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

Abstract

The present invention relates to compounds of formula (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, 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(Cs-6cycloalkyl)C1-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl or C1-3alkyloxy;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, haloC1-3alkyl and (=O);R1Brepresents H or halo;R1Crepresents H, methyl, or halo;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 Ci-4alkyl, haloC1-3alkyl, Ci-4alkyloxy, 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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl 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

[0006] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable carrier or diluent.In a further aspect, the invention relates to a method of activating TMEM175 using a compound of Formula (I)O R2Hor a stereoisomeric form thereof, whereinX 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl 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, haloC1-3alkyl and (=O);R1Brepresents H or halo;R1Crepresents H, methyl, or halo;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 Ci-4alkyl, haloC1-3alkyl, Ci-4alkyloxy, 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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl 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 notoFor to a compound of Formula (I) as described herein for use in activating TMEM175. In a yet further aspect, the invention relates to a method of reducing aSyn aggregation using a compound of Formula (I) as described herein, or to a compound of Formula (I) as described herein for use in the reduction of aSyn aggregation. In a further aspect, the invention relates to method of treating Parkinson’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as described herein. In another aspect, the invention relates to a compound of Formula (I) as described herein, for use as a medicament, or to a compound of Formula (I) as described herein, for use in the treatment of Parkinson’s disease. The invention also relates to the use of a compound according to the general Formula (I) as described herein, for the manufacture of a medicament, in particular, for the treatment of Parkinson’s disease.DESCRIPTION OF THE FIGURESFigure 1 depicts the structure of the TMEM175 ligand-bound complex with a representative analogue obtained by cryo electron microscopy at a resolution of 2.90 Å.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.

[0007] In a particular embodiment, the invention relates to compounds of Formula (I)O R2Hor a stereoisomeric form thereof, as described herein, whereinX represents CH 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;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, haloC1-3alkyl and (=O);R1Brepresents H or Br;R1Crepresents H, methyl or halo, in particular H, or methyl;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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof,with the proviso that the compound is noto

[0008] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl; R1Bis H or Br;R1Crepresents H or halo, in particular 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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a and / or carbon b;R4Brepresents independently, halo or Ci -4al kyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof,with the proviso that the compound is not

[0009] In a further embodiment, the invention relates to a compound of Formula (I), or a steroisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, fluoro, chloro, methyl, trifluoromethyl and methoxy;R1Bis H;R1Crepresents 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 and oxazolyl, each of which may be unsubstituted or substituted with one or two substituents each independently selected from methyl and methoxy;R4Arepresents fluoro when present at either of carbon a and / or carbon b;R4Brepresents fluoro when present at carbon c and / or carbon d;m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof,with the proviso that the compound is not

[0010] In a further embodiment, the invention relates to a compound of Formula (I)

[0011] or a steroisomeric form thereof, as described herein, whereinX represents CH 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O);R1Brepresents H or Br;R1Crepresents H, methyl, or halo;R2represents C1-3alkyl;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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0012] In a further embodiment, the invention relates to a compound of Formula (I), or a steroisomeric form thereof, as described herein, whereinX represents CH 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O);R1Brepresents H or Br;R1Crepresents H, or methyl;R2represents C1-3alkyl;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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0013] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl; R1Bis H or Br;R1Crepresents H, methyl, or halo;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;R4Arepresents independently, halo when present at carbon a and / or carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0014] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl; R1Bis H or Br;R1Crepresents 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;R4Arepresents independently, halo when present at carbon a and / or carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0015] In a further embodiment, the invention relates to a compound of Formula (I), or a steroisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, fluoro, chloro, methyl, trifluoromethyl, methoxy, ethoxy and isopropoxy;R1Bis H;R1Crepresents H, methyl, or halo;R2represents methyl or ethyl;ring A represents a phenyl or a pyridinyl;R3is selected from the group consisting of difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy;R4Arepresents fluoro when present at either of carbon a and / or carbon b;R4Brepresents fluoro when present at carbon c and / or carbon d;m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0016] In a further embodiment, the invention relates to a compound of Formula (I), or a steroisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of H, fluoro, chloro, methyl, trifluoromethyl and methoxy;R1Bis H;R1Crepresents 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;R4Arepresents fluoro when present at either of carbon a and / or carbon b;R4Brepresents fluoro when present at carbon c and / or carbon d;m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0017] In a further embodiment, the invention relates to a compound of Formula (I), or a steroisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of fluoro, chloro, and trifluoromethyl;R1Bis H;R1Crepresents H;R2represents methyl; andwhereinR3is selected from the group consisting of difluoromethoxy and trifluoromethoxyR4Arepresents fluoro when present at either of carbon a and / or carbon b;m represents 0, 1 or 2;or a pharmaceutically acceptable salt thereof.

[0018] In another embodiment, the present invention relates to a compound having Formula (I)O R2Hor a stereoisomeric form thereof, whereinX represents CH, CCH3 or N;R1Ais selected from the group consisting ofCi-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom; C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl 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, haloC1-3alkyl and (=O);R1Brepresents H or halo;R1Crepresents H, methyl, or halo;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 haloC1-3alkyl, 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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl 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.

[0019] In a particular embodiment, the invention relates to compounds of Formula (I)O R2Hor a stereoisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting ofCi-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O);R1Brepresents H or Br;R1Crepresents H, or methyl;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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof,

[0020] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents CH or N;R1Ais selected from the group consisting of Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl;R1Bis H or Br;R1Crepresents 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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a and / or carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0021] Therefore, in one aspect, the present invention relates to a compound having Formula (I)or a stereoisomeric form thereof, whereinX represents CCH3 or N, in particular 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy;(Ci-4alkyloxy)Ci-4alkyl;(Ci-4alkyloxy)Ci-4alkyloxy;(Cs-6cycloalkyl)C1-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl or C1-3alkyloxy;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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O);R1Brepresents H or halo;R1Crepresents H, methyl, or halo;R2represents C1-3alkyl;ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms; R3is selected from the group consisting of Ci-4alkyl, haloC1-3alkyl, Ci-4alkyloxy, 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;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl 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.

[0022] In a particular embodiment, the invention relates to compounds of Formula (I)O R2Hor a stereoisomeric form thereof, as described herein, 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; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl 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, C1-3alkyl, C1-3alkyloxy, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-3alkyl, haloC1-3alkyl and C1-3alkyloxy; a 5- or 6-membered heterocyclyl containing one or twoheteroatoms 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, haloC1-3alkyl and (=O); anda 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy;C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and 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, haloC1-3alkyl and (=O);R1Brepresents H or Br;R1Crepresents H, or methyl;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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0023] In a particular embodiment, the invention relates to compounds of Formula (I), or a stereoisomeric form thereof, as described herein, whereinX represents N;R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl; R1Bis H or Br;R1Crepresents 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 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;R4Arepresents independently, halo when present at carbon a and / or carbon b;R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d; m represents 0, 1 or 2;n represents 0 or 1;or a pharmaceutically acceptable salt thereof.

[0024] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2represents methyl.

[0025] In a particular embodiment, the invention relates to a compound of Formula (I) as described herein, wherein R2represents ethyl.

[0026] In a further particular embodiment, the compound of Formula (I) as described herein,has the Formula (IA)

[0027] In a further particular embodiment, the compound of Formula (I) as described herein,has the Formula (IB)

[0028] In a further particular embodiment, the compound of Formula (IA) has in particular the structure according to Formula (IA-1) or (IA-2)

[0029] In a further particular embodiment, the compound of Formula (IB) has in particular the structure according to Formula (IB-1) or (IB-2)

[0030] In a further particular embodiment, the invention relates to a compound of Formula (I), as described herein, wherein R3is not Ci-4alkyl or 5-membered heteroaryl.

[0031] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isF FF For a pharmaceutically acceptable salt thereof.

[0032] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isor a pharmaceutically acceptable salt thereof.

[0033] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0034] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isFF, or For a pharmaceutically acceptable salt thereof.

[0035] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0036] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isor a pharmaceutically acceptable salt thereof.5

[0037] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0038] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isor a pharmaceutically acceptable salt thereof.

[0039] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isor a pharmaceutically acceptable salt thereof.

[0040] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isor a pharmaceutically acceptable salt thereof.

[0041] In a further particular embodiment, the invention relates to a compound of Formula (I), 5 wherein the compound isFFFF FFor a pharmaceutically acceptable salt thereof.

[0042] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0043] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isFFn FF For a pharmaceutically acceptable salt thereof.

[0044] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0045] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0046] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0047] In a further particular embodiment, the invention relates to a compound of Formula (I), wherein the compound isor a pharmaceutically acceptable salt thereof.

[0048] As already mentioned, the compounds of Formula (I) as described herein, and compositions comprising the compounds of Formula (I), can be used for activating ion channel TMEM175. In particular, the compounds of Formula (I) as described herein, may be used for reducing aSyn aggregation in vitro or in vivo. In particular, the invention relates to a method of reducing aSyn aggregation in a tissue, or a subject in vitro or in vivo, comprising administering a compound of Formula (I). In another aspect, the invention relates to a compound of Formula (I) as described herein, for use in the reduction of aggregation of aSyn in a tissue, or a subject in vitro or in vivo, in particular a subject in vivo.DEFINITIONS

[0049] 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.

[0050] ‘Cy-qcycloalkyl’ (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 cylic structure through a common carbon atom.

[0051] The term ‘halo’, when used herein, preferably includes fluoro, chloro, bromo and iodo, in particular fluoro, chloro or bromo, in particular fluoro or chloro.

[0052] ‘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.

[0053] ‘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.

[0054] The symbol ” represents a chemical bond with point of attachment, wherein thepoint of attachment is

[0055] The symbol ■ is used as meaning the same spatial arrangement in chemical structures shown herein. Analogously, the symbol >1is used as meaning the same spatial arrangement in chemical structures shown herein.

[0056] 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.

[0057] 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’.

[0058] ‘The term ‘6-membered heteroaryl containing one or two nitrogen atoms’ represents a 6-membered heteroaromatic ring containing one or two nitrogen atoms; particular examples of such rings include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0059] 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.

[0060] 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).

[0061] 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.

[0062] 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.

[0063] 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 afree 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.

[0064] In one embodiment, the invention relates to compounds of Formula (I) as defined herein, in free base form.

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

[0066] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0067] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0068] The instant compounds may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond.

[0069] 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.

[0070] 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.

[0071] Absolute configurations are specified according to the Cahn-Ingold-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.

[0072] 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 preferablyless 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.

[0073] The compounds may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents.

[0074] 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

[0075] 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.

[0076] 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.

[0077] 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).

[0078] Final compounds according to Formula (I) as described herein can be prepared:(IV)A = Ph- or 6-membered heteroaryl- LG = Br or Cl

[0079] 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;

[0080] Intermediates of Formula (III) can be prepared by reacting an Intermediate of Formula (IV) with an intermediate of Formula (V) in presence of a suitable base such as, for example, N, N-diisopropylethylamine, in a suitable solvent such as, for example, dichloromethane, at a suitable temperature such as, for example, 0 °C;

[0081] Alternatively, final compounds according to Formula (I) can be prepared:A = Ph- or 6-membered heteroaryl-

[0082] 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 (HATU) or O-(7-Azabenzotriazole-1-yl)-N, N, N’, N’-tetramethyluronium tetrafluoroborate (TATU) or Chloro-N, N, N', N'-tetramethylformamidinium Hexafluorophosphate (TCFH), with a suitable base such as, for example, 1-methyl-1H-imidazole or triethylamine, in a suitable solvent such as, for example, dichloromethane or acetonitrile, at a suitable temperature such as, for example, room temperature;

[0083] 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, ina suitable solvent such as, for example, tetrahydrofuran or methanol, at a suitable temperature such as, for example, room temperature;

[0084] Intermediate of Formula (VII) can be prepared by reacting the Intermediate of Formula (IX) with an intermediate of Formula (VIII) in presence of a suitable base such as, for example, for example, cesium carbonate, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 50°C;

[0085] Intermediate compounds according to Formula (IX) can be prepared:

[0086] By reacting an intermediate of Formula (X) in presence of a suitable acid such as, for example trifluoroacetic acid at a suitable temperature such as, for example, 100°C;

[0087] Intermediate of Formula (X) can be prepared by reacting the Intermediate of Formula (XII) with an intermediate of Formula (XI) in presence of a suitable base such as, for example potassium carbonate, in presence of a suitable catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0), in presence of a suitable ligand such as, for example, tricyclohexylphosphine, in a suitable solvent such as, for example, dioxane and water, at a suitable temperature such as, for example, 90°C;

[0088] Intermediate compounds according to Formula (IX) can be prepared:

[0089] By reacting an intermediate of Formula (XIV) in presence of a suitable base such as, for example sodium hydride, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example 80°C;

[0090] Intermediate of Formula (XIV) can be prepared by reacting an intermediate of Formula (XV) in presence of a N, N-dimethylformamide dimethyl acetal, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, 80°C;

[0091] Final compounds according to Formula (la) and to Formula (lb) can be prepared:A = Ph- or 6-membered heteroaryl-

[0092] By purifying a racemic intermediate of Formula (I) by a suitable method such as, for example, supercritical fluid chromatography or crystallization;

[0093] Alternatively, final compounds according to Formula (XVI) can be prepared:(XVII) (XVI)A = Ph- or 6-membered heteroaryl-

[0094] By reacting an Intermediate of Formula (XVII) with an intermediate of Formula (V) in presence of a suitable coupling agent such as, for example, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) or O-(7-Azabenzotriazole-1-yl)-N, N, N’, N’-tetramethyluronium tetrafluoroborate (TATU) or Chloro-N, N, N', N'-tetramethylformamidinium Hexafluorophosphate (TCFH), with a suitable base such as, for example, 1-methyl-1H-imidazole or triethylamine, in a suitable solvent such as, for example, dichloromethane or acetonitrile, at a suitable temperature such as, for example, room temperature;

[0095] Intermediate of Formula (XVII) can be prepared by reacting the Intermediate of Formula (XVIII) in presence of a suitable base such as, for example lithium hydroxide or sodium hydride, in a suitable solvent such as, for example, tetra hydrofuran or methanol, at a suitable temperature such as, for example, room temperature;

[0096] Intermediate of Formula (XVIII) can be prepared by reacting the Intermediate of Formula (XIX) with an intermediate of Formula (VIII) in presence of a suitable base such as, for example, for example, cesium carbonate, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 50°C;

[0097] Alternatively, intermediate compounds according to Formula (XIX) can be prepared:(XXI) (XX) (XIX)

[0098] By reacting an intermediate of Formula (XX) in presence of a suitable base such as, for example sodium hydride, in a suitable solvent such as, for example, dimethylformamide, at a suitable temperature such as, for example, 80°C;

[0099] Intermediate of Formula (XX) can be prepared by reacting an intermediate of Formula (XXI) in presence of a N, N-dimethylformamide dimethyl acetal, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, 80°C;

[0100] Final compounds according to Formula (XVIa) and to Formula (XVIb) can be prepared:(XVI) (XVIa) (XVIb)A = Ph- or 6-membered heteroaryl-

[0101] By purifying a racemic final compound of Formula (XVI) by a suitable method such as, for example, supercritical fluid chromatography or crystallization.EXAMPLES GENERAL PREPARATION AND ANALYTICAL PROCESSES

[0102] 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.

[0103] 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).

[0104] 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

[0105] 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).

[0106] 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.

[0107] 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.

[0108] 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.

[0109] Table: LCMS Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes).FLOW METHOD MOBILE RUN INSTRUMENT COLUMN GRADIENT CODE PHASE TIME COLT YMC- packAgilent 1260 A: HCOOH From 95% A to 5%ODS- 2.6Infinity DAD 0.1% in A in 4.8 min, held1 AQ C18 6 TOF-LC / MS water, B: for 1.0 min, to 95%(50 x 4.6 35G6224A CH3CN A in 0.2 min.mm, 3pm)FLOW METHOD MOBILE RUN INSTRUMENT COLUMN GRADIENT CODE PHASE TIME COLTWaters: A: 0.1%WatersAcquity® NH4HCO3 From 100% A to: BEH 0.62 UPLC® in 95% H2O 5% A in 2.10min,(1.7pm, 3.5 DAD and + 5% to 0% A in 0.9min,2.1*100 55 SQD2 and CH3CN to 5% A in 0.5minmm)ELSD B: CH3CNA: 0.1%Waters: WatersNH4HCO3 From 100% A toAcquity®: BEH 0.6in 95% H2O 5% A in 2.10min,3 UPLC® (1.7pm, 3.5+ 5% to 0% A in 0.9min,DAD and 2.1*100 55CH3CN to 5% A in 0.5minSQD mm)B: CH3CNA: 10mMWaters: Waters CH3COONHAcquity®: BEH 4 From 100% A to 0.84UPLC® (1.7pm, in 95% H2O 5% A in 1.3 min, 2 DAD and 2.1*50m + 5% hold 0.7min 55 SQD2 m) CH3CNB: CH3CNA: 0.1%Waters: WatersNH4HCO3Acquity®: BEH From 100% A to 0.8in 95% H2O5 UPLC® (1.7pm, 5% A in 1.3 min, 2 + 5%DAD and 2.1*50m hold 0.7min 55CH3CNSQD2 m)B: CH3CNA: 0.1%Waters: WatersNH4HCO3 From 100% A toAcquity®: BEH 0.6in 95% H2O 5% A in 2.10min,6 UPLC® (1.7pm, 3.5+ 5% to 0% A in 0.9min,DAD and 2.1*100 55CH3CN to 5% A in 0.5minSQD mm)B: CH3CNFLOW METHOD MOBILE RUN INSTRUMENT COLUMN GRADIENT CODE PHASE TIME COLTPhenomAgilent 1290 enexA: 0.1% From 90% A toInfinity II Kin etex 1.2HCOOH in 10% A in 1.9 min,7 HPLC DAD C18 (50 2.5H2O held for 0.4 min, toLC / MSD x 2.1 60B: CH3CN 90% A in 0.2 minG6125C mm, 1.7pm)PhenomAgilent 1290 enexA: 0.1% From 90% A toInfinity II Kin etex 1.2HCOOH in 10% A in 1.6 min,8 HPLC DAD C18 (50 2.2H2O held for 0.4 min, toLC / MSD iQ x 2.1 60B: CH3CN 90% A in 0.2 min.G6160A mm, 1.7pm)A: 10mMWaters: Waters CH3COONHFrom 100% A toAcquity®: BEH 4 0.69 5% A in 2.10min,UPLC® (1.7pm, in 95% H2O 3.5 to 0% A in 0.9min,DAD and 2.1*100 + 5% 55to 5% A in 0.5minSQD mm) CH3CNB: CH3CNA: 10 mMWaters: WatersNH4HCO3From 100 % A to 5Acquity®: BEH 0.6in 95 % H2O % A in 2.10 min, to10 UPLC® (1.7 pm, 3.5+ 5 % 0 % A in 0.9 min, toDAD and 2.1 * 100 55CH3CN 5 % A in 0.5 minSQD mm)B: CH3CNA: 0.1 %Waters: WatersNH4HCO3From 100 % A to 5Acquity®: BEH 0.6in 95 % H2O % A in 2.10 min, to11 UPLC® (1.7 pm, 3.5+ 5 % 0 % A in 0.9 min, toDAD and 2.1 * 100 55CH3CN 5 % A in 0.5 minSQD2 mm)B: CH3CNFLOW METHOD MOBILE RUN INSTRUMENT COLUMN GRADIENT CODE PHASE TIME COLTWaters: Waters A: 10 mMAcquity®: BEH CH3COONH From 95 % A to 5 0.84 in 95 %12 UPLC®- (1.7 pm, H2O + 5 % % A in 1.3 min, 2.0 DAD and 2.1 * 50 CH3CN held for 0.7 min 55 SQD mm) B: CH3CNPhenomenex A: 5mM 5 - 98% B over 2.5EVOAmmonium min, 98%B for 2 0.8 Shimadzu C1813 bicarbonate min, 98-5%B over 5.0UHPLC 2.6pm in H2O, 0.1 min, 5%B over 402.0x50 m B: AON 0.4 minmAquity 5 - 98% B over 2.5A: 5mMUPLC min, 98%B for 1.050.6 BEH Ammonium min, 98-5%B over14 Agilent C18 4.0Acetate in 0.05 min, 5%B1.7pm 40 2.1x50m H2O B: AON overm 0.4 minA: 0.1%Phenomenex Formic acid 5 - 98% B over 2.5EVO min, 98%B f15 Shimadzu in Water, B: or 1 0.7C18 min, 98-5%B over 4.0 UHPLC 0.05%2.6pm Formic acid 0.1 min, 5%B over 35 2.0x50 m inm 0.4 minAcetonitrileA: 0.1%Waters: Waters NH4HCO3 From 100% A toAcquity®: BEH 0.616 UPLC®- in 95% H2O 5% A in 2.10min,DAD and (1.7pm, + 5% 3.5 to 0% A in 0.9min,SQD2 and 2.1*100 CH3CN 55 ELSD mm) to 5% A in 0.5minB: MeOHSFC-MS (SUPERCRITICAL FLUID CHROMATOGRAPHY / MASS SPECTROMETRY)GENERAL PROCEDUREThe SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.SFC Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes).FLOW METHOD RUN COLUMN MOBILE PHASE GRADIENT CODE TIME COLTFrom 5% A to 60%Phenomenex 2.5MeOH / Liq CO₂ A in 7min, held for1 (100x4.6mm, 112 min of 60% A,3.0um) 35then 5% A in 2 minFrom 5% A to 60%Phenomenex 2.5EtOH / Liq CO₂ A in 7min, held for2 (100x4.6mm, 112 min of 60% A,3.0um) 35then 5% A in 2 minFrom 5% A to 60%Phenomenex 2.52prop / Liq CO₂ A in 7min, held for3 (100x4.6mm, 112 min of 60% A,3.0um) 35then 5% A in 2 minNUCLEAR MAGNETIC RESONANCE

[0110] For a number of compounds, 1H NMR spectra were recorded on a Bruker Avance III spectrometer operating at 300 or 400 MHz, on a Bruker Avance III-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, CDCl₃), 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.EXPERIMENTAL PART

[0111] Hereinafter, the term “m.p.” means melting point, “aq.” means aqueous, “rt” means room temperature, “DIPEA” means N, N-diiso-propylethylamine, “DIPE” means diisopropylether, “HATLI” means Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium, “TATLI” means O-(7-Azabenzotriazole-1-yl)-N, N, N’, N’-tetramethyluronium tetrafluoroborate, “NMI” means 1-methylimidazole, “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, “T3P” means propylphosphonic anhydride, “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” means1,1'-bis(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:

[0112] 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 beendesignated 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.

[0113] 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.

[0114] 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.2. When two or more stereogenic centers have been designated as "orx", the absolute stereochemistry of each stereogenic center is undetermined but the each of the stereogenic centers has been resolved and the compound itself has been isolated as a single stereoisomer and is diastereomerically enriched.Specifically:a. For any pair of stereogenic centers designated as "orx" with different numerical parts in the notation (e.g., two stereogenic centers designed as "or1" and "or2" respectively), each stereogenic center is independently defined according to (2) (vide supra).b. When any pair of stereogenic centers is designated as "orx" with identical numerical parts in the notation (e.g., two stereogenic centers each designated as "or1"), the relative stereochemistry is indicated, but the absolute configurations of these stereogenic centers have not been determined.3. When a stereogenic center is designated as "&x", it denotes that the compound is a racemic mixture at the indicated center.For example,FFstereoisomers4. When two or more stereogenic centers have been designated asit denotes that the compound is a mixture of stereoisomers.Specifically:a. For any pair of stereogenic centers designated as "&x " with different numerical parts in the notation (e.g., two stereogenic centers designated as "&1" and "&2" respectively), the compound is a mixture of stereoisomers where each of the stereogenic center varies independently.b. For any pair of stereogenic centers designated as "&x" with identical numerical parts in the notation (e.g., two stereogenic centers each denoted with "&1"), the compound is a mixture of stereoisomers with relative stereochemistry.

[0115] The structure of the TMEM175 ligand-bound complex with a representative analogue was obtained by cryo electron microscopy at a resolution of 2.80 angstrom. The picture 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 theligand is well defined and the isomer of R-stereoconfiguration, i.e. compound having a generalFormula (IB) (IB), gives the best fit to this density.

[0116] PREPARATION OF INTERMEDIATESSynthesis of 2-(6-chloro-1-oxoisoquinolin-2(1 / 7)-yl)propanoic acid (1-1)I-2 1-1LiOH (390 mg, 16.285 mmol) was added to a solution consisting of I-2 (1.5 g, 5.36 mmol), THF (30 mL), and water (15 mL) in a round bottom flask, and the mixture stirred at rt for 18 h. The reaction mixture was then treated with 1 M aqueous HCl until pH 1. The water layer is extracted twice with DOM. Combined organic layers are dried over MgSO4, filtered and evaporated under vacuum to obtain 1-1 (1.2 g, 84 % yield) as a solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 12.95 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.58- 7.43 (m, 2H), 6.65 (d, J = 7.5 Hz, 1H), 5.29 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H). LCMS Rt = 1.10 min, 99% (UV), m / z (ES+) = 252.1; m / z (ES-) = 250.1 (method 2).Synthesis of 2-(1-oxoisoquinolin-2(1 / 7)-yl)propanoic acid (I-3)LiOHTHF / H2OI-4 I-3Lithium hydroxide monohydrate (308 mg, 7.34 mmol) was added to a solution consisting of I-4 (600 mg, 2.45 mmol), methanol (15 mL), and water (15 mL) in a 100 mL round bottom flask, and the mixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with EtOAc (20 mL). The aqueous layer was treated with HCI 1 M until pH 3 and extracted with DCM / MeOH (9:1) (6x25 mL). The organic phase was dried over MgSO4 anhydrous, filtered and concentrated in vacuo to afford I-3 (449 mg, 80% yield) as a white solid. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-d6) 5 ppm 12.92 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.78 - 7.62 (m, 2H), 7.56 - 7.42 (m, 2H), 6.66 (d, J = 7.5 Hz, 1 H), 5.30 (q, J = 7.2 Hz, 1 H), 1.58 (d, J = 7.3 Hz, 3H). LCMS Rt = 0.64 min, 95% (UV), m / z (ES+) = 218.1; m / z (ES-) = 250.1 (method 7).Synthesis of 2-(2-methoxy-5-oxo-1,6-naphthyridin-6(5 / 7)-yl)propanoic acid (I-5)I-6 I-5Lithium hydroxide monohydrate (321 mg, 7.65 mmol) was added to a solution consisting of I-6 (700 mg, 2.53 mmol), methanol (8 mL), and water (8 mL) in a 25 mL round bottom flask, and the mixture stirred at rt for 2.5 h. The reaction was treated with HCI 1 M until pH 3 and extracted with DCM (3x25 mL). The organic phase was dried over MgSO4 anhydrous, filtered and concentrated in vacuo to afford I-5 (630 mg, 68% yield) as a white foam. The crude product was used as such in the next step.1H NMR (400 MHz, DMSO-d6) 5 ppm 1.59 (d, J = 7.25 Hz, 3 H), 3.97 (s, 3 H), 5.28 (q, J = 7.25 Hz, 1 H), 6.57 (d, J = 7.63 Hz, 1 H), 6.91 (d, J = 8.77 Hz, 1 H), 7.71 (d, J = 7.63 Hz, 1 H), 8.29 - 8.40 (m, 1 H). LCMS Rt = 0.52 min, 99% (UV), m / z (ES+) = 249.1; m / z (ES-) = 250.1 (method 8).Synthesis of 2-(1-oxo-6-(trifluoromethyl)isoquinolin-2(1H)-yl)propanoic acid (I-7)LiOHTHF / H2OLithiuym hydroxide monohydrate (413 mg, 9.835 mmol) was added to a solution consisting of I-8 (1.05 g, 3.352 mmol), THF (10 mL), and water (3.4 mL) in a 50 mL round bottom flask, and the mixture was stirred at rt for 1 hour. The reaction mixture was then treated with Aq. 1 M HCI until pH=2 and product was extracted with DCM: MeOH (8:2) (20mL x2). The resulting organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford I-7 (917 mg, 77%) as a white foam. Product was used in the next step without further purification.Synthesis of 2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanoic acid (1-11)Lithiuym hydroxide monohydrate (188.3 mg, 4.5 mmol) was added to a solution consisting of 1-12 (470 mg, 1.5 mmol), methanol (5 mL), and water (5 mL) in a 100 mL round bottom flask, and themixture stirred at rt for 16 h. The reaction was concentrated partially and extracted with EtOAc (20 mL). The aqueous layer was treated with HCl 1 M until PH 3 and extracted with DCM / MeOH (9:1) (3x25 mL). The organic phase was dried over MgSO4 anhydrous, filtered and concentrated in vacuo to give 1-11 (268 mg, 62%) as a yellow solid. The crude product was used as such in the next step.

[0117] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ethyl 2-(6-chloro-1-oxoisoquinolin-2(1 / 7)-yl)propanoate (I-2)CsCOgDMF I-2Ethyl 2-bromopropionate [535-11-5] (2.2 mL, 16.9 mmol) was added to a mixture of 6-chloroisoquinolin-1(2 / 7)-one [131002-09-0] (2.0 g, 11.1 mmol) and Cs2CO3 (5.5 g, 16.881 mmol) in DMF (25 mL). The resulting mixture was stirred at 50 °C for 2 hours. The mixture was cooled down to room temperature and diluted with aq. sat. NH4CI (100 mL) and EtOAc (200 mL). The phases were separated and the organic phase washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO₂, 0:100 to 50:50 EtOAc: Heptane) to afford I-2 (3 g, 91 % yield) as a light yellow solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.33 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.39 (dt, J = 11.8, 5.9 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.64 (q, J = 7.4 Hz, 1H), 4.25 -4.13 (m, 2H), 1.66 (d, J = 7.4 Hz, 3H), 1.26 (q, J = 7.3 Hz, 3H). LCMS Rt = 1.93 min, 98% (UV), m / z (ES+) = 280.1; m / z (ES-) = 250.1 (method 6).Synthesis of ethyl 2-(1-oxoisoquinolin-2(1 / 7)-yl)propanoate (I-4)CsCOgDMF I-4

[0118] Cesium carbonate (4.48 g, 13.7 mmol) was added to a round bottom flask of 100 mL containing a solution consisting of Isocarbostyril [491-30-5] (1.00 g, 6.9 mmol), ethyl 2-bromopropionate [535-11-5] (1.38 mL, 10.6 mmol) and in dry DMF (20 mL). The reaction was stirred at rt for 72 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 column chromatography (SiO₂, 0:100 to 30:70 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford I-4 (1.667 g, 94% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.20 (d, J = 7.9 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.29 (q, J = 7.2 Hz, 1H), 4.19 - 4.06 (m, 2H), 1.59 (d, J = 7.2 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). LCMS Rt = 1.08 min, 95% (UV), m / z (ES+) = 246.1; m / z (ES-) = 250.1 (method 7).Synthesis of ethyl 2-(2-methoxy-5-oxo-1,6-naphthyridin-6(5 / 7)-yl)propanoate (I-6)Cesium carbonate (1.5 g, 4.5 mmol) was added to a 50 ml round bottom flask containing a stirring solution of 1-13 (500 mg, 2.3 mmol), ethyl 2-bromopropionate [535-11-5] (455 pL, 3.5 mmol) and in dry DMF (15 mL). The reaction was stirred at rt for 16 hours. The reaction was diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic phase was dried over MgSO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by column chromatography (SiO2, 0:100 to 30:70 EtOAc: Heptane). The desired fractions were collected and concentrated to dryness in vacuo to afford I-6 (710 mg, 99% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 - 1.20 (m, 3 H), 1.59 (d, J = 7.15 Hz, 3 H), 3.97 (s, 3 H), 4.11 (q, J = 7.06 Hz, 2 H), 5.28 (q, J = 7.12 Hz, 1 H), 6.59 (d, J = 7.63 Hz, 1 H), 6.84 - 7.06 (m, 1 H), 7.73 (d, J = 7.63 Hz, 1 H), 8.29 - 8.44 (m, 1 H). LCMS Rt = 0.79 min, 95% (UV), m / z (ES+) = 277.1; m / z (ES-) = 250.1 (method 8).Synthesis of ethyl 2-(1-oxo-6-(trifluoromethyl)isoquinolin-2(1H)-yl)propanoate (I-8)In a round bottom flask of 50 mL, ethyl 2-bromopropionate (0.37 mL, 2.812 mmol) was added to a stirred solution of 1-14 (500 mg, 2.346 mmol) and cesium carbonate (2.55 g, 4.691 mmol) in DMF (7 mL). The reaction was stirred at rt for 16h. The reaction was diluted with EtOAc (2 x 20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and concentrated 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% EtOAc / Heptane) to give I-8 (597 mg, 80%) as a yellowish solid.Synthesis of ethyl 2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanoate (1-12)Ethyl bromoacetate (2.51 mL, 19.333 mmol) was added to a stirred solution of 1-15 (2.76 g, 12.889 mmol), cesium carbonate (14.5 g, 44.465 mmol) in dry DMF (26 mL) at rt. The resulting mixture was stirred for 1.5 h at 50 °C. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were dried over anhydrous MgSO4, filtered, concentrated to dryness in vacuo to give a brown oil. The oil was subjected to purification by silica gel chromatography (40 g silica irregular 40-60 pm 60A; 0-90% DCM / heptane) to yield I-12 (1.35 g, 30%) as a yellowish oil.Synthesis of ethyl 2-(2-ethoxy-5-oxo-1,6-naphthyridin-6-yl)propanoate (I-39)oI -40 I-39Ethyl 2-bromopropanoate (0.085 mL, 0.653 mmol) was added to a stirred solution of I-40 (115 mg, 0.544 mmol), and cesium carbonate (0.443 g, 1.360 mmol) in dry DMF (1 mL) at rt. The resulting mixture was stirred for 16 h at 50 °C. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x10 ml). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give a yellow oil. This oil was subjected to purification by silica gel chromatography (12 g silica irregular 40-60 pm 60A; 0-20% EtOAc / heptane) to yield I-39 (103 mg, 65%) as a yellowish oil.Synthesis of ethyl 2-(6-ethoxy-1-oxoisoquinolin-2(1H)-yl)propanoate (I-42)Ethyl bromoacetate (0.412 mL, 3.17 mmol) was added to a 50 mL round bottom flask containing a rt stirred solution, consisting of 6-Ethoxyisoquinolin-1(2H)-one [918662-49-4] (500 mg, 2.643 mmol), cesium carbonate (1.9 g, 5.9 mmol) in dry DMF (4.94 mL). The resulting mixture was stirred for 3 h at 50 °C. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (90 ml). The combined extracts were dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo. The product was subjected by silica gel columns chromatography (80 g silica irregular 40-60 pm 60A; 0-20% EtOAc / heptane) to yield I-42 (706 mg, 91%) as a yellow oil.Synthesis of ethyl 2-[5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6-yl]butanoate (I-43)Ethyl 2-bromobutyrate (0.33 mL, 2.24 mmol) was added portionwise to a stirred solution of 1-15 (400 mg, 1.87 mmol), and cesium carbonate (0.913 g, 2.8 mmol) in DMF (3.6 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 MgSO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The oil wassubjected to purification by silica gel chromatography (20 g irregular 40-60 pm; 0-30% Heptane / EtOAc) to yield 1-43 (528 mg, 83%) as a yellowish oil.

[0119] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.(Aza)-quinolinone ProductONH0[214045-85-9] 1-10O oNH0[214045-85-9] I-25(+ reagent = [3196-15-4])Synthesis of 2-methoxy-1,6-naphthyridin-5(6 / 7)-one (1-13)NaH ODMF1-13

[0120] NaH (522 mg, 13.0 mmol) was added to a 250 mL round bottom flask containing a stirred solution consisting of 1-16 (2.22 g, 10.0 mmol) in DMF dry (20 mL) at rt. Then, the mixture was stirred at 80°C for 5h. Then, HCI (1M) was added and the pH was adjusted to pH = 5 and the solid was filtered in vacuo and dried to yield 1-13 (752 mg, 42% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 11.41 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1 H), 6.45 (d, J = 7.3 Hz, 1 H), 3.96 (s, 3H). LCMS Rt = 0.39 min, 99% (UV), m / z (ES+) = 177.0; m / z (ES-) = n.d. (method 8).Synthesis of 2-ethoxy-6H-1,6-naphthyridin-5-one (I-40)o O1-41 I -40NaH (60% dispersion in mineral oil (53 mg, 1.326 mmol) was added to a stirred solution of 1-41 (0.24 g, 1.02 mmol) in dry DMF (2 ml) at rt. The mixture was stirred at 80°C for 2h. Then, HCI 1M was added and the pH was adjusted to pH=5 and the solid was filtrated in vacuo and dried to yield I-40 (120 mg, 56%) as a beige solid. The crude was used in the next step without purification.Synthesis of (E)- / V-((dimethylamino)methylene)-6-methoxy-2-methylnicotinamide (1-16)OZNA- o1-16

[0121] / V, / V-Dimethylformamide dimethyl acetal [4637-24-5] (32.5 mL, 244.0 mmol) was added to a 250ml round bottom flask containing a stirring solution, consisting of 6-methoxy-2-methylnicotinamide [1824114-08-0] (1.80 g, 11.0 mmol) at rt. The mixture was stirred at 100°C for 16 h. Then, the solvent was concentrated in vacuo to yield an orange oil that was triturated with pentane (5 mL), filtrated and dried in vacuo to afford 1-16 (2.22 g, 83% yield) as a yellowish solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.57 (s, 1H), 8.40 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 3.96 (s, 3H), 3.17 (d, J = 4.2 Hz, 6H), 2.81 (s, 3H). LCMS Rt = 0.29 min, 90% (UV), m / z (ES+) = 222.1; m / z (ES-) = n.d. (method 8).Synthesis of (NE)-N-(dimethylaminomethylene)-6-ethoxy-2-methyl-pyridine-3-carboxamide (I- 41)[1824093-75-5] |_41N, N-Dimethylformamide dimethyl acetal (3.25 mL, 24.417 mmol) was added to 6-ethoxy-2-methyl-3-pyridinecarboxamide [1824093-75-5] (0.2 g, 1.11 mmol) at rt. The mixture was stirred at 100°C for 1.5 h. The solvent was concentrated in vacuo to yield a yellow solid that was triturated with pentane (7 ml), filtrated and dried in vacuo to afford 1-41 (240 mg, 87%) as a lightyellow solid.Synthesis of 2-(trifluoromethyl)-1,6-naphthyridin-5(6 / 7)-one (1-15)O"1-15

[0122] / V, / V-dimethylformamide dimethyl acetal [4637-24-5] (856 pL, 6.4 mmol) was added to a 50 ml round bottom flask containing a stirring solution, consisting in ethyl 2-methyl-6-(trifluoromethyl)nicotinate [380355-65-7] (1.5 g, 6.4 mmol) and DMF (5 mL) at rt. The mixture was stirred at 100°C for 16 h. Then, / V, / V-dimethylformamide dimethyl acetal (856 pL, 6.4 mmol) was added and the mixture was stirred at 100°C for 16h. Then, the solvent was concentrated in vacuo to yield an orange oil. NH3 in MeOH (18 mL) was added and the mixture was stirred at 60°C for 5h. Then, the solvent was concentrated in vacuo and the solid was precipitated with DCM: pentane (1:1) and dried in vacuo. It was purified by column chromatography (SiO₂, 0:100 to 10:90 MeOH: DCM to afford 1-15 (259 mg, 15 % yield) as an orange solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 10.64 (s, 1H), 8.86 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1 H), 6.92 (d, J = 7.5 Hz, 1 H). LCMS Rt = 0.52 min, 99% (UV), m / z (ES+) = 215.0; m / z (ES-) = n.d. (method 8)Synthesis of 6-(trifluoromethyl)isoquinolin-1(2 / 7)-one (1-14)O TFA DCM1-14

[0123] The reaction was set up in eight batches of the same quantity of 1-17 (90 mg each one): In a microwave vial were charged 1-17 (720 mg, 2.3 mmol) and TFA (16 mL), was stirred at 100°C for 3h. The solvent was concentrated in vacuo and DCM (5 mL) was added. The crude was neutralizated with NaHCCh until pH = 7. The organic phase was separated, dried over MgSO₄, filtered, and the solvent removed in vacuo to afford 1-14 (540 mg, 100% yield) as an orange solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 10.93 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 12.1, 4.7 Hz, 1H), 7.23 (s, 1H), 6.63 (d, J = 7.2 Hz, 1H). LCMS Rt = 0.69 min, 96% (UV), m / z (ES+) = 214.0; m / z (ES-) = n.d. (method 8)Synthesis of (E)- / V-(tert-butyl)-2-(2-ethoxyvinyl)-4-(trifluoromethyl)benzamide (1-17)

[0124] A bottle glass pressure of 150 mL was charged with (E)-2-(2-Ethoxyvinyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane [1201905-61-4] (1.3 mL, 6.2 mmol), 1-18 (2.0 g, 6.2 mmol), K2CO3 (2.56 g, 18.5 mmol)), 1,4-dioxane (30 mL), and H2O (15 mL) that had been sparged with nitrogen for 5 min. Then, Pd(dba)2 (178 mg, 0.31 mmol) was then added and subsequently capped and heated at 90 °C for 5 h with stirring. The reaction was cooled at rt, diluted with water (25 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (SiO₂, 0:100 to 100:0 EtOAc: Heptane) to afford 1-17 (1.79 g, 89% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.56 (d, J = 5.3 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.44-7.37 (m, 2H), 7.02-6.96 (m, 1H), 6.08 (d, J= 12.9 Hz, 1H), 5.60 (s, 1H), 3.92 (q, J = 7.0 Hz, 2H), 1.47 (s, 9H), 1.35 (t, J = 7.0 Hz, 3H). LCMS Rt = 1.16 min, 97% (UV), m / z (ES+) = 316.1; m / z (ES-) = n.d. (method 8)Synthesis of 2-bromo- / V-(tert-butyl)-4-(trifluoromethyl)benzamide (1-18)

[0125] In a 250 mL round bottom flask, thionyl chloride (8.2 mL, 112 mmol) was added dropwise over a period of 20 min to a solution of 2-bromo-4-(trifluoromethyl)benzoic acid [328-89-2] (3 g, 11 mmol) in DCM (60 mL) and the reaction mixture was stirred at rt for 3 hours. The mixture was concentrated in vacuo and re-dissolved in DCM (60 mL). tert-Butylamine (5.9 mL, 56 mmol) was added dropwise over a period of 5 min to the acid chloride solution and the reaction stirred at rt for 16 h. The reaction mixture was quenched with sat. NaHCCh (aq.) (50 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with sat. NaHCCh (aq.), dried over MgSO₄, filtered, and concentrated in vacuo to yield 1-18(3.6 g, 95% yield) as a colourless solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.83 (s, 1H), 7.63- 7.56 (m, 2H), 5.61 (d, J = 44.7 Hz, 1 H), 1.49 (s, 9H). LCMS Rt = 0.98 min, 95% (UV), m / z (ES+) = 323.9; m / z (ES-) = nd. (method 8)Synthesis of 2-bromo- / V-(4-(1-methyl-1 H-pyrazol-3-yl)phenyl)propanamide (1-19)O

[0126] 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 DCM (300 mL) at 0°C. The mixture was stirred for 1 hour. The mixture was quenched via the addition of aq. sat. NH4CI and extracted with EtOAc (2x). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, 100:0 to 0:100 EtOAc: heptane) to afford 1-19 (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 5).Synthesis of 2-bromo- / V-(4-(thiazol-2-yl)phenyl)propanamide (I-20)I-20

[0127] 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 MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0:100 to 50:50 EtOAc: Heptanes) to afford I-20 (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 6).

[0128] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Amine ProductSynthesis of 3-fluoro-4-(1-methyl-1 / 7-pyrazol-3-yl)aniline (I-22)Tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (55 mg, 0.047 mmol) was added to a degassed solution of 4-bromo-3-fluoroaniline [656-65-5] (150 mg, 0.79 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole [1020174-04-2] (197 mg, 0.95 mmol) and Na2CC>31M (2.4 mL, 2.4 mmol). Then, water was added into the reaction mixture and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, 0:100 to 100:0 EtOAC: Heptane) to afford I-22 (65 mg, 37% yield). LCMS Rt = 0.70 min, 85% (UV), m / z (ES+) = 192.2; m / z (ES-) = 310.0 (method 4).

[0129] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ethyl 5-fluoro-6-(1-methyl-1 / 7-pyrazol-3-yl)pyridin-3-amine (I-26)

[0130] Stannous chloride [7772-99-8] (389 mg, 2.05 mmol) was added in one portion to a solution of I-27 (96 mg, 0.41 mmol) in EtOH (10 mL) and the mixture was stirred at 70 °C for 9 h. The solvent was evaporated. The residue was dissolved in EtOAc. Aqueous 1 M Na2COs was added and the mixture was stirred vigorously for a few minutes. The whole mixture (emulsion) was filtered on dicalite and the filter was rinsed with EtOAc. The layers of the filtrate were separated and the organic layer was dried on MgSO4, filtered, and the solvent was evaporated to give I-26 (127 mg, 95 % yield) as a brown solid, dried under vacuum at 45 °C and used without further purification. LCMS Rt = 1.06 min, 59% (UV), m / z (ES+) = 193.1; m / z (ES-) = n.d. (method 6)Synthesis of ethyl 3-fluoro-2-(1-methyl-1 / 7-pyrazol-3-yl)-5-nitropyridine (I-27)I-27Bis(triphenylphosphine)palladium(ll)chloride,NaCO3, Dioxane, Water

[0131] Bis(triphenylphosphine)palladium(ll)chloride [13965-03-2] (16 mg, 0.023 mmol) was added to a mixture of 2-chloro-3-fluoro-5-nitropyridine [1079179-12-6] (82 mg, 0.46 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / 7-pyrazole [1020174-04-2] (135 mg, 0.65 mmol) and sodium carbonate (148 mg, 1.39 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted and the combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (SiO2, 100:0 to 20:80 heptane: EtOH / EtOAc 1 / 3) to afford I-27 (96 mg, 88 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 9.27 (dd, 1H, J = 0.8, 2.1 Hz), 8.67 (dd, 1 H, J = 2.2, 10.6 Hz), 7.92 (d, 2H, J = 2.3 Hz), 6.96 (dd, 1 H, J = 1.6, 2.2 Hz), 3.99 (s, 4H).LCMS Rt = 1.48 min, 95% (UV), m / z (ES+) = 223.1; m / z (ES-) = 221.1 (method 6)

[0132] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Synthesis of ethyl 6-(thiazol-2-yl)pyridin-3-amine (I-29)Bis(tributyltin), Pd2(dba)3Pd(PPh3)4TricyclohexylphosphineDioxane, Water

[0133] A solution of 5-amino-2-bromopyridine (150 mg, 0.867 mmol), tricyclohexylphosphine (24 mg, 0.08 mmol) and bis(tributyltin) (507 pL, 0.95 mmol) in 1,4-dioxane (3 mL) was bubbled with N2 for 5 min. Then, Pd2(dba)3(40 mg, 43 pmol) was added and the reaction stirred at 90 °C overnight. Then, 2-bromothiazole (78 pL, 0.88 mmol) and Pd(PPha)4 (100 mg, 0.09 mmol) were added to the reaction and the resultant mixture stirred at 100 °C overnight. 2-bromothiazole (39 pL, 0.43 mmol) was added and the reaction mixture stirred at 110 °C for 4 h. The reaction mixture was quenched with a 1 M solution of NaOH and diluted with water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were dried over MgSCU, filtered and evaporated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (SiO₂, 0:100 to 100:0 DCM: DCM / MeOH(9:1)) to afford I-29 (88 mg, 55% yield) as a brown solid.1H NMR (400 MHz, Chloroform-d) 5 ppm 8.1-8.1 (m, 1H), 8.0-8.0 (m, 1H), 7.82 (d, 1H, J = 3.2 Hz), 7.31 (d, 1H, J = 3.2 Hz), 7.05 (dd, 1H, J = 2.8, 8.5 Hz), 3.94 (s, 2H). LCMS Rt = 0.57 min, 96% (UV), m / z (ES+) = 177.9; m / z (ES-) = 175.9 (method 5)

[0134] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Reactant Reactant ProductSynthesis of ethyl 2-fluoro-4-(thiazol-2-yl)aniline (1-31)Bis(triphenylphosphine)palladium(ll) dichloride,DMF

[0135] 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 MgSCU, filtered and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (SiO₂, 100:0 to 90:10 DCM: MeOH) to afford 1-31 (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 6)

[0136] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Reactant Reactant ProductBr— J— NH2Er"F [jN'*> — { y— NH2N= / [1256276-41-1]I-32[121359-48-6]Synthesis of 2-(6-fluoro-1-oxoisoquinolin-2(1H)-yl)propanoyl chloride (I-33)I-9 I-331-chloro-N, N,2-trimethylpropenylamine [26189-59-3] (113 pL, 1.01 g / mL, 0.85 mmol) was added to a solution of I-9 (100 mg, 0.40 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-33 (102 mg) as a solid. It was used without further purification.Synthesis of 4,6-difluoro-3-hydroxy-3,4-dihydroisoquinolin-1(2 / 7)-one (I-34)[140681-55-6][214045-85-9] I-34Selectfluor [140681-55-6] (1.19 g, 3.37 mmol) was added to an oven-dried 100 mL round-bottomed flask stirring solution, consisting of 6-Fluoroisoquinolin-1(2 / 7)-one [214045-85-9] (500 mg, 3.06 mmol), acetonitrile (28 mL) and water (400 pL) to give a heterogeneous mixture. The heterogeneous mixture was stirred at rt for 18 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x3). The combined extracts were dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give a I-34 (581 mg, 67%) as a white solid. The crude product was used as such in the next step.Synthesis of 4,6-difluoro-3-hydroxy-3,4-dihydroisoquinolin-1(2 / 7)-one (I-35)F OHF+r° F OI-34 I-35Triflic acid [1493-13-6] (1.8 mL, 20.42 mmol) was added to an oven-dried 10 mL round-bottomed flask stirring solution, consisting of I-34 (581 mg, 2.92 mmol) and DCM (10 mL) at 0°C under a nitrogen atmosphere to give a yellow solution. The yellow reaction mixture was stirred at rt for 16 h. After, the reaction mixture was basified with NaHCCh (aq. solution saturated) until pH=8 (10 mL) and extracted with DCM (3 x 10 mL). The organic layer was separated, dried over anhydrousMg2SC>4, filtered and concentrated to dryness in vacuo to give I-35 (527 mg, crude) as a white solid. The crude product was used as such in the next step.Synthesis of 6-chloro-4-fluoro-3-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (I-36)I-36Selectfluor (1.08 g, 3.06 mmol) was added to an oven-dried 100 mL round-bottomed flask stirring solution, consisting of 6-Chloroisoquinolin-1(2H)-one (500 mg, 2.78 mmol), acetonitrile (25 mL) and water (362 pL) to give a heterogeneous mixture. The heterogeneous mixture was stirred at rt for 18 h.The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x3). The combined extracts were dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give I-36 (585 mg, 771%) as a white solid. The crude product was used as such in the next step.Synthesis of 6-chloro-4-fluoroisoquinolin-1(2H)-one (I-37)Triflic acid (1.7 mL, 18.993 mmol) was added to stirred solution of I-36 (585 mg, 2.713 mmol) in DCM (10 mL) at 0°C under a nitrogen atmosphere, to give an yellow solution. The yellow reaction mixture was stirred at rt for 16 h. Afterwards, the reaction mixture was basified with NaHCOs (aq. solution saturated) until pH=8 (10 mL) and extracted with DCM: MeOH (9:1) (3 x 10 mL). The organic layer was separated, dried over anhydrous Mg2SC>4, filtered and concentrated to dryness in vacuo to give I-37 (246 mg, crude) as a pink solid. The crude product was used as such in the subsequent step.PREPARATION OF FINAL COMPOUNDSSynthesis of 2-(6-chloro-1-oxoisoquinolin-2(1 / 7).-yl)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)propanamide (F-1)

[0137] TCFH [94790-35-9] (0.39 g, 1.38 mmol) was added to a round-bottomed flask containing a stirring solution, consisting of 1-1 (0.29 g, 1.15 mmol), 4-(1-Methyl-1 / 7-pyrazol-3-yl)aniline [916766-82-0] (0.2 g, 1.16 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 MgSO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (SiO₂, 5:95 to 0:100 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-1 (167 mg, 34% yield) as a white solid.Synthesis of 2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)-N-(4- (trifluoromethoxy)phenyl)propanamide (F-90)Propylphosphonic anhydride 50% in ethyl acetate (1.6 mL, 2.79 mmol) was added to a mixture of 1-11 (400 mg, 1.40 mmol), 4-(trifluoromethoxy)aniline (0.191 mL, 1.39 mmol) and DIPEA (0.975 mL, 5.6 mmol) in DMF (4.2 mL) and the reaction was stirred at room temperature for 16h. The mixture was diluted with water (10 mL) and then extracted with EtOAc (2 x 20 mL). The extracts were combined, dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give a brownish solid. This solid was subjected to purification by silica gel chromatography (25 g silica irregular 40-60 pm 60A; 0-30% EtOAc / heptane) to yield F-90 (380 mg, 60%) as a white solid.Synthesis of N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanamide (F-195)T3P, DIPEA, DMFF-195 Propylphosphonic anhydride 50% in ethyl acetate (1.6 mL, 2.79 mmol) was added to a mixture of 1-11 (400 mg, 1.40 mmol), 2-fluoro-6-(trifluoromethyl)pyridin-3-amine (252 mg, 1.39 mmol) and DIPEA (0.974 mL, 5.6 mmol) in DMF (6.2 mL) and the reaction was stirred at room temperature for 16 h. The reaction was rechargued with DIPEA (0.5 mL, 2.795 mmol) and propylphosphonic anhydride (0.832 mL, 1.398 mmol) and it was allowed to stirr for 72 h at rt. The mixture was diluted with water (10 mL) and then extracted with EtOAc (2 x 50 mL). The extracts were combined, dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (25 g silica irregular 40-60 pm 60A; 0-20% EtOAc / heptane). The product was subjected to HPLC (Phenomenex Gemini 5 pm C1830x100 mm column, gradient 30-73% (v / v) AON / water (25 mM NH₄HCO₃)). The compound-containing fractions were concentrated to dryness in vacuo to yield F-195 (160 mg, 26%) as a white solidSynthesis of N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(1-oxo-6-(trifluoromethyl)isoquinolin- 2(1H)-yl)propanamide (F-196)T3P, DIPEA, DMFF-196 T3P 50% in ethyl acetate (3.8 mL, 6.429 mmol) was added to a mixture in a 50 mL round bottom flask consisting of 3-(Trifluoromethoxy)aniline (579 mg, 3.215 mmol), I-7 (917 mg, 3.215 mmol) and DIPEA (2.24 mL, 12.881 mmol) in DMF (10 mL) and the reaction was stirred at room temperature for 16h. The mixture was diluted with water (10 mL) and then extracted with EtOAc (2 x 20 mL). The extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (25 g silica irregular 40-60 pm 60A; 0-90% DCM / heptane) and then HPLC (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 give F-196 (50 mg, 3%) as a whitish solid.

[0138] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATU, TATU or T3P may be used as coupling reagents, DIPEA, TEA or NMI may be used as bases and DMF may be used as solvent.Amine Carboxylic acid Final compoundXJH2NX'X^N■XX-V[916766-82-0] 1-11 F-8rVci-X-o^.- XJH2NX'X^No5V[916766-82-0] I-3 F-9rV2XJH NX'X^NXX" X"[916766-82-0] I-9 F-10rVXJH2NX'X^NX G-V"[916766-82-0] I-5 F-11H2N^^ _1 1F[135900-33-3] Xi-T"I-9 F-87T Jl IFF xi" X" F[135900-33-3] I-9 F-91XX'oxiiV[117519-15-0] Cl 1-1 F-197Synthesis of 2-(6-chloro-1-oxoisoquinolin-2(1 / 7 -yl)- / V-(4-(thiazol-2-yl)phenyl)propanamide (F-12)TCFH, methylimidazole,MeCN

[0139] 1 -Methylimidazole [616-47-7] (90 pL, 1.14 mmol) and TCFH [207915-99-9] (0.12 g, 0.43 mmol) were added to a solution of 1-1 (75 mg, 0.28 mmol) and 4-(thiazol-2-yl)aniline [193017-26-4] (55 mg, 0.31 mmol) in ACN (2 mL). The mixture was stirred at rt 16h. The mixture was diluted up with water and EtOAc and the phases separated. The organic phase was washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0:100 to 100:0 EtOAc: heptanes). To the resulting yellow solid was added MeOH and the solid was filtered to obtain F-12 (38 mg, % yield) as a white solid.Synthesis of 2-(6-fluoro-1-oxoisoquinolin-2(1 / 7)-yl)- / V-(4-(thiazol-2-yl)phenyl)propenamide (F-13)o

[0140] A mixture of 6-fluoroisoquinolin-1(2 / 7)-one [214045-85-9] (80 mg, 0.49 mmol), I-20 (183 mg, 0.59 mmol), Cs2CO3 [534-17-8] (240 mg, 0.74 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-13 (103 mg, 53% yield).Synthesis of 2-(1 -oxo-6-(trifluoromethyl)isoquinolin-2(1 H)-y I)- N- (4- (th iazol-2-yl)phenyl)propanamide (F-14)O

[0141] A mixture of 6-(trifluoromethyl)isoquinolin-1(2 / 7).-one [1184916-59-3] (80 mg, 0.38 mmol), I-20 (140 mg, 0.45 mmol), Cs2CO3 [534-17-8] (183 mg, 0.56 mmol) in DMF (1.3 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-14 (55 mg, 33% yield).Synthesis of 2-(6-fluoro-1-oxoisoquinolin-2(1 / 7)-yl)- / V-(4-(trifluoromethoxy)phenyl)propenamide (F-15)Cs2CO3DMF

[0142] A mixture of 6-fluoroisoquinolin-1(2 / 7)-one [214045-85-9] (80 mg, 0.49 mmol), 1-19 (184mg, 0.59 mmol), Cs2CO3 [534-17-8] (240 mg, 0.74 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-5pm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) to afford F-15 (125 mg, 65% yield).Synthesis of 2-(6-chloro-4-fluoro-1 -oxo-2-isoquinolyl)-N-[4-(trifluoromethoxy)- phenyl]propenamide (F-201)1-37 F-2011-19 (466 mg, 1.494 mmol) was added to a stirred solution of I-37 (246 mg, 1.245 mmol) and cesium carbonate (608 mg, 1.867 mmol) in DMF (4 mL). The reaction was stirred at 50°C for2h. The reaction was diluted with EtOAc (2 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 brown solid. The solid was subjected to purification by silica gel chromatography (40 g irregular 40-60 pm; 0- 80% DCM / Heptane) to give a white solid. The solid (363 mg) was subjected to HPLC (XBridge 5m C18, 30 X 100 mm column, gradient 75-100% (v / v) MeOH / water (25 mM NH₄HCO₃)). The compound-containg fractions were lyophilized to give F-201 (110 mg) as a white solid.

[0143] Additional analogs were obtained according to the above procedure substituting the reagents as appropriate.Intermediate Intermediate Final compoundO U 1H1 JUFr^j^NHCI^ r / MA 0NnBrH[131002-09-0]1-21 F-16? IH7X -=FBrHci- oi-V n c;1-19 [491-30-5] F-17Or^j^NH7X -=Fu IHBrHxxc sNri1-19 [131002-09-0] F-18p 0 U 1H1 JUFF / [k^Z^T\l kNHr / ANnBrH[214045-85-9]1-21 F-19O CFNHA JUFrCAsriBrH FT TF1-21 [1184916-59-3] F-20ONHH In^AH7X -=F NnBrHFi1-19[1184916-59-3]ffFfFF-21Synthesis of (*R)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(1-oxoisoquinolin-2(1 / 7)-yl)propanamide (F-22) and (*S)- / V-(4-(1-methyl-1 / 7-pyrazol-3-yl)phenyl)-2-(1-oxoisoquinolin-2(1 / 7).-yl)propanamide (F-23)

[0144] The racemic F-9 (242 mg, 0.65 mmol) was purified by preparative SFC (stationary phase: Phenomenex Lux i-Amylose-A 150x4.6 mm, 5um, Mobile phase: 50% CO₂ / iPrOH + 0.1% DEA) to afford F-22 (94.1 mg, 38% yield) as a beige solid and F-23 (95 mg, 39% yield) as a beige solid.Synthesis of (R)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-92) and (S)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-93)F-90 (368 mg) was subjected to preparative SFC (Stationary phase: i-amylose-1 5 pm 250 x 30 mm, Mobile phase: 30% 2-Prop + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-92 (150 mg, 24%) and the second fraction was collected as compound F-93 (135 mg, 21%) both as white solids.Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanamide (F-99) and (S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanamide (F-100)Racemic F-195 (149.5 mg) was subjected to preparative SFC (Stationary phase: i-amylose-A 5 pm 250 x 30 mm, Mobile phase: 20% EtOH+ 0.1% DEA) to yield two fractions: the first fraction was collected as compound F-99 (65 mg, 10%) as a beige solid and the second fraction was collected as compound F-100 (60 mg, 9%) as a white solid.Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(1-oxo-6- (trifluoromethyl)isoquinolin-2(1H)-yl)propanamide (F-101) and (S)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)-2-(1-oxo-6-(trifluoromethyl)isoquinolin-2(1H)-yl)propanamide (F-The solid F-196 (175 mg) was purified by preparative SFC (Stationary phase: Phenomenex Lux Cellulose-1 5pm 150x21.2 mm, Mobile phase: CO2, ISO 35% 2-propanol + 0.1% DEA) to get the separated enantiomers. Both fractions were diluted with water (10 mL) and extracted with EtOAc (2 x 20mL). The combined organic layers of both fractions were collected and concentrated in vacuo to give a first fraction collected as compound F-101 (44 mg, yield 15%) as white solid and a second fraction collected as compound F-102 (62.7 mg, yield 22%) as a pale brown solid.Synthesis of (R)-2-(6-chloro-4-fluoro-1-oxoisoquinolin-2(1 H)-yl)-N-(4- (trifluoromethoxy)phenyl)propanamide (F-107) and (S)-2-(6-chloro-4-fluoro-1-oxoisoquinolin- 2(1 H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-108)Racemic F-201 (101 mg) was purified by preparative SFC (Stationary phase: Phenomenex Lux Cellulose-1 5pm 150x21.2 mm, Mobile phase: CO2, ISO 30% 2-propanol + 0.1% DEA). The compound-containg fractions were lyophilized to give F-107 (40.3 mg, yield 7%) and F-108 (37.8 mg, yield 7%) as white solids.Synthesis of (R)-2-(2-ethoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)-N-(4- (trifluoromethyl)phenyl)propanamide (F-191) and (S)-2-(2-ethoxy-5-oxo-1,6-naphthyridin-6(5H)- yl)-N-(4-(trifluoromethyl)phenyl)propanamide (F-192)Racemic F-188 (190 mg) was subjected to preparative SFC (Stationary phase: i-Amylose-A 5 pm 250 x 30 mm, Mobile phase: 60% MeOH + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-191 (82.1 mg, 22%) and the second fraction was collected as compound F-192 (78 mg, 20%), both as white solids.Synthesis of (R)-2-(2-ethoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)propanamide (F-193) and (S)-2-(2-ethoxy-5-oxo-1,6-naphthyridin- 6(5H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-194)F-187 (117 mg) was subjected to preparative SFC (Stationary phase: i-Amylose-A 5 pm 250 x 30 mm, Mobile phase: 50% MeOH + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-193 (46 mg, 12%) and the second fraction was collected as compound F-194 (49 mg, 13%) both as white solids.Synthesis of (R)-2-(6-ethoxy-1-oxoisoquinolin-2(1H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3- yl)propenamide (F-202) and (S)-2-(6-ethoxy-1-oxoisoquinolin-2(1H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)propenamide (F-190)The racemic F-189 (222 mg) was subjected to preparative SFC (Stationary phase: l-Amylose-A 5 pm 250 x 30 mm, Mobile phase: 30% PropOH + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound (F-202) (70 mg, 16%) and the second fraction as compound (F-190) (79 mg, 18%), both as white solids.Synthesis of (R)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-oxo-2-(trifluoromethyl)-1,6- naphthyridin-6(5H)-yl)butanamide (F-206) and (S)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2- (5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)butanamide (F-207)Racemic F-205 (120 mg) was subjected to preparative SFC (Stationary phase: i-Amylose-35 pm 250 x 30 mm, Mobile phase: 35% CO₂ / EtOH + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-206 (95 mg, 27%) and the second fraction was collected as compound F-207 (94 mg, 26%) both as white solids.Synthesis of (R)-N-(2,3-difluoro-4-(trifluoromethyl)phenyl)-2-(5-oxo-2-(trifluoromethyl)-1,6- naphthyridin-6(5H)-yl)propanamide (F-210) and (S)-N-(2,3-difluoro-4-(trifluoromethyl)phenyl)-2- (5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanamide (F-211)Racemic F-203 (84 mg) was subjected to preparative SFC (Stationary phase: Amylose-1 5 pm 250 x 30 mm, Mobile phase: 20% 2-Prop + 0.1% DEA) and lyophilized to yield two fractions: the first fraction was collected as compound F-210 (36 mg, 9%) and the second fraction was collected as F-211 (37 mg, 10%), both as white solids.

[0145] Additional analogs were obtained according to the above procedure substituting the reagents as appropriate.Racemic Final compound Final compoundH H U I H F JOLXXT XX-16 FF-24 F-25uHF-17F-26 F-27Racemic Final compound Final compoundII H^X / N\X\| ¥ |‘(*R)n I 1 LxFF-18 o A Xcr o F X X x F-28 F-29oW u,F-5s<7 OdV'Oy SX.7 F-30 F-31N?H\ ¥ | (W ¥ 1CIA / M oF-12s7clzOON^N'QrN F-32 F-33 s¥ H i HF-19 XX>N<^N''CXF< FF^iN?VxO^ F-34 F-35HEH1 ¥ ¥ 1 LFFyW oF-21:vOiN?V¥lo¥F-36 F-37H Hxx / ^ X / N\X\I ¥ ¥ il ¥FF-15 XX / '\ / ' 0 FF-38F, OiA F-39N^OL0¥ H H XXX^ X / NX\\ ¥IIICR)¥ ¥FAXXX0XXxXMF-13FxCN^N<xrF-40 F-41 s¥NRacemic Final compound Final compoundHEH\ ¥ ¥R¥ ¥ 1F^A¥^^ ° V^NF-14FF sJ^ ^FF06^x1^ S^Z F-42 F-43II H\ ¥ ¥r¥ ¥ 1F-7 FV 'N- ■xdZ'x^v F-45F-449 Hz\ / \ / \ / r-\X\\ ¥ ¥r¥ ¥ 1F-8F4 I N—F ^= / ■XG"^¥ >F-47F-469 H| 10¥¥¥ / NF-10FT N—.joi-Vn^F-49F-48N H| ¥ pw ¥ 1o VKAF-1.xi4!x,u.N-_yF-51F-50Uf H?ANA> oF-11F-53F-529: HFniN^N^dVNF-2rT N—F¥iN(Vx6i^N.N_F-80 F-81Racemic Final compound Final compoundft HF-3rFCC<^ A N—FxAso^,yF-82 F-83ft H| ¥ Yew I I IF-4 A\^A A O AF 0 FF¥CNXN^QOIFF-84 F-85ft 1 HF-87 Y(*R¥ VY To ^NA0AFFF-88rA A F-8'9" XV: ft HF-91 F^ JXL / IWJ / N(‘R?uX I XF FF-94 F-95ft 3 H fF-98 A 4;F-97 F-96NEH f f Y ¥< X j F-197=A ^¥:c|zW 0 U^FF-103 F-104ft i H fF-198 XX^N(^x XX< F, JOA A,F FFF-105 F-106?FH rV j A wF-189 o A A ^F N ¥< FF F-202Synthesis of (*R)- / V-(4-(difluoromethoxy)-3-fluorophenyl)-2-(6-fluoro-1-oxoisoquinolin-2(1 H)-yl)propanamide (F-54) and (*S)- / V-(4-(difluoromethoxy)-3-fluorophenyl)-2-(6-fluoro-1-oxoisoquinolin-2(1 H)-yl)propanamide (F-55)

[0146] TCFH [207915-99-9] (361 mg, 1.29 mmol) was added in one portion to a solution of I-9 (202 mg, 0.859 mmol), 4-difluoromethoxy-3-fluoroaniline (CAS [83190-01-6], 117 pL, 0.945 mmol, 1.1 eq.), and 1 -methylimidazole [616-47-7] (144 pL, 1.80 mmol) in dry acetonitrile (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and was extracted with dichloromethane. The aqueous layer was extracted again with dichloromethane. The combined organic layer was dried over MgSO₄and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 100:0 to 70:30 heptane: EtOH / EtOAc 1 / 3) to afford the racemic brown solid (305 mg, 87% yield). The racemic mixture was purified by preparative SFC (stationary phase: Phenomenex Lux Celullose-1 5 pm 150 x 21.2 mm, Mobile phase: 25% MeOH + 0.1 % DEA) to afford F-54 (110 mg, 32% yield) as a white solid and F-55 (111 mg, 33% yield) as a white solid.

[0147] Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate. HATU or TATU may be used as coupling reagents, DIPEA, TEA or NMI may be used as bases and DMF may be used as solvent.Amine Carboxy Final compound Final compoundlie acid1? H[10687I-9 JOO^ONTjtf7-33-2]Fj05^N'CyFF-56 F-57IJ? H1[1003865-65- I-9 oFJO6(^NA03] F^F F^F F-58 F-599: H\ T 7(*R)T II n[12357I-92-58-7] F^F F^F F FF-60 F-619EH 9: H| T II(*R)Y II T \ T ^(’sjY Y TI-26 I-9FNFNF-62 F-63N?H f 9 = H 1| || |(*RY T T [ if YsY T TI-28 I-9 ° M\xNuLN-_uLN-_F-64 F-659 T HI-29 I-9 XO™J TQLSFY Y ru F-66 N- / F-679: H fI-30 I-9 XO™T vCs Y Y iYF-68 N- / F-69Amine Carboxy Final compound Final compoundlie acid9 < H H r H[19301I-24 XX JN(*^NYX XY\XTNXX 7-26-4] X XF-70 F-71? T H U I H[13516J3J(< XX o59-13- I-96] X XF-72 F-73? = H j? 1 H( If W Y n w Y;I-32 I-9 F N-y F 1 N »X / F-74 F-75??H 7 H! H 71-31 I-9 w *< TX XsXF-76 F-77Synthesis of (*R)-2-(6-fluoro-1-oxoisoquinolin-2(1 / 7)-yl)- / V-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-78) and (*S)-2-(6-fluoro-1-oxoisoquinolin-2(1 / 7)-yl)- / V-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propanamide (F-79)DichloroethanePyridine Dichloroethane

[0148] 1-Chloro- / V, / \ / ,2-trimethylpropenylamine (113 pL, 0.85 mmol) was added to a solution of I-9 (100 mg, 0.40 mmol) in dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The volatiles were removed in vacuo. To the resulting solid was added dichloroethane (2 mL), 3-amino-2-fluoro-6-(trifluoromethyl)pyridine (75 mg, 0.42 mmol) andpyridine (0.2 mL, 2.48 mmol). The resulting mixture was stirred at rt 16 h. The mixture was diluted up with water and dichloromethane and the layers separated. The organic phase was washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0:100 to 100:0 MeOH: DCM) to afford a solid. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) to afford the racemic mixture as a white solid. This racemic mixture was purified by preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) to afford F-78 (20 mg, 13% yield) and F-79 (20 mg, 13% yield) as white solids.Synthesis of 2-(6-fluoro-1-oxoisoquinolin-2(1 H)-yl)-N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)propenamide (F-98)I-33A solution of I-33 (100 mg, 0.394 mmol), 3-amino-2-fluoro-6-(trifluoromethyl)pyridine [117519-15-0] (75 mg, 0.416 mmol) and pyridine (0.2 mL, 0.98 g / mL, 2.48 mmol) in DCE (2 mL) was stirred at rt 16 h. The mixture was diluted up with water and DCM and the phases separated. The organic phase was washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified twice via flash column chromatography (from 0:100 to 10:100 (MeOH: DCM). A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) yielding F-98 (55 mg, 34% yield) as a white solid.Synthesis of (*R)-2-(4,6-difluoro-1-oxoisoquinolin-2(1 H)-yl)-N-(4- (trifluoromethoxy)phenyl)propanamide (F-199) and (*S)-2-(4,6-difluoro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(trifluoromethoxy)phenyl)propanamide (F-200)Cs2CO3DMFCesium carbonate (944 mg, 2.898 mmol) was added in a 25 mL round bottom flask consisting of I-35 (350 mg, 1.932 mmol), 1-19 (724 mg, 2.319 mmol) and DMF (5.8 mL) at rt. The mixture was stirred at 50°C for 2 h to give a heterogeneous mixture. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried over MgSO₄, filtered and concentered in vacuo to give a white solid. The solid was subjected to silica gel chromatography (25 g, dry on silica; irregular silica 40-60 pm 60A; 0-25% EtOAc / Heptane) to yield a white solid. Then, the solid was triturated with Et20. The resultant solid was purified by preparative SFC (Stationary phase: Phenomenex Lux Cellulose-1 5pm 150 x 21.2 mm, Mobile phase: CO2, ISO 35% methanol + 0.1% DEA). The two isolated fractions were diluted with water (10 mL) and extracted with EtOAc (2 x 20mL). The combined organic layers of both fractions were collected and concentrated in vacuo to give a F-199 (89.4 mg, 11% yield) as white solid and F-200 (93.4 mg, 11% yield) as a white solid.Synthesis of rac-(R)-2-(2-ethoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)-N-(2-fluoro-6- (trifluoromethyl)pyridin-3-yl)propanamide (F-187)I-39 F-187 LiHMDS solution (1 M in THF) (1.8 mL, 1.8 mmol) was added dropwise via syringe to a 50 mL round-bottomed flask containing a stirring solution consisting of I-39 (260 mg, 0.896 mmol), 3- amino-2-fluoro-6-(trifluoromethyl)pyridine [117519-15-0] (161 mg, 0.896 mmol) and dry THF (8.6 mL) at 0 °C and under N2 atmosphere to give an orange homogeneous solution. This mixture wasstirred at rt for 1h. The mixture was diluted with EtOAc (3 x 20 mL) and washed with NH4CI (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The solid was subjected to silica gel chromatography (25 g, irregular 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 45-85% (v / v) ACN / water (25 mM NH₄HCO₃)). The compound-containing fractions were collected and lyophilized to yield F-187 (127 mg, 33%) as a white solid.Synthesis of 2-(2-ethoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)-N-(4- (trifluoromethyl)phenyl)propanamide (F-188)I-39 F-188 LiHMDS solution (1 M in THF) (1.86 mL, 1.86 mmol) was added dropwise via syringe to a stirred solution consisting of I-39 (270 mg, 0.930 mmol), and 4-(trifluoromethyl)aniline (0.117 ml, 0.930 mmol) in dry THF (9 mL) at 0 °C and under N2 atmosphere to give an orange homogeneous solution. This mixture was stirred at rt for 1h. The mixture was diluted with EtOAc (3 x 20 mL) and washed with NH4CI (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, irregular silica 40-60 pm 60 A; 0-20% EtOAc / heptane). The compoundcontaining fractions were collected and lyophilized to yield F-188 (201 mg, 53%) as a white solid.Synthesis of 2-(6-ethoxy-1-oxo-2-isoquinolyl)-N-[2-fluoro-6-(trifluoromethyl)-3-pyridyl]propenamide (F-189)[117519-15-0]THFI -42F-189A solution of LiHMDS (1 M in THF) (3.1 mL, 3.1 mmol) was added dropwise via syringe to a stirred solution I-42 (300 mg, 1.037 mmol), 2-fluoro-6-(trifluoromethyl)pyridin-3-amine [117519-15-0] (187 mg, 1.037 mmol) in dry THF (10.4 mL) at 0 °C under a N2 atmosphere to give an orange homogeneous solution, which was further stirred at rt for 1 h. The mixture was diluted with NH4CI (10 mL) and extracted with EtOAc (60 mL). The combined extracts were dried over anhydrousMgSO₄, filtered and concentrated to dryness in vacuo to give an orange solid. The solid was subjected to silica gel chromatography (25 g silica irregular 40-60 pm 60 A; 0-15% Heptane / EtOAc) to give a yellow solid, which was subjected to HPLC (Water Xbridge 10 pm (C18), 30 x 100 mm column, gradient 30-73% (v / v) MeCN / water (25 mM NH₄HCO₃)). The compound-containing fractions were lyophilized to yield (F-189) (238 mg, 54%) as a white solid.Synthesis of N-(2,3-difluoro-4-(trifluoromethyl)phenyl)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)propanamide (F-203)A LiHMDS solution (1 M in THF) (2.4 mL, 2.4 mmol) was added dropwise via syringe to stirred solution of 1-12 (250 mg, 0.796 mmol), 2,3-difluoro-4-(trifluoromethyl)aniline (157 mg, 0.796 mmol) in dry THF (8 mL) at 0 °C and under N2 atmosphere to give an orange homogeneous solution. This mixture was stirred at rt for 2.5 h then it was diluted with EtOAc (3 x 20 mL) and washed with NH4CI (20 mL). The organic layer was dried over MgSO₄, filtered and concentrated to dryness in vacuo to give a yellow solid. The solid was subjected to purification by silica gel chromatography (25 g, irregular silica 40-60 pm 60 A; 0-20% EtOAc / heptane) and then HPLC (Water Xbridge 10 pm (C18), 30 x 100 mm column, gradient 45-85% (v / v) ACN / water (25 mM NH₄HCO₃)). The compound-containing fractions were collected and lyophilized to yield F-203 (95 mg, 25%) as a white solidSynthesis of N-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-oxo-2-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl)butanamide (F-205)A LiHMDS solution (1 M in THF) (2.3 mL, 2.28 mmol) was added dropwise via syringe to a stirred solution of I-43 (250 mg, 0.762 mmol), and 2-fluoro-6-(trifluoromethyl)-3-pyridinamine (137 mg, 0.762 mmol) in dry THF (7.6 mL) at 0 °C and under N2 atmosphere to give an orangehomogeneous solution. This mixture was stirred at rt for 1 h, then it was diluted with NH4CI (10 mL 0) and extracted with EtOAc (60 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give an orange solid. The solid was subjected to purification by silica gel chromatography (20 g silica irregular 40-60 pm 60 A; 0-20% Heptane / EtOAc) and then 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-205 (227 mg, 64%) as a white solid.Additional analogs were synthesized according to the above procedure substituting the reagents as appropriate.Intermediate Aniline Final compoundFO CUF.oMF F F F1-12 [69409-98-9] F-204Additional analogs were synthesized according to one of the above procedures substituting the reagents, the reactants and the purification methods as appropriate.ZI &$ %Final compound Co. No Rt [M+H]+ [M-H]- Methode areaQF-109 0.99 92 378.2 376.1 4F-110 2.21 100 429.2 427.2 10FU3O^NXJTFF-110_1 2.21 100 429.2 427.2 10F-111 2.08 97 397.3 395.3 10F-112 2.09 100 397.3 395.3 104 F-113 1.88 100 361.3 359.3 10tl '"F-114 1.88 100 427.0 425.1 10t- F-115 2.17 99 413.2 411.2 10F-116 1.95 100 379.2 n.d 10O„N PXQ o ® -INHXX F-117 1.98 100 398.3 396.2 10F-117_1 1.98 100 398.2 396.2 10F-118 2.28 100 397.2 395.2 10IL N <psr>lA?FF-118_1 2.26 100 397.2 395.2 10 o2 Hbtb ■'?"ttt itt rf e- SF----C ° ° F-119 1.88 100 361.3 359.4 10F<s> ° f^iiF F F U. NprjAFF-119_1 1.88 100 361.3 359.4 10 TT NO2 HF-120 2.27 100 397.2 395.2 10F-120_1 2.28 100 397.2 395.2 10< VXN& IYNY^NF-121 1.79 100 395.3 393.2 10F-122 1.71 100 362.3 360.3 104 F-123 2.00 99 408.3 406.3 10^^ / ...o=IZ IZF-124 2.18 100 409.4 407.3 10 0 t o. F-125 1.97 100 377.3 n.d 10 F W MVWNQT^NAAFFF-125_1 1.97 100 377.3 n.d 10 S:HF-126 1.81 100 380.2 n.d 10F-127 1.92 100 413.2 411.3 10 ClO0^S< / 'NF-128 2.44 100 410.2 408.2 167o cF-129 1.96 100 379.2 377.3 10 IZ LL ZI LL ZI LL ZI ZI(8 I0ttt i "--- ° F-130 1.94 100 379.2 377.3 10F.FF F3>< Vll ‘^(S)°NorlJkFF-130_1 1.94 100 379.2 377.3 10 TT No -HF-131 1.74 100 362.2 360.3 10F-131_1 1.74 100 362.2 360.3 10F^fsn> F-132 2.13 97 413.1 411.3 9F-132_1 2.12 100 413.1 411.3 9Fu^sn>F-133 1.94 100 390.4 388.3 10 x°) £n0- ( o= H ZI ZI TlF-134 2.14 100 391.1 389.2 10 0o0"n' -nF-135 2.12 100 375.2 373.2 10F-136 1.59 100 390.3 n.d 10,’O?ySXVF-136_1 1.59 100 390.3 n.d 10F-137 2.17 98 409.3 407.3 10F-137_1 2.17 100 409.3 407.3 10I O C z F-138 1.09 96 412.1 410.1 4 if& %IZ ZI dQz"IZ ZI F-139 1.00 99 413.1 411.1 4 o a / (sX "0- ° °" ■fzvXo °S-N< V o\7 \7 F-140 1.11 92 412.3 410.4 4 X \7 X^^XXXX^N^XXX^ F-141 1.11 97 412.1 410.1 4F-142 1.71 100 410.3 408.4 10R R N JZN—WX(S)9 r TNNprVk F-142_1 1.71 100 410.3 408.4 10 X N OHS-NF-143 1.99 100 412.3 410.4 10 XQ^-CCS-NF(S)O^NorlJU AA F-143_1 1.99 100 412.3 410.4 10 o -HF-144 1.11 99 412.1 410.1 4 X^N^XXtN? AFV il<. VA^ Ni(esd)A o A fxyANF-144_1 1.11 99 412.1 410.1 4 o -Hn3Hm ^ oN / nAA F-145 2.65 99 402.2 400.2 12L / ° F HC[f^l N^AZ>(R|f)°NC^^jiAJAS F-146 1.93 98 412.2 410.4 10 L7F-146_1 1.93 98 412.2 410.4 10F-147 1.95 100 428.1 426.3 10;<CQ.YS. Xjri?F-148 2.00 100 408.1 406.3 10;ioaV6x■<CQy. Cri?F-149 1.99 100 428.2 426.3 10?3(S)o NF-149_1 1.98 100 428.2 426.3 10 J £ Hu:HF-150 2.06 100 444.2 442.2 10 C (R) 0hchAJ^SI U N FF-150_1 2.06 100 444.2 442.2 10,joi^:xjy.o n3H fFW Pr<7 ° ^(R, ONY¥ F-151 2.00 99 430.2 428.2 10 t "o IZF-151_1 2.00 99 430.2 428.2 10 0o ~ _.n iV'Ou F-152 1.98 100 408.4 406.2 10F-153 1.83 100 392.2 390.5 10 g-NF-154 1.93 100 413.2 411.3 10 ■'CQY1!ZPF-155 2.08 100 413.4 411.3 10u:HCA f^Y\^^i(^R)YONxA F-156 2.00 100 408.2 406.3 10XzF-156_1 2.00 100 408.2 406.3 10F-157 2.08 100 n.d 411.3 10FFxAA(S)0^¥°YFULN^NXJ F F-157_1 2.08 100 n.d 411.3 10 o -HF-158 2.02 98 428.4 426.4 13~n JAB7239WOPCT1° HF[Mf Q°=? sdTf Y Y F-159 1.81 100 397.4 395.2 10°y o^o\=L7ZI^KA 9I / -\ZnN.fl Yp 7 z zNC°”^ Y \ / \ / F-160 1.91 100 395.2 393.3 10 A^VIR) O MYSIZ=A^W? / FjodN&Kt\sF-160_1 1.91 100 395.2 393.3 10N^7FF Xn'\F-161 2.04 100 441.2 439.3 10FACQY. XJ"FF Xn'\F-162 1.89 100 442.2 440.2 14^^CQyBCr°TFF-163 2.07 100 428.2 426.2 14N3H _ NFP[ YW F-164 2.04 100 396.2 394.2 150SJF-165 1.86 99 396.2 394.2 14F-166 2.01 100 430.2 428.2 10,€d&hiY.°3HFffVY^lV F-166_1 2.01 100 430.2 428.2 10L / H3HCIA n^M?^ oNri F-167 1.78 98 397.3 395.3 9ZN'NF-168 1.88 98 407.1 405.2 2uHF-169 1.83 96 409.3 407.2 11ZN~N“'CQY-XT' F-170 2.15 100 355.2 353.2 2F-174 3.94 99 427.1 n.d 10- HFF-175 3.71 99 428.1 n.d 1ro > XtO,F-176 3.71 99 428.1 n.d 1F TX^ -Crr' F-177 4.08 99 413.0 n.d 1F-178 3.85 99 430.0 n.d 1F-179 3.85 99 430.0 n.d 1 XQy, XXo -HFF-180 3.41 99 414.0 n.d 1FlU^vN (s)° r"^YQrANAJ)° Y F F F-181 3.93 97 427.1 n.d 10 -H" T| JAB7239WOPCT1H IHP Qy°= F-185 1.89 99 442.2 440.4 14(S) 0F / N-NZIz z\ / \ / F-186 2.1 97 396.2 n.d. 14 z\=ADDITIONAL CHARACTERISING DATA LCMS FINAL % UV LCMS CODERT [M+H]+[M-H]- COMPOUND AREAF-1 3.4 95 407.1 n.d. 1F-2 1.77 100 409.2 407.4 2F-3 1.85 98 409.3 407.3 3F-4 1.05 93 377.0 375.3 4F-5 1.82 99 376.0 n.d. 2F-6 2.2 100 361.2 359.3 2F-7 3.76 97 441.2 n.d. 2F-8 3.46 99 442.2 n.d. 2395.1 2F-9 3.29 97 n.d.[M+Na]F-10 3.14 99 391.1 n.d. 1F-11 3.057 99 404.1 n.d. 1F-12 1.98 100 410.2 408.4 2F-13 1.89 100 394.2 392.3 6F-14 2.07 100 444.2 442.3 3F-15 2.06 100 395.3 393.4 2F-16 2.18 100 395.2 393.3 6F-17 2.05 100 377.2 375.3 6F-18 2.19 99 411.2 409.3 6F-19 2.04 100 379.3 377.4 2F-20 2.18 100 429.2 427.4 2F-21 2.2 100 445.3 443.3 2F-22 3.02 99 373.1 n.d. 1F-23 3.02 99 373.1 n.d. 1FINAL % UV LCMS CODE RT [M+H]+[M-H]- COMPOUND AREAF-24 2.16 100 395.2 393.3 2 F-25 2.16 100 395.2 393.3 2 F-26 2.05 100 377.2 375.3 6 F-27 2.05 100 377.2 375.3 6 F-28 2.2 98 411.2 409.3 6 F-29 2.2 100 410.1 409.3 6 F-30 1.82 100 376.2 374.4 2 F-31 1.82 100 376.2 374.4 2 F-32 2 100 410.2 408.3 2 F-33 2 100 410.3 408.2 2 F-34 2.03 100 379.1 377.4 2 F-35 2.03 1000 379.1 377.4 2 F-36 2.2 100 445.3 443.4 2 F-37 2.2 100 445.3 443.3 2 F-38 2.04 100 395.2 393.4 2 F-39 2.04 100 395.2 393.4 2 F-40 1.85 100 394.2 392.4 2 F-41 1.85 100 394.2 392.4 2 F-42 2.04 100 444.3 442.3 2 F-43 2.04 100 444.3 442.3 2 F-44 3.763 99 441.2 n.d. 2 F-45 3.764 99 441.2 n.d. 2 F-46 3.285 99 422.2 n.d. 1 F-47 3.324 99 422.2 n.d. 1 F-48 3.158 98 391.1 n.d. 1 F-49 3.140 99 391.1 n.d. 1 F-50 3.453 99 407.1 n.d. 1 F-51 99 3,453 407.2 n.d. 1 F-52 3.037 99 404.2 n.d. 1 F-53 3.018 99 404.3 n.d. 1 F-54 1.96 100 393.2 n.d. 3 F-55 1.96 100 393.2 n.d. 3 F-56 1.88 100 380.2 378.2 3 F-57 1.89 100 380.2 378.2 3FINAL % UV LCMS CODE RT [M+H]+[M-H]- COMPOUND AREAF-58 1.92 100 395.1 393.2 3 F-59 1.92 100 395.1 393.2 3 F-60 2.08 100 413.3 411.3 2 F-61 2.08 100 413.3 411.3 2 F-62 1.66 99 410.5 408.3 3 F-63 1.66 98 410.5 408.3 3 F-64 1.85 100 427.3 425.5 2 F-65 1.85 100 427.3 425.5 2 F-66 1.78 100 395.4 393.2 3 F-67 1.78 100 395.4 393.2 3 F-68 1.90 99 413.3 411.2 3 F-69 1.90 100 413.3 411.2 3 F-70 2.00 100 408.3 406.4 2 F-71 2.00 100 408.3 406.4 2 F-72 1.77 100 378.3 376.4 2 F-73 1.77 100 378.3 376.4 2 F-74 1.79 100 413.4 411.3 3 F-75 1.79 100 413.4 411.3 3 F-76 1.92 100 412.1 410.3 2 F-77 1.92 100 412.1 410.3 2 F-78 2.00 100 398.3 396.3 3 F-79 2.00 99 398.3 396.3 3 F-80 1.79 100 409.3 407.3 2 F-81 1.79 100 409.3 407.4 2 F-82 1.85 98 409.3 407.3 3 F-83 1.85 100 409.3 407.3 3 F-84 1.91 100 375.3 n.d. 6 F-85 1.91 100 375.3 n.d. 6 F-87 1.94 95 396.2 394.3 2 F-88 1.94 97 n.d 394.3 9 F-89 1.94 100 n.d 394.3 9 F-90 3.97 99 446.0 n.d 1 F-91 1.20 96 431.1 429.1 4 F-92 3.97 99 446.0 n.d 1FINAL % UV LCMS CODE RT [M+H]+[M-H]- COMPOUND AREAF-93 3.97 99 446.0 n.d 1 F-94 2.14 99 n.d 429.2 6 F-95 2.14 100 n.d 429.2 6 F-96 2.00 99 398.3 396.1 10 F-97 2.00 100 398.3 396.1 10 F-98 1.98 100 398.2 396.3 10 F-99 3.81 99 449.0 n.d. 1 F-100 3.81 99 449.0 n.d. 1 F-101 4.08 99 448.0 n.d. 1 F-102 4.08 99 448.0 n.d. 1 F-103 2.09 100 414.2 412.3 9 F-104 2.09 100 414.2 412.3 9 F-105 3.91 99 397.0 n.d. 1 F-106 3.91 99 397.0 n.d. 1 F-107 4.42 98 429.1 n.d. 1 F-108 4.42 98 429.1 n.d. 1 F-187 3.95 99 425.1 n.d 1 F-188 4.06 99 406.1 n.d 1 F-189 3.99 99 424.2 n.d 1 F-190 3.99 99 424.2 n.d 1 F-191 4.06 99 406.2 n.d 1 F-192 4.06 99 406.2 n.d 1 F-193 3.95 99 425.2 n.d 1 F-194 3.95 99 425.2 n.d 1 F-195 3.82 99 449.0 n.d. 1 F-196 4.08 99 448.0 n.d. 1 F-197 2.11 100 414.3 412.3 11 F-198 3.91 99 397.1 n.d. 1 F-199 4.07 99 397.0 n.d. 1 F-200 4.07 99 413.0 n.d. 1 F-201 4.31 99 397.0 n.d. 1 F-202 3.99 99 424.2 n.d 1 F-203 4.13 99 466.1 n.d. 1 F-204 4.06 99 448.1 n.d. 1FINAL % UV LCMS CODERT [M+H]+[M-H]- COMPOUND AREAF-205 4.11 99 463.1 n.d. 1F-206 4.11 99 463.1 n.d. 1F-207 4.11 98 463.1 n.d. 1F-208 4.06 99 448.1 n.d. 1F-209 4.07 99 448.1 n.d. 1F-210 4.13 99 466.1 n.d. 1F-211 4.14 99 466.1 n.d. 1SFC ANALYTICAL DATARt means retention time (in minutes), [M+H]+ means the protonated mass of the compound, method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds.Final Compound Rt, UV area, Isomer elution order MethodF-92 Rt: 3.37, Area: 99%, 1steluting isomer 3F-93 Rt: 4.47, Area: 99%, 2ndeluting isomer 3F-99 Rt: 3.59, Area: 99%, 1steluting isomer 2F-100 Rt: 5.54, Area: 99%, 2ndeluting isomer 2F-101 Rt: 4.52, Area: 98%, 1steluting isomer 3F-102 Rt: 5.68, Area: 99%, 2ndeluting isomer 3F-107 Rt: 4.41, Area: 99%, 1steluting isomer 3F-108 Rt: 5.50, Area: 99%, 2ndeluting isomer 3F-191 Rt: 4.89, Area: 99%, 1steluting isomer 1F-192 Rt: 8.38, Area: 99%, 2ndeluting isomer 1F-193 Rt: 3.84, Area: 99%, 1steluting isomer 1F-194 Rt: 6.50, Area: 99%, 2ndeluting isomer 1F-202 Rt: 4.35, Area: 99%, 1steluting isomer 3F-190 Rt: 5.45, Area: 99%, 2ndeluting isomer 3F-206 Rt: 3.64, Area: 99%, 1steluting isomer 2F-207 Rt: 6.06, Area: 99%, 2ndeluting isomer 2F-210 Rt: 3.21, Area: 99%, 1steluting isomer 3F-211 Rt: 4.03, Area: 99%, 2ndeluting isomer 3NMR DATAOF FINAL COMPOUNDSCo.1H NMR CHARACTERIZATIONNo.1H NMR (400 MHz, DMSO-d6) d ppm 1.67 (d, J = 7.34 Hz, 3 H), 3.85 (s, 3 H), 5.64 (d, J = 7.44 Hz, 1 H), 6.62 (d, J = 2.19 Hz, 1 H), 6.69 (d, J = 7.63 F-1 Hz, 1 H), 7.52 (dd, J = 8.68, 2.10 Hz, 1 H), 7.59 - 7.65 (m, 3 H), 7.68 - 7.76 (m, 3 H), 7.83 (d, J = 2.00 Hz, 1 H), 8.21 (d, J = 8.68 Hz, 1 H), 10.21 - 10.54 (m, 1 H).1H NMR (CHLOROFORM-d, 400 MHz) d ppm 8.71 (s, 1H), 8.50 (dd, 1H, J = 5.7, 8.9 Hz), 8.24 (t, 1H, J = 8.4 Hz), 7.5-7.5 (m, 2H), 7.35 (d, 1H, J = 2.2 F-2 Hz), 7.33 (d, 1H, J = 7.6 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 Hz), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.58 (d, 1H, J = 7.6 Hz), 6.47 (d, 1H, J = 2.3 Hz), 5.87 (q, 1H, J = 7.2 Hz), 3.92 (s, 3H), 1.73 (d, 3H, J = 7.2 Hz)1H NMR (CHLOROFORM-d, 400 MHz) d ppm 8.91 (s, 1H), 8.45 (dd, 1H, J = 5.7, 8.9 Hz), 7.87 (t, 1H, J = 8.5 Hz), 7.60 (dd, 1H, J = 2.1, 13.1 Hz), 7.37 (d, F-3 1 H, J = 2.3 Hz), 7.34 (d, 1 H, J = 7.6 Hz), 7.22 (dt, 1 H, J = 2.5, 8.7 Hz), 7.16 (ddd, 2H, J = 2.3, 6.1, 8.7 Hz), 6.62 (dd, 1H, J = 2.3, 3.9 Hz), 6.59 (d, 1H, J = 7.6 Hz), 5.82 (q, 1 H, J = 7.2 Hz), 3.94 (s, 3H), 1.71 (d, 3H, J = 7.2 Hz).1H NMR (CHLOROFORM-d, 400 MHz) d ppm 8.70 (brs, 1H), 8.46 (dd, 1H, J = 5.7, 8.9 Hz), 7.50 (d, 2H, J = 8.1 Hz), 7.3-7.3 (m, 2H), 7.2-7.3 (m, 2H), F-47.06 (d, 2H, J = 8.1 Hz), 6.58 (d, 1H, J = 7.3 Hz), 6.42 (t, 1H, J = 73.9 Hz), 5.79 (q, 1 H, J = 7.2 Hz), 1.71 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, DMSO-d6) d ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.67 (q, J = 7.2 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 7.50 - 7.55 (m, 1 H), 7.57 (d, J = 7.5 F-5Hz, 1 H), 7.67 - 7.77 (m, 5 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 2 H), 8.24 (d, J = 8.0 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.68 (d, J = 7.5 Hz, 3 H), 5.60 - 5.67 (m, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 7.48 - 7.53 (m, 1 H), 7.53 - 7.56 (m, 1 H), F-67.66 - 7.76 (m, 4 H), 7.79 - 7.84 (m, 2 H), 8.20 - 8.24 (m, 1 H), 10.67 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 10.38 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.79 (dd, J = 8.5, 1.5 Hz, 1H), 7.74-7.67 (m, 4H), 7.61 F-7(d, J = 8.7 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.2 Hz, 1 H), 5.67 (q, J = 7.3 Hz, 1 H), 3.86 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) d ppm 10.41 (s, 1H), 8.83 (d, J = 8.3 Hz, 1 H), 7.98 (t, J = 8.5 Hz, 2H), 7.75 - 7.65 (m, 3H), 7.61 (d, J = 8.7 Hz, 2H), F-86.90 (d, J = 7.9 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.65 (q, J = 7.3 Hz, 1 H), 3.86 (s, 3H), 1.72 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) d ppm 10.37 (s, 1H), 8.23 (d, J = 8.0 Hz, F-91 H), 7.76 - 7.66 (m, 5H), 7.62 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1 H),7.51 (t, J = 7.4 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.2 Hz, 1 H), 5.67 (q, J = 7.3 Hz, 1H), 3.86 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) d ppm 10.37 (s, 1H), 8.28 (dd, J = 8.9, 5.9 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.64 - 7.59 (m, 3H), F-10 7.52 (dd, J = 9.9, 2.6 Hz, 1 H), 7.35 (td, J = 8.8, 2.6 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.64 (q, J = 7.3 Hz, 1 H), 3.86 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) d ppm 1.68 (d, J = 7.34 Hz, 3 H), 3.86 (s, 3 H), 3.99 (s, 3 H), 5.63 (q, J = 7.25 Hz, 1 H), 6.55 - 6.68 (m, 2 H), 6.91 (d, J = F-118.77 Hz, 1 H), 7.61 (d, J = 8.77 Hz, 2 H), 7.67 - 7.76 (m, 3 H), 7.80 (d, J = 7.72 Hz, 1 H), 8.34 - 8.41 (m, 1 H), 10.40 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 7.53 (dd, J = 8.7, 2.1 Hz, 1 H), 7.65 F-12 (d, J = 7.6 Hz, 1 H), 7.72 - 7.74 (m, 2 H), 7.74 - 7.76 (m, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 3.3 Hz, 1 H), 7.90 - 7.94 (m, 2 H), 8.22 (d, J = 8.6 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 7.36 (td, J = 8.8, 2.6 Hz, 1 H), 7.53 F-13(dd, J = 9.9, 2.6 Hz, 1 H), 7.62 - 7.76 (m, 4 H), 7.87 - 7.94 (m, 3 H), 8.29 (dd, J = 8.9, 5.9 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.71 (d, J = 7.3 Hz, 3 H), 5.63 - 5.69 F-14 (m, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 7.71 - 7.81 (m, 5 H), 7.87 - 7.94 (m, 3 H), 8.19 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = F-15 7.4 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.31 - 7.38 (m, 3 H), 7.51 - 7.73 (m, 4 H), 8.28 (dd, J = 8.9, 5.9 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.62 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 7.53 (dd, J = 8.6, 2.1 Hz, 1 H), 7.64 F-16(d, J = 7.6 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.79 - 7.86 (m, 3 H), 8.21 (d, J = 8.6 Hz, 1 H), 10.69 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = F-17 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.49 - 7.57 (m, 2 H), 7.65 - 7.77 (m, 4 H), 8.23 (d, J = 8.0 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) d ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.53 (dd, J F-18= 8.6, 2.1 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 7.84 (d, J = 2.1 Hz, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 6 ppm 1.68 (d, J = 7.32 Hz, 3 H), 5.62 (q, J = 7.28 Hz, 1 H), 6.71 (d, J = 7.52 Hz, 1 H), 7.35 (td, J = 8.83, 2.61 Hz, 1 H), F-19 7.53 (dd, J = 9.88, 2.56 Hz, 1 H), 7.62 (d, J = 7.52 Hz, 1 H), 7.69 (d, J = 8.57 Hz, 2 H), 7.82 (d, J = 8.57 Hz, 2 H), 8.28 (dd, J = 8.94, 5.90 Hz, 1 H), 10.69 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 (d, J = 7.32 Hz, 3 H), 5.65 (q, J = F-20 7.32 Hz, 1 H), 6.89 (d, J = 7.52 Hz, 1 H), 7.66 - 7.74 (m, 3 H), 7.77 - 7.85 (m, 3 H), 8.19 (s, 1 H), 8.41 (d, J = 8.36 Hz, 1 H), 10.70 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = F-21 7.2 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.69 - 7.82 (m, 4 H), 8.19 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 10.54 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.37 (s, 1H), 8.23 (d, J = 8.0 Hz, 1 H), 7.75 - 7.66 (m, 5H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1 H), F-227.53 - 7.48 (m, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.2 Hz, 1 H), 5.67 (q, J = 7.3 Hz, 1H), 3.85 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.37 (s, 1H), 8.23 (d, J = 8.0 Hz, 1 H), 7.76 - 7.66 (m, 5H), 7.65 - 7.60 (m, 2H), 7.56 (d, J = 7.6 Hz, 1 H), 7.51 F-23(ddd, J = 8.2, 6.9, 1.5 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.67 (q, J = 7.3 Hz, 1 H), 3.85 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.4 Hz, 3 H), 5.62 (q, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.53 (dd, J = 8.6, 2.1 Hz, 1 H), 7.64 F-24(d, J = 7.6 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.81 (d, J = 8.6 Hz, 2 H), 7.84 (d, J = 2.1 Hz, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 10.49 - 10.88 (m, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.62 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 7.53 (dd, J = 8.7, 2.1 Hz, 1 H), 7.63 F-25(d, J = 7.6 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 2 H), 7.82 (d, J = 8.6 Hz, 2 H), 7.84 (d, J = 2.0 Hz, 1 H), 8.21 (d, J = 8.6 Hz, 1 H), 10.70 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = F-26 7.3 Hz, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.49 - 7.58 (m, 2 H), 7.66 - 7.78 (m, 4 H), 8.23 (d, J = 8.0 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = F-27 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.48 - 7.58 (m, 2 H), 7.66 - 7.78 (m, 4 H), 8.23 (d, J = 8.2 Hz, 1 H), 10.52 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = 7.2 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.53 (dd, J F-28= 8.6, 2.1 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 7.84 (d, J = 2.1 Hz, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 6 ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.53 (dd, J F-29= 8.7, 2.1 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.68 - 7.75 (m, 2 H), 7.84 (d, J = 2.1 Hz, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.67 (q, J = 7.4 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 7.52 (td, J = 7.4, 1.4 Hz, 1 H), 7.57 F-30(d, J = 7.6 Hz, 1 H), 7.68 - 7.77 (m, 5 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.90 - 7.94 (m, 2 H), 8.24 (d, J = 8.0 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.67 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 7.52 (ddd, J = 8.1, 6.8, 1.4 Hz, 1 H), F-317.57 (d, J = 7.6 Hz, 1 H), 7.67 - 7.78 (m, 5 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.90 - 7.95 (m, 2 H), 8.24 (d, J = 8.0 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 7.53 (dd, J = 8.6, 2.1 Hz, 1 H), 7.64 F-32 (d, J = 7.6 Hz, 1 H), 7.72 - 7.74 (m, 2 H), 7.74 - 7.77 (m, 1 H), 7.84 (d, J = 2.1 Hz, 1 H), 7.88 (d, J = 3.2 Hz, 1 H), 7.90 - 7.96 (m, 2 H), 8.22 (d, J = 8.7 Hz, 1 H), 10.60 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 7.53 (dd, J = 8.7, 2.1 Hz, 1 H), 7.64 F-33(d, J = 7.6 Hz, 1 H), 7.71 - 7.77 (m, 3 H), 7.84 (d, J = 2.1 Hz, 1 H), 7.88 (d, J = 3.3 Hz, 1 H), 7.90 - 7.94 (m, 2 H), 8.22 (d, J = 8.7 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 (d, J = 7.32 Hz, 3 H), 5.62 (q, J = 7.35 Hz, 1 H), 6.70 (d, J = 7.63 Hz, 1 H), 7.35 (td, J = 8.83, 2.51 Hz, 1 H), F-34 7.52 (dd, J = 9.88, 2.56 Hz, 1 H), 7.62 (d, J = 7.63 Hz, 1 H), 7.69 (d, J = 8.78 Hz, 2 H), 7.81 (d, J = 8.57 Hz, 2 H), 8.27 (dd, J = 8.88, 5.85 Hz, 1 H), 10.69 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 (d, J = 7.32 Hz, 3 H), 5.62 (q, J = 7.32 Hz, 1 H), 6.70 (d, J = 7.63 Hz, 1 H), 7.35 (td, J = 8.83, 2.61 Hz, 1 H), F-35 7.52 (dd, J = 9.88, 2.56 Hz, 1 H), 7.62 (d, J = 7.63 Hz, 1 H), 7.69 (d, J = 8.67 Hz, 2 H), 7.81 (d, J = 8.57 Hz, 2 H), 8.27 (dd, J = 8.94, 5.91 Hz, 1 H), 10.68 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.60 - 5.67 F-36 (m, 1 H), 6.88 (d, J = 7.5 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.64 - 7.81 (m, 4 H), 8.18 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 10.55 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.63 (q, J = F-37 7.2 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.67 - 7.81 (m, 4 H), 8.18 (s, 1 H), 8.41 (d, J = 8.5 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 6 ppm 1.67 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = 7.3 Hz, 1 H), 6.69 (d, J = 7.5 Hz, 1 H), 7.30 - 7.37 (m, 3 H), 7.52 (dd, J = F-389.9, 2.6 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.67 - 7.73 (m, 2 H), 8.27 (dd, J = 8.9, 5.9 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.66 (d, J = 7.3 Hz, 3 H), 5.61 (q, J = 7.3 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 7.30 - 7.38 (m, 3 H), 7.52 (dd, J = F-399.8, 2.6 Hz, 1 H), 7.61 (d, J = 7.5 Hz, 1 H), 7.66 - 7.74 (m, 2 H), 8.27 (dd, J = 8.9, 5.9 Hz, 1 H), 10.53 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 (d, J = 7.3 Hz, 3 H), 5.64 (q, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 7.35 (td, J = 8.9, 2.6 Hz, 1 H), 7.52 F-40(dd, J = 9.9, 2.6 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.71 - 7.76 (m, 3 H), 7.86 - 7.94 (m, 3 H), 8.28 (dd, J = 8.9, 5.9 Hz, 1 H), 10.57 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.69 (d, J = 7.3 Hz, 3 H), 5.61 - 5.76 (m, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 7.35 (td, J = 8.9, 2.6 Hz, 1 H), 7.52 (dd, J F-41= 9.9, 2.6 Hz, 1 H), 7.62 - 7.76 (m, 4 H), 7.86 - 7.95 (m, 3 H), 8.28 (dd, J = 8.9, 5.9 Hz, 1 H), 10.58 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 (d, J = 7.3 Hz, 3 H), 5.66 (q, J = F-42 7.3 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 7.71 - 7.93 (m, 8 H), 8.19 (s, 1 H), 8.42 (d, J = 8.4 Hz, 1 H), 10.59 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 (d, J = 7.3 Hz, 3 H), 5.66 (q, J = F-43 7.3 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 7.71 - 7.93 (m, 8 H), 8.19 (s, 1 H), 8.42 (d, J = 8.4 Hz, 1 H), 10.59 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.39 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.79 (dd, J = 8.5, 1.6 Hz, 1H), 7.76-7.67 (m, 4H), 7.61 F-44(d, J = 8.8 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.67 (q, J = 7.3 Hz, 1 H), 3.86 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.39 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.79 (dd, J = 8.5, 1.6 Hz, 1H), 7.74-7.67 (m, 4H), 7.61 F-45(d, J = 8.7 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.66 (q, J = 7.3 Hz, 1H), 3.85 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.40 (s, 1H), 8.83 (d, J = 8.1 Hz, 1 H), 7.98 (t, J = 8.4 Hz, 2H), 7.71 (dd, J = 12.0, 5.0 Hz, 3H), 7.61 (d, J = 8.5 F-46Hz, 2H), 6.90 (d, J = 7.8 Hz, 1 H), 6.62 (d, J = 1.4 Hz, 1 H), 5.65 (q, J = 7.4 Hz, 1 H), 3.85 (s, 3H), 1.72 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.40 (s, 1H), 8.83 (d, J = 8.3 Hz, F-471 H), 7.98 (t, J = 8.4 Hz, 2H), 7.76 - 7.67 (m, 3H), 7.61 (d, J = 8.3 Hz, 2H),6.90 (d, J = 7.8 Hz, 1 H), 6.62 (s, 1 H), 5.65 (q, J = 7.4 Hz, 1 H), 3.85 (s, 3H), 1.72 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.38 (s, 1H), 8.28 (dd, J = 8.9, 5.9 Hz, 1 H), 7.76 - 7.67 (m, 3H), 7.64 - 7.59 (m, 3H), 7.52 (dd, J = 9.8, 2.4 Hz, F-481 H), 7.35 (td, J = 8.8, 2.5 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 6.66 - 6.59 (m, 1 H), 5.64 (q, J = 7.2 Hz, 1 H), 3.86 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.38 (s, 1H), 8.28 (dd, J = 8.9, 5.9 Hz, 1 H), 7.76 - 7.66 (m, 3H), 7.65 - 7.59 (m, 3H), 7.52 (dd, J = 9.8, 2.4 Hz, F-491 H), 7.35 (td, J = 8.8, 2.5 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 2.2 Hz, 1 H), 5.64 (q, J = 7.3 Hz, 1 H), 3.86 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5 ppm ppm 1.67 (d, J = 7.34 Hz, 3 H), 3.85 (s, 3 H), 5.64 (q, J = 7.18 Hz, 1 H), 6.62 (d, J = 2.19 Hz, 1 H), 6.69 (d, J = F-50 7.63 Hz, 1 H), 7.52 (dd, J = 8.63, 2.05 Hz, 1 H), 7.62 (t, J = 8.96 Hz, 3 H), 7.68 - 7.73 (m, 3 H), 7.83 (d, J = 2.00 Hz, 1 H), 8.21 (d, J = 8.68 Hz, 1 H), 10.38 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.67 (d, J = 7.25 Hz, 3 H), 3.85 (s, 3 H), 5.60 - 5.66 (m, 1 H), 6.62 (d, J = 2.29 Hz, 1 H), 6.69 (d, J = 7.63 Hz, 1 F-51H), 7.48 - 7.57 (m, 1 H), 7.62 (t, J = 8.96 Hz, 3 H), 7.67 - 7.73 (m, 3 H), 7.83 (d, J = 2.00 Hz, 1 H), 8.21 (d, J = 8.58 Hz, 1 H), 10.38 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 (d, J = 7.34 Hz, 3 H), 3.86 (s, 3 H), 3.99 (s, 3 H), 5.64 (q, J = 7.22 Hz, 1 H), 6.59 - 6.66 (m, 2 H), 6.92 (d, J = F-528.77 Hz, 1 H), 7.62 (d, J = 8.58 Hz, 2 H), 7.68 - 7.74 (m, 3 H), 7.81 (d, J = 7.72 Hz, 1 H), 8.38 (d, J = 8.77 Hz, 1 H), 10.40 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 (d, J = 7.34 Hz, 3 H), 3.86 (s, 3 H), 3.99 (s, 3 H), 5.63 (q, J = 7.25 Hz, 1 H), 6.59 - 6.66 (m, 2 H), 6.92 (d, J = F-538.77 Hz, 1 H), 7.62 (d, J = 8.68 Hz, 2 H), 7.68 - 7.77 (m, 3 H), 7.80 (d, J = 7.82 Hz, 1 H), 8.34 - 8.42 (m, 1 H), 10.40 (s, 1 H).1H NMR (400 MHz, Chloroform-d) 5 ppm 10.60 (s, 1H), 8.28 (dd, 1H, J = 6.0, 8.9 Hz), 7.7-7.8 (m, 1 H), 7.60 (d, 1 H, J = 7.6 Hz), 7.52 (dd, 2H, J = 2.6, F-549.9 Hz), 7.16 (t, 1H, J = 73.5 Hz), 7.0-7.4 (m, 3H), 6.70 (d, 1H, J = 7.6 Hz), 5.59 (q, 1 H, J = 7.3 Hz), 1.66 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.60 (s, 1H), 8.28 (dd, 1H, J = 5.9, 8.9 Hz), 7.74 (d, 1H, J= 13.8 Hz), 7.61 (d, 1H, J = 7.5 Hz), 7.52 (dd, 1H, J = F-552.6, 9.9 Hz), 7.0-7.4 (m, 3H), 7.17 (t, 1H, J = 72.9 Hz), 6.70 (d, 1H, J = 7.6 Hz), 5.60 (q, 1 H, J = 7.3 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.91 (br s, 1H), 8.91 (d, 1H, J = 2.4 F-56Hz), 8.2-8.3 (m, 2H), 7.87 (d, 1H, J = 8.6 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.53(dd, 1H, J = 2.6, 9.9 Hz), 7.35 (dt, 1H, J = 2.6, 8.8 Hz), 6.71 (d, 1H, J = 7.5 Hz), 5.61 (q, 1 H, J = 7.3 Hz), 1.69 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.91 (br s, 1H), 8.91 (d, 1H, J = 2.4 Hz), 8.2-8.3 (m, 2H), 7.88 (d, 1H, J = 8.6 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.53 F-57(dd, 1H, J = 2.6, 9.9 Hz), 7.35 (dt, 1H, J = 2.6, 8.9 Hz), 6.71 (d, 1H, J = 7.5 Hz), 5.61 (q, 1 H, J = 7.3 Hz), 1.69 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 8.85 (br s, 1H), 8.47 (dd, 1H, J = 5.6, 8.9 Hz), 8.1-8.2 (m, 1H), 7.32 (d, 1H, J = 7.6 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 F-58Hz), 7.17 (dd, 1H, J = 2.4, 9.1 Hz), 6.8-6.9 (m, 2H), 6.43 (t, 1H, J = 73.3 Hz), 6.58 (d, 1 H, J = 7.5 Hz), 5.88 (q, 1 H, J = 7.2 Hz), 1.73 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 8.80 (br s, 1H), 8.48 (dd, 1H, J = 5.6, 8.9 Hz), 8.2-8.2 (m, 1 H), 7.31 (d, 1 H, J = 7.5 Hz), 7.22 (dt, 1 H, J = 2.5, 8.6 F-59Hz), 7.17 (dd, 1H, J = 2.4, 9.1 Hz), 6.9-6.9 (m, 2H), 6.43 (t, 1H, J = 73.4 Hz), 6.58 (d, 1 H, J = 7.5 Hz), 5.86 (q, 1 H, J = 7.2 Hz), 1.73 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.28 (br s, 1H), 8.28 (dd, 1H, J = 5.9, 8.9 Hz), 7.89 (t, 1 H, J = 8.9 Hz), 7.59 (d, 1 H, J = 7.6 Hz), 7.5-7.5 (m, 2H), F-607.35 (dt, 1 H, J = 2.6, 8.8 Hz), 7.22 (td, 1 H, J = 1.2, 9.0 Hz), 6.69 (d, 1 H, J = 7.5 Hz), 5.73 (q, 1 H, J = 7.3 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.28 (br s, 1H), 8.28 (dd, 1H, J = 6.0, 8.9 Hz), 7.90 (t, 1 H, J = 8.8 Hz), 7.60 (d, 1 H, J = 7.6 Hz), 7.5-7.5 (m, 2H), F-617.35 (dt, 1 H, J = 2.6, 8.9 Hz), 7.22 (td, 1 H, J = 1.2, 9.0 Hz), 6.69 (d, 1 H, J = 7.6 Hz), 5.74 (q, 1 H, J = 7.3 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.89 (s, 1H), 8.50 (dd, 1H, J = 5.7, 8.9 Hz), 8.01 (ddd, 1H, J = 1.9, 7.0, 8.9 Hz), 7.68 (ddd, 1H, J = 2.3, 7.3, 9.2 F-64 Hz), 7.39 (d, 1H, J = 2.3 Hz), 7.31 (d, 1H, J = 7.5 Hz), 7.2-7.3 (m, 1H), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.62 (dd, 1H, J = 2.3, 3.8 Hz), 6.59 (d, 1H, J = 7.5 Hz), 5.86 (q, 1 H, J = 7.2 Hz), 3.9-4.0 (m, 3H).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.88 (s, 1H), 8.50 (dd, 1H, J = 5.7, 9.0 Hz), 8.0-8.0 (m, 1 H), 7.68 (ddd, 1 H, J = 2.3, 7.3, 9.2 Hz), 7.39 (d, 1 H, J F-65 = 2.3 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.2-7.3 (m, 1H), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.62 (dd, 1H, J = 2.3, 3.8 Hz), 6.59 (d, 1H, J = 7.5 Hz), 5.86 (q, 1H, J = 7.2 Hz), 3.95 (s, 3H), 1.74 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) δ ppm 9.22 (s, 1H), 8.68 (dd, 1H, J = 0.9, 2.4 Hz), 8.43 (dd, 1H, J = 5.5, 8.9 Hz), 8.1-8.2 (m, 1H), 8.1-8.1 (m, 1H), 7.87 F-66 (d, 1 H, J = 3.2 Hz), 7.38 (d, 1 H, J = 3.2 Hz), 7.33 (d, 1 H, J = 7.6 Hz), 7.2-7.2 (m, 2H), 6.62 (d, 1 H, J = 7.6 Hz), 5.84 (q, 1 H, J = 7.2 Hz), 1.74 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 6 ppm 9.21 (s, 1H), 8.68 (dd, 1H, J = 0.9, 2.4 Hz), 8.43 (dd, 1H, J = 5.6, 8.9 Hz), 8.1-8.2 (m, 1H), 8.1-8.1 (m, 1H), 7.87 F-67 (d, 1 H, J = 3.2 Hz), 7.38 (d, 1 H, J = 3.2 Hz), 7.32 (d, 1 H, J = 7.6 Hz), 7.2-7.2 (m, 2H), 6.62 (d, 1 H, J = 7.6 Hz), 5.84 (q, 1 H, J = 7.2 Hz), 1.75 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 9.12 (s, 1H), 8.78 (dd, 1H, J = 8.3, 9.6 Hz), 8.51 (dd, 1 H, J = 5.7, 8.9 Hz), 8.03 (d, 1 H, J = 8.3 Hz), 7.87 (d, 1 H, F-68 J = 3.2 Hz), 7.41 (d, 1H, J = 3.2 Hz), 7.29 (d, 1H, J = 7.6 Hz), 7.2-7.3 (m, 1H), 7.18 (dd, 1H, J = 2.5, 9.0 Hz), 6.61 (d, 1H, J = 7.6 Hz), 5.84 (q, 1H, J = 7.2 Hz), 1.76 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 9.13 (s, 1H), 8.78 (dd, 1H, J = 8.3, 9.6 Hz), 8.51 (dd, 1 H, J = 5.7, 8.9 Hz), 8.03 (d, 1 H, J = 8.3 Hz), 7.87 (d, 1 H, F-69 J = 3.2 Hz), 7.41 (d, 1H, J = 3.2 Hz), 7.29 (d, 1H, J = 7.6 Hz), 7.26 (s, 1H), 7.18 (dd, 1H, J = 2.5, 9.0 Hz), 6.61 (d, 1H, J = 7.6 Hz), 5.84 (q, 1H, J = 7.2 Hz), 1.76 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.81 (s, 1H), 8.46 (dd, 1H, J = 5.6, 8.9 Hz), 7.9-7.9 (m, 2H), 7.82 (d, 1H, J = 3.3 Hz), 7.3-7.7 (m, 2H), 7.33 (d, F-70 1H, J = 7.3 Hz), 7.28 (d, 1H, J = 3.3 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 Hz), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.58 (d, 1H, J = 7.3 Hz), 5.57 (t, 1H, J = 7.8 Hz), 2.39 (quind, 1 H, J = 7.3, 14.4 Hz), 2.0-2.1 (m, 2H), 1.02 (t, 3H, J = 7.3 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.81 (s, 1H), 8.46 (dd, 1H, J = 5.7, 8.9 Hz), 7.9-7.9 (m, 2H), 7.82 (d, 1H, J = 3.3 Hz), 7.62 (d, 2H, J = 8.7 Hz), 7.33 (d, 1 H, J = 7.6 Hz), 7.28 (d, 1 H, J = 3.3 Hz), 7.22 (dt, 1 H, J = 2.5, 8.7 F-71Hz), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.58 (d, 1H, J = 7.3 Hz), 5.57 (t, 1H, J = 7.8 Hz), 2.39 (quind, 1H, J = 7.4, 14.4 Hz), 2.0-2.1 (m, 2H), 1.02 (t, 3H, J = 7.3 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 9.29 (s, 1H), 8.36 (dd, 1H, J = 5.6, 8.7 Hz), 7.94 (d, 2H, J = 7.9 Hz), 7.3-7.7 (m, 3H), 7.36 (d, 1H, J = 7.6 Hz), F-727.1-7.2 (m, 3H), 6.59 (d, 1H, J = 7.3 Hz), 5.89 (q, 1H, J = 7.2 Hz), 1.73 (d, 3H, J = 7.1 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 9.29 (s, 1H), 8.37 (dd, 1H, J = 5.6, 8.7 Hz), 7.9-8.0 (m, 2H), 7.6-7.7 (m, 3H), 7.36 (d, 1H, J = 7.6 Hz), 7.1-7.2 F-73(m, 3H), 6.59 (d, 1H, J = 7.3 Hz), 5.88 (q, 1H, J = 7.1 Hz), 1.73 (d, 3H, J = 7.1 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 10.07 (s, 1H), 8.47 (d, 1H, J = 1.0 F-74 Hz), 8.28 (dd, 1H, J = 2.0, 12.5 Hz), 8.21 (dd, 1H, J = 5.6, 8.7 Hz), 7.97 (d, 1H, J = 3.1 Hz), 7.43 (d, 1H, J = 3.1 Hz), 7.33 (d, 1H, J = 7.3 Hz), 7.1-7.2(m, 2H), 6.62 (d, 1H, J = 7.6 Hz), 5.91 (q, 1H, J = 7.1 Hz), 1.73 (d, 3H, J = 7.1 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 10.10 (s, 1H), 8.4-8.5 (m, 1H), 8.28 (dd, 1H, J = 2.0, 12.5 Hz), 8.20 (dd, 1H, J = 5.6, 8.7 Hz), 7.97 (d, 1H, J F-75= 3.2 Hz), 7.43 (d, 1H, J = 3.2 Hz), 7.33 (d, 1H, J = 7.6 Hz), 7.1-7.2 (m, 2H), 6.62 (d, 1H, J = 7.6 Hz), 5.91 (q, 1H, J = 7.1 Hz), 1.73 (d, 3H, J = 7.1 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.94 (br s, 1H), 8.51 (dd, 1H, J = 5.7, 9.0 Hz), 8.36 (t, 1 H, J = 8.3 Hz), 7.83 (d, 1 H, J = 3.2 Hz), 7.73 (dd, 1 H, F-76J = 1.9, 11.5 Hz), 7.67 (d, 1H, J = 8.3 Hz), 7.3-7.3 (m, 2H), 7.2-7.3 (m, 2H), 6.59 (d, 1 H, J = 7.6 Hz), 5.86 (q, 1 H, J = 7.4 Hz), 1.74 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.94 (br s, 1H), 8.51 (dd, 1H, J = 5.7, 8.9 Hz), 8.36 (t, 1 H, J = 8.2 Hz), 7.83 (d, 1 H, J = 3.2 Hz), 7.73 (dd, 1 H, F-77 J = 1.9, 11.6 Hz), 7.67 (d, 1H, J = 8.7 Hz), 7.32 (s, 1H), 7.3-7.3 (m, 1H), 7.2- 7.2 (m, 1H), 7.18 (dd, 1H, J = 2.5, 9.0 Hz), 6.59 (d, 1H, J = 7.5 Hz), 5.86 (q, 1 H, J = 7.3 Hz), 1.74 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.70 (d, J = 7.3 Hz, 3 H) 5.71 - 5.83 (m, 1 H) 6.71 (d, J = 7.5 Hz, 1 H) 7.36 (td, J = 8.9, 2.6 Hz, 1 H) 7.53 (dd, J = F-789.8, 2.5 Hz, 1 H) 7.62 (d, J = 7.6 Hz, 1 H) 7.88 (d, J = 8.2 Hz, 1 H) 8.27 (dd, J = 8.9, 6.0 Hz, 1 H) 8.70 (t, J = 8.7 Hz, 1 H) 10.75 (s, 1 H).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.70 (d, J = 7.3 Hz, 3 H) 5.77 (q, J = 7.3 Hz, 1 H) 6.71 (d, J = 7.6 Hz, 1 H) 7.35 (td, J = 8.8, 2.6 Hz, 1 H) 7.53 (dd, F-79J = 9.9, 2.6 Hz, 1 H) 7.62 (d, J = 7.6 Hz, 1 H) 7.88 (d, J = 8.2 Hz, 1 H) 8.27 (dd, J = 8.9, 5.9 Hz, 1 H) 8.70 (t, J = 8.7 Hz, 1 H) 10.75 (br s, 1 H).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.72 (s, 1H), 8.50 (dd, 1H, J = 5.7, 8.9 Hz), 8.24 (t, 1 H, J = 8.4 Hz), 7.5-7.5 (m, 2H), 7.35 (d, 1 H, J = 2.3 Hz), F-80 7.33 (d, 1H, J = 7.6 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 Hz), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.58 (d, 1H, J = 7.6 Hz), 6.47 (d, 1H, J = 2.3 Hz), 5.87 (q, 1H, J = 7.2 Hz), 3.92 (s, 3H), 1.73 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.72 (br d, 1H, J = 2.9 Hz), 8.50 (dd, 1 H, J = 5.7, 8.9 Hz), 8.24 (t, 1 H, J = 8.4 Hz), 7.5-7.5 (m, 2H), 7.35 (d, F-81 1H, J = 2.3 Hz), 7.33 (d, 1H, J = 7.3 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 Hz), 7.17 (dd, 1H, J = 2.5, 9.1 Hz), 6.58 (d, 1H, J = 7.3 Hz), 6.47 (d, 1H, J = 2.3 Hz), 5.87 (q, 1 H, J = 7.2 Hz), 3.92 (s, 3H), 1.73 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) 5 ppm 8.87 (s, 1H), 8.45 (dd, 1H, J = 5.6, F-82 8.9 Hz), 7.88 (t, 1H, J = 8.5 Hz), 7.60 (dd, 1H, J = 2.1, 13.1 Hz), 7.37 (d, 1H, J = 2.3 Hz), 7.33 (d, 1H, J = 7.6 Hz), 7.22 (dt, 1H, J = 2.6, 8.7 Hz), 7.1-7.2(m, 2H), 6.62 (dd, 1H, J = 2.3, 3.9 Hz), 6.59 (d, 1H, J = 7.6 Hz), 5.81 (q, 1H, J = 7.2 Hz), 3.94 (s, 3H), 1.71 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) δ ppm 8.86 (s, 1H), 8.46 (dd, 1H, J = 5.7, 8.9 Hz), 7.88 (t, 1H, J = 8.5 Hz), 7.60 (dd, 1H, J = 2.1, 13.0 Hz), 7.37 (d, 1H, F-83 J = 2.3 Hz), 7.33 (d, 1H, J = 7.6 Hz), 7.22 (dt, 1H, J = 2.5, 8.7 Hz), 7.16 (dt, 2H, J = 2.3, 8.4 Hz), 6.63 (dd, 1H, J = 2.3, 3.9 Hz), 6.59 (d, 1H, J = 7.6 Hz), 5.81 (q, 1H, J = 7.2 Hz), 3.94 (s, 3H), 1.71 (d, 3H, J = 7.2 Hz).1H NMR (400 MHz, Chloroform-d) δ ppm 9.22 (s, 1H), 8.3-8.4 (m, 1H), 7.5- 7.6 (m, 2H), 7.36 (d, 1H, J = 7.6 Hz), 7.1-7.2 (m, 2H), 7.0-7.0 (m, 2H), 6.59 F-84(d, 1 H, J = 7.6 Hz), 6.41 (t, 1 H, J = 74.0 Hz), 5.88 (q, 1 H, J = 7.2 Hz), 1.71 (d, 3H, J = 7.1 Hz).1H NMR (400 MHz, Chloroform-d) δ ppm 9.20 (brs, 1H), 8.3-8.4 (m, 1H), 7.5-7.6 (m, 2H), 7.36 (d, 1H, J = 7.5 Hz), 7.1-7.2 (m, 2H), 7.00 (d, 2H, J = F-858.9 Hz), 6.59 (d, 1 H, J = 7.4 Hz), 6.41 (t, 1 H, J = 74.9 Hz), 5.87 (q, 1 H, J = 7.1 Hz), 1.71 (d, 3H, J = 7.1 Hz).1H NMR (DMSO-d6, 400 MHz) δ ppm 10.70 (s, 1H), 8.55 (d, 1H, J = 2.7 Hz), 8.27 (dd, 1H, J = 5.9, 8.9 Hz), 8.20 (dd, 1H, J = 2.8, 8.8 Hz), 7.61 (d, F-87 1 H, J = 7.5 Hz), 7.52 (dd, 1 H, J = 2.5, 9.8 Hz), 7.35 (dt, 1 H, J = 2.6, 8.9 Hz), 7.30 (d, 1 H, J = 8.9 Hz), 6.70 (d, 1 H, J = 7.6 Hz), 5.60 (q, 1 H, J = 7.2 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (DMSO-d6, 400 MHz) δ ppm 10.71 (brs, 1H), 8.56 (d, 1H, J = 2.3 Hz), 8.28 (dd, 1H, J = 5.9, 8.9 Hz), 8.21 (dd, 1H, J = 2.8, 8.8 Hz), 7.61 (d, F-88 1 H, J = 7.6 Hz), 7.52 (dd, 1 H, J = 2.6, 9.9 Hz), 7.35 (dt, 1 H, J = 2.6, 8.9 Hz), 7.30 (d, 1 H, J = 8.9 Hz), 6.70 (d, 1 H, J = 7.6 Hz), 5.61 (q, 1 H, J = 7.3 Hz), 1.68 (d, 3H, J = 7.3 Hz).1H NMR (DMSO-d6, 400 MHz) δ ppm 10.71 (brs, 1H), 8.56 (d, 1H, J = 2.3 Hz), 8.28 (dd, 1H, J = 6.0, 8.9 Hz), 8.21 (dd, 1H, J = 2.7, 8.9 Hz), 7.61 (d, F-89 1 H, J = 7.6 Hz), 7.52 (dd, 1 H, J = 2.5, 9.8 Hz), 7.35 (dt, 1 H, J = 2.6, 8.9 Hz), 7.30 (d, 1 H, J = 8.8 Hz), 6.71 (d, 1 H, J = 7.5 Hz), 5.62 (q, 1 H, J = 7.3 Hz), 1.68 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (s, 1 H), 8.82 (d, J = 8.30 Hz, 1 H), 7.97 (dd, J = 8.06, 3.86 Hz, 2 H), 7.70 (d, J = 9.06 Hz, 2 H), 7.33 (d, J = F-90 8.77 Hz, 2 H), 6.89 (d, J = 7.82 Hz, 1 H), 5.62 (q, J = 7.18 Hz, 1 H), 1.71 (d, J = 7.25 Hz, 3 H).1H NMR (CHLOROFORM-d, 400 MHz) 6 ppm 9.08 (br s, 1H), 8.50 (dd, 1H, J = 5.7, 8.9 Hz), 8.05 (ddd, 1H, J = 2.5, 7.5, 9.6 Hz), 7.3-7.3 (m, 1H), 7.1-7.2 F-91 (m, 2H), 7.0-7.1 (m, 1H), 6.60 (d, 1H, J = 7.5 Hz), 5.81 (q, 1H, J = 7.3 Hz), 1.7-1.8 (m, 3H).1H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (s, 1 H), 8.82 (d, J = 8.20 Hz, 1 H), 7.97 (dd, J = 8.06, 3.77 Hz, 2 H), 7.73-7.67 (m, 2 H), 7.33 (d, J = 8.77 F-92 Hz, 2 H), 6.89 (d, J = 7.82 Hz, 1 H), 5.62 (q, J = 7.22 Hz, 1 H), 1.71 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.54 (s, 1 H), 8.82 (d, J = 8.30 Hz, 1 H), 7.97 (dd, J = 8.06, 4.05 Hz, 2 H), 7.70 (d, J = 9.06 Hz, 2 H), 7.33 (d, J = F-93 8.77 Hz, 2 H), 6.90 (d, J = 7.82 Hz, 1 H), 5.62 (q, J = 7.28 Hz, 1 H), 1.72 (d, J = 7.25 Hz, 3 H).1H NMR (DMSO-d6, 400 MHz) δ ppm 10.49 (brs, 1H), 8.27 (dd, 1H, J = 6.0, 8.9 Hz), 7.7-7.7 (m, 1 H), 7.59 (d, 1 H, J = 7.6 Hz), 7.52 (dd, 1 H, J = 2.6, 9.9 F-94 Hz), 7.3-7.4 (m, 2H), 6.69 (d, 1 H, J = 7.6 Hz), 5.71 (q, 1 H, J = 7.2 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (DMSO-d6, 400 MHz) δ ppm 10.49 (brs, 1H), 8.27 (dd, 1H, J = 5.9, 8.9 Hz), 7.71 (t, 1 H, J = 8.3 Hz), 7.59 (d, 1 H, J = 7.6 Hz), 7.52 (dd, 1 H, J = F-95 2.6, 9.9 Hz), 7.42 (br t, 1 H, J = 8.4 Hz), 7.35 (dt, 1 H, J = 2.6, 8.8 Hz), 6.69 (d, 1H, J = 7.5 Hz), 5.71 (q, 1H, J = 7.4 Hz), 1.67 (d, 3H, J = 7.3 Hz).1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (d, J = 7.3 Hz, 3 H) 5.77 (q, J = 7.3 Hz, 1 H) 6.71 (d, J = 7.6 Hz, 1 H) 7.35 (td, J = 8.8, 2.6 Hz, 1 H) 7.53 (dd, F-96 J = 9.9, 2.6 Hz, 1 H) 7.62 (d, J = 7.6 Hz, 1 H) 7.88 (d, J = 8.2 Hz, 1 H) 8.27 (dd, J = 8.9, 5.9 Hz, 1 H) 8.70 (t, J = 8.7 Hz, 1 H) 10.75 (br s, 1 H)1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (d, J = 7.3 Hz, 3 H) 5.71 - 5.83 (m, 1 H) 6.71 (d, J = 7.5 Hz, 1 H) 7.36 (td, J = 8.9, 2.6 Hz, 1 H) 7.53 (dd, J = F-97 9.8, 2.5 Hz, 1 H) 7.62 (d, J = 7.6 Hz, 1 H) 7.88 (d, J = 8.2 Hz, 1 H) 8.27 (dd, J = 8.9, 6.0 Hz, 1 H) 8.70 (t, J = 8.7 Hz, 1 H) 10.75 (s, 1 H)1H NMR (400 MHz, DMSO-d6): δ ppm 1.69 (d, J = 7.3 Hz, 3 H) 5.76 (q, J = 7.2 Hz, 1 H) 6.71 (d, J = 7.5 Hz, 1 H) 7.35 (td, J = 8.8, 2.6 Hz, 1 H) 7.53 (dd, F-98 J = 9.9, 2.6 Hz, 1 H) 7.62 (d, J = 7.6 Hz, 1 H) 7.87 (d, J = 8.3 Hz, 1 H) 8.27 (dd, J = 8.9, 5.9 Hz, 1 H) 8.69 (t, J = 8.7 Hz, 1 H) 10.74 (br s, 1 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.81 (s, 1 H), 8.82 (d, J = 8.20 Hz, 1 H), 8.69 (t, J = 8.77 Hz, 1 H), 7.98 (t, J = 8.15 Hz, 2 H), 7.88 (d, J = 8.30 F-99 Hz, 1 H), 6.90 (d, J = 7.92 Hz, 1 H), 5.79 (q, J = 7.25 Hz, 1 H), 1.74 (d, J = 7.25 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.81 (s, 1 H), 8.82 (d, J = 8.30 Hz, 1 H), 8.69 (t, J = 8.77 Hz, 1 H), 7.98 (t, J = 8.15 Hz, 2 H), 7.88 (d, J = 8.20 F-100 Hz, 1 H), 6.90 (d, J = 7.82 Hz, 1 H), 5.79 (q, J = 7.31 Hz, 1 H), 1.74 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.78 (s, 1 H), 8.73-8.67 (m, 1 H), 8.40 (d, J = 8.39 Hz, 1 H), 8.19 (s, 1 H), 7.88 (d, J = 8.20 Hz, 1 H), 7.79 (dd, F-101 J = 8.49, 1.62 Hz, 1 H), 7.72 (d, J = 7.63 Hz, 1 H), 6.89 (d, J = 7.53 Hz, 1 H), 5.79 (q, J = 7.15 Hz, 1 H), 1.72 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.79 (s, 1 H), 8.74-8.67 (m, 1 H), 8.40 (d, J = 8.39 Hz, 1 H), 8.20 (s, 1 H), 7.88 (d, J = 8.20 Hz, 1 H), 7.80 (dd, F-102 J = 8.54, 1.48 Hz, 1 H), 7.72 (d, J = 7.63 Hz, 1 H), 6.90 (d, J = 7.53 Hz, 1 H), 5.80 (q, J = 7.09 Hz, 1 H), 1.72 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.40 (br s, 1 H) 8.86 (t, J = 8.7 Hz, 1 H) 8.42 (d, J = 8.6 Hz, 1 H) 7.51 - 7.55 (m, 2 H) 7.49 (dd, J = 8.6, F-103 2.0 Hz, 1 H) 7.27 (d, J = 7.9 Hz, 1 H) 6.59 (d, J = 7.6 Hz, 1 H) 5.83 (q, J = 7.2 Hz, 1 H) 1.76 (d, J = 7.3 Hz, 3 H)1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.42 (br s, 1 H) 8.85 (t, J = 8.7 Hz, 1 H) 8.42 (d, J = 8.7 Hz, 1 H) 7.51 - 7.55 (m, 2 H) 7.49 (dd, J = 8.6, F-104 2.0 Hz, 1 H) 7.28 (d, J = 7.6 Hz, 1 H) 6.59 (d, J = 7.6 Hz, 1 H) 5.85 (q, J = 7.2 Hz, 1 H) 1.74 - 1.79 (m, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.72 (brs, 1 H), 8.73-8.66 (m, 1 H), 8.36-8.30 (m, 1 H), 7.92 (d, J = 7.53 Hz, 1 H), 7.87 (d, J = 8.20 Hz, 1 H), F-105 7.57 (dd, J = 9.25, 2.48 Hz, 1 H), 7.53-7.48 (m, 1 H), 5.75 (q, J = 7.09 Hz, 1 H), 1.70 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.71 (br s, 1 H), 8.70 (t, J = 8.73 Hz, 1 H), 8.36-8.31 (m, 1 H), 7.93 (d, J = 7.53 Hz, 1 H), 7.88 (d, J = 8.20 Hz, F-106 1 H), 7.58 (dd, J = 9.25, 2.48 Hz, 1 H), 7.54-7.48 (m, 1 H), 5.76 (q, J = 7.25 Hz, 1 H), 1.70 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.51 (s, 1 H), 8.26 (dd, J = 8.68, 1.91 Hz, 1 H), 7.92 (d, J = 7.44 Hz, 1 H), 7.83 (d, J = 2.00 Hz, 1 H), 7.72- F-107 7.66 (m, 3 H), 7.33 (d, J = 8.49 Hz, 2 H), 5.59 (q, J = 7.25 Hz, 1 H), 1.68 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.51 (s, 1 H), 8.26 (dd, J = 8.68, 1.81 Hz, 1 H), 7.92 (d, J = 7.44 Hz, 1 H), 7.83 (d, J = 2.00 Hz, 1 H), 7.72- F-108 7.66 (m, 3 H), 7.33 (d, J = 8.77 Hz, 2 H), 5.59 (d, J = 7.25 Hz, 1 H), 1.68 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.45-10.13 (m, 1 H), 8.70 (t, J = 8.77 Hz, 1 H), 8.34 (d, J = 8.87 Hz, 1 H), 7.87 (d, J = 8.20 Hz, 1 H), 7.78 (d, F-187 J = 7.82 Hz, 1 H), 6.88 (d, J = 8.77 Hz, 1 H), 6.60 (d, J = 7.82 Hz, 1 H), 5.75 (q, J = 7.31 Hz, 1 H), 4.45 (q, J = 7.06 Hz, 2 H), 1.69 (d, J = 7.25 Hz, 3 H), 1.36 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.70 (s, 1 H), 8.35 (d, J = 8.77 Hz, 1 H), 7.84-7.74 (m, 3 H), 7.69 (br d, J = 8.68 Hz, 2 H), 6.88 (d, J = 8.77 Hz, F-188 1 H), 6.60 (d, J = 7.72 Hz, 1 H), 5.59 (q, J = 7.18 Hz, 1 H), 4.45 (q, J = 7.06 Hz, 2 H), 1.68 (d, J = 7.34 Hz, 3 H), 1.36 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.71 (s, 1H), 8.75 - 8.63 (m, 1H), 8.14 - 8.05 (m, 1H), 7.89 - 7.83 (m, 1H), 7.54 - 7.47 (m, 1H), 7.14 - 7.12 (m, F-189 1H), 7.08 - 7.03 (m, 1H), 6.64 - 6.60 (m, 1H), 5.79 - 5.71 (m, 1H), 4.19 - 4.13 (m, 2H), 1.70 - 1.63 (m, 3H), 1.42 - 1.35 (m, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.72 (s, 1H), 8.69 (t, J = 8.7 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.5 Hz, F-190 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.5, 8.9 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.75 (q, J = 7.2 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 1.67 (d, J = 7.3 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.70 (s, 1 H), 8.35 (d, J = 8.87 Hz, 1 H), 7.83-7.75 (m, 3 H), 7.68 (d, J = 8.68 Hz, 2 H), 6.88 (d, J = 8.77 Hz, 1 F-191 H), 6.60 (d, J = 7.72 Hz, 1 H), 5.59 (d, J = 7.34 Hz, 1 H), 4.45 (q, J = 7.09 Hz, 2 H), 1.68 (d, J = 7.34 Hz, 3 H), 1.37 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.70 (s, 1 H), 8.35 (d, J = 8.77 Hz, F-1921 H), 7.83-7.76 (m, 3 H), 7.68 (d, J = 8.77 Hz, 2 H), 6.88 (d, J = 8.77 Hz, 1H), 6.60 (d, J = 7.72 Hz, 1 H), 5.60 (d, J = 7.34 Hz, 1 H), 4.45 (q, J = 7.03 Hz, 2 H), 1.68 (d, J = 7.34 Hz, 3 H), 1.37 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.77 (s, 1 H), 8.70 (s, 1 H), 8.34 (d, J = 8.87 Hz, 1 H), 7.87 (d, J = 8.20 Hz, 1 H), 7.78 (d, J = 7.82 Hz, 1 H), 6.89 F-193 (d, J = 8.77 Hz, 1 H), 6.60 (d, J = 7.82 Hz, 1 H), 5.75 (d, J = 7.34 Hz, 1 H), 4.45 (q, J = 7.06 Hz, 2 H), 1.69 (d, J = 7.34 Hz, 3 H), 1.37 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.77 (br s, 1 H), 8.69 (t, J = 8.73 Hz, 1 H), 8.34 (d, J = 8.77 Hz, 1 H), 7.85 (d, J = 8.20 Hz, 1 H), 7.78 (d, J = F-194 7.82 Hz, 1 H), 6.88 (d, J = 8.77 Hz, 1 H), 6.59 (d, J = 7.72 Hz, 1 H), 5.74 (d, J = 7.34 Hz, 1 H), 4.45 (q, J = 7.03 Hz, 2 H), 1.68 (d, J = 7.34 Hz, 3 H), 1.36 (t, J = 7.06 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.80 (s, 1 H), 8.82 (d, J = 8.30 Hz, 1 H), 8.69 (t, J = 8.73 Hz, 1 H), 7.98 (t, J = 8.06 Hz, 2 H), 7.88 (d, J = 8.20 F-195 Hz, 1 H), 6.91 (d, J = 7.82 Hz, 1 H), 5.79 (q, J = 7.25 Hz, 1 H), 1.74 (d, J = 7.25 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.82-10.74 (m, 1 H), 8.70 (t, J = 8.77 Hz, 1 H), 8.40 (d, J = 8.39 Hz, 1 H), 8.19 (s, 1 H), 7.88 (d, J = 8.20 Hz, F-196 1 H), 7.79 (dd, J = 8.54, 1.67 Hz, 1 H), 7.72 (d, J = 7.63 Hz, 1 H), 6.89 (d, J = 7.63 Hz, 1 H), 5.79 (q, J = 7.28 Hz, 1 H), 1.71 (d, J = 7.25 Hz, 3 H)1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.39 (br s, 1 H) 8.86 (t, J = 8.6 Hz, 1 H) 8.42 (d, J = 8.7 Hz, 1 H) 7.52 - 7.56 (m, 2 H) 7.49 (dd, J = 8.7, F-197 2.0 Hz, 1 H) 7.26 - 7.29 (m, 1 H) 6.59 (d, J = 7.6 Hz, 1 H) 5.83 (q, J = 7.2 Hz, 1 H) 1.76 (d, J = 7.2 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.76 (s, 1 H), 8.70 (t, J = 8.73 Hz, 1 F-198 H), 8.36-8.30 (m, 1 H), 7.90 (dd, J = 17.64, 7.82 Hz, 2 H), 7.59-7.48 (m, 2 H), 5.76 (q, J = 7.34 Hz, 1 H), 1.71 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, CHLOROFORM-d): δ ppm 8.87 (br s, 1 H), 8.50-8.42 (m, 1 H), 7.57-7.52 (m, 2 H), 7.42 (dd, J = 8.77, 2.38 Hz, 1 H), 7.36-7.29 (m, F-199 2 H), 7.14 (d, J = 8.87 Hz, 2 H), 5.81 (q, J = 7.12 Hz, 1 H), 1.72 (d, J = 7.15 Hz, 3 H)1H NMR (400 MHz, CHLOROFORM-d): δ ppm 8.78 (brs, 1 H), 8.48 (ddd, J F-200= 8.87, 5.44, 1.72 Hz, 1 H), 7.57-7.53 (m, 2 H), 7.43 (dd, J = 8.73, 2.53 Hz,1 H), 7.35-7.30 (m, 2 H), 7.15 (d, J = 8.77 Hz, 2 H), 5.79 (q, J = 6.99 Hz, 1 H), 1.71 (d, J = 7.15 Hz, 3 H)1H NMR (400 MHz, DMSO-d6) : δ ppm 10.51 (s, 1 H), 8.28-8.24 (m, 1 H), 7.92 (d, J = 7.44 Hz, 1 H), 7.83 (d, J = 2.00 Hz, 1 H), 7.71-7.67 (m, 3 H), F-201 7.33 (d, J = 8.87 Hz, 2 H), 5.59 (q, J = 7.28 Hz, 1 H), 1.68 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.72 (s, 1H), 8.69 (t, J = 8.7 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, F-202 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.5, 9.0 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.75 (q, J = 7.3 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 1.67 (d, J = 7.3 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.76 (s, 1 H), 8.82 (d, J = 8.30 Hz, F-203 1 H), 8.00-7.91 (m, 3 H), 7.59 (t, J = 7.53 Hz, 1 H), 6.90 (d, J = 7.82 Hz, 1 H), 5.77 (q, J = 7.28 Hz, 1 H), 1.74 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (brs, 1H), 8.82 (d, J = 8.3 Hz, 1H), 8.13 (t, J = 8.1 Hz, 1H), 7.97 (dd, J = 6.6, 8.0 Hz, 2H), 7.76 (dd, J = 1.6, F-204 10.9 Hz, 1H), 7.56 (br d, J = 8.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.78 (q, J = 7.2 Hz, 1H), 1.73 (d, J = 7.3 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.79 (s, 1H), 8.77 (d, J = 8.2 Hz, 1 H), 8.63 (t, J = 8.7 Hz, 1 H), 7.91 (dd, J = 8.2, 9.3 Hz, 2H), 7.81 (d, J = 8.2 F-205 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 5.76 (dd, J = 5.1, 10.6 Hz, 1H), 2.26 - 2.03 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.87 (s, 1H), 8.84 (d, J = 8.3 Hz, 1 H), 8.70 (t, J = 8.7 Hz, 1 H), 7.99 (dd, J = 8.2, 9.4 Hz, 2H), 7.88 (d, J = 8.1 F-206 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 5.83 (dd, J = 5.2, 10.5 Hz, 1H), 2.35 - 2.11 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.87 (br s, 1H), 8.84 (d, J = 8.3 Hz, 1 H), 8.70 (t, J = 8.8 Hz, 1 H), 7.99 (dd, J = 8.2, 9.6 Hz, 2H), 7.88 (d, J = 8.2 F-207 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.83 (dd, J = 5.1, 10.4 Hz, 1H), 2.32 - 2.09 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (brs, 1H), 8.83 (d, J = 8.3 Hz, F-2081H), 8.14 (t, J = 8.2 Hz, 1H), 7.98 (dd, J = 5.9, 8.1 Hz, 2H), 7.77 (dd, J = 1.7,11.0 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.79 (q, J = 7.2 Hz, 1H), 1.74 (d, J = 7.3 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (s, 1H), 8.83 (d, J = 8.3 Hz,1H), 8.14 (t, J = 8.1 Hz, 1H), 7.98 (dd, J = 5.9, 8.1 Hz, 2H), 7.77 (dd, J = 1.8, F-209 11.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.79 (q, J =7.3 Hz, 1H), 1.74 (d, J = 7.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.76 (s, 1 H), 8.82 (d, J = 8.30 Hz, F-210 1 H), 8.00-7.91 (m, 3 H), 7.59 (t, J = 7.53 Hz, 1 H), 6.90 (d, J = 7.82 Hz, 1H), 5.77 (q, J = 7.28 Hz, 1 H), 1.74 (d, J = 7.34 Hz, 3 H)1H NMR (400 MHz, DMSO-d6): δ ppm 10.75 (br s, 1 H), 8.82 (d, J = 8.30F-211 Hz, 1 H), 8.00-7.90 (m, 3 H), 7.58 (br t, J = 7.92 Hz, 1 H), 6.90 (d, J = 7.82Hz, 1 H), 5.77 (d, J = 7.25 Hz, 1 H), 1.73 (d, J = 7.34 Hz, 3 H)BIOLOGICAL ASSAYS FLUORESCENT IMAGING PLATE READER (FLIPR) ASSAYInducible human TMEM175 cells were seeded at 6,000 cells / well in a PDL-coated black, clear bottomed 1536 well plate (Corning 9141BC). Cells were induced with 1ug / mL tetracycline 18-36 hours at 30C with 5% CO2in 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 HEPES5mM D (+) glucose1mM MgCl22mM CaCl2FLIPR data:Co. No. EC50(µM) Co. No. EC50(µM) F-1 0.062 F-32 0.0435 F-2 0.17 F-33 2.22 F-3 0.0577 F-34 0.311 F-4 0.272 F-35 12.5 F-5 0.157 F-36 0.215 F-6 1.4 F-37 12.6 F-7 0.141 F-38 0.11 F-8 0.16 F-39 4.56 F-9 0.381 F-40 0.0323 F-10 0.149 F-41 6.77 F-11 0.125 F-42 0.0787 F-12 0.0528 F-43 1.16 F-13 0.0473 F-44 0.0711 F-14 0.0363 F-45 7.35 F-15 0.174 F-46 0.122 F-16 0.326 F-47 6.71 F-17 0.4 F-48 0.0734 F-18 0.13 F-49 12.5 F-19 0.249 F-50 0.0466 F-20 0.261 F-51 5.43 F-21 0.317 F-52 0.0989 F-22 0.335 F-53 11.5 F-23 12.5 F-54 0.344 F-24 0.23 F-56 0.359 F-25 8.78 F-58 0.192 F-26 0.373 F-60 0.0888 F-27 10.8 F-61 5.06 F-28 0.256 F-62 0.247 F-29 10.7 F-64 0.0173 F-30 0.1 F-66 0.117 F-31 10 F-68 0.0328Co. No. EC50 (pM) Co. No. EC50 (pM) F-70 0.0805 F-113 0.492 F-72 0.0974 F-114 0.0193 F-74 0.209 F-116 0.351 F-76 0.0759 F-117 0.226 F-78 0.145 F-118 0.314 F-80 0.0662 F-119 0.292 F-82 0.0572 F-120 0.303 F-84 0.136 F-121 0.136 F-87 0.212 F-124 0.241 F-88 0.0726 F-125 0.241 F-89 1.59 F-127 0.0361 F-90 0.354 F-130 0.223 F-91 0.442 F-131 0.426 F-92 0.485 F-132 0.114 F-93 6.25 F-132_1 7.52 F-94 0.398 F-133 0.142 F-95 3.13 F-134 0.589 F-97 0.145 F-135 2.57 F-98 0.153 F-136 0.39 F-99 0.162 F-137 0.392 F-100 2.83 F-142 0.121 F-101 0.233 F-143 0.179 F-102 5 F-144 0.109 F-103 4.32 F-146 0.0659 F-104 0.0737 F-148 1.46 F-105 0.0483 F-149 0.35 F-106 2.54 F-149_1 3.13 F-107 0.117 F-150 0.0528 F-108 4.59 F-150_1 3.13 F-109 0.131 F-151 0.029 F-110 0.258 F-151_1 2.27 F-111 0.166 F-152 0.348 F-112 0.531 F-153 1.4Co. No. EC50(µM) Co. No. EC50(µM) F-154 1.17 F-174 0.566 F-155 0.859 F-175 0.0843 F-156 0.109 F-176 3.65 F-156_1 3.13 F-177 0.262F-157 0.543 F-178 0.0695 F-157_1 3.13 F-179 2.33F-158 0.987 F-180 0.237 F-159 0.0718 F-181 6.25 F-160 0.313 F-185 3.13 F-160_1 3.13 F-186 3.13F-161 0.494 F-195 0.426 F-162 0.579 F-196 0.199 F-163 0.267 F-197 0.167 F-164 1.06 F-198 0.0899 F-165 0.393 F-199 0.0814 F-166 0.0559 F-200 2.71 F-166_1 3.13 F-201 0.35F-167 0.073F-168 1.09F-169 0.0323F-170 0.167CASPASE 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 mL conical tube, and the cryovial was rinsed with 2 mL of Test Medium, which was then added to the suspension. Additional Test Medium was slowly added to achieve a final volume of 25- 30 mL. The mixture was centrifuged at 1200 RPM for 7 minutes, and the supernatant was aspirated without disturbing thepellet. 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 (1000x) and LPS (1 pg / mL final) was prepared in dH2O (1000*). Both were stored at -80°C, avoiding freeze-thaw cycles beyond three. A 4x 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 4x 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.Co. No. AC50(µM)44 >2554 >25148 >2578 >12.9ADDITIONAL ASSAYS THERMODYNAMIC SOLUBILITY MEASUREMENTIntroduction:Thermodynamic solubility represents the concentration of a compound in solution inequilibrium 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 UPLC analysis.Materials & method:FaSSIF solution is prepared by weighing 2.082 g of Biorelevant® FaSSIF Buffer Concentrate into a suitable container with screw cap and made up to volume (50 mL) by adding 48.25 mL purified water at room temperature. The buffer is placed on stirrer plate with PTFE magnet to stir for 1 minute. If required pH is adjusted to 6.5 with NAOH 1N or HCI 1N. 112 mg of Biorelevant ® FaSSIF / FeSSIF / FaSSGF powder is added to the container and stirred until fully dissolved. It is allowed to equilibrate at room temperature for two hours.FeSSIF solution is prepared by weighing 4.070 g of Biorelevant® FeSSIF Buffer Concentrate into a suitable container with screw cap and made up to volume (50 mL) by adding 46.50 mL purified water at room temperature. The buffer is placed on stirrer plate with PTFE magnet to stir for 1 minute. If required pH is adjusted to 5.0 with NAOH 1N or HCI 1N. 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’.Compound Agg_FaSSIF Agg_FeSSIFNumber (pg / mL) (pg / mL)99 4 25FaSSIF = 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. Blood was removed as much as possible via cardiac puncture. Residual blood was removed by saline perfusion (~20mL) via the left cardiac ventricle. After perfusion, whole brain was resected, washed with saline and blotted dry before being stored at -75°C until the day of bioanalysis.Plasma protein bindingThe plasma protein binding (fuplasma) of test compounds was assessed through equilibrium dialysis, using the Rapid Equilibrium Dialysis (RED) approach. The diluted plasma (25% v / v) was spiked with test compound (1 pM) and dialyzed against pH 7.4 buffer (6 h, 37 °C), which was separated by a semi-permeable membrane. At the end of the incubation period, aliquots were removed from the protein containing and protein free compartments, prior to sample preparation and subsequent sample analysis by LC-MS / MS. The fraction unbound (fu) was calculated by dividing the chromatographic peak area ratio in buffer by the peak area ratio in plasma. The fu was mathematically converted to match the fu in 100% plasma. In each experiment, warfarin and propranolol were included as reference control compounds.Brain tissue bindingThe brain tissue binding (fubrain) of test compounds was assessed through equilibrium dialysis using the RED approach. Rat brain homogenate (1:9 tissue: PBS) was spiked with test compound (1 pM) and dialyzed against PBS (pH 7.4) (6 h, 37 °C, 5% CO2, 150 rpm), which was separated from the brain homogenate by a semi-permeable membrane. At the end of the incubation period, aliquots were removed from the protein containing and protein free compartments, prior to sample preparation and subsequent sample analysis by LC-MS / MS. The fraction unbound (fu) was calculated by dividing the chromatographic peak area ratio in buffer by the peak area ratio in brain homogenate. The fu was mathematically converted to match the fu in 100% brain. In 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:_ Cbrain,t fibroinK-Puu, brain 7! c^plasma, t J “-plasmaFinal MDCK- KpuuCompound MDR1 (ER) (brain)40 1.73 0.272 1.42 0.26

Claims

1. CLAIMS2.What is claimed:

1. A compound of Formula (I)4.O R2H6. 8.or a stereoisomeric form thereof, wherein9.X represents CH, CCH3 or N;10.R1Ais selected from the group consisting of11.H,12.halo,13.Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;14.C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;15.C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy;16.(Ci-4alkyloxy)Ci-4alkyl;17.(Ci-4alkyloxy)Ci-4alkyloxy;18.(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl or Ci-3alkyloxy;19.5- 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, haloC1-3alkyl and (=O);20.R1Brepresents H or halo;21.R1Crepresents H, methyl, or halo;22.R2represents Ci-3alkyl;23.ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;24.R3is selected from the group consisting of Ci-4alkyl, haloC1-3alkyl, Ci-4alkyloxy, 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;25.R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;26.R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d;27.m represents 0, 1 or 2;28.n represents 0, 1 or 2;29.or a pharmaceutically acceptable salt thereof,30.with the proviso that the compound is not31.

33.

34.

2. The compound for use according to claim 1, wherein the compound reduces alpha-synuclein aggregation.

3. The compound for use according to claim 1 or 2, for use in the treatment of Parkinson’s disease.

4. A compound having Formula (I)37.O R2H39. 41.or a stereoisomeric form thereof, wherein42.X represents CH, CCH3 or N;43.R1Ais selected from the group consisting of44.H,45.halo,46.Ci-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;47.C1-6alkyloxy optionally substituted with one or more substituents each independently selected from the group consisting of halo; hydroxy; cyano; C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; a 4-, 5- or 6-membered heterocyclyl containing one or two heteroatoms each independently selected from nitrogen and oxygen, said 4-, 5- or 6- heterocyclyl being optionally substituted with one or two substituents, each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkyloxy, haloC1-3alkyl and (=O); and a 6- or 7-membered saturated fused or spirobicyclic ring containing a nitrogen or oxygen atom;48.C3-6cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy; said C3-6cycloalkyl optionally forming a 6-, 7- or 8-membered spiro bicyclic and optionally containing an oxygen atom;49.C3-6cycloalkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl and Ci-3alkyloxy;50.(Ci-4alkyloxy)Ci-4alkyl;51.(Ci-4alkyloxy)Ci-4alkyloxy;52.(C3-6cycloalkyl)Ci-3alkyloxy optionally substituted with one or two substituents each independently selected from the group consisting of halo, Ci-3alkyl, haloC1-3alkyl or Ci-3alkyloxy;53.5- 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, haloC1-3alkyl and (=O);54.R1Brepresents H or halo;55.R1Crepresents H, methyl, or halo;56.R2represents Ci-3alkyl;57.ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;58.R3is selected from the group consisting of Ci-4alkyl, haloC1-3alkyl, Ci-4alkyloxy, 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;59.R4Arepresents independently, halo when present at carbon a, and R4Arepresents halo or cyano when present at carbon b;60.R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d;61.m represents 0, 1 or 2;62.n represents 0, 1 or 2;63.or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not65.

67.

69.

70.

5. The compound according to claim 4, wherein71.X represents CH or N;72.R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl;73.R1Bis H or Br;74.R1Crepresents H; R2represents Ci-3alkyl;75.ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;76.R3is selected from the group consisting of haloCi-4alkyl, haloCi-4alkyloxy, and 5-membered heteroaryl which may be unsubstituted or substituted with one or more substituents each independently selected from Ci-4alkyl or Ci-4alkyloxy;77.R4Arepresents independently, halo when present at carbon a and / or carbon b;78.R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d;79.m represents 0, 1 or 2;80.n represents 0 or 1;81.or a pharmaceutically acceptable salt thereof,82.with the proviso that the compound is not84.

86.

87.

6. The compound according to claim 4, wherein88.X represents CH or N;89.R1Ais selected from the group consisting of H, halo, Ci-4alkyl, Ci-4alkyloxy and haloCi-4alkyl;90.R1Bis H or Br;91.R1Crepresents H, methyl, or halo;92.R2represents Ci-3alkyl;93.ring A represents a phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms;94.R3is selected from the group consisting of haloCi-4alkyl, and haloCi-4alkyloxy;95.R4Arepresents independently, halo when present at carbon a and / or carbon b;96.R4Brepresents independently, halo or C1-4alkyl when present at carbon c and / or carbon d;97.m represents 0, 1 or 2;98.n represents 0 or 1;99.or a pharmaceutically acceptable salt thereof.

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

8. The compound according to claim 4, wherein102.X represents CH or N;103.R1Ais selected from the group consisting of fluoro, chloro, and trifluoromethyl;104.R1Bis H;105.R1Crepresents H;106.R2represents methyl; and108. 110.wherein R3is selected from the group consisting of difluoromethoxy and trifluoromethoxy R4Arepresents fluoro when present at either of carbon a and / or carbon b;111.m represents 0, 1 or 2;112.or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 4 to 8, having Formula (IB)115.

116. (IB), or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 4, wherein the compound is119.

121.

123.

125.

127.

129.

131.

132. F F134.

136.

138.

139. F140.F141.F142.F143.,-cdV-n..

144.

146.

148.

150.

152. 154.or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound as defined in any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

12. A 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 activating TMEM175.

13. A compound of Formula (I) as claimed in any one of claims 4 to10, or a pharmaceutical composition as claimed in claim 11, for use in a method of reducing aggregation of aSyn in a tissue, or a subject in vitro or in vivo, in particular a subject in vivo.

14. A compound of Formula (I) as claimed in any one of claims 4 to 10, or a pharmaceutical composition as claimed in claim 11, for use as a medicament.

15. A compound of Formula (I) as claimed in any one of claims 4 to 10, or a pharmaceutical composition as claimed in claim 11, for use in a method of treating Parkinson’s disease in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I) as claimed in any one of claims 1 to 9, or a pharmaceutical composition as claimed in claim 10.

Images