N-phenyl-2-(4-oxo-quinazolin-3(4H)-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 (I) as TMEM175 modulators for reducing alpha-synuclein aggregation for the treatment of Parkinson's disease.

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, C1- salkyloxy, 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 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, C1- salkyloxy, 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 C3- 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 C1- salkyloxy;(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- salkyloxy;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-3alkyl 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 the group consisting of 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 H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R1Dis H or Ci-3alkyl;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of H; chloro; haloCi-4alkyl; haloCi-4alkyloxy; (Ci- 4alkyloxy)Ci-4alkyl; SF5; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from the group consisting of 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 Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; pyridinyl; 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, C3- ecycloalkyl, Ci-3alkyloxyCi-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, C3- ecycloalkyl, Ci-3alkyloxyCi-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) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0007] In a further aspect, the invention relates to a compound of 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, C1- salkyloxy, 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 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, C1- salkyloxy, 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 C1- salkyloxy;(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 C1- salkyloxy;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-3alkyl 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 the group consisting of 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 H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R1Dis H or Ci-3alkyl;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is 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 heteroarylwhich 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 Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, C3- 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, C3- ecycloalkyl, Ci-3alkyloxyCi-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, C3- ecycloalkyl, Ci-3alkyloxyCi-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 notfor use in activating TMEM175, more in particular, 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

[0008] Figure 1 Depicts the structure of the TMEM175 ligand-bound complex with compound F-266 obtained by cryo electron microscopy at a resolution of 2.90 A.DETAILED DESCRIPTION OF THE INVENTIONThe 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, X represents CH, 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 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 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- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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; and NR1AaR1Ab; whereinR1Aais selected from 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-3alkyl 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 the group consisting of 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 H or halo;R1Drepresents H or CH3;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or R2represents cyclopropyl;ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of H; 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 or Ci-4alkyloxy; phenyl; and 5- or 6-membered heterocyclyl containing a oxygen or a nitrogen atom; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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

[0010] In a further embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, wherein X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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 halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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; andNR1AaR1Ab; whereinR1Aais selected from 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-3alkyl 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 the group consisting of 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 H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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 or Ci-4alkyloxy; phenyl; and 5- or 6- membered heterocyclyl containing a oxygen or a nitrogen atom; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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

[0011] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH, CCH3 or N; R1Ais selected from the group consisting of 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 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 groupconsisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 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 halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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); andPhenyl;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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 or Ci-4alkyloxy; phenyl; and 5- or 6- membered heterocyclyl containing a oxygen or a nitrogen atom; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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

[0012] In a further embodiment, the compound of Formula (I), or a steroisomeric form thereof, as defined herein, wherein X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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, eachindependently 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- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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; and 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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 X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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 C1- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or bromo;R1Drepresents H;R2represents 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; and 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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 or a solvate thereof, with the proviso that the compound is not

[0014] In a further embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, as described herein, whereinX represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 groupconsisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 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 halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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; andNR1AaR1Ab; whereinR1Aais selected from 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-3alkyl 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 the group consisting of 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 optionallysubstituted 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 H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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; phenyl; and 5- or 6-membered heterocyclyl containing a oxygen or a nitrogen atom; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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.

[0015] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, wherein X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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 halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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); and Phenyl;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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; phenyl; and 5- or 6-membered heterocyclyl containing a oxygen or a nitrogen atom; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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.

[0016] In a further embodiment, the compound of Formula (I), or a steroisomeric form thereof, as defined herein, wherein X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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 C1- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or halo; R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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 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 further embodiment, the compound of Formula (I), or a steroisomeric form thereof, as defined herein, whereinX represents CH, CCH3 or N;R1Ais selected from the group consisting of halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo;Ci-ealkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents 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 (C1- 4alkyloxy)Ci-4alkyl; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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.

[0018] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein X represents CH, CCH3 or N;R1Ais selected from the group consisting of 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 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 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 C1- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or bromo;R1Drepresents H;R2represents 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; and haloCi-4alkyloxy; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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 or a solvate thereof.

[0019] In a further embodiment, the invention relates to a compound of Formula (I) as described hereinabove, without the proviso, wherein 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, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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; and n represents 0, 1 or 2; or a pharmaceutically acceptable salt or a solvate thereof.

[0020] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, whereinX represents CH, or N;R1Ais selected from the group consisting of 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 5- or 6-membered heterocyclylcontaining 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 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- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or bromo;R1Drepresents H;R2represents 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 CF3; OCF3; and pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from fluoro;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from fluoro; m represents 0, 1 or 2; n represents 0, 1 or 2;or a pharmaceutically acceptable salt or a solvate thereof, with the proviso that the compound is not

[0021] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein X represents CH, or N;R1Ais selected from the group consisting ofhalo;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 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 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- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or bromo;R1Drepresents H;R2represents 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 CF3; and OCF3; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from fluoro;R4Bis, when present at carbon c and / or carbon d, independently selected at each position from fluoro; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt or a solvate thereof.

[0022] In a further particular embodiment, the invention relates to a compound of Formula (I) as described hereinabove, wherein ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of CF3; OCF3; and pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Ais, when present at carbon a and / or carbon b, independently selected at each position from fluoro; andR4Bis, when present at carbon c and / or carbon d, independently selected at each position from fluoro; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt or a solvate thereof.

[0023] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R1Ais selected from one or more of the following options (i) to (xiv):

[0024] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R1Ais selected from the group consisting of halo (for example, fluoro, chloro), haloCi-4alkyl (for example, trifluoromethyl), haloCi-4alkyloxy (for example, trifluoromethoxy), and Ci-4alkyloxy (for example methoxy, ethoxy, isopropoxy).

[0025] In a particular embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R1Ais selected from the group consisting of fluoro, chloro, haloCi- 4alkyl (for example, trifluoromethyl), haloCi-4alkyloxy (for example, trifluoromethoxy),cyclopropyl, and 5- or 6-membered saturated heterocyclyl containing an oxygen atom.

[0026] In another embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Ais selected from the group consisting of fluoro, chloro, and trifluoromethyl.

[0027] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein one of R1Bor R1Cis halo (for example, Br) and the other is H; or R1Band R1Cboth represent hydrogen. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R1Drepresents hydrogen. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2represents methyl or ethyl. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2represents methyl. 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. 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, and trifluoromethoxy. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein ring A represents phenyl or pyridinyl. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R3represents difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, or a 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl and isothiazolyl, each of which may be optionally substituted with one or two substituents each independently selected from methyl and methoxy. In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R3represents difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0028] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl and methoxy;R1B, R1Cand R1Deach represent H;R2represents methyl or ethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, and isothiazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy;R4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d; 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

[0029] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, ethoxy and isopropoxy;R1Band R1Ceach independently selected from H and halo; and R1Dis H;R2represents methyl or ethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy; andR4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof,

[0030] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl and methoxy;R1B, R1Cand R1Deach represent H;R2represents methyl or ethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy; andR4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d; m represents 0, 1 or 2; n represents 0, 1 or 2;or a pharmaceutically acceptable salt thereof,

[0031] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl and methoxy;R1B, R1Cand R1Deach represent H;R2represents methyl or ethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, trifluoromethoxy, and 5-membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, and isothiazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy;R4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d; 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

[0032] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl and methoxy;R1B, R1Cand R1Deach represent H;R2represents methyl or ethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, and trifluoromethoxy; andR4Ais fluoro, when present at carbon a and / or carbon b; and R4Bis fluoro, when present at carbon c and / or carbon d; m represents 0, 1 or 2; n represents 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0033] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IA)

[0034] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IB)

[0035] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC’)whereinX is CH or CCH3;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and trifluoromethoxy; and R4Aand R4Aare each independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC’)X is CH or CCH3; in particular CH;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, and trifluoromethoxy; andR4Aand R4Aare each independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.

[0036] In a yet further embodiment, the compound of Formula (I) as described herein, has the Formula (IC’) and has in particular the Formula (IC’b)or a pharmaceutically acceptable salt thereof.

[0037] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC’-1)X is CH or CCH3;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and trifluoromethoxy; and R4Aand R4Aare each independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.In a further particular embodiment, the compound of Formula (I) as described herein, has theFormula (IC’-1)whereinX is CH or CCH3; in particular CH;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, and trifluoromethoxy; andR4Aand R4Aare each independently selected from hydrogen and fluoro;or a pharmaceutically acceptable salt thereof.

[0038] In a yet further embodiment, the compound of Formula (I) as described herein, has the Formula (IC’-1) and has in particular the Formula (IC’-1b)or a pharmaceutically acceptable salt thereof.

[0039] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC’-2)whereinX is CH or CCH3;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and trifluoromethoxy; and R4Ais selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.In a further particular embodiment, the compound of Formula (I) as described herein, has theFormula (IC’-2)X is CH or CCH3; in particular CH;R1Ais halo, in particular fluoro or chloro, trifluoromethyl, trifluoromethoxy, or Ci-3alkyloxy, in particular methoxy, ethoxy or isopropoxy; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, and trifluoromethoxy; andR4Ais selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.

[0040] In a yet further embodiment, the compound of Formula (I) as described herein, has the Formula (IC’-2) and has in particular the Formula (IC’-2b)or a pharmaceutically acceptable salt thereof.

[0041] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC)whereinR1Ais halo, in particular fluoro or chloro, or trifluoromethyl; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and trifluoromethoxy; and R4Aand R4Aare each independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.

[0042] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC)whereinR1Ais halo, in particular fluoro; ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of trifluoromethyl and trifluoromethoxy; and R4Aand R4Aare each independently selected from hydrogen and fluoro;or a pharmaceutically acceptable salt thereof.

[0043] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC-1)whereinR1Ais halo, in particular fluoro or chloro, or trifluoromethyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and trifluoromethoxy;R4Ais hydrogen or fluoro; andR4Ais hydrogen or fluoro; or a pharmaceutically acceptable salt thereof.

[0044] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC-1)whereinR1Ais halo, in particular fluoro;R3is selected from the group consisting of trifluoromethyl and trifluoromethoxy;R4Ais hydrogen or fluoro; andR4Ais hydrogen or fluoro; or a pharmaceutically acceptable salt thereof.

[0045] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC-2)whereinR1Ais halo, in particular fluoro or chloro, or trifluoromethyl;R3is selected from the group consisting of trifluoromethyl, difluoromethoxy and trifluoromethoxy; in particular difluoromethoxy and tifluoromethoxy; and R4Ais hydrogen or fluoro; or a pharmaceutically acceptable salt thereof.

[0046] In a further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC-2)whereinR1Ais halo, in particular fluoro;R3is selected from the group consisting of trifluoromethyl and trifluoromethoxy; and R4Ais hydrogen or fluoro; or a pharmaceutically acceptable salt thereof.

[0047] In a yet further particular embodiment, the compound of Formula (I) as described herein, has the Formula (IC) and is selected from any one of Formula (IC-1 a), (IC-1 b), (IC-(IC-2a) (IC-2b) or a pharmaceutically acceptable salt thereof.

[0048] Therefore, in one aspect, the present invention relates to a compound having Formula (I)or a stereoisomeric form thereof, whereinX represents 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- salkyloxy, 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 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- salkyloxy, 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 C3- 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 C1- salkyloxy;(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 C1- salkyloxy;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-3alkyl 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 the group consisting of 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 H, halo, Ci-3alkyl, Ci-3alkyloxy, phenyl, and cyano;R1Dis H or Ci-3alkyl;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is selected from the group consisting of H; chloro; haloCi-4alkyl; haloCi-4alkyloxy; (Ci- 4alkyloxy)Ci-4alkyl; SFs; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from the group consisting of 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 Ci-4alkyl, haloCi-salkyl, Ci-4alkyloxy, Cs-ecycloalkyl and cyano; phenyl; pyridinyl; 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, C3- ecycloalkyl, Ci-3alkyloxyCi-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, C3- ecycloalkyl, Ci-3alkyloxyCi-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 of Formula (I) as described herein, whereinR1Ais selected from the group consisting of 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 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 groupconsisting of halo, Ci-3alkyl, haloCi-salkyl and Ci-3alkyloxy; a 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- salkyloxy;(Ci-4alkyloxy)Ci-4alkyl; and(Ci-4alkyloxy)Ci-4alkyloxy;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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; and 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy; andR4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein R3is not 5-membered heteroaryl; phenyl; pyridinyl; or e- membered heterocyclyl.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isIn a further embodiment, the invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isIn a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as5 described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.In a further embodiment, the present invention relates to a compound of Formula (I) as described herein, wherein the compound isor a pharmaceutically acceptable salt thereof.

[0049] As already mentioned, the compounds of Formula (I) as described herein, and compositions comprising the compounds of Formula (I) as described herein, 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) as described herein. 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

[0050] 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.

[0051] ‘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.

[0052] The term ‘halo’, when used herein, preferably includes fluoro, chloro, bromo and iodo, in particular fluoro, chloro or bromo, in particular fluoro or chloro.

[0053] ‘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.

[0054] ‘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.

[0055] The symbol” represents a chemical bond with point of attachment, wherein the point of attachment i

[0056] The symbolis used as meaning the same spatial arrangement in chemical structures shown herein. Analogously, the symbol > is used as meaning the same spatial arrangement in chemical structures shown herein.

[0057] 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.

[0058] 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’.

[0059] 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 pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0060] 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.

[0061] 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).

[0062] 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.

[0063] As used herein, the term ‘composition’ is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[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 the nomenclature 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-By 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 solvent such 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 (V) with an intermediate of Formula (IV) 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, / \ / , / \ / ’, / \ / ’- tetramethyluronium tetrafluoroborate (TATLI) or Chloro-A / , A / , A / ', 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; alternatively, the step of (VI) to (I) can proceed via two steps, through the formation of the corresponding acid chloride, formed by reaction of Intermediate of Formula (VI) with a suitable acylating agent such as, for example, 1-chloro-N,N,2- trimethylpropenylamine in a suitable solvent such as, for example, 1 ,2-dichloroethane, at a suitable temperature such as, for example, room temperature; the corresponding acid chloride can then be reacted with the Intermediate of Formula (V) in presence of a suitable base such as for example, pyridine, in a suitable solvent such as, for example, 1 ,2- dichloroethane, 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, cesium carbonate, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 50°C;

[0081] Alternatively, final compounds according to Formula (I) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting an intermediate of Formula (VII) 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;

[0082] Alternatively, final compounds according to Formula (I) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting a final compound of Formula (XI) with an intermediate of Formula (X) in presence of a suitable base such as, for example potassium phosphate, in presence ofa suitable catalyst such as, for example, Bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, in a suitable solvent such as, for example, dioxane and water, at a suitable temperature such as, for example, 100°C;

[0083] Alternatively, final compounds according to Formula (I) can be prepared:(XI) (I)A = Ph- or 6-membered heteroaryl-By reacting a compound of Formula (XI) with an intermediate of Formula (XVI), under photolysis conditions, in presence of a suitable base such as, for example quinuclidine, in presence of a suitable catalysts such as, for example, (4,4'-di-tert-butyl- 2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(ll I) hexafluorophosphate and bis(1 ,1- dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide, in presence of phthalimide in a suitable solvent such as, for example, dimethylsulfoxide, at a suitable temperature such as, for example room temperature;

[0084] Alternatively, final compounds according to Formula (I’) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting an intermediate of Formula (XVII) with an intermediate of Formula (XVIII) in presence of a suitable base such as, for example, Triethylamine, in presence of copper(ll) acetate, in a suitable solvent such as, for example, anisole, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (XVIII) can be prepared by reacting the Intermediate of Formula (XXI) in presence of formic acid, in presence of a suitable acid such as, forexample acetic acid, in a suitable solvent such as, for example, diethyl ether or heptane, at a suitable temperature such as, for example, 55°C;Intermediate of Formula (XXI) can be prepared by reacting the Intermediate of Formula (XXII) in presence of POCh, in presence of a suitable base such as, for example triethylamine, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 25°C;Intermediate of Formula (XVII) can be prepared by reacting the Intermediate of Formula (XIX) in presence of a suitable acid such as, for example HCI, in a suitable solvent such as, for example, dioxane, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (XIX) can be prepared by reacting the Intermediate of Formula (XX) with intermediate of Formula (V) in presence of a suitable coupling reagent such as, for example HATU, in presence of a suitable base such as, for example, diisopropylethylamine, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, room temperature;

[0085] Final compounds according to Formula (XII) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting a compound of Formula (XI) with an intermediate of Formula (XIII), under electrolysis conditions, in presence of a suitable base such as, for example quinuclidine, in presence of a suitable catalyst such as, for example, Nickel(ll) chloride ethylene glycol dimethyl ether complex, in presence of a suitable ligand such as, for example, 4,4'-dimethoxy-2,2'-bipyridine, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, room temperature;

[0086] Final compounds according to Formula (XIV) can be prepared:A = Ph- or 6-membered heteroaryl-By reacting compound of Formula (XI) with an intermediate of Formula (XV), in presence of a suitable base such as, for example cesium carbonate, in presence of a suitable catalyst such as, for example, [Dicyclohexyl(2',6'-diisopropoxy-2- biphenylyl)phosphine-KP](methanesulfonatato-KO)[2'-(methylamino-KN)-2-biphenylyl-5 KC2]palladium (RuPhosPdG4), in a suitable solvent such as, for example, dioxane, at a suitable temperature such as, for example, 85°C;

[0087] Final compounds according to Formula (IA) and to Formula (IB) can be prepared:(IA) (IB)A = Ph- or 6-membered heteroaryl-10 - By purifying a racemic intermediate of Formula (I) by a suitable method such as, for example, supercritical fluid chromatography or crystallization; compounds of Formula (IA) and (IB) can alternatively be obtained through an enantioselective route, conveniently at the stage of Intermediate of Formula (VI), through purification of the corresponding ester (XXIII) and subsequent hydrolysis:Followed by reacting the intermediate of formula (VIA) or (VI B) with an intermediate of Formula (V) as previously described, i.e. in presence of a suitable coupling agent such as, for example, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATLI) with a suitable base such as, for example, DI PEA in a suitable solvent such as, for example, dichloromethane or acetonitrile, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (VIA) and Intermediate of Formula (VIB) can be prepared by reacting an intermediate of Formula (XXI HA) or intermediate of Formula (XXI I IB), respectively, in presence of a suitable acid such as, for example hydrochloric acid, in a suitable solvent such as, for example, 1 ,4-dioxane, at a suitable temperature such as, for example, room temperature;Intermediate of Formula (XXI HA) and intermediate of Formula (XXI I IB) can be prepared by purifying a racemic intermediate of Formula (XXIII) by a suitable method such as, for example, supercritical fluid chromatography;Intermediate of Formula (XXIII) can be prepared by reacting the Intermediate of Formula (VI) in presence of a suitable liquid alcoholate such as, for example, tert-butyl acetate, in the presence of 1 ,1 ,1 -trifluoro-N-trifluoromethanesulfonylmethanesulfonamide, in a suitable solvent such as, for example, dichloromethane, at a suitable temperature such as, for example, 0 °C. In case of racemization of final compounds of Formula (IA) or Formula (IB) synthesized according to this procedure, the samples can be purified by preparative SFC.EXAMPLESGENERAL PREPARATION AND ANALYTICAL PROCESSES

[0088] 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.

[0089] 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).

[0090] 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

[0091] 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).

[0092] 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.

[0093] 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.

[0094] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “rt” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”UPLC” Ultra Performance Liquid Chromatography.

[0095] 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.Table: SFC Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes).NUCLEAR MAGNETIC RESONANCE

[0096] 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, CDCI3), DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxide), METHANOL-d4 (deuterated methanol), as solvents. Chemical shifts (5) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.MELTING POINTS

[0097] Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method.

[0098] Method A: For a number of compounds, melting points were determined with a DSC823e (Mettler Toledo) apparatus. Melting points were measured with a temperature gradient of 10 °C / minute. Standard maximum temperature was 300 °C.

[0099] Method B :For a number of compounds, melting points were determined in open capillary tubes on a Mettler Toledo MP50. Melting points were measured with a temperature gradient of 10 °C / minute. Maximum temperature was 300 °C. The melting point data was read from a digital display and checked from a video recording systemOPTICAL ROTATIONThe optical rotation was measured using a Rudolph Research Analytical Autopol V Plus polarimeter. [O]D20 indicates the optical rotation measured with light at the wavelength of the D- line of sodium (589 nm) at a temperature of 20°C. The cell pathlength is 1 dm. Behind the actual value the concentration and solvent of the solution which was used to measure the optical rotation are mentioned.EXPERIMENTAL PART

[0100] Hereinafter, the term “m.p.” means melting point, “aq.” means aqueous, “rt” means room temperature, ‘DI PEA’ means A / . / V-diiso- propylethylamine, “DIPE” means diisopropylether, ‘NMI’ means 1 -methylimidazole, ‘HATLI’ means Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium, “TATLI” means O-(7- Azabenzotriazole-1-yl)- / V, / V, / \ / ’, / \ / ’-tetramethyluronium tetrafluoroborate, “TCFH” means Chloro- N,N,N',N'-tetramethylformamidinium Hexafluorophosphate, “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 ,1'-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:

[0101] 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). In intermediates / compounds wherein bonds are indicated either with a bold wedge or a wedge of parallel 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.

[0102] 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.

[0103] 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 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. For example,2. When a stereogenic center is designated as "&x", it denotes that the compound is a racemic mixture at the indicated center. For example,indicates a mixture of the following two stereoisomers3. When two or or more stereogenic centers have been designated as "&x", it denotes that the compound is a mixture of stereoisomers. 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 varies independently.

[0104] The structure of the TMEM175 ligand-bound complex with compound F-266 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 ligandis well defined and the isomer of R-stereoconfiguration, i.e. that with R2Aas in Formula (I’B)

[0105]

[0106] PREPARATION OF INTERMEDIATESSynthesis of 2-bromo- / V-(4-(1-methyl-1 H-pyrazol-3-yl)phenyl)propanamide (1-1)

[0107] 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 MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 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 4)Synthesis of 2-bromo- / V-(4-(1-methyl-1 H-pyrazol-3-yl)phenyl)propanamide (I-2)

[0108] 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 DIPEA (5.5 mL, 32 mmol) in DOM (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 11).Synthesis of 2-bromo- / V-(4-(thiazol-2-yl)phenyl)propanamide (I-3)

[0109] 2-Bromopropanoyl chloride [7148-74-5] (0.4 mL, 4.01 mmol) was added dropwise to a solution of 4-(1 ,3-thiazol-2-yl)aniline (707 mg, 4.01 mmol) and DIPEA (2.07 mL, 12.04 mmol) in DCM (20 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 DCM (2x). The combined organic phases were dried over MgSCL and concentrated in vacuo. The residue was purified by flash column chromatography (SiC>2, 0:100 to 50:50 EtOAc: Heptanes) to afford I-3 (740 mg, 59% yield) as a yellow powder. LCMS Rt = 1.73 min, 100% (UV), m / z (ES+) = 312.0; m / z (ES-) = 310.0 (method 2).Synthesis of 2-bromo-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (I-37)I-372-Bromopropanoyl chloride (0.28 mL, 2.809 mmol) was added dropwise to a 0 °C mixture in a 100 mL round bottom flask consisting of 2-fluoro-6-(trifluoromethyl)-3-pyridinamine (0.5 g, 2.776 mmol), DIPEA (0.263 mL, 1.508 mmol) and DCM (14 mL) and the mixture was stirred at rt for 20 h. The mixture was diluted with NH4CI (30 mL) and then extracted with DCM (3 x 20 mL). The extracts were combined, dried over anhydrous MgSCL, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (12 g, irregular silica 40-60 pm 60 A; 0-10% EtOAc / heptane) to yield I-37 (550 mg, 58%) as a white solid.Synthesis of 2-bromo-N-[2-fluoro-6-(trifluoromethyl)-3-pyridyl]butanamide (1-42)2-Bromobutyryl chloride (0.151 mL, 0.740 mmol) was added dropwise to a mixture of 2-fluoro-6- (trifluoromethyl)-3-pyridinamine (250 mg, 1.4 mmol), DIPEA (0.129 mL, 0.740 mmol) and DCM (6.9 mL) at 0 °C and the mixture was stirred at rt for 1 h. The mixture was diluted with NH4CI (10 mL) and then extracted with DCM (2 x 80 mL). The extracts were combined, dried over anhydrous MgSCL, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (25 g, irregular silica 40-60 pm 60 A; 0-20% EtOAc / heptane) to yield I-42 (287 mg, 59%)as a yellowish solid.

[0110] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 2-amino-3-hydroxy- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)propanamide (I-6)I-7 1-6

[0111] HCI (4M in 1 ,4-dioxane, 1.5 mL) was added to a solution of I-7 (210 mg, 0.583 mmol) in DMC (3 mL). The resulting mixture was stirred at room temperature for 2 hours, when LCMS analysis indicated full conversion of the starting material. The mixture was concentrated in vacuo and the residue dried under high vacuum overnight to afford I-6 (168 mg, quant.) as a white solid. LCMS Rt = 0.52 min, 95% (UV), m / z (ES+) = 262.3; m / z (ES-) = 259.3 (method 4).

[0112] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ferf-butyl-(3-hydroxy-1-((4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)amino)-1-oxopropan-2- yl)carbamate (I-7)

[0113] DI PEA (0.125 mL, 0.731 mmol) was added to a solution of (tert-butoxycarbonyl)serine [3262-72-4] (150 mg, 0.583 mmol), HATLI (389 mg, 1.02 mmol) and 4-(1-methyl-1h-pyrazol-3- yl)aniline [916766-82-0] (165 mmol, 0.95 mmol) in DMF (7 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with aq. sat. NH4CI (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried overMgSC>4 and concentrated in vacuo. The residue was purified via flash column chromatography (SiC>2, 0:100 to 100:0 EtOAc: Heptanes) to afford I-7 (220 mg, 84% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 1 .24 (br s, 1 H), 1 .39 (s, 7 H), 2.66 - 2.73 (m, 1 H), 3.63 (br s, 2 H), 3.86 (s, 3 H), 4.15 (br d, J = 6.7 Hz, 1 H), 4.93 (br t, J = 5.5 Hz, 1 H), 6.61 (d, J = 2.1 Hz, 1 H), 6.74 (br d, J = 7.6 Hz, 1 H), 7.60 - 7.67 (m, 2 H), 7.67 - 7.73 (m, 3 H), 9.95 (s, 1 H). LCMS Rt= 1.48 min, 98% (UV), m / z (ES+) = 361.2; m / z (ES-) = 359.4 (method 2).

[0114] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4 / 7)-yl)propanoic acid (1-14)

[0115] Lithium hydroxide monohydrate (353 mg, 8.41 mmol) was added to a solution consisting of 1-15 (880 mg, 2.80 mmol), methanol (17 mL), and water (17 mL) in a 50 mL round bottom flask,and the mixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with AcOEt (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 (717 mg, 85% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.56 (s, 1 H), 8.35 (d, J = 8.3 Hz, 1 H), 8.05 (s, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 5.29 (q, J = 7.3 Hz, 1 H), 1 .68 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.91 min, 95% (UV), m / z (ES+) = 287.0; m / z (ES-) = n.d. (method 12).Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4 / 7)-yl)propanoic acid (1-16)1-17 1-16

[0116] LiOH (0.34 g, 14.191 mmol) was added to a solution of 1-17 (1.5 g, 5.7 mmol), THF (9.3 mL), and water (4.6 mL) in a round bottom flask, and the mixture stirred at rt for 4 h. The THF was evaporated and the reaction mixture was then treated with 1 M aqueous HCI until pH 1 until a white precipitate was formed. The solid was filtered and dried to obtain 1-16 (1190 mg, 79% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.47 (d, J = 6.3 Hz, 1 H), 8.21 (dd, J = 8.8, 6.3 Hz, 1 H), 7.57 - 7.37 (m, 2H), 5.25 (q, J = 7.3 Hz, 1 H), 1.66 (d, J = 7.3 Hz, 3H).LCMS Rt = 0.38 min, 99% (UV), m / z (ES+) = 237.1 ; m / z (ES-) = n.d. (method 12)Synthesis of ethyl 2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)propanoate (I-47) and 2-(7-ethoxy-4- oxoquinazolin-3(4H)-yl)propanoic acid (I-48)Ethyl 2-bromopropionate (1.618 g, 1.160 mL, 1.2 eq, 8.935 mmol) was added to a suspension of 7-ethoxyquinazolin-4(3H)-one [36467-71-7] (1460 mg, 1 eq, 7.446 mmol) and cesium carbonate (6.065 g, 2.5 eq, 18.61 mmol) in dry DMF (15 mL) at room temperature. The reaction mixture was stirred at 50 °C overnight. 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-47 (337 mg, 1.16 mmol, yield 15%, 100% Purity) as a colourless thickoil. The aqueous layer was acidified to pH~2 with aqueous HCI (1 M) and 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 I-48 (1048 mg, 3.9 mmol, yield 52%, 97% Purity) as a brown solid, used without further purification.

[0117] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ethyl 2-(7-fluoro-4-oxoquinazolin-3(4 / 7)-yl)propanoate (1-15)

[0118] Cesium carbonate (2.8 g, 8.8 mmol) was added to a round bottom flask of 100 mL containing a solution consisting of I-20 (0.9 g, 4.4 mmol), ethyl 2-bromopropionate [535-11-5] (860pL, 6.6 mmol) and in DMF (15 mL). The reaction was stirred at rt for 16 hours. The reaction was diluted with water (150 mL) and extracted with EtOAc (50 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 flash chromatography (SiO2, 0:100 to 30:70 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford 1-15 (1 .29 g, 89% yield) as a white solid.1H NMR (400 MHz, DMSO, d6) d 8.57 (s, 1 H), 8.35 (d, J = 8.3 Hz, 1 H), 8.06 (s, 1 H), 7.88 (dd, J = 8.4, 1.6 Hz, 1 H), 5.33 (q, J = 7.2 Hz, 1 H), 4.22 - 4.09 (m, 2H), 1.68 (d, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). LCMS Rt = 1.31 min, 95% (UV), m / z (ES+) = 315.2; m / z (ES-) = n.d. (method 12)Synthesis of ethyl 2-(7-fluoro-4-oxoquinazolin-3(4 / 7)-yl)propanoate (1-17)

[0119] A mixture of 7-fluoroquinazolin-4(3 / - / )-one [16499-57-3] (3.0 g, 18.3 mmol), ethyl 2- bromopropionate [535-11-5] (3.1 mL, 23.8 mmol), CS2CO3 (14.9 g, 45.7 mmol) in DMF (66 mL) was stirred at 50 °C for 2 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 MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 100:0 to 40:60 EtOAC: Heptane) to afford 1-17 (3.85 g, 80% yield). LCMS Rt = 1.61 min, 100% (UV), m / z (ES+) = 265.3; m / z (ES-) = n.d.Synthesis of methyl 2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)butanoate (I-49)Methyl 2-bromobutyrate (217 mg, 138 pL, 1 eq, 1.20 mmol) was added to a suspension of 7- ethoxyquinazolin-4(3H)-one (235 mg, 1 eq, 1.20 mmol) and CS2CO3 (976 mg, 2.5 eq, 3.00 mmol) in dry DMF (5.0 mL) at room temperature. The reaction mixture was stirred at 50 °C overnight. 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 organiclayer 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-49 (88 mg, 0.30 mmol, yield 25%, 100% Purity) as a thick brown oil. Synthesis of methyl 2-(7-chloro-4-oxoquinazolin-3(4H)-yl)butanoate (I-50)Ethyl 2-Bromobutyrate (0.292 mL, 1.99 mmol) was added portionwise to a 50 round-bottomed flask containing a stirred solution of 7-Chloro-4-hydroxyquinazoline (300 mg, 1.66 mmol), cesium carbonate (812 mg, 2.49 mmol) and DMF (5 mL). The reaction was stirred for 1 h at 50 °C to give a brown heterogeneous solution. The mixture was diluted with EtOAc, extracted (2 x 60 mL) and washed with water (20 mL). The organic layer was dried over MgSCL, filtered and concentrate to dryness in vacuo to give a brown solid. The solid was subjected to silica gel chromatography (12 g irregular 40-60 pm; 0-30% Heptane / EtOAc) to yield I-50 (460 mg, 93%) as a white solid.

[0120] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 7-(trifluoromethyl)quinazolin-4(3 / 7)-one (I-20)

[0121] 2-Amino-4-(trifluoromethyl)benzoic acid [402-13-1] (1.0 g, 4.9 mmol) and formamide [75- 12-7] (1.16 mL, 29.25 mmol) were added at rt to a round bottom flask of 25 mL to give an orange suspension. The mixture was stirred for 6 h at 140 °C. Ice was added to give a pale yellow solid. The pale yellow solid was filtered and washed with water (3x10 mL) and dried in vacuo to afford I-20 (939 mg, 89% yield) as a beige solid. LCMS Rt = 0.76 min, 99% (UV), m / z (ES+) = 215.1 ; m / z (ES-) = n.d. (method 12)Synthesis of methyl 4-bromo-2-isocyanobenzoate (I-24)ii. POCI3Et3N, THFI-24

[0122] To a vial was added formic acid [64-18-6] (4.0 mL, 109 mmol), acetic anhydride [108-24- 7] (10 mL, 109 mmol) and it was stirred at 55 °C for 2 h. To a solution of methyl 2-amino-4- bromobenzoate [135484-83-2] (10 g, 4 mmol) in Et20 and heptane was added dropwise formic anhydride. The reaction was stirred at rt for 2 h. before DCM was added. It was extracted and the organic layer was collected and dried over MgSCL. The resulting solid was cooled in THF at 0°C, before POCI3 [10025-87-3] (2.9 mL, 31 mmol) was added. To the resulting mixture was added, dropwise, triethylamine [121-44-8] (8.6 mL, 62 mmol) and it was stirred at 25 °C for 16h. The mixture was concentrated to dryness to afford I-24 (3 g, 80% yield).Synthesis of ethyl 2-fluoro-4-(thiazol-2-yl)aniline (I-25)Bis(triphenylphosphine)palladium(ll) dichloride, DMF

[0123] A mixture of 4-bromo-2-fluoroaniline [367-24-8] (500 mg, 2.63 mmol), 2- (tributylstannyl)thiazole [121359-48-6] (1.24 mL, 3.95 mmol) in DMF (26 mL) was sparged with N2, then bis(triphenylphosphine)palladium(ll) dichloride [13965-03-2] (184 mg, 0.26 mmol) was added and the reaction was heated at 80 °C for 1 h. Then, water was added to the reaction mixture and the aqueous phase extracted three times with EtOAc. The combined organic layers were dried over MgSCL, filtered and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (SiC>2, 100:0 to 90:10 DCM:MeOH) to afford I-25 (270 mg, 44% yield) as a black gum. LCMS Rt = 1.54 min, 90% (UV), m / z (ES+) = 195.1 ; m / z (ES-) = 193.1 (method 2)Synthesis of tert-butyl (R)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanoate (l-26a) and tert-butyl(S)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanoate (l-26b)

[0124] To a stirred solution of 1-16 (202 g, 855 mmol) in tert-butyl acetate (4040 mL) were added 1 ,1 ,1-trifluoro-N-trifluoromethanesulfonylmethanesulfonamide [37595-74-7] (529 g, 1881.44 mmol) in DCM (2020 mL) dropwise at 0°C under N2 atmosphere. The reaction mixture was stirred at 0°C for 3 hours. The mixture was basified to pH 7-8 with Na2COs (aq.). The resulting mixture was extracted with DCM (2x2 L). The combined organic layers were washed with brine (2x2 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(7-fluoro-4-oxoquinazolin-3-yl)propanoate (150 g, 60.00%) as a white solid. The compound tert-butyl 2-(7-fluoro-4-oxoquinazolin-3-yl)propanoate (150 g, 513.15 mmol, 1 eq.) was purified by the following conditions Column: XA CHIRALPAK IA, 5*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH: DCM=3: 1 ; Flow rate: 150 mL / min; Gradient (B%): isocratic 30% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.56; RT2(min): 4.16; Sample Solvent: MEOH: DCM=3: 1 ; Injection Volume: 1.1 mL to afford (70 g, 46.67%) (l-26a, R) and (70 g, 46.67%) (l-26b, S) as a light yellow oil.Synthesis of (2R)-2-(7-fluoro-4-oxoquinazolin-3-yl)propanoic acid (1-16a)

[0125] A solution of l-26a (70 g, 239 mmol) in dioxane (350 mL) and HCI in 1 ,4-dioxane (4.0 M, 1400 mL) was stirred at RT for 24 hours. The product was precipitated by the addition of MTBE (2.5 L). The precipitated solids were collected by filtration and washed with MTBE (3x1 L). This resulted in 1-16a (2R)-2-(7-fluoro-4-oxoquinazolin-3-yl)propanoic acid (51.1215 g, 91.93%) as a white solid.Synthesis of (2S)-2-(7-fluoro-4-oxoquinazolin-3-yl)propanoic acid (1-16b)

[0126] Intermediate 1-16b was synthetized according to the above procedure substituting the starting material as appropriate.Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanoyl chloride (I-27)

[0127] 1-Chloro-N,N,2-trimethylpropenylamine [26189-59-3] (113 pL, 0.854 mmol) was added to a solution of 1-16 (100 mg, 0.423 mmol) in DCE (5 mL). The reaction mixture was stirred at room temperature for 30 min. The volatiles were removed in vacuo to obtain I-28 (107 mg, yield assumed quantitative, purity not determined) as a solid.Synthesis of 2-fluoro-4-(oxazol-2-yl)aniline (I-29)

[0128] 4-Amino-3-fluorophenylboronic acid pinacol ester [819058-34-9] (500 mg, 2.11 mmol), 2-bromooxazole [125533-82-6] (468 mg, 3.16 mmol), potassium phosphate tribasic [7778-53-2] (1.34 g, 6.33 mmol) were dissolved in dioxane (12 ml) and distilled water (4 ml) and sparged with N2 for 10 min, then bis(diphenylphosphino)ferrocene)palladium(ll) dichloride [72287-26-4] (154 mg, 0.211 mmol) was added and the reaction was stirred at 100 °C for 4 hours. Brine was added to the reaction mixture and the aqueous phase extracted twice with EtOAc. The combined organic layers were dried over MgSC>4, filtered and concentrated under vacuum to afford I-29 (358 mg, yield 87%) as a brown oil. LCMS Rt = 1.36 min, 92% (UV), m / z (ES+) = 179.1 (method 2).PREPARATION OF FINAL COMPOUNDSSynthesis of / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4 / - / )-yl)propenamide (F-1)

[0129] TCFH [94790-35-9 ] (485 mg, 1.73 mmol) was added to a 50 mL round-bottomed flask containing a stirring solution, consisting of 1-14 (412 mg, 1.44 mmol), 4-(1-Methyl-1 / 7-pyrazol-3- yl)aniline [916766-82-0] (250 mg, 1.44 mmol), 1-methyl-1 / - / -imidazole (400 pL, 5.04 mmol) in ACN (10 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 purified by column chromatography (SiC>2, 0:100 to 100:0 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford F-1 (377 mg, 58% yield) as a beige solid.Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4 / 7)-yl)-N-(4-(1-methyl-1 / 7-pyrazol-3- yl)phenyl)propenamide (F-2)MeCN

[0130] TCFH [94790-35-9] (0.388 g, 1.383 mmol) was added to a round-bottomed flask containing a stirring solution, consisting of 1-16 (0.27 g, 1.15 mmol), 4-(1-Methyl-1 / 7-pyrazol-3- yl)aniline [916766-82-0 ] (0.2 g, 1.155 mmol), 1-methyl-1H-imidazole [616-47-7] (0.32 mL, 4.03 mmol) in ACN (10 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 purified by column chromatography (SiC>2, 0:100 to 100:0 AcOEt: Heptane). The desired fractions were collected and concentrated to dryness in vacuo. The solid obtained was triturated with diethyl ether and then, it was filtered to afford F-2 (236 mg, 50% yield) as a white solid.Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)propenamide (F-148)

[0131] 3-Amino-2-fluoro-6-(trifluoromethyl)pyridine [117519-15-0] (210 mg, 1.17 mmol) and pyridine (503 mg, 512 pL, 6.36 mmol) were added to a suspension of I-27 (270 mg, 1.06 mmol) in 1 ,2-Dichloroethane (5.0 mL) and the reaction was stirred at room temperature for 2 hours. The solid was isolated by filtration, washing with water, and dried overnight under vacuum at 50 °C to afford F-148 as a white solid.Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)propenamide(F-149)

[0132] F-149 was synthetized according to the procedure described for F-148, substituting the reagent as appropriate.

[0133] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATLI orTATU may be used as coupling reagents, TEA,DIPEA or NMI may be used as bases and DMF may be used as solvent.Synthesis of 2-(7-chloro-4-oxoquinazolin-3(4 / 7)-yl)- / V-(4-(thiazol-2-yl)phenyl)propenamide (F-6)

[0134] A mixture of 7-chloroquinazolin-4(3 / 7)-one [31374-18-2] (80 mg, 0.44 mmol), I-3 (165 mg, 0.53 mmol), CS2CO3 [534-17-8] (216 mg, 0.66 mmol) in DMF (1.3 mL) was stirred at50°C for 2 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. The crude was purified by column chromatography (SiC>2, 0:100 to 100:0 to EtOAc: Heptane) to afford F-6 (70 mg, 38% yield).Synthesis of 2-(7-fluoro-4-oxoquinazolin-3(4 / 7)-yl)- / V-(4-(thiazol-2-yl)phenyl)propenamide (F-7)

[0135] A mixture of 7-fluoroquinazolin-4(3 / 7)-one [16499-57-3] (80 mg, 0.49 mmol), I-3 (182.013 mg, 0.585 mmol), CS2CO3 [534-17-8] (397 mg, 1.22 mmol) in DMF (1.8 mL) was stirred at 50 °C for 2 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 MgSO4 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-7 (41 mg, 21% yield).Synthesis of 2-(7-bromo-4-oxoquinazolin-3(4 / 7)-yl)- / V-(4-(1-methyl-1 / 7-pyrazol-3- yl)phenyl)propanamide (F-8)

[0136] A mixture of 7-bromo-4(3 / 7)-quinazolinone [194851-16-6] (3.38 g, 15 mmol), 1-1 (5.08 g, 16.5 mmol) and CS2CO3 (12.2 g, 37.5 mmol) in DMF (75 mL) was heated at 65°C for 2 hours. The mixture was diluted with water (50 mL), aq. sat. NH4CI (50 mL) and EtOAc (200 mL), upon which a white precipitate started to form. The solids were filtered off and washed with water and Et20 to afford a white solid. The filtrate was transferred to a separation funnel, the phases were separated and the organic phase washed with water (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The solid residue was triturated with ACN and filtered to afford F-8 (2.23 g, 32% yield) as a white solid.Synthesis of rac-(R)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl) propenamide (F-10)A mixture of 7-fluoroquinazolin-4(3h)-one [16499-57-3] (300 mg, 1.828 mmol), I-2 (627.447 mg, 2.01 mmol), CS2CO3 (893.26 mg, 2.742 mmol) in DMF (1.8 mL) was stirred at 50 °C for 2 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) yielding F-10 (180 mg, yield 25%).Synthesis of 2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-444)7-Chloro-8-methyl-4(3 / 7)-quinazolinone (539 mg, 1.726 mmol) was added to a stirred solution of 2-bromo-N-[4-(trifluoromethoxy)phenyl]propanamide (280 mg, 1.439 mmol) and cesium carbonate (703 mg, 2.158 mmol) in DMF (4.3 mL). The reaction was stirred at 50°C for 2h. The reaction was diluted with EtOAc (2 x 20 mL) and washed with water (20 mL). The organic layer was dried over MgSCL, filtered and concentrate to dryness in vacuo to give a brown solid. The solid was subjected to purification by silica gel chromatography (25 g irregular 40-60 pm; 0-70% DCM / Heptane) to give F-444 (10.0 mg, 2%) as a white solid.Synthesis of 2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-485)7-Chloro-8-methyl-4(3 / 7)-quinazolinone 860193-24-4](245 mg, 1.259 mmol) was added to a sealed tube containing a stirred solution of I-37 (476 mg, 1.511 mmol), and cesium carbonate (613 mg, 1.884 mmol) in DMF (3.7 mL). The reaction was stirred for 1.5 h at 50 °C to give a beige heterogeneous solution. The mixture was diluted with EtOAc (3 x 20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and concentrate to dryness in vacuo to give a yellow oil. The solid was subjected to purification by silica gel chromatography (25 g, dry load silica 40-60 pm 60 A; 0-15% EtOAc / heptane) to give a white solid, which was subjected to HPLC (Water Xbridge 10 pm (C18), 30 x 100 mm column, gradient 41-83% (v / v) ACN / water (25 mM NH4HCO3)). The compound-containing fractions were collected and lyophilized to yield F-485 (318 mg, 57%) as a white solid.Synthesis of N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)butanamide (F-433)I-20 (130 mg, 0.607 mmol) was added portionwise to a stirred solution of I-42 (240 mg, 0.728 mmol), and cesium carbonate (297 mg, 0.911 mmol) in DMF (1.8 mL). The reaction was stirred for 1 h at 50 °C to give a beige heterogeneous solution. The mixture was diluted with EtOAc (2 x 60 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and concentrate to dryness in vacuo to give a brown solid. The solid was subjected to purification by silica gel chromatography (25 g irregular 40-60 pm; 0-20% Heptane / EtOAc) to give a white solid, which was subjected to HPLC (Water Xbridge 5 pm (C18), 30 x 100 mm column, gradient 45-85% (v / v) ACN / water (25 mM NH4HCO3)). The compound-containing fractions were lyophilized to yield F-433 (199 mg, 70%) as a white solid.

[0137] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of / V-(2-cyano-4-(trifluoromethoxy)phenyl)-2-(7-fluoro-4-oxoquinazolin-3(4 / 7)- yl)propenamide (F-39)

[0138] 1-17 (100 mg, 0.38 mmol) and 5-amino-2-(trifluoromethoxy)benzonitrile [1261523-71-0] (76.5 mg, 0.38 mmol) were dissolved in THF (3 mL). The resulting mixture was purged with N2 and cooled to 0 °C. Then LiHDMS (0.76 mL, 0.76 mmol, 1 M in THF) was added dropwise to the mixture. The resulting mixture was stirred at 0 °C and warm to rt for 3 h. The mixture was quenched with aq.NH4CI (15 mL) and H2O (10 mL), then extracted with EtOAc (15 mL x3). The combined extracts were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiC>2, 0:100 to 5:95 MeOH:DCM) to afford F-39 (87 mg, 55% yield) as a white powder.Synthesis of 2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)butanamide (F-188)□HMDS solution (1 M in THF) (2.036 mL, 2.036 mmol) was added dropwise via syringe to a stirred solution of I-50 (300 mg, 1.018 mmol), and 2-fluoro-6-(trifluoromethyl)-3-pyridinamine (183.3 mg, 1.018 mmol) indry THF (10.2 mL) at 0 °C and under N2 atmosphere to give an orange homogeneous solution. This mixture was stirred at rt for 16 h to give an orange homogeneous solution. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (60 mL). Thecombined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give a brown solid. The product was subjected to purification by silica gel chromatography (25 g silica irregular 40-60 pm 60 A; 0-20% Heptane / EtOAc) to yield F-188 (170 mg, 38%) as a white solid.

[0139] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of 2-(7-bromo-4-oxoquinazolin-3(4 / 7)-yl)-3-hydroxy- / V-(4-(1-methyl-1 / 7-pyrazol-3- yl)phenyl)propanamide (F-45),

[0140] I-6 (41 mg, 0.17 mmol), I-24 (76 mg, 0.25 mmol) and Cu(OAc)2 (3 mg, 0.02 mmol) were charged to a 4 mL screwcap vial. Anisole (2 mL) was added, followed by triethylamine (0.094 mL, 0.68 mmol). The resulting mixture was stirred at 65 °C for 16 hours. The mixture was cooled down to room temperature, diluted with aq. sat. NaHCCh (40 mL) and extracted with DCM (3 x 50 mL). The combined organic fractions were dried over MgSCL 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-45 (46 mg, 0.098 mmol, 58% yield) as a white solid.

[0141] Additional analogs were synthesized starting from I-24 according to the above procedure substituting the reagents as appropriate.Synthesis of A / - (4- ( 1 -methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxo-7-phenylquinazolin-3(4 / 7)- yl)propanamide (F-49)

[0142] F-8 (50 mg, 0.11 mmol), phenylboronic acid [98-80-6] (20.2 mmol, 0.17 mmol),PdCh(dppf) (8 mg, 0.01 mmol) and K3PO4 (70 mg, 0.33 mmol) were charged to a microwave vial.The vial was evacuated and backfilled with nitrogen before degassed 1 ,4-dioxane (1.5 mL) and water (0.15 mL) were added. The resulting mixture was heated at 100 °C for 1 hour. The mixture was cooled down to room temperature, diluted with DCM and filtered over celite. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiC>2, 50:50 to 100:0 EtOAc: Heptanes) to afford F-49 (43 mg, 0.095 mmol, 96% yield) as a white solid.Synthesis of 2-(7-(cyclobutyl(methyl)amino)-4-oxoquinazolin-3(4 / 7)-yl)- / \ / -(4-(1-methyl-1 / 7- pyrazol-3-yl)phenyl)propenamide (F-50)Dioxane

[0143] In the glove box, a solution of F-8 (45 mg, 0.1 mmol), N-methylcyclobutanamine (24.4 mg, 0.2 mmol) and RuPhosPdG4 (8.5 mg, 0.01 mmol) was prepared in dioxane (1 mL). CS2CO3 (98 mg, 0.3 mmol) was added as a solid. The vials were sealed, removed from the glove box and heated at 85 °C for 18 h. After reaction completion, the reaction mixtures were diluted with ethyl acetate (2 mL) and water (1 mL). An aqueous extraction was performed on the Tecan™ liquid handler with ethyl acetate (x3) and water. The organic layers from the extraction wereevaporated to dryness and dissolved in DMSO (0.6 mL) and MeOH (2.4 mL). The solutions were filtered and submitted for HTP. 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-50 (6.85 mg, 15% yield).

[0144] Additional analogs were synthesized according to the above procedure starting from F-8 substituting the reagents as appropriate.Synthesis of 2-(7-(2-methoxybutyl)-4-oxoquinazolin-3(4 / 7)-yl)-N-(4-(1-methyl-1 / 7-pyrazol-3- yl)phenyl)propenamide (F-71)

[0145] In the glove box, a solution of scaffold F-8 (33.9 mg, 0.075 mmol), (4,4'-di-tert- butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(ll I) hexafluorophosphate [676525-77-2] (2.0 mg, 2.2 pmol), Bis(1 , 1 -dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide (2.2 mg, 4.5 pmol), quinuclidine (16.7 mg, 0.15 mmol) and phthalimide (11.0 mg, 0.1 mmol) was prepared in DMSO (1 mL). In a separate vial, 2-methoxybutan-1-ol [15467-25-1] (15.8 mg, 0.15 mmol) and 5,7-ditert- butyl-3-phenyl-1 ,3-benzoxazol-3-ium tetrafluoroborate (79 mg, 0.2 mmol) were suspended in dioxane (1 mL), and pyridine (16 pL, 0.2 mmol) was added. The mixture was stirred for 15 min, and the mixture was filtered via syringe filter into the scaffold solution. The reaction mixtures were sealed, removed from the glove box and irradiated at 445 nm, power setting 3 / 5 on the Lumidox® lamp plate for 18 h. After reaction completion, volatiles were removed under a stream of nitrogen, and then diluted with ethyl acetate (2 mL) and water (1 mL). An aqueous extraction was performed on the Tecan™ liquid handler with ethyl acetate (x3) and water. The organic layers from the extraction were evaporated to dryness and dissolved in DMSO (0.6 mL) and MeOH (2.4 mL). The solutions were filtered and submitted for HTP. 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-71 (5.2 mg, 15% yield).

[0146] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.

[0147] In the table above, for example F-85 and F-86, the following method may be used: a purification was performed via preparative SFC (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 20mM NH4OH). The skilled person can also identify other methods / techniques.Synthesis of 2-(7-((-1 ,1-difluoropropan-2-yl)oxy)-4-oxoquinazolin-3(4 / 7)-yl)- / V-(4-(1-methyl-1 / 7- pyrazol-3-yl)phenyl)propenamide (F-93)

[0148] The electrolysis was performed in 2 undivided cells using a Vapourtec™ IonElectrochemical Flow Reactors (reactor volume = 2 x 0.15 mL, spacer membrane 0.125 mm) using 4 glassy carbon (GC) electrodes (active surface area: A = 2 x 12 cm2) connected to a function generator BK precision 4055B and a multimeter. The 2 cells are separated by 20 cm tubbing of 1 mm diameter (0.15 mL volume). A solution of F-8 (27.1 mg, 0.06 mmol), 1 ,1- difluoropropan-2-ol [431-04-9] (19.3 mg, 0.2 mmol), quinuclidine (17.8 mg, 0.16 mmol) in anhydrous DMF (1 mL) was placed in 8 mL vial screw cap with hole with PTFE / silicone septum. A stock solution of NiCh.glyme (0.009 M, 15 mol%) and 4,4'-dimethoxy-2,2'-bipyridine (0.011 M, 18 mol%) in anhydrous DMF. Both stock solutions were injected via two 1-mL sample loops (0.06mmol of aryl halide injected, 0.05 M final cone.). Then, solutions were pumped into a chip mixer (0.2 mL) and the electrochemical reactor. The reactor temperature was set at 22 °C with the total flow rate of 0.05 mL / min, the voltage was set at 4 V (8.0 Vpp) with an alternating polarity frequency of 1.5 Hz. The solution was collected automatically into a glass vial from 50 min (after the pumps started) to 130 min (4 mL). The reactor, needle and sample loops were automatically rinsed for 3 min with DMF at a 0.5 mL / min flow rate and the following reaction automatically starts. The solvent was removed under nitrogen blowing at 45 °C overnight. Crude mixtures were dissolved in 600 pL of DMSO, filtered over DMT resin for nickel scavenging. The resin was washed 2 times with ACN (1.2 mL). 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 affordF-93 (2.43 mg, 9% yield).

[0149] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of (*R)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxoquinazolin-3(4 / 7)- yl)propenamide (F-101) and (*S)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxoquinazolin- 3(4 / 7)-yl)propenamide (F-102)F-102

[0150] A mixture of 4-hydroxyquinazoline [491-36-1] (100 mg, 0.68 mmol), 1-1 (232 mg, 0.75 mmol) and CS2CO3 [534-17-8] (557 mg, 1.71 mmol) in DMF (3.5 mL) was heated at 65 °C for overnight. The mixture was diluted with EtOAc and washed with aq. sat. NH4CI. The organic layer was separated and the water layer was extracted again with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, silica, 100:0 to 20:80 heptane:EtOAc). The resulting racemic product was purified by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to afford F-101 (80 mg, 31% yield %) and F-102 (40 mg, 16% yield).Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of (*S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(4-oxo-7-(trifluoromethoxy)- quinazolin-3(4H)-yl)propanamide (F-195) and (*R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(4-oxo-7-(trifluoromethoxy)-quinazolin-3(4H)-yl)propanamide (F-196)

[0151] LiHMDS 1 M in THF (247 mg, 1.48 mL, 2.5 eq, 1.48 mmol) was added to a stirring solution of I-45 (224 mg, 1 eq, 590 pmol) and 3-amino-2-fluoro-6-(trifluoromethyl)pyridine [117519-15-0](106 mg, 1 eq, 590 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). The resulting racemic product was purified by Prep SFC (Stationary phase: OJ 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-196 (45 mg, 94 pmol, 16% yield) and F-195 (44 mg, 95 pmol, 16% yield).Synthesis of (R)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)propanamide (F-451) and (S)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)propanamide (F-452)□ HMDS (194 mg, 1.16 mL, 1.0 molar, 2 eq, 1.16 mmol) was added dropwise to a solution of I-47 (168 mg, 1 eq, 579 pmol) and 3-amino-2-fluoro-6-(trifluoromethyl)pyridine (104 mg, 1 eq, 579 pmol) in dry THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture 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 25 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 IH 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-451 (78 mg, 0.18 mmol, yield 32%, 100% Purity) and F-452 (78 mg, 0.18 mmol, yield31%, 98% Purity), both as white solids.Synthesis of (R)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)butanamide (F-473) and (S)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)butanamide (F-474)□HMDS (0.10 g, 0.61 mL, 1.0 molar, 2 eq, 0.61 mmol) was added dropwise to a solution of I-49 (88 mg, 1 eq, 0.30 mmol) and 2-fluoro-6-(trifluoromethyl)pyridin-3-amine (55 mg, 1 eq, 0.30 mmol) in dry THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture 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 onExtrelut NT3, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage Star 25 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 IH 20 x 250 mm, Mobile phase: CO2, EtOH) to give F- 473 (46 mg, 0.10 mmol, yield 34%, 97% Purity) and F-474 (45 mg, 0.10 mmol, yield 34%, 100% Purity), both as white solids.Additional analogs were synthesized according to the above procedure substituting the reagentsSynthesis of (*S)-N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(7-fluoro-4-oxoquinazolin-3(4H)- yl)propanamide (F-197) and (*R)-N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(7-fluoro-4- oxoquinazolin-3(4H)-yl)propanamide (F-200)1 -methylimidazole [616-47-7] (118.9 pL, 1.5 mmol) and TCFH [207915-99-9] (158.5 mg, 0.56 mmol) were added to a solution of 1-16 (100 mg, 0.37 mmol) and 2-fluoro-4- (trifluoromethyl)aniline [69409-98-9] (80.9 mg, 0.45 mmol) in ACN (1.8 mL). The reaction mixture was stirred for 4 h rt. The mixture was diluted with ACN and filtered. A purification wasperformed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 30x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN). The resulting racemic product was purified by Prep SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% iPrNH2) to give F-197 (9 mg, 6% yield) and F-200 (9 mg, 6% yield).Synthesis of (R)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-479) and (S)-2-(7-ethoxy-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-480)HATLI (258 mg, 1.3 eq, 678 pmol) was added to a solution of I-48 (141 mg, 1 eq, 521 pmol), 4- (trifluoromethoxy)aniline (92.4 mg, 71 pL, 1 eq, 521 pmol), and DIPEA (135 mg, 182 pL, 2 eq, 1.04 mmol) in dry Acetonitrile (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue 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 Star 25 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: OD 20 x 250 mm, Mobile phase: CO2, EtOH) to give F-479 (46 mg, 0.11 mmol, yield 21 %, 100% Purity) and F-480 (44 mg, 0.10 mmol, yield 20%, 100% Purity), both as white solids.Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATU, TATU or TsP (propylphoshonic anhydride) may be used as coupling reagents, TEA, DIPEA or NMI may be used as bases and DMF may be used as solvent.Synthesis of (*R)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4 / 7)-yl)propenamide (F-103) and (*S)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(4-oxo-7- (trifluoromethyl)quinazolin-3(4 / 7)-yl)propenamide (F-104)

[0152] The racemic F-1 (377 mg, 0.85 mmol) was purified by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to afford F-103 (126 mg, 33% yield) and F-104 (127 mg, 33% yield).Synthesis of (R)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy) phenyl)propenamide (F-128) and (S)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propenamide (F-127)The racemic F-10 (170 mg) was purified by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to afford F-127 (73 mg,)( OR: -21.380(589 nm, c 0.29 w / v %, DMF, 20 °C)) and F-128 (70 mg) (OR:+24.670(589 nm, c 0.3 w / v %, DMF, 20 °C))Synthesis of (R)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)propanamide (F-151) and (S)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-The racemic F-148 (55 mg) was purified by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to yield two fractions: the first fraction was collected as compound F-151 and the second fraction was collected as compound F-152 as white solids.Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)butanamide (F-193) and (S)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)butanamide (F-192)F-188 (150 mg) was subjected to preparative SFC (Stationary phase: amylose-A 5 pm 250 x 30 mm, Mobile phase: 20% MeOH + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-192 (30 mg, 7%) and the second fraction was collected as compound F-193 (57 mg, 13%), both as white solids.Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)butanamide (F-441) and (S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)butanamide (F-440)Racemic F-433 (174 mg) was subjected to preparative SFC (Stationary phase: amylose 3 5 pm 250 x 30 mm, Mobile phase: 25% EtOH + 0.1% DEA) and the 2 isolated fractions were then repurified by HPLC (Water Xbridge 5 pm (C18), 30 x 100 mm column, gradient 55-95% (v / v) ACN / water (25 mM NH4HCO3)) to yield two fractions, which were lyophilized. The first fraction was collected as compound F-441 (65 mg, 23%) and the second fraction was collected as compound F-440 (59 mg, 21%) both as yellow solids.Synthesis of (R)-2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-467) and (S)-2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-468)Racemic F-444 (352 mg) was purified by preparative SFC (Stationary phase: Phenomenex Lux Cellulose-1 5pm 150 x 21.2 mm, Mobile phase: CO2, ISO 35% 2-propanol + 0.1% DEA). Two compound-containing fractions were collected and lyophilized to give a first fraction collected as compound F-468 (91.8 mg, 15%) and a second fraction collected as compound F-467 (75.3 mg, 12%), as white solids.Synthesis of (R)-2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-487) and (S)-2-(7-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-486)F-485 (308 mg) was subjected to preparative SFC (Stationary phase: Amylose-1 5 pm 250 x 30 mm, Mobile phase: 40% 2-Prop + 0.1% DEA). The 2 collected fractions were repurified by HPLC (Water Xbridge 5 pm (C18), 30 x 100 mm column, gradient 55-100% (v / v) MeOH / water (25 mM NH4HCO3)). The compound-containing fractions were lyophilized and the first fraction was collected as compound F-486 (43.2 mg, 8%) as a white solid and the second fraction was collected as F-487 (70.1 mg, 13%) as a white solid.

[0153] 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).Additional analogues were synthesized according to one of the above procedures substituting the reagents, the reactants and the purification methods as appropriate.ADDITIONAL CHARACTERISING DATA - LC-MS LCMS:ANALYTICAL SFC 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) ASSAY

[0154] Inducible human TMEM175 cells were seeded at 6,000 cells / well in a PDL-coated black, clear bottomed 1536 well plate (Corning 9141 BC). 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 room temperature. 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 1-10s. 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 HEPES 5mM D (+) glucose 1 mM MgCL 2mM CaCLFLIPR Data of selected compounds: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 >12 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 mLconical 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.A selection of compounds was tested 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 1 N or HCI 1 N. 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 INtestinal 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. Procedure 1): 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. Procedure 2): Following terminal blood sample collection (32pL), animals were decapitated following CO2 or isoflurane induction, brains collected and stored at -20°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 samplepreparation 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 each experiment, 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; 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-salkyl, Ci-salkyloxy, 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; 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-salkyl, Ci-salkyloxy, 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-salkyl, haloCi-salkyl and Ci-salkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-salkyl, haloCi-salkyl and Ci-salkyloxy;(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 the group consisting of 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-salkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from H, halo, Ci-salkyl, Ci-salkyloxy, phenyl, and cyano;R1Dis H or Ci-salkyl;R2represents Ci-salkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;R3is 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 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 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, C3- ecycloalkyl, Ci-3alkyloxyCi-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, C3- ecycloalkyl, Ci-3alkyloxyCi-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 notfor use in activating TMEM175.

2. The compound for use according to claim 1, for use in a method of treating Parkinson’s disease.

3. 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; 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-salkyl, Ci-salkyloxy, 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; 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-salkyl, Ci-salkyloxy, 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-salkyl, haloCi-salkyl and Ci-salkyloxy; said C3- 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-salkyl, haloCi-salkyl and Ci-salkyloxy;(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 the group consisting of 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-salkyloxy, (Ci-3alkyloxy)Ci-3alkyl, cyclopropyl, OH, and CH3C(=O)-;R1Band R1Care each independently selected from H, halo, Ci-salkyl, Ci-salkyloxy, phenyl, and cyano;R1Dis H or Ci-salkyl;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; or cyclopropyl; ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of H; chloro; haloCi-4alkyl; haloCi-4alkyloxy; (Ci- 4alkyloxy)Ci-4alkyl; SF5; SCF3; Cs-ecycloalkyl optionally substituted with one or two substituents, each independently selected from the group consisting of 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, C3- ecycloalkyl and cyano; -O-(5-membered heteroaryl) which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl, haloCi-salkyl, C1- 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-3alkyloxyCi-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, C3- ecycloalkyl, Ci-3alkyloxyCi-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 not4. The compound according to claim 3, having Formula (I)or a stereoisomeric form thereof, as described herein, whereinX represents CH, CCH3 or N;R1Ais selected from the group consisting of 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; a 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-salkyl, Ci-salkyloxy, 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, Cisalkyl, haloCi-salkyl and Ci-salkyloxy; a 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-salkyl, Ci-salkyloxy, 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 halo, Ci-salkyl, haloCi-salkyl and Ci-salkyloxy;Cs-ecycloalkyloxy optionally substituted with one or two substituents each independently selected from halo, Ci-salkyl, haloCi-salkyl and Ci-salkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;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-salkyl, Ci-salkyloxy, haloCi-salkyl and (=0);phenyl; andNR1AaR1Ab; whereinR1Aais selected from 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 the group consisting of 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(=0)-;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents Ci-3alkyl, which is unsubstituted or substituted with -OH, -OCH3, cyano, or with 1 , 2 or 3 fluoro substituents; 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; phenyl; and 5- or 6-membered heterocyclyl containing a oxygen or a nitrogen atom; and R4Ais, when present at carbon a and / or carbon b, independently selected at each position from the group consisting of halo 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.

5. The compound according to claim 4, whereinX represents CH, CCH3 or N;R1Ais selected from the group consisting of halo;Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo;Ci-ealkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo;R1Band R1Care each independently selected from H or halo;R1Drepresents H;R2represents 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 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.

6. The compound according to any one of claims 3 to 5, wherein R1Ais selected from the group consisting of halo, haloCi-4alkyl, haloCi-4alkyloxy (for example, trifluoromethoxy), and C1- 4alkyloxy.

7. The compound according to any one of claims 4 to 6, wherein R2is methyl or ethyl.

8. The compound according to any one of claims 4 to 7, wherein the compound has the formula (IB)or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 4, wherein the compound isor a pharmaceutically acceptable salt thereof.

10. The compound according to claim 4, wherein the compound isor a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound as defined in any one of claims 4 to10, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

12. The compound as claimed in any one of claims 4 to 10, for use in a method of reducing aSyn aggregation in a tissue, or a subject in vitro or in vivo, comprising administering a compound of Formula (I) as defined in any one of claims 4 to 10, or a pharmaceutical composition as defined in claim 18.

13. The compound as claimed in any one of claims 4 to 10, for use in activating TMEM175.

14. The compound as claimed in any one of claims 4 to 10 or a pharmaceutical composition as claimed in claim 11 , for use in a method of treating Parkinson’s disease.

15. 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 defined in any one of claims 1 to 17, or a pharmaceutical composition as defined in claim 18.

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