N-phenyl-2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide derivatives as TMEM175 modulators for reducing alpha-synuclein aggregation for the treatment of parkinson's disease

Abstract

The present invention relates to compounds of formula (l) as TMEM175 modulateurs for reducing alapha-synuclein aggregation for the treatment of Parkinson's didease

Description

TMEM175 MODULATOR COMPOUNDSFIELD OF THE INVENTION

[0001] The present disclosure relates to small molecule activators of ion channel TMEM175, to compositions comprising said compounds, and to uses of said compounds.BACKGROUND OF THE INVENTION

[0002] Transmembrane protein 175 (TMEM175) is a non-canonical lysosomal potassium ion channel expressed on (endo)lysosomes. It regulates lysosomal membrane potential and pH in neurons. Genetic variants in TMEM175 are associated with altered risk to neurodegenerative disorders associated with a-synuclein (aSyn) accumulation and aggregation: TMEM175 loss of function leads to lysosomal dysfunction, which in turn results in increased aSyn accumulation and aggregation in vitro and in vivo. Over-expression of TMEM175 reduces aSyn pathology in vivo. It is therefore hypothesized that a TMEM175 activator may reduce aSyn aggregation. WO2022109268 (Denali, published 27 May 2022), WO2022232632 (Denali, published 3 November 2022) and WO2023288039 (Denali, published 27 May 2022), describe NLRP3 modulators. W02025006723 (Caraway, published 2 January 2025), discloses TMEM175 agonist compounds.

[0003] Despite aSyn pathological prevalence in a range of neurodegenerative diseases, no adequate small molecule TMEM175 activators are approved that prevent or reduce aSyn aggregation. Consequently, there is a need for novel small molecules that act as activators of ion channel TMEM175, and which therefore may reduce aSyn aggregation. In particular, there is a need for novel small molecules that act as activators of ion channel TMEM175 that display an appropriate balance of properties, such as for example, appropriate potency, brain penetration, solubility and / or toxicity profile.SUMMARY OF THE INVENTION

[0004] The present disclosure relates to small molecule activators of ion channel TMEM175, displaying a good balance of properties, and compositions comprising said compounds.

[0005] Therefore, in one aspect, the present invention relates to a compound having Formula (I)or a stereoisomeric form thereof, whereinX represents CH, C-halo, CCH3 or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; said Cs-ecycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aais selected from H, CH3 and CH2CH3; andR1Abis selected from the group consisting ofCi-4alkyl optionally substituted with one or two substituents, each independently selected from the group consisting of fluoro, hydroxy, cyano, and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen and which is optionally substituted with Ci-3al kyl or (=0);C2-4alkynyl;Cs-ecycloalkyl which may be monocyclic, or form a 5-, 6- or 7-membered spiro or fused bicyclic and optionally contain an oxygen atom and which may be optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy; and5- or 6-membered heterocyclic monocyclic ring containing a nitrogen or an oxygen atom and which is optionally substituted with one or two halo substituents; or R1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; Cl; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; pyridinyl;and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, C3- ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; with the proviso that when R3is a Cs-ecycloalkyl, a 5-membered heteroaryl, an -O-(5-membered heteroaryl), phenyl, pyridinyl or a 5- or e- membered heterocyclyl, then R4Aadditionally may be optionally attached at carbon r;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

[0006] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable carrier or diluent. In a further aspect, the invention relates to a compound of Formula (I) as described herein, for use in activating TMEM175. In a yet further aspect, the invention relates to a compound of Formula (I) as described herein, for use in the reduction of aSyn aggregation. In a further aspect, the invention relates to method of treating Parkinson’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as described herein. In another aspect, the invention relates to a compound of Formula (I) as described herein, for use as a medicament, or to a compound of Formula (I) as described herein, for use in the treatment of Parkinson’s disease. The invention also relates to the use of a compound according to the general Formula (I) as described herein, for the manufacture of a medicament, in particular, for the treatment of Parkinson’s disease.DESCRIPTION OF THE FIGURES

[0007] Figure 1 Depicts the structure of the TMEM175 ligand-bound complex with a representative analogue obtained by cryo electron microscopy at a resolution of 2.90 A.DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention provides novel compounds that act as activators of ion channel TMEM175, and which therefore may reduce aSyn aggregation.

[0009] In a particular embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, as described herein, whereinX represents CH, C-halo, CCH3 or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

[0010] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH, C-halo, or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0);Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; cyano; Cs-ecycloalkyl optionally substituted with oneor two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0);Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is bound at carbon b or carbon r and is selected from the group consisting of H; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SFs; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents eachindependently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; and 5- or e- membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

[0011] In a further embodiment, the invention relates to a compound of Formula (I), as described herein, having Formula (I’)or a stereoisomeric form thereof, whereinX represents CH, C-halo, or N;R1Ais selected from the group consisting of H; halo;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

[0012] In a further embodiment, the invention relates to a compound of Formula (I’) as described herein, whereinX represents CH, or N;R1Ais selected from the group consisting ofH; fluoro, chloro;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one heteroatom selected from oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, and haloCi-salkyl; andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

[0013] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R3is not

[0014] In a particular embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, as described herein, wherein X represents CH, C-halo, CCH3 or N;R1Ais selected from the group consisting ofH;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or twosubstituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -0-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; and 5- or e- membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0015] In a further embodiment, the invention relates to a compound of Formula (I), as described herein, having Formula (I’)or a stereoisomeric form thereof, wherein X represents CH, C-halo, or N;R1Ais selected from the group consisting ofH;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0016] In a further embodiment, the invention relates to a compound of Formula (I’) as described herein, whereinX represents CH, or N;R1Ais selected from the group consisting ofH;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one heteroatom selected from oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, and haloCi-salkyl; andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2;or a pharmaceutically acceptable salt thereof.

[0017] In a particular embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, as described herein, whereinX represents C-halo, CCH3 or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; and 5- or e- membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2;n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof,

[0018] In a further embodiment, the invention relates to a compound of Formula (I), as described herein, having Formula (I’)or a stereoisomeric form thereof, whereinX represents C-halo, or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy,Cs-ecycloalkyl and cyano; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0019] In a further embodiment, the invention relates to a compound of Formula (I’) as described herein, whereinX represents N;R1Ais selected from the group consisting ofH; fluoro, chloro;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one heteroatom selected from oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, and haloCi-salkyl; andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0020] Therefore, in one aspect, the present invention relates to a compound having Formula (I)or a stereoisomeric form thereof, whereinX represents CH, C-halo, CCH3 or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl andCi-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; said Cs-ecycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aais selected from H, CH3 and CH2CH3; andR1Abis selected from the group consisting ofCi-4alkyl optionally substituted with one or two substituents, each independently selected from the group consisting of fluoro, hydroxy, cyano, and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen and which is optionally substituted with Ci-3al kyl or (=0);C2-4alkynyl;Cs-ecycloalkyl which may be monocyclic, or form a 5-, 6- or 7-membered spiro or fused bicyclic and optionally contain an oxygen atom and which may be optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy; and5- or 6-membered heterocyclic monocyclic ring containing a nitrogen or an oxygen atom and which is optionally substituted with one or two halo substituents;or R1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; Cl; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; -0-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi- salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; pyridinyl; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, C3- ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; with the proviso that when R3is a Cs-ecycloalkyl, a5-membered heteroaryl, an -0-(5-membered heteroaryl), phenyl, pyridinyl or a 5- or e- membered heterocyclyl, then R4Aadditionally may be optionally attached at carbon r;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0021] In a particular embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, as described herein, whereinX represents CH, C-halo, CCH3 or N; in particular CH, C-halo or CCH3;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-aalkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and (Ci-4alkyloxy)Ci-4alkyl;; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof,

[0022] In a further embodiment, the invention relates to a compound of Formula (I), as described herein, having Formula (I’)or a stereoisomeric form thereof, whereinX represents CH, C-halo, or N; in particular CH;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and (Ci-4alkyloxy)Ci- 4alkyl;; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof,

[0023] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents fluoro, chloro, trifluoromethyl, phenyloxy and cyclobutyloxy substituted with methyl.

[0024] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents fluoro, chloro, Ci-4alkyl optionally substituted with oneor more halo substituents and Ci-4alkyloxy optionally substituted with one or more halo substituents.

[0025] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents fluoro, chloro, trifluoromethyl, methoxy, ethoxy and isopropoxy.

[0026] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents fluoro, chloro, trifluoromethyl, methoxy and ethoxy.

[0027] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents Ci-4alkyl optionally substituted with one or more halo substituents and Ci-4alkyloxy optionally substituted with one or more halo substituents.

[0028] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents trifluoromethyl, methoxy, ethoxy and isopropoxy.

[0029] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Arepresents trifluoromethyl, methoxy and ethoxy.

[0030] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2Arepresents methyl or ethyl.

[0031] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2Arepresents methyl.

[0032] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; and R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano.

[0033] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl containingone or two nitrogen atoms; and R3is selected from the group consisting of haloCi-4alkyl; haloCi- 4alkyloxy; and (Ci-4alkyloxy)Ci-4alkyl.

[0034] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; and R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano.

[0035] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; and R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, or a 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy.

[0036] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R3is 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci- 4alkyl, haloCi-salkyl, ecycloalkyl and cyano; with the proviso that R3is not

[0037] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d.

[0038] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IA)

[0039] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IB)

[0040] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (I’A)

[0041] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (I’B)

[0042] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (l’B-1 )

[0043] In a further particular embodiment, the compound of Formula (I) as described herein, without the disclaimer, has the Formula (l’B-2)

[0044] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX, when present, is CH or N;R1Arepresents fluoro, chloro, Ci-4alkyl optionally substituted with one or more halo substituents and Ci-4alkyloxy optionally substituted with one or more halo substituents;R1Band R1Care each hydrogen;R2Ais methyl or ethyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and (Ci-4alkyloxy)Ci- 4alkyl;R4Ais F, and m is 0, 1 or 2; andR4Bis F, and n is selected from 0, 1 , or 2, and n’ is selected from 0 or 1.

[0045] In a particular embodiment, the invention relates to a compound of Formula (I), (IA), (IB), (I’A), or (I’B) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; and R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0046] In a particular embodiment, the invention relates to a compound of Formula (I), (IA), (IB), (I’A) or (I’B) as described herein, wherein ring A represents a phenyl or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; and R3is selected from the group consisting of difluoromethoxy and trifluoromethoxy.

[0047] In a particular embodiment, the invention relates to a compound of Formula (I), (IA), (IB), (I’A) or (I’B) as described herein, whereinwhereinR3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; in particular R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, or a 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy; in particular R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; in particular R3is selected from trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular R3is selected from difluoromethoxy and trifluoromethoxy;R4Ais F, and m is 0, 1 or 2; andR4Bis F, and n is selected from 0, 1 , or 2, and n’ is selected from 0 or 1.

[0048] In a particular embodiment, the invention relates to a compound of Formula (I), or (I’B) as described herein, whereinR3is selected from the group consisting of haloCi-4alkyl and haloCi-4alkyloxy; in particular R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy; in particular R3is selected from trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular R3is selected from trifluoromethyl and trifluoromethoxy;R4Ais F, and m is 0, 1 or 2; andR4Bis F, and n is selected from 0, 1 , or 2, and n’ is selected from 0 or 1.

[0049] In a further embodiment, the invention relates to a compound of Formula (I), as described herein, having Formula (I’)or a stereoisomeric form thereof, whereinX represents CH, C-halo, or N;R1Ais selected from the group consisting ofH;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy,Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound as described herein, wherein R3is not 5-membered heteroaryl, phenyl pyridyl or a 6-membered heterocyclyl.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.or a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof. In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaoror a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.In a further embodiment, the invention relates to a compound of formulaor a pharmaceutically acceptable salt thereof.

[0050] As already mentioned, the compounds of Formula (I) as described herein, and compositions comprising the compounds of Formula (I), can be used for activating ion channel TMEM175. In particular, the compounds of Formula (I) as described herein, may be used for reducing aSyn aggregation in vitro or in vivo. In particular, the invention relates to a method of reducing aSyn aggregation in a tissue, or a subject in vitro or in vivo, comprising administering a compound of Formula (I). In another aspect, the invention relates to a compound of Formula (I) as described herein, for use in the reduction of aggregation of aSyn in a tissue, or a subject in vitro or in vivo, in particular a subject in vivo.DEFINITIONS

[0051] Unless otherwise specified, ‘Cx-qalkyl’ groups (where x and q are integers, and q is the upper limit of the range), for example ‘Ci-qalkyl’ groups, defined herein may be straight-chain or be branched-chain.

[0052] ‘Cy.q cycloalkyl’ (where y and q are integers, y having as lower limit 3, and q is the upper limit of the range), for example ‘Ca-q cycloalkyl’ refers to an alkyl group that is cyclic. Where indicated, the ‘cycloalkyl’ can form a spiro bicyclic structure, when joint to another cyclic structure through a common carbon atom.

[0053] The term ‘halo’, when used herein, preferably includes fluoro, chloro, bromo and iodo, in particular fluoro, chloro or bromo, in particular fluoro or chloro.

[0054] ‘Ci-qalkoxy’ groups (where q is the upper limit of the range) refers to the radical of formula ‘-OCi-qalkyl’, where ‘Ci-qalkyl’ is a Ci-qalkyl group as defined herein.

[0055] ‘HaloCi-q alkyl’ (where q is the upper limit of the range) groups refer to Ci-qalkyl groups, as defined herein, where such group is substituted by one or more (e.g. 1, 2, 3) halo. Similarly, ‘haloCi-qalkoxy’ represents a corresponding -OCi-qalkyl group that are substituted by one or more (e.g. 1 , 2, 3) halo.

[0056] The symbol” represents a chemical bond with point of attachment, wherein the point of attachment i

[0057] The symbol—is used as meaning the same spatial arrangement in chemical structures shown herein. Analogously, the symbol >1is used as meaning the same spatial arrangement in chemical structures shown herein.

[0058] The term "subject" or “patient” as used herein, refers to a human, who is or has been the object of treatment, observation or experiment. Unless otherwise stated, “subject” or “patient” includes non-symptomatic humans, presymptomatic humans and human patients.

[0059] The expression ‘and / or’ represents the alternatives when both elements as defined are used together or in the alternative, e.g. the expression ‘carbon a and / or carbon b’ encompasses both, ‘carbon a and carbon b, and carbon a or carbon b’.

[0060] The term ‘6-membered heteroaryl containing one or two nitrogen atoms’ represents a 6-membered heteroaromatic ring containing one or two nitrogen atoms; particular examples of such rings include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0061] The term ‘5-membered heteroaryl’ represents a 5-membered heteroaromatic ring containing one or two heteroatoms each independently selected from N, O and S; particular examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4- thiadiazolyl, 1 ,3,4-thiadiazolyl, and triazolyl. Particular examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, and 1 ,3,4-thiadiazolyl. Particular examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.

[0062] The term ‘heterocyclyl’ represents a saturated ring having at least one heteroatom, in particular one or two independently selected, as indicated, e.g. N, O. 5-membered heterocyclyl encompass, for example, tetrahydrofuranyl, pyrrolidinyl, 6-membered heterocyclyl encompass, for example, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl. The term ‘heterocyclyl’, when indicated, can also form a fused bicycle (when two cycles have two atoms in common) or a spiro bicycle (when two cycles are joint through one carbon atom).

[0063] The term ‘substituted’ means that the specified group or moiety bears one or more substituents (1 , or 1 or 2, or 1 , 2 or 3, or 1 , 2, 3 or 4 substituents). The term ‘unsubstituted’ means that the specified group bears no substituents. The term ‘optionally substituted’ means that the specified group is unsubstituted or substituted by one or more substituents. Where the term ‘substituted’ is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.

[0064] The term ‘pharmaceutically acceptable salt(s)’ include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound as provided herein with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound provided herein in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0065] In one embodiment, the invention relates to compounds of Formula (I) as defined herein, in free base form.

[0066] In one embodiment, the invention relates to compounds of Formula (I) as defined herein, in pharmaceutically acceptable salt form.

[0067] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0068] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0069] The instant compounds may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond.

[0070] Compounds as provided herein may contain one or more asymmetric carbon atoms and may therefore exhibit enantiomerism or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired isomers may be made by reaction of an appropriate enantiomeric starting material under conditions which will not cause racemisation or epimerisation, or by reaction of an appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by resolution, including dynamic resolution, for example salt formation with a homochiral acid followed by separation of the diastereomeric salts by conventional means such as crystallization, or by reaction with an appropriate chiral reagent or chiral catalyst.

[0071] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated. Where stereochemistry is specified by a solid or dashed wedge representing a particular configuration, then that stereoisomer is so specified and defined.

[0072] Absolute configurations are specified according to the Cahn-lngold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate polarized light.

[0073] When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer.

[0074] The compounds may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents.

[0075] The names of the compounds were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (CAS) using Advanced Chemical Development, Inc., software (ACD / Name product version 10.01 ; Build 15494, 1 Dec 2006) or according to thenomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC) using Advanced Chemical Development, Inc., software (ACD / Name product version 10.01.0.14105, October 2006). In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated.PREPARATIVE EXAMPLES

[0076] Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow. The instant compounds can generally be prepared by a succession of steps, each of which is known to the skilled person.

[0077] The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkalination. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase or a chiral supercritical fluid chromatography (SFC). Said stereochemically enriched isomeric forms may also be derived from the corresponding stereochemically enriched isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0078] The absolute configuration of the compounds reported herein can be determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separate enantiomer(s) which were obtained by asymmetric synthesis, followed by vibrational circular dichroism (VCD) analysis of the particular enantiomer(s).

[0079] Final compounds according to Formula (I) as described herein can be prepared:A = Ph- or 6-membered heteroaryl- LG = Br or ClBy reacting an intermediate of Formula (III) with an intermediate of Formula (II) in presence of a suitable base such as, for example, sodium hydride, in a suitable solventsuch as, for example, DMF, at a suitable temperature such as, for example, room temperature;Intermediates of Formula (III) can be prepared by reacting an Intermediate of Formula (IV) with an intermediate of Formula (V) in presence of a suitable base such as, for example, / V, / V-diisopropylethylamine, in a suitable solvent such as, for example, dichloromethane, at a suitable temperature such as, for example, 0 °C;

[0080] Alternatively, final compounds according to Formula (I) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting an Intermediate of Formula (VI) with an intermediate of Formula (V) in presence of a suitable coupling agent such as, for example, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATLI) or O-(7-Azabenzotriazole-1-yl)- / V, / V, / V\ / V’-tetramethyluronium tetrafluoroborate (TATII) or Chloro-A / , / , / ', / '- tetramethylformamidinium Hexafluorophosphate (TCFH), with a suitable base such as, for example, 1-methyl-1 H-imidazole or triethylamine, in a suitable solvent such as, for example, dichloromethane or acetonitrile, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (VI) can be prepared by reacting the Intermediate of Formula (VII) in presence of a suitable base such as, for example lithium hydroxide or sodium hydride, in a suitable solvent such as, for example, tetrahydrofuran or methanol, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (VII) can be prepared by reacting the Intermediate of Formula (IX) with an intermediate of Formula (VIII) in presence of a suitable base such as, for example, for example, cesium carbonate, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 50°C;

[0081] Intermediate compounds according to Formula (IX) can be prepared:By reacting an intermediate of Formula (X) in presence of a suitable reductive reagent such as, for example, hydrogen in presence of palladium on charco, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (X) can be prepared by reacting the Intermediate of Formula (XI) in presence of a suitable acid such as, for example trifluoroacetic acid at a suitable temperature such as, for example, 100°C;Intermediate of Formula (XI) can be prepared by reacting the Intermediate of Formula (XIII) with an intermediate of Formula (XII) in presence of a suitable base such as, for example potassium carbonate, in presence of a suitable catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0), in presence of a suitable ligand such as, for example, tricyclohexylphosphine, in a suitable solvent such as, for example, dioxane and water, at a suitable temperature such as, for example 90°C;

[0082] Alternatively, intermediate compounds according to Formula (IX) can be prepared:By reacting an intermediate of Formula (XIV) in presence of a amonia, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, 80°C;Intermediate of Formula (XIV) can be prepared by reacting the Intermediate of Formula (XV) with Methyl potassium 2-(boc-aminoethyl)trifluoroborate, in presence of a suitable base such as, for example triethylamine, in presence of a suitable catalyst such as, for example, Bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example 80°C;

[0083] Alternatively, final compounds according to Formula (I) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting an intermediate of Formula (VII) with an intermediate of Formula (V) in presence of a suitable base such as, for example, Lithium bis(trimethylsilyl)amide, in a suitable solvent such as, for example, tetrahydrofuran, at a suitable temperature such as, for example, 0°C;

[0084] Final compounds according to Formula (XVI) can be prepared:By reacting an intermediate of Formula (XVIII) with an intermediate of Formula (XVII) in presence of a suitable base such as, for example, potassium phosphate, in presence of a suitable catalyst such as, for example, GPhos Pd G4, in a suitable solvent such as, for example, dioxane and water, at a suitable temperature such as, for example, 90°C;Intermediate of Formula (XVIII) can be prepared by reacting the Intermediate of Formula (VII) with an intermediate of Formula (XIX), in presence of a suitable base such as, for example Lithium bis(trimethylsilyl)amide, in a suitable solvent such as, for example, tetrahydrofuran, at a suitable temperature such as, for example, room temperature;

[0085] Alternatively, final compounds according to Formula (XVI) can be prepared:By reacting an intermediate of Formula (XXI) with an intermediate of Formula (XX) in presence of a suitable base such as, for example, potassium phosphate, in presence of a suitable catalyst such as, for example, GPhos Pd G4, in a suitable solvent such as, for example, dioxane and water, at a suitable temperature such as, for example, 90°C;Intermediate of Formula (XXI) can be prepared by reacting the Intermediate of Formula (XVIII) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane, inpresence of a suitable base such as, for example, potassium acetate, in a suitable solvent such as, for example, dioxane, at a suitable temperature such as, for example 80°C;

[0086] Final compounds according to Formula (IA) and to Formula (IB) can be prepared:A = Ph- or 6-membered heteroaryl-By purifying a racemic intermediate of Formula (I) by a suitable method such as, for example, supercritical fluid chromatography or crystallization;

[0087] Final compounds according to Formula (XXII) can be prepared:By reacting an intermediate of Formula (XXIII) with an intermediate of Formula (III) in presence of a suitable base such as, for example, sodium hydride, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, room temperature;

[0088] Final compounds according to Formula (XXIV) can be prepared:By reacting a final compound of Formula (XXV) with an intermediate of Formula (XXVI) in presence of a suitable base such as, for example, sodium terbutoxide, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 100°C.EXAMPLESGENERAL PREPARATION AND ANALYTICAL PROCESSES

[0089] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0090] In the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. Reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SFC).

[0091] The starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.ANALYTICAL PARTLC-MS (LIQUID CHROMATOGRAPHY / MASS SPECTROMETRY)GENERAL PROCEDURE

[0092] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0093] Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

[0094] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and / or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]-, etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0095] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass SelectiveDetector, “rt” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”UPLC” Ultra Performance Liquid Chromatography.

[0096] Table: LCMS Method codes (Flow expressed in mL / min; column temperature (T) in °C;Run time in minutes).SFC-MS (SUPERCRITICAL FLUID CHROMATOGRAPHY / MASS SPECTROMETRY) GENERAL PROCEDUREThe SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.SFC Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes).NUCLEAR MAGNETIC RESONANCE

[0097] For a number of compounds, 1 H NMR spectra were recorded on a Bruker Avance III spectrometer operating at 300 or 400 MHz, on a Bruker Avance lll-HD operating at 400 MHz, on a Bruker Avance NEO spectrometer operating at 400 MHz, on a Bruker Avance Neo spectrometer operating at 500 MHz, or on a Bruker Avance 600 spectrometer operating at 600 MHz, using CHLOROFORM-d (deuterated chloroform, CDCh), DMSO-cftS (deuterated DMSO, dimethyl-d6 sulfoxide), METHANOL-cM (deuterated methanol), as solvents. Chemical shifts (5) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.EXPERIMENTAL PART

[0098] Hereinafter, the term “m.p.” means melting point, “aq.” means aqueous, “rt” means room temperature, “DIPEA” means A / , / V-diiso- propylethylamine, “DI PE” means diisopropylether, “HATLI” means Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium, “TATLI” O-(7-Azabenzotriazole-1-yl)- / V, / \ / , / \ / ’, / \ / ’- tetramethyluronium tetrafluoroborate, “TCFH” Chloro-N,N,N',N'-tetramethylformamidinium Hexafluorophosphate, “NMI” means 1 -methylimidazole, “THF” means tetrahydrofuran, “DMF” means dimethylformamide, “DCM’ means dichloromethane, “EtOH” means ethanol, ‘EtOAc’ means ethyl acetate, “AcOH” means acetic acid, “iPrOH” means isopropanol, “iPrNH2” means isopropylamine, “ACN” means acetonitrile, “MeOH” means methanol, “rac” means racemic, “sat.” means saturated, “SFC” means supercritical fluid chromatography, “SFC-MS” means supercritical fluid chromatography / mass spectrometry, “LC-MS” means liquid chromatography / mass spectrometry, “HPLC” means high-performance liquid chromatography, “RP” means reversed phase, “LIPLC” means ultra-performance liquid chromatography, “Rt” means retention time (in minutes), “[M+H]+” means the protonated mass of the free base of the compound, “TBAI” means tetrabutyl ammonium iodide, “TBACI” means tetrabutyl ammonium chloride, “TFA” means trifuoroacetic acid, “Et20” means diethylether, “DMSO” means dimethylsulfoxide, “SiCh” means silica, “MW” means microwave or molecular weight, “min” means minutes, “h” means hours, “quant” means quantitative, “n.d.” means not determined, “Cpd” means compound, “DMA” means dimethylacetamide, “UV” means ultraviolet light, “DAD” means diode array detector, “BPin” means boronic acid pinacol, “NMR” means nuclear magnetic resonance, “MS” means mass spectrometry, “Tol” means toluene, “ES” means electrospray, “dppf’ means 1,T-b / s(diphenylphosphino)ferrocene,”BuOH” means n-butanol, “TLC” means thin layer chromatography, “DCE” means 1,2-dichloroethane, “STAB” means sodium triacetoxyborohydride, “KOAc” means potassium acetate, “PE” means petrol ether.Note on stereochemistry:

[0099] Whenever the notation “RS” is indicated herein, it denotes that the compound is a racemic mixture at the indicated stereo-center, unless otherwise indicated. The stereochemical configuration for stereo-centers in some compounds has been designated “(R)” or “(S)” when the mixture(s) was separated or originated from enantiomerically enriched starting materials; for some compounds, the stereochemical configuration at the indicated centers has been designated as “*R” or “*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically / diastereomerically enriched. The enantiomeric excess of compounds reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separated enantiomer(s). Enantiomers In intermediates / compounds wherein bonds are indicated either with a bold wedge or a wedge ofparallel lines while the stereocenters are designated (RS), the representation indicates that the sample is a mixture of stereoisomers, one stereoisomer having the indicated substituents or groups projected above or below the plane of the drawing as represented, one stereoisomer having the substituents or groups in the opposite projection below or above the plane of the drawing.

[0100] The absolute configuration of chiral centers (indicated as R and / or S) can be rationalized. The synthesis of all final compounds started from intermediates of known absolute configuration in agreement with literature precedent or obtained from appropriate synthetic procedures. The assignment of the absolute configuration of additional stereocenters can then be assigned by standard NMR methods. Alternative methods include cryo electron microscopy, or vibrational circular dichroism (VCD). Enantiomers can be differentiated by elution order under SFC conditions from the racemic mixture.

[0101] Alternatively, the stereoconfiguration around stereogenic centres has been designated using the "V3000 enhanced stereochemical notation”. The stereochemical centers are indicated with the labels “abs," "&x", or "orx", where x is an integer (e.g., 1 or 2). For clarity, the meanings of the stereochemical notations in the table are as follows:1. A stereogenic center designated as "orx", indicates that the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically enriched.2. When two or more stereogenic centers have been designated as "orx", the absolute stereochemistry of each stereogenic center is undetermined but the each of the stereogenic centers has been resolved and the compound itself has been isolated as a single stereoisomer and is diastereomerically enriched.Specificaly: a. For any pair of stereogenic centers designated as "orx" with different numerical parts in the notation (e.g., two stereogenic centers designed as "or1" and "or2" respectively), each stereogenic center is independently defined according to (2) (vide supra).For example,b. When any pair of stereogenic centers is designated as "orx" with identical numerical parts in the notation (e.g., two stereogenic centers each designated as "or1"), the relative stereochemistry is indicated, but the absolute configurations of these stereogenic centers have not been determined.For example,indicates one of the one of the following "trans" stereoisomers:3. When a stereogenic center is designated as "&x", it denotes that the compound is a racemic mixture at the indicated center. For4. When two or more stereogenic centers have been designated as "orx", it denotes that the compound is a mixture of stereoisomers. Specifically: a. For any pair of stereogenic centers designated as "&x " with different numerical parts in the notation (e.g., two stereogenic centers designed as "&1" and "&2" respectively), the compound is a mixture of stereoisomers where each of the stereogenic center vary independently. For example,indicates a mixtureb. For any pair of stereogenic centers designated as "&x" with identical numerical parts in the notation (e.g., two stereogenic centers each denoted with "&1"), the compound is a mixture of stereoisomers with relative stereochemistry. For example,indicates a mixture of the two"trans" stereoisomers:The structure of the TMEM175 ligand-bound complex with a representative analogue was obtained by cryo electron microscopy at a resolution of 2.80 angstrom. Figure 1 shows the obtained complex with TMEM175 protein depicted as a ribbon, the ligand shown as sticks, and the density around the ligand at the 2.0 isodensity surface as a mesh. The density of the ligand is well defined and the isomer of R-stereoconfiguration, i.e. that with R2Aas in Formula (I’B) (I’B), gives the best fit to this densityPREPARATION OF INTERMEDIATESSynthesis of 2-bromo- / V-(4-(1-methyl-1 H-pyrazol-3-yl)phenyl)propanamide (1-1)2-Bromopropanoyl chloride [7148-74-5] (2.95 mL, 1.7 g / mL, 29.26 mmol) was added dropwise to a solution of 4-(1-methyl-1 / 7-pyrazol-3-yl)aniline [916766-82-0] (5.0 g, 28.9 mmol) and DI PEA (5 mL, 28.9 mmol) in DCM (100 mL) at 0°C. The mixture was stirred for 4 hours. The mixture was quenched via the addition of aq. sat. NH4CI and extracted with EtOAc (2x). The combined organic phases were dried over MgSCL and concentrated in vacuo. The residue was purified by flash column chromatography (SiC>2, 100:0 to 0:100 EtOAc: heptane) to afford 1-1 (5.4 g, 58 % yield) as a beige powder. LCMS Rt = 0.84 min, 97% (UV), m / z (ES+) = 308.2; m / z (ES-) = n.d. (method 7)Synthesis of 2-bromo- / V-(4-(1-methyl-1 H-pyrazol-3-yl)phenyl)propanamide (I-2)2-Bromopropanoyl chloride [7148-74-5] (6 mL, 60 mmol) was added dropwise to a solution of 4- trifluoromethoxylaniline [461-82-5] (8 mL, 60 mmol) and DI PEA (5.5 mL, 32 mmol) in DCM (300 mL) at 0 °C. The mixture was stirred for 1 hour. The mixture was quenched via the addition of aq. sat. NH4CI and extracted with EtOAc (2x). The combined organic phases were dried over MgSCL and concentrated in vacuo. The residue was purified via flash column chromatography (SiC>2, 100:0 to 0:100 EtOAc: heptane) to afford I-2 (14.6 g, 46.9 mmol, 78% yield) as a white solid. LCMS Rt = 1.06 min, 94% (UV), m / z (ES+) = 312.0; m / z (ES-) = 310.0 (method 6).

[0102] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.

[0103] Synthesis of 2-(2-chloro-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7)-yl)- / \ / -(4-(1- methyl-1 / 7-pyrazol-3-yl)phenyl)propanamide (I-5 / F-78)

[0104] LiHMDS (1 m in THF, 5 mL, 5.31 mmol) was added dropwise to a solution of 4- (1 -methyl-1 / 7-pyrazol-3-yl)aniline [916766-82-0] (368 mg, 2.12 mmol) in dry THF (18 mL) at 0°C. The mixture was stirred for 10 minutes before a solution of I-6 (500 mg, 1.77 mmol) was added dropwise. The resulting mixture was stirred for another 2 hours. The reaction was quenched via the addition of aq. sat. NaHCCh (50 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, 100:0 to 0:100EtOAc: heptane) to afford I-5 / F-78 (470 mg, 1.15 mmol, 65% yield) as a white solid. LCMS Rt = 1.63 min, 99% (UV), m / z (ES+) = 410.2; m / z (ES-) = n.d (method 8)Synthesis of ethyl-2-(2-chloro-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7)-yl)propanoate (I-6)

[0105] NaH (60% wt. in mineral oil, 223 mg, 5.6 mmol) was added to a solution of 2- chloro-7,8-dihydro-1 ,6-naphthyridin-5(6 / - / )-one [1226898-93-6] (850 mg, 4.66 mmol) in THF (9 mL). The mixture was stirred at room temperature for 10 minutes, when ethyl 2- bromoproprionate [535-11-5] (0.91 mL, 6.98 mmol) was added in one portion. The resulting mixture was heated to 65 °C for 2 hours. The mixture was cooled down to room temperature and diluted with aq. Sat. NH4CI (50 mL). The mixture was diluted with EtOAc (50 mL) and the phases separated. The organic phase was washed with water (50 mL) and brine (50 mL), dried over MgSCL and concentrated in vacuo. The residue was purified via flash column chromatography (SiC>2, 100:0 to 0:100 EtOAc: heptane) to afford I-6 (981 mg, 3.47 mmol, 75% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 1.21 (t, J = 7.1 Hz, 3 H), 1.45 (d, J = 7.4 Hz, 2 H), 3.03 - 3.11 (m, 1 H), 3.20 (ddd, J = 16.7, 8.4, 5.6 Hz, 1 H), 3.52 - 3.65 (m, 2 H), 4.08 - 4.20 (m, 2 H), 5.35 (q, J = 7.4 Hz, 1 H), 7.26 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H). LCMS Rt = 0.86 min, 84% (UV), m / z (ES+) = 283.1 ; m / z (ES-) = 281.1 (method 6)

[0106] Synthesis of ethyl-2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanoate(I-7)

[0107] Cesium carbonate (1.480 g, 4.54 mmol) was added to a solution consisting of 6- fluoro-3,4-dihydroisoquinollin-1(2 / - / )-one [214045-84-8] (750 mg, 4.54 mmol), ethyl 2- bromopropionate [535-11-5] (887 pL, 6.81 mmol) and in dry DMF (12 mL). The reaction was stirred at rt for 16 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL). The organic phase was dried over MgSCU, filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by column chromatography (SiC>2, 0:100 to 30:70 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford I-7 (1.05 g, 85% yield) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 7.91 (dd, J = 8.3, 6.0 Hz, 1 H), 7.17 (dd, J = 14.9, 5.9 Hz, 2H), 5.18 - 4.96 (m, 1 H), 4.23 - 4.10 (m, 2H), 3.53 (dtd, J = 18.7, 12.5, 5.9 Hz, 2H), 3.04 - 2.95 (m, 2H), 1.45 - 1.39 (m, 3H), 1.17 (t, J = 5.6 Hz, 3H). LCMS Rt = 0.84 min, 98% (UV), m / z (ES+) = 266.1 ; m / z (ES-) = n.d. (method 12)

[0108] Synthesis of ethyl-2-(1-oxo-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 / 7)- yl)propanoate (I-9)

[0109] Cesium carbonate (0.337 g, 1 .03 mmol) was added to a round bottom flask of 25 mL containing a solution consisting of 1-10 (111 mg, 0.52 mmol), ethyl 2-bromopropionate [535- 11-5] (101 pL, 0.78 mmol) and in DMF (2 mL). The reaction was stirred at rt for 16 hours. The reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL). The organic phase was dried over MgSO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by column chromatography (SiO2, 0:100 to 60:40 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford I-9 (157 mg, 94% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.06 (d, J = 8.0 Hz, 1 H),7.75 (s, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 5.20 - 4.96 (m, 1 H), 4.25 - 4.03 (m, 2H), 3.71 - 3.48 (m,2H), 3.09(t, J = 6.5 Hz, 2H), 1.43 (d, J = 7.3 Hz, 3H), 1.18 (td, J = 7.1 , 3.0 Hz, 3H). LCMS Rt = 1.41 min, 97% (UV), m / z (ES+) = 316.0; m / z (ES-) = n.d. (method 11)Synthesis of ethyl 2-(5-oxo-2-(trifluoromethyl)-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7),-yl)propanoate(1-11)

[0110] Cesium carbonate (664 mg, 2.04 mmol) was added to a solution consisting of I- 12 (220 mg, 1.02 mmol), ethyl 2-bromopropionate [535-11-5] (200 pL, 1.54 mmol) and in dry DMF (5 mL). The reaction was stirred at 50 °C for 16 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL). The organic phase was dried over MgSCL, filtered and concentrated to dryness in vacuo. The product was purified by flash column chromatography (SiC>2, 0:100 to 50:50 AcOEt: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford 1-11 (337 mg, quant.) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.45 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 5.09 (t, J = 7.3 Hz, 1 H), 4.21 - 4.03 (m, 2H), 3.79 - 3.59 (m, 2H), 3.23 (t, J = 6.6 Hz, 2H), 1.45 (d, J = 7.3 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). LCMS Rt = 0.86 min, 99% (UV), m / z (ES+) = 317.1 ; m / z (ES-) = n.d. (method 12)Synthesis of ethyl 2-(2-methoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)propanoate (I-70)Ethyl 2-bromopropionate (580 mg, 416 pL, 1.2 eq, 3.21 mmol) was added to a suspension of 2- methoxy-7,8-dihydro-1 ,6-naphthyridin-5(6H)-one (476 mg, 1 Eq, 2.67 mmol) and CS2CO3 (2.18 g, 2.5 eq, 6.68 mmol) in dry DMF (5.0 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with water (15 mL) and EtOAc (5 mL) and the layers were separated. The aqueous layer was extracted again with EtOAc (10 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent wasevaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) to give I-70 (600 mg, 2.1 mmol, yield 80%, 99% purity) as a thick colourless oil.Synthesis of ethyl 2-(2-ethoxy-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propanoate (I-74)Ethyl 2-bromopropionate (1.173 g, 841.4 pL, 1.2 eq, 6.479 mmol) was added to a suspension of I-75 (1070 mg, 1 Eq, 5.400 mmol) and Cesium carbonate (4.398 g, 2.5 Eq, 13.50 mmol) in dry DMF (15 mL) at room temperature. The reaction mixture was stirred at 50 °C for 24 h. The reaction mixture was diluted with water (150 mL) and EtOAc (100 mL) and the layers were separated. The aqueous layer was extracted again with EtOAc (100 mL). The combined organic layer was dried on MgSO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 50 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) to give I-74 (1240 mg, 4.24 mmol, yield 78%, 100% Purity) as a colourless thick oil.Synthesis of ethyl 2-(2-isopropoxy-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propanoate (I-81)Ethyl 2-bromopropionate (488 mg, 350 pL, 1.2 eq, 2.70 mmol) was added to a suspension of I- 88 (483 mg, 1 eq, 2.25 mmol) and CS2CO3 (1.83 g, 2.5 eq, 5.62 mmol) in dry DMF (5.0 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with water (15 mL) and EtOAc (5 mL) and the layers were separated. The aqueous layer was extracted again with EtOAc (10 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) to give I- 81 (444 mg, 1.4 mmol, yield 64 %, 99% Purity) as a thick colourless oil.Synthesis of methyl 2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)butanoate (l-83a)Methyl 2-bromobutyrate (564 mg, 359 pL, 1 eq, 3.12 mmol) was added to a suspension of I-75 (605 mg, 1 eq, 3.12 mmol) and CS2CO3 (2.54 g, 2.5 Eq, 7.79 mmol) in dry DMF (5.0 mL) at room temperature. The reaction mixture was stirred at 50 °C for 24 h. The reaction mixture was diluted with water (15 mL) and EtOAc (5 mL) and the layers were separated. The aqueous layer was extracted again with EtOAc (10 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) to give I- 83a (731 mg, 1.9 mmol, yield 62 %, 77% Purity) as a thick colourless oil.

[0111] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 6-ethoxy-3,4-dihydroisoquinolin-1 (2 / - / )-one (I-75)[22246-02-2]A suspension of 2-chloro-7,8-dihydro-1 ,6-naphthyridin-5(6H)-one [1226898-93-6] (2007 mg, 1 eq., 10.99 mmol) in sodium ethoxide (21% in EtOH) [141-52-6] (10.68 g, 12.3 mL, 3 eq, 32.97 mmol) was stirred at 50°C for 5.5 h. The reaction mixture was diluted with saturated aqueous NH4CI (15 mL). The precipitate was filtered and washed with water (10 mL) to give I-75 (1486 mg, 7.5 mmol, 68% yield) as a light orange solid, dried under vacuum at 45°C and used without further purification.Synthesis of 2-isopropoxy-7,8-dihydro-1 ,6-naphthyridin-5(6H)-one (I-88)Isopropanol (20 mL) was added dropwise to NaH 60 % in mineral oil (1.095 g, 5 eq, 27.38 mmol) at 0 °C under nitrogen atmosphere. After 10 min, solid 2-chloro-5,6,7,8-tetrahydro-1 ,6- naphthyridin-5-one (1000 mg, 1 Eq, 5.476 mmol) was added to the white suspension and the mixture was stirred at 60 °C overnight. The solvent was evaporated and the residue was suspended in saturated aqueous NH4CI (10 mL) and filtered. The solid was washed with water (10 mL) to give I-88 (483 mg, 2.2 mmol, yield 41 %, 96% Purity) as an off-white solid, dried under vacuum at 45 °C and used without further purification.Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 6-(trifluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (I-80)A flask was charged with 5-(trifluoromethoxy)-1 -indanone [173252-76-1] (1.00 g, 1 eq., 4.63 mmol), methanesulfonic acid (7.4 g, 5.0 ml, 17 eq., 77 mmol) and DCM (10 ml). Sodium azide [26628-22-8] (451 mg, 1.5 eq., 6.94 mmol) was added and the mixture was stirred for 4h at room temperature. Then the reaction was diluted with NaOH (1.0 M in H2O 100 mL) and DCM. Layers were separated and the aqueous layer was extracted with DCM (2 times). Combined organic layers were washed with water, brine, dried with MgSCL and evaporated. The product was purified by flash column chromatography (SiC>2, 0:100 to 100:0 EtOAc: Heptane) to obtain I-80 (414 mg,1.8 mmol, 38% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.12 (d, J = 8.6 Hz, 1 H) 7.18 (br d, J = 8.7 Hz, 1 H) 7.07 (d, J= 2.4 Hz, 1 H) 6.24 (br s, 1 H) 3.60 (td, J = 6.6,2.8 Hz, 2 H) 3.03 (t, J = 6.6 Hz, 2 H). LCMS Rt = 1.58 min, 99 % (UV), m / z (ES+) = 232.1 ; m / z (ES-) = 230.1. (METHOD S)Synthesis of ethyl 2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanoic acid (1-14)I-8 1-14

[0112] Lithium hydroxide monohydrate (185 mg, 4.41 mmol) was added to a solution consisting of I-8 (413 mg, 1.47 mmol), methanol (10 mL), and water (10 mL) in a 100 mL round bottom flask, and the mixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with EtOAc (20 mL). The aqueous layer was treated with HCI 1 M until pH 3 and extracted with DCM / MeOH (9:1) (6x25 mL). The organic phase was dried over MgSCL anhydrous, filtered and concentrated in vacuo to give 1-14 (365 mg, 97% yield) as a white solid. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-d6) 5 ppm 12.74 (s, 1 H), 7.85 (d, J = 8.2 Hz, 1 H), 7.42 (dd, J = 10.7, 2.5 Hz, 2H), 5.05 (q, J = 7.3 Hz, 1 H), 3.60 - 3.46 (m, 2H), 3.04 - 2.92 (m, 2H), 1.39 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.69 min, 99% (UV), m / z (ES+) = 254.1 ; m / z (ES-) = nd (method 12)

[0113] Synthesis of 2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / - / )-yl)propanoic acid (I- 15)I-7 1-15

[0114] Lithium hydroxide monohydrate (500 mg, 11.9 mmol) was added to a solution consisting of I-7 (1.05 g, 3.96 mmol), methanol (20 mL), and water (20 mL) in a 100 mL round bottom flask, and the mixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with EtOAc (20 mL). The aqueous layer was treated with HCI 1 M until PH 3 and extracted with DCM / MeOH (9:1) (6x25 mL). The organic phase was dried over MgSCL anhydrous, filtered and concentrated in vacuo to give 1-15 (780 mg, 82% yield) as a white solid. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-d6) 5 ppm 12.66 (s, 1 H), 7.94 - 7.89 (m, 1H), 7.17 (dd, J = 13.9, 5.8 Hz, 2H), 5.06 (q, J = 7.3 Hz, 1 H), 3.59 - 3.46 (m, 2H), 3.03 - 2.93 (m, 2H), 1.39 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.57 min, 99% (UV), m / z (ES+) = 238.1; m / z (ES-) = nd (method 12)Synthesis of 2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanoic acid (1-16)

[0115] Lithium hydroxide monohydrate (63 mg, 1.5 mmol) was added to a solution consisting of I-9 (157 mg, 0.50 mmol), methanol (2 mL), and water (2 mL) in a 10 mL round bottom flask, and the mixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with EtOAc (20 mL). The aqueous layer was treated with HCI 1 M until pH 3 and extracted with DCM / MeOH (9:1) (6x25 mL). The organic phase was dried over MgSO4 anhydrous, filtered and concentrated in vacuo to give 1-16 (122 mg, 84% yield) as a white solid. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-d6) 5 ppm 12.82 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.78 - 7.68 (m, 2H), 5.07 (q, J = 7.4 Hz, 1 H), 3.64 - 3.49 (m, 2H), 3.14 - 2.98 (m, 2H), 1.41 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.86 min, 99% (UV), m / z (ES+) = 288.1; m / z (ES-) = nd (method 11)Synthesis of 2-(5-oxo-2-(trifluoromethyl)-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7),-yl)propanoic acid (1-17)

[0116] Lithium hydroxide monohydrate (245 mg, 5.84 mmol) was added to a solution consisting of 1-11 (610 mg, 1.93 mmol), methanol (5 mL), and water (5 mL) in a 50 mL round bottom flask, and the mixture stirred at rt for 16 h. Then, HCL (1M) was added until pH = 5 and the mixture was extracted with DCM (2 x 10 mL). The organic phase was dried over MgSCL, filtered and concentrated to dryness in vacuo to afford 1-17 (553 mg, quant.) as a white solid. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-cftS) 5 ppm 12.86 (s, 1 H), 8.45 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 5.07 (q, J = 7.3 Hz, 1 H), 3.75 - 3.62 (m, 2H), 3.22 (t, J = 6.6 Hz, 2H), 1.44 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.60 min, 99% (UV), m / z (ES+) = 289.1; m / z (ES-) = nd (method 12)Synthesis of 2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)propanoic acid (I-73)A mixture of I-74 (1211 mg, 1 eq, 4.142 mmol) and LiOH (496.1 mg, 5 eq, 20.71 mmol) in MeOH (10 mL), THF (10 mL), and water (10 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with water (200 mL) and HCI (1 M in water) was added until pH~2. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layer was dried on MgSCL, filtered, and the solvent was evaporated to give I-73 (938 mg, 3.5 mmol, yield 84%, 98% Purity) as a white solid.

[0117] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ethyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2 / 7)-one (1-10)

[0118] In a 50 mL round bottom flask, Pd / C (210 mg, 0.197 mmol) was added at rt to a solution consisting of 1-19 (210 mg, 0.985 mmol), ethanol (10 ml) under nitrogen atmosphere.Then, the mixture was stirred under H2 atmosphere at 50 °C for 16 hours. Pd / C (210 mg, 0.197 mmol) was added at rt under nitrogen atmosphere. Then, the mixture was stirred under H2 atmosphere at 50 °C for 16 hours. The mixture was filtered through of pad of celite and solvent was concentrated to dryness in vacuo to afford a grey solid. The grey solid was purified by chromatography column (SiC>2, 100:0 to 3:97 MeOH:DCM). The desired fractions were collected and concentrated to dryness in vacuo to yield 1-10 (111 mg, 52% yield) as a beige solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.18 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 3.41 (td, J = 6.6, 2.8 Hz, 2H), 3.01 (t, J = 6.6 Hz, 2H). LCMS Rt = 0.93 min, 99% (UV), m / z (ES+) = 216.0; m / z (ES-) = nd (method 11)

[0119] Synthesis of ethyl-6-(trifluoromethyl)isoquinolin-1(2 / - / )-one (1-19)

[0120] The reaction was set up in eight batches of the same quantity of I-20 (90 mg each one). In a microwave vial were charged I-20 (720 mg, 2.3 mmol) and TFA (16 mL), was stirred at 100°C for 2h. The solvent was concentrated in vacuo and DCM (5 mL) was added. The crude was neutralized with NaHCCh until pH = 7. The organic phase was separated, dried over MgSCL, filtered, and the solvent removed in vacuo to yield 1-19 (463 mg, 76% yield) as an orange solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 10.97 (s, 1 H), 8.53 (d, J = 8.4 Hz, 1 H), 7.89 - 7.82 (m, 1 H), 7.72 (t, J = 7.8 Hz, 1 H), 7.24 (s, 1 H), 6.63 (d, J = 7.2 Hz, 1 H). LCMS Rt = 0.73 min, 80% (UV), m / z (ES+) = 214.1 ; m / z (ES-) = nd (method 12)

[0121] Synthesis of (E)- / V-(tert-butyl)-2-(2-ethoxyvinyl)-4-(trifluoromethyl)benzamide (I-20)

[0122] A bottle glass pressure of 150 mL was charged (E)-2-(2-Ethoxyvinyl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane [1201905-61-4] (1.3 mL , 6.2 mmol), 1-21 (2.0 g, 6.2 mmol), K2CO3 (2.56 g, 18.5 mmol)), 1 ,4-dioxane (30 mL), and H2O (15 mL) that had been sparged with nitrogen for 5 min. Then, Pd(dba)2 (178 mg, 0.31 mmol) was then added and subsequently capped and heated at 90 °C for 5 h with stirring. The reaction was cooled at rt, diluted with water (25 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated in vacuo. The crude was subjected to silica gel chromatography (SiC>2, 100:0 to 0:100 EtOAc: heptane). The desired fractions were collected and concentrated to dryness in vacuo to yield I-20 (1 .79 g, 89% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.56 (d, J = 5.3 Hz, 1 H), 7.46 (t, J = 8.2 Hz, 1 H), 7.44 - 7.37 (m, 2H), 7.02 - 6.96 (m, 1 H), 6.08 (d, J = 12.9 Hz, 1 H), 5.60 (s, 1 H), 3.92 (q, J = 7.0 Hz, 2H), 1.47 (s, 9H), 1.35 (t, J = 7.0 Hz, 3H). LCMS Rt = 1.16 min, 97% (UV), m / z (ES+) = 316.1 ; m / z (ES-) = nd (method 12)

[0123] Synthesis of 2-bromo- / V-(tert-butyl)-4-(trifluoromethyl)benzamide (1-21)

[0124] In a 250 mL round bottom flask, thionyl chloride (8.2 mL, 112 mmol) was added dropwise over a period of 20 min to a solution of 2-bromo-4-(trifluoromethyl)benzoic acid [328- 89-2] (3 g, 11 mmol) in DCM (60 mL) and the reaction mixture was stirred at rt for 3 hours. The mixture was concentrated in vacuo and re-dissolved in DCM (60 mL). tert-Butylamine (5.9 mL, 56 mmol) was added dropwise over a period of 5 min to the acid chloride solution and the reaction stirred at rt for 16 h. The reaction mixture was quenched with sat. NaHCCh (aq.) (50 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with sat. NaHCOs (aq.), dried over MgSCL, filtered, and concentrated in vacuo to yield 1-21 (3.6 g, 95% yield) as a colourless solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.83 (s, 1 H), 7.63 - 7.56 (m, 2H), 5.61 (d, J = 44.7 Hz, 1 H), 1 .49 (s, 9H). LCMS Rt = 0.98 min, 95% (UV), m / z (ES+) = 323.9; m / z (ES-) = nd (method 12)

[0125] Synthesis of 2-(trifluoromethyl)-7,8-dihydro-1 ,6-naphthyridin-5(6 / 7)-one (1-12)

[0126] I-22 (436 mg, 1.88 mmol) was dissolved in NH3 in MeOH (50mL). The reaction was heated at 80 °C for 40h. The resulting mixture was diluted with DCM (30 mL) and filtered with celite. The filtrated was concentrated in vacuo. The product was diluted with water (10 mL) and extracted with DCM (2 X 10 mL). The organic phase was dried over MgSCL, filtered and concentrated to dryness in vacuo. The product was subjected to silica gel chromatography (SiC>2, 50:50 to 75:25 EtOAc: heptane). The desired fractions were collected and concentrated to dryness in vacuo to yield 1-12 (245 mg, 59% yield) as a white solid.1H NMR (400 MHz, DMSO- d6) 5 ppm 8.16 (s, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 2H), 7.09 (dd, J = 17.0, 10.7 Hz, 1 H), 6.44 (dd, J = 17.0, 2.1 Hz, 1 H), 5.64 (dd, J = 10.6, 2.1 Hz, 1 H). LCMS Rt = 0.55 min, 98% (UV), m / z (ES+) = 217.0; m / z (ES-) = nd (method 12)Synthesis of methyl 6-(trifluoromethyl)-2-vinylnicotinate (I-22)

[0127] Methyl 2-bromo-6-(trifluoromethyl)nicotinate [144740-56-7] (650 mg, 2.06 mmol) was dissolved in EtOH (8mL) with potassium 2-(boc-aminoethyl)trifluoroborate [13682-77-4] (331 mg, 2.47 mmol) and TEA (287 mL, 2.06 mmol) under N2 atmosphere. Then, Pd(dppf)Ch (87 mg, 0.11 mmol) was added. The reaction was heated at 80°C for 4h under N2 atmosphere. The mixture was concentrated was practically concentrated and the mixture was diluted with water (10 mL) and extracted with DCM (2 X 10 mL). The organic phase was dried over MgSCL, filtered and concentrated to dryness in vacuo. The product was subjected to silica gel chromatography (SiC>2, 0:100 to 20:80 EtOAc: heptane). The desired fractions were collected and concentrated to dryness in vacuo to yield I-22 (436 mg, 91 % yield) as a yellowish solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.43 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.47 (dd, J = 16.9, 10.6 Hz, 1 H), 6.49 (dd, J = 16.9, 2.0 Hz, 1 H), 5.77 - 5.65 (m, 1 H), 3.92 (s, 3H). LCMS Rt = 1.02 min, 99% (UV), m / z (ES+) = 323.1 ; m / z (ES-) = nd (method 12)Synthesis of 1-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)cyclopropane-1 -carboxylic acid (I-23)

[0128] TFA (0.55 mL, 7.21 mmol, 6 eq) was added to a solution of I-24 (483 mg, 1.20 mmol, 1 eq) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 16h. Full conversion. The solvent was removed under reduced pressure and the crude product used to the next step without further purification. I-23 (390 mg, 98% yield). LCMS Rt = 1.02 min, 75% (UV), m / z (ES+) = 250.1 ; m / z (ES-) = 248.1 (method 9)Synthesis of tert-butyl 1-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 H)-yl)cyclopropane-1- carboxylate (I-24)

[0129] NaH (60% dispersion in mineral oil) (130 mg, 3.24 mmol, 1.5 eq) was added to a solution of trimethylsulfoxonium iodide (714 mg, 3.24 mmol, 1.5 eq) in DMSO-d6 (22 mL) at O°C and the resultant mixture stirred for 20 min at 0°C. Then, a solution of I-25 (700 mg, 2.16 mmol, 1 eq) in THF (11 mL) was slowly added to the reaction and the resultant mixture stirred at room temperature for 3h. Full conversion. The reaction mixture was quenched by addition of a sat. solution of NH4CI and then the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over MgSCL, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography (SiC>2, 100:0 to 30:70 Heptane: EtOAc / EtOH (3:1)) yielding I-24 (483 mg, 55% yield). LCMS Rt = 1.06 min, 76% (UV), m / z (ES+) = 305.1 ; m / z (ES-) = 306.1 (method 13)Synthesis of tert-butyl 2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)acrylate (I-25)

[0130] tert-butyl propiolate [13831-03-3] (457 pL, 3.33 mmol, 1.1 eq) was added to a solution of 6-fluoro-3,4-dihydroisoquinolin-1 (2 / 7)-one [214045-84-8] (500 mg, 3.03 mmol, 1 eq) and PPha (873 mg, 3.33 mmol, 1.1 eq) in DCM (25 mL) at 0°C. The reaction mixture was then stirred at room temperature for 16h. The solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (SiC>2, 100:0 to 50:50Heptane: EtOAc / EtOH (3:1)) yielding I-25 (700 mg, 71 % yield) as an orange. LCMS Rt = 1.94 min, 90% (UV), m / z (ES+) = 292.2; m / z (ES-) = n.d. (method 9)Synthesis of 2-(1-oxo-3,4-dihydroisoquinolin-2(1 / - / )-yl)- / V-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propanamide (I-26)

[0131] The mixture of I-27 (13.0 g, 34.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1 ,3,2-dioxaborolane [73183-34-3] (13.2 g, 52.0 mmol) and KOAc (10.4 g, 104.9 mmol) in dioxane (200 mL). The mixture was purged with N2 for three times and Pd(dppf)Ch (1 .3 g, 1 .8 mmol) added. The reaction mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was quenched with aq.NH4CI (400 mL) and H2O (100 mL), then extracted with EtOAc (200 mL x3). The combined extracts were dried over anhydrous Na2SO4, filtered and the filtratewas concentrated to dryness in vacuo to give a black oil. The black oil was subjected to column chromatography (SiC>2, 100:0 to 50:50 ether: ethyl acetate) to afford I-26 (11.5 g, 67% yield) as white solid. LCMS Rt = 1.86 min, 86% (UV), m / z (ES+23) = 443.3; m / z (ES-) = n.d. (method 3) Synthesis of / V-(4-bromophenyl)-2-(1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanamide (I-27)

[0132] 1-13 (15.5 g, 53.0 mmol) and 4-bromoaniline [106-40-1] (11.0 g, 63.9 mmol) was dissolved in THF (300 mL). The resulting mixture was purged with N2 and cooled to 0 °C. Then LiHDMS (130 mL, 130 mmol, 1 M in THF) was added dropwise to the mixture. TLC showed the reaction was completed. The mixture was quenched with aq.NH4CI (300 mL) and H2O (200 mL), then extracted with EtOAc (200 mL x3) The combined extracts was dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated to dryness in vacuo to give a yellow oil. The black oil was subjected to column chromatography (SiC>2, 100:0 to 50:50 ether: ethyl acetate). The pure fractions were collected and the solvent was evaporated under vacuum, lyophilized to dryness to give I-27 (19.5 g, 67% yield) as white solid. LCMS Rt = 1.78 min, 99% (UV), m / z (ES+23) = 373.1 ; m / z (ES-) = n.d. (method 3)

[0133] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.PREPARATION OF FINAL COMPOUNDSSynthesis of (*R)-2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanoic acid F-1 and (*S)-2-(6-chloro-1 -oxo-3, 4-dihydroisoquinolin-2(1 / 7)-yl)propanoic acid (F-2)

[0134] TCFH [207915-99-9] (326 mg, 1.16 mmol) was added in one portion to a solution of 1-14 (268 mg, 1.06 mmol), 4-(thiazol-2-yl)aniline [193017-26-4] (205 mg, 1.16 mmol), and1 -methylimidazole [616-47-7] (177 pL, 2.22 mmol) in dry ACN (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and was extracted with EtOAc. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 100:0 to 70:30 heptane: EtOH: EtOAc 1 / 3). The resulting-white solid was purified by via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to afford F-1 (145 mg, 33% yield) as white solid and F-2 (142 mg, 33% yield) as white solid.Synthesis of (R)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)propanamide (F-385) and (S)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-386)HATLI (277 mg, 1.3 eq, 728 pmol) was added to a solution of I-73 (151 mg, 1 eq, 560 pmol), 3- amino-2-fluoro-6-(trifluoromethyl)pyridine (101 mg, 1 eq, 560 pmol), and DIPEA (145 mg, 195 pL, 2 eq, 1.12 mmol) in dry Acetonitrile (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, then at 60 °C for 2 days. The reaction mixture was diluted with EtOAc (5 mL) and saturated aqueous NaHCCh (10 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (5 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then by reverse phase chromatography (Stationary phase: RP XBridge Prep C18 OBD- 5pm, 50x150mm or 30x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) to give the racemic product as a white solid. This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-385 (11 mg, 26 pmol, yield 5%, 100% Purity) and F-386 (10 mg, 23 pmol, yield 4%, 100% Purity).

[0135] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATLI or TATU may be used as coupling reagents, DIPEA, TEA or NMI may be used as bases, and DMF may be used as solvent.

[0136] Synthesis of / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(1-oxo-6-(trifluoromethyl)-3,4- d i hyd roisoq ui nol i n-2( 1 / 7)-yl)propenamide (F-3)

[0137] TCFH [207915-99-9] (232 mg, 0.83 mmol) was added to a 25 mL round-bottomed flask containing a stirring solution, consisting of 1-16 (208 mg, 0.69 mmol), 4-(1-Methyl-1 H-pyrazol- 3-yl)aniline [916766-82-0] (119 mg, 0.69 mmol), 1-methyl-1H-imidazole [616-47-7] (192 pL, 2.42 mmol) in ACN (5 mL). The reaction mixture was stirred at rt for 16 h. The resulting mixture was diluted DCM (20 mL) and extracted with a solution of NaHCCh sat. (2 x 20 mL). The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated in vacuo. The crude was subjected to silica gel chromatography (SiC>2, 100:0 to 0:100 heptane:EtOH:EtOAc). The desired fractions were collected and concentrated to dryness in vacuo. The resulting beige solid was purified by HPLC (Phenomenex, Gemini 5 pm C18, 30 x 100 mm column, gradient 59-17% (v / v) ACN:MeOH (1 :1) / water (25mM NH4HCO3) to afford F-3 (98 mg, 31% yield) as a white solid.

[0138] Synthesis of 2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)- / V-(4-(1-methyl-1 / 7- pyrazol-3-yl)phenyl)propenamide (F-4)

[0139] TCFH [207915-99-9] (485 mg, 1.73 mmol) was added to a 50 mL round-bottomed flask containing a stirring solution, consisting of 1-14 (365 mg, 1.44 mmol), 4-(1-Methyl-1 / 7-pyrazol- 3-yl)aniline [916766-82-0] (249 mg, 1.44 mmol), 1-methyl-1H-imidazole [616-47-7] (399 pL, 5.03 mmol) in ACN (10 mL). The reaction mixture was stirred for 16h at rt. The resulting mixture was diluted with an aqueous solution of NaHCCh sat. (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated in vacuo. The crude was purified by column chromatography (SiC>2, 100:0 to 0:100 heptane: EtOH:EtOAc) to afford F-4 (307 mg, 50 % yield) as a white solid.Synthesis of 2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)-N-(4-(1-methyl-1 / 7-pyrazol- 3-yl)phenyl)propenamide (F-5)

[0140] TCFH [207915-99-9] (487 mg, 1.74 mmol) was added to a 50 mL round-bottomed flask containing a stirring solution, consisting of 1-15 (343 mg, 1.45 mmol), 4-(1-Methyl-1 / 7-pyrazol- 3-yl)aniline [916766-82-0] (250 mg, 1.44 mmol), 1-methyl-1H-imidazole [616-47-7] (401 pL, 5.06 mmol) in ACN (10 mL). The reaction mixture was stirred for 16h at rt. The resulting mixture was diluted with an aqueous solution of NaHCCh sat. (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated in vacuo. The crude was subjected to silica gel chromatography (SiC>2, 100:0 to 0:100 heptane:EtOH:EtOAc). The desired fractions were collected and concentrated to dryness in vacuo to afford F-5 (349 mg, 60% yield) as a white solid.Synthesis of / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(5-oxo-2-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5 / 7)-yl)propenamide (F-6)

[0141] TCFH [207915-99-9] (410 mg, 1.46 mmol) was added to a 50 mL round-bottomed flask containing a stirring solution, consisting of 1-17 (350 mg, 1.21 mmol), 4-(1-Methyl-1 / 7-pyrazol- 3-yl)aniline [916766-82-0] (211 mg, 1.22 mmol), 1-methyl-1H-imidazole [616-47-7] (338 pL, 4.26 mmol) in ACN (10 mL). The reaction mixture was stirred for 16h at rt. The resulting mixture was diluted with an aqueous solution of NaHCCh sat. (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated in vacuo. The crude was subjected to silica gel chromatography (SiC>2, 100:0 to 0:100 heptane:EtOH:EtOAc). The desired fractions were collected and concentrated to dryness in vacuo. The resulting white solid was purified by reverse phase (Phenomenex Gemini C18 100x30mm 5pm Column; from 70% [0.1% HCOOH] - 30% [ACN:MeOH (1 :1)] to 27% [0.1% HCOOH] - 73% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated. The product was treated with sat. NaHCCh. The mixture was extracted with DCM (10 mL x 2). The organics phases were combined and concentrated to dryness in vacuo to afford F-6 (268 mg, 49 % yield) as a white solid.Synthesis of 2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(6-(trifluoromethoxy)pyridin-3-yl)propenamide (I-76 / F-477)HATLI (277 mg, 1.3 eq, 728 pmol) was added to a solution of I-73 (151 mg, 1 eq, 560 pmol), 6- (trifluoromethoxy)pyridin-3-amine (99.7 mg, 1 eq, 560 pmol), and DI PEA (145 mg, 195 pL, 2 eq, 1.12 mmol) in dry Acetonitrile (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (10 mL) and saturated aqueous NaHCCh (10 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (5 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then by reverse phase chromatography (Stationary phase: RP XBridge Prep C18 OBD-5pm, 50x150mm or 30x150mm, Mobile phase: 0.1 % NH4HCO3 solution in water + 5% CH3CN, CH3CN) to give F-477 (101 mg, 0.23 mmol, yield 42%, 98% Purity) as a white solid.

[0142] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATLI, TATLI, or T3P may be used as coupling reagents, DIPEA, TEA or NMI may be used as bases, and DMF may be used as solvent.Synthesis of 4 2-(1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)- / V-(4-(thiazol-2-yl)phenyl)propenamide(F-7)MeCN

[0143] A solution of HATU (63.9 mg, 168 pmol) in DMF (8.77 mg, 120 pmol) was dispensed to a vial containing 4-(thiazol-2-yl)aniline (26.4 mg, 150 pmol). DI PEA (105 pL, 600 pmol) was added and the resulting solution was stirred for 5 minutes it was added to 1-18 (26.3 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 16 hours. It was placed under a nitrogen blower until all DMF had evaporated. To the resulting residue was added DMSO (1 mL) and MeOH (2 mL) and the resulting mixture was filtered. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford F-7 (19.6 mg, 42% yield).

[0144] Additional analogs were synthesized according to the above procedure starting from I- 18 substituting the reagents as appropriate. TCFH or TATLI may be used as coupling reagents, DI PEA, TEA or NMI may be used as bases, and DMF may be used as solvent.Synthesis of 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)- / V-(4-(1-methyl-1 / 7-pyrazol-3- yl)phenyl)propanamide (F-58)

[0145] NaH (60% wt. in mineral oil, 27 mg, 0.664 mmol) was added to a solution of 6-bromo- 3,4-dihydro-2 / 7-isoquinolin-1-one [147497-32-3] (50 mg, 0.22 mmol) in THF (1 mL). The mixture was stirred for 10 minutes before solid 1-1 (75 mg, 0.24 mmol) was added in one portion. The resulting mixture was heated at 65 °C for 16 hours. The mixture was neutralized via the addition of AcOH (50 L) and concentrated in vacuo. The residue was dissolved in MeOH (20 mL), filtered and purified via preparative RP-HPLC (1 x 20 mL injection, Stationary phase: RP XBridge Prep C18 OBD-10pm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford F-58 (8 mg, 0.018 mmol, 8% yield) off-white solid.

[0146] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 2-(2-chloro-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7)-yl)- / V-(4-(1-methyl-1 / 7- pyrazol-3-yl)phenyl)propenamide (F-78)

[0147] LiHMDS (1.06M in THF, 0.304 mL, 0.32 mmol) was added to a solution of 4-(1-methyl- 1 / 7-pyrazol-3-yl)aniline [916766-82-0] (51 mg, 0.30 mmol) in THF (2.5 mL) at 0 °C. The mixture was stirred for 15 minutes before solid I-6 (70 mg, 0.25 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with aq. sat. NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, 0:100 to 100:0 EtOAc: Heptanes) to afford F-78 (41 mg, 0.1 mmol, 40% yield) as a white solid.Synthesis of 2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)propenamide (F-471)□ HMDS solution (1 M in THF) (2.57 mL, 2.57 mmol) was added dropwise via syringe to a 100 mL round-bottomed flask containing a stirring solution consisting of I-74 (250 mg, 0.855 mmol), 5-Amino-2-(trifluoromethyl)pyridine (139 mg, 0.855 mmol) and dry THF (8.5 mL) at 0 °C and under N2 atmosphere to give an orange homogeneous solution. This mixture was stirred at rt for 1 h to give an orange homogeneous solution. The mixture was diluted with NH4CI (10 mL) and extracted with EtOAc (60 mL). The combined extracts were dried over anhydrous MgSCL, filtered and concentrated to dryness in vacuo to give an orange solid. The solid was subjected to silica gel chromatography (25 g silica irregular 40-60 pm 60 A; 0-50% Heptane / EtOAc) and then HPLC (Water Xbridge 10 pm (C18), 30 x 100 mm column, gradient 30-80% (v / v) ACN / water (25 mM NH4HCO3)). The compound-containing fractions were lyophilized to yield F-471 (229 mg, yield 65%) as a white solid.

[0148] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 2-(2-chloro-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5 / 7)-yl)- / \ / -(4-(1-methyl-1 / 7- pyrazol-3-yl)phenyl)propenamide (F-97)

[0149] MeOH (25 pL, 0.61 mmol) was added to a mixture of F-78 (25 mg, 0.061 mmol) and solid KOfBu (17 mg, 0.152 mmol) in DMF (0.25 mL). The resulting mixture was heated at 100 °C. The mixture was cooled down to room temperature, quenched via the addition of AcOH (100 pL) and concentrated in vacuo. The residue was purified via preparative RP-HPLC (1 x 20 mL injection, Stationary phase: RP XBridge Prep C18 OBD-10pm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford F-97 (35 mg, 0.086 mmol, 75% yield) as a white solid.Synthesis of / V-(4-(oxazol-2-yl)phenyl)-2-(1-oxo-3,4-dihydroisoquinolin-2(1 / 7)-yl)propanamide (F- 98)

[0150] A mixture of I-26 (100 mg, 0.20 mmol), 2-bromooxazole [125533-82-6] (51 mg, 0.35 mmol), potassium phosphate tribasic [7778-53-2] (130 mg, 0.61 mmol) in 1 ,4 dioxane (3 mL) and water (0.7 mL) was purged with nitrogen. Then GPhos Pd G4 (19 mg, 0.02 mmol) was added and the mixture was stirred at 90 °C for 3 hours. The mixture was cooled down to room temperature and diluted with aq. sat. NH4CI and extracted with EtOAc (x3). The organic phase was dried over MgSC>4 and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 30x150mm, Mobile phase: CH3CN) to afford F-98 (9 mg, 12% yield).

[0151] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of / \ / -(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(5-oxo-2-phenoxy-7,8-dihydro-1,6- naphthyridin-6(5 / - / )-yl)propanamide (F-116)

[0152] A solution of F-78 / I-5 (29 mg, 70 pmol) in DMF (0.28 mL,) was added to individual1 Dram vials containing phenol [108-95-2] (6.0 mg, 0.35 mmol) and KOfBu (24 mg, 0.21 mmol) in DMF (0.1 mL / well). The vial was closed under air and heated at 100 °C for 1 hour. The vial was opened and the volatiles removed under a stream of nitrogen. To the solid residue was added DMSO (1 mL) and MeOH (2 mL) and the vial was filtered and it was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford F-116 (14.2 mg, 43% yield).

[0153] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of / V-(2,3-difluoro-4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(1-oxo-3,4- dihydroisoquinolin-2(1 / 7)-yl)propanamide (F-127)

[0154] I-56 was treated with solution of GPhos Pd G4 (9.21 mg, 10.0 pmol), 1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 h-pyrazole [1020174-04-2] (52.0 mg, 250 pmol) in 1 ,4-dioxane (1.6 m) and solution of potassium phosphate (63.7 mg, 300 pmol) in distilled water (0.4 mL) was added. It was stirred at 90°C overnight, concentrated, extracted on Tecan™ (2 x 2 mL ethyl acetate), concentrated, treated with metal scavenger for 30 mins, filtered and diluted with 3 mL of ACN / MeOH (1 :1). It was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford F-127 (6.16 mg, 15% yield).

[0155] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of (*R)-2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7),-yl)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)propanamide (F-160) and (*S)-2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1 / 7),-yl)- / V-(4-(1 -methyl-1 / 7-pyrazol-3-yl)phenyl)propanamide (F-161 )

[0156] The racemic F-4 (307 mg, 0.75 mmol) was purified by preparative SFC (stationary phase: Phenomenex Lux Celullose-1 5 pm 150 x 21.2 mm, Mobile phase: 25% MeOH + 0.1 % DEA) to afford F-160 (73 mg, 23 % yield) as a white solid and F-161 (58 mg, 18% yield) as a white solid.Synthesis of (R)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(6- (trifluoromethoxy)pyridin-3-yl)propenamide (F-212) and (S)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)-N-(6-(trifluoromethoxy)pyridin-3-yl)propenamide (F-213)The racemic F-477 (101 mg, 0.23 mmol, 42 %, 98% Purity) was separated into its stereoisomers by preparative SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-212 (47 mg, 0.11 mmol, 19%, 98% Purity) and F-213 (39 mg, 92 pmol, 16%, 100% Purity).Synthesis of (R)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(6- (trifluoromethyl)pyridin-3-yl)propenamide (F-460) and (S)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)propenamide (F-461)The racemic F-471 (101 mg, 0.23 mmol, 42 %, 98% Purity) was separated into its stereoisomers by preparative SFC (Stationary phase: l-Amylose-A 5 pm 250 x 30 mm, Mobile phase: 40% EtOH + 0.1 % DEA) and lyophilized to give F-460 (86 mg, yield 24%) and F-461 (85 mg, yield 24%).

[0157] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. In the table below, compounds may be separated or isolated using usual separation techniques such as, for example, preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2). More specific techniques may also be used.Synthesis of (*R)-2-(2-isopropoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(4- (trifluoromethoxy)phenyl)propanamide (F-231) and (*S)-2-(2-isopropoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)-N-(4-(trifluoromethoxy)phenyl)propenamide (F-232)F-232□ HMDS 1 M in THF (265 mg, 1.58 mL, 1.0 molar, 2.5 eq, 1.58 mmol) was added to a stirring solution of 1-81 (196 mg, 1 eq, 633 pmol) and 4-(trifluoromethoxy)aniline [461-82-5] (112 mg, 85.0 pL, 1 eq, 633 pmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL) and the mixture was extracted twice with EtOAc (5 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then (Stationary phase: RP XBridge Prep C18 OBD-5 pm, 50 x 150 mm or 30 x 150 mm, Mobile phase: 0.1 % NH4HCO3 solution in water + 5 % CH3CN, CH3CN) to give the racemic product (183 mg, 0.39 mmol, 61 %, 93% Purity). This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: AD 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-231 (72 mg, 0.16 mmol, 26% yield, 100% Purity) and F-232 (72 mg, 0.16 mmol, 26% yield, 100% Purity).Synthesis of (R)-N-(2,3-difluoro-4-(trifluoromethoxy)phenyl)-2-(2-ethoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)butanamide (F-237) and (S)-N-(2,3-difluoro-4-(trifluoromethoxy)phenyl)-2- (2-ethoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)butanamide (F-238)LiHMDS 1 M in THF (342 mg, 2.04 mL, 1.0 molar, 2.5 eq, 2.04 mmol) was added to a stirring solution of I-83 (310 mg, 1 eq, 817 pmol) and 2.3-difluoro 4-trifluoromethoxyaniline (174 mg, 1 eq, 817 pmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL) and the mixture was extracted twice with EtOAc (5 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (Stationary phase: RP XBridge Prep C18 OBD-5 pm, 50 x 150 mm or 30 x 150 mm, Mobile phase: 0.1 % NH4HCO3 solution in water + 5 % CH3CN, CH3CN) to give the racemic product. This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: IG 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-237 (79 mg, 0.17 mmol, yield 20 %, 100% Purity) and F-238 (72 mg, 0.15 mmol, yield 19 %, 100% Purity).Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-methoxy-5-oxo-7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl)propenamide (F-248) and (S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-methoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)propanamide (F-249)□HMDS 1 M in THF (299 mg, 1.79 mL, 1.0 molar, 2.5 Eq, 1.79 mmol) was added to a stirring solution of I-70 (201 mg, 1 eq, 715 pmol) and 3-amino-2-fluoro-6-(trifluoromethyl)pyridine (129 mg, 1 eq, 715 pmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL) and the mixture was extracted twice with EtOAc (5 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (Stationary phase: RP XBridge Prep C18 OBD- 5 pm, 50 x 150 mm or 30 x 150 mm, Mobile phase: 0.1 % NH4HCO3 solution in water + 5 % CH3CN, CH3CN) to give the racemic product. This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: IG 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-248 (17 mg, 41 pmol, yield 6%, 100% Purity) and F-249 (18 mg, 44 pmol, yield 6%, 100% Purity).Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-isopropoxy-5-oxo-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl)propenamide (F-457) and (S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)-2-(2-isopropoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)propenamide (F-456)□ HMDS (98 mg, 0.59 mL, 1.0 molar, 2 Eq, 0.59 mmol) was added dropwise to a solution of 1-81 (91 mg, 1 eq, 0.29 mmol) and 2-fluoro-6-(trifluoromethyl)pyridin-3-amine (53 mg, 1 Eq, 0.29 mmol) in dry THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was diluted with saturated aqueous NH4CI (20 mL) and the mixture was extracted twice with EtOAc (10 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then by preparative reverse phase column chromatography (Stationary phase: RP XBridge Prep C18 OBD-5pm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) to give the racemic product as a white solid. This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, EtOH) to F-457 (19 mg, 43 pmol, yield 15 %, 100% Purity) and F-456 (20 mg, 45 pmol, yield 15 %, 100% Purity).Synthesis of (R)-2-(2-isopropoxy-5-oxo-7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl)-N-(6- (trifluoromethyl)pyridin-3-yl)propenamide (F-458) and (S)-2-(2-isopropoxy-5-oxo-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)propenamide (F-459)□HMDS (98 mg, 0.59 mL, 1.0 molar, 2 eq, 0.59 mmol) was added dropwise to a solution of 1-81 (91 mg, 1 eq, 0.29 mmol) and 5-amino-2-(trifluoromethyl)pyridine (48 mg, 1 eq, 0.29 mmol) in dry THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was diluted with saturated aqueous NH4CI (20 mL) and the mixture was extracted twice with EtOAc (10 mL). The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) and then (Biotage Sfar 10 g; eluent: heptane: EtOH / EtOAc 1 / 3 100:0 to 70:30) to give the racemic product. This fraction was separated into its stereoisomers by preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-458 (39 mg, 92 pmol, yield 31 %, 100% Purity)and F-459 (39 mg, 92 pmol, yield 31 %, 100% Purity). Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Additional compounds were synthesized according to one of the above procedures substituting the reagents, the reactants and the purification methods as appropriate.ADDITIONAL CHARACTERISING DATALCMS:SFC ANALYTICAL DATARt means retention time (in minutes), [M+H]+ means the protonated mass of the compound, method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds.NMR DATAOF FINAL COMPOUNDSBIOLOGICAL ASSAYSFLUORESCENT IMAGING PLATE READER (FLIPR) ASSAYInducible human TMEM175 cells were seeded at 6,000 cells / well in a PDL-coated black, clear bottomed 1536 well plate (Corning 9141BC). Cells were induced with 1ug / mL tetracycline 18-36 hours at 30C with 5% CO2 in a humidified atmosphere. After incubation, plating media was removed by light spin with the Bluecat Bluewasher and 6uL of the Thallium Indicator Dye (Molecular Devices C# R8223) was added to the plate and incubated 1 hour at roomtemperature. Test compounds and control compounds were spotted using a Labcyte Echo 555 and incubated 5 minutes at room temperature. While dye loading, the 4X thallium agonist plate was made according to Molecular Devices protocol (C# R8223) by adding 10uL / well of 3mM thallium (0.75mM final) to black, solid bottom plate (Corning 9146BC). The cell plate and agonist plates are transferred to FLIPR. Fluorescence was read for 10 seconds at 1 read / sec before 2pL addition of thallium, then read an additional 90 seconds. Data was calculated as a ratio of maximum response at time 20-30s over the average at time 1-1 Os. This ratio was normalized using an internal positive control as 100% and DMSO as 0%.Plating Media Assay Buffer - pH 7.4DMEM 138mM NaCI10% FBS 4mM KCI1X Penicillin / Streptomycin 10mM HEPES5mM D (+) glucose1 mM MgCh 2mM CaCh FLIPR data:CASPASE ASSAY IN HUMAN MONOCYTES.Selected compounds of the invention have been tested for NLRP3 modulatory activity and were found to be devoid of such activity (AC50 >9 to >25 pM) when tested in a Caspase assay in human monocytes.Monocyte Preparation. A vial of CD14+ monocytes (5-20 x 106 cells / mL) was thawed in a 37°C water bath. 1 mL of pre-warmed monocyte Test Medium (RPMI 1640 Medium, no phenol Red, from Life Technologies with 10% heat inactivated FBS and 25 mM HEPES from 1 M solution) was added dropwise to the thawed cells. The cell suspension was transferred to a 50 mL conical tube, and the cryovial was rinsed with 2 mL of Test Medium, which was then added to the suspension. Additional Test Medium was slowly added to achieve a final volume of 25- 30 mL. The mixture was centrifuged at 1200 RPM for 7 minutes, and the supernatant was aspirated without disturbing the pellet. The pellet was resuspended in 3-5 mL of Test Medium and cell counts were obtained using AO / PI ViaCount Reagent on a Nexcelom Auto 2000. The cell suspension was diluted to 1.33 x 106 cells / mL in Test Medium. Activity on NLRP3: NLRP3 trigger preparation. Nigericin (5 pg / mL final) was prepared in 100% EtOH (1000*) and LPS (1 pg / mL final) was prepared in dH2O (1000*). Both were stored at -80°C, avoiding freeze-thaw cycles beyond three. A 4* trigger stock was made by combining 24 pL of nigericin and 24 pL of LPS stock in 6 mL of Test Medium. Assay protocol. Caspase1-Glo reagent (Promega) was prepared according to the standard protocol, warming it to room temperature or 37°C, and mixing it gently. MG132 was added while stirring to enhance dissolution. In a 1536-well white opaque plate, compounds (max 20 nL = 25 pM from 5 mM stock) or DMSO were acoustically dispensed, followed by a 1-minute centrifugation at 1000 RPM. 3 pL of the cell suspension was added to each well using a dispenser, and the cells were incubated at 37°C with 5% CO2 for 45-60 minutes. Compound dispensation post-plating was permissible to improve cell distribution. The NLRP3 pathway was activated by adding 1 pL of the 4* trigger to each well. For controls, Test Media without S11 the trigger was dispensed. The plate was centrifuged at 800 RPM for 1 minute (optional), and incubated at 37°C for 40 minutes. Stimulation was stopped by adding 3 pL of Caspase1-Glo reagent to each well. If bubbles persisted, the plate was centrifuged at 1500 RPM for 1 minute without the lid. Plates were incubated at room temperature for 60-90 minutes, protecting them from light; lid removal was performed to avoid wetting. Luminescence was read using a PheraStar at a gain of 3600, with dwell time adjusted to 0.1 or 0.2 seconds based on required precision.Results in this assay.ADDITIONAL ASSAYSTHERMODYNAMIC SOLUBILITY MEASUREMENTIntroduction:Thermodynamic solubility represents the concentration of a compound in solution in equilibrium with an excess of undissolved substance at the end of the dissolution process. The purpose of a thermodynamic solubility assay in FASSIF and FESSIF in to investigate the effect of food on the absorption of an active compound in animals.Assay principle:In a typical thermodynamic solubility assay solid material is separated from the liquid phase by filtration after an incubation period. The filtrate is analyzed for compound in solution by LIPLC analysis.Materials & method:FaSSIF solution is prepared by weighing 2.082 g of Biorelevant ® FaSSIF Buffer Concentrate into a suitable container with screw cap and made up to volume (50 mL) by adding 48.25 mL purified water at room temperature. The buffer is placed on stirrer plate with PTFE magnet to stir for 1 minute. If required pH is adjusted to 6.5 with NAOH 1N or HCI 1N. 112 mg of Biorelevant ® FaSSIF / FeSSIF / FaSSGF powder is added to the container and stirred until fully dissolved. It is allowed to equilibrate at room temperature for two hours.FeSSIF solution is prepared by weighing 4.070 g of Biorelevant ® FeSSIF Buffer Concentrate into a suitable container with screw cap and made up to volume (50 mL) by adding 46.50 mL purified water at room temperature. The buffer is placed on stirrer plate with PTFE magnet to stir for 1 minute. If required pH is adjusted to 5.0 with NAOH 1 N or HCI 1 N. 560 mg of Biorelevant ® FaSSIF / FeSSIF / FaSSGF powder is added to the container and stirred until fully dissolved.About 2.5 mg of the compound to be tested is accurately weighed using a microbalance and added to 0.5 ml of each solvent (FaSSIF or FeSSIF) in a 20-ml clear glass vial. A magnetic stirring bar is added to the mixtures. The mixtures are stirred at ambient temperature for 24 hours. Insoluble material is removed by filtration and the concentration of drug in the filtrate is measured using an appropriate UPLC method and at least 3 reference standards for quantification.Reporting:Solubility results are reported in pg / mL or mg / mL. If clear solution were obtained after 24-hour incubation, the result is preceded by “>’. If the concentration is below the lowest reference standard, the result is reported as ‘< lowest reference standard’.FaSSIF = fasted state simulated instestinal fluid, FeSSIF = fed state simulated intestinal fluidMOUSE PHARMACOKINETIC STUDIESMale nonfasted BALB / c mice (n = 3 per terminal timepoint) were dosed p.o. with test compound. Following test compound administration, animals were co-housed (n= 3-5) until the end of sample collection. Brain Kp is determined using terminal sampling at different timepoints (e.g. 2,6 or 24 h post-dose). Terminal blood samples (30 pL) were collected in K2-EDTA containing tubes. Following terminal blood sample collection, animals were euthanized by CO2 induction. Blood was removed as much as possible via cardiac puncture. Residual blood was removed by saline perfusion (~20mL) via the left cardiac ventricle. After perfusion, whole brain was resected, washed with saline and blotted dry before being stored at -75°C until the day of bioanalysis.Plasma protein bindingThe plasma protein binding (fupiasma) of test compounds was assessed through equilibrium dialysis, using the Rapid Equilibrium Dialysis (RED) approach. The diluted plasma (25% v / v) was spiked with test compound (1 pM) and dialyzed against pH 7.4 buffer (6 h, 37 °C), which was separated by a semi-permeable membrane. At the end of the incubation period, aliquots were removed from the protein containing and protein free compartments, prior to sample preparation and subsequent sample analysis by LC-MS / MS. The fraction unbound (fu) was calculated by dividing the chromatographic peak area ratio in buffer by the peak area ratio in plasma. The fu was mathematically converted to match the fu in 100% plasma. In each experiment, warfarin and propranolol were included as reference control compounds.Brain tissue bindingThe brain tissue binding (fubrain) of test compounds was assessed through equilibrium dialysis using the RED approach. Rat brain homogenate (1 :9 tissue:PBS) was spiked with test compound (1 pM) and dialyzed against PBS (pH 7.4) (6 h, 37 °C, 5% CO2, 150 rpm), which was separated from the brain homogenate by a semi-permeable membrane. At the end of the incubation period, aliquots were removed from the protein containing and protein free compartments, prior to sample preparation and subsequent sample analysis by LC-MS / MS. The fraction unbound (fu) was calculated by dividing the chromatographic peak area ratio in buffer by the peak area ratio in brain homogenate. The fu was mathematically converted to match the fu in 100% brain. In eachexperiment, verapamil, fluoxetine and venlafaxine were included as reference control compounds.Calculation of brain KpuuUnbound brain to plasma concentration ratio (Kpuu, brain) was calculated according to the following equation:

Claims

CLAIMSWhat is claimed:1 . A compound having Formula (I)or a stereoisomeric form thereof, whereinX represents CH, C-halo, CCH3 or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Ci-ealkyloxy optionally substituted with one or more substituents, each independently selected from the group consisting of halo; hydroxy; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; said Cs-ecycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); phenyl;O-phenyl; andNR1AaR1Ab; whereinR1Aais selected from H, CH3 and CH2CH3; andR1Abis selected from the group consisting ofCi-4alkyl optionally substituted with one or two substituents, each independently selected from the group consisting of fluoro, hydroxy, cyano, and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen and which is optionally substituted with Ci-3al kyl or (=0);C2-4alkynyl;Cs-ecycloalkyl which may be monocyclic, or form a 5-, 6- or 7-membered spiro or fused bicyclic and optionally contain an oxygen atom and which may be optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy; and5- or 6-membered heterocyclic monocyclic ring containing a nitrogen or an oxygen atom and which is optionally substituted with one or two halo substituents; or R1Aaand R1Ab, together with the nitrogen atom to which they are attached, form a saturated 4-, 5- or 6-membered heterocyclic ring optionally containing a further nitrogen or oxygen atom wherein said 4-, 5- or 6-membered heterocyclic ring may optionally form a 7- or 8-membered spiro- or fused bicyclic structure, and which may further be optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R2Arepresents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; and R2Brepresents H; or R2Aand R2Btogether with the carbon atom to which they are bound, form a cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is bound at carbon b or carbon r and is selected from the group consisting of H; Cl; haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; SF5; SCF3; cyano; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from halo and Ci-3alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; pyridinyl; and 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; with the proviso that when R3is a Cs-ecycloalkyl, a 5-membered heteroaryl, an -O-(5-membered heteroaryl), phenyl, pyridinyl or a 5- or 6-membered heterocyclyl, then R4Aadditionally may be optionally attached at carbon r; R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not2. The compound according to claim 1 , having Formula (I’)or a stereoisomeric form thereof, whereinX represents CH, C-halo, or N;R1Ais selected from the group consisting ofH; halo;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one or two heteroatoms each independently selected from nitrogen and oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloCi-salkyl and (=0); andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; (Ci-4alkyloxy)Ci-4alkyl; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy,Cs-ecycloalkyl and cyano; and 5- or 6-membered heterocyclyl containing one or two heteroatomseach independently selected from oxygen and nitrogen and optionally being substituted with Ci-3alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, whereinX represents CH, or N;R1Ais selected from the group consisting ofH; fluoro, chloro;Ci-4alkyl optionally substituted with one or more halo substituents;Ci-ealkyloxy optionally substituted with one or more halo substituents;Cs-ecycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloCi-salkyl or Ci-3alkyloxy;5- or 6-membered heterocyclyl bound through an available carbon atom and containing one heteroatom selected from oxygen, and optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, and haloCi-salkyl; andO-Phenyl;R1Band R1Care each independently selected from the group consisting of H, halo, Ci-3alkyl, Ci-3alkyloxy, and cyano;R2Arepresents Ci-3alkyl;ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo, Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, haloCi-salkyloxy, Cs-ecycloalkyl, (Ci-3alkyloxy)Ci-3alkyl, and cyano;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from the group consisting of halo and cyano; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein R1Ais fluoro, chloro, Ci-4alkyl optionally substituted with one or more halo substituents and Ci-4alkyloxy optionally substituted with one or more halo substituents.

5. The compound according to any one of claims 1 to 4, wherein, ring A represents a phenyl or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; and R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, or a 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 4, wherein ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; and R3is selected from the group consisting of haloCi-4alkyl; haloCi-4alkyloxy; and (Ci-4alkyloxy)Ci-4alkyl.

7. The compound according to any one of claims 1 to 6, wherein R2Ais methyl or ethyl.

8. The compound according to claim 7, wherein R2Ais methyl.

9. The compound according to claim 1, having Formula (IB)or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein the compound isor a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

12. A compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, for use in a method of activating TMEM175.

13. A compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, for use in a method of reducing aSyn aggregation in a tissue, or a subject in vitro or in vivo.

14. A compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, for use as a medicament.

15. A compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, for use in a method of treating Parkinson’s disease or, a method of treating Parkinson’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11.

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