 100% de.

[0439] B.4.7. Synthesis of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2-difluoroethanol hydrochloride b18-(S) A solution of benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b17-(S) (900 mg, 2.45 mmol) in a 4N solution of HCl in 1,4-dioxane (6 mL) was stirred at 60 °C for 48 h. The reaction mixture was concentrated under vacuum and dried under high vacuum (oven) at 45 °C for 72 h to give 650 mg of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2-difluoroethanol hydrochloride b18-(S) as a solid, which was used in the next step without further purification. Yield (crude): 93% Yield (crude): 93%

[0440] B.5. Synthesis of (2S)-2-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-1,1-difluoropropan-2-ol hydrochloride b20-(S) [ka]

[0441] B.5.1. Synthesis of benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19-(S) and benzyl (1S,4aR,5R,8aS)-5-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19-(R) To a solution of benzyl (1S,4aR,5R,8aS)-5-(2,2-difluoroacetyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b16 (1.55 g, 4.24 mmol) in 2-MeTHF (30 mL) was added a 3 M solution of methylmagnesium chloride in THF (1.70 mL) at 0 °C, and the reaction mixture was stirred at rt overnight. Next, a 3 M solution of methylmagnesium chloride in THF (1.00 mL, 3.00 mmol) was added again at rt, and the reaction mixture was stirred for 1 h. The reaction mixture was then quenched with HO (5 mL) and stirred for 1 h. Next, a 1 N aqueous solution of HCl (5 mL) was added dropwise, and the reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with HO. The aqueous layer was extracted with EtOAc (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 1.60 g of benzyl (1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19 (yield: 90%, Acetic acid LCMS method 1 (ES) + ):382(M+H) + ).

[0442] Chiral separation of racemic b19 (SFC, Chiralpak AD Daicel®, 20 μm, 279×50 mm, 360 mL / min, 220 nm, 30° C., elution: EtOH 20%-CO2 80%) gave: -640 mg of benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19-(S) Yield: 44% Basic LCMS Method 2 (ES + ):382(M+H) + , purity 97.

[0443] Chiral analysis (LC, Chiralpak AD Daicel (registered trademark), 3μm, 150x4.6mm, 1.5mL / min, 220nm, 30℃, elution: EtOH / DEA 100 / 0.1): RT 1.85 min, 100% de.

[0444] - 270 mg of benzyl (1S,4aR,5R,8aS)-5-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19-(R) Yield: 19% Basic LCMS Method 2 (ES + ):382(M+H) + , 91 purity.

[0445] Chiral analysis (LC, Chiralpak AD Daicel (registered trademark), 3μm, 150x4.6mm, 1.5mL / min, 220nm, 30℃, elution: EtOH / DEA 100 / 0.1): RT 2.34 min, 93% de.

[0446] B.5.2. Synthesis of (2S)-2-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-1,1-difluoropropan-2-ol hydrochloride b20-(S) A solution of benzyl (1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxylate b19-(S) (630 mg, 1.65 mmol) in a 4 N solution of HCl in 1,4-dioxane (4.00 mL) was stirred for 48 hours at 60° C. The reaction mixture was evaporated in vacuo to give 450 mg of (2S)-2-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-1,1-difluoropropan-2-ol hydrochloride b20-(S), which was used in the next step without further purification. Yield (crude): 91%

[0447] B.6. Synthesis of (1S)-1-[(1S,3R,4aS,5S,8aR)-3-(hydroxymethyl)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoro-ethanol b38 [ka]

[0448] B.6.1. Synthesis of (2R)-2-amino-3-(2-bromophenyl)propan-1-ol b22 (2R)-2-Amino-3-(2-bromophenyl)propanoic acid b21 (34.0 kg, 139 mol) and THF (238 L) were charged to a reactor. Sodium borohydride (15.6 kg, 413 mol) was added slowly at 20–30 °C. A solution of I2 (35.3 kg, 139 mol) in dry THF (20 L) was added slowly at 0–10 °C, and the reaction mixture was stirred at 70 °C for 12 h. The reaction was quenched with MeOH (70 L) at 0 °C and heated to 80 °C for 30 min. The mixture was cooled and concentrated in vacuo. The crude residue was suspended in 2N aqueous NaOH (30 L) and then filtered. The filter cake was dried under vacuum to give 31.0 kg of (2R)-2-amino-3-(2-bromophenyl)propan-1-ol b22 as a white solid, which was used in the next step without further purification.

[0449] Yield (crude): 97% 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.7 Hz, 1H), 7.21 - 7.29 (m, 2H), 7.07 - 7.15 (m, 1H), 3.66 (dd, J = 10.5, 3.6 Hz, 1H), 3.41 (dd, J = 10.5, 7.2 Hz, 1H), 3.18 - 3.29 (m, 1H), 2.95 (dd, J = 13.5, 5.5 Hz, 1H), 2.70 (dd, J = 13.5, 8.2 Hz, 1H), 1.51 - 1.91 (m, 3H).

[0450] B.6.2. Synthesis of (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one b23 (2R)-2-Amino-3-(2-bromophenyl)propan-1-ol b22 (31.0 kg, 135 mol) and DCM (220 L) were charged to a reactor. Bis(trichloromethyl)carbonate (13.9 kg, 47.1 mol) was added at rt, followed by slow addition of DIPEA (39.1 kg, 303 mol) at 0–10 °C. The reaction mixture was stirred at 0–10 °C for 1 h, then washed twice with HO (50 L), dried over anhydrous NaSO, and filtered to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one b23 as a solution in dichloromethane, which was used directly in the next step without further purification.

[0451] Synthesis of (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b24 A solution of (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one b23 (135 mol) in DCM (220 L) was charged to a reactor and cooled to 0–5 °C. Trimethylsilyl triflate (35.9 kg, 162 mol) and paraformaldehyde (13.3 kg, 148 mol) were added at 0–5 °C, followed by stirring at 15–20 °C for 2 h. HO (170 L) was added to the mixture, which was extracted twice with DCM (50 L). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under vacuum. A mixture of petroleum ether: EtOAc (1:1, 45 L) was added. The mixture was stirred at rt for 6 h, then the resulting solid was filtered and dried to give 29.0 kg of (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b24 as an off-white solid.

[0452] Yield: 80% 1 H NMR (400 MHz, CDCl3): δ 7.45 - 7.52 (m, 1H), 7.08 - 7.14 (m, 2H), 4.83 (d, J = 17.0 Hz, 1H), 4.62 (t, J = 8.4 Hz, 1H), 4.36 (d, J = 17.0 Hz, 1H), 4.21 (dd, J = 8.6, 4.9 Hz, 1H), 3.91 - 3.99 (m, 1H), 3.25 (dd, J = 16.3, 4.2 Hz, 1H), 2.67 (dd, J = 16.1, 11.0 Hz, 1H).

[0453] B.6.3. Synthesis of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol b25 EtOH (120 L) and HO (60.0 L) were mixed in a reactor. (10aR)-9-Bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b24 (29.7 kg, 111 mol) was added, followed by the slow addition of NaOH (13.3 kg, 332 mol) at 15–20 °C. The reaction mixture was stirred at 90 °C for 2 h and then cooled to rt. HO (300 L) was added to the centrifuged mixture. The centrifuge cake was dried in a circulating oven to give 23.7 kg of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol b25 as a white solid, which was used in the next step without further purification.

[0454] Yield (crude): 88% 1 H NMR (400 MHz, CDCl3): δ 7.37 - 7.47 (m, 1H), 6.95 - 7.08 (m, 2H), 4.00 - 4.10 (m, 2H), 3.85 (dd, J = 10.9, 3.7 Hz, 1H), 3.57 (dd, J = 10.9, 7.9 Hz, 1H), 3.06 (ddt, J = 11.3, 7.6, 4.1, 4.1 Hz, 1H), 2.79 (dd, J = 17.1, 4.4 Hz, 1H), 2.40 (dd, J = 17.1, 10.9 Hz, 1H), 1.93 (br s, 2H).

[0455] B.6.4. Synthesis of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b26 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol b25 (23.7 kg, 97.8 mol) and DCM (240 L) were charged to a reactor. DMAP (120 g, 978 mmol) and imidazole (13.3 kg, 196 mol) were added. tert-Butyldimethylsilyl chloride (17.7 kg, 117 mol) was added slowly at 15-20 °C, and the mixture was stirred for 12 h. A saturated solution of NH4Cl (100 L) was added to the mixture. The organic phase was washed with HO (50 L), dried over anhydrous NaSO, filtered, and concentrated under vacuum to give 37.6 kg of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b26 as a yellow oil, which was used in the next step without further purification.

[0456] Yield (crude): 93% 1 H NMR (400 MHz, CDCl3): δ 7.36 - 7.45 (m, 1H), 7.01 (d, J = 4.6 Hz, 1H), 4.01 - 4.13 (m, 2H), 3.84 (dd, J = 9.9, 3.7 Hz, 1H), 3.64 (dd, J = 9.8, 7.2 Hz, 1H), 2.96 - 3.08 (m, 1H), 2.75 (dd, J = 17.0, 4.2 Hz, 1H), 2.44 (dd, J = 17.0, 10.8 Hz, 1H), 1.76 - 2.20 (m, 2H), 0.89 - 0.97 (m, 9H), 0.08 - 0.14 (m, 6H).

[0457] B.6.5. Synthesis of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b27 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane b26 (3.42 kg, 8.31 mol) and THF (30 L) were charged to a reactor. NCS (1.17 kg, 8.73 mol) was added slowly at rt. The reaction mixture was stirred at rt for 30 min, and then a solution of KOH (1.52 kg, 27.0 mol) in dry MeOH (7 L) was added slowly at rt. The mixture was stirred at rt for 1 h, quenched with water (10 L), and extracted with a solution of petroleum ether: EtOAc (1:2, 5 L). The organic layer was washed with brine (10 L), dried over anhydrous Na2SO4, and filtered. This overall procedure was carried out in parallel on 10 batches of equal size, and the 10 reaction filtrates were combined and concentrated under vacuum to give 28.0 kg of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b27 as a crude brown oil, which was used in the next step without further purification.

[0458] Yield (crude): 95% 1 H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 1.2 Hz, 1H), 7.12 - 7.25 (m, 2H), 4.03 (dd, J = 9.5, 4.0 Hz, 1H), 3.67 - 3.77 (m, 2H), 3.07 (dd, J = 17.0, 6.2 Hz, 1H), 2.68 (dd, J = 17.1, 10.9 Hz, 1H), 0.88 - 0.91 (m, 9H), 0.07 (d, J = 1.5 Hz, 6H).

[0459] B.6.6. Synthesis of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b28 [(3R)-5-Bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane b27 (3.10 kg, 8.75 mol) and THF (20 L) were charged to a reactor. The mixture was cooled to 0 °C, and a 3 M solution of methylmagnesium chloride in THF (11.6 L, 34.8 mol) was added. The mixture was stirred at rt for 12 h. The reaction was quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted twice with petroleum ether: EtOAc (3:1, 5 L). The organic layer was washed with brine (10 L), dried over anhydrous Na2SO4, and filtered. This overall procedure was carried out in parallel in nine batches of equal size, and the nine reaction filtrates were combined and concentrated under vacuum. The crude residue was purified by normal phase column chromatography (elution: 9% EtOAc in petroleum ether) to give 4.60 kg of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane b28 as a brown oil.

[0460] Yield: 16% 1 H NMR (400 MHz, DMSO-d6): δ 7.41 (dd, J = 7.7, 0.9 Hz, 1H), 7.12 - 7.18 (m, 1H), 7.03 - 7.11 (m, 1H), 4.12 (q, J = 6.8 Hz, 1H), 3.62 (d, J = 5.7 Hz, 2H), 3.07 - 3.17 (m, 1H), 2.67 - 2.76 (m, 1H), 2.26 (dd, J = 16.9, 10 Hz, 1H), 2.12 (br s, 1H), 1.32 (d, J = 6.8 Hz, 3H), 0.84 - 0.93 (m, 9H), 0.07 (d, J = 0.9 Hz, 6H).

[0461] B.6.7. Synthesis of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol hydrochloride b29 To a solution of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (51.9 g, 140 mmol) b28 in iPrOH (100 mL) was added dropwise a 4 N solution of HCl in 1,4-dioxane (200 mL, 800 mmol) at 0 °C, and the resulting mixture was allowed to warm to rt overnight. The reaction mixture was concentrated in vacuo to give 44.3 g of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol b29 as the hydrochloride salt, which was used in the next step without further purification.

[0462] Yield (crude): 97% Basic LCMS Method 2 (ES + ): 256 / 258 (M+H) +

[0463] B.6.8. Synthesis of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b30 To a solution of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol hydrochloride b29 (44.0 g, 140 mmol) in DCM (400 mL) and DMF (100 mL), 1,1'-carbonyldiimidazole (44.2 g, 273 mmol) was added at rt. The reaction mixture was stirred for 15 min, and DIPEA (115 mL, 660 mmol) was added dropwise. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with a 1N aqueous solution of HCl (2 × 500 mL) and HO (500 mL). The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give 41.2 g of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydroxazolo[3,4-b]isoquinolin-3-one b30, which was used in the next step without further purification.

[0464] Yield (crude): quantitative Acic LCMS Method 1 (ES +): 282 / 284 (M+H) + .

[0465] B.6.9. Synthesis of (5S,10aR)-9-hydroxy-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b31 To a solution of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b30 (41.2 g, 136 mmol) in 1,4-dioxane (340 mL) was added KOH (18.5 g, 296 mmol) in HO (85.0 mL). The reaction mixture was flushed with nitrogen at 95 °C. Next, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (804 mg, 1.86 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.17 g, 3.46 mmol) were added, and the reaction mixture was stirred at 95 °C for 3 h. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The resulting residue was poured into DCM (500 mL) and washed with a 1N aqueous solution of HCl (250 mL). The organic and aqueous layers were separated. The suspended solid in the aqueous layer was filtered and dried under vacuum at 45 °C overnight to give 15.6 g of (5S,10aR)-9-hydroxy-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b31 as an off-white solid, which was used in the next step without further purification.

[0466] Yield (crude): 52% Acic LCMS Method 1 (ES + ): 220 (M+H) +

[0467] B.6.10. Synthesis of (5S,10aR)-9-hydroxy-5-methyl-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one (mixture of 8 epimers) b32 To a solution of (5S,10aR)-9-hydroxy-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one b31 (15.6 g, 71.2 mmol) in iPrOH (150 mL) was added 1N aqueous NaOH (14.0 mL, 14.0 mmol) and Rh / C JM Type 20D (2.10 g, 1.00 mmol). The autoclave was pressurized with 50 bar H2. The reaction mixture was heated to 100 °C with vigorous stirring for 3 days. Rh / C JM Type 20D (1.00 g, 0.486 mmol) was added, and the reaction mixture was again pressurized with 50 bar H2 and heated at 100 °C overnight. The reaction mixture was cooled to rt. The reaction mixture was filtered through a pad of Celite®. Rh / C JM Type 20D (5 g, 2.43 mmol) was added, and the reaction mixture was again pressurized with 50 bar H2 and heated at 100 °C overnight. The reaction mixture was filtered sequentially through a pad of Celite® and via an SPE syringe, then concentrated under vacuum. The crude residue was poured into 0.5 N aqueous NaOH (200 mL), and the aqueous layer was extracted with IPAC (3 x 250 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 8.80 g of (5S,10aR)-9-hydroxy-5-methyl-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b32 as a mixture of eight epimers, which was used in the next step without further purification.

[0468] Yield (crude): 44% Acic LCMS Method 1 (ES + ): 226 (M+H) + .

[0469] B.6.11. Synthesis of isomeric mixture b33: (5S,5aS,9aR,10aR)-5-methyl-5,5a,6,7,8,9a,10,10a-octahydro-1H-oxazolo[3,4-b]isoquinoline-3,9-dione b33-A and (5S,5aR,9aS,10aR)-5-methyl-5,5a,6,7,8,9a,10,10a-octahydro-1H-oxazolo[3,4-b]isoquinoline-3,9-dione b33-B To a solution of (5S,10aR)-9-hydroxy-5-methyl-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b32 (26.6 mmol, 6.00 g) in DCM (250 mL) was added Dess-Martin periodinane (53.3 mmol, 23.3 g). The reaction mixture was stirred at rt for 48 h. The reaction mixture was diluted with DCM (500 mL) and washed successively with saturated aqueous sodium carbonate (2 x 200 mL) and brine (150 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 5.00 g of crude (5S,5aS,9aR,10aR)-5-methyl-5,5a,6,7,8,9a,10,10a-octahydro-1H-oxazolo[3,4-b]isoquinoline-3,9-dione b33 as a mixture of trans-epimers b33-A and b33-B, which was used in the next step without further purification.

[0470] Yield (crude): 84% Basic LCMS Method 1 (ES + ): 224 (M+H) + .

[0471] Stereochemical assignments were made according to literature. The trans isomer is favored. The crude product was characterized as a mixture of primarily trans isomers: (5S,5aS,9aR,10aR)-5-methyl-5,5a,6,7,8,9a,10,10a-octahydro-1H-oxazolo[3,4-b]isoquinoline-3,9-dione b33-A and (5S,5aR,9aS,10aR)-5-methyl-5,5a,6,7,8,9a,10,10a-octahydro-1H-oxazolo[3,4-b]isoquinoline-3,9-dione b33-B. The cis isomers were present in trace amounts and considered marginal. These were discarded in the next step of the synthesis, with multiple purification steps. [ka]

[0472] B.6.12. Synthesis of Isomer Mixture b34: (5S,5aS,9R,9aR,10aR)-5-methyl-3-oxo-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinoline-9-carbaldehyde b34-A and (5S,5aR,9S,9aS,10aR)-5-methyl-3-oxo-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinoline-9-carbaldehyde b34-B To a solution of (methoxymethyl)triphenylphosphonium chloride (10.7 g, 31.5 mmol) in THF (100 mL) was added sodium tert-butoxide (2.88 g, 29.1 mmol) at −78 °C under argon. The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was cooled again to −78 °C, and then the isomeric mixture b33 (5.00 g, 22.4 mmol) was added. The reaction mixture was then stirred at rt for 3 days, diluted with EtOAc (300 mL), and washed sequentially with a saturated aqueous solution of sodium carbonate (100 mL) and brine (100 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 10% EtOAc in heptane) to remove residual triphenylphosphine oxide. The residue was diluted with a mixture of 1N aqueous HCl (50 mL) and THF (50 mL), then the mixture was stirred at rt overnight, HO (100 mL) was added, and the mixture was extracted with DCM (3 × 200 mL). The organic layer was washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give 2.80 g of b34 as a mixture of isomers b34-A and b34-B, which was used in the next step without further purification.

[0473] Yield (crude): 53% Basic LCMS Method 1 (ES + ): 238 (M+H) +

[0474] Stereochemical assignments were made according to literature. Equatorial aldehyde is preferred. The crude product was a mixture of predominantly trans isomers with equatorial aldehyde: (5S,5aS,9R,9aR,10aR)-5-methyl-3-oxo-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinoline-9-carbaldehyde b34-A and It was identified as (5S,5aR,9S,9aS,10aR)-5-methyl-3-oxo-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinoline-9-carbaldehyde b34-B.

[0475] The other minor isomers were deemed marginal and were discarded in the subsequent synthetic steps during multiple purification processes. [ka]

[0476] B.6.13. Isomer Mixture b35: Synthesis of (5S,5aS,9R,9aR,10aR)-5-methyl-9-(2,2,2-trifluoro-1-hydroxy-ethyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b35-A and (5S,5aR,9S,9aS,10aR)-5-methyl-9-(2,2,2-trifluoro-1-hydroxy-ethyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b35-B To a solution of isomeric mixture b34 (2.80 g, 11.8 mmol) and (trifluoromethyl)trimethylsilane (2.52 g, 17.7 mmol) in DMF (40 mL) under argon at 0 °C, cesium fluoride (272 g, 17.7 mmol) was added. The reaction mixture was stirred at 0 °C for 5 min. After quenching with a saturated aqueous solution of NH4Cl (10 mL), the reaction mixture was extracted with EtOAc (150 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to afford 2.90 g of b35 as a mixture of isomers (5S,5aS,9R,9aR,10aR)-5-methyl-9-(2,2,2-trifluoro-1-hydroxy-ethyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b35-A and (5S,5aR,9S,9aS,10aR)-5-methyl-9-(2,2,2-trifluoro-1-hydroxy-ethyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b35-B, which was used in the next step without further purification.

[0477] Yield (crude): 80% Basic LCMS Method 1 (ES+ ): 308 (M+H) + [ka]

[0478] B.6.14. Isomer Mixture b36: Synthesis of (5S,5aS,9R,9aR,10aR)-5-methyl-9-(2,2,2-trifluoroacetyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b36-A and (5S,5aR,9S,9aS,10aR)-5-methyl-9-(2,2,2-trifluoroacetyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b36-B Dess-Martin periodinane (7.21 g, 16.5 mmol) was added to a solution of the isomeric mixture b35 (3.38 g, 11.0 mmol) in DCM (50 mL) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM (150 mL) and then washed sequentially with a 1 N aqueous solution of HCl (50 mL), a saturated aqueous solution of sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give 2.20 g of b36 as a mixture of (5S,5aS,9R,9aR,10aR)-5-methyl-9-(2,2,2-trifluoroacetyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b36-A and (5S,5aR,9S,9aS,10aR)-5-methyl-9-(2,2,2-trifluoroacetyl)-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b36-B, which was used in the next step without further purification.

[0479] Yield (crude): 76% Basic LCMS Method 1 (ES + ): 306 (M+H) + [ka]

[0480] B.6.15. Synthesis of Isomer Mixture b37: (5S,5aR,9S,9aS,10aR)-5-methyl-9-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b37-A and (5S,5aS,9R,9aR,10aR)-5-methyl-9-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b37-B Lithium tri-sec-butylborohydride (4.70 g, 5.40 mmol) was added dropwise to a solution of the isomeric mixture b36 (1.10 g, 3.60 mmol) in THF (50 mL) at −78° C. The mixture was stirred overnight while warming to rt. The reaction mixture was diluted with DCM (150 mL) and washed successively with 1 N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give 1.10 g of b37 as a mixture of isomers (5S,5aR,9S,9aS,10aR)-5-methyl-9-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-1,5,5a,6,7,8,9,9a,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b37-A and (5S,5aS,9R,9aR,10aR)-5-methyl-9-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-1,5,5a,6,7,8,9,9a,10,10a-decahydrooxazolo[3,4-b]isoquinolin-3-one b37-B), which was used in the next step without further purification.

[0481] Yield (crude): 100% Basic LCMS Method 1 (ES + ): 308 (M+H) + [ka]

[0482] B.6.16. Synthesis of Isomer Mixture b38: (1S)-1-[(1S,3R,4aS,5S,8aR)-3-(Hydroxymethyl)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol b38-A and (1R)-1-[(1S,3R,4aR,5R,8aS)-3-(Hydroxymethyl)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol b38-B The isomeric mixture b37 (1.10 g, 3.58 mmol) was dissolved in a mixture of 4N aqueous NaOH (2 mL) and EtOH (6 mL). The reaction mixture was stirred at 80 °C overnight. The volatiles were removed under reduced pressure. The reaction mixture was extracted with DCM (3 × 15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was diluted with MeOH (10 mL) and eluted through an ion-exchange column packed with an acidic polymer (Waters™ PoraPak Rxn CX 60 cc Vac Cartridge, 5 g of sorbent per cartridge, 80 μm). The compound was trapped by the acidic polymer. After rinsing the polymer, the compound was extracted with a 2 M solution of ammonia. Evaporation of the volatiles afforded 700 mg of b38 as a mixture of isomers (1S)-1-[(1S,3R,4aS,5S,8aR)-3-(hydroxymethyl)-1-methyl-1,2,3,4,4a,5,6,7,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol b38-A and (1R)-1-[(1S,3R,4aR,5R,8aS)-3-(hydroxymethyl)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol b38-B as a white solid, which was used in the next step without purification.

[0483] Yield: 69% Basic LCMS Method 1 (ES + ): 282 (M+H) + [ka]

[0484] Example C. Synthesis of Compounds of Formula (I) C.1. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile 1-A and 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile 1-B [ka]

[0485] C.1.1. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c1 To a solution of 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b11 (9.40 g, 24.0 mmol) in DMF (40 mL) was added cesium fluoride (7.40 g, 48.0 mmol) at rt. The reaction mixture was then cooled to 5 °C, and (trifluoromethyl)trimethylsilane (0.7 mL, 492 mmol) was added dropwise over 30 min. The reaction mixture was stirred overnight at rt. IPAC (150 mL) was added to the reaction mixture, followed by 5N aqueous HCl (200 mL). The reaction mixture was stirred at rt for 72 h and washed sequentially with 1N aqueous HCl (100 mL) and water (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 10.7 g of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c1 as a white foam, which was used in the next step without further purification.

[0486] Yield (crude): 92% Basic LCMS Method 2 (ES + ): 459 (M+H) + .

[0487] C.1.2. Synthesis of [(1S)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-[5-yl]-2,2,2-trifluoroethyl]benzoate c2-A and [(1R)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2-B 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c1 (143 mg, 0.31 mmol) in DCM (1.6 mL) was added pyridine (110 μL, 1.37 mmol), DMAP (8.00 mg, 65.0 μmol), and benzoyl chloride (73.0 μL, 0.62 mmol) at rt. The reaction mixture was stirred overnight, and then benzoyl chloride (36.0 μL, 0.31 mmol) was added at rt. The reaction mixture was stirred at rt for 4 h, then diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC using 5% 90 / 10 MeOH / NHOH in DCM to give 120 mg of [1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2, a mixture of isomers c2-A and c2-B (yield: 68%, basic LCMS method 2 (ES)). + ):563 / 565(M+H) + ) was obtained.

[0488] Chiral separation of [1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2 (SFC, IA, 50 × 266 mm, 360 mL / min, 220 nm, 30 °C, elution: MeOH 20%-CO 2 80%) gave: - 44.0 mg of [(1S)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2-A as a pink solid. Yield: 25%. Basic LCMS Method 2 (ES + ):563 / 565(M+H) + , 98% purity. Chiral analysis (LC, IA, 150 * 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.10 min, 98% de

[0489] - 54.0 mg of [(1R)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2-B as a pink solid. Yield: 31%. Basic LCMS Method 2 (ES + ):563 / 565(M+H) + , 99% purity.

[0490] Chiral analysis (LC, AS, 150 * 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.59 min, 98% de.

[0491] C.1.3. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile 1-A and 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile 1-B To a solution of [(1S)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2-A (44.0 mg, 78.0 μmol) in EtOH (390 μL) was added a solution of KOH (5.20 mg, 79.0 μmol) in HO / EtOH (1:1, 70.0 μL) at rt, and the reaction mixture was stirred for 2 h at rt and then concentrated in vacuo. The crude residue was taken up in EtOAc, and the solution was washed with HO. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC using 5% of a 90 / 10 MeOH / NH4OH solution in DCM to give 24.0 mg of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 1A as a white solid.

[0492] Yield: 67%. Acid LCMS method 2 (ES + ): 459 / 461 (M+H) + , 100% purity. Basic LCMS Method 3 (ES + ): 459 / 461 (M+H) +, 100% purity. 1 H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.05 (dd, J= 7.0, 2.7 Hz, 1H), 4.61 - 4.41 (m, 0.5H), 4.38 - 4.26 (m, 0.5H), 4.24 - 4.07 (m, 2H), 4.07 - 3.87 (m, 5H), 3.26 - 3.12 (m, 0.5H), 2.66 (m, 0.5H), 2.03 - 1.82 (m, 1H), 1.75 (t, J = 13.8 Hz, 1H), 1.68 - 1.47 (m, 3H), 1,46-1.23 (m, 4H), 1.22 - 0.70 (m, 5H). Chiral analysis (LC, ID, 150 x 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 1.70 min, 98% de.

[0493] X-ray diffraction of Example 1-A: A block-shaped single crystal of Example 1-A was selected and mounted on a tilted MiTeGen MicroLoops E sample holder. Single-crystal X-ray diffraction data were collected using an Oxford Diffraction Gemini R Ultra diffractometer (Mo Kα, graphite monochromator, Ruby CCD area detector). Data collection, unit cell determination, and data reduction were performed using the CrysAlis PRO software package. The structure was solved using the intrinsic phasing method in the SHELXT 2014 / 54 structure solution program with Olex22 and shelXle3, and |F| was calculated using SHELXL-2016 / 65. 2 The structure was refined using full-matrix least-squares. Non-hydrogen atoms were refined anisotropically. All hydrogen atom positions were determined from the electron density map. The hydrogen atoms of most carbon atoms were placed in their calculated positions using riding mode, with the temperature coefficient fixed at 1.2 times Ueq of the parent carbon atom (1.5 times for methyl groups).

[0494] C 22 H 26 Crystal data of ClF3N2O3 (M=458.90g / mol): orthorhombic, space group P212121(no.19), a=8.4587(2)Å, b=10.3992(4)Å, c=25.2267(7)Å, V=2219.05(11)Å 3 ,Z=4,T=295K,μ(MoKα)=0.223mm 1,Dcalc=1.374g / cm 3 11,408 reflections were measured (4.236°≦2Θ≦55.752°), 5,283 unique (Rint=0.0204, Rsigma=0.0300) were used in all calculations. The final R1 was 0.0421 (I>2σ(I)), and wR 2 was 0.1055 (all data).

[0495] The absolute configuration was established by anomalous dispersion effects in diffraction measurements of this crystal. The Flack x parameter, determined using the quotient [(I+)-(I-)] / [(I+)+(I-)] of 2219, equal to -0.01(3), indicated the absolute configuration shown in Section C.1. (Example 1-A) above.

[0496] 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile 1-B Compound 1-B can be synthesized by a similar method starting from [(1R)-1-[(1S,4aR,5R,8aS)-2-[2-(2-chloro-6-cyano-3-methoxyphenyl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-5-yl]-2,2,2-trifluoroethyl]benzoate c2-B.

[0497] Yield: 68%. Acid LCMS method 2 (ES +): 459 / 461 (M+H) + , 98% purity. Basic LCMS Method 3 (ES + ): 459 / 461 (M+H) + , 98% purity. Chiral analysis (LC, ID, 150 x 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / heptane / DEA 50 / 50 / 0.1): RT 2.07 min, 99% de.

[0498] C.2. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-6-methoxybenzonitrile 2 [ka]

[0499] C.2.1. Synthesis of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol hydrochloride c3 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile. A suspension of 1-A (1.50 g, 3.27 mmol) in 2N aqueous LiOH (150 mL) was stirred at 130 °C for 3 days. The reaction mixture was extracted with DCM (3 × 50 mL). The organic layer was washed with 1N aqueous HCl (3 × 50 mL). The acidic aqueous layer was concentrated under vacuum to give 850 mg of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol hydrochloride c3 as a white solid, which was used in the next step without further purification.

[0500] Yield (crude): 90%. Acid LCMS method 1 (ES + ): 252 (M+H) + .

[0501] C.2.2. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-6-methoxybenzonitrile 2 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-6-methoxybenzonitrile 2 was prepared according to Method A by reacting (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol hydrochloride c3 with 2-(6-chloro-2-cyano-3-methoxyphenyl)acetic acid a9 in the presence of HBTU and base in DMF. Compound 2 was purified by reverse phase column chromatography (acidic LCMS preparative) and isolated as a white solid.

[0502] Yield: 55%. Basic LCMS Method 3 (ES + ): 459 / 461 (M+H) + , 100% purity. Acid LCMS method 2 (ES + ): 459 / 461 (M+H) + , 100% purity.

[0503] The following compounds can be synthesized following a method similar to Method A: [Table 7-1] [Table 7-2]

[0504] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-2-methoxypyridin-4-yl)ethanone 3 Basic LCMS Method 3 (ES + ):468 / 470 / (M+H) + , 100% purity. Acid LCMS method 2 (ES + ):468 / 470 / (M+H) + , 100% purity.

[0505] 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-(trideuteriomethoxy)benzonitrile 5 Basic LCMS method 3 (ES + ):462 / 464(M+H) + , purity 100%. Acid LCMS method 2 (ES + ):462 / 464(M+H) + , purity 100%.

[0506] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethanone 11 Basic LCMS method 3 (ES + ):479 / 481(M+H) + , purity 97%. Acid LCMS method 2 (ES + ):479 / 481(M+H) + , purity 98%.

[0507] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone 12 Basic LCMS method 3 (ES + ):469 / 471 / 473(M+H) + , purity 100%.

[0508] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)ethanone 14 Basic LCMS method 3 (ES + ):496 / 498 / 500(M+H) + , purity 100%.

[0509] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indol-4-yl)ethanone 27 Basic LCMS method 3 (ES + ):491 / 493 / 495(M+H) + , purity 96%.

[0510] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[2,6-dichloro-3-(difluoromethoxy)phenyl]ethanone 19 Basic LCMS method 3 (ES + ):504 / 506 / 508(M+H) + , purity 99%.

[0511] 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c4 Basic LCMS method 3 (ES + ):509 / 511 / 513(M+H) + , purity 97%.

[0512] C.3. Synthesis of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[1-hydroxyethyl]-4-pyridyl]ethanone isomer A 9-A and 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[1-hydroxyethyl]-4-pyridyl]ethanone isomer B 9-B [ka]

[0513] C.3.1. Synthesis of 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid c5 To a solution of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c4 (11.7 g, 23.0 mmol) in THF (100 mL) was added dropwise 1N aqueous HCl (40 mL), and the reaction mixture was stirred overnight at room temperature for 3 days. EtOAc (300 mL) was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium bicarbonate (150 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under vacuum to give 11.0 g of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c5, which was used in the next step without further purification.

[0514] Yield: 100% Acid LCMS method 1 (ES + ): 481 / 483 / 485 (M+H) + .

[0515] C.3.2. Synthesis of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer A 9-A and 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxyethyl)-4-pyridyl]ethanone isomer B 9-B To a suspension of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c5 (9.53 g, 19.8 mmol) in MeOH (100 mL) was added sodium borohydride (824 mg, 21.8 mmol) portionwise at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then stirred overnight at room temperature and quenched with water (50 mL) and 1 N aqueous HCl (50 mL). The resulting mixture was stirred for 1 h and extracted with DCM (4 × 250 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 9.60 g of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone 9 as a mixture of isomers 9-A and 9-B as a white solid (yield: 96%, LCMS method 1 (ES)). +):483 / 485 / 487(M+H) + ).

[0516] Chiral separation of the above mixture 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone 9 (SFC, IG Daicel®, 20 μm, 250×50 mm, 360 mL / min, 220 nm, 30° C., elution: iPrOH 25%-CO 2 75%) gave the following: - 3.60 g of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer A 9-A as a solid.

[0517] Yield: 39% (after precipitation with iPrOH) Basic LCMS Method 3 (ES + ):483 / 485 / 487(M+H) + , 100% purity. Acid LCMS method 2 (ES + ):483 / 485 / 487(M+H) + , 100% purity. Chiral analysis (LC, Chiralpak IA Daicel®, 3 μm, 150x4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 1.91 min, 100% de.

[0518] X-ray diffraction of Example 9-A: A colorless, block-shaped single crystal was selected and mounted on a MiTeGen MicroMounts sample holder. Single-crystal X-ray diffraction data were collected at 100(2)K using an Oxford Diffraction Gemini® Ultra diffractometer (CuKα, multi-layer mirror, Ruby CCD area detector). Data collection, unit cell determination, and data reduction were performed using the CrysAlis PRO software package. The structure was solved by intrinsic phasing using the SHELXT 2015 structure solution program with Olex2 and shelXle, and refined by full-matrix least-squares on |F|2 using SHELXL-2018 / 3. Non-hydrogen atoms were refined anisotropically. The 3,5-dichloro-2-[(1S)-1-hydroxyethyl]pyridin-4-yl}ethan-1-one group is disordered over two positions in both molecules of the asymmetric unit. The structure contains one molecule of disordered butanone, and the solvent was taken into account using the PLATON SQUEEZE procedure. The hydrogen atoms were placed in their calculated positions in multiplicative mode, with the temperature coefficient fixed at 1.2 times the Ueq of the parent carbon atom (1.5 times for the methyl group).

[0519] C 42 H 54 N4O6F6C l4 (C 21 H 27 Crystal data for two molecules of Cl2F3N2O3 (M = 966.7 g / mol): orthorhombic, space group P212121 (number 19), a = 8.57039 (10) Å, b = 16.19438 (16) Å, c = 35.7015 (3) Å, V = 4955.08 (9) Å 3 , Z=4, T=100(2)K, λ(CuKα)=1.54184, μcalc=2.767g / cm 3 27552 reflections were measured (4.95° ≤ 2Θ ≤ 134.23°), resulting in 8714 independent reflections (Rint = 0.0253, Rsigma = 0.0227), which were used in all calculations. 1 is 0.0395 (I>2σ(I)), and wR 2 was 0.1090 (all data).

[0520] The absolute configuration was established by anomalous dispersion effects in crystalline diffraction measurements. The Flack x parameter, determined using the quotient [(I+)-(I-)] / [(I+)+(I-)] of 3403, was equal to -0.002(5), indicating the absolute configuration shown in Section C.3; supra (Example 9-A). The asymmetric unit contains two molecules of Example 9-A and one molecule of disordered butanone.

[0521] - 3.50 g of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B 9-B as a solid.

[0522] Yield: 38% (after precipitation with iPrOH) Basic LCMS Method 3 (ES + ):483 / 485 / 487(M+H) + ,100% purity. Acid LCMS method 2 (ES + ):483 / 485 / 487(M+H) + ,100% purity . Chiral analysis (LC, Chiralpak IA Daicel®, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 2.29 min, 94% de.

[0523] C.4 Synthesis of 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile isomer A 6-A and 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile isomer B 6-B [ka]

[0524] To a solution of difluoromethyltrimethylsilane (65.0 mg, 0.51 mmol) and 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile b11 (100 mg, 0.26 mmol) in DMF (5 mL) was added cesium fluoride (79.0 mg, 0.51 mmol). The reaction mixture was stirred overnight at rt, diluted with EtOAc (150 mL), and washed with a 1N aqueous solution of HCl (50 mL), a saturated aqueous solution of sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified sequentially by normal-phase column chromatography (elution: 50% EtOAc in heptane) and then reverse-phase column chromatography (basic LCMS preparative) to give 40.0 mg of 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxyethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 6 as a mixture of isomers 6-A and 6-B (yield: 35%, basic LCMS method 2 (ES + ):441 / 443(M+H) + , 94% purity).

[0525] Chiral separation (SFC, ID, 50%) of the above mixture 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 6 * 258 mm, 360 mL / min, 220 nm, 30°C, elution: EtOH 25% - CO2 75% gave: - 7.00 mg of 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile isomer A 6-A as a white solid.

[0526] Yield: 6%. Basic LCMS Method 3 (ES + ):441 / 443(M+H) + , 100% purity. Acid LCMS method 2 (ES + ):441 / 443(M+H) + ,100% purity. Chiral analysis (LC, ID, 3 μm, 150 × 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.27 min, 100% de.

[0527] - 7.00 mg of 2-[2-[(1S,4aR,5R,8aS)-5-(2,2-difluoro-1-hydroxy-ethyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile isomer B 6-B as a white solid.

[0528] Yield: 6%. Basic LCMS Method 3 (ES + ):441 / 443(M+H)+ , 100% purity. Acid LCMS method 2 (ES + ):441 / 443(M+H) + ,100% purity. Chiral analysis (LC, ID, 3 μm, 150 × 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.93 min, 100% de.

[0529] C.5. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a 5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile isomer A 7-A and 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile isomer B 7-B [ka]

[0530] C.5.1. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoroacetyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c6 To a solution of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c1 (1.49 g, 3.25 mmol) in DCM (15 mL) was added Dess-Martin Periodinane (1.42 g, 3.25 mmol) portionwise at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. Dess-Martin Periodinane (140 mg, 0.32 mmol) was added again at room temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL), followed by the addition of a 1N aqueous solution of NaOH (50 mL). The reaction mixture was stirred at room temperature for an additional 30 min and then washed successively with a 1 N aqueous solution of NaOH (25 mL) and HO (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give 1.29 g of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoroacetyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c6 as a white foam, which was used in the next step without further purification.

[0531] Yield (crude): 87%. Basic LCMS Method 2 (ES + ): 457 (M+H) + .

[0532] C.5.2. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile isomer A7-A and 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile isomer B7-B A 3 M solution of methylmagnesium chloride in THF (328 μL, 985 μmol) was added dropwise to a solution of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2,2,2-trifluoroacetyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile c6 (150 mg, 0.39 mmol) in THF (4.00 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 1 h, then diluted with EtOAc (150 mL) and washed sequentially with a 1 N aqueous solution of HCl (50 mL), a saturated aqueous solution of sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (basic LCMS preparative followed by SFC separation (SiO2, 22 × 250 mm, 60 mL / min, 220 nm, 40 °C, elution: EtOH 5%-CO2 95%) to give 70.0 mg of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 7 as a mixture of isomers 7-A and 7-B (yield: 45%, basic LCMS method 2 (ESC)). + ):473 / 475(M+H) + ).

[0533] Chiral separation of the above mixture 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methylethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 7 (SFC, IG, 50 × 250 mm, 360 mL / min, 220 nm, 30 °C, elution: MeOH 25%-CO2 75%) gave the following: - 2.00 mg of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile isomer A 7-A as a white solid.

[0534] Yield: 1% Basic LCMS Method 3 (ES + ):473 / 475(M+H) + , 97% purity. Acid LCMS method 2 (ES + ):473 / 475(M+H) + , 96% purity. Chiral analysis (LC, IG, 3μm, 150x4.6mm, 1.5mL / min, 220nm, 30℃, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.89 min, 100% de.

[0535] - 5.00 mg of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile isomer B 7-B as a white solid. Yield: 3%. Basic LCMS Method 3 (ES + ):473 / 475(M+H) + , 99% purity. Acid LCMS method 2 (ES +):473 / 475(M+H) + , 99% purity. Chiral analysis (LC, IG, 3 μm, 150 x 4.6 mm, 1.5 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane / DEA 50 / 50 / 0.1): RT 3.64 min, 100% de.

[0536] C.6. Synthesis of 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer A 8-A and 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer B 8-B [ka]

[0537] C.6.1. Synthesis of (1S,4aR,8aS)-2-[2-(5-chloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c7 (1S,4aR,8aS)-2-[2-(5-chloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c7 was prepared according to Method A by reacting (1S,4aR,8aS)-1-methyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinolin-5-one b8-peak 2 (626 mg, 3.07 mmol) with 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid a32 (759 mg, 3.38 mmol) in the presence of HBTU (1.28 g, 3.38 mmol) and 4-methylmorpholine (933 mg, 9.22 mmol) in DMF (40 mL). c7 was used in the next step without purification.

[0538] Yield (crude): 61% Acid LCMS method 1 (ES + ): 374 / 376 (M+H) + .

[0539] C.6.2. Synthesis of (1S,4aR,8aS)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c8 To a stirred solution of (1S,4aR,8aS)-2-[2-(5-chloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c7 (673 mg, 1.80 mmol) in THF (15.0 mL) was added NCS (294 mg, 2.20 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 h, then diluted with EtOAc (150 mL) and washed successively with 1 N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 650 mg of (1S,4aR,8aS)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c8, which was used in the next step without further purification.

[0540] Yield (crude): 88%. Acid LCMS method 1 (ES + ): 408 / 410 / 412 (M+H) +

[0541] C.6.3. Synthesis of 1-[(1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone c9 Under argon at −78 °C, a 1.6 M solution of nBuLi in hexane (0.49 mL, 0.78 mmol) was added to a solution of methoxymethyl(triphenyl)phosphonium chloride (250 mg, 0.73 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was cooled again to −78 °C before the addition of (1S,4aR,8aS)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-5-one c8 (200 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with 1 N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 0–80% EtOAc in heptane) to afford 100 mg of a mixture of Z and E isomers of 1-[(1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone c9.

[0542] Yield: 47%. Acid LCMS method 1 (ES + ): 436 / 438 / 440 (M+H) +

[0543] C.6.4. Synthesis of (1S,4aR,8aS)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-5-carbaldehyde c10 To a solution of 1-[(1S,4aR,5E,8aS)-5-(methoxymethylene)-1-methyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone c9 (210 mg, 0.48 mmol) in THF (2 mL) was added 1N aqueous HCl (20.0 mmol, 2.00 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous sodium carbonate (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 95.0 mg of (1S,4aR,8aS)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-5-carbaldehyde c10, which was used in the next step without further purification.

[0544] Yield: 47%. Basic LCMS Method 3 (ES + ): 422 / 424 / 426 (M+H) + , 89% purity. Acid LCMS method 2 (ES + ): 422 / 424 / 426 (M+H) + , 87% purity.

[0545] C.6.5. Synthesis of 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer A 8-A and 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer B 8-B Cesium fluoride (130 mg, 0.88 mmol) was added to a solution of trimethyl(trifluoromethyl)silane (125 mg, 0.88 mmol) and 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile c10 (185 mg, 0.44 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with 1N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase column chromatography (basic LCMS preparative) to give 90.0 mg of 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 8 (mixture of isomers 8-A and 8-B) (yield: 42%, basic LCMS method 2 (ES + ):492 / 494 / 496(M+H) + ).

[0546] Chiral separation of the above mixture 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 8 (SFC, ID, 50x258mm, 360mL / min, 220nm, 30°C, elution: EtOH 20%-CO2 80%) gave: -35.0 mg of 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer A 8-A Yield: 39% Basic LCMS Method 3 (ES + ):492 / 494 / 496(M+H) + , 100% purity. Acid LCMS method 2 (ES + ):492 / 494 / 496(M+H) + , 100% purity.

[0547] Chiral analysis (LC, IE3, 150x4.6mm, 1.5mL / min, 220nm, 30°C, elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 2.53min, 100% de.

[0548] -35.0 mg of 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone isomer B8-B Yield: 39% Basic LCMS Method 3 (ES + ):492 / 494 / 496(M+H) + , 99% purity. Acid LCMS method 2 (ES + ):492 / 494 / 496(M+H) + , 100% purity. Chiral analysis (LC, IE3, 150x4.6mm, 1.5mL / min, 220nm, 30°C, elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 3.74min, 100% de.

[0549] C.7. Synthesis of (1S,4aR,5R,8aS)-N-(2,6-dichlorophenyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxamide 10 [ka]

[0550] To a stirred solution of (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2,2-trifluoroethanol hydrochloride c3 (46.0 mg, 0.16 mmol) in DCM (1 mL) were added 2,6-dichlorophenyl isocyanate (34.0 mg, 0.18 mmol) and EtN (68.0 μL, 0.48 mmol) sequentially at rt. The reaction mixture was stirred at rt for 1 h, diluted with DCM (50 mL), and washed with a 1N aqueous solution of HCl (20 mL) and brine (20 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase column chromatography (basic LCMS preparative) to give 26.0 mg of (1S,4aR,5R,8aS)-N-(2,6-dichlorophenyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxamide 10 as a white solid.

[0551] Yield: 37%. Acid LCMS method 2 (ES + ): 439 / 441 / 443 (M+H) + , 92% purity.

[0552] C.8. Synthesis of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone 13 [ka]

[0553] 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c5 (100 mg, 0.21 mmol) was added dropwise to a stirred solution of 100 mg of methyllithium in diethoxymethane (0.21 mL, 0.62 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with a saturated aqueous solution of NaHCO (50 mL) and brine (3 × 50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by SFC (DIOL 10 μm Kromasil®, 50 × 250 mm, 360 mL / min, 220 nm, 30 °C, elution: EtOH 10%-CO2 90%) to give 27.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2[3,5-dichloro-2-(1-hydroxy-1-methylethyl)-4-pyridyl]ethanone 13 as a gum.

[0554] Yield: 26%. Basic LCMS Method 3 (ES + ): 497 / 499 / 501 (M+H) + , 96% purity.

[0555] C.9. 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer A Synthesis of 15-A and 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer B 15-B [ka]

[0556] C.9.1. Synthesis of methyl 4-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3,5-dichloro-pyridine-2-carbaldehyde c11 To a solution of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone 12 (254 mg, 0.54 mmol) in 1,4-dioxane (8 mL), manganese dioxide (188 mg, 2.17 mmol) was added and the suspension was stirred at 70 °C overnight. The reaction mixture was filtered and the volatiles removed under vacuum to give 242 mg of 4-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3,5-dichloropyridine-2-carbaldehyde c11.

[0557] Yield (crude): 96%. Basic LCMS Method 2 (ES + ): 467 / 469 / 471 (M+H) + .

[0558] C.9.2. 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer A Synthesis of 15-A and 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer B 15-B To a stirred solution of 4-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3,5-dichloropyridine-2-carbaldehyde c11 (242 mg, 0.52 mmol) and cesium fluoride (318 mg, 2.10 mmol) in DMF (6 mL) was added dropwise difluoromethyl(trimethyl)silane (0.22 mL, 1.6 mmol). The reaction mixture was stirred at rt for 2 h, diluted with EtOAc (200 mL), and washed with brine (3 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 20–100% EtOAc in heptane) to give 82.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone 15 as a mixture of isomers 15-A and 15-B (yield: 30%, basic LCMS method 2 (ES)). + ):519 / 521 / 523(M+H) + ).

[0559] Chiral separation of 72 mg of the above diastereoisomeric mixture 15 (SFC, DIOL 10 μm Kromasil®, 50×250 mm, 360 mL / min, 220 nm, 30° C., elution: EtOH 10%-CO 2 90%) gave: -28.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer A 15-A Yield: 10% Basic LCMS Method 3 (ES+ ):519 / 521 / 523(M+H) + , 100% purity. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 4.6×150 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 1.90 min, 100% de.

[0560] -6.00 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-ethyl)-4-pyridyl]ethanone isomer B 15-B was isolated after further purification by normal phase column chromatography (elution: 20-100% EtOAc in heptane). Yield: 2% Basic LCMS Method 3 (ES + ):519 / 521 / 523(M+H) + , purity 97%. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 4.6×150 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 2.21 min, 90% de.

[0561] C.10. 1-[(1S,4aR,5R,8aS)-1-Methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone isomer A Synthesis of 16-A and 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone isomer B 16-B [ka]

[0562] 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c5 (290 mg, 0.60 mmol) and cesium fluoride (370 mg, 2.4 mmol) in DMF (10 mL) were added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with brine (3 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 0 to 70% EtOAc in heptane) to give 60.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone 16 as a mixture of isomers 16-A and 16-B (yield: 19%, basic LCMS Method 2 (ES)). + ):533 / 535 / 537(M+H) + ).

[0563] Chiral separation of 50 mg of the above diastereoisomeric mixture 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone (LC, AD, 10 μm, 250 x 10 mm, 4.8 mL / min, 220 nm, 30 °C, elution: EtOH / n-heptane 30 / 70) gave the following: - After further purification by reversed-phase column chromatography (basic LCMS preparative) 12.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone isomer A 16-A as a solid. Yield: 4%. Basic LCMS Method 3 (ES + ):533 / 535 / 537(M+H) + , 88% purity. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 4.6×150 mm, 1.5 mL / min, 220 nm, 30°C, elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 1.89 min, 100% de.

[0564] After further purification by reversed-phase column chromatography (basic LCMS preparative), 12.0 mg of 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone isomer B 16-B was obtained as a solid. Yield: 4% Basic LCMS Method 3 (ES + ):533 / 535 / 537(M+H) + , 89% purity. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 4.6×150 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 30 / 70 / 0.1): RT 2.15 min, 100% de.

[0565] C.11. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer A 17-A and 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B 17-B [ka]

[0566] C.11.1. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c12 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c12 was prepared according to Method A from (1S)-1-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2,2-difluoroethanol hydrochloride b18-(S) in the presence of HBTU and DIPEA in DMF to give 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67. The crude product was used in the next step without further purification.

[0567] Yield (crude): 78%. Acid LCMS method 1 (ES+ ): 491 / 493 / 495 (M+H) + .

[0568] C.11.2. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c13 To a solution of crude 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c12 (235 mg, 0.41 mmol) in THF (5 mL) was added 1N aqueous HCl (2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 220 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c13, which was used in the next step without further purification.

[0569] Yield (crude): 78%. Acid LCMS method 1 (ES + ): 463 / 465 / 467 (M+H) + , 87% purity.

[0570] C.11.3. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer A 17-A and 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B 17-B To a solution of crude 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c13 (220 mg, 0.32 mmol) in EtOH (6 mL) was added sodium borohydride (14.0 mg, 0.37 mmol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with HO (5 mL) and stirred for 1 h. Then, a 1N aqueous solution of HCl (2 mL) was added, and the mixture was stirred for an additional 1 h. HO (25 mL) was added, and the aqueous layer was extracted with DCM (2 × 50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase column chromatography (YMC Triart C18 column, 10 μm, 80 × 204 mm, elution: 5–95% ACN in H2O + 0.025% NH4OH) to give 153 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxyethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone 17 as a mixture of isomers 17-A and 17-B (yield: 88%, LCMS method 2 (ES)). + ):465 / 467 / 469(M+H) + ).

[0571] Chiral separation of the above mixture 17 (SFC, Chiralpak AD Daicel®, 20 μm, 279×50 mm, 360 mL / min, 220 nm, 30° C., elution: iPrOH 20%-CO 2 80%) gave the following: - 40.0 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-(1-hydroxyethyl]-)-4-pyridyl]ethanone isomer A 17-A, as a solid. Yield: 30% Basic LCMS Method 3 (ES + ):465 / 467 / 469(M+H) + , 99% purity. Acid LCMS method 2 (ES + ):465 / 467 / 469(M+H) + , 99% purity. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 1.54 min, 100% de.

[0572] - 42.0 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-(1-hydroxyethyl]-)-4-pyridyl]ethanone isomer B 17-B, as a solid. Yield: 31% Basic LCMS Method 3 (ES + ):465 / 467 / 469(M+H) + , 96% purity. Acid LCMS method 2 (ES + ):465 / 467 / 469(M+H) + , 98% purity. Chiral analysis (LC, Chiralpak AD Daicel®, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 1.87 min, 98% de.

[0573] C.12. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone 18-A and 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B 18-B [ka]

[0574] C.12.1. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c14 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c14 was prepared according to Method A by reacting (2S)-2-[(1S,4aR,5R,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-1,1-difluoro-propan-2-ol hydrochloride b20-(S) with 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67 in the presence of HBTU and DIPEA in DMF. The crude product was used in the next step without further purification.

[0575] Yield (crude): 85%. Acid LCMS method 1 (ES + ): 505 / 507 / 509 (M+H) + , 93% purity.

[0576] C.12.2. Synthesis of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c15 To a solution of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c14 (236 mg, 0.431 mmol) in THF (5 mL) was added 1N aqueous HCl in HO (2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 234 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c15, which was used in the next step without further purification.

[0577] Yield (crude): 88% Acid LCMS method 1 (ES + ): 477 / 479 / 481 (M+H) + .

[0578] C.12.3. 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-Difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer A 18-A and 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-Difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B Synthesis of 18-B 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c15 (234 mg, 0.38 mmol) in EtOH (6 mL) was added at 0 °C, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with HO (5 mL) and stirred for 1 h. 1N aqueous HCl solution (2 mL) was then added, and the mixture was stirred for an additional 1 h at room temperature. HO (25 mL) was added, and the aqueous layer was extracted with DCM (2 × 50 mL). The organic layer was dried over MgSO, filtered, and concentrated under vacuum to give a crude residue, which was purified by reverse-phase column chromatography (YMC Triart C column, 10 μm, 80×204 mm, elution: 5–95% ACN in H2O + 0.025% NH4OH) to give 142 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone 18 as a mixture of isomers 18-A and 18-B (yield: 68%, LCMS method 2 (ES)). + ):479 / 481 / 483(M+H) + , purity 88%).

[0579] Chiral separation of the above mixture 18 (SFC, Chiralpak AD Daicel®, 20 μm, 279×50 mm, 360 mL / min, 220 nm, 30° C., elution: iPrOH 25%-CO 2 75%) gave the following: - 44.0 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanol isomer A 18-A, as a solid. Yield: 34%. Basic LCMS Method 3 (ES + ):479 / 481 / 483(M+H) + ,98% purity. Acidic LCMS method 2 (ES + ):479 / 481 / 483(M+H) + ,98% purity. Chiral analysis (LC, Chiralpak IG Daicel®, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 3.93 min, 100% ee.

[0580] - 39.0 mg of 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanol isomer B 18-B, as a solid. Yield: 30 Basic LCMS Method 3 (ES + ):479 / 481 / 483(M+H) + ,97% purity. Acid LCMS method 2 (ES + ):479 / 481 / 483(M+H) + ,99% purity. Chiral analysis (LC, Chiralpak IG Daicel®, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: iPrOH / n-heptane / DEA 50 / 50 / 0.1): RT 6.17 min, 97% ee.

[0581] C.13. Synthesis of 2-[2-[(1S,4aS,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 20 and 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 21 [ka]

[0582] C.13.1. Synthesis of 2-[2-[(1S,4aS,5R,8aS)-5-ethynyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile c16 To a stirred solution of 2-[2-[(1S,4aR,8aS)-5-formyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile b11 (5.00 g, 13.0 mmol) in MeOH (50 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (15.0 mmol, 3.00 g) and K2CO3 (3.60 g, 26.0 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature and then diluted with EtOAc (150 mL) and washed sequentially with 1N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 10–90% EtOAc in heptane) to give 4.70 g of 2-[2-[(1S,4aS,5R,8aS)-5-ethynyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile c16.

[0583] Yield: 95%. Acid LCMS method 1 (ES + ): 385 / 387 / 389 (M+H) + .

[0584] C.13.2. Synthesis of 2-[2-[(1S,4aS,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 20 Under argon at −78°C, a 2.5 M solution of n-BuLi in hexane (8.70 mL, 21.7 mmol) was added to a solution of 2-[2-[(1S,4aS,5R,8aS)-5-ethynyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile c16 (3.70 g, 9.60 mmol) in THF (100 mL). The reaction mixture was stirred at −78°C for 15 min. Acetone (2.80 mL, 38.0 mmol) was added. The reaction mixture was stirred at −78°C for 15 min and then at room temperature for 2 h. After quenching with saturated aqueous NH4Cl (20 mL), the reaction mixture was diluted with EtOAc (150 mL) and washed successively with 1 N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 12 to 100% EtOAc in heptane) to give 1.80 g of 2-[2-[(1S,4aS,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 20 as a solid.

[0585] Yield: 42%. Acid LCMS method 1 (ES + ): 443 / 445 / 447 (M+H) + .

[0586] C.13.3. Synthesis of 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 21 2-[2-[(1S,4aS,5R,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 20 (650 mg, 1.51 mmol) and Pd / C 20% (Johnson Matthey Type 91 Pearl, 15.6 mg, 0.029 mmol) were mixed in EtOH (10 mL) and 1,4-dioxane (10 mL) in a sealed autoclave. The suspension was subjected to 6 bar H2 with vigorous stirring at room temperature for 4 h. The reaction mixture was filtered through a pad of Celite®, and the volatiles were removed under reduced pressure. The crude residue was purified by normal phase column chromatography (elution: 10–90% EtOAc in heptane) to give 436 mg of 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 21 as a solid.

[0587] Yield: 64%. Basic LCMS Method 3 (ES + ): 447 / 449 (M+H) + , 90% purity. Acid LCMS method 2 (ES + ): 447 / 449 (M+H) + , 87% purity.

[0588] C.14. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 22 [ka]

[0589] C.14.1. Synthesis of 4-[(1S,4aS,5S,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride c17 To a screw-cap vial was added 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile 21 (300 mg, 0.67 mmol) dissolved in 1,4-dioxane (2 mL) and 2 M aqueous LiOH (8.00 mL, 16.0 mmol). The reaction mixture was subjected to microwave irradiation at 150 °C for 1 h. The mixture was extracted with DCM (5 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was diluted with EtOAc and extracted with 1 N aqueous HCl. The aqueous layer was concentrated under vacuum to give 185 mg of 1-[(1S,4aS,5S,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride c17 as a white solid.

[0590] Yield (crude): 100%. Acid LCMS method 1 (ES + ): 240 (M+H) + .

[0591] C.14.2. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 22 1-[(1S,4aS,5S,8aS)-5-(3-Hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 22 was prepared according to Method A by reacting 4-[(1S,4aS,5S,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride c17 with 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid a33 in the presence of HBTU and EtN (3 equivalents) in DMF. The crude residue was purified by reverse-phase column chromatography (acid LCMS preparative) to give 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 22 as a white solid.

[0592] Yield: 23% Basic LCMS Method 3 (ES + ): 480 / 482 / 484 (M+H) + , 95% purity. Acid LCMS method 2 (ES + ): 480 / 482 / 484 (M+H) + , 91% purity.

[0593] C.15. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone 23 [ka]

[0594] 1-[(1S,4aS,5S,8aS)-5-(3-Hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[(3,5-dichloro)-2-(hydroxymethyl)-4-pyridyl]ethanone 23 was prepared according to Method A by reacting 4-[(1S,4aS,5S,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2-methylbutan-2-ol hydrochloride c17 with 2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]acetic acid a28 in the presence of HBTU and EtN (3 equivalents) in DMF. The crude residue was purified by reverse-phase column chromatography (conditions: Eternity XT 200 g C18 column, 10 μm, 50 × 200 mm, 70 mL / min, 215 nm, 35 °C, elution: HO / ACN + NH4OH 0.025%) to give 110 mg of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone 23 as a white solid.

[0595] Yield: 17% Basic LCMS Method 3 (ES + ): 457 / 459 / 461 (M+H) + , 97% purity. Acid LCMS method 2 (ES + ): 457 / 459 / 461 (M+H) + , 94% purity.

[0596] C.16. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(-1-hydroxyethyl)-4-pyridyl]ethanone isomer A 24-A and 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxyethyl)-4-pyridyl]ethanone isomer B 24-B [ka]

[0597] C.16.1. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c18 1-[(1S,4aS,5S,8aS)-5-(3-Hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c18 was prepared according to Method A by reacting 4-[(1S,4aS,5S,8aS)-1-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride c17 with 2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]acetic acid a67 in the presence of HBTU and EtN (3 equivalents) in DMF. The crude residue was purified by normal phase column chromatography (elution: 6 to 100% EtOAc in heptane).

[0598] Yield: 53% Acid LCMS method 1 (ES +): 497 / 499 / 501 (M+H) + .

[0599] C.16.2. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c19 1-[(1S,4aS,5S,8aS)-5-(3-Hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-ethoxyvinyl)-4-pyridyl]ethanone c18 (550 mg, 1.10 mmol) was dissolved in acetone (10 mL). 1N aqueous HCl (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give 519 mg of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c19.

[0600] Yield (crude): quantitative Acid LCMS method 1 (ES + ): 469 / 471 / 473 (M+H) + .

[0601] C.16.3. Synthesis of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(-1-hydroxyethyl)-4-pyridyl]ethanone isomer A 24-A and 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(-1-hydroxyethyl)-4-pyridyl]ethanone isomer B 24-B Sodium borohydride (76.0 mg, 2.00 mmol) was added to a solution of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(2-acetyl-3,5-dichloro-4-pyridyl)ethanone c19 (470 mg, 1.00 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with DCM (150 mL) and washed sequentially with 1N aqueous HCl (50 mL), saturated aqueous sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (elution: 6 to 100% EtOAc in heptane) to give 472 mg of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl)-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-([(1S * )-1-Hydroxyethyl])-4-pyridyl]ethanone 24 was obtained as a mixture of isomers 24-A and 24-B (yield: 100%, acid LCMS Method 1 (ES + ):471 / 473 / 475(M+H) + ).

[0602] Chiral separation of the above diastereoisomeric mixture 24 (LC, LuxCell4, 5 μm, 250×10 mm, 4.8 mL / min, 220 nm, 30° C., elution: EtOH / n-heptane / DEA 30 / 70 / 0.1) gave: - 150 mg of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-([(1S * )-1-Hydroxyethyl]-4-pyridyl)ethanone isomer A24-A. Yield: 32%. Basic LCMS Method 3 (ES + ):471 / 473 / 475(M+H) + ,94% purity. Acid LCMS method 2 (ES + ):471 / 473 / 475(M+H) + ,93% purity. Chiral analysis (LC, LuxCell 4, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: EtOH / n-heptane / DEA 30 / 70 / 0.1): RT 2.72 min, 100% ee.

[0603] - 150 mg of 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-([(1S * )-1-Hydroxyethyl]-4-pyridyl)ethanone isomer B 24-B. Yield: 32%. Basic LCMS (ES + ) Law 3:471 / 473 / 475(M+H) + , 90% purity. Acid LCMS (ES + ) Law 2:471 / 473 / 475(M+H) + ,87% purity. Chiral analysis (LC, LuxCell 4, 3 μm, 150×4.6 mm, 1.5 mL / min, 220 nm, 30° C., elution: EtOH / n-heptane / DEA 30 / 70 / 0.1): RT 2.96 min, 97% ee.

[0604] C.17. Synthesis of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2H-triazol-4-yl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 25 [ka]

[0605] A mixture of 2-[2-[(1S,4aS,5R,8aS)-5-ethynyl-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxy-benzonitrile c16 (222 mg, 0.52 mmol), sodium azide (68.0 mg, 1.04 mmol), sodium ascorbate (10.4 mg, 0.052 mmol), copper(II) sulfate pentahydrate (13.0 mg, 0.052 mmol), and trimethylsilyl azide (189 mg, 1.56 mmol) in 1-butanol (2 mL) and water (2 mL) was stirred at 80 °C for 6 days. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with a 1N aqueous solution of HCl (50 mL), a saturated aqueous solution of sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: 6 to 100% EtOAc in heptane) to afford 60.0 mg of 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2H-triazol-4-yl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile 25 as a solid.

[0606] Yield: 27% Basic LCMS Method 3 (ES + ): 428 / 430 (M+H) + , 93% purity. Acid LCMS method 2 (ES + ): 428 / 430 (M+H) + , 90% purity.

[0607] C.18. 1-[(1S,3R,4aR,5R,8aS)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 26-A and 1-[(1S,3R,4aS,5S,8aR)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone Synthesis of 26-B [ka]

[0608] To a solution of the isomeric mixture b38 (700 mg, 2.50 mmol) in DMF (8 mL) was added 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid a33 (970 mg, 3.70 mmol), HBTU (1.10 g, 3.00 mmol), and EtN (1.10 mL, 7.50 mmol) sequentially at rt. The reaction mixture was stirred at rt for 15 h, then diluted with DCM (150 mL), washed sequentially with a 1N aqueous solution of HCl (50 mL), a saturated aqueous solution of sodium carbonate (50 mL), and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. Purification of the crude residue (SFC, P4VP Daicel®, 5 μm, 50×174 mm, 220 nm, 360 mL / min, 30° C., elution: MeOH 10%-CO 2 90%) gave two fractions:

[0609] Fraction 1 was re-purified by chiral SFC (Chiralpak AD Daicel®, 20 μm, 50×279 mm 220 nm, 360 mL / min, 35° C., elution: MeOH 15%-CO 2 85%) to give 46.0 mg of 1-[(1S,3R,4aR,5R,8aS)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone 26-A as a white solid.

[0610] Yield: 3% Basic LCMS Method 3 (ES + ): 522 / 524 / 526 (M+H) + , 97% purity. Acid LCMS method 2 (ES + ): 522 / 524 / 526 (M+H) + , 100% purity. 1 H NMR (500 MHz, DMSO-d6, 75 °C): δ 7.59 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 5.91 (d, J= 7.0 Hz, 1H), 4.52 (t, J = 6.1 Hz, 1H), 4.42 (d, J = 16.5 Hz, 1H), 4.16 (d, J = 16.5 Hz, 1H), 4.10 - 4.02 (m, 1H), 4.00 (s, 3H), 3.80 - 3.69 (m, 2H), 3.65 - 3.41 (broad peak, 2H), 2.22 - 2.12 (m, 1H), 1.88 (d, J= 12.9 Hz, 1H), 1.78 (dt, J = 13.0, 3.3 Hz, 1H), 1.64 (d, J = 12.2 Hz, 1H), 1.48 - 1.19 (m, 9H), 1.02 - 0.92 (m, 1H). Chiral analysis (SFC Chiralpak AD, 3μm, 3x150mm, 3mL / min, 30℃, elution: MeOH20%-CO280%): RT 0.74 min, 100% de.

[0611] Fraction 2 was repurified by chiral SFC (IC, 20 μm, 50 × 266 mm, 220 nm, 360 mL / min, 35 °C, MeOH 25% - CO 2 75%) to give 270 mg of 1-[(1S,3R,4aS,5R,8aS)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethenone 26-B as a white solid.

[0612] Yield: 26% Basic LCMS Method 3 (ES + ): 522 / 524 / 526 (M+H) + , 100% purity. Acid LCMS method 2 (ES + ): 522 / 524 / 526 (M+H) + , 99% purity. 1H NMR (500 MHz, DMSO-d6, 75 °C): δ 7.59 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 5.86 (d, J= 6.7 Hz, 1H), 4.65 - 4.42 (broad peak, 1H), 4.34 (dd, J = 18.5 Hz, 2H), 4.22 - 4.12 (m, 2H), 4.00 (s, 3H), 3.67 (dd, J = 5.8 Hz, 2H), 3.62 - 3.40 (broad peak, 1H), 1.99 (ddd, J = 13.6, 6.0, 3.8 Hz, 1H), 1.80 (dt, J= 12.6, 2.9 Hz, 1H), 1.73 - 1.53 (m, 4H), 1.53 - 1.28 (m, 4H), 1.20 (d, J= 6.7 Hz, 3H), 1.12 - 1.00 (m, 1H). Chiral analysis (SFC Chiralpak IC, 3μm, 3x150mm, 3mL / min, 30℃, elution: MeOH20%-CO280%): RT2.26min, 99% de.

[0613] X-ray diffraction of Example 26-A: A colorless, block-shaped single crystal was selected and mounted on a MiTeGen MicroMounts sample holder. Single-crystal X-ray diffraction data were collected at 100(2)K using an Oxford Diffraction Gemini R Ultra diffractometer (Mo Kα, graphite monochromator, Ruby CCD area detector). Data collection, unit cell determination, and data reduction were performed using the CrysAlis PRO software package. The structure was solved by the intrinsic phasing method using the SHELXT 2015 structure solving program, and |F| was calculated using SHELXL-2018 / 3 with Olex2 and shelXle. 2 The data were refined using full-matrix least-squares. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were positioned in the calculated positions using riding mode, with the temperature coefficient fixed at 1.2 times Ueq of the parent carbon atom (1.5 times for methyl groups).

[0614] The asymmetric unit contains two molecules of example (26‐B) and one molecule of disordered butanone.

[0615] C 23 H 28 C l2 Crystal data for F3N3O3 (M = 522.4 g / mol): tetragonal, space group P43212 (no. 96), a = b = 12.0001(3) Å, c = 35.1592(11) Å, V = 5063.0(3) Å 3 ,Z=8,T=100(2)K,λ(MoKα)=0.71073,μcalc=1.371g / cm 3 26,173 reflections were measured (4.63° ≤ 2Θ ≤ 52.74°), and 5,174 independent reflections (Rint = 0.0505, Rsigma = 0.0325) were used in all calculations. The final R1 was 0.0516 (I > 2σ(I)), and R2 was 0.1089 (all data).

[0616] The absolute configuration was established by anomalous dispersion effects in crystalline diffraction measurements. The Flack x parameter, determined using the quotient [(I+)-(I-)] / [(I+)+(I-)] of 1843, was equal to 0.00(3), indicating the absolute configuration indicated in Section C.18 above (Example 26-B). The asymmetric unit contains one molecule of Example 26-B.

[0617] D. cAMP HTRF assay. The compounds of the present invention do not directly activate dopamine D1 receptors, but rather potentiate the effects of D1 agonists or dopamine, the endogenous ligand of the D1 receptor, via an allosteric mechanism, and are therefore D1 positive allosteric modulators (D1 PAMs).

[0618] D1 agonists, including dopamine, directly activate dopamine D1 receptors. This assay can measure the effect of the example compounds in the absence of dopamine ("activation assay") and in the presence of dopamine ("potentiation assay").

[0619] The activation assay measures the stimulation of cyclic adenosine monophosphate (cAMP) production in an HTRF assay, with 100% activation defined as the maximum increase in cAMP with increasing concentrations of the endogenous agonist dopamine. When tested, the example compounds lack significant direct agonist-like activity, in that they produce less than 20% activation (compared to the maximum response of dopamine) when present at a concentration of 10 μM.

[0620] The potentiation assay measures the ability of compounds to increase the levels of cAMP produced by a low-threshold concentration of dopamine. The concentration of dopamine used ([EC 20 ]) is designed to stimulate 20% of the maximal response (100%) seen with increasing concentrations of dopamine. To measure this potentiation, increasing concentrations of the compound are used to measure the [EC 20 ] and measure the potentiation effect as an increase in cAMP production. 50 is the −log10 of the concentration of compound that produces 50% enhancement of cAMP levels, and Erel is the relative potency, defined as the maximal % enhancement produced by a compound compared to the maximal response produced by increasing concentrations of dopamine (Erel of 1 = maximal response of dopamine).

[0621] The specific conditions under which the compounds were tested are described below. Method D1 Cell Culture Cells were cultured at 37°C in a humidified atmosphere of 5% CO. Cells were grown in DMEM-F12 + GlutaMAX™-I medium (GIBCO®, Invitrogen, Merelbeke, Belgium) containing 10% fetal bovine serum (BioWhittaker®, Lonza, Verviers, Belgium), 400 μg / mL Geneticin (GIBCO®), 100 IU / mL penicillin, and 100 IU / mL streptomycin (Pen-Strep solution, BioWhittaker®). LMtk (Ltk-) mouse fibroblasts expressing dopamine D1 receptors (BioSignal Inc, Montreal, Canada, now Perkin Elmer) were used because they have been shown to efficiently couple and confer robust functional responses (Wats et al., 1995).

[0622] cAMP assay Measurement of changes in intracellular cyclic adenosine monophosphate (cAMP) was determined using the HTRF cAMP kinetic assay kit from CisBio (Codres, France). This assay, which uses homogeneous time-resolved fluorescence technology, is based on the competition between native cAMP produced by the cells and cAMP labeled with the dye d2. Tracer binding is determined by an anti-cAMP antibody labeled with cryptate. The effect of the compound alone (agonism) was determined by performing the assay in the absence of dopamine, while the effect of the compound as a positive allosteric modulator (PAM) was determined by measuring the EC 20 Cells (20,000 per well) were cultured in 384-well plates in the presence of isobutylmethylxanthine (Sigma, final 0.1 mM), various concentrations of test compound (usually 10 -9.5 M~10 -4.5The cells were incubated for 1 hour at room temperature in the presence and absence of dopamine (final 1.1 nM) in a final volume of 20 μL HBSS (Lonza, calcium, magnesium, HEPES buffer 20 mM, pH 7.4) containing 1.1 nM of dopamine. The reaction was then terminated, and cells were lysed by adding 10 μL of d2 detection reagent in lysis buffer and 10 μL of Crypto reagent in lysis buffer according to the manufacturer's instructions. This was then incubated for an additional 60 minutes at room temperature, and the change in the HTRF fluorescence emission ratio was determined using a laser-excited Envision plate reader (Perkin Elmer, Zaventem, Belgium) according to the manufacturer's instructions. All incubations were performed in duplicate, and the results were compared to a concentration-effect curve for dopamine (10 -11 M to 10 -6 M).

[0623] Data analysis Data were analyzed using Excel and PRISM (GraphPad Software), and pEC was calculated using a four-parameter logistic equation (DeLean et al., 1978). 50 Erel was calculated by subtracting the basal response from the maximum response of the test compound, and expressed as a relative percentage when the value obtained with dopamine was set at 100%.

[0624] When tested in the cAMP HTRF assay, the exemplary compounds of formula (I) according to the Examples exhibit values ​​as displayed in Table A below: [Table 8]

[0625] E.GABA A Automated patch clamp testing of receptor cells Human GABA A CHO-K1 cells stably expressing the receptor α1, β2, and γ2 subunits were used. Cells were harvested with trypsin and maintained at room temperature in serum-free medium. Before testing, cells were washed and resuspended in extracellular solution.

[0626] Patch clamp testing Human GABA A Experiments on α1β2γ2 channels were performed using an automated patch clamp assay (IonFlux™ HT). A The external solution for recording currents consisted of 137 mM sodium chloride, 4 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 10 mM HEPES, and 10 mM glucose. Both the external and internal solutions were titrated with NaOH or KOH to pH 7.35 and 7.3, respectively. The internal pipette solution contained 70 mM potassium fluoride, 60 mM potassium chloride, 70 mM sodium chloride, 5 mM HEPES, 5 mM EGTA, and 4 mM magnesium ATP. The final concentration of vehicle used for compound dilution was 0.33% DMSO in each well. Bicuculline (0.032–100 μM) was used as a positive control inhibitor. GABA (15 μM) was used as an agonist. All recordings were obtained from a holding potential of -60 mV.

[0627] The order of compound addition was as follows: EC 80 A single addition of 15 μM GABA was made to establish a baseline response. Each compound concentration was added for 30 seconds, followed by the addition of 15 μM GABA in the presence of compound for 2 seconds. This process was repeated with the next increasing concentration of compound. The peak inward current in response to the addition of GABA in the presence of a single compound concentration was measured. All compound data was normalized to the baseline peak current induced by the 2-second addition of 15 μM GABA.

[0628] When tested in the above assay, at a concentration of 10 μM, the compounds of formula (I) according to the Examples exhibited GABAergic activity as shown in Table B below. A The receptor inhibition rate is shown. [Table 9]

[0629] F. In Vitro Assessment of CYP3A4 Inhibitory Potential Using Cryopreserved Human Microsomes The purpose of the human microsome assay is to characterize the inhibitory potency of compounds of formula (I) by measuring CYP3A4 activity after co-incubation of compounds of formula (I) with midazolam, a specific CYP3A4 substrate.

[0630] For this purpose, cryopreserved human microsomes (pooled donors) were dispensed into 48-well collagen-coated plates at a final concentration of 0.25 mg / ml. UCB compounds were then added to duplicate wells at a concentration of 20 μM. After a 30-minute incubation, midazolam was added at a concentration of 2.5 μM. After 15 minutes, an aliquot was removed and placed in an equal volume of methanol containing an internal standard. The sample was centrifuged at 2500 rpm for 20 minutes at 4°C. An aliquot of the supernatant was diluted with deionized water, and the concentration of 1-hydroxymidazolam was quantified using a standard LC-MS / MS method.

[0631] This concentration is compared to the concentration obtained after incubation with midazolam at the same concentration and without pre-incubation with UCB compounds. Results are expressed as % inhibition.

[0632] When tested in the above assay, the compounds of formula (I) according to the Examples exhibit a percentage inhibition of CYP3A4 as shown in Table C below.

[0633] Inhibition rates greater than about 70% and less than about 80% are indicated by +.

[0634] Inhibition rates of greater than about 60% and less than or equal to about 70% are indicated by ++.

[0635] Inhibition rates of greater than about 40% and less than or equal to about 60% are indicated by +++.

[0636] Inhibition rates of greater than about 20% and less than or equal to about 40% are indicated by ++++.

[0637] Inhibition rates of approximately 20% or less are indicated by +++++. [Table 10]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 where: Z is CH ２ or represents NH; R ４ is hydroxy, halogen and C １‐６ C optionally substituted with one or more substituents selected from alkyl １‐６ alkyl; or hydroxy and C １‐６ C optionally substituted with one or more substituents selected from alkyl １‐６ Alkyne; or halogen, cyano, C １‐６ Alkyl and C １‐６ C optionally substituted by one or more substituents selected from alkoxy ５‐８ represents heteroaryl; R ５ is hydrogen or C optionally substituted by one or more substituents selected from hydroxy and halogen １‐６ represents alkyl; and G is (G ａ ), (G ｂ ) and (G ｃ represents an aromatic group selected from the group consisting of: 【Chemistry 2】 where: asterisk( ＊ ) represents the point of attachment of G to Z in formula (I); X represents CH, C—F or N; R １ is hydrogen; or C optionally substituted by one or more substituents selected from hydroxy and halogen １‐６ Alkyl or C １‐６ represents alkoxy; R ２ and R ３ independently represent halogen or cyano; X １ represents CH or N; R ａ is hydrogen or C １‐６ represents alkyl; and R ｂ is C １‐６ represents alkyl or halogen.

2. A compound of formula (I) according to claim 1, represented by formula (IA): or a pharmaceutically acceptable salt thereof. 【Chemistry 3】 Here, G, R ４ , R ５ , Z and X are as defined in claim 1.

3. A compound of formula (I) according to claim 1, represented by formula (IA-a), or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 Here, G, R ４ , R ５ , Z and X are as defined in claim 1.

4. Z is CH ２ 2. A compound of formula (I) according to claim 1, wherein

5. R ４ is substituted with one or more hydroxy and one or more halogen １‐６ Alkyl; one or more C １‐６ C substituted with alkyl and one or more hydroxy １‐６ Alkyl; one or more hydroxy and one or more C １‐６ C substituted with alkyl １‐６ 2. A compound of formula (I) according to claim 1, which represents an alkyne.

6. G is (G ｃ 2. A compound of formula (I) according to claim 1, wherein

7. A compound of formula (I) according to claim 1, represented by formula (IB-aa), or a pharmaceutically acceptable salt thereof. 【Chemistry 5】 where: R ６ and R ７ are independently hydrogen or C optionally substituted with one or more halogens. １‐６ represents alkyl; and G, R ５ , and X are as defined in claim 1.

8. R １ is substituted by one or more hydroxy １‐６ C substituted with alkyl, one or more hydroxy and one or more halogen １‐６ Alkyl, C １‐６ Alkoxy or C substituted with one or more halogens １‐６ A compound of formula (I) according to any one of claims 1 to 7, which represents alkoxy.

9. R ５ A compound of formula (I) according to any one of claims 1 to 8, wherein represents hydrogen.

10. R ６ is hydrogen or C １‐６ represents alkyl, and R ７ is C １‐６ 8. A compound of formula (IB-aa) according to claim 7, which represents alkyl, which group may be optionally substituted with one or more halogens.

11. A compound of formula (IB-aa) according to claim 7, wherein G is (G ｃ ) represents; X represents C—H or N; R １ is one or more hydroxy or C １‐６ C substituted with alkoxy １‐６ represents alkyl; R ２ and R ３ independently represent halogen or cyano; R ５ represents hydrogen; R ６ is hydrogen or C １‐６ represents alkyl; and R ７ is C substituted with one or more halogens １‐６ Represents alkyl.

12. The compound of claim 1 selected from the group consisting of: 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxybenzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-6-methoxybenzonitrile; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-2-methoxypyridin-4-yl)ethanone; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-(trideuteriomethoxy)benzonitrile; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,6-dichloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-7-fluoro-1H-indazol-4-yl)ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indol-4-yl)ethenone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[2,6-dichloro-3-(difluoromethoxy)phenyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aR,5R,8aS)-5-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 1-[(1S,4aR,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; 1-[(1S,4aR,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; (1S,4aR,5R,8aS)-N-(2,6-dichlorophenyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2-carboxamide; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-1-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aR,5R,8aS)-5-[(1S)-2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aS,8aS)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 2-[2-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]-3-chloro-4-methoxy-benzonitrile; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-(hydroxymethyl)-4-pyridyl]ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1S)-1-hydroxyethyl]-4-pyridyl]ethanone; 1-[(1S,4aS,5S,8aS)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-[3,5-dichloro-2-[(1R)-1-hydroxyethyl]-4-pyridyl]ethanone; 2-[2-[(1S,4aR,5R,8aS)-1-methyl-5-(2H-triazol-4-yl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxoethyl]-3-chloro-4-methoxybenzonitrile; 1-[(1S,3R,4aR,5R,8aS)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone; and 1-[(1S,3R,4aS,5S,8aR)-3-(hydroxymethyl)-1-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone.

13. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use in therapy.

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use in the treatment and / or prevention of diseases and / or disorders in which D1 receptors play a role.

15. 13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic treatment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

16. The pharmaceutical composition of any one of claims 13 to 15, further comprising a pharmaceutically acceptable carrier.

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