Aniline-based modulators of the nuclear receptor TLX (NR2e1)

Abstract

The present invention refers to novel compounds and their use as therapeutic agents in human medicine. The compounds of the present invention can be used in the treatment and / or prevention of a disease caused by and / or associated with insufficient TLX activity. Further, the present invention refers to a method of comprising administering an effective amount of the novel compounds.

Description

[0001] 1 220860PWO Modulators of the nuclear receptor TLX (NR2E1) Field of the invention 5The present invention refers to novel compounds and their use as therapeutic agentsin human medicine. The compounds of the present invention can be used in the treatment and / or prevention of a disease caused by and / or associated with insufficient TLX activity. Further, the present invention refers to a method of comprisingadministering an effective amount of the novel compounds.10 Background of the invention The tailless homologue receptor TLX (NR2E1) is an orphan member of the nuclear receptor superfamily of ligand-activated transcription factors and almost exclusively15 expressed in neural stem cells (NSC) and retinal progenitor cells1–5. Several lines of evidence ascribe TLX remarkable therapeutic potential in neurodegenerative pathologies. In vitro and in vivo observations suggest that the transcription factor is required to maintain NSC proliferation as a master regulator of20 NSC homeostasis2,6,7. It mainly acts as transcriptional repressor of tumor suppressor genes like p21 and the phosphatase and tensin homologue (PTEN) to prevent NSC differentiation8. TLX knockout in rodents resulted in abnormal brain development and TLX mutations have been associated with disturbances in neurogenesis, cognitive impairment and mental disorders pointing to great therapeutic potential of25 pharmacological TLX modulation in neurodegeneration9–13. Further, recent findings also link TLX to a range of cancers, including prostate cancer and glioma forms. Specifically, TLX is upregulated in treatment-resistant prostate cancer and has been shown to inhibit oncogene-induced senescence20-22.30 However, only very few ligands have been reported for the orphan nuclear receptor TLX to date (Figure 1) 3. 2 220860PWO WO 2022 / 140643 A1 discloses small molecules that function through the ligandbinding domain of the nuclear receptor TLX, and their use for promoting neurogenesis and treating disorders associated with TLX, including neurological disorders such as Alzheimer's disease. However, the described molecules show a highly complex5 molecular structure, leading to a time-, cost- and energy-consuming synthesisprocedure. WO 2017 / 123996 A1 discloses compounds capable of modulating activity of TLX. Themodulation may comprise downregulating TLX expression and / or modulating TET3. In10 addition, methods of delivering shRNAs using dendrimer nanoparticles into glioblastoma stem cells are provided. The methods and compositions are useful for treating and preventing the progression of brain cancer, e.g., glioblastoma. The disclosed molecules for enhancing TLX activity are, however, not suitable for amonotherapeutic use. 15 WO 2017 / 156491 A1 discloses methods of treating neurodevelopmental disorders such as schizophrenia, bipolar disorder or depression. The methods entail inhibiting expression of miR-219 or overexpressing TLX thereby promoting proliferation of neural stem cells in the subjects. The agent to increase expression or activity of TLX may be20 an agent to chemically modify TLX or a vector expressing a gene encoding TLX. A portion of TLX may be used as the agent to increase expression or activity of TLX, such as the Dpi domain of TLX. The retinoid BMS453 (Figure 1, TLX agonist A)14, ccrp2 (Figure 1, TLX agonist B)1525 and propranolol16have been reported as TLX agonists capable of enhancing the repressive function of TLX and oleic acid (Figure 1, TLX agonists C)17 is considered asa potential endogenous TLX ligand. However, lack of selectivity and incomplete validation compromise the available synthetic TLX agonists14,18,19.30 Faudone G. et al.19 describe TLX agonist 1 (Figure 1), which has been obtained byfragment screening and rational fragment fusion as a new TLX agonist scaffold withpromising potency, efficacy and selectivity. It activated the repressor activity of TLX ina hybrid reporter gene assay, enhanced TLX dimerization in a homogenous time- 3 220860PWO resolved fluorescence resonance energy transfer (HTRF) assay and bound to the recombinant TLX ligand binding domain (LBD) in ITC19. With this orthogonally validated profile, TLX agonist 1 is among the best characterized ligands of the orphanreceptor TLX to date. However, TLX agonist 1 is not suitable as a drug due to5 insufficient potency, lack of specificity and inadequate physicochemical properties. Figure 1. TLX agonists known in the literature14,15,17,19.10 Since it is considered that TLX is an appealing target for the treatment of neurodegenerative diseases, the development of TLX modulators with enhancedpotency, efficacy, affinity and specificity is of highest interest.Especially in view of a growing number of patients with neurodegenerative diseases15 caused by and / or associated with insufficient TLX activity such as Morbus Alzheimer,Morbus Parkinson, dementia or multiple sclerosis, there is an urgent need to provide improved TLX modulators harboring – in comparison to known TLX agonists – a highertarget engagement, improved TLX binding affinity and efficacy, improvedpharmacokinetic properties, and improved specificity.20 The inventors combined aromatic and / or heteroaromatic ring systems with alkyl, alkenyl and / or cycloalkyl moieties and / or halogen atoms to provide TLX modulatorswith a simplified and optimized molecular structure, however high TLX affinity andtarget engagement. It was an object of the present invention to provide novel and more25 active TLX modulators. 4 220860PWO Summary of the Invention The present disclosure provides a compound of formula (I) or a salt or solvate thereof: 5 or a compound of formula (II) or a salt or solvate thereof:10 wherein15 R1 is -R1a or -NH-CO-R1a,R1ais an aromatic or heteroaromatic ring system optionally comprising at least one heteroatom selected from N, O and Swhich is optionally substituted;R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -20 CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6 alkynylene-R2a, or -C1-C6 alkyl, wherein alkyl and alkynylene is optionallysubstituted; R3 and R4 are independently selected from H, OH, C1-C6 alkyl, C2-C6alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, wherein25 alkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted; nis 0, 1 or 2,R2a is a saturated, unsaturated or aromatic monocyclic orbicyclic ring system optionally comprising at least one 5 220860PWO heteroatom selected from N, O and S which is optionally substituted; R5is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or R5and R2 together form a ring which is optionally substituted, and5 R6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8 cycloalkyl, OC3-C8 cycloalkyl, cyano, CO-C1-C6 alkyl andhalo, wherein alkyl, alkenyl, alkynyl and cycloalkyl areoptionally substituted, e.g. by halo;10 m is 1, 2 or 3;with the proviso that compound (I) or (II) is not15 20 . The present disclosure further provides a compound of formula (Ia) or a salt or solvatethereof: 25 or a compound of formula (IIa) or a salt or solvate thereof: 6 220860PWO 5 wherein R1 is -R1a or -NH-CO-R1a,R1a is an aromatic or heteroaromatic ring system optionallycomprising at least one heteroatom selected from N, O and10 S which is optionally substituted; R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6 alkynylene-R2a, -C1-C6alkyl or -H, wherein alkyl and alkynylene is optionallysubstituted; 15 R3and R4are independently selected from H, OH, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted; nis 0, 1 or 2,20 R2a is a saturated, unsaturated or aromatic monocyclic orbicyclic ring system optionally comprising at least oneheteroatom selected from N, O and S which is optionally substituted; R5is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, or R5and25 R2 together form a ring which is optionally substituted, andR6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8 cycloalkyl, OC3-C8 cycloalkyl, cyano, CO-C1-C6 alkyl and halo, wherein alkyl, alkenyl, alkynyl and cycloalkyl are30 optionally substituted, e.g. by halo; mis 1, 2 or 3;with the proviso that compound (Ia) or (IIa) is not 7 220860PWO 5 Afurther aspect of the present invention relates a pharmaceutical composition10 comprising the compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate thereof asan active agent and a pharmaceutically acceptable carrier. Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof or a pharmaceutical composition as described above15 for use in medicine. Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof or a pharmaceutical composition as described abovefor use in the prevention and / or treatment of a disease caused by and / or associated20 with insufficient TLX activity. Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof or a pharmaceutical composition as described abovefor use in the prevention and / or treatment of a neurodegenerative disease, a disease25 linked to a defect in neurogenesis, a mental disorder e.g. bipolar disorders orSchizophrenia, a retinal dysfunction e.g. retinopathy, a retinal dystrophy or an age- related macular degeneration, a retinoblastoma or a central nervous system tumor, e.g. glioblastoma, neuroblastoma or astrocytoma.30 Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof for use in the prevention and / or treatment of aneurodegenerative disease caused by and / or associated with insufficient TLX activity. 8 220860PWO Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof or a pharmaceutical composition as described abovefor use in the prevention and / or treatment of a disease selected from MorbusAlzheimer, Morbus Parkinson, dementia, multiple sclerosis, amyotrophic lateral 5 sclerosis or Huntington’s disease. Still a further aspect of the invention relates to a compound of formula (I), (Ia), (II) or(IIa) or a salt or solvate thereof or a pharmaceutical composition as described abovefor use as described above as a monotherapy or as a combination therapy with at least10 one further medicament. Still a further aspect of the invention relates to a method of preventing and / or treatinga disease caused by and / or associated with insufficient TLX activity comprisingadministering to a subject in need thereof an effective amount of a compound of15 formula (I), (Ia), (II) or (IIa) or a salt or solvate thereof or a pharmaceutical compositionas described above. Embodiments of the invention 20 In the following, specific embodiments of the invention are disclosed as follows: 1. A compound of formula (I) or a salt or solvate thereof: wherein25 R1 is -R1a or -NH-CO-R1a,R1ais an aromatic or heteroaromatic ring system optionally comprising at least one heteroatom selected from N, O and Swhich is optionally substituted; 9 220860PWO R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6 alkynyl-R2a or -C1-C6alkyl, wherein alkyl and alkynyl is optionally substituted;R3and R4are independently selected from H, OH, C1-C6 alkyl, C2-C6 5alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted; nis 0, 1 or 2,R2a is a saturated, unsaturated or aromatic monocyclic or10 bicyclic ring system optionally comprising at least oneheteroatom selected from N, O and S which is optionally substituted; R5is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or R5and R2together form a ring which is optionally substituted;15 R6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8 cycloalkyl, OC3-C8 cycloalkyl, cyano, CO-C1-C6 alkyl andhalo, wherein alkyl, alkenyl, alkynyl and cycloalkyl areoptionally substituted, e.g. by halo;20 m is 1, 2 or 3;or a compound of formula (Ia) or a salt or solvate thereof: wherein25 R1 is -R1a or -NH-CO-R1a,R1ais an aromatic or heteroaromatic ring system optionally comprising at least one heteroatom selected from N, O and Swhich is optionally substituted; 10 220860PWO R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6-alkynyl-R2a , -C1-C6 alkylor -H, wherein alkyl and alkynyl is optionally substituted;R3and R4are independently selected from H, OH, C1-C6 alkyl, C2-C6 5alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted; nis 0, 1 or 2;R2a is a saturated, unsaturated or aromatic monocyclic or10 bicyclic ring system optionally comprising at least oneheteroatom selected from N, O and S which is optionally substituted; R5is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or R5and R2together form a ring which is optionally substituted;15 R6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8 cycloalkyl, OC3-C8 cycloalkyl, cyano, CO-C1-C6 alkyl and halo, wherein alkyl, alkenyl, alkynyl and cycloalkyl areoptionally substituted, e.g. by halo; and20 m is 1, 2 or 3;with the proviso that compound (I) or (Ia) is not25 30 2. The compound (I) of embodiment 1 having the formula (II), or a salt or solvatethereof: 11 220860PWO 5 wherein R1, R2, R5and R6are defined as in compound (I); or the compound (IIa) of embodiment 1 having the formula (IIa), or a salt or solvate10 thereof: 15 wherein R1, R2, R5and R6are defined as in compound (Ia),20 with the proviso that compound (II) or (IIa) is not25 3. The compound of embodiment 1 or 2 wherein R1a is a monocyclic ring, e.g., a 5-30 membered or 6-membered ring which is optionally substituted. 4. The compound of embodiment 3 wherein R1a is selected from pyrrolyl, e.g., pyrrol-1-yl, furyl, thiophenyl, e.g. thiophen-2-yl, or thiophen-3-yl, imidazolyl, e.g. imidazol-1- 12 220860PWO yl, imidazol-4-yl or imidazol-5-yl, pyrazolyl, e.g. pyrazol-1-yl, pyrazol-3-yl or pyrazol-4- yl, oxazolyl, isoxazolyl, e.g., isoxazol-4-yl, thiazolyl, e.g., thiazol-2-yl or thiazol-4-yl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, e.g., 1,2,4-triazol-3-yl, which are optionally substituted. 5 5. The compound of embodiment 3 wherein R1a is selected from phenyl, pyridinyl, e.g.,pyridin-3-yl, or pyridin-4-yl, pyrimidinyl, e.g. pyrimidin-5-yl, or pyrazidinyl which are optionally substituted.10 6. The compound of embodiment 1 or 2 wherein R1a is a bicyclic ring, e.g., a 7-membered, 8-membered, 9-membered or 10-membered ring which is optionally substituted. 7. The compound of embodiment 6 wherein R1a is selected from indolyl, e.g., indol-1-15 yl, indol-3-yl, or indol-5-yl, indolinyl, e.g., indolin-5-yl, indazolyl, e.g., indazol-5-yl, pyrrolopyridinyl, e.g., pyrrolopyridin-5-yl, pyrazolopyridinyl, benzoimidazolyl, e.g., benzoimidazol-1-yl, benzofuranyl, e.g., benzofuran-5-yl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, e.g., imidazopyridine-7-yl, or benzothiophenyl, e.g. benzothiophen- 5-yl, benzothiazolyl, benzoisothiazolyl which are optionally substituted. 20 8. The compound of any one of embodiments 1-7 wherein R1a is substituted with oneor more substituents independently selected from OH, CN, NO2, halo, e.g., F, Cl, Br, or I, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, OC1-C6alkyl, OC2-C6alkenyl, OC2-C6alkynyl, SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 alkynyl, CO-C1-C6 alkyl, COOH, COOC1-25 C6 alkyl, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, wherein each alkyl, alkenyl or alkenyl substituent on R1amay be substituted with OH, CN, halo, OC1-C3 alkyl, COOH, COOC1-C3 alkyl, NH2, NH(C1-C3 alkyl), (C1-C3 alkyl)2, or any combination thereof.30 9. The compound of any one of embodiments 1-4 or 8 wherein R1 is selected from: 13 220860PWO 5 10. The compound of any one of embodiments 1-3, 5 or 8 wherein R1 is selected from:10 15 11. The compound of any one of embodiments 1-2 or 6-8 wherein R1 is selected from: 14 220860PWO 5 12. The compound of any one of embodiments 1-11 wherein R2 is -CO-R2a, -CO-10 (C(R3R4))n-R2a, -SO2-R2a, or -SO2-(C(R3R4))n-R2a.13. The compound of any one of embodiments 1-12 wherein R3 and R4 areindependently selected from H, OH, C1-C4 alkyl, trifluoromethyl, fluoro and cyclopentyl.15 14. The compound of any one of embodiments 1-13 wherein R2a is a monocyclic ring,e.g., a 3-membered, 4-membered, 5-membered or 6-membered ring which is optionally substituted. 15. The compound of embodiment 14 wherein R2a is selected from cyclopropyl,20 cyclobutyl, oxetanyl, cyclopentyl, pyrazolyl, e.g. pyrazol-3-yl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, cyclohexyl, piperidinyl, e.g., piperidin-3-yl, morpholinyl, phenyl, and pyridinyl, e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, which are optionally substituted. 15 220860PWO 16. The compound of any one of embodiments 1-13 wherein R2a is a bicyclic ring, e.g.an 8-membered, 9-membered, or 10-membered bicyclic ring which is optionally substituted. 517. The compound of embodiment 16 wherein R2a is selected from naphthyl, e.g.,naphth-1-yl or naphth-2-yl, quinolinyl, e.g., quinon-4-yl, is quinolinyl, quinazolinyl,tetrahydroquinolinyl, indolyl, e.g., indol-3-yl, indazolyl, benzoimidazolyl, benzofuranyl, benzoxazolyl, benzodioxolyl, pyrrolopyridinyl, imidazopyridinyl, e.g., imidazopyridine- 7-yl, or benzothiophenyl, e.g. benzothiophen-2-yl, benzothiazolyl which are optionally10 substituted. 18. The compound of any one of embodiments 1-17 wherein R2a is substituted withone or more substituents independently from OH, CN, NO2, halo, e.g., F, Cl, Br or I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OC1-C6 alkyl, OC2-C6 alkenyl, OC2-C6 alkynyl,15 SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 alkynyl, CO-C1-C6 alkyl, COOH, COOC1-C6 alkyl, NH(C1-C6alkyl) and N(C1-C6alkyl)2, wherein each alkyl, alkenyl or alkynyl substituent on R2amay be substituted with OH, CN, halo, OC1-C3 alkyl, COOH, COOC1-C3 alkyl, NH2, NH(C1-C3 alkyl), (C1-C3 alkyl)2, or any combination thereof. 20 19. The compound of any one of embodiments 1-18 wherein R2ais not substituted with NH2. 20. The compound of any one of embodiments 1-15 or 18-19 wherein R2 is selected25 from: 16 220860PWO 510 21. The compound of any one of embodiments 1-13 or 16-19 wherein R2 is selectedfrom: 15 17 220860PWO 5 22. The compound of any one of embodiments 1-21 wherein R5 is H.10 23. The compound of any one of embodiments 1-22 wherein R6 is selected from H,halo, e.g., Cl, CN, C1-C4 alkyl, e.g. CF3, C1-C4 alkoxy, e.g., OCF3, CO-CH3, or OH.24. The compound of any one of embodiments 1-23 wherein:15 R1 is imidazolyl, pyridyl or pyrrolopyridinyl, particularly , R2 is -CO-(C(R3R4))n-R2a or -SO2-(C(R3R4))n-R2a, wherein R3 and R4are particularly H, and n is particularly 0 or 1,20 R2a is phenyl optionally substituted,particularly phenyl substituted with one or more substituents selected from halo, e.g., F, or Cl, C1-C6 alkyl, e.g., CF3, CN, 18 220860PWO NH(C1-C6 alkyl), O(C1-C6 alkyl) and N(C1-C6 alkyl)2, e.g., N(CH3)2,and ,,5 R5is H, and R6 is H, CF3, Cl, or OCF3.10 25. The compound of any one of embodiments 1-24, wherein n is 0.26. The compound of any one of embodiments 1-24, wherein n is 1.27. A pharmaceutical composition comprising the compound of formula (I), (Ia), (II) or15 (IIa) or a salt or solvate thereof of any one of embodiments 1-26 as an active agentand a pharmaceutically acceptable carrier. 28. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 26 for use in20 medicine. 29. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate thereof of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 27 for use in theprevention and / or treatment of a disease caused by and / or associated with insufficient25 TLX activity. 19 220860PWO 30. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 27 for use in theprevention and / or treatment of a neurodegenerative disease, a disease linked to a5 defect in neurogenesis, a mental disorder e.g. bipolar disorders or Schizophrenia, aretinal dysfunction e.g. retinopathy, a retinal dystrophy or an age-related maculardegeneration, a retinoblastoma or a central nervous system tumor, e.g. glioblastoma,neuroblastoma or astrocytoma.10 31. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 27 for use in theprevention and / or treatment of a neurodegenerative disease caused by and / or associated with insufficient TLX activity.15 32. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 27 for use in theprevention and / or treatment of a disease selected from Morbus Alzheimer, Morbus Parkinson, dementia, multiple sclerosis, amyotrophic lateral sclerosis or Huntington’sdisease. 20 33. A compound of formula (I), (Ia), (II) or (IIa) or a salt or solvate of any one ofembodiments 1-26 or a pharmaceutical composition of embodiment 27 for use of anyone of embodiments 28-32 as a monotherapy or as a combination therapy with at leastone further medicament. 25 34. A method of preventing and / or treating a disease caused by and / or associated withinsufficient TLX activity comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (Ia), (II) or (IIa).30 20 220860PWO Detailed description The present invention relates to a novel class of TLX modulators with substantially enhanced potency. These compounds are useful as medicaments and high-quality 5 chemical tools. Early pharmacological studies have demonstrated that a loss of TLX or diminished TLX activity is associated with bipolar disorders, cognitive impairment, and neurodegeneration, suggesting great therapeutic potential in this context. However,10 ligand discovery for TLX is at a very early stage. Potent and selective TLX modulatorsare still needed.Surprisingly, highly affine TLX modulators have been created, showing an enhancedpotency, efficacy and improved physicochemical properties. In particular, the obtained15 TLX modulators show due to their structural buildup an ideal interaction with andbinding to the target TLX, “TLX” in the sense of the present invention refers to human tailless homologue of drosophila (TLX, NR2E1), an orphan nuclear receptor (NR). TLX is considered as a20 master regulator of neurogenesis. Its expression in adults is almost limited to neuronal stem cells (NSC), which it seems to maintain in an undifferentiated, proliferative state. “TLX modulator” in the sense of the present invention refers to any natural or synthetic compound capable of interacting with the TLX receptor under activating or suppressingits activity. The term “modulator” comprises agonists and antagonists of the TLX25 receptor. Thus, a first aspect of the present invention is directed to a compound of formula (I),(Ia), (II) or (IIa) or a salt or solvate thereof as described herein.30 The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated. 21 220860PWO In particular embodiments, R1a is a monocyclic ring, e.g., a 5-membered or 6-membered ring, preferably a 5-membered ring, which is optionally substituted.In preferred embodiments, R1a is selected from pyrrolyl, e.g., pyrrol-1-yl, furyl,5 thiophenyl, e.g. thiophen-2-yl, or thiophen-3-yl, imidazolyl, e.g. imidazol-1-yl, imidazol- 4-yl or imidazol-5-yl, pyrazolyl, e.g. pyrazol-1-yl, pyrazol-3-yl or pyrazol-4-yl, oxazolyl, isoxazolyl, e.g., isoxazol-4-yl, thiazolyl, e.g., thiazol-2-yl or thiazol-4-yl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, e.g., 1,2,4-triazol-3-yl, which are optionally substituted.10 In further preferred embodiments, R1a is selected from phenyl, pyridinyl, e.g., pyridin-3-yl, or pyridin-4-yl, pyrimidinyl, e.g. pyrimidin-5-yl, or pyrazidinyl which are optionallysubstituted. In other embodiments, R1a is a bicyclic ring, e.g., a 7-membered, 8-membered, 9-15 membered or 10-membered ring, preferably a 9-membered or 10-membered ring, more preferably a 9-membered ring, which is optionally substituted. Preferably, R1a isselected from indolyl, e.g., indol-1-yl, indol-3-yl, or indol-5-yl, indolinyl, e.g., indolin-5- yl, indazolyl, e.g., indazol-5-yl, pyrrolopyridinyl, e.g., pyrrolopyridin-5-yl, pyrazolopyridinyl, benzoimidazolyl, e.g., benzoimidazol-1-yl, benzofuranyl, e.g.,20 benzofuran-5-yl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, e.g., imidazopyridine- 7-yl, or benzothiophenyl, e.g. benzothiophen-5-yl, benzothiazolyl, benzoisothiazolyl which are optionally substituted. The terms "cyclic", "bicyclic” and "cycloalkyl" for R1amean that such cyclic or bicyclic25 residue is directly linked by a chemical bond to the aromatic ring to which R1ais bound or is directly linked by a chemical bond to the C- atom contained in -NH-CO-R1a.Optionally, R1a may be substituted with one or more substituents. The one or moresubstituents may be independently selected from OH, CN, NO2, halo, e.g., F, Cl, Br,30 or I, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, OC1-C6alkyl, OC2-C6alkenyl, OC2-C6alkynyl, SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 alkynyl, CO-C1-C6 alkyl, COOH, COOC1- C6 alkyl, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, wherein each alkyl, alkenyl or 22 220860PWO alkenyl substituent on R1amay be substituted with OH, CN, halo, OC1-C3 alkyl, COOH, COOC1-C3alkyl, NH2, NH(C1-C3alkyl), (C1-C3alkyl)2, or any combination thereof. In a preferred embodiment, R1 is selected from:510 Still in another preferred embodiment, R1 is selected from:15 23 220860PWO In a further preferred embodiment, R1 is selected from:510 R2may be an aliphatic or aromatic, acyclic or cyclic, saturated or unsaturated hydrocarbon, which is optionally substituted. In another embodiment according formula (Ia), R2 may be H.15 In certain embodiments, R2 is -CO-R2a, -CO-(C(R3R4))n-R2a or SO2(C(R3R4))n-R2awherein n is 0, 1 or 2. In certain embodiments, R2a may be a monocyclic ring, e.g., a 3-membered, 4-20 membered, 5-membered or 6-membered ring, preferably a 5-membered or 6- membered ring, which is optionally substituted. Preferably, R2a is selected fromcyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, pyrazolyl, e.g. pyrazol-3-yl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,4-triazolyl, 1,2,3- 24 220860PWO triazolyl, cyclohexyl, piperidinyl, e.g., piperidin-3-yl, morpholinyl, phenyl, and pyridinyl, e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, which are optionally substituted. In certain embodiments, R2a is a bicyclic ring, e.g. an 8-membered, 9-membered, or5 10-membered bicyclic ring which is optionally substituted. Preferably, R2ais a 9- membered, or 10-membered bicyclic ring which is optionally substituted. Preferably,R2ais selected from naphthyl, e.g., naphth-1-yl or naphth-2-yl, quinolinyl, e.g., quinon- 4-yl, isoquinolinyl, quinazolinyl, tetrahydroquinolinyl, indolyl, e.g., indol-3-yl, indazolyl, benzoimidazolyl, benzofuranyl, benzoxazolyl, benzodioxolyl, pyrrolopyridinyl,10 imidazopyridinyl, e.g., imidazopyridine-7-yl, or benzothiophenyl, e.g. benzothiophen-2- yl, benzothiazolyl which are optionally substituted. The terms "cyclic", "bicyclic” and "cycloalkyl" for R2amean that such cyclic or bicyclic residue is directly linked by a chemical bond to the C- atom contained -CO-R2a or -CO-15 (C(R3R4))n-R2a. R2amay be substituted with one or more substituents. The one or more substituents may be independently selected from OH, CN, NO2, halo, e.g., F, Cl, Br or I, C1-C6 alkyl, e.g. CH3 or CF3, C2-C6 alkenyl, C2-C6 alkynyl, OC1-C6 alkyl, e.g., OCF3, OC2-C620 alkenyl, OC2-C6alkynyl, SC1-C6alkyl, SC2-C6alkenyl, SC2-C6alkynyl, CO-C1-C6alkyl, COOH, COOC1-C6 alkyl, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, wherein each alkyl, alkenyl or alkynyl substituent on R2a may be substituted with OH, CN, halo, e.g., fluoro,OC1-C3 alkyl, C1-C4 alkyl, COOH, COOC1-C3 alkyl, NH2, NH(C1-C3 alkyl), (C1-C3alkyl)2, or any combination thereof. 25 In certain embodiments, R2ais not substituted by NH2. In certain embodiments, R3 and R4 may be independently selected from H, OH, C1-C4alkyl, trifluoromethyl, fluoro and cyclopentyl. Preferably, R3and R4are independently30 selected from H, C1-C4 alkyl or trifluoromethyl.In preferred embodiments, R2is selected from: 25 220860PWO 5 10 15 In another preferred embodiment, R2 is selected from: 26 220860PWO 5 In a preferred embodiment, R2 is H.10 In another preferred embodiment, R5 is H.In a preferred embodiment, R6 is selected from H, halo, CN, C1-C4 alkyl, e.g. CF3, C1-C4 alkoxy, e.g., OCF3, CO-CH3, or OH, even more preferably R6 is selected from CF3,15 Cl, C1-C4 alkyl, or OCF3.In a preferred embodiment, the compound of formula (I) is as follows:1 is imidazolyl, pyridyl or pyrrolopyridinyl, particularly , 27 220860PWO R2 is -CO-(C(R3R4))n-R2a or -SO2-(C(R3R4))n-R2a, wherein R3 and R4are particularly H, and n is particularly 0 or 1,R2ais phenyl optionally substituted, particularly phenyl substituted with one or more substituents 5selected from halo, e.g., F or Cl, C1-C6 alkyl, e.g., CF3, CN, O(C1-C6 alkyl), NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, e.g., N(CH3)2, and 10 R5is H, and R6 is H, CF3, Cl or OCF3.In certain embodiments of the compounds of formula (I), (Ia), (II) or (IIa), n is 0. In15 certain embodiments of the compounds of formula (I), (Ia), (II) or (IIa), n is 1. In individual residues of compounds of formula (I), (Ia), (II) or (IIa), the following generaldefinitions apply:20 The definitions of atoms in the compounds of formula (I), (Ia), (II) or (IIa) encompassall possible isotopes including stable and unstable isotopes. For example, the term “H” encompasses hydrogen isotopes including deuterium. The term “optionally substituted” includes “unsubstituted” and “substituted”, e.g.,25 “mono- and polysubstituted”. 28 220860PWO The term "C1-C6 alkyl" includes linear and branched alkyl residues which are optionallysubstituted. It comprises all isomers of the corresponding saturated aliphatichydrocarbon groups containing one to six carbon atoms; this includes methyl, ethyl, n- 5propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3- pentyl,2-methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, and all hexyl-isomers. The term "C2-C6 alkenyl" comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to six carbon atoms linked by (i.e. 10 comprising) one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, and all hexenyl-isomers. The terms "C2-C6 alkynyl" and "C2-C6 alkynylene" comprise all isomers of thecorresponding unsaturated acetylenic hydrocarbon groups containing two to six carbon15 atoms linked by (i.e. comprising) one or more triple bonds; this includes ethynyl, all propynyl-isomers, all butynyl-isomers, all pentynyl-isomers, and all hexynyl-isomers. The terms "alkynyl” and “alkynylene” also include compounds having one or more triplebonds and one or more double bonds. 20 The term "C3-C8cycloalkyl" comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl.25 The term “OC1-C6 alkyl" or “C1-C6 alkoxy” comprises all isomers of the correspondingsaturated aliphatic hydrocarbon groups containing one to six carbon atoms, wherein one of the one to six carbon atoms is singularly bonded to oxygen. The term “OC2-C6 alkenyl” or “C2-C6 alkenyloxy” comprises all isomers of the30 corresponding unsaturated olefinic hydrocarbon groups containing two to six carbon atoms linked by (i.e. comprising) one or more double bonds, wherein one of the two to six carbon atoms is singularly bonded to oxygen. 29 220860PWO The term “OC2-C6 alkynyl” or “C2-C6 alkynyloxy” comprises all isomers of thecorresponding unsaturated acetylenic hydrocarbon groups containing two to six carbon atoms linked by (i.e. comprising) one or more triple bonds, wherein one of the two to six carbon atoms is singularly bonded to oxygen.5 The term “OC3-C8 cycloalkyl” or “C3-C8 cycloalkyloxy” comprises the correspondingsaturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure, wherein one of the three to eight carbon atoms is singularly bonded to oxygen. 10 The term “halo” as used herein includes -F, -Cl, -Br and -I if not indicated differently. Inpreferred embodiments, the term halo refers to -F or -Cl.In a "bicyclic ring", the carbon atoms are arranged in a bicyclic ring structure. The15 bicyclic ring structure includes fused, bridged and spiro systems.In case a carbon atom is replaced by a heteroatom selected from O, N, or S, thenumber of substituents on the respective heteroatom is adapted according to itsvalency, e.g. a - CR2- group may be replaced by a -NR-, -O- or -S- group.20 The term “phenyl” includes phenyl residues which are optionally substituted. Preferred substituents of phenyl include -OH, halo, -C1-C4 alkyl, -OC1-C4 alkyl, -NH(C1-C4 alkyl),N(C1-C4alkyl)2or deuterium. 25 Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom or an atropoisomeric bond, the invention relates to the D form, the L form and D, L mixtures and also, where more than one asymmetric carbon atomor atropoisomeric bond is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms or atropoisomeric bonds, and30 which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a 30 220860PWO corresponding optically active or diastereomeric compound then being obtained as the end product. Compounds of the invention also include tautomeric forms. Tautomeric forms result 5 from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acidpairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and10 annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, and 1H-and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. 15 The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting20 materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a25 mixture of isomers or as separated isomeric forms. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include30 tritium and deuterium. The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood 31 220860PWO to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are included within the term "salt(s)" as used herein (and may be formed, for example, where the substituents 5 comprise an acid moiety such as a carboxyl group and an amino group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.10 Acid addition salts may be formed with inorganic acids and organic acids and include, but are not limited to, acetate, benzoate, hydrobromide, hydrochloride, citrate, lactate, phosphate, tosylate and trifluoroacetate salts. Exemplary salts resulting from theaddition of acid include acetates (such as those formed with acetic acid or trihaloacetic15 acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, chlorates,20 bromates, iodates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates,25 toluenesulfonates such as tosylates, undecanoates, and the like. Base addition salts can be formed with inorganic bases and organic bases and include, but are not limited to, ammonium, sodium, potassium, calcium, magnesium salts or salts derived from primary, secondary, and tertiary amines. Exemplary salts resulting30 from the addition of base (formed, for example, where the substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) 32 220860PWO such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N- methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, 5 bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. Also included are solvates and hydrates of the compounds of formula (I) and solvates10 of their salts. The compounds of the present invention may be able to target the TLX receptor. Specific examples of compounds falling under the scope of formula (I), (Ia), (II) or (IIa)are shown in Tables 1 to 4.15 In the Tables, the TLX relative reporter activity is expressed as EC50 (in µM) for eachlisted compound. “EC50” refers to a measure of the concentration of a compound which induces a biological response halfway between the baseline and maximum after a specified exposure time. In particular, EC50can be defined as the concentration20 required to obtain a 50% effect and is commonly used as a measure of a drug's potency. The EC50 is measured via a hybrid reporter gene assay, employing thetransfection of a reporter (firefly luciferase with Gal4 response element), a control gene(Renilla luciferase), a transcriptional activator (Gal4-VP16) and a hybrid receptorconsisting of the TLX ligand binding domain (LBD) and the Gal4 DNA binding domain25 (DBD). Agonism on Gal4-TLX is visible as decrease in reporter activity (<1) in relationto the DMSO control (relative reporter activity = 1) and inverse agonism is observedas increase in reporter activity (>1). Minimal remaining reporter activity or maximumreporter activity after treatment with the compounds is stated in brackets below theEC50 value. Representative dose-response curves are depicted in Figure 1.30 Further, in the Tables 1-4, the Kd values of some compounds are shown. “Kd” refers todissociation constant. It describes the binding affinity that the compounds of theinvention have for TLX (in µM). The Kd value is measured via isothermal titration 33 220860PWO calorimetry (ITC) using the TLX LBD. Figure 2 shows representative isotherms at 25°Cas well as the corresponding fitting of the heat of binding. Table 1: 5 34 22 18 0.60±0.26(0.14±0.08)19 > 1020 1.4±0.3(0.21±0.07)21 1.7±0.5(0.30±0.09)22 0.20±0.05(0.14±0.04) 0.36 35 220860PWO 36 2208 47 0.99±0.18(0.14±0.08)48 H 3.9±1.6(0.49±0.11)49 H (0.70±0.06at 100 µM)50 H 9.1±0.7(0.19±0.05) 37 220860PWO 38 220 inverse agonist76 H IC5019±7 µM(2.6±0.4)77 H 13±4(0.18±0.13)78 H 6.6±2.1(0.28±0.07)79 0.41±0.11(0.26±0.05)80 0.30±0.07(0.12±0.06) 39 220 (0.31±0.08)91 0.19±0.02(0.27±0.03)92 0.27±0.09(0.28±0.08)93 0.4±0.1(0.43±0.05)94 0.4±0.1(0.57±0.03) 40 22 103 0.05±0.01(0.61±0.05)104 0.015±0.004(0.56±0.04)105 0.04±0.01(0.53±0.02) 41 220860PWO 42 220860PWO 43 220860PWO Table 2: 5 44 220860PWO Table 3: Table 4:5 45 220860PWO In certain embodiments, a compound of the present invention has an EC50 for TLXactivation of about 15 µM or less, particularly of about 0.5 µM or less and moreparticularly of about 0.1 µM or less.5 In particular embodiments, a compound of the present invention selectively activates the TLX receptor. In further embodiments, a compound of the present invention has a Kd for the TLX of10 about 2 µM or less, particularly of about 0.5 µM or less and more particularly of about0.2 µM or less. 46 220860PWO Pharmaceutical In a further aspect, the present invention is directed to a pharmaceutical compositioncomprising a compound as described herein or a salt or solvate thereof as an active5 agent and a pharmaceutically acceptable carrier. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings10 and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts”15 refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the20 present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these25 compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in 22 and 23, each of which is incorporated herein by reference in its entirety.30 In some embodiments, the compound can be provided as a prodrug. The term "prodrug”, as employed herein, denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and / or solvate thereof. 47 220860PWO The composition may be a solid dosage form, e.g. a tablet, a capsule etc. or a liquid dosage form, e.g. a solution, emulsion, suspension, or the like. It is administered in any suitable way, e.g. orally, parenterally, by inhalation, by ocular application, by5 intramuscular application, by nasal application and / or by transdermal application. The carrier may be any suitable pharmaceutical carrier as known in the art. The compound of formula (I), (Ia); (II) or (IIa) is administered in a therapeutically effective dose whichmay be determined by the skilled practitioner based on the subject and the disorder to be treated. 10 Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminum stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar or vegetable or animal fats and oils, or solid15 high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavorings and / or sweeteningagents, if desired. Liquid medicinal forms can be sterilized and / or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents,20 emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and / or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses,25 carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such30 as polyethylene glycol. 48 220860PWO Suitable solvents, suspending agents and solubilizers are water or water-misciblesolvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve,5 cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound,10 preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilizate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent. The preparations are produced, aliquoted and15 sealed under the customary antimicrobial and aseptic conditions. Use in medicine The transcription factor TLX is known as being an essential factor for neuronal health,20 suggesting a promising therapeutic potential in neurodegenerative diseases. Thus, a further aspect of the invention provides the compound of formula (I) asdescribed above or the salt or solvate thereof or the pharmaceutical composition asdescribed above for use in medicine, e.g., in human or veterinary medicine.25 The compounds of formula (I), (Ia); (II) or (IIa) may be administered to a subject, e.g.,a human subject, in need thereof for preventing a disease (particularly to a subjectbeing at risk of acquiring a disease) or for treating a disease (particularly to a subject already suffering from a disease). 30 As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of 49 220860PWO the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or 5 symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease; and (3) slowing down disease progression. The term "treating” also encompasses post-treatment care. 10 In some other embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display15 the pathology or symptomatology of the disease. In a further aspect, the invention provides the compound of formula (I), (Ia); (II) or (IIa)as described above or the salt or solvate thereof or the pharmaceutical composition asdescribed above for use in the prevention and / or treatment of a disease caused by20 and / or associated with insufficient TLX activity. In a further aspect, the invention provides the compound of formula (I), (Ia), (II) or (IIa)as described above or the salt or solvate thereof or the pharmaceutical composition as described above for use in the prevention and / or treatment of a neurodegenerative25 disease, a disease linked to a defect in neurogenesis, a mental disorder e.g. bipolar disorders or Schizophrenia, a retinal dysfunction e.g. retinopathy, a retinal dystrophy or an age-related macular degeneration, a retinoblastoma or a central nervous system tumor, e.g. glioblastoma, neuroblastoma or astrocytoma.30 In a further aspect, the invention provides the compound of formula (I), (Ia), (II) or (IIa)as described above or the salt or solvate thereof or the pharmaceutical composition as described above for use in the prevention and / or treatment of a neurodegenerative 50 220860PWO disease caused by and / or associated with insufficient TLX activity. Preferably, theneurodegenerative disease is Alzheimer's disease, dementia, or Parkinson's disease.In a further aspect, the invention provides the compound of formula (I), (Ia), (II) or (IIa)5 as described above or the salt or solvate thereof or the pharmaceutical composition as described above for use in the prevention and / or treatment of a disease selected from Morbus Alzheimer, Morbus Parkinson, dementia, multiple sclerosis, amyotrophic lateral sclerosis or Huntington’s disease.10 In a further aspect, the invention provides the compound of formula (I), (Ia), (II) or (IIa)as described above or the salt or solvate thereof or the pharmaceutical composition as described above for use as a monotherapy or as a combination therapy with at leastone further medicament.15 The term “monotherapy” refers to a therapy form in which the compound of formula (I),(Ia), (II) or (IIa) as described above or the salt or solvate thereof or the pharmaceuticalcomposition as described above is the only active agent during therapy. The term “combination therapy” refers to a therapy form in which the compound of20 formula (I), (Ia), (II) or (IIa) as described above or the salt or solvate thereof or thepharmaceutical composition as described above may be administered in combinationwith at least one further active agent in form of a sequence therapy or as simultaneouscombination therapy, e.g. therapeutically active compounds useful in the treatment of the above indicated diseases, wherein the at least one further active agent is different25 from a compound of formula (I), (Ia), (II) or (IIa). In particular, the at least one furtheractive agent is suitable for the treatment of a neurodegenerative disease as described above. More particularly, a compound of formula (I), (Ia), (II) or (IIa) may be used incombination therapy with levodopa, benserazide, opicapone, entacapone, tolcapone, bromocriptine, pergolide, pramipexole, ropinirole, rotigotine, piribedil, cabergoline,30 apomorphine, safinamide, selegiline, rasagiline, lisuride, amantadine, donzepezil, rivastigmine, galantamine, memantine, glucocorticoids, glatiramer acetate, interferon beta, cladribine, teriflunomide, dimethyl fumarate, fingolimod, ozanimod, siponimod, 51 220860PWO lecanemab, natalizumab, ofatumumab, alemtuzumab, or ocrelizumab, azathioprine, ormethotrexate. The combined active agents may be administered as a free combination of individual5 active agents or are administered in form of a single pill. In a further aspect, the invention provides a method of preventing and / or treating adisease caused by and / or associated with insufficient TLX activity comprising administering to a subject in need thereof an effective amount of a compound of10 formula (I), (Ia), (II) or (IIa) as described above.The method of use of the present invention relates to the use in vivo, in vitro, and ex vivo, respectively. 15 The compounds of the invention may be used in human medicine. Suitable administration forms are topical or systemic including enteral, oral, rectal, andparenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular,20 intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations. Particular preference is given to using oral, or parenteral, e.g. intravenous or intramuscular of thecompounds according to the invention. The customary galenic preparation forms, such25 as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwash, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems30 including implants and devices, and with liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used. 52 220860PWO Further, the compounds of formula (I), (Ia), (II) or (IIa) are also useful for non-medicalapplications, e.g., in the fields of basic research, diagnostics and / or drug screening. Further, the invention is described in detail by the following figures and examples. 5 Examples General procedure A (Suzuki-coupling). A 50-100 mL Schlenk flask was chargedwith a stir bar, the boronic acid / pinacol ester (1 eq.) and potassium phosphate (3 eq.). 10 The flask was evacuated and backfilled with nitrogen three times. The previously de- gassed (3 freeze thaw-cycles) solvent mixture (dioxane / water = 85:15), together with the Pd catalyst (10 mol%) and the heteroaryl bromide (1.5-2 eq.) was added and the reaction mixture was stirred at 100°C under reflux and nitrogen atmosphere. After completion of the reaction, the solution was cooled down to room temperature (rt) and15 the solvents were evaporated. The residue was taken up in EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, concentrated and purified by flash column chromatography and if necessary, again by reverse phase (RP)column chromatography to give the respective compound. General procedure B (Ullmann coupling). A 20 mL reaction tube was charged with20 the heterocycle (1 mmol, 1 eq.), the aryl bromide (1.5-2 eq.), CuI (10 mol%) and N,N- dimethyl -1,2-diamino cyclohexane (20 mol%).5 mL of sat. K2CO3 in water were addedand the reaction mixture was stirred for 24-48h at 100°C open to air. After cooling down to rt, the mixture was filtered over celite and eluted with EtOAc. The phases wereseparated, and the aqueous layer was extracted two more times with EtOAc. The25 combined organic layers were washed with brine and dried over Na2SO4, and the crudeproduct was purified by flash column chromatography and if necessary, again by RP column chromatography to yield the desired compounds. General procedure C (amide coupling with SOCl2). The carboxylic acid (1 eq.) wasdissolved in SOCl2(2-4 mL) and heated to reflux for 2-2.5h. The mixture was cooled30 down to rt and the solvent was evaporated. To the prepared acyl chloride was addedchloroform (2-5 mL), the amine (1 – 2 eq.) and if noted triethylamine (1.2 – 2 eq.) at0°C. The reaction mixture was flushed with N2, allowed to warm up to rt and stirred for 12-72h. After completion of the reaction, the solvent was evaporated, and the residue 53 220860PWO was taken up in aq. NaOH. The mixture was extracted with EtOAc (3x) and the combined organic layers were washed with water and brine, then dried over Na2SO4and concentrated. The crude products were purified by flash column chromatography and if necessary, again by RP column chromatography to yield the desired amides. 5 General procedure D (amide coupling with TCFH / NMI).The carboxylic acid (1-1.5 eq.) together with the amine (1-2 eq.) and N-methylimidazole (2 eq.) was dissolved in acetonitrile or DMF (2-8 mL) and upon stirring, TCFH (1.2-1.5 eq.) was added. The mixture was heated to 80°C for 16-24h. After completion of the reaction, the solventwas evaporated, and the residue was taken up in aq. NaOH. The mixture was extracted10 with EtOAc (3x), and the combined organic layers were washed with water and brine,then dried over Na2SO4 and concentrated. The crude products were purified by flash column chromatography and if necessary, again by RP column chromatography to yield the desired amides. General procedure E (amide coupling with HATU / DIPEA). To a mixture of the15 carboxylic acid (1 eq.) and HATU (1.2 eq.) dissolved in dry DMF (1 mL) was added DIPEA (1.2-2.4 eq.) and the mixture was stirred for 20-30 min at rt. The amine (1.2eq.), dissolved in DMF (0.5 mL) was added and the solution was stirred at 80°C overnight. The solvent was evaporated, and the residue was taken up in EtOAc andwashed with 5% HCl. The aqueous layer was extracted three more times with EtOAc,20 and the combined organic layers were washed with 1M NaOH, water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash columnchromatography and if necessary, again by RP column chromatography to give the respective compound. In the following, the synthesis and characterization of compounds of formula (I), (Ia),25 (II) and (IIa) and precursors thereof is described in detail.156: 2-butoxyquinoline-4-carboxylic acid. To a solution of 1-butanol (366 µL, 4 mmol,2 eq.) in 2 mL of dry DMF, stirred under N2-atmosphere, was added NaH (241 mg, 6mmol, 3 eq.) and the mixture was stirred for 1h at rt. 2-chloroquinolone-4-carboxylicacid (428 mg, 2 mmol, 1 eq.), dissolved in 2 mL of dry DMF was added dropwise and30 the mixture was stirred at 80°C overnight. After cooling down to rt, water was added,and the solvents were evaporated. The residue was redissolved in water and acidified with 5% HCl. This aqueous mixture was extracted with EtOAc (4x) and the combined 54 220860PWO organic extracts were dried over Na2SO4. The solvent was evaporated, and theremaining oil was diluted with water and lyophilized to yield the product as a yellowish- white solid (quant). 1H NMR (400 MHz, MeOD) δ 8.35 (dd, J = 8.3, 1.5 Hz, 1H), 7.80(dd, J = 8.5, 0.7 Hz, 1H), 7.64 – 7.58 (m, 1H), 7.43 – 7.37 (m, 1H), 7.10 (s, 1H), 4.455 (t, J = 6.6 Hz, 2H), 1.88 – 1.76 (m, 2H), 1.61 – 1.47 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, DMSO) δ 161.26, 146.33, 146.01, 128.37, 125.88, 125.14,123.07, 121.12, 110.21, 64.75, 30.04, 18.16, 12.00. 157: 3-butoxy1-naphthoic acid. 3-Hydroxynapthoic acid (93 mg, 0.50 mmol, 1 eq) and1-chlorobutane (183 µL, 1.75 mmol, 3.5 eq.) were dissolved in 2 mL of dry DMF. K2CO310 (188 mg, 1.36 mmol, 2.8 eq.) was added and the solution was heated stepwise to 100°C. After stirring for one night, the reaction was allowed to cool down to rt and acidified with conc. HCl. The mixture was extracted with EtOAc (3x) and the combinedorganic layers were dried over Na2SO4and concentrated in vacuo. The remaining oil was taken up in EtOH (5 mL), NaOH (128 mg, 3.2 mmol, 6.4 eq.) was added and the15 mixture was stirred at rt for two nights. The solvent was evaporated and the remaining solid was redissolved in water. Acidifying with conc. HCl gave a precipitate that was collected by filtration. The crude product was loaded onto a pad of silica and eluted with MeOH in EtOAc, then EtOH. Removal of the solvents in vacuo and lyophilization yielded the product as a yellowish-white solid (123 mg, quant.). 1H NMR (400 MHz,20 DMSO) δ 13.21 (s, 1H), 8.70 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 9.9 Hz, 1H), 7.70 (d, J =2.7 Hz, 1H), 7.58 (d, J = 2.6 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.47 – 7.42 (m, 1H), 4.12 (t,J = 6.5 Hz, 2H), 1.82 – 1.71 (m, 2H), 1.48 (h, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, DMSO) δ 168.13, 155.08, 135.13, 129.41, 127.46, 126.63,126.00, 125.39, 124.97, 122.07, 111.77, 67.58, 30.65, 18.76, 13.73.25 158: 2-butoxyisonicotinic acid. To a solution of 1-butanol (1.83 mL, 20 mmol, 2 eq.) in4 mL of dry DMF, stirred under N2-atmosphere, was added NaH (1.2 g, 30 mmol, 3 eq.) and the mixture was stirred for 1h at rt. 2-chloroisonicotinic acid (1.6 g, 10 mmol, 1eq.), dissolved in 20 mL of dry DMF was added dropwise and the mixture was stirred at 80°C overnight. After cooling down to rt, water was added, and the solvents were30 evaporated. The residue was redissolved in water and acidified with 5% HCl. This aqueous mixture was extracted with EtOAc (4x) and the combined organic extracts were dried over Na2SO4. The solvent was evaporated, and the remaining oil waspurified by flash column chromatography (DCM / MeOH gradient) and lyophilized to 55 220860PWO yield the product as a yellowish solid (1.48 g, 76%).1H NMR (400 MHz, DMSO) δ 13.61(s, 1H), 8.31 – 8.29 (m, 1H), 7.36 (dd, J = 5.2, 1.4 Hz, 1H), 7.16 – 7.13 (m, 1H), 4.28(t, J = 6.6 Hz, 2H), 1.74 – 1.64 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz,3H). 13C NMR (101 MHz, DMSO) δ 165.88, 164.10, 148.02, 141.41, 115.74, 110.28,5 65.68, 30.49, 18.74, 13.70. 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide. Preparation according to general procedure E from 4-quinolinecarboxylic acid (86 mg, 0.50 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)aniline (126 mg, 0.52 mmol, 1.1 eq.). Further purified by RP column10 chromatography to yield the product as a white solid (27 mg, 13%). 1H NMR (400 MHz,MeOD) δ 9.01 (d, J = 4.4 Hz, 1H), 8.31 – 8.25 (m, 2H), 8.20 – 8.09 (m, 3H), 7.89 –7.84 (m, 1H), 7.77 (d, J = 4.5 Hz, 1H), 7.75 – 7.69 (m, 2H), 7.41 (s, 1H), 2.28 (s, 3H).13C NMR (126 MHz, MeOD-d4) δ 168.05, 151.13, 149.37, 143.56, 142.20, 140.43,139.82, 136.37, 133.99 (q, J = 33.0 Hz), 131.73, 129.97, 129.31, 126.47, 125.79,15 124.92 (q, J = 272.0 Hz), 120.47, 116.61, 116.34 (q, J = 4.2 Hz), 116.08, 114.41 (q, J= 4.0 Hz), 13.20. HRMS (GC / EI+): m / z calculated 396.1192 for C21H15F3N4O, found396.1193 ([M]+). 3: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-naphthamide.Preparation according to general procedure C from 1-naphthalenecarboxylic acid (12820 mg 0.75 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (217 mg, 0.90 mmol, 1.2 eq.). Purification by RP column chromatography yielded a whitesolid (70 mg 24%). 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.29 – 8.23 (m, 2H),8.21 (d, J = 1.5 Hz, 1H), 8.18 – 8.15 (m, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.07 – 8.01 (m,1H), 7.84 (dd, J = 7.1, 1.2 Hz, 1H), 7.77 – 7.74 (m, 1H), 7.68 – 7.58 (m, 3H), 7.51 –25 7.47 (m, 1H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO) δ 167.87, 141.40, 138.97,138.08, 135.02, 133.77, 133.20, 131.01 (q, J = 32.2 Hz), 130.78, 129.57, 128.44,127.26, 126.56, 125.89, 125.08, 125.00, 127.88 – 119.28 (m), 114.60, 114.24, 114.12– 113.66 (m), 111.98 – 111.60 (m), 13.57. HRMS (DEP / EI+): m / z calculated 395.1240for C22H16F3N3O, found 395.1245 ([M]+).30 4: 2-hydroxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide. Preparation according to general procedure D from 2-hydroxyquinolie-4-carboxylic acid (141 mg, 0.74 mmol, 1.4 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- 56 220860PWO (trifluoromethyl)aniline (126 mg, 0.52 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (65 mg, 30%). 1H NMR (400 MHz, DMSO) δ 8.25– 8.19 (m, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.62 –7.53 (m, 1H), 7.50 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.80 (s,5 1H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO) δ 164.90, 161.13, 145.12, 140.62,139.36, 139.01, 138.09, 135.05, 131.16, 131.06 (q, J = 31.7 Hz), 125.83, 127.90 –118.80 (m), 122.27 (d, J = 11.6 Hz), 120.59, 115.82, 115.72, 114.91, 114.23, 114.20,112.35, 13.56. HRMS (GC / EI+): m / z calculated 412.1141 for C21H15F3N4O2, found412.1143 ([M]+).10 159: 2-ethoxyquinoline-4-carboxylic acid. To a solution of ethanol (600 µL, 10 mmol, 2eq.) in 6 mL of dry DMF, stirred under N2, was added NaH (15 mmol, 3 eq.) and the mixture was stirred at rt for 1h. A solution of 2-chloroquinoline-4-carboxylic acid (1080mg, 5 mmol, 1 eq.) in 5 mL of dry DMF was added dropwise and the mixture was stirred at 75°C overnight for 22h. After cooling down to rt, water was added, and the solvents15 were evaporated. The residue was redissolved in water and acidified with 5% HCl. This aqueous mixture was extracted with EtOAc (5x) and the combined organic extracts were dried over Na2SO4. The solvent was evaporated, and the remaining oil wasdiluted with water and lyophilized to yield 1.161 g (quant.) of a brown-white solid. 1HNMR (400 MHz, DMSO) δ 8.51 (dd, J = 8.5, 1.4 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.77 –20 7.67 (m, 1H), 7.55 – 7.46 (m, 1H), 7.34 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 1.39 (t, J =7.0 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 167.00, 161.00, 146.89, 139.84, 130.10,127.37, 125.52, 125.07, 121.39, 114.18, 14.36. 5: 2-ethoxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide. Preparation according to general procedure D from 159 (162 mg, 0.7425 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (200 mg, 0.83 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a paleyellow solid (189 mg, 58%). 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 8.22 (s, 2H),8.10 (d, J = 10.6 Hz, 2H), 7.90 – 7.68 (m, 3H), 7.50 (s, 2H), 7.31 (s, 1H), 4.54 (d, J =7.7 Hz, 2H), 2.18 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 165.29,30 160.90, 146.50, 144.24, 140.76, 139.00, 135.01, 131.65 – 130.50 (m), 130.37, 127.30,125.19, 124.97, 123.57 (d, J = 272.9 Hz), 120.98, 114.80, 114.19, 114.16 – 113.95 (m),112.44 – 112.06 (m), 111.70, 61.74, 14.41, 13.55. HRMS (FIA / ESI+): m / z calculated440.1454 for C23H19F3N4O2, found 441.1536 ([M+H]+). 57 220860PWO 6: 2-butoxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-isonicotinamide. Preparation according to general procedure C from 158 (197 mg, 1.01mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (372 mg, 1.54 mmol, 1.5 eq.). After purification, the product was lyophilized to yield a white solid (233 5mg, 56%). 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.29– 8.24 (m, 1H), 8.23 – 8.18 (m, 1H), 8.15 – 8.10 (m, 1H), 7.79 – 7.74 (m, 1H), 7.50 –7.46 (m, 1H), 7.44 (dd, J = 5.3, 1.5 Hz, 1H), 7.34 (s, 1H), 4.32 (t, J = 6.6 Hz, 2H), 2.20 –2.16 (m, 3H), 1.78 – 1.67 (m, 2H), 1.51 – 1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13CNMR (101 MHz, DMSO) δ 164.18, 163.92, 147.95, 144.28, 140.74, 138.99, 137.98,10 134.98, 130.92 (q, J = 32.0 Hz), 123.59 (q, J = 272.9 Hz), 115.04, 114.78, 114.35,114.17, 112.12, 108.95, 65.70, 30.53, 18.77, 13.71, 13.56. HRMS (DEP / EI+): m / zcalculated 418.1611 for C21H21F3N4O2, found 418.1614 ([M]+). 7: 3-butoxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-naphthamide. Preparation according to general procedure C from 157 (41 mg, 0.1715 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (87 mg, 0.36 mmol, 2.1 eq.). After purification, the product was lyophilized to yield a white solid (35 mg, 45%). 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.28 – 8.24 (m, 1H), 8.22 –8.20 (m, 1H), 8.18 – 8.13 (m, 2H), 7.91 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 1.8 Hz, 1H),7.57 – 7.48 (m, 4H), 7.46 – 7.39 (m, 1H), 4.16 (t, J = 6.5 Hz, 2H), 2.18 (d, J = 1.0 Hz,20 3H), 1.85 – 1.74 (m, 2H), 1.58 – 1.44 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (101MHz, DMSO) δ 167.15, 155.30, 141.31, 138.98, 138.05, 135.03, 135.00, 134.89,131.00 (d, J = 32.4 Hz), 127.35, 126.95, 125.06, 125.02, 124.65, 122.31, 118.74,114.73, 114.26, 114.02, 111.81, 109.53, 67.63, 30.72, 18.82, 13.74, 13.58. HRMS(DEP / EI+): m / z calculated 467.1815 for C26H24F3N3O2, found 467.1808 ([M]+)25 8: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide.Preparation according to general procedure D from isonicotinic acid (298 mg, 2.39mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (625 mg, 2.59 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid(78 mg, 9%). 1H NMR (500 MHz, DMSO) δ 8.83 (d, J = 6.1 Hz, 2H), 8.26 (s, 1H), 8.2130 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 6.1 Hz, 2H), 7.77 (s, 1H), 7.50 (s, 1H), 2.18 (s, 3H).13C NMR (126 MHz, DMSO) δ 164.66, 150.47, 141.48 – 141.18 (m), 141.25 – 140.79(m), 139.00, 138.02, 135.03, 131.63 – 130.11 (m), 125.16 – 122.28 (m), 121.58, 58 220860PWO 115.24, 114.80 – 114.40 (m), 114.23, 112.27 – 112.01 (m), 13.58. HRMS (GC / EI+): m / zcalculated 346.1036 for C17H13F3N4O, found 346.1035 ([M]+).9: 2-chloro-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-isonicotinamide. Preparation according to general procedure D from 2-5 chloroisonicotinic acid (132 mg, 0.82 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)aniline (244 mg, 1.01 mmol, 1.2 eq.). Further purification by RPcolumn chromatography yielded a white solid (161 mg, 51%). 1H NMR (400 MHz,DMSO) δ 10.97 (s, 1H), 8.67 (dd, J = 5.1, 0.7 Hz, 1H), 8.26 – 8.22 (m, 2H), 8.21 (d, J= 1.4 Hz, 1H), 8.12 – 8.06 (m, 1H), 8.06 – 8.01 (m, 1H), 7.90 (dd, J = 5.1, 1.5 Hz, 1H),10 7.82 – 7.77 (m, 1H), 7.48 (t, J = 1.3 Hz, 1H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO)δ 163.05, 150.97, 150.94, 144.65, 140.48, 139.02, 138.03, 134.99, 130.98 (q, J = 32.4 Hz), 127.93 – 119.12 (m), 122.27, 121.26, 115.09, 114.45 (d, J = 4.2 Hz), 114.15,112.41 (d, J = 3.9 Hz), 13.56. HRMS (FIA / ESI+): m / z calculated 380.0646 forC17H12ClF3N4O, found 381.0730 ([M+H]+).15 10: 2-methoxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-isonicotinamide. Preparation according to general procedure C from 2-methoxyisonicotinic acid (77 mg, 0.50 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)aniline (121 mg, 0.50 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (30 mg, 16%). 1H NMR (400 MHz, DMSO) δ 8.3820 (d, J = 5.3 Hz, 1H), 8.28 – 8.22 (m, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.52 –7.42 (m, 2H), 7.35 (s, 1H), 3.93 (s, 3H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO) δ164.69, 164.54, 148.31, 145.04, 141.55, 139.39, 138.39, 135.41, 131.32 (q, J = 32.2Hz), 124.03 (q, J = 272.2 Hz), 115.62, 115.39, 114.97 (d, J = 4.2 Hz), 114.62, 112.56 –112.24 (m), 109.34, 54.12, 13.98. HRMS (GC / EI+): m / z calculated for C18H15F3N4O225 376.1141, found 376.1143 ([M]+).11: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide.Preparation according to general procedure D from benzoic acid (117 mg, 0.96 mmol,1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (407 mg, 1.69 mmol, 1.8 eq.). Further purification by RP column chromatography yielded a white solid (13730 mg, 42%). 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 8.20(d, J = 1.4 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.02 – 7.96 (m, 2H), 7.75 – 7.71 (m, 1H),7.68 – 7.61 (m, 1H), 7.60 – 7.54 (m, 2H), 7.48 (t, J = 1.3 Hz, 1H), 2.18 (d, J = 1.0 Hz, 59 220860PWO 3H). 13C NMR (101 MHz, DMSO) δ 166.06, 141.34, 138.94, 137.95, 134.97, 134.10,132.18, 130.86 (q, J = 32.4 Hz), 128.59, 127.74, 123.66 (d, J = 272.5 Hz), 114.93,114.21, 111.64 (q, J = 3.8 Hz), 13.57. HRMS (FIA / ESI+): m / z calculated 345.1083 forC18H14F3N3O, found 346.1164 ([M+H]+). 512: N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (246 mg, 1.02 mmol, 1 eq.), benzyl bromide (122 µL, 1.02 mmol, 1 eq.) and potassium carbonate (146 mg, 1.05 mmol, 1 eq.) were dissolved in 2 mL of dry DMF and stirred at 90°C overnight. After cooling to rt, the mixture was diluted with EtOAc and washed with brine. The organic layer was dried10 over Na2SO4, concentrated and purified by flash column and RP column chromatography to yield a yellowish oily solid (47 mg, 11%).1H NMR (400 MHz, MeOD)δ 7.95 – 7.90 (m, 1H), 7.42 – 7.36 (m, 2H), 7.37 – 7.30 (m, 2H), 7.28 – 7.21 (m, 1H),7.21 – 7.16 (m, 1H), 6.95 – 6.89 (m, 1H), 6.88 – 6.81 (m, 2H), 4.40 (s, 2H), 2.23 (s,2H).13C NMR (101 MHz, MeOD) δ 152.01, 140.20, 139.99, 139.83, 135.98, 134.00 (q,15 J = 32.6 Hz), 129.66, 128.40, 128.24, 125.32 (q, J = 271.5 Hz), 115.98, 109.08 – 108.69(m), 108.18, 105.75 – 105.41 (m), 48.11, 13.17.13: 4-chloro-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide.Preparation according to general procedure C from 4-chlorobenzoic acid (99 mg, 0.64mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (169 mg, 0.7020 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid(34 mg, 14%). 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.29 – 8.24 (m, 1H), 8.23– 8.18 (m, 1H), 8.12 (s, 1H), 8.07 – 7.99 (m, 2H), 7.74 (s, 1H), 7.70 – 7.62 (m, 2H),7.51 – 7.46 (m, 1H), 2.18 (d, J = 1.0 Hz, 3H). 13C NMR (126 MHz, DMSO) δ 164.99,141.30, 138.96, 137.96, 137.03, 135.00, 132.88, 130.88 (q, J = 32.3 Hz), 129.73,25 128.69, 123.66 (q, J = 272.7 Hz), 115.05, 114.38 (q, J = 4.1 Hz), 114.22, 111.76 (q, J= 3.8 Hz), 13.58. HRMS (GC / EI+): m / z calculated for C18H13ClF3N3O 379.0694, found380.0772 ([M+H]+) . 14: 3,4-dichloro-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-benzamide. 3,4-dichlorobenzoyl chloride (109 mg, 0.52 mmol, 1 eq.) was dissolved in30 4 mL of dry chloroform and stirred at 0°C. 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (151 mg, 0.63 mmol, 1.2 eq.) was added, the mixture was flushed with N2, allowed to warm up to rt and stirred for 2h. The solvent was 60 220860PWO evaporated, and the residue was taken up in aq. NaOH. The suspension was extractedwith EtOAc, and the combined organic layers were washed with brine, dried overNa2SO4and concentrated. The crude product was purified by flash column chromatography to yield a white solid (165 mg, 67%). 1H NMR (400 MHz, DMSO) δ5 8.28 – 8.22 (m, 2H), 8.20 (s, 1H), 8.13 – 8.07 (m, 1H), 7.97 (dd, J = 8.4, 2.1 Hz, 1H),7.85 (d, J = 8.4 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.48 (s, 1H), 2.18 (s, 3H). 13C NMR (101MHz, DMSO) δ 163.71, 141.19, 138.96, 137.95, 135.13 – 134.78 (m), 134.52, 131.43,130.94, 130.86 (q, J = 32.0 Hz), 129.64, 128.12, 127.78 – 119.17 (m), 115.07, 114.44(d, J = 3.8 Hz), 114.18, 112.06 – 111.63 (m), 13.56. HRMS (ESI+): m / z calculated for10 C18H12Cl2F3N3O 413.0304, found 414.0377 ([M+H]+) . 15: 4-methoxy-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide.Preparation according to general procedure D from 4-methoxybenzoic acid (212 mg,1.39 mmol, 1.5 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (218 mg, 0.90 mmol, 1 eq.). Further purification by RP column chromatography yielded a15 white solid (77 mg, 23%). 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.31 – 8.26 (m,1H), 8.19 (d, J = 1.4 Hz, 1H), 8.16 – 8.12 (m, 1H), 8.05 – 7.96 (m, 2H), 7.73 – 7.67 (m,1H), 7.48 (t, J = 1.3 Hz, 1H), 7.16 – 7.06 (m, 2H), 3.85 (s, 3H), 2.18 (s, 3H). 13C NMR(126 MHz, DMSO) δ 165.40, 162.38, 141.59, 138.92, 137.92, 134.97, 130.81 (q, J =32.0 Hz), 129.78, 126.07, 123.70 (q, J = 272.7 Hz), 114.85, 114.28 – 114.05 (m),20 113.83, 111.34 (q, J = 3.9 Hz), 55.53, 13.58. HRMS (DEP / EI+): m / z calculated375.1189 for C19H16F3N3O2, found 375.1189 ([M]+).16: 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide.p-toluyl chloride (68 µL, 0.50 mmol, 1 eq.) was dissolved in 5 mL of dry chloroform andstirred at 0°C. 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (153 mg, 0.6325 mmol, 1.3 eq.) was added, the mixture was flushed with N2, allowed to warm up to rtand stirred overnight. The solvent was evaporated, and the residue was taken up inaq. NaOH. The suspension was extracted with EtOAc, and the combined organiclayers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography to yield a white solid (152 mg,30 85%).1H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 8.32 – 8.26 (m, 1H), 8.20 (d, J = 1.4Hz, 1H), 8.17 – 8.14 (m, 1H), 7.95 – 7.88 (m, 2H), 7.74 – 7.68 (m, 1H), 7.48 (q, J = 1.2Hz, 1H), 7.41 – 7.34 (m, 2H), 2.40 (s, 3H), 2.18 (d, J = 1.0 Hz, 3H). 13C NMR (126MHz, DMSO) δ 165.86, 142.35, 141.47, 138.93, 137.93, 134.98, 131.22, 131.34 – 61 220860PWO 130.37 (m), 129.12, 127.80, 123.68 (q, J = 272.7 Hz), 114.89, 114.22, 111.49 (q, J =3.8 Hz), 21.07, 13.58. HRMS (DEP / EI+): m / z calculated for C19H16F3N3O 359.1240,found 359.1244 ([M]+).17: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-(trifluoromethyl)-5 benzamide. Preparation according to general procedure D from 4-(trifluoromethyl)benzoic acid (120 mg, 0.61 mmol, 1.2 eq.) and 3-(4-methyl-1H- imidazol-1-yl)-5-(trifluoromethyl)aniline (122 mg, 0.51 mmol, 1 eq.). Further purification by RP column yielded a white solid (126 mg, 60%). 1H NMR (400 MHz, DMSO) δ 10.90(s, 1H), 8.28 (t, J = 2.0 Hz, 1H), 8.24 – 8.17 (m, 3H), 8.15 – 8.11 (m, 1H), 7.97 (s, 1H),10 7.95 (s, 1H), 7.79 – 7.73 (m, 1H), 7.49 (s, 1H), 2.18 (s, 3H).13C NMR (101 MHz, DMSO)δ 164.89, 140.99, 138.99, 137.99, 137.88, 135.00, 131.85 (q, J = 32.2 Hz), 130.92 (q,J = 32.4 Hz), 128.69, 125.60 (q, J = 3.7 Hz), 123.86 (q, J = 272.7 Hz), 123.61 (q, J =272.6 Hz), 115.07, 114.67 – 114.31 (m), 114.20, 112.30 – 111.77 (m), 13.56. HRMS(GC / EI+): m / z calculated 413.0957 for C19H13F6N3O, found 413.0957 ([M]+).15 18: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.Preparation according to general procedure D from phenylacetic acid (102 mg, 0.75mmol, 1.4 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (135 mg, 0.56 mmol, 1 eq.). Further purification by RP column chromatography yielded a whitesolid (129 mg, 64%). 1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 8.17 (d, J = 1.4 Hz,20 1H), 8.06 – 8.01 (m, 1H), 7.97 – 7.90 (m, 1H), 7.69 – 7.63 (m, 1H), 7.47 – 7.42 (m,1H), 7.37 – 7.30 (m, 4H), 7.30 – 7.22 (m, 1H), 3.70 (s, 2H), 2.16 (s, 3H). 13C NMR (101MHz, DMSO) δ 170.03, 141.26, 138.91, 138.07, 135.31, 134.98, 130.97 (q, J = 32.4Hz), 129.24, 128.37, 126.73, 123.57 (q, J = 272.7 Hz), 114.21, 113.73, 113.21 – 112.86(m), 111.53 – 111.16 (m), 43.32, 13.54.25 19: 3-(4-methyl-1H-imidazol-1-yl)-N-phenethyl-5-(trifluoromethyl)aniline. In a heated25 mL Schlenk flask, 21 (51 mg, 0.14 mmol, 1 eq.) was dissolved in dry THF (3 mL)and stirred under N2-atmosphere at 0°C. LiAlH4 (0.30 mmol, 2.1 eq.) was added slowly and the mixture was allowed to warm up to rt and stirred for 22h, then diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4,30 concentrated and purified by flash column and RP column chromatography to yield a white solid (12 mg, 25%). 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.34 – 7.22 (m,5H), 7.22 – 7.14 (m, 1H), 6.90 (s, 1H), 6.87 – 6.78 (m, 2H), 3.43 (t, J = 7.1 Hz, 2H), 62 220860PWO 2.91 (t, J = 7.1 Hz, 2H), 2.24 (s, 3H). 13C NMR (101 MHz, MeOD) δ 152.10, 140.85,140.11, 133.88 (q, J = 32.0 Hz), 129.88, 129.53, 127.35, 125.36 (q, J = 272.1 Hz),108.55 (q, J = 3.8 Hz), 107.74, 105.29 (q, J = 4.0 Hz), 45.81, 36.39, 13.16.20: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-(pyridin-3-5 yl)acetamide. Preparation according to general procedure D from 3-pyridylacetic acidhydrochloride (329 mg, 1.89 mmol, 2.4 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (189 mg, 0.78 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (30 mg, 11%). 1H NMR (500 MHz, DMSO) δ10.79 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.92 (s,10 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.45 (s, 1H), 7.40 – 7.34 (m, 1H), 3.79 –3.74 (m, 2H), 2.16 (s, 3H). 13C NMR (126 MHz, DMSO) δ 169.51, 150.31, 147.97,141.14, 139.06 – 138.72 (m), 138.16 – 137.96 (m), 136.96, 134.99, 131.02, 130.98 (q,J = 32.3 Hz), 123.56 (q, J = 272.7 Hz), 123.44, 114.37 – 113.95 (m), 113.79, 113.13 (d,J = 4.3 Hz), 111.38 (d, J = 4.0 Hz), 40.12, 13.55. HRMS (GC / EI+): m / z calculated for15 C18H15F3N4O 360.1192, found 360.1194 ([M]+).21: N-(3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-phenylpropanamide.Preparation according to general procedure D from 3-phenylpropanoic acid (125 mg,0.83 mmol, 1.6 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (123 mg, 0.51 mmol, 1 eq.). Further purification by RP column chromatography yielded a20 white solid (148 mg, 78%). 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.16 (d, J = 1.4Hz, 1H), 8.03 – 7.97 (m, 1H), 7.94 – 7.89 (m, 1H), 7.67 – 7.62 (m, 1H), 7.46 – 7.41 (m,1H), 7.34 – 7.23 (m, 4H), 7.22 – 7.14 (m, 1H), 2.94 (t, J = 7.6 Hz, 2H), 2.69 (dd, J =8.3, 7.0 Hz, 2H), 2.17 (s, 3H). 13C NMR (101 MHz, DMSO) δ 171.28, 141.25, 140.90,138.90, 138.04, 134.96, 130.93 (q, J = 32.0 Hz), 128.37, 128.23, 126.03, 127.86 –25 119.42 (m), 114.19, 113.62, 113.16 – 112.75 (m), 111.37 – 110.91 (m), 37.94, 30.48,13.54. HRMS (DEP / EI+): m / z calculated 373.1396 for C20H18F3N3O, found 373.1387([M]+). 22: 2-(2-chlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 2-chlorophenylacetic30 acid (122 mg, 0.72 mmol, 1.3 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (134 mg, 0.56 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (152 mg, 69%). 1H NMR (400 MHz, DMSO) δ 63 220860PWO 10.76 (s, 1H), 8.19 – 8.15 (m, 1H), 8.03 (t, J = 2.0 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.70– 7.64 (m, 1H), 7.49 – 7.40 (m, 3H), 7.38 – 7.27 (m, 2H), 3.90 (s, 2H), 2.16 (s, 3H). 13CNMR (101 MHz, DMSO) δ 168.90, 141.23, 138.92, 138.11, 134.98, 133.73, 133.34,132.37, 131.03 (q, J = 32.7 Hz), 129.04, 128.82, 127.13, 123.57 (q, J = 272.8 Hz),5 114.21, 113.62, 113.14 – 112.78 (m), 111.52 – 111.11 (m), 40.84, 13.54. HRMS(DEP / EI+): m / z calculated 393.0850 for C19H15ClF3N3O, found 393.0853 ([M]+).23: 2-(3-chlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure B from 3-chlorophenylaceticacid (129 mg, 0.76 mmol, 1.6 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5-10 (trifluoromethyl)aniline (117 mg, 0.49 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (99 mg, 52%).1H NMR (400 MHz, MeOD) δ 8.12– 8.06 (m, 2H), 7.89 – 7.84 (m, 1H), 7.59 – 7.54 (m, 1H), 7.43 – 7.37 (m, 1H), 7.37 –7.24 (m, 4H), 3.74 (s, 2H), 2.25 (d, J = 1.0 Hz, 3H). 13C NMR (101 MHz, MeOD) δ171.95, 142.39, 140.38, 139.68, 138.44, 138.41, 136.23, 135.37, 133.78 (q, J = 32.815 Hz), 131.10, 130.39 (d, J = 1.9 Hz), 128.71 (d, J = 2.2 Hz), 128.24, 129.40 – 120.47(m), 115.97, 115.84 – 115.44 (m), 113.88 – 113.34 (m), 44.11, 13.18. HRMS (GC / EI+):m / z calculated 393.0850 for C19H15ClF3N3O, found 393.0851 ([M]+).24: 2-(4-chlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-acetamide. 2-(4-Chlorophenyl)acetyl chloride (85 µL, 0.58 mmol, 1.1 eq.) was20 dissolved in 6 mL of dry chloroform and stirred at 0°C.3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)aniline (127 mg, 0.52 mmol, 1 eq.) was added, the mixture was flushed with N2, allowed to warm up to rt and stirred overnight. The solvent wasevaporated and the residue was taken up in aq. NaOH. The suspension was extracted with EtOAc and the combined organic layers were washed with brine, dried over25 Na2SO4 and concentrated. The crude product was purified by flash column chromatography to yield a white solid (168 mg, 81%). 1H NMR (400 MHz, DMSO) δ10.69 (s, 1H), 8.17 (d, J = 1.4 Hz, 1H), 8.05 – 7.99 (m, 1H), 7.94 – 7.89 (m, 1H), 7.70– 7.64 (m, 1H), 7.44 (s, 1H), 7.42 – 7.33 (m, 4H), 3.72 (s, 2H), 2.16 (s, 3H). 13C NMR(101 MHz, DMSO) δ 169.65, 141.16, 138.91, 138.06, 134.96, 134.27, 131.47, 131.18,30 130.96 (q, J = 32.2 Hz), 128.26, 123.55 (q, J = 272.6 Hz), 114.18, 113.74, 113.07 (q, J= 3.9 Hz), 111.37 (q, J = 3.2 Hz), 42.38, 13.53. 64 220860PWO 25: 2-(2,4-dichlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 2,4-dichlorophenylacetic acid (114 mg, 0.55 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1- yl)-5-(trifluoromethyl)aniline (163 mg, 0.67 mmol, 1.2 eq.). Further purification by RP5 column chromatography yielded a white solid (145 mg, 62%). 1H NMR (400 MHz,DMSO) δ 10.78 (s, 1H), 8.17 (s, 1H), 8.05 – 8.00 (m, 1H), 7.94 – 7.89 (m, 1H), 7.70 –7.65 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.53 – 7.39 (m, 3H), 3.91 (s, 2H), 2.16 (s, 3H).13C NMR (101 MHz, DMSO) δ 168.52, 141.14, 138.92, 138.10, 134.97, 134.72,133.65, 132.56, 132.43, 131.00 (q, J = 32.1 Hz), 128.47, 127.23, 123.55 (q, J = 273.010 Hz), 114.18, 113.63, 113.22 – 112.77 (m), 111.51 – 111.11 (m), 40.19, 13.53.26: 2-(2,6-dichlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 2,6-dichlorophenylacetic acid (193 mg, 0.50 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1- yl)-5-(trifluoromethyl)aniline (142 mg, 0.59 mmol, 1.2 eq.). Further purification by RP15 column chromatography yielded a white solid (51 mg, 24%). 1H NMR (400 MHz,Acetone) δ 10.71 (s, 1H), 8.17 – 8.12 (m, 1H), 8.11 – 8.06 (m, 1H), 8.02 – 7.97 (m,1H), 7.64 – 7.58 (m, 1H), 7.49 (d, J = 0.9 Hz, 1H), 7.47 (s, 1H), 7.40 – 7.32 (m, 2H),4.20 (s, 2H), 2.20 (s, 3H). 13C NMR (126 MHz, Acetone) δ 168.25, 142.51, 140.32,139.33, 136.82, 135.52, 132.89, 132.47 (q, J = 32.5 Hz), 130.14, 128.85, 124.54 (q, J20 = 272.1 Hz), 114.83, 114.44, 113.93 (q, J = 4.1 Hz), 111.96 (q, J = 3.9 Hz), 39.50, 13.78.HRMS (DEP / EI+): m / z calculated 427.0460 for C19H14Cl2F3N3O, found 427.0465([M]+). 27: 2-(2,3-dichlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 2,3-25 dichlorophenylacetic acid (107 mg, 0.51 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1- yl)-5-(trifluoromethyl)aniline (145 mg, 0.60 mmol, 1.2 eq.). Further purification by RPcolumn chromatography yielded a white solid (105 mg, 48%). 1H NMR (400 MHz,DMSO) δ 10.79 (s, 1H), 8.18 (s, 1H), 8.06 – 8.00 (m, 1H), 7.94 – 7.89 (m, 1H), 7.71 –7.65 (m, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.36 (t, J = 7.8 Hz,30 1H), 3.98 (s, 2H), 2.16 (s, 3H). 13C NMR (101 MHz, DMSO) δ 168.50, 141.14, 138.92,138.11, 136.08, 134.99, 131.87, 131.61, 131.06, 131.02 (q, J = 32.0 Hz), 129.27,128.00, 127.73 – 119.23 (m), 114.20, 113.63, 113.23 – 112.78 (m), 111.61 – 111.13(m), 41.66, 13.52. 65 220860PWO 28: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-(2-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 2-(trifluoromethyl)phenylacetic acid (105 mg, 0.51 mmol, 1 eq.) and 3-(4-methyl-1H- imidazol-1-yl)-5-(trifluoromethyl)aniline (152 mg, 0.63 mmol, 1.2 eq.). Further 5purification by RP column chromatography yielded a white solid (113 mg, 51%). 1HNMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.17 (d, J = 1.4 Hz, 1H), 8.04 – 7.99 (m, 1H),7.94 – 7.88 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.59 – 7.47 (m, 2H),7.47 – 7.42 (m, 1H), 3.99 (s, 2H), 2.16 (s, 3H). 13C NMR (101 MHz, DMSO) δ 168.97,141.17, 138.91, 138.11, 134.96, 133.60, 133.32 – 133.09 (m), 132.29, 131.02 (q, J =10 32.4 Hz), 127.58 (q, J = 29.7 Hz), 127.52, 125.65 (q, J = 5.7 Hz), 124.48 (q, J = 274.0Hz), 123.54 (q, J = 272.9 Hz), 114.18, 113.57, 112.92 (q, J = 3.9 Hz), 111.29 (q, J = 3.4Hz), 40.19, 13.52. 29: 2-(2-cyanophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 2-cyanophenylacetic15 acid (113 mg, 0.68 mmol, 1.3 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (122 mg, 0.51 mmol, 1 eq.). Further purification by RP columnchromatography yielded a pale yellow solid (121 mg, 62%).1H NMR (500 MHz, DMSO)δ 10.86 (s, 1H), 8.18 (s, 1H), 8.05 – 8.00 (m, 1H), 7.91 (s, 1H), 7.85 (d, J = 7.6 Hz,1H), 7.73 – 7.66 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H),20 4.02 (s, 2H), 2.16 (s, 3H). 13C NMR (126 MHz, DMSO) δ 168.36, 141.04, 138.94,138.77, 138.12, 134.99, 133.18, 132.73, 131.18, 131.52 – 130.59 (m), 127.84, 123.55(q, J = 272.7 Hz), 117.84, 114.20, 113.74, 113.09 (q, J = 4.0 Hz), 112.73, 111.48 (q, J= 3.7 Hz), 41.28, 13.54. 30: 4-chloro-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-25 naphthamide. Preparation according to general procedure C from 4-chloro-1-naphthoic acid (48 mg, 0.23 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (66 mg, 0.27 mmol, 1.2 eq.). Further purification by RP columnchromatography yielded a white solid (66 mg, 68%). 1H NMR (400 MHz, DMSO) δ11.12 (s, 1H), 8.37 – 8.29 (m, 2H), 8.27 – 8.23 (m, 1H), 8.23 – 8.20 (m, 1H), 8.16 –30 8.12 (m, 1H), 7.91 – 7.70 (m, 5H), 7.50 (s, 1H), 2.18 (s, 3H). 13C NMR (101 MHz,DMSO) δ 167.04, 141.19, 138.98, 138.08, 135.02, 133.46, 133.21, 131.18, 130.86,130.83, 130.54, 129.98, 128.29, 128.22, 126.06, 125.91, 125.53, 124.16, 127.80 – 66 220860PWO 119.40 (m), 114.69, 114.22, 113.95, 111.95, 13.57. HRMS (GC / EI+): m / z calculated429.0850 for C22H15ClF3N3O, found 429.0850 ([M]+).31: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1H-indole-3-carboxamide. Preparation according to general procedure C from indole-3-carboxylic5 acid (96 mg, 0.59 mmol, 1 eq.) and 3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (199 mg, 0.83 mmol, 1.4 eq.). Further purification by RP columnchromatography yielded a white solid (53 mg, 23%). 1H NMR (400 MHz, DMSO) δ11.87 (s, 1H), 10.17 (s, 1H), 8.35 (s, 1H), 8.32 – 8.27 (m, 1H), 8.25 – 8.18 (m, 2H),8.16 – 8.11 (m, 1H), 7.67 – 7.61 (m, 1H), 7.56 – 7.45 (m, 2H), 7.26 – 7.13 (m, 2H), 2.1910 (d, J = 0.9 Hz, 3H). 13C NMR (126 MHz, DMSO) δ 163.64, 142.08, 138.88, 137.98,136.32, 135.00, 130.82 (q, J = 32.3 Hz), 129.42, 126.30, 123.78 (q, J = 272.7 Hz),122.46, 121.06, 120.99, 114.29, 114.09, 113.46 (q, J = 4.0 Hz), 112.19, 110.53 (q, J =3.9 Hz), 109.80, 13.59. HRMS (DEP / EI+): m / z calculated 384.1192 for C20H15F3N4O,found 384.1196 ([M]+).15 32: 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure B from imidazole (217 mg, 3.15 mmol, 1 eq.) and 3-bromo-5- (trifluoromethyl)aniline (566 µL, 4.00 mmol, 1.3 eq.). Further purification by RP columnchromatography yielded a white solid (43 mg, 6%). 1H NMR (400 MHz, MeOD) δ 8.11(s, 1H), 7.54 (s, 1H), 7.14 (s, 1H), 7.01 – 6.96 (m, 2H), 6.92 (t, J = 2.0 Hz, 1H). 13C20 NMR (101 MHz, MeOD) δ 152.21, 139.92, 136.95, 134.02 (q, J = 32.2 Hz), 130.26,125.29 (q, J = 271.7 Hz), 119.71, 110.69 (q, J = 4.0 Hz), 110.42, 106.30 (q, J = 3.8 Hz).33: 3-(1H-pyrrol-1-yl)-5-(trifluoromethyl)aniline. Preparation from 2,5-dimethoxy-tetrahydrofuran (333 µL, 2.54 mmol, 1 eq.) and 5-(trifluoromethyl)benzene-1,3-diamine(447 mg (2.54 mmol, 1 eq.) in water / DMF = 1:1. FeCl3 (4 mg, 0.03 mmol, 1 mol%) was25 added and the reaction mixture was stirred at 60°C for 4h. Purification by flash columnchromatography by RP column chromatography (water / acetonitrile gradient), followedby lyophilization yielded an orange-white crystalline solid (166 mg, 29%).1H NMR (400MHz, DMSO) δ 7.29 (t, J = 2.2 Hz, 2H), 6.93 (dt, J = 7.3, 2.1 Hz, 2H), 6.74 (d, J = 2.0Hz, 1H), 6.25 (t, J = 2.2 Hz, 2H), 5.79 (s, 2H). 13C NMR (101 MHz, DMSO) δ 150.73,30 141.37, 131.02 (q, J = 31.4 Hz), 124.15 (q, J = 272.2 Hz), 119.00, 110.60, 107.38,106.78 (q, J = 4.0 Hz), 102.76 (q, J = 3.9 Hz). 67 220860PWO 34: 3-(1H-benzo[d]imidazol-1-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure B from benzimidazole (241 mg, 2.02 mmol, 1 eq.) and 3-bromo-5- (trifluoromethyl)aniline (354 µL, 2.50 mmol, 1.2 eq.). Tetrabutylammonium bromide (32 mg, 0.10 mmol, 5 mol%) was added for better solubility. Further purification by RP5 column chromatography yielded a white solid (166 mg, 30%). 1H NMR (400 MHz,DMSO) δ 8.56 (s, 1H), 7.80 – 7.74 (m, 1H), 7.64 – 7.58 (m, 1H), 7.40 – 7.28 (m, 2H),7.11 – 7.07 (m, 1H), 7.06 – 7.01 (m, 1H), 6.99 – 6.93 (m, 1H), 6.03 (s, 1H). 13C NMR(126 MHz, DMSO) δ 151.13, 143.83, 143.17, 137.47, 132.83, 131.36 (q, J = 31.6 Hz),123.97 (q, J = 272.4 Hz), 123.55, 122.58, 120.04, 111.24, 110.74, 108.73 (d, J = 3.910 Hz), 106.28 (d, J = 4.0 Hz).35: N-(3-(1H-benzo[d]imidazol-1-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide. Preparation according to general procedure C from quinoline-4-carboxylic acid (99 mg, 0.57 mmol, 1.25 eq.) and EH182 (127 mg, 0.46 mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid (112 mg, 56%).15 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 9.10 (d, J = 4.3 Hz, 1H), 8.74 (s, 1H), 8.43– 8.38 (m, 1H), 8.37 – 8.32 (m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H),7.94 – 7.90 (m, 1H), 7.90 – 7.80 (m, 3H), 7.79 – 7.69 (m, 2H), 7.44 – 7.32 (m, 2H). 13CNMR (101 MHz, DMSO) δ 165.99, 150.35, 148.00, 143.95, 143.31, 141.01, 140.90,137.27, 132.65, 131.30 (q, J = 32.2 Hz), 130.15, 129.53, 127.84, 125.26, 123.71,20 124.97 – 122.11 (m), 120.21, 119.43, 117.83, 115.78 – 115.29 (m), 115.01 – 114.63(m), 110.65. HRMS (GC / EI+): m / z calculated 432.1192 for C24H15F3N4O, found 36: 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure B from 4-methyl-1H-pyrazole (63 mg, 1.50 mmol, 1 eq.) and 3-bromo-5- (trifluoromethyl)aniline (283 µL, 2.00 mmol, 1.3 eq.) to yield a white solid (107 mg,25 30%). 1H NMR (400 MHz, DMSO) δ 8.25 – 8.22 (m, 1H), 7.56 – 7.52 (m, 1H), 7.25 –7.22 (m, 1H), 7.15 – 7.12 (m, 1H), 6.75 – 6.72 (m, 1H), 5.83 (s, 2H), 2.08 (s, 3H). 13CNMR (101 MHz, DMSO) δ 150.61, 141.75, 141.13, 130.82 (q, J = 32.0 Hz), 126.20,127.92 – 119.91 (m), 117.88, 107.13 – 106.86 (m), 105.90, 101.22 – 100.93 (m), 8.71.160: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline. This30 intermediate was prepared from 3-bromo-5-(trifluoromethyl)aniline (1390 µL, 9.82 mmol, 1 eq.) and bis(pinacolato)diboron (2742 mg, 10.80 mmol, 1.1 eq.). Potassiumacetate (2923 mg, 29.78 mmol, 3 eq.) and Pd(dppf)Cl2· DCM (209 mg, 0.26 mmol, 3 mol%) and dry dioxane (60 mL) were added under N2 atmosphere and the mixture was 68 220860PWO stirred at 90°C overnight. Purification by flash column chromatography andlyophilization yielded the compound as a yellowish crystalline solid (2608 mg, 93%). 1H NMR (400 MHz, DMSO) δ = 7.19 – 7.14 (m, 1H), 7.02 – 6.97 (m, 1H), 6.96 – 6.90(m, 1H), 5.59 (s, 2H), 1.28 (s, 12H). 13C NMR (101 MHz, DMSO) δ = 149.04, 129.405 (d, J = 30.5 Hz), 125.88, 123.31, 123.17, 116.80, 111.89, 83.87, 24.66. 37: 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (140 mg, 0.49 mmol, 1 eq.) and 4-bromo-1-methyl-1H-pyrazole (76 µL, 0.73 mmol, 1.5 eq.). Further purification by RP columnchromatography yielded a pale yellow solid (53 mg, 46%). 1H NMR (400 MHz, DMSO)10 δ = 8.11 (s, 1H), 7.78 (s, 1H), 6.95 (s, 2H), 6.68 (s, 1H), 5.54 (s, 2H), 3.85 (s, 3H). 13CNMR (126 MHz, DMSO) δ = 149.77, 136.00, 134.18, 130.38 (q, J = 30.6 Hz), 128.13,127.92 – 121.29 (m), 121.28, 113.18, 108.56 (q, J = 4.1 Hz), 107.43 (q, J = 4.0 Hz),38.66. 38: 3-(1H-Pyrazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according to general15 procedure A from 1H-pyrazol-4-ylboronic acid (68 mg, 0.58 mmol, 1.1 eq.) and 3- bromo-5-(trifluoromethyl)aniline (80 µL, 0.55 mmol, 1 eq.). Further purification by RPcolumn chromatography yielded a white solid (28 mg, 22%). 1H NMR (400 MHz,MeOD) δ 7.94 (s, 2H), 7.12 – 7.05 (m, 2H), 6.82 – 6.77 (m, 1H). 13C NMR (101 MHz,MeOD) δ 150.51, 135.72, 133.00 (q, J = 31.5 Hz), 125.90 (q, J = 271.4 Hz), 122.98,20 115.75, 111.82 (q, J = 3.9 Hz), 110.06 (q, J = 3.9 Hz).39: 3-(isoxazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (168 mg, 0.58 mmol, 1 eq.) and 4-bromoisoxazole (162 mg, 1.09mmol, 1.9 eq.). Further purification by RP column chromatography yielded a white solid(27 mg, 20%). 1H NMR (400 MHz, MeOD) δ 9.07 (s, 1H), 8.81 (s, 1H), 7.12 – 7.10 (m,25 1H), 7.10 – 7.07 (m, 1H), 6.91 – 6.85 (m, 1H).13C NMR (126 MHz, MeOD-d4) δ 156.00,150.97, 148.99, 133.36 (q, J = 31.7 Hz), 131.71, 125.67 (q, J = 271.5 Hz), 122.22,116.16, 112.16 (q, J = 4.0 Hz), 111.28 (q, J = 3.9 Hz).40: 3-(trifluoromethyl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)aniline. Preparationaccording to general procedure A from 1,3,5-trimethyl-1H-pyrazole-4-boronic acid30 pinacol ester (133 mg, 0.56 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (119µL, 0.84 mmol, 1.5 eq.). Further purification by RP column chromatography yielded awhite solid (20 mg, 13%). 1H NMR (400 MHz, MeOD) δ 6.88 – 6.85 (m, 1H), 6.78 – 69 220860PWO 6.75 (m, 1H), 6.73 – 6.70 (m, 1H), 3.75 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H). 13C NMR(101 MHz, MeOD) δ 140.85, 136.44, 129.02, 127.35, 123.09 (q, J = 31.2 Hz), 116.42(q, J = 271.4 Hz), 110.51, 110.30, 106.03 (q, J = 4.0 Hz), 100.66 (q, J = 4.0 Hz), 26.47,2.77, 0.60. 541: 3-(3,5-dimethylisoxazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (155 mg, 0.70 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (148 µL, 1.04 mmol, 1.5 eq.). Further purification by RP column chromatography yielded awhite solid (85 mg, 48%). 1H NMR (400 MHz, DMSO) δ 6.88 – 6.83 (m, 1H), 6.81 –10 6.75 (m, 1H), 6.75 – 6.70 (m, 1H), 5.71 (s, 2H), 2.39 (s, 3H), 2.21 (s, 3H). 13C NMR(101 MHz, DMSO) δ 165.32, 157.95, 149.91, 130.36 (q, J = 31.1 Hz), 128.59 – 120.10(m), 117.29, 115.45, 111.84 – 111.59 (m), 108.68 (d, J = 3.8 Hz), 11.34, 10.44.42: 3-(5-b -1H-pyrazol-3-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (162 mg, 0.56 mmol, 1 eq.) and 3-bromo-5-methyl-1H-pyrazole15 (143 mg, 0.87 mmol, 1.5 eq.). Further purification by RP column chromatographyyielded a white solid (58 mg, 43%). 1H NMR (400 MHz, DMSO) δ 7.21 (s, 1H), 7.16 (s,1H), 6.80 – 6.75 (m, 1H), 6.38 (s, 1H), 2.25 (s, 3H). 13C NMR (101 MHz, DMSO) δ149.20, 141.06, 134.86, 130.13 (q, J = 30.9 Hz), 124.53 (q, J = 272.3 Hz), 113.75,108.84 (d, J = 3.7 Hz), 108.73 (d, J = 4.1 Hz), 101.30, 10.98.20 43: 3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)aniline. Preparation accordingto general procedure A from 160 (139 mg, 0.48 mmol, 1 eq.) and 3-bromo-1-methyl-1H-1,2,4-triazole (95 mg, 0.58 mmol, 1.2 eq.). Further purification by RP columnchromatography yielded a white solid (33 mg, 28%). 1H NMR (400 MHz, DMSO) δ 8.52(s, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 6.86 (s, 1H), 5.75 (s, 2H), 3.91 (s, 3H). 13C NMR25 (101 MHz, DMSO) δ 160.41, 145.72, 132.54, 130.21 (q, J = 30.7 Hz), 127.75 – 120.11(m), 114.06, 109.79 (d, J = 3.8 Hz), 108.75 (d, J = 4.2 Hz), 36.01.44: 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)aniline. Preparation accordingto general procedure A from 160 (145 mg, 0.50 mmol, 1 eq.) and 3-bromo-1,5-dimethyl-1H-pyrazole (98 mg, 0.56 mmol, 1.1 eq.). Further purification by RP column30 chromatography yielded a white solid (73 mg, 57%). 1H NMR (400 MHz, DMSO) δ 7.20(s, 1H), 7.11 (s, 1H), 6.74 (s, 1H), 6.42 (s, 1H), 5.58 (s, 2H), 3.75 (s, 3H), 2.27 (s, 3H). 70 220860PWO 13C NMR (126 MHz, DMSO) δ 149.66, 147.56, 139.99, 135.16, 130.08 (q, J = 30.7Hz), 124.58 (q, J = 272.3 Hz), 113.23, 108.30 (q, J = 4.0 Hz), 102.25, 36.06, 10.77.45: N-(3-amino-5-(trifluoromethyl)phenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide.Preparation according to general procedure D from 1,5-dimethyl-1H-pyrazole-3-5 carboxylic acid (126 mg, 0.88 mmol, 1 eq.) and 5-(trifluoromethyl)benzene-1,3-diamine (190 mg, 1.08 mmol, 1.2 eq.). Further purification by RP column chromatographyyielded a white solid (149 mg, 57%). 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 7.36– 7.33 (m, 1H), 7.31 – 7.28 (m, 1H), 6.59 – 6.52 (m, 2H), 5.56 (s, 2H), 3.83 (s, 3H),2.30 (d, J = 0.8 Hz, 3H).13C NMR (101 MHz, DMSO) δ 160.31, 149.73, 144.58, 140.66,10 140.24, 129.74 (q, J = 31.7 Hz), 124.50 (q, J = 272.0 Hz), 108.13, 106.01, 104.88,103.95, 36.49, 10.71. 46: N-(3-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5-(trifluoromethyl)phenyl)-quinoline-4-carboxamide. Preparation according to general procedure C fromquinoline-4-carboxylic acid (191 mg, 1.11 mmol, 1.25 eq.) and 48 (264 mg, 0.88 mmol,15 1 eq.). Further purification by RP column chromatography yielded a white solid (163mg, 41%). 1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 10.39 (s, 1H), 9.06 (d, J = 4.2Hz, 1H), 8.64 – 8.58 (m, 1H), 8.21 – 8.11 (m, 2H), 8.07 – 7.94 (m, 2H), 7.90 – 7.82 (m,1H), 7.80 – 7.75 (m, 1H), 7.74 – 7.67 (m, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 2.31 (s, 3H).13C NMR (101 MHz, DMSO) δ 165.71, 160.63, 150.33, 147.96, 144.28, 141.48 (d, J =20 5.6 Hz), 140.81, 140.35, 139.83, 130.01, 129.50, 129.83 – 129.03 (m), 127.70, 125.22,124.05 (d, J = 272.2 Hz), 123.90, 119.35, 114.75, 112.43 – 111.94 (m), 111.24 – 110.79(m), 106.22, 36.55, 10.72. HRMS (ESI-): m / z calculated for C23H18F3N5O2 453.1407,found 452.1337 ([M-H]-). 47: N-(3-(2-(2-chlorophenyl)acetamido)-5-(trifluoromethyl)phenyl)-1,5-dimethyl-1H-25 pyrazole-3-carboxamide. Preparation according to general procedure C from 2-chlorophenylacetic acid (173 mg, 1.01 mmol, 1.3 eq.) and 48 (237 mg, 0.79 mmol, 1eq.). Further purification by RP column chromatography yielded a white solid (128 mg,36%). 1H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 10.29 (s, 1H), 8.40 – 8.34 (m, 1H),7.92 – 7.79 (m, 2H), 7.50 – 7.40 (m, 2H), 7.37 – 7.26 (m, 2H), 6.58 (s, 1H), 3.88 (s,30 2H), 3.84 (s, 3H), 2.31 (s, 3H). 13C NMR (126 MHz, DMSO) δ 168.53, 160.57, 144.28,140.77, 140.19, 140.16, 133.69, 133.68, 132.24, 129.50 (q, J = 31.5 Hz), 129.00, 71 220860PWO 128.67, 127.07, 124.04 (q, J = 272.4 Hz), 113.71, 111.34 (q, J = 4.2 Hz), 109.99 (q, J= 3.4 Hz), 106.18, 40.78, 36.53, 10.71. 48: 3-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline. Preparation accordingto general procedure A from 160 (149 mg, 0.52 mmol, 1 eq.) and 4-bromo-1,5-dimethyl-5 1H-pyrazole (128 mg, 0.71 mmol, 1.4 eq.). Further purification by RP columnchromatography yielded a white solid (90 mg, 68%). 1H NMR (400 MHz, DMSO) δ 7.53(s, 1H), 6.86 – 6.80 (m, 1H), 6.77 – 6.70 (m, 2H), 5.59 (s, 2H), 3.77 (s, 3H), 2.35 (s,3H). 13C NMR (101 MHz, DMSO) δ 149.75, 136.24, 135.33, 135.08, 130.17 (q, J =30.7 Hz), 124.55 (q, J = 272.3 Hz), 118.97, 115.46, 110.44 – 110.19 (m), 107.32 –10 107.05 (m), 36.33, 10.14. 49: 3-(1,2-dimethyl-1H-imidazol-4-yl)-5-(trifluoromethyl)aniline. Preparation accordingto general procedure A from 160 (149 mg, 0.52 mmol, 1 eq.) and 4-bromo-1,2-dimethyl-1H-imidazole (102 mg, 0.56 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (39 mg, 29%). 1H NMR (400 MHz, DMSO) δ 7.4715 (s, 1H), 7.20 – 7.15 (m, 1H), 7.11 – 7.06 (m, 1H), 6.66 – 6.60 (m, 1H), 5.49 (s, 2H),3.56 (s, 3H), 2.30 (s, 3H). 13C NMR (101 MHz, DMSO) δ 149.49, 144.90, 137.26,136.32, 129.91 (q, J = 30.5 Hz), 124.69 (d, J = 272.2 Hz), 117.62, 112.43, 107.82 –107.56 (m), 107.25 – 106.94 (m), 32.53, 12.50.50: 3-(1-Methyl-1H-indol-3-yl)-5-(trifluoromethyl)aniline. Preparation according to20 general procedure A from 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (137 mg, 0.51 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (81 µL, 0.56 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a yellow oily solid (96 mg, 64%). 1H NMR (400 MHz, DMSO) δ 7.87 (d, J = 8.0 Hz, 1H),7.73 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.27 – 7.12 (m, 3H), 7.02 (s, 1H), 6.72 (s, 1H),25 5.62 (s, 2H), 3.83 (s, 3H). 13C NMR (101 MHz, DMSO) δ 149.88, 137.25, 136.99,130.26 (q, J = 30.7 Hz), 128.15, 125.12, 124.69 (q, J = 272.1 Hz), 121.63, 119.89,119.14, 114.76, 114.04, 110.35, 109.72 (q, J = 3.4 Hz), 106.63 (q, J = 3.8 Hz), 32.57.161: N-(3-bromo-5-(trifluoromethyl)phenyl)-2-phenylacetamide. Preparation accordingto general procedure D from phenylacetic acid (686 mg, 5.04 mmol, 1 eq.) and 3-30 bromo-5-(trifluoromethyl)aniline (800 µL, 5.55 mmol, 1.1 eq.) to give a pale-yellow solid (1.24 g, 69%). 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 8.15 – 8.09 (m, 1H), 8.01– 7.95 (m, 1H), 7.64 – 7.59 (m, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.29 – 7.23 (m, 1H), 3.68 72 220860PWO (s, 2H). 13C NMR (101 MHz, DMSO) δ 170.06, 141.35, 135.22, 131.24 (q, J = 32.3 Hz),129.20, 128.37, 126.74, 124.87, 123.08 (q, J = 272.8 Hz), 122.37, 122.11 (q, J = 3.2Hz), 114.21 (q, J = 3.9 Hz), 43.30.51: N-(3-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.5 Preparation according to general procedure A from 161 (110 mg, 0.31 mmol, 1 eq.)and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (92 mg, 0.34 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid (87 mg, 69%). 1H NMR (400 MHz, DMSO) δ 10.58 (s, 1H), 8.25 (s, 1H), 7.97 – 7.89(m, 3H), 7.61 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.41 – 7.31 (m, 4H), 7.30 – 7.16 (m,10 3H), 3.85 (s, 3H), 3.72 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.78, 140.49, 137.37,137.22, 135.60, 130.07 (q, J = 31.4 Hz), 129.21, 128.92, 128.36, 126.64, 125.57 (q, J= 272.4 Hz), 124.88, 121.88, 120.28, 119.54, 118.91, 116.89 (q, J = 4.1 Hz), 112.96,111.59 (q, J = 4.1 Hz), 110.56, 43.41, 32.67.162: N-benzyl-3-bromo-5-(trifluoromethyl)aniline. 3-Bromo-5-(trifluoromethyl)aniline15 (866 µL, 6.00 mmol, 1 eq.), benzyl bromide (1.08 mL, 9.00 mmol, 1.5 eq.) and K2CO3(1.28 g, 9.25 mmol, 1.5 eq.) were dissolved in dry DMF (8 mL) and the reaction mixture was stirred at 90°C for 20h. After cooling to rt, the mixture was diluted with EtOAc, washed with brine (3x), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography and lyophilized to give a pale yellow oil (1.02 g, 62%).20 1H NMR (400 MHz, DMSO) δ 7.38 – 7.33 (m, 4H), 7.29 – 7.23 (m, 1H), 7.05 (t, J = 5.9Hz, 1H), 6.99 – 6.95 (m, 1H), 6.94 – 6.91 (m, 1H), 6.88 – 6.85 (m, 1H), 4.33 (d, J = 5.9Hz, 2H).13C NMR (101 MHz, DMSO) δ 150.54, 138.81, 131.39 (q, J = 31.7 Hz), 128.47,127.26, 127.00, 123.47 (q, J = 273.5 Hz), 122.79, 117.32, 114.11 – 113.34 (m), 107.93– 107.40 (m), 45.95.25 52: N-benzyl-3-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl)aniline. Preparationaccording to general procedure A from 162 (102 mg, 0.31 mmol, 1 eq.) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (93 mg, 0.35 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a yellowish oily solid (96 mg, 82%).1H NMR (400 MHz, MeOD) δ 7.51 – 7.44 (m, 1H), 7.40 – 7.21 (m, 7H), 7.2030 – 7.13 (m, 1H), 7.06 (s, 1H), 7.04 – 6.97 (m, 2H), 6.77 – 6.72 (m, 1H), 4.36 (s, 2H),3.72 (s, 3H).13C NMR (101 MHz, MeOD) δ 150.64, 140.94, 139.02, 138.72, 132.58 (q,J = 31.1 Hz), 129.60, 128.19, 127.95, 127.13, 126.13 (q, J = 271.6 Hz), 122.85, 120.93, 73 220860PWO 120.43, 116.77, 114.94, 112.39 (q, J = 3.6 Hz), 110.61, 107.58 (q, J = 3.4 Hz), 32.85,32.82. 53: 3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)aniline. Preparationaccording to general procedure A from 160 (144 mg, 0.5 mmol, 1 eq.) and 3-bromo-1-5 methyl-1H-pyrrolo[2,3-b]pyridine (163 mg, 0.75 mmol, 1.5 eq.). Further purification by RP column chromatography yielded a white solid (55 mg, 38 %). 1H NMR (400 MHz,DMSO) δ 8.34 (dd, J = 4.6, 1.5 Hz, 1H), 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.98 (s, 1H),7.25 – 7.18 (m, 2H), 7.07 – 7.02 (m, 1H), 6.77 – 6.71 (m, 1H), 5.64 (s, 2H), 3.87 (s,3H). 13C NMR (101 MHz, DMSO) δ 149.97, 147.87, 142.90, 136.24, 130.42 (q, J =10 30.7 Hz), 128.13, 127.65, 126.40 – 122.87 (m), 117.40, 116.18, 114.53, 112.43, 109.53– 109.19 (m), 107.08 – 106.78 (m), 30.96.54: 3-(thiazol-2-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (143 mg, 0.50 mmol, 1 eq.) and 2-bromothiazole (68 µL, 0.75mmol, 1.5 eq.). Further purification by RP column chromatography yielded a white solid15 (27 mg, 22%). 1H NMR (400 MHz, MeOD) δ 7.87 (d, J = 3.3 Hz, 1H), 7.62 (d, J = 3.3Hz, 1H), 7.45 – 7.38 (m, 2H), 7.01 – 6.98 (m, 1H). 13C NMR (126 MHz, MeOD-d4) δ169.25, 151.24, 144.49, 136.05, 133.36 (q, J = 31.9 Hz), 125.53 (q, J = 271.6 Hz),121.15, 116.15, 113.11 (q, J = 3.8 Hz), 111.88 (q, J = 4.1 Hz).55: 3-(5-methylthiazol-2-yl)-5-(trifluoromethyl)aniline. Preparation according to general20 procedure A from 160 (160 mg, 0.56 mmol, 1 eq.) and 2-bromo-5-methylthiazole (79µL, 0.75 mmol, 1.5 eq.). Further purification by RP column chromatography yielded awhite solid (38 mg, 29%). 1H NMR (400 MHz, MeOD) δ 7.55 – 7.50 (m, 1H), 7.36 –7.31 (m, 2H), 6.99 – 6.95 (m, 1H), 2.53 (d, J = 1.2 Hz, 3H).13C NMR (126 MHz, MeOD-d4) δ 167.36, 149.88, 142.18, 136.66, 136.27, 133.36 (q, J = 32.0 Hz), 125.45 (q, J =25 271.6 Hz), 116.51, 113.58 (q, J = 3.9 Hz), 112.52 (q, J = 4.0 Hz), 11.82.56: 3-(5-methylthiophen-2-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 5-methylthiphene-2-boronic acid (71 mg, 0.5 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (74 µL, 0.53 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a pale yellow solid (18 mg, 14%).1H NMR (40030 MHz, MeOD) δ 7.16 (d, J = 3.6 Hz, 1H), 7.08 – 7.06 (m, 1H), 7.03 – 7.00 (m, 1H), 6.83– 6.78 (m, 1H), 6.76 – 6.74 (m, 1H), 2.53 – 2.46 (m, 3H). 13C NMR (101 MHz, MeOD) 74 220860PWO δ150.64, 142.12, 141.13, 137.61, 132.99 (q, J = 31.4 Hz), 127.43, 127.90 – 124.08(m), 124.70, 115.30, 111.39 – 111.17 (m), 110.68 – 110.40 (m), 15.25.57: 3-(3,5-dimethylthiophen-2-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (144 mg, 0.5 mmol, 1 eq.) and 2-bromo-3,5-dimethyl5 thiophene (149 mg, 101 µL, 0.75 mmol, 1.5 eq.). Further purification by RP columnchromatography yielded a colorless liquid (103 mg, 76 %). 1H NMR (400 MHz, DMSO)δ 6.89 – 6.83 (m, 1H), 6.81 – 6.76 (m, 1H), 6.76 – 6.70 (m, 1H), 6.67 (s, 1H), 5.72 (s,2H), 2.40 (s, 3H), 2.20 (s, 3H). 13C NMR (101 MHz, DMSO) δ 149.81, 137.44, 135.82,133.53, 133.21, 130.15 (q, J = 31.1 Hz), 130.08, 128.46 – 120.11 (m), 116.45, 111.1910 – 110.91 (m), 108.29 – 107.99 (m), 14.86, 14.79.58: 1-(5-(3-amino-5-(trifluoromethyl)phenyl)thiophen-2-yl)ethan-1-one. Preparationaccording to general procedure A from 160 (150 mg, 0.52 mmol, 1 eq.) and 2-acetyl-5-bromothiophene (66 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (70 mg, 49%). 1H NMR (400 MHz, DMSO) δ 7.9315 (d, J = 3.9 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.15 (s, 2H), 6.88 (s, 1H), 5.83 (s, 2H),2.54 (s, 3H). 13C NMR (101 MHz, DMSO) δ 190.68, 150.44, 150.23, 142.99, 135.05,134.26, 130.85 (q, J = 31.4 Hz), 125.59, 124.17 (q, J = 272.4 Hz), 114.01, 110.16 –109.87 (m), 109.03 – 108.75 (m), 26.39.59: methyl 5-(3-amino-5-(trifluoromethyl)phenyl)thiophene-2-carboxylate. Preparation20 according to general procedure A from 160 (144 mg, 0.5 mmol, 1 eq.) and methyl 5-bromothiophene 2-carboxylate (167 mg, 100 µL, 0.75 mmol, 1.5 eq.). Further purification by RP column chromatography yielded a with solid (112 mg, 74 %). 1HNMR (400 MHz, DMSO) δ 7.79 (d, J = 4.0 Hz, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.15 –7.10 (m, 2H), 6.91 – 6.85 (m, 1H), 5.83 (s, 2H), 3.84 (s, 3H). 13C NMR (101 MHz,25 DMSO) δ 161.68, 150.24, 149.47, 134.77, 134.09, 131.55, 130.88 (q, J = 31.0 Hz),125.26, 128.31 – 119.62 (m), 113.95, 110.19 – 109.76 (m), 109.09 – 108.73 (m), 52.35.60: 5-(3-amino-5-(trifluoromethyl)phenyl)thiophene-2-carboxamide. Preparationaccording to general procedure B from 160 (149 mg, 0.52 mmol, 1.1 eq.) and 5-bromo-2-thiophenecarboxamide (100 mg, 0.47 mmol, 1 eq.). Further purification by reverse30 phase column chromatography (water / acetonitrile gradient) and lyophilization yielded awhite solid (84 mg, 63%). 1H NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.73 (d, J = 3.9Hz, 1H), 7.51 (d, J = 3.9 Hz, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 5.79 (s, 2H). 75 220860PWO 13C NMR (101 MHz, DMSO) δ 162.66, 150.17, 146.75, 139.57, 134.74, 130.76 (q, J =31.1 Hz), 129.74, 124.89, 124.25 (q, J = 272.4 Hz), 113.80, 109.79 – 109.23 (m),108.93 – 108.39 (m).61: N-(5-(3-amino-5-(trifluoromethyl)phenyl)thiophen-2-yl)acetamide. Preparation5 according to general procedure B from 160 (160 mg, 0.56 mmol, 1.2 eq.) and N-(5-bromothiophen-2-yl)acetamide (110 mg, 0.48 mmol, 1 eq.). Further purification by reverse phase column chromatography (water / acetonitrile gradient) and lyophilization yielded a white solid (62 mg, 43%). 1H NMR (400 MHz, DMSO) δ 7.23 (d, J = 4.0 Hz,1H), 7.01 – 6.98 (m, 1H), 6.97 – 6.94 (m, 1H), 6.72 – 6.67 (m, 1H), 6.60 (d, J = 4.0 Hz,10 1H), 5.66 (s, 2H), 2.08 (s, 3H). 13C NMR (101 MHz, DMSO) δ 166.46, 149.97, 139.92,135.96, 132.11, 130.52 (q, J = 30.9 Hz), 124.42 (q, J = 271.0 Hz), 121.19, 112.71,111.24, 107.71, 107.68, 22.53. 62: 3-(5-methylthiophen-3-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (147 mg, 0.51 mmol, 1 eq.) and 4-bromo-2-15 methylthiophene (86 µL, 0.77 mmol, 1.5 eq.). Further purification by RP columnchromatography yielded a white solid (57 mg, 44%). 1H NMR (400 MHz, DMSO) δ 7.59(d, J = 1.6 Hz, 1H), 7.18 (s, 1H), 7.16 – 7.10 (m, 2H), 6.85 (s, 1H), 5.52 (s, 2H), 2.48(s, 3H). 13C NMR (101 MHz, DMSO) δ 147.53, 140.40, 140.06, 137.05, 130.45 (q, J =30.9 Hz), 124.42, 124.37 (q, J = 272.1 Hz), 119.73, 115.78, 111.18, 109.73, 15.04.20 63: 1-(4-(3-amino-5-(trifluoromethyl)phenyl)thiophen-2-yl)ethan-1-one. Preparationaccording to general procedure A from 160 (144 mg, 0.5 mmol, 1 eq.) and 2-acetyl-4-bromo thiophene (159 mg, 99 µL, 0.75 mmol, 1.5 eq.) to yield a yellowish solid (136 mg, 96 %). 1H NMR (400 MHz, DMSO) δ 8.33 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 1.5 Hz,1H), 7.22 – 7.18 (m, 1H), 7.18 – 7.14 (m, 1H), 6.87 – 6.81 (m, 1H), 5.67 (s, 2H), 2.6125 (s, 3H).13C NMR (101 MHz, DMSO) δ 191.08, 149.93, 144.77, 141.79, 135.81, 132.34,130.56 (q, J = 31.1 Hz), 129.88, 128.78 – 120.10 (m), 114.41, 109.87 – 109.45 (m),109.15 – 108.81 (m), 26.70.64: N-(3-(5-acetylthiophen-3-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide.Preparation according to general procedure C from quinoline-4-carboxylic acid (11830 mg, 0.68 mmol, 1.4 eq.) and 66 (137 mg, 0.48 mmol, 1 eq.). Further purification by RPcolumn chromatography yielded a pale yellow solid (37 mg, 17%). 1H NMR (400 MHz,MeOD) δ 9.01 (d, J = 4.4 Hz, 1H), 8.36 – 8.26 (m, 3H), 8.21 (d, J = 1.5 Hz, 1H), 8.18 76 220860PWO –8.11 (m, 2H), 7.91 – 7.82 (m, 2H), 7.77 (d, J = 4.4 Hz, 1H), 7.76 – 7.70 (m, 1H), 2.65(s, 3H). 13C NMR (126 MHz, MeOD-d4) δ 192.74, 167.71, 151.34, 149.42, 146.77,143.59, 142.56, 141.33, 137.97, 132.92, 132.88 (q, J = 32.3 Hz), 131.62, 130.21,129.22, 126.58, 125.73, 128.73 – 122.11 (m), 122.25, 120.52, 119.89 (q, J = 3.6 Hz),5 116.98 (q, J = 3.9 Hz), 27.07.65: N-(3-(5-acetylthiophen-3-yl)-5-(trifluoromethyl)phenyl)-2-(2-chlorophenyl)-acetamide. Preparation according to general procedure C from 2-chlorophenylaceticacid (mg, 0.68 mmol, 1.4 eq.) and 66 (100 mg, 0.35 mmol, 1 eq.). Further purificationby RP column yielded a pale yellow solid (mg, 17%). 1H NMR (400 MHz, DMSO) δ10 10.67 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.19 – 8.13 (m, 1H),8.05 – 8.00 (m, 1H), 7.87 – 7.81 (m, 1H), 7.50 – 7.41 (m, 2H), 7.38 – 7.27 (m, 2H),3.91 (s, 2H), 2.62 (s, 3H). 13C NMR (101 MHz, DMSO) δ 191.07, 168.72, 145.12,140.71, 140.52, 135.97, 133.71, 133.48, 132.34, 132.23, 130.74, 130.38 (q, J = 31.8Hz), 129.02, 128.76, 127.10, 128.15 – 119.88 (m), 119.82, 117.58 – 117.24 (m), 114.5915 – 114.10 (m), 40.81, 26.72.66: 3-(thiazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (140 mg, 0.49 mmol, 1 eq.) and 4-bromothiazole (67 µL, 0.75mmol, 1.5 eq.). Further purification by RP column chromatography yielded a yellowish-white solid (50 mg, 41%). 1H NMR (400 MHz, MeOD) δ 9.04 (d, J = 2.0 Hz, 1H), 7.9020 (d, J = 1.9 Hz, 1H), 7.47 – 7.43 (m, 2H), 6.95 – 6.89 (m, 1H). 13C NMR (126 MHz,MeOD-d4) δ 156.50, 155.35, 150.67, 137.05, 133.00 (q, J = 31.6 Hz), 125.83 (q, J =271.5 Hz), 116.54 (d, J = 1.5 Hz), 115.47, 112.63 (q, J = 4.1 Hz), 111.65 (q, J = 4.0 Hz).67: 3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (147 mg, 0.51 mmol, 1 eq.) and 4-bromo-2-methylthiazole (6225 µL, 0.56 mmol, 1.1 eq.). Further purification by RP column chromatography yielded awhite solid (77 mg, 59%). 1H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.45 – 7.39 (m,1H), 7.35 – 7.29 (m, 1H), 6.83 – 6.77 (m, 1H), 5.67 (s, 2H), 2.71 (s, 3H). 13C NMR (126MHz, DMSO) δ 165.56, 152.97, 149.88, 135.64, 130.30 (q, J = 30.9 Hz), 124.52 (q, J= 272.3 Hz), 114.58, 114.52, 109.28 (q, J = 4.0 Hz), 108.89 (q, J = 3.9 Hz), 18.89.30 68: 1-(4-(3-Amino-5-(trifluoromethyl)phenyl)thiazol-2-yl)ethan-1-one. Preparationaccording to general procedure A from 160 (167 mg, 0.58 mmol, 1.2 eq.) and 1-(4-bromothiazol-2-yl)ethenone (100 mg, 0.47 mmol, 1 eq.). Further purification by RP 77 220860PWO column chromatography yielded a yellow solid (126 mg, 94%). 1H NMR (400 MHz,DMSO) δ 8.60 (s, 1H), 7.52 – 7.47 (m, 1H), 7.44 – 7.38 (m, 1H), 6.91 – 6.86 (m, 1H),5.79 (s, 2H), 2.72 (s, 3H). 13C NMR (101 MHz, DMSO) δ 191.31, 166.39, 155.42,150.07, 134.80, 130.52 (q, J = 31.2 Hz), 128.81 – 120.07 (m), 122.81, 114.51, 109.675 (q, J = 3.8 Hz), 109.39 (q, J = 4.2 Hz), 25.89 (d, J = 1.8 Hz).69: 3-(pyrimidin-5-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from pyrimidine-5-boronic acid (63 mg, 0.51 mmol, 1 eq.) and 3-bromo-5- (trifluoromethyl)aniline (74 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (54 mg, 45%). 1H NMR (400 MHz, DMSO) δ 9.2010 (s, 1H), 9.07 (s, 2H), 7.19 – 7.15 (m, 1H), 7.14 – 7.11 (m, 1H), 6.98 – 6.93 (m, 1H),5.80 (s, 2H). 13C NMR (101 MHz, DMSO) δ 157.62, 154.78, 150.23, 135.68, 132.88,130.90 (q, J = 31.1 Hz), 128.47 – 120.08 (m), 115.24, 110.11 (q, J = 3.9 Hz), 109.86(q, J = 3.9 Hz).70: 4'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-amine. Preparation according to15 general procedure A from 4-tolylboronic acid (71 mg, 0.50 mmol, 1 eq.) and 3-bromo- 5-(trifluoromethyl)aniline (74 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (49 mg, 39%). 1H NMR (400 MHz, DMSO) δ 7.49(d, J = 8.3 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 7.08 – 7.02 (m, 1H), 7.00 – 6.94 (m, 1H),6.85 – 6.80 (m, 1H), 5.66 (s, 2H), 2.34 (s, 3H). 13C NMR (101 MHz, DMSO) δ 149.94,20 141.88, 137.24, 136.71, 130.39 (q, J = 30.9 Hz), 129.54, 126.45, 123.18 (q), 115.03,109.86 – 109.59 (m), 108.50 – 108.27 (m), 20.66.71: 3-(2-methylpyrimidin-5-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (144 mg, 0.50 mmol, 1 eq.) and 5-bromo-2-methylpyrimidine (57 µL, 0.53 mmol, 1.1 eq.). Further purification by RP column25 chromatography yielded a white solid (79 mg, 63%). 1H NMR (400 MHz, DMSO) δ 8.94(s, 2H), 7.13 (s, 1H), 7.10 (s, 1H), 6.93 (s, 1H), 5.78 (s, 2H), 2.66 (s, 3H). 13C NMR(101 MHz, DMSO) δ 166.54, 154.76, 150.19, 135.84, 130.84 (q, J = 31.1 Hz), 129.74,125.69 (q), 114.96, 109.97 – 109.74 (m), 109.70 – 109.44 (m), 25.32.72: 3-(5,6-dimethylpyridin-3-yl)-5-(trifluoromethyl)aniline. Preparation according to30 general procedure A from 160 (146 mg, 0.51 mmol, 1 eq.) and 5-bromo-2,3-dimethylpyridine (73 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (48 mg, 35%). 1H NMR (400 MHz, DMSO) δ 8.49 78 220860PWO (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.10 – 7.06 (m, 1H), 7.05 – 7.01 (m, 1H),6.90 – 6.84 (m, 1H), 5.71 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H).13C NMR (101 MHz, DMSO)δ 156.28, 150.05, 143.84, 139.06, 134.94, 132.68, 131.34, 130.62 (q, J = 31.6 Hz),126.15 – 122.93 (m), 115.01, 109.81 (d, J = 4.0 Hz), 108.90 (d, J = 3.9 Hz), 22.01,5 18.57. 73: 1-(5-(3-amino-5-(trifluoromethyl)phenyl)pyridin-3-yl)ethan-1-one. Preparationaccording to general procedure A from 160 (144 mg, 0.50 mmol, 1 eq.) and 3-acetyl-5-bromopyridine (71 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography lyophilization yielded a white solid (59 mg, 42%). 1H NMR (400 MHz,10 DMSO) δ 9.11 (d, J = 2.0 Hz, 1H), 9.05 (d, J = 2.3 Hz, 1H), 8.42 (t, J = 2.2 Hz, 1H),7.20 – 7.15 (m, 2H), 6.97 – 6.91 (m, 1H), 5.79 (s, 2H), 2.70 (s, 3H). 13C NMR (101MHz, DMSO) δ 197.48, 151.25, 150.22, 148.63, 138.02, 135.07, 133.37, 132.02,130.83 (q, J = 31.5 Hz), 124.38 (q), 115.50, 110.42 – 110.11 (m), 109.77 – 109.46 (m),27.19.15 74: N-(3-(5-acetylpyridin-3-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.Preparation according to general procedure A from 161 (110 mg, 0.31 mmol, 1 eq.)and 5-acetylpyridine-3-boronic acid (57 mg, 0.33 mmol, 1.1 eq.). Further purificationby RP column chromatography yielded a white solid (76 mg, 62%). 1H NMR (400 MHz,DMSO) δ 10.69 (s, 1H), 9.16 (d, J = 2.0 Hz, 1H), 9.12 (d, J = 2.3 Hz, 1H), 8.53 – 8.4820 (m, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.43 – 7.21 (m, 5H), 3.71 (s, 2H), 2.71(s, 3H).13C NMR (101 MHz, DMSO) δ 197.34, 169.97, 151.42, 149.04, 140.73, 138.10,134.15, 133.65, 132.05, 130.54 (q, J = 31.8 Hz), 129.21, 128.36, 126.69, 123.91 (q, J= 274.5 Hz), 121.09, 118.73 – 118.05 (m), 115.34 – 114.75 (m), 43.35, 27.20.75: 3-(pyridin-3-yl)-5-(trifluoromethyl)aniline. Preparation according to general25 procedure A from 3-pyridylboronic acid (111 mg, 0.90 mmol, 1.2 eq.) and 3-bromo-5-(trifluoromethyl)aniline (106 µL, 0.75 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (174 mg, 98%). 1H NMR (400 MHz, DMSO) δ8.82 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.05 – 7.98 (m, 1H), 7.52 – 7.44(m, 1H), 7.12 – 7.08 (m, 1H), 7.08 – 7.04 (m, 1H), 6.94 – 6.88 (m, 1H), 5.75 (s, 2H).30 13C NMR (101 MHz, DMSO) δ 150.13, 148.92, 147.55, 138.94, 135.11, 134.22, 131.28– 130.29 (m), 123.89, 115.32, 110.34 – 109.83 (m), 109.55 – 108.96 (m). 79 220860PWO 76: 3'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-amine. Preparation according togeneral procedure A from 3-tolylboronic acid (70 mg, 0.50 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (74 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a yellow oil (29 mg, 23%). 1H NMR (400 MHz, DMSO) δ 7.445 – 7.40 (m, 1H), 7.40 – 7.31 (m, 2H), 7.23 – 7.16 (m, 1H), 7.09 – 7.03 (m, 1H), 7.01 –6.95 (m, 1H), 6.88 – 6.81 (m, 1H), 5.67 (s, 2H), 2.37 (s, 3H). 13C NMR (101 MHz,DMSO) δ 149.95, 142.12, 139.60, 138.17, 130.40 (q, J = 30.6 Hz), 128.87, 128.54,127.29, 128.79 – 120.36 (m), 123.76, 115.33, 109.96 (d, J = 4.2 Hz), 108.58 (d, J = 3.8Hz), 21.06.10 77: 3-(pyridin-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 4-pyridylboronic acid (63 mg, 0.50 mmol, 1 eq.) and 3-bromo-5- (trifluoromethyl)aniline (74 µL, 0.53 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (50 mg, 42%). 1H NMR (400 MHz, DMSO) δ 8.67– 8.61 (m, 2H), 7.66 – 7.60 (m, 2H), 7.20 – 7.15 (m, 1H), 7.14 – 7.10 (m, 1H), 6.98 –15 6.92 (m, 1H), 5.82 (s, 2H).13C NMR (101 MHz, DMSO) δ 150.31 – 150.18 (m), 146.57,139.10, 131.42 – 130.01 (m), 128.10 – 120.01 (m), 121.28, 115.15, 110.22 – 110.00(m), 109.97 – 109.74 (m).78: 3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 3-bromo-5-(trifluoromethyl)aniline (106 µL, 0.75 mmol, 1.5 eq.) and20 2-methyl-pyridine-4-boronic acid (68.5 mg, 0.5 mmol, 1 eq.). Further purification by RPcolumn chromatography yielded a white solid (43 mg, 34%). 1H NMR (500 MHz,Acetone) δ 8.51 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.40 (dd, J = 5.2, 1.8 Hz, 1H), 7.29 –7.25 (m, 1H), 7.22 – 7.17 (m, 1H), 7.07 – 7.02 (m, 1H), 5.31 (s, 2H), 2.55 (s, 3H). 13CNMR (126 MHz, Acetone) δ 160.04, 150.96, 150.67, 148.38, 141.25, 132.65 (q, J =25 31.5 Hz), 125.54 (q, J = 271.5 Hz), 121.59, 119.44, 116.66, 112.05 (q, J = 4.1 Hz),111.49 (q, J = 3.8 Hz), 24.63.79: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)quinoline-4-carboxamide.Preparation according to general procedure C from 78 (127 mg, 0.50 mmol, 1 eq.) andquinoline-4-carboxylic acid (210 mg, 1.21 mmol, 2.4 eq.). Further purification by RP30 column chromatography yielded a white solid (83 mg, 40%). 1H NMR (400 MHz,MeOD) δ 9.01 (d, J = 4.4 Hz, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.40 – 8.35 (m, 1H), 8.32– 8.28 (m, 1H), 8.28 – 8.26 (m, 1H), 8.19 – 8.11 (m, 1H), 7.90 – 7.85 (m, 1H), 7.85 – 80 220860PWO 7.82 (m, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.69 – 7.64 (m, 1H), 7.58(dd, J = 5.4, 2.4 Hz, 1H), 2.63 (s, 3H). 13C NMR (101 MHz, MeOD) δ 168.04, 160.37,151.11, 150.24, 149.34, 149.22, 143.72, 141.47, 141.35, 133.34 (q, J = 32.3 Hz),131.69, 129.93, 129.27, 129.54 – 120.91 (m), 126.46, 125.82, 123.13, 122.89, 120.885 – 120.60 (m), 120.49, 120.43, 118.59 – 118.31 (m), 23.91. HRMS (GC / EI+): m / zcalculated 407.1240 for C23H16F3N3O, found 407.1239 ([M]+).80: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.Phenylacetylchloride (173 mg, 1.12 mmol, 2.7 eq.) was dissolved in 4 mL of dry chloroform and stirred at 0°C.78 (103 mg, 0.41 mmol, 1.eq.) was added, the mixture10 was flushed with N2, allowed to warm up to rt and stirred for 2h. The solvent wasevaporated, and the residue was taken up in aq. NaOH. The suspension was extractedwith EtOAc, and the combined organic layers were washed with brine, dried overNa2SO4and concentrated. After purification the product was yielded as a white solid (77 mg, 51%). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 5.4 Hz, 1H), 8.21 – 8.16 (m,15 1H), 8.06 – 8.00 (m, 1H), 7.72 – 7.67 (m, 1H), 7.60 – 7.55 (m, 1H), 7.49 (dd, J = 5.5,1.9 Hz, 1H), 7.41 – 7.29 (m, 4H), 7.29 – 7.23 (m, 1H), 3.74 (s, 2H), 2.60 (s, 3H). 13CNMR (101 MHz, MeOD) δ 172.75, 160.27, 150.16, 149.31, 141.76, 141.09, 136.37,133.13 (q, J = 32.4 Hz), 130.21, 129.67, 128.11, 129.43 – 120.94 (m), 122.55, 120.41,119.89 (q, J = 4.3 Hz), 117.86 (q, J = 3.9 Hz), 44.77, 23.87. HRMS (GC / EI+): m / z20 calculated 370.1287 for C21H17F3N2O, found 371.1363 ([M+H]+).81: 2-(2-chlorophenyl)-N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure C from 2-chlorophenylaceticacid (mg, 0.68 mmol, 1.4 eq.) and 78 (100 mg, 0.35 mmol, 1 eq.). Further purificationby RP column chromatography yielded a white solid (107 mg, 84%). 1H NMR (40025 MHz, DMSO) δ 10.73 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.24 – 8.18 (m, 1H), 8.15 – 8.09(m, 1H), 7.81 – 7.75 (m, 1H), 7.62 – 7.57 (m, 1H), 7.50 (dd, J = 5.3, 1.8 Hz, 1H), 7.48– 7.43 (m, 2H), 7.38 – 7.27 (m, 2H), 3.91 (s, 2H), 2.55 (s, 3H). 13C NMR (101 MHz,DMSO) δ 168.81, 158.91, 149.73, 145.76, 140.70, 139.46, 133.71, 133.43, 132.34,130.50 (q, J = 31.7 Hz), 129.02, 128.77, 127.11, 123.89 (q, J = 272.5 Hz), 120.67,30 118.54, 118.16 – 117.71 (m), 115.71 – 115.22 (m), 40.84, 24.05.82: 3,4-dichloro-N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide. 3,4-Dichlorobenzoylchloride (197 mg, 0.94 mmol, 2 eq.) was dissolved in 4 mL of dry 81 220860PWO chloroform and stirred at 0°C. 78 (117 mg, 0.46 mmol, 1.eq.) was added, the mixturewas flushed with N2, allowed to warm up to rt and stirred for 2h. The solvent wasevaporated, and the residue was taken up in aq. NaOH. The suspension was extractedwith EtOAc, and the combined organic layers were washed with brine, dried over5 Na2SO4and concentrated. After purification the product was yielded as a white solid (26 mg, 13%). 1H NMR (400 MHz, MeOD) δ 8.58 (d, J = 5.3 Hz, 1H), 8.45 – 8.40 (m,1H), 8.35 – 8.30 (m, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.3, 2.1 Hz, 1H), 7.86– 7.83 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.60 (dd, J = 5.3, 1.8 Hz,1H), 2.66 (s, 3H). 13C NMR (101 MHz, MeOD) δ 165.73, 160.38, 150.54, 148.67,10 141.72, 140.96, 136.96, 136.01, 133.51, 132.71 (q, J = 32.5 Hz), 132.06, 131.01,128.98, 126.71 (q), 123.47, 122.64, 120.32, 120.27 – 120.13 (m), 118.57, 24.32.HRMS (GC / EI+): m / z calculated 424.0351 for C20H13Cl2F3N2O, found 424.0354 ([M]+).83: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)acetamide. Acetylchloride(179 µL, 2.52 mmol, 8 eq.) was dissolved in 4 mL of dry chloroform and stirred at 0°C.15 78 (80 mg, 0.32 mmol, 1.eq.) was added, the mixture was flushed with N2, allowed towarm up to room temperature and stirred for 2h. The solvent was evaporated, and theresidue was taken up in aq. NaOH. The suspension was extracted with EtOAc, andthe combined organic layers were washed with brine, dried over Na2SO4 and concentrated. After purification the product was yielded as a white solid (11 mg, 12%).20 1H NMR (400 MHz, MeOD) δ 8.49 (d, J = 5.0 Hz, 1H), 8.17 – 8.11 (m, 1H), 8.06 – 8.00(m, 1H), 7.72 – 7.66 (m, 1H), 7.59 – 7.57 (m, 1H), 7.50 (dd, J = 5.4, 2.4 Hz, 1H), 2.61(s, 3H), 2.18 (s, 3H). 13C NMR (101 MHz, MeOD) δ 172.06, 160.27, 150.16, 149.35,141.79, 141.04, 133.10 (q, J = 32.4 Hz), 125.28 (q, J = 271.8 Hz), 122.80, 122.35,120.41, 119.82 – 119.58 (m), 117.83 – 117.57 (m), 23.98, 23.88. HRMS (FIA / ESI+):25 m / z calculated 294.0974 for C15H13F3N2O, found 295.1050 ([M+H]+).84: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-naphthamide. 2-Naphtoylchloride (173 µL, 1.06 mmol, 2.1 eq.) was dissolved in 4 mL of dry chloroform and stirred at 0°C.78 (126 mg, 0.50 mmol, 1.eq.) was added, the mixture was flushed withN2, allowed to warm up to room temperature and stirred for 2h. The solvent was30 evaporated, and the residue was taken up in aq. NaOH. The suspension was extractedwith EtOAc, and the combined organic layers were washed with brine, dried overNa2SO4and concentrated. After purification the product was yielded as a white solid (46 mg, 22%). 1H NMR (400 MHz, MeOD) δ 8.55 – 8.52 (m, 1H), 8.49 (d, J = 5.3 Hz, 82 220860PWO 1H), 8.41 – 8.38 (m, 1H), 8.28 – 8.25 (m, 1H), 8.03 – 7.96 (m, 3H), 7.95 – 7.92 (m,1H), 7.77 – 7.74 (m, 1H), 7.66 – 7.54 (m, 3H), 7.54 (dd, J = 5.4, 1.8 Hz, 1H), 2.61 (s,3H). 13C NMR (101 MHz, MeOD) δ 168.96, 160.27, 150.16, 149.33, 141.94, 140.97,136.53, 133.99, 133.11 (q, J = 32.3 Hz), 132.84, 130.17, 129.54, 129.42, 129.21,5 128.85, 128.02, 125.07, 124.01 (q), 123.45, 122.83, 120.43, 120.09 (q, J = 3.8 Hz),118.78 (q, J = 3.9 Hz), 23.91. HRMS (DEP / EI+): m / z calculated 406.1287 forC24H17F3N2O, found 406.1288 ([M]+)85: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)benzo[b]thiophene-2-carboxamide. Preparation according to general procedure C from benzo[b]thiophene-10 2-carboxylic acid (180 mg, 1.01 mmol, 2 eq.) and 78 (128 mg, 0.51 mmol, 1 eq.).Further purification by RP column chromatography yielded a white solid (44 mg, 21%).1H NMR (400 MHz, MeOD) δ 8.56 (d, J = 5.3 Hz, 1H), 8.46 – 8.40 (m, 1H), 8.31 – 8.28(m, 2H), 8.03 – 7.98 (m, 2H), 7.82 (dt, J = 2.4, 1.2 Hz, 1H), 7.69 – 7.66 (m, 1H), 7.59(dd, J = 5.3, 1.8 Hz, 1H), 7.56 – 7.47 (m, 2H), 2.65 (s, 3H).13C NMR (101 MHz, MeOD)15 δ 162.89, 160.36, 150.44, 148.85, 142.70, 141.60, 141.03, 140.71, 140.39, 132.86 (q,J = 32.6 Hz), 128.03, 127.57, 126.68, 126.34, 129.50 – 120.96 (m), 123.86, 123.29,122.71, 120.37, 120.21 – 119.94 (m), 118.55 – 118.34 (m), 24.20. HRMS (DEP / EI+):m / z calculated 412.0852 for C22H15F3N2OS, found 412.0852 ([M]+).86: N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)cyclobutanecarboxamide.20 Preparation according to general procedure C from cyclobutanecarboxylic acid (96 µL,1.00 mmol, 2 eq.) and 78 (126 mg, 0.50 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (44 mg, 36%). 1H NMR (400 MHz, MeOD) δ 8.49(d, J = 5.3 Hz, 1H), 8.22 – 8.17 (m, 1H), 8.10 – 8.01 (m, 1H), 7.72 – 7.66 (m, 1H), 7.62– 7.57 (m, 1H), 7.51 (dd, J = 5.4, 1.8 Hz, 1H), 3.37 – 3.33 (m, 1H), 2.61 (s, 3H), 2.4525 – 2.31 (m, 2H), 2.31 – 2.17 (m, 2H), 2.14 – 1.86 (m, 2H). 13C NMR (101 MHz, MeOD)δ 176.55, 160.28, 150.16, 149.42, 141.95, 141.02, 133.10 (q, J = 32.4 Hz), 123.96 (q),122.82, 122.48, 120.42, 119.59 (q, J = 3.6 Hz), 117.81 (q, J = 4.1 Hz), 41.68, 26.07,23.88, 19.03. HRMS (FIA / ESI+): m / z calculated 334.1288 für C18H17F3N2O, found335.1363 ([M+H]+).30 87: 2-(6-methoxynaphthalen-2-yl)-N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)-phenyl)propenamide. Preparation according to general procedure C from 2-(6-methoxy-2-naphthyl)propanoic acid (233 mg, 1.01 mmol, 2 eq.) and 78 (128 mg, 0.51 83 220860PWO mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid(28 mg, 12%). 1H NMR (400 MHz, MeOD) δ 9.33 – 9.16 (m, 1H), 8.45 (s, 1H), 8.19 –8.12 (m, 1H), 8.09 – 8.02 (m, 1H), 7.95 – 7.79 (m, 2H), 7.69 – 7.62 (m, 1H), 7.58 –7.49 (m, 2H), 7.49 – 7.43 (m, 1H), 7.35 (dd, J = 41.8, 9.1 Hz, 1H), 5.49 (s, 1H), 4.03 –5 3.95 (m, 1H), 3.95 (d, J = 16.7 Hz, 3H), 2.58 (d, J = 1.9 Hz, 3H), 1.63 – 1.55 (m, 3H).13C NMR (101 MHz, MeOD) δ 175.80 – 175.64 (m), 160.20, 157.24, 150.07, 149.35,141.89, 140.95, 137.77, 133.96, 133.05 (q, J = 32.4 Hz), 132.69, 131.57, 130.97,127.94 – 127.70 (m), 127.18, 126.16, 129.46 – 121.02 (m), 122.83, 122.61, 120.41,119.89 – 119.58 (m), 118.05 – 117.74 (m), 116.50, 57.86, 57.69, 23.84, 19.00. HRMS10 (DEP / EI+): m / z calculated 464.1706 for C27H23F3N2O2, found 464.1703 ([M]+).88: 5-methyl-N-(3-(2-methylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide. Preparation according to general procedure D from 5-methyl-1H-pyrazole-3-carboxylic acid (82mg, 0.64 mmol, 1.6 eq.) and 78 (101 mg, 0.40 mmol, 1eq.). Further purification by RP column chromatography yielded a white solid (38 mg,15 26%). 1H NMR (400 MHz, MeOD) δ 8.59 (d, J = 5.3 Hz, 1H), 8.47 – 8.45 (m, 1H), 8.43(s, 1H), 7.81 (s, 1H), 7.73 – 7.68 (m, 1H), 7.62 (dd, J = 5.3, 1.8 Hz, 1H), 6.66 (s, 1H),2.67 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, MeOD) δ 163.06, 160.35, 150.56,148.66, 148.01, 142.20, 141.77, 140.82, 132.62 (q, J = 32.3 Hz), 126.78 (q), 123.08,122.61, 120.30, 119.82 – 119.21 (m), 118.41 – 117.72 (m), 106.03, 24.39, 10.86.20 HRMS (DEP / EI+): m / z calculated 360.1192 for C18H15F3N4O, found 360.1197 ([M]+).89: 1-(4-(3-amino-5-(trifluoromethyl)phenyl)pyridin-2-yl)ethan-1-one. Preparationaccording to general procedure A from 160 (153 mg, 0.53 mmol, 1.1 eq.) and 1-(4-bromopyridin-2-yl)ethanone (100 mg, 0.49 mmol, 1 eq.). Further purification by RPcolumn chromatography a pale yellow solid (53 mg, 39%). 1H NMR (400 MHz, DMSO)25 δ 8.78 (dd, J = 5.0, 0.8 Hz, 1H), 8.12 (dd, J = 1.9, 0.8 Hz, 1H), 7.95 (dd, J = 5.1, 1.9Hz, 1H), 7.28 – 7.23 (m, 1H), 7.21 – 7.16 (m, 1H), 7.00 – 6.95 (m, 1H), 5.84 (s, 2H),2.68 (s, 3H). 13C NMR (101 MHz, MeOD) δ 208.84, 163.18, 159.83, 159.53, 157.14,147.80, 140.36 (q, J = 31.2 Hz), 134.30, 137.98 – 129.49 (m), 127.63, 124.63, 119.94(q, J = 3.9 Hz), 119.30 (q, J = 4.0 Hz), 35.28.30 90: 3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (140 mg, 0.49 mmol, 1 eq.) and 4-bromo-2,6-dimethylpyridine (97 mg, 0.52 mmol, 1 eq.). Further purification by RP column 84 220860PWO chromatography yielded a white solid (28 mg, 22%). 1H NMR (400 MHz, MeOD) δ 7.30(s, 2H), 7.18 – 7.14 (m, 1H), 7.14 – 7.10 (m, 1H), 7.01 – 6.96 (m, 1H), 2.55 (s, 6H). 13CNMR (126 MHz, MeOD) δ 159.30, 151.05, 150.71, 141.26, 133.24 (q, J = 31.6 Hz),125.73 (q, J = 271.4 Hz), 119.83, 117.07, 112.69 (q, J = 4.0 Hz), 112.27 (q, J = 3.9 Hz),5 23.78. 91: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.Preparation according to general procedure A from 161 (108 mg, 0.30 mmol, 1 eq.)and (2,6-dimethylpyridin-4-yl)boronic acid (61 mg, 0.39 mmol, 1.3 eq.). Further purification by RP column chromatography yielded a white solid (93 mg, 80%). 1H NMR10 (400 MHz, DMSO) δ 10.65 (s, 1H), 8.21 – 8.16 (m, 1H), 8.14 – 8.09 (m, 1H), 7.76 –7.71 (m, 1H), 7.40 – 7.30 (m, 6H), 7.30 – 7.23 (m, 1H), 3.70 (s, 2H), 2.49 (s, 6H). 13CNMR (101 MHz, DMSO) δ 169.93, 158.16, 146.11, 140.68, 139.66, 135.42, 130.40 (q,J = 31.6 Hz), 129.22, 128.36, 126.69, 123.88 (q, J = 272.4 Hz), 120.70, 117.87 (q, J =3.8 Hz), 117.73, 115.36 (q, J = 4.2 Hz), 43.35, 24.00.15 92: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(o-tolyl)acetamide.Preparation according to general procedure D from 90 (78 mg, 0.29 mmol, 1 eq.) ando-tolylacetic acid (59 mg, 0.39 mmol, 1.3 eq.). Further purification by RP columnchromatography yielded a white solid (53 mg, 45%). 1H NMR (400 MHz, DMSO) δ10.62 (s, 1H), 8.23 – 8.17 (m, 1H), 8.14 – 8.08 (m, 1H), 7.77 – 7.71 (m, 1H), 7.37 (s,20 2H), 7.30 – 7.25 (m, 1H), 7.21 – 7.13 (m, 3H), 3.74 (s, 2H), 2.50 (s, 6H), 2.31 (s, 3H).13C NMR (101 MHz, DMSO) δ 169.86, 158.16, 146.12, 140.69, 139.66, 136.69,134.10, 130.40 (q, J = 31.8 Hz), 130.13, 129.92, 126.85, 125.80, 123.91 (q, J = 272.7Hz), 120.68, 117.97 – 117.76 (m), 117.72, 115.48 – 115.26 (m), 40.96, 23.99, 19.38.93: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(m-tolyl)acetamide.25 Preparation according to general procedure D from 90 (64 mg, 0.24 mmol, 1 eq.) andm-tolylacetic acid (47 mg, 0.31 mmol, 1.3 eq.). Further purification by RP columnchromatography yielded a white solid (52 mg, 54%). 1H NMR (400 MHz, DMSO) δ10.69 (s, 1H), 8.25 – 8.18 (m, 1H), 8.16 – 8.11 (m, 1H), 7.79 – 7.74 (m, 1H), 7.45 (s,2H), 7.23 (t, J = 7.5 Hz, 1H), 7.19 – 7.12 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 2.53 (s, 6H),30 2.30 (s, 3H). 13C NMR (126 MHz, DMSO) δ 170.02, 157.71, 146.84, 140.76, 139.36,137.42, 135.30, 130.43 (q, J = 31.7 Hz), 129.85, 128.27, 127.33, 126.28, 123.90 (q, J 85 220860PWO =272.7 Hz), 120.77, 118.18, 117.96 (q, J = 3.9 Hz), 115.56 (q, J = 4.1 Hz), 43.33,23.55, 20.98. 94: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(p-tolyl)acetamide.Preparation according to general procedure D from 90 (65 mg, 0.24 mmol, 1 eq.) and5 p-tolylacetic acid (53 mg, 0.35 mmol, 1.5 eq.). Further purification by RP columnchromatography yielded a white solid (53 mg, 54%). 1H NMR (400 MHz, DMSO) δ10.60 (s, 1H), 8.20 – 8.15 (m, 1H), 8.13 – 8.09 (m, 1H), 7.75 – 7.71 (m, 1H), 7.36 (s,2H), 7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 3.64 (s, 2H), 2.49 (s, 6H), 2.28(s, 3H).13C NMR (101 MHz, DMSO) δ 170.10, 158.16, 146.12, 140.71, 139.64, 135.74,10 132.34, 130.38 (q, J = 31.7 Hz), 129.05, 128.91, 123.91 (q, J = 272.6 Hz), 120.69,117.83 (q, J = 3.9 Hz), 117.72, 115.34 (q, J = 3.9 Hz), 42.99, 24.00, 20.64.95: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(2-methoxyphenyl)-acetamide. Preparation according to general procedure D from 90 (80 mg, 0.30 mmol,1 eq.) and 2-methoxyphenylacetic acid (63 mg, 0.37 mmol, 1.21 eq.). Further15 purification by RP column chromatography yielded a white solid (73 mg, 59%). 1H NMR(400 MHz, DMSO) δ 10.54 (s, 1H), 8.24 – 8.19 (m, 1H), 8.13 – 8.08 (m, 1H), 7.75 –7.70 (m, 1H), 7.36 (s, 2H), 7.30 – 7.20 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 6.91 (t, J =7.4 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 2H), 2.49 (s, 6H). 13C NMR (101 MHz, DMSO) δ169.98, 158.15, 157.26, 146.17, 140.86, 139.62, 131.01, 130.38 (q, J = 31.7 Hz),20 128.23, 123.94 (q, J = 272.6 Hz), 123.62, 120.56, 120.17, 117.72, 117.67 – 117.55 (m),115.49 – 114.99 (m), 110.69, 55.42, 37.78, 23.99.96: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(2-fluorophenyl)-acetamide. Preparation according to general procedure D from 90 (81 mg, 0.30 mmol,1 eq.) and 2-fluorophenylacetic acid (69 mg, 0.45 mmol, 1.5 eq.). Further purification25 by RP column chromatography yielded a white solid (68 mg, 56%).1H NMR (400 MHz,DMSO) δ 10.70 (s, 1H), 8.23 – 8.17 (m, 1H), 8.12 – 8.07 (m, 1H), 7.77 – 7.73 (m, 1H),7.45 – 7.39 (m, 1H), 7.37 (s, 2H), 7.36 – 7.30 (m, 1H), 7.24 – 7.15 (m, 2H), 3.80 (s,2H), 2.50 (s, 6H). 13C NMR (101 MHz, DMSO) δ 168.90, 160.69 (d, J = 244.3 Hz),158.17, 146.10, 140.60, 139.69, 132.10 (d, J = 4.4 Hz), 130.42 (q, J = 31.8 Hz), 128.9830 (d, J = 8.2 Hz), 124.27 (d, J = 3.3 Hz), 123.90 (q, J = 272.9 Hz), 122.42 (d, J = 15.8Hz), 120.69, 118.04 – 117.83 (m), 117.73, 115.52 – 115.28 (m), 115.05 (d, J = 21.5 Hz),36.38, 23.98. 86 220860PWO 97: 2-(2-chlorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 90 (115 mg, 0.43 mmol,1 eq.) and 2-chlorophenylacetic acid (78 mg, 0.46 mmol, 1.1 eq.). Further purificationby RP column chromatography yielded a white solid (110 mg, 63%). 1H NMR (4005 MHz, DMSO) δ 10.72 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.50 – 7.41 (m,2H), 7.39 – 7.28 (m, 4H), 3.91 (s, 2H), 2.50 (s, 6H). 13C NMR (101 MHz, DMSO) δ168.80, 158.17, 146.11, 140.66, 139.70, 133.72, 133.44, 132.35, 130.44 (q, J = 31.5Hz), 129.02, 128.78, 127.11, 123.91 (q, J = 272.7 Hz), 120.62, 117.86 (q, J = 3.8 Hz),117.72, 115.31 (q, J = 4.3 Hz), 40.84, 24.01.10 98: 2-(2,3-difluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 90 (67 mg, 0.25 mmol,1 eq.) and 2-(2,3-difluorophenyl)acetic acid (55 mg, 0.31 mmol, 1.3 eq.). Further purification by RP column chromatography yielded a white solid (53 mg, 50%). 1H NMR(400 MHz, DMSO) δ 10.76 (s, 1H), 8.22 – 8.17 (m, 1H), 8.11 – 8.06 (m, 1H), 7.78 –15 7.73 (m, 1H), 7.41 – 7.31 (m, 3H), 7.27 – 7.15 (m, 2H), 3.87 (d, J = 1.4 Hz, 2H), 2.49(s, 6H). 13C NMR (101 MHz, DMSO) δ 168.35, 158.17, 149.68 (dd, J = 244.3, 12.8 Hz),148.44 (dd, J = 245.3, 12.6 Hz), 146.08, 140.51, 139.71, 130.44 (q, J = 32.0 Hz),127.21 (t, J = 3.3 Hz), 125.06 (d, J = 12.5 Hz), 124.51 (dd, J = 6.6, 4.7 Hz), 123.89 (q,J = 272.5 Hz), 120.73, 118.00 (q, J = 3.7 Hz), 117.73, 116.08 (d, J = 16.8 Hz), 115.4120 (q, J = 3.6 Hz), 36.16, 24.01.99: 2-(2,4-difluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 90 (64 mg, 0.24 mmol,1 eq.) and (2,4-difluorophenyl)acetic acid (59 mg, 0.34 mmol, 1.4 eq.). Further purification by RP column chromatography yielded a white solid (43 mg, 42%). 1H NMR25 (400 MHz, DMSO) δ 10.73 (s, 1H), 8.22 – 8.17 (m, 1H), 8.11 – 8.06 (m, 1H), 7.77 –7.73 (m, 1H), 7.52 – 7.41 (m, 1H), 7.37 (s, 2H), 7.23 (td, J = 9.8, 2.6 Hz, 1H), 7.07 (td,J = 8.7, 2.6 Hz, 1H), 3.79 (s, 2H), 2.49 (s, 7H). 13C NMR (101 MHz, DMSO) δ 168.76,161.44 (dd, J = 245.1, 12.0 Hz), 160.66 (dd, J = 234.9, 12.2 Hz), 158.18, 146.11,140.58, 139.70, 133.10 (dd, J = 9.7, 6.0 Hz), 130.44 (q, J = 31.7 Hz), 123.91 (q, J =30 272.8 Hz), 120.71, 118.80 (dd, J = 16.2, 3.6 Hz), 117.94 (q, J = 3.8 Hz), 117.74, 115.40(q, J = 3.3 Hz), 111.23 (dd, J = 21.3, 3.4 Hz), 103.60 (t, J = 26.0 Hz), 35.76, 24.01 (d,J = 2.7 Hz). 87 220860PWO 100: 2-(2,5-difluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-acetamide. Preparation according to general procedure D from 90 (65 mg, 0.24 mmol,1 eq.) and 2,5-difluorophenyl)acetic acid (56 mg, 0.32 mmol, 1.3 eq.). Further purification by RP column chromatography yielded a white solid (31 mg, 31%). 1H NMR5 (400 MHz, DMSO) δ 10.74 (s, 1H), 8.22 – 8.17 (m, 1H), 8.11 – 8.06 (m, 1H), 7.78 –7.73 (m, 1H), 7.37 (s, 2H), 7.34 – 7.21 (m, 2H), 7.21 – 7.14 (m, 1H), 3.82 (d, J = 1.5Hz, 2H), 2.50 (s, 10H). 13C NMR (101 MHz, DMSO) δ 168.36, 157.87 (dd, J = 239.4,2.2 Hz), 157.17 (dd, J = 240.8, 2.2 Hz), 146.09, 140.51, 139.71, 130.43 (q, J = 31.6Hz), 124.37 (dd, J = 19.0, 8.8 Hz), 123.90 (q, J = 272.5 Hz), 120.73, 118.47 (dd, J =10 24.4, 4.7 Hz), 118.05 – 117.91 (m), 117.73, 116.40 (dd, J = 24.9, 8.9 Hz), 115.52 –115.25 (m), 115.17 (dd, J = 24.3, 8.8 Hz), 36.19, 24.00 (d, J = 2.3 Hz).101: 2-(2,6-difluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 90 (65 mg, 0.24mmol, 1 eq.) and 2,6-difluorophenylacetic acid (57 mg, 0.32 mmol, 1.3 eq.). Further15 purification by RP column chromatography yielded a white solid (61 mg, 60%).1H NMR(400 MHz, DMSO) δ 10.84 (s, 1H), 8.25 – 8.21 (m, 1H), 8.09 – 8.05 (m, 1H), 7.80 –7.75 (m, 1H), 7.50 – 7.36 (m, 3H), 7.12 (t, J = 7.8 Hz, 2H), 2.52 (s, 6H). 13C NMR (126MHz, DMSO) δ 167.84, 162.11 (d, J = 8.2 Hz), 160.15 (d, J = 8.4 Hz), 157.73, 146.78,140.51, 139.44, 130.47 (q, J = 31.9 Hz), 129.44 (t, J = 10.3 Hz), 127.72 – 120.19 (m),20 120.76, 118.15, 118.10 (d, J = 3.9 Hz), 115.67 – 115.50 (m), 111.42 – 111.35 (m), 111.25– 111.20 (m), 111.35 – 111.01 (m), 29.92 (t, J = 2.4 Hz), 23.54.102: 2-(2-chloro-6-fluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)-phenyl)acetamide. Preparation according to general procedure D from 90 (65 mg, 0.25mmol, 1 eq.) and 2-chloro-6-fluorophenylacetic acid (58 mg, 0.31 mmol, 1.3 eq.). 25 Further purification by RP column chromatography yielded a white solid (46 mg, 43%). 1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.23 – 8.17 (m, 1H), 8.09 – 8.03 (m, 1H),7.78 – 7.73 (m, 1H), 7.43 – 7.34 (m, 4H), 7.29 – 7.23 (m, 1H), 3.95 (s, 2H), 2.49 (s,6H). 13C NMR (101 MHz, DMSO) δ 167.65, 161.30 (d, J = 247.0 Hz), 158.17, 146.07,140.50, 139.73, 134.99 (d, J = 5.7 Hz), 130.45 (q, J = 31.9 Hz), 129.67 (d, J = 9.8 Hz),30 125.13 (d, J = 3.2 Hz), 123.88 (q, J = 272.5 Hz), 121.64 (d, J = 18.9 Hz), 120.61, 118.12– 117.87 (m), 117.72, 115.54 – 115.06 (m), 114.20 (d, J = 22.7 Hz), 33.92, 24.00. 88 220860PWO 103: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)acetamide. Preparation according to general procedure D from90 (65 mg, 0.25 mmol, 1 eq.) and 2-chloro-6-fluorophenylacetic acid (62 mg, 0.27mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid 5(62 mg, 54%). 1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.20 – 8.14 (m, 1H), 8.07– 8.01 (m, 1H), 7.78 – 7.73 (m, 1H), 7.65 – 7.55 (m, 3H), 7.37 (s, 2H), 4.00 (s, 2H),2.49 (s, 6H). 13C NMR (101 MHz, DMSO) δ 167.55, 161.60 (d, J = 246.1 Hz), 158.17,146.05, 140.45, 139.78, 130.48 (q, J = 31.8 Hz), 130.03 – 129.39 (m), 123.87 (q, J =272.5 Hz), 121.92 – 121.59 (m), 121.22 (d, J = 18.1 Hz), 120.55, 119.65 (d, J = 22.910 Hz), 117.97 (q, J = 3.8 Hz), 117.72, 115.52 – 115.00 (m), 32.87, 23.98.104: 2-(2-(difluoromethoxy)-6-fluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)acetamide. Preparation according to general procedure D from90 (69 mg, 0.26 mmol, 1 eq.) and 2-(2-(difluoromethoxy)-6-fluorophenyl)acetic acid (70mg, 0.30 mmol, 1.2 eq.). Further purification by RP column chromatography yielded a15 white solid (56 mg, 47%). 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.21 – 8.16 (m,1H), 8.08 – 8.03 (m, 1H), 7.77 – 7.72 (m, 1H), 7.47 – 7.39 (m, 0H), 7.37 (s, 2H), 7.24(t, J = 73.5 Hz, 1H), 7.16 (t, J = 8.6 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 3.83 (s, 2H), 2.50(s, 6H).13C NMR (101 MHz, DMSO) δ 168.09, 161.30 (d, J = 245.1 Hz), 158.17, 150.62(d, J = 7.8 Hz), 146.10, 140.54, 139.71, 130.44 (q, J = 31.7 Hz), 129.32 (d, J = 10.220 Hz), 123.90 (q, J = 272.5 Hz), 120.66, 118.02 – 117.85 (m), 117.73, 116.56 (t, J = 258.2Hz), 115.49 – 115.23 (m), 114.77 (d, J = 19.2 Hz), 113.90 (d, J = 3.2 Hz), 112.07 (d, J= 22.2 Hz), 30.65, 24.00. 105: 2-(2-(difluoromethoxy)-6-fluorophenyl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)acetamide. Preparation according to general procedure D from25 90 (70 mg, 0.26 mmol, 1 eq.) and 2-fluoro-6-methoxyphenylacetic acid (67 mg, 0.30mmol, 1.3 eq.). Further purification by RP column chromatography yielded a white solid (62 mg, 54%). 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.24 – 8.18 (m, 1H), 8.10– 8.04 (m, 1H), 7.76 – 7.71 (m, 1H), 7.37 (s, 2H), 7.35 – 7.26 (m, 1H), 6.87 (d, J = 8.4Hz, 1H), 6.82 (t, J = 8.7 Hz, 1H), 3.80 (s, 3H), 3.74 (d, J = 1.3 Hz, 2H), 2.50 (s, 6H).30 13C NMR (101 MHz, DMSO) δ 168.84, 161.33 (d, J = 242.4 Hz), 158.63 (d, J = 8.4 Hz),158.16, 146.14, 140.73, 139.65, 130.40 (q, J = 31.9 Hz), 128.80 (d, J = 10.5 Hz),123.92 (q, J = 272.6 Hz), 120.54, 117.72, 115.39 – 115.05 (m), 110.97 (d, J = 18.6 Hz),107.33 (d, J = 22.6 Hz), 106.89 (d, J = 2.1 Hz), 56.15, 30.34, 24.01. 89 220860PWO 106: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-1-methyl-1H-indole-3-carboxamide. Preparation according to general procedure D from 90 (82 mg, 0.31mmol, 1 eq.) and 1-methylindole-3-carboxylic acid (66 mg, 0.38 mmol, 1.2 eq.). Further5 purification by RP column chromatography yielded a white solid (37 mg, 29%).1H NMR(400 MHz, DMSO) δ 10.16 (s, 1H), 8.42 – 8.38 (m, 1H), 8.36 – 8.33 (m, 1H), 8.32 (s,1H), 8.24 (d, J = 7.8 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.42 (s,2H), 7.32 – 7.26 (m, 1H), 7.25 – 7.19 (m, 1H), 3.91 (s, 3H), 2.52 (s, 6H). 13C NMR (126MHz, DMSO) δ 163.26, 158.15, 146.40, 141.43, 139.45, 136.93, 132.99, 130.28 (q, J10 = 31.6 Hz), 126.68, 124.11 (q, J = 272.7 Hz), 122.47, 121.27, 121.15, 121.00, 117.77,117.09 (q, J = 3.8 Hz), 115.68 (q, J = 3.8 Hz), 110.56, 108.90, 33.22, 24.05.107: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-3-phenylpropiolamide.Preparation according to general procedure D from 90 (65 mg, 0.24 mmol, 1 eq.) andphenylpropiolic acid (56 mg, 0.38 mmol, 1.6 eq.). Further purification by RP column15 chromatography yielded a white solid (27 mg, 28%). 1H NMR (400 MHz, Acetone) δ8.29 – 8.25 (m, 1H), 8.24 – 8.21 (m, 1H), 7.81 – 7.77 (m, 1H), 7.63 (dt, J = 6.9, 1.5 Hz,2H), 7.58 – 7.46 (m, 3H), 7.38 (s, 2H), 2.53 (s, 6H). 13C NMR (126 MHz, Acetone) δ159.52, 151.94, 147.66, 141.63, 141.08, 133.40, 132.40 (q, J = 32.1 Hz), 131.57,129.87, 125.04 (q, J = 272.2 Hz), 122.24, 120.82, 119.95 (q, J = 3.9 Hz), 118.77, 117.0220 (q, J = 4.0 Hz), 86.07, 84.22, 24.58.108: 2-(Benzo[d][1,3]dioxol-5-yl)-N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)-phenyl)acetamide. 1,3-Benzodioxol-5-ylacetyl chloride (44 µL, 0.31 mmol, 1 eq.) wasdissolved in 6 mL of dry chloroform and stirred at 0°C. 90 (82 mg, 0.31 mmol, 1 eq.)was added, the mixture was flushed with N2, allowed to warm up to rt and stirred25 overnight. The solvent was evaporated and the residue was taken up in aq. NaOH. The suspension was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column and RP column chromatography to yield a pale yellow solid(23 mg, 17%). 1H NMR (400 MHz, Acetone) δ 9.69 (s, 1H), 8.25 – 8.20 (m, 1H), 8.1930 – 8.12 (m, 1H), 7.72 – 7.68 (m, 1H), 7.33 (s, 2H), 6.93 (d, J = 1.7 Hz, 1H), 6.85 (dd, J= 7.9, 1.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.97 (s, 2H), 3.69 (s, 2H), 2.51 (s, 6H). 13CNMR (126 MHz, DMSO) δ 170.60, 159.25, 148.54, 147.60, 147.43, 141.67, 141.19, 90 220860PWO 132.01 (q, J = 32.1 Hz), 129.75, 124.91 (q, J = 271.7 Hz), 123.14, 121.62, 118.86 (q,J = 4.0 Hz), 118.50, 116.42 (q, J = 4.2 Hz), 110.37, 108.75, 101.82, 44.17, 24.36.109: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-1-phenylcyclopropane-1-carboxamide. Preparation according to general procedure C from 1-5 phenylcyclopropanecarboxylic acid (157 mg, 0.97 mmol, 2.4 eq.) and 90 (112 mg, 0.42mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid(97 mg, 59%). 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 8.24 – 8.19 (m, 1H), 8.17 –8.12 (m, 1H), 7.75 – 7.70 (m, 1H), 7.46 – 7.40 (m, 2H), 7.40 – 7.34 (m, 4H), 7.33 –7.27 (m, 1H), 2.49 (s, 6H), 1.51 (q, J = 4.2 Hz, 2H), 1.16 (q, J = 4.3 Hz, 2H). 13C NMR10 (126 MHz, DMSO) δ 171.87, 158.10, 146.10, 140.50, 139.63, 139.24, 130.07 (q, J =31.8 Hz), 129.18, 128.59, 127.16, 123.97 (q, J = 272.7 Hz), 121.95, 117.98 (q, J = 3.9Hz), 117.68, 116.67 (q, J = 4.2 Hz), 31.73, 24.00, 15.01.110: N-benzyl-3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)aniline. Preparationaccording to general procedure A from 162 (111 mg, 0.34 mmol, 1 eq.) and (2,6-15 dimethylpyridin-4-yl)boronic acid (68 mg, 0.44 mmol, 1.3 eq.). Further purification byRP column chromatography yielded a yellow solid (95 mg,79%). 1H NMR (400 MHz,DMSO) δ 7.42 – 7.31 (m, 4H), 7.29 – 7.22 (m, 3H), 7.16 – 7.13 (m, 1H), 7.12 – 7.10(m, 1H), 6.95 – 6.92 (m, 1H), 6.89 (t, J = 5.9 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 2.46 (s,6H). 13C NMR (101 MHz, DMSO) δ 157.91, 149.74, 147.19, 139.63, 139.34, 130.6120 (q, J = 31.0 Hz), 128.46, 127.39, 126.95, 124.45 (q, J = 273.4 Hz), 117.74, 113.51,110.07 (q, J = 3.6 Hz), 108.80 (q, J = 3.1 Hz), 46.24, 24.02.111: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide. Benzoylchloride (50 µL, 0.43 mmol, 1.2 eq.) was dissolved in 6 mL of dry chloroform and stirred at 0°C. 90 (96 mg, 0.36 mmol, 1 eq.) was added, the mixture was flushed with N2,25 allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and the residue was taken up in aq. NaOH. The suspension was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by RP column chromatography to yield a white solid (80 mg, 60%). 1H NMR (400 MHz, DMSO) δ30 10.65 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 8.05 – 7.98 (m, 2H), 7.81 (s, 1H), 7.67 – 7.54(m, 3H), 7.42 (s, 2H), 2.51 (s, 6H). 13C NMR (101 MHz, DMSO) δ 165.97, 158.17, 91 220860PWO 146.15, 140.72, 139.47, 134.19, 132.08, 130.41 (q, J = 9.0 Hz), 128.54, 127.71, 124.00(q, J = 272.5 Hz), 121.94, 118.22 (q, J = 3.5 Hz), 117.73, 116.54 (q, J = 4.0 Hz), 24.03.163: 3-bromo-N-phenethyl-5-(trifluoromethyl)aniline. 3-Bromo-5-(trifluoromethyl)-aniline (866 µL, 6.00 mmol, 1.5 eq.), 2-phenylethylbromide (540 µL, 4.00 mmol, 1 eq.)5 and K2CO3 (756 mg, 5.47 mmol, 1.4 eq.) were dissolved in dry DMF (4 mL) and the reaction mixture was stirred at 90°C for 20h. After cooling to rt, the mixture was diluted with EtOAc, washed with brine (3x), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography and lyophilized to give a yellow oil (201 mg, 15%).1H NMR (400 MHz, MeOD) δ 7.31 – 7.16 (m, 6H), 6.93 – 6.90 (m, 1H), 6.9010 – 6.87 (m, 1H), 6.78 – 6.72 (m, 1H), 3.34 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H).13C NMR (101 MHz, MeOD) δ 151.90, 140.74, 133.81 (q, J = 32.1 Hz), 129.81, 129.53,127.36, 125.03 (q, J = 271.8 Hz), 124.34, 118.52, 115.59 (q, J = 4.0 Hz), 108.47 (q, J= 4.1 Hz), 45.75, 36.19. 112: N-benzyl-3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)aniline. Preparation15 according to general procedure A from 163 (100 mg, 0.29 mmol, 1 eq.) and (2,6-dimethylpyridin-4-yl)boronic acid (63 mg, 0.41 mmol, 1.4 eq.). Further purification byRP column chromatography yielded a yellowish oily solid (54 mg,50%). 1H NMR (400MHz, DMSO) δ 7.36 – 7.27 (m, 6H), 7.26 – 7.18 (m, 1H), 7.13 – 7.08 (m, 2H), 6.95 –6.90 (m, 1H), 6.35 (t, J = 5.4 Hz, 1H), 3.42 – 3.37 (m, 2H), 2.88 (t, J = 7.3 Hz, 2H), 2.4820 (s, 6H). 13C NMR (101 MHz, DMSO) δ 157.89, 149.85, 147.24, 139.75, 139.62, 130.63(q, J = 31.0 Hz), 128.80, 128.35, 126.15, 124.42 (q, J = 272.5 Hz), 117.78, 112.98,110.03 – 109.62 (m), 108.99 – 108.20 (m), 44.28, 34.76, 24.01.164: N-(3-bromo-5-(trifluoromethyl)phenyl)benzenesulfonamide. 3-Bromo-5-(trifluoromethyl)aniline (1.44 mL, 10.00 mmol, 2.0 eq.) was dissolved in 35 mL of dry25 dichloromethane and stirred at 0°C. Pyridine (1.21 mL, 15.00 mmol, 3.0 eq.) andbenzenesulfonyl chloride (645 µL, 5.00 mmol, 1 eq.) were added and the mixture wasallowed to warm up to room temperature and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with sat. NH4Cl, sat. NaHCO3 and brine, then dried over Na2SO4and concentrated. The crude product was purified by flash30 column and RP column chromatography to yield a white solid (465 mg, 24%). 1H NMR(400 MHz, DMSO) δ 11.02 (s, 1H), 7.83 – 7.81 (m, 1H), 7.81 – 7.78 (m, 1H), 7.70 –7.64 (m, 1H), 7.63 – 7.57 (m, 3H), 7.54 – 7.48 (m, 1H), 7.40 – 7.35 (m, 1H). 13C NMR 92 220860PWO (101 MHz, DMSO) δ 140.20, 138.62, 133.60, 131.60 (q, J = 32.7 Hz), 129.64, 126.64,125.15, 122.98 (q, J = 3.9 Hz), 122.83, 122.72 (q, J = 273.3 Hz), 114.24 (q, J = 4.2Hz). 113: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide.5 Preparation according to general procedure A from 164 (122 mg, 0.32 mmol, 1 eq.)and (2,6-dimethylpyridin-4-yl)boronic acid (60 mg, 0.38 mmol, 1.2 eq.). Furtherpurification by RP column chromatography yielded a white solid (32 mg, 25%). 1HNMR (400 MHz, Acetone) δ 7.94 – 7.86 (m, 2H), 7.81 – 7.76 (m, 1H), 7.75 – 7.70 (m,1H), 7.69 – 7.62 (m, 1H), 7.62 – 7.53 (m, 3H), 7.26 (s, 2H), 2.51 (s, 6H). 13C NMR (10110 MHz, Acetone) δ 158.38, 146.13, 140.87, 139.48, 139.32, 133.08, 131.51 (q, J = 32.2Hz), 129.12, 126.93, 123.62 (q, J = 272.0 Hz), 121.86, 119.07 (q, J = 3.7 Hz), 117.51,116.39 (q, J = 3.9 Hz), 23.42.114: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-1-phenylmethane-sulfonamide. Benzylsulfonyl chloride (161 mg, 0.85 mmol, 2.1 eq.) was dissolved in 515 mL of dry dichloromethane and stirred at 0°C. 90 (108 mg, 0.41 mmol, 1 eq.) andDIPEA (212 µL, 1.22 mmol, 3.0 eq.) were added and the mixture was allowed to warm up to room temperature and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with sat. NH4Cl, sat. NaHCO3 and brine, then dried over Na2SO4and concentrated. The crude product was purified by flash column and20 RP column chromatography to yield a white solid (25 mg, 14%). 1H NMR (400 MHz,MeOD) δ 7.48 (d, J = 1.9 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.38 – 7.34 (m, 1H), 7.34 –7.29 (m, 2H), 7.28 – 7.21 (m, 5H), 4.43 (s, 2H), 2.57 (s, 6H). 13C NMR (101 MHz,MeOD) δ 159.46, 149.99, 145.52, 141.23, 133.02 (q, J = 32.0 Hz), 132.19, 131.48,129.46, 129.38, 125.40 (q, J = 271.7 Hz), 122.43, 119.89, 117.83 – 117.42 (m), 59.54,25 23.82, 23.80. 115: Phenyl (3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)carbamate. To astirred solution of 90 (86 mg, 0.32 mmol, 1 eq.) in dry DCM at 0°C was addedTriethylamine (91 µL, 0.65 mmol, 2.0 eq.) and Phenyl chloroformate (98 µL, 0.78mmol, 2.4 eq.). After 30 min, the mixture was allowed to warm up to rt and stirred30 overnight. The reaction was stopped by adding water and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column and RP column chromatography 93 220860PWO to yield a white solid (41 mg, 33%). 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.17– 8.11 (m, 1H), 7.96 – 7.91 (m, 1H), 7.77 – 7.72 (m, 1H), 7.48 – 7.41 (m, 2H), 7.36 (s,2H), 7.30 – 7.24 (m, 3H), 6.77 – 6.72 (m, 1H), 2.49 (s, 6H). 13C NMR (101 MHz,Acetone) δ 158.29, 151.62, 150.60, 146.53, 140.44, 140.27, 131.25 (q, J = 32.2 Hz),5 129.07, 125.35, 125.30 – 122.15 (m), 121.52, 120.05, 117.86 – 117.61 (m), 117.51,114.90 – 114.44 (m), 23.36.116: 1-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-3-phenylurea. To astirred solution of phenyl isocyanate (54 µL, 0.50 mmol, 1 eq.) in dry DCM (3 mL) at0°C was added 90 (146 mg, 0.55 mmol, 1.1 eq.) and triethylamine (156 µL, 1.12 mmol,10 2.3 eq.). The mixture was allowed to warm up to rt and stirred for overnight, then dilutedwith water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. Purification by flash column and RP column chromatography yielded 69 mg (36%) of a white solid. 1H NMR (400 MHz, Acetone) δ8.61 (s, 1H), 8.33 (s, 1H), 8.11 – 8.08 (m, 1H), 8.07 – 8.03 (m, 1H), 7.66 – 7.60 (m,15 1H), 7.58 – 7.56 (m, 1H), 7.55 – 7.54 (m, 1H), 7.36 – 7.34 (m, 2H), 7.32 – 7.27 (m,2H), 7.05 – 7.00 (m, 1H), 2.52 (s, 6H). 13C NMR (101 MHz, Acetone) δ 159.46, 153.46,148.07, 142.63, 141.42, 140.51, 132.29 (q, J = 32.1 Hz), 129.74, 125.27 (q, J = 271.8Hz), 123.56, 121.20, 119.90, 118.78, 117.81 (q, J = 3.8 Hz), 115.95 (q, J = 4.0 Hz),24.64.20 117: 3-(6-methylpyridin-3-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (155 mg, 0.54 mmol, 1 eq.) and 5-bromo-2-methylpyridine (105 mg, 0.61 mmol, 1.1 eq.). Further purification by RP columnchromatography yielded a white solid (93 mg, 69%). 1H NMR (400 MHz, DMSO) δ 8.67(d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.1, 2.5 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.10 – 7.0525 (m, 1H), 7.05 – 7.00 (m, 1H), 6.90 – 6.85 (m, 1H), 5.72 (s, 2H), 2.50 (s, 3H). 13C NMR(126 MHz, DMSO) δ 157.38, 150.08, 146.73, 138.98, 134.41, 132.21, 130.64 (q, J =30.9 Hz), 124.42 (q, J = 272.2 Hz), 123.17, 115.03, 109.81 (q, J = 4.1 Hz), 108.96 (q,J = 3.9 Hz), 23.68.118: 3-(1-methyl-1H-indol-5-yl)-5-(trifluoromethyl)aniline. Preparation according to30 general procedure A from 3-bromo-5-(trifluoromethyl)aniline (212 µL, 1.50 mmol, 1.5 eq.) and 1-methylindole-5-boronic acid (175 mg, 1.0 mmol, 1 eq.). Further purification by RP column chromatography yielded a pale yellow oil (104 mg, 36%). 1H NMR (400 94 220860PWO MHz, MeOD) δ 7.77 – 7.72 (m, 1H), 7.42 – 7.32 (m, 2H), 7.17 – 7.13 (m, 2H), 7.12 (d,J = 3.1 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.46 (dd, J = 3.1, 0.7 Hz, 1H), 3.75 (s, 3H). 13CNMR (101 MHz, MeOD) δ 150.17, 145.82, 138.03, 132.82, 133.23 – 132.06 (m),130.86, 130.47, 126.06 (q, J = 271.4 Hz), 121.78, 119.96, 117.79, 113.64 (q, J = 4.05 Hz), 110.50, 110.00 (q, J = 3.8 Hz), 102.18, 32.86.119: 3-(benzofuran-5-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (159 mg, 0.55 mmol, 1 eq.) and 5-bromobenzufurane (76 µL,0.61 mmol, 1.1 eq.). Further purification by RP column chromatography yielded acolourless oil (87 mg, 57%). 1H NMR (400 MHz, DMSO) δ 8.04 (d, J = 2.2 Hz, 1H),10 7.87 (dd, J = 2.0, 0.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 8.6, 1.9 Hz, 1H),7.13 – 7.07 (m, 1H), 7.05 – 6.98 (m, 2H), 6.87 – 6.82 (m, 1H), 5.68 (s, 2H). 13C NMR(101 MHz, DMSO) δ 154.11, 149.92, 146.78, 142.40, 134.92, 130.39 (q, J = 30.8 Hz),127.89, 124.54 (q, J = 272.1 Hz), 123.40, 119.41, 115.62, 111.59, 110.25 (q, J = 3.7Hz), 108.25 (q, J = 4.0 Hz), 107.02.15 120: 3-(benzo[b]thiophen-5-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (143 mg, 0.50 mmol, 1 eq.) and 5-bromobenzo[b]thiophene (144 mg, 0.68 mmol, 1.4 eq.). Further purification by RPcolumn chromatography yielded a colourless oil (104 mg, 72%). 1H NMR (400 MHz,MeOD) δ 8.05 – 8.00 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.63 – 7.52 (m, 2H), 7.41 (d, J20 = 5.5 Hz, 1H), 7.21 – 7.17 (m, 1H), 7.17 – 7.14 (m, 1H), 6.96 – 6.90 (m, 1H). 13C NMR(101 MHz, MeOD) δ 150.58, 144.42, 141.77, 140.63, 138.10, 132.93 (q, J = 31.5 Hz),128.33, 125.94 (q, J = 271.6 Hz), 125.17, 124.54, 123.72, 122.80, 117.72, 113.43 (q,J = 4.0 Hz), 110.78 (q, J = 3.9 Hz).121: 3-(1H-indol-5-yl)-5-(trifluoromethyl)aniline. Preparation according to general25 procedure A from 160 (150 mg, 0.52 mmol, 1 eq.) and 5-bromoindole (160 mg, 0.82mmol, 1.6 eq.). Further purification by RP column chromatography yielded a yellowsolid (79 mg, 55%). 1H NMR (400 MHz, MeOD) δ 7.76 (dd, J = 1.8, 0.8 Hz, 1H), 7.44(dt, J = 8.4, 0.9 Hz, 1H), 7.34 (dd, J = 8.5, 1.8 Hz, 1H), 7.26 (d, J = 3.1 Hz, 1H), 7.19 –7.16 (m, 1H), 7.14 – 7.11 (m, 1H), 6.89 – 6.83 (m, 1H), 6.50 (dd, J = 3.1, 0.9 Hz, 1H).30 13C NMR (101 MHz, MeOD) δ 150.21, 146.05, 137.49, 132.81 (d, J = 3.5 Hz), 133.16– 132.10 (m), 129.97, 126.45, 130.33 – 121.88 (m), 121.73, 119.62, 117.82, 113.93 –113.41 (m), 112.46, 110.11 – 109.68 (m), 102.83. 95 220860PWO 122: 3-(imidazo[1,2-a]pyridin-7-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (145 mg, 0.50 mmol, 1 eq.) and 7-bromoimidazo[1,2-a]pyridine (123 mg, 0.62 mmol, 1.2 eq.). Further purification by RP columnchromatography yielded a white solid (61 mg, 44%). 1H NMR (400 MHz, DMSO) δ 8.625 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 7.81 – 7.76 (m, 1H), 7.62 (s, 1H), 7.23 – 7.18 (m, 2H),7.15 (s, 1H), 6.92 – 6.87 (m, 1H), 5.73 (s, 2H). 13C NMR (101 MHz, DMSO) δ 150.05,144.76, 139.83, 135.40, 134.10, 130.62 (q, J = 30.9 Hz), 127.08, 124.43 (q, J = 272.4Hz), 114.96, 113.41, 113.05, 111.18, 109.81 (q, J = 4.0 Hz), 109.24 (q, J = 3.3 Hz).123: N4',N4'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3,4'-diamine. Preparation10 according to general procedure A from 4-(dimethylamino)benzeneboronic acid (63 mg, 0.38 mmol, 1 eq.) and 3-bromo-5-(trifluoromethyl)aniline (60 µL, 0.42 mmol, 1.1 eq.).Further purification by RP column chromatography yielded a white solid (62 mg,59%).1H NMR (400 MHz, MeOD) δ 7.48 – 7.40 (m, 2H), 7.10 – 7.03 (m, 2H), 6.85 –6.75 (m, 3H), 4.86 (s, 2H), 2.93 (s, 6H). 13C NMR (101 MHz, MeOD) δ 151.92, 150.21,15 144.29, 132.71 (q, J = 31.2 Hz), 129.48, 128.40, 126.04 (q, J = 271.4 Hz), 116.55 (d,J = 1.5 Hz), 114.05, 112.51 (q, J = 4.1 Hz), 109.80 (q, J = 3.9 Hz), 40.77.124: 3-(indolin-5-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (144 mg, 0.50 mmol, 1 eq.) and 5-bromoindoline (116 mg, 0.58mmol, 1.2 eq.). Further purification by RP column chromatography yielded a white solid20 (53 mg, 38%). 1H NMR (400 MHz, MeOD) δ 7.35 – 7.31 (m, 1H), 7.25 – 7.20 (m, 1H),7.06 – 7.03 (m, 1H), 7.03 – 7.00 (m, 1H), 6.83 – 6.80 (m, 1H), 6.70 (d, J = 8.1 Hz, 1H),3.51 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 8.3 Hz, 2H). 13C NMR (101 MHz, MeOD) δ 153.14,150.22, 144.92, 132.67 (q, J = 31.3 Hz), 132.53, 131.89, 127.17, 126.03 (q, J = 271.3Hz), 124.07, 116.91, 112.81 (q, J = 4.1 Hz), 111.10, 109.87 (q, J = 3.7 Hz), 48.28,25 30.68. 125: 3-(1-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (165 mg, 0.58 mmol, 1 eq.) and 5-bromo-1-methyl-1H-indazole (124 mg, 0.58 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (101 mg, 60%). 1H NMR (400 MHz, DMSO) δ30 8.10 (d, J = 1.0 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.72 (dt, J = 8.8, 0.9 Hz, 1H), 7.65 (dd, J= 8.8, 1.7 Hz, 1H), 7.15 – 7.10 (m, 1H), 7.08 – 7.02 (m, 1H), 6.86 – 6.81 (m, 1H), 5.67(s, 2H), 4.07 (s, 3H). 13C NMR (126 MHz, DMSO) δ 149.93, 142.44, 139.28, 132.93, 96 220860PWO 132.19, 130.41 (q, J = 30.7 Hz), 125.42, 124.57 (q, J = 272.4 Hz), 124.06, 118.60,115.49, 110.24 – 110.05 (m), 108.13 (q, J = 3.9 Hz), 35.46.126: 3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)aniline. Preparationaccording to general procedure A from 160 (193 mg, 0.67 mmol, 1 eq.) and 5-bromo-5 1-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.69 mmol, 1 eq.). Further purification byRP column chromatography yielded a white solid (123 mg, 63%). 1H NMR (400 MHz,DMSO) δ 8.49 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 3.4 Hz, 1H),7.14 – 7.08 (m, 1H), 7.08 – 7.03 (m, 1H), 6.88 – 6.83 (m, 1H), 6.52 (d, J = 3.4 Hz, 1H),5.69 (s, 2H), 3.85 (s, 3H). 13C NMR (126 MHz, DMSO) δ 149.98, 147.20, 141.14,10 140.75, 131.02, 127.63, 126.51, 124.54 (q, J = 272.2 Hz), 119.93, 115.48, 110.21 (q, J= 4.0 Hz), 108.20 (q, J = 3.9 Hz), 99.28, 30.97.127: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide. Preparation according to general procedure A from 161 (144 mg,0.40 mmol, 1 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-15 pyrrolo[2,3-b]pyridine (120 mg, 0.44 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid (125 mg, 76%). 1H NMR (400 MHz, DMSO) δ10.62 (s, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.07 (s,1H), 7.70 (s, 1H), 7.59 (d, J = 3.4 Hz, 1H), 7.32 (s, 1H), 7.26 (t, J = 6.8 Hz, 1H), 6.55(d, J = 3.4 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.89,20 147.34, 141.21, 140.87, 140.56, 135.52, 131.30, 130.30 (q, J = 31.2 Hz), 129.22,128.36, 126.86, 126.68, 126.66, 124.08 (q, J = 272.2 Hz), 120.82, 120.01, 118.14 –117.73 (m), 113.76 – 113.40 (m), 99.43, 43.38, 30.99.128: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-1-phenylcyclopropane-1-carboxamide. Preparation as described for compound 10925 using half of the prepared acyl chloride solution (0.48 mmol, 1.2 eq.) and 127 (119 mg,0.41 mmol, 1 eq.). Purification by RP column chromatography yielded a white solid(118 mg, 67%). 1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.55 (d, J = 2.2 Hz, 1H),8.24 (d, J = 2.2 Hz, 1H), 8.20 – 8.15 (m, 1H), 8.10 – 8.04 (m, 1H), 7.72 – 7.66 (m, 1H),7.58 (d, J = 3.4 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.41 – 7.34 (m, 2H), 7.33 – 7.27 (m, 1H),30 6.54 (d, J = 3.4 Hz, 1H), 3.85 (s, 3H), 1.52 (q, J = 2.8 Hz, 2H), 1.16 (q, J = 2.8 Hz, 2H).13C NMR (126 MHz, DMSO) δ 171.79, 147.31, 140.47, 140.36, 139.72, 131.25, 129.97(q, J = 31.4 Hz), 129.14, 128.59, 127.13, 126.79, 126.61, 124.13 (q, J = 272.6 Hz), 97 220860PWO 122.05, 119.95, 117.99 (q, J = 4.2 Hz), 114.78 (q, J = 4.3 Hz), 99.38, 31.76, 30.99,15.02. 129: N-benzyl-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)aniline.Preparation according to general procedure A from 162 (133 mg, 0.40 mmol, 1 eq.)5 and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (127 mg, 0.47 mmol, 1.2 eq.). Further purification by RP columnchromatography yielded a colorless oily solid (134 mg, 87%). 1H NMR (400 MHz,MeOD) δ 8.33 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.34– 7.28 (m, 3H), 7.26 – 7.17 (m, 1H), 7.06 – 7.02 (m, 1H), 7.01 – 6.96 (m, 1H), 6.86 –10 6.80 (m, 1H), 6.48 (d, J = 3.5 Hz, 1H), 4.38 (s, 2H), 3.83 (s, 3H). 13C NMR (101 MHz,MeOD) δ 151.03, 148.35, 142.24, 142.08, 140.70, 132.97 (q, J = 31.4 Hz), 131.93,129.92, 129.57, 128.66, 128.34, 128.07, 125.93 (q, J = 271.8 Hz), 122.57, 115.42,112.44 (q, J = 4.3 Hz), 108.66 (q, J = 4.2 Hz), 100.88, 48.32, 31.61.130: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)15 benzamide. Benzoyl chloride (50 µL, 0.43 mmol, 1.2 eq.) was dissolved in 6 mL of dry chloroform and stirred at 0°C.127 (102 mg, 0.35 mmol, 1 eq.) was added, the mixturewas flushed with N2, allowed to warm up to room temperature and stirred overnight.The solvent was evaporated and the residue was taken up in aq. NaOH. The suspension was extracted with EtOAc and the combined organic layers were washed20 with brine, dried over Na2SO4and concentrated. The crude product was purified by RP column chromatography to yield a white solid (100 mg, 72%). 1H NMR (400 MHz,DMSO) δ 10.63 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.43 – 8.37 (m, 1H), 8.31 (d, J = 2.2Hz, 1H), 8.30 – 8.27 (m, 1H), 8.07 – 7.99 (m, 2H), 7.77 (s, 1H), 7.67 – 7.54 (m, 4H),6.57 (d, J = 3.5 Hz, 1H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO) δ 165.98, 147.35,25 141.25, 140.69, 140.58, 134.35, 131.99, 131.30, 130.19 (q, J = 31.7 Hz), 128.52,127.73, 126.83, 126.68, 124.16 (q, J = 272.3 Hz), 122.03, 120.01, 118.27 (q, J = 3.9Hz), 114.71 (q, J = 3.9 Hz), 99.42, 31.01.131: 3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenethyl-5-(trifluoromethyl)aniline.Preparation according to general procedure A from 163 (100 mg, 0.29 mmol, 1 eq.)30 and 1-methyl-5-(4,4,5,5-tetraMethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (96 mg, 0.35 mmol, 1.2 eq.). Further purification by RP column chromatography yielded a colorless oily solid (55 mg, 48%). 1H NMR (400 MHz, 98 220860PWO DMSO) δ 8.54 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 3.5 Hz, 1H),7.31 (d, J = 4.4 Hz, 4H), 7.22 (h, J = 4.0 Hz, 1H), 7.10 (d, J = 9.1 Hz, 2H), 6.90 – 6.84(m, 1H), 6.52 (d, J = 3.4 Hz, 1H), 6.31 (t, J = 5.5 Hz, 1H), 3.85 (s, 3H), 3.46 – 3.36 (m,2H), 2.89 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 149.74, 147.21, 141.29,5 140.87, 139.65, 130.99, 130.54 (q, J = 30.8 Hz), 128.75, 128.31, 127.69, 126.67,126.09, 124.55 (q, J = 272.9 Hz), 119.89, 113.35, 110.10 (q, J = 4.2 Hz), 106.76 (q, J= 3.9 Hz), 99.28, 44.29, 34.77, 30.94. 132: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide. Preparation according to general procedure A from 164 (119 mg,10 0.31 mmol, 1 eq.) and 1-methyl-5-(4,4,5,5-tetraMethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (102 mg, 0.38 mmol, 1.2 eq.). Further purification by RP columnchromatography yielded a white solid (120 mg, 89%). 1H NMR (400 MHz, DMSO) δ10.90 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.89 – 7.81 (m, 2H),7.69 – 7.66 (m, 1H), 7.65 – 7.56 (m, 5H), 7.38 – 7.32 (m, 1H), 6.55 (d, J = 3.5 Hz, 1H),15 3.85 (s, 3H). 13C NMR (101 MHz, DMSO) δ 147.35, 141.37, 141.10, 139.56, 139.12,133.29, 131.39, 130.66 (q, J = 31.9 Hz), 129.51, 126.84, 126.73, 126.19, 123.73 (q, J= 272.6 Hz), 121.29, 119.96, 118.80 – 118.58 (m), 114.26 – 113.57 (m), 99.48, 31.00.133: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-1-phenylmethanesulfonamide. Benzylsulfonyl chloride (161 mg, 0.85 mmol, 2.0 eq.) was20 dissolved in 5 mL of dry dichloromethane and stirred at 0°C.127 (122 mg, 0.42 mmol,1 eq.) and DIPEA (219 µL, 1.25 mmol, 3.0 eq.) were added and the mixture was allowed to warm up to room temperature and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with sat. NH4Cl, sat. NaHCO3and brine, then dried over Na2SO4 and concentrated. The crude product was purified by flash25 column and RP column chromatography to yield a white solid (34 mg, 19%). 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.53 – 7.49 (m,1H), 7.50 – 7.47 (m, 1H), 7.42 (d, J = 3.5 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.29 – 7.22 (m,3H), 6.58 (d, J = 3.5 Hz, 1H), 4.47 (s, 2H), 3.90 (s, 3H). 13C NMR (101 MHz, MeOD) δ148.61, 143.73, 142.68, 142.17, 133.01 (q, J = 32.0 Hz), 132.23, 132.20, 131.09,30 129.52, 128.96, 128.84, 125.48 (q, J = 272.0 Hz), 122.64, 122.41, 118.54 (q, J = 3.5Hz), 115.46 (q, J = 3.8 Hz), 101.03, 59.42, 31.64 (d, J = 1.9 Hz). 99 220860PWO 134: N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-1-(2-(trifluoromethyl)phenyl)methanesulfonamide. 127 (160 mg, 0.55 mmol, 1.1 eq.) wasdissolved in 6 mL of dry dichloromethane and stirred at 0°C. 2-(trifluoromethyl)- benzylsulfonyl chloride (127 mg, 0.49 mmol, 1 eq.) and DIPEA (260 µL, 1.49 mmol, 3 5 eq.) were added and the mixture was allowed to warm up to rt and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with 5% HCl and brine, then dried over Na2SO4 and concentrated. The crude product was purified by flash column and RP column chromatography to yield a white solid (154 mg, 60%). 1HNMR (400 MHz, DMSO) δ 10.65 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.23 (d, J = 2.2 Hz,10 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.70 – 7.66 (m, 4H), 7.61 (d, J = 3.5 Hz, 1H), 7.59 – 7.51(m, 1H), 7.42 – 7.38 (m, 1H), 6.57 (d, J = 3.4 Hz, 1H), 4.80 (s, 2H), 3.87 (s, 3H). 13CNMR (101 MHz, DMSO) δ 147.36, 141.35, 141.22, 139.87, 133.92, 132.43, 131.37,130.82, 130.51, 129.23, 128.45 (q, J = 29.8 Hz), 127.06 – 126.96 (m), 126.87, 126.48(q, J = 5.4 Hz), 126.39, 124.00 (q, J = 274.4 Hz), 123.84 (q, J = 272.5 Hz), 120.36,15 119.95, 118.30 – 117.96 (m), 113.08 – 112.69 (m), 99.45, 54.82, 31.01.135: 1-(2-fluorophenyl)-N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide. 127 (171 mg, 0.59 mmol, 1.1 eq.) wasdissolved in 6 mL of dry dichloromethane and stirred at 0°C. (2- fluorophenyl)methanesulfonyl chloride (113 mg, 0.54 mmol, 1 eq.) and DIPEA (274 µL,20 1.60 mmol, 3 eq.) were added and the mixture was allowed to warm up to rt and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with 5% HCl and brine, then dried over Na2SO4and concentrated. The crude product was purified by flash column and RP column chromatography to yield a white solid (136 mg, 55%). 1H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.2225 (d, J = 2.2 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.65 – 7.64 (m, 1H), 7.61 (d, J = 3.4 Hz, 1H),7.44 (td, J = 7.6, 1.8 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.23 – 7.11 (m, 2H), 6.58 (d, J = 3.4Hz, 1H), 4.66 (s, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.89 (d, J = 248.1Hz), 147.34, 141.25, 141.18, 140.66, 133.31 (d, J = 3.2 Hz), 131.33, 130.85 (d, J = 8.3Hz), 130.54 (q, J = 31.7 Hz), 126.87, 126.58, 124.41 (d, J = 3.6 Hz), 123.93 (q, J =30 272.5 Hz), 120.31, 119.95, 117.99 – 117.26 (m), 116.76 (d, J = 14.8 Hz), 115.40 (d, J= 21.8 Hz), 113.37 – 112.76 (m), 99.45, 51.43, 31.14 – 30.83 (m).136: 1-(2-chloro-6-fluorophenyl)-N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide. 127 (98 mg, 0.34 mmol, 1.1 eq.) was 100 220860PWO dissolved in 6 mL of dry dichloromethane and stirred at 0°C. (2-Chloro-6- fluorophenyl)methanesulfonyl chloride (73 mg, 0.30 mmol, 1 eq.) and DIPEA (157 µL, 0.92 mmol, 3 eq.) were added and the mixture was allowed to warm up to rt and stirred overnight, then concentrated. The residue was taken up in EtOAc and washed with 5% 5 HCl and brine, then dried over Na2SO4and concentrated. The crude product was purified by flash column and RP column chromatography to yield a white solid (52 mg, 34%). 1H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.22 (d, J= 2.2 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.69 – 7.66 (m, 1H), 7.61 (d, J = 3.5 Hz, 1H), 7.46– 7.37 (m, 2H), 7.37 – 7.32 (m, 1H), 7.29 – 7.22 (m, 1H), 6.57 (d, J = 3.4 Hz, 1H), 4.7610 (d, J = 1.5 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO) δ 161.54 (d, J = 251.6Hz), 147.35, 141.22, 141.20, 140.21, 135.50 (d, J = 4.8 Hz), 131.58 (d, J = 9.9 Hz),131.38, 130.57 (q, J = 31.5 Hz), 126.85, 126.48, 125.74 (d, J = 3.3 Hz), 123.89 (q, J =272.8 Hz), 119.96, 119.79, 118.08 – 117.59 (m), 116.10 (d, J = 17.8 Hz), 114.71 (d, J= 22.2 Hz), 112.67 – 112.17 (m), 99.45, 49.98, 31.00.15 137: phenyl(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-carbamate. To a stirred solution of 127 (91 mg, 0.31 mmol, 1 eq.) in dry DCM at 0°Cwas added triethylamine (88 µL, 0.63 mmol, 2.0 eq.) and phenyl chloroformate (95 µL,0.75 mmol, 2.4 eq.). After 30 min, the mixture was allowed to warm up to rt and stirred20 overnight. The reaction was stopped by adding water and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column and RP column chromatography to yield a white solid (58 mg, 45%). 1H NMR (400 MHz, Acetone) δ 9.61 (s, 1H), 8.62(d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19 – 8.17 (m, 1H), 8.07 – 8.03 (m, 1H),25 7.75 – 7.70 (m, 1H), 7.49 (d, J = 3.5 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.31 – 7.24 (m, 3H),6.56 (d, J = 3.5 Hz, 1H), 2.87 (s, 3H). 13C NMR (101 MHz, Acetone) δ 151.61, 150.65,147.70, 141.56, 141.32, 140.09, 131.14 (q, J = 31.9 Hz), 130.47, 129.05, 126.97,126.52, 125.28, 124.06 (q, J = 271.8 Hz), 121.53, 120.18, 120.15, 117.85 (q, J = 3.9Hz), 113.09 – 112.78 (m), 99.27, 30.15.30 138: 1-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-3-phenylurea. To a stirred solution of phenyl isocyanate (58 µL, 0.53 mmol, 1 eq.) in dryDCM (3 mL) at 0°C was added 127 (171 mg, 0.59 mmol, 1.1 eq.) and triethylamine 101 220860PWO (168 µL, 1.20 mmol, 2.3 eq.). The mixture was allowed to warm up to rt and stirred for overnight, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. Purification by flash columnand RP column chromatography yielded 19 mg (9%) of a white solid. 1H NMR (4005 MHz, Acetone) δ 8.60 (d, J = 2.2 Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.24 (d, J = 2.2Hz, 1H), 8.09 – 8.04 (m, 1H), 8.04 – 8.01 (m, 1H), 7.64 – 7.61 (m, 1H), 7.59 – 7.55 (m,2H), 7.49 (d, J = 3.5 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.06 – 6.98 (m, 1H), 6.56 (d, J = 3.5Hz, 1H), 3.92 (s, 3H). 13C NMR (101 MHz, Acetone) δ 153.27, 148.71, 142.41, 142.31,142.26, 140.40, 131.99 (q, J = 31.7 Hz), 131.44, 129.52, 128.29, 127.54, 125.25 (q, J10 = 271.8 Hz), 123.25, 121.18, 121.13, 119.63, 117.81 (q, J = 4.1 Hz), 114.02 (q, J = 4.1Hz), 100.30, 31.19. 139: 3-(1H-indol-4-yl)-5-(trifluoromethyl)aniline. Preparation according to generalprocedure A from 160 (147 mg, 0.51 mmol, 1 eq.) and 4-bromo-1H-indole (65 µL, 0.56mmol, 1.1 eq.). Further purification by RP column chromatography yielded a colourless15 oily solid (84 mg, 60%). 1H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 7.46 – 7.39 (m,2H), 7.20 – 7.15 (m, 1H), 7.15 – 7.13 (m, 1H), 7.06 (dd, J = 7.3, 1.0 Hz, 1H), 7.02 –6.99 (m, 1H), 6.88 – 6.83 (m, 1H), 6.55 – 6.49 (m, 1H), 5.69 (s, 2H). 13C NMR (101MHz, DMSO) δ 149.77, 142.61, 136.38, 132.21, 130.03 (q, J = 31.1 Hz), 125.96,125.37, 128.84 – 120.06 (m), 121.30, 118.31, 116.90, 111.64 – 111.28 (m), 111.22,20 108.37 – 107.85 (m), 100.03.140: N-(3-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide.Preparation according to general procedure A from 161 (110 mg, 0.31 mmol, 1 eq.)and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (92 mg, 0.34 mmol, 1.1 eq.). Further purification by RP column chromatography yielded a white solid25 (87 mg, 69%). 1H NMR (400 MHz, DMSO) δ 10.58 (s, 1H), 8.25 (s, 1H), 7.97 – 7.89(m, 3H), 7.61 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.41 – 7.31 (m, 4H), 7.30 – 7.16 (m,3H), 3.85 (s, 3H), 3.72 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.78, 140.49, 137.37,137.22, 135.60, 130.07 (q, J = 31.4 Hz), 129.21, 128.92, 128.36, 126.64, 125.57 (q, J= 272.4 Hz), 124.88, 121.88, 120.28, 119.54, 118.91, 116.89 (q, J = 4.1 Hz), 112.96,30 111.59 (q, J = 4.1 Hz), 110.56, 43.41, 32.67.141: 3-(1-methyl-1H-indol-4-yl)-5-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 160 (195 mg, 0.68 mmol, 1.1 eq.) and 4-bromo-1-methyl- 102 220860PWO 1H-indole (132 mg, 0.62 mmol, 1 eq.). Further purification by RP columnchromatography yielded a colourless oily solid (108 mg, 61%). 1H NMR (400 MHz,DMSO) δ 7.46 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.28 – 7.20 (m, 1H), 7.15– 7.12 (m, 1H), 7.10 (dd, J = 7.3, 0.9 Hz, 1H), 7.02 – 6.96 (m, 1H), 6.91 – 6.84 (m, 1H),5 6.50 (dd, J = 3.2, 0.9 Hz, 1H), 3.83 (s, 3H). 13C NMR (101 MHz, DMSO) δ 149.81,142.33, 136.85, 132.46, 130.26, 130.06 (q, J = 30.9 Hz), 125.72, 124.60 (q, J = 272.2Hz), 121.41, 118.49, 116.93, 111.61 – 111.25 (m), 109.45, 108.46 – 107.87 (m), 99.24,32.68 (d, J = 2.7 Hz).165: N-(3-bromophenyl)-2-butoxyquinoline-4-carboxamide. Preparation according to10 general procedure C from 156 (249 mg, 1.01 mmol, 1 eq.) and 3-bromoaniline (131µL, 1.20 mmol, 1.2 eq.). After the purification, the product was lyophilized to yield a yellowish-white solid (228 mg, 57%). 1H NMR (400 MHz, MeOD) δ 8.08 (t, J = 1.9 Hz,1H), 8.04 (dd, J = 8.3, 1.5 Hz, 1H), 7.86 (dd, J = 8.8, 1.0 Hz, 1H), 7.71 – 7.64 (m, 2H),7.48 – 7.43 (m, 1H), 7.35 – 7.27 (m, 2H), 7.12 (s, 1H), 4.51 (t, J = 6.5 Hz, 2H), 1.88 –15 1.79 (m, 2H), 1.61 – 1.50 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO)δ 164.95, 161.08, 146.43, 144.75, 140.29, 130.85, 130.28, 127.26, 126.78, 125.14,124.89, 122.33, 121.56, 121.10, 118.78, 111.45, 65.54, 30.49, 18.80, 13.73. 142: 2-butoxy-N-(3-(4-methyl-1H-imidazol-1-yl)phenyl)quinoline-4-carboxamide.Preparation from 165 (60 mg, 0.15 mmol, 1 eq.) and 4-methylimidazole (25 mg, 0.3020 mmol, 2 eq.) following a Buchwald-coupling procedure catalyzed by Me4tButylXphosPd (in situ from Me4tButylXphos (1.6 mg, 0.003 mmol) and Pd(dba)2 (1.4 mg, 0.002mmol)) with K3PO4(127 mg, 0.60 mmol, 4 eq.) in dry dioxane (1.3 mL). The reaction mixture was stirred at 120°C for 22h. Further purification by RP columnchromatography yielded a white solid (46 mg, 77%). 1H NMR (400 MHz, DMSO) δ25 10.93 (s, 1H), 8.11 – 8.03 (m, 2H), 7.87 – 7.83 (m, 1H), 7.76 – 7.70 (m, 1H), 7.69 –7.64 (m, 1H), 7.55 – 7.46 (m, 2H), 7.41 – 7.35 (m, 2H), 7.25 (s, 1H), 4.48 (t, J = 6.6Hz, 2H), 2.18 (s, 3H), 1.84 – 1.73 (m, 2H), 1.49 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz,3H). 13C NMR (101 MHz, DMSO) δ 164.98, 161.11, 146.47, 144.83, 139.95, 137.35,130.31 (d, J = 3.0 Hz), 127.29, 125.20, 124.88, 121.16, 118.15, 116.00, 111.84, 111.43,30 65.56, 30.50, 18.82, 13.74, 13.58. 166: N-(3-bromophenyl)-2-(2-chlorophenyl)acetamide. Preparation according togeneral procedure B from 2-chlorophenylacetic acid (371 mg, 2.17 mmol, 1 eq.) and 103 220860PWO 3-bromoaniline (284 µL, 2.61 mmol, 1.2 eq.) to yield a white solid (637 mg, 90%). 1HNMR (400 MHz, DMSO) δ 10.40 (s, 1H), 7.96 (t, J = 1.9 Hz, 1H), 7.52 – 7.47 (m, 1H),7.46 – 7.40 (m, 2H), 7.34 – 7.21 (m, 4H), 3.85 (s, 2H). 13C NMR (126 MHz, DMSO) δ168.31, 140.73, 133.68, 133.63, 132.23, 130.77, 129.00, 128.67, 127.07, 125.80, 5 121.57, 121.36, 117.77, 40.79. 143: 2-(2-chlorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)phenyl)acetamide.Preparation from 166 (158 mg, 0.49 mmol, 1 eq.) and 4-methylimidazole (82 mg, 1.00mmol, 2.1 eq.) based on a Buchwald-coupling procedure catalyzed byMe4tButylXphosPd (in situ from Me4tButylXphos (4.4 mg, 0.009 mmol) and Pd(dba)210 (6.3 mg, 0.01 mmol)) with K3PO4(424 mg, 2.00 mmol, 4 eq.) in dry dioxane (2.4 mL). The reaction mixture was stirred at 120°C for 22h. Further purification by RP columnchromatography yielded a white solid (74 mg, 47%). 1H NMR (400 MHz, DMSO) δ10.45 (s, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.51 – 7.39 (m, 4H), 7.38– 7.23 (m, 4H), 3.88 (s, 2H), 2.16 (s, 3H). 13C NMR (126 MHz, DMSO) δ 168.31,15 140.45, 138.47, 137.33, 134.60, 133.70, 132.28, 130.22, 129.00, 128.67, 127.07, 117.05, 114.97, 114.22, 110.70, 40.80, 13.57. 144: 3-(2-methylpyridin-4-yl)aniline. Preparation according to general procedure Afrom 2-methylpyridine-4-boronic acid (83 mg, 0.61 mmol, 1.2 eq.) and 3-bromoaniline (54 µL, 0.50 mmol, 1 eq.). Further purification by RP column chromatography yielded20 a white solid (32 mg, 34%). 1H NMR (400 MHz, MeOD) δ 8.38 (d, J = 5.4 Hz, 1H), 7.51– 7.49 (m, 1H), 7.44 – 7.41 (m, 1H), 7.25 – 7.16 (m, 1H), 7.07 – 7.02 (m, 1H), 7.02 –6.98 (m, 1H), 6.83 – 6.75 (m, 1H), 2.56 (s, 3H). 13C NMR (101 MHz, MeOD) δ 159.54,151.72, 149.80, 149.58, 139.87, 130.88, 122.60, 120.30, 117.51, 117.29, 114.54, 23.80. HRMS (FIA / ESI+): m / z calculated 184.0995 for C12H13N2, found 185.107225 ([M+H]+). 145: 3-methyl-5-(2-methylpyridin-4-yl)aniline. Preparation according to generalprocedure A from 2-methylpyridine-4-boronic acid (115 mg, 0.84 mmol, 1.2 eq.) and 3- bromo-5-methylaniline (87 µL, 0.70 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (98 mg, 70%). 1H NMR (400 MHz, DMSO) δ 8.4330 (d, J = 5.2 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.32 (dd, J = 5.2, 2.1 Hz, 1H), 6.74 – 6.71 (m,1H), 6.73 – 6.67 (m, 1H), 6.50 – 6.44 (m, 1H), 5.15 (s, 2H), 2.22 (s, 3H). 13C NMR (101MHz, DMSO) δ 158.27, 149.30, 149.24, 148.30, 138.71, 138.05, 120.27, 118.25, 104 220860PWO 115.29, 115.17, 109.33, 24.11, 21.22. HRMS (GC / EI+): m / z calculated 198.1151 forC13H14N2, found 198.1152 ([M]+).146: 3-(2-methylpyridin-4-yl)-4-(trifluoromethyl)aniline. Preparation according togeneral procedure A from 2-methylpyridine-4-boronic acid (83 mg, 0.60 mmol, 1.2 eq.) 5 and 3-bromo-4-(trifluoromethyl)aniline (73 µL, 0.50 mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid (53 mg, 42%). 1H NMR (400 MHz,DMSO) δ 8.46 (d, J = 5.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J =4.6 Hz, 1H), 6.67 (dd, J = 8.2, 2.7 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 5.96 (s, 2H). 13CNMR (101 MHz, DMSO) δ 157.46, 151.80, 148.36, 139.44, 127.56 (q, J = 5.2 Hz),10 125.07 (q, J = 271.2 Hz), 122.77, 120.76, 115.28, 112.76 (q, J = 30.1 Hz), 112.15,23.98. HRMS (FIA / ESI+): m / z calculated 252.0869 für C13H11F3N2, found 253.0945([M+H]+). 147: 3-methoxy-5-(2-methylpyridin-4-yl)aniline. Preparation according to generalprocedure A from 2-methylpyridine-4-boronic acid (83 mg, 0.60 mmol, 1.2 eq.) and 3-15 bromo-4-methoxyaniline (69 µL, 0.50 mmol, 1 eq.). Further purification by RP columnchromatography yielded a brown oily solid (35 mg, 32%). 1H NMR (500 MHz, MeOD-d4) δ 8.35 (d, J = 5.3 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 5.3 Hz, 1H), 6.65 – 6.60 (m,1H), 6.56 – 6.52 (m, 1H), 6.41 – 6.36 (m, 1H), 3.78 (s, 3H), 2.54 (s, 3H). 13C NMR (101MHz, MeOD) δ 162.48, 159.28, 151.35, 150.78, 149.31, 140.65, 122.38, 120.11,20 107.44, 103.31, 102.41, 55.49, 23.61. HRMS (FIA / ESI+): m / z calculated 214.1101 forC13H14N2O, found 215.1177 ([M+H]+).148: 3-amino-5-(2-methylpyridin-4-yl)benzonitrile. Preparation according to generalprocedure A from 2-methylpyridine-4-boronic acid (85 mg, 0.62 mmol, 1.2 eq.) and 3- amino-5-benzonitrile (59 µL, 0.50 mmol, 1 eq.). Further purification by RP column25 chromatography yielded a white solid (33 mg, 31%). 1H NMR (500 MHz, MeOD-d4) δ8.44 (d, J = 5.3 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J = 5.3, 2.0 Hz, 1H), 7.25 – 7.23 (m,1H), 7.23 – 7.22 (m, 1H), 7.01 – 6.97 (m, 1H), 2.59 (s, 3H).13C NMR (101 MHz, MeOD)δ 160.03, 151.36, 149.95, 149.69, 141.33, 122.66, 120.27, 119.98, 119.49, 118.36,118.04, 114.59, 23.85. HRMS (FIA / ESI+): m / z calculated 209.0947 for C13H11N3, found30 210.1024 ([M+H]+).149: 3-(2-methylpyridin-4-yl)-4-(trifluoromethoxy)aniline. Preparation according togeneral procedure A from 2-methylpyridine-4-boronic acid (82 mg, 0.60 mmol, 1.2 eq.) 105 220860PWO and 3-amino-4-(trifluoromethoxy)aniline (75 µL, 0.50 mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid (52 mg, 38%). 1H NMR (500 MHz,MeOD-d4) δ 8.43 (d, J = 5.2 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J = 5.3 Hz, 1H), 7.12 (d, J= 9.0 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 2.58 (s, 3H). 13C NMR5 (101 MHz, MeOD) δ 159.33, 149.24, 149.14, 148.38, 138.09 (q, J = 1.9 Hz), 134.51,125.07, 124.24, 122.76, 121.98 (q, J = 254.9 Hz), 117.03, 116.80, 23.81. HRMS(FIA / ESI+): m / z calculated 268.0818 for C13H12F3N2O, found 269.0895 ([M+H]+).150: 3-chloro-5-(2-methylpyridin-4-yl)aniline. Preparation according to generalprocedure A from 2-methylpyridine-4-boronic acid (81 mg, 0.59 mmol, 1.2 eq.) and 3-10 amino-5-chloroaniline (60 µL, 0.49 mmol, 1 eq.). Further purification by RP columnchromatography yielded a white solid (50 mg, 46%). 1H NMR (400 MHz, MeOD) δ 8.40(d, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.40 (ddd, J = 5.4, 1.9, 0.7 Hz, 1H), 6.93 – 6.91 (m,1H), 6.90 – 6.89 (m, 1H), 6.76 – 6.75 (m, 1H), 2.57 (s, 3H).13C NMR (101 MHz, MeOD)δ 159.80, 151.62, 150.46, 149.77, 141.47, 136.55, 122.61, 120.26, 116.37, 115.97,15 112.54, 23.83. HRMS (FIA / ESI+): m / z calculated 218.0605 for C12H11ClN2, found219.0682 ([M+H]+).151: 1-(2-amino-4-(2-methylpyridin-4-yl)phenyl)ethan-1-one. Preparation according togeneral procedure A from 2-methylpyridine-4-boronic acid (118 mg, 0.86 mmol, 1.2 eq.) and 1-(2-amino-4-bromophenyl)ethenone (153 mg, 0.70 mmol, 1 eq.). Further20 purification by RP column chromatography yielded a yellow solid (20 mg, 13%). 1HNMR (400 MHz, MeOD) δ 8.45 (d, J = 5.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.57 –7.55 (m, 1H), 7.50 – 7.47 (m, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.4, 1.9 Hz,1H), 2.60 (s, 3H), 2.58 (s, 3H). 13C NMR (101 MHz, MeOD) δ 202.24, 159.91, 152.90,150.29, 149.86, 144.64, 134.29, 122.72, 120.35, 118.88, 116.39, 114.68, 27.91, 23.86.25 HRMS (FIA / ESI+): m / z calculated 226.1101 for C14H15N2O, found 227.1177 ([M+H]+).152: 3-(2-methylpyridin-4-yl)-5-(trifluoromethoxy)aniline. Preparation according togeneral procedure A from 2-methylpyridine-4-boronic acid (83 mg, 0.60 mmol, 1.2 eq.) and 3-bromo-5-(trifluoromethoxy)aniline (76 µL, 0.51 mmol, 1 eq.). Further purification by RP column chromatography yielded a white solid (70 mg, 52%). 1H NMR (400 MHz,30 MeOD) δ 8.42 (d, J = 5.3 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.43 – 7.40 (m, 1H), 6.98 –6.93 (m, 1H), 6.82 – 6.76 (m, 1H), 6.67 – 6.61 (m, 1H), 2.58 (s, 3H). 13C NMR (101MHz, MeOD) δ 159.90, 152.19 – 152.13 (m), 152.10, 150.37, 149.85, 141.59, 123.25 106 220860PWO (q), 122.63, 120.30, 112.56, 108.46, 108.23, 23.83. HRMS (GC / EI+): m / z calculated268.0818 for C13H11F3N2O, found 268.0817 ([M]+).153: 3,4-dichloro-5-(2-methylpyridin-4-yl)aniline. Preparation according to generalprocedure A from 2-methylpyridine-4-boronic acid (70 mg, 0.51 mmol, 1 eq.) and 3- 5bromo-4,5-dichloroaniline (70 µL, 0.51 mmol, 1 eq.). Further purification by RP columnchromatography yielded a yellow solid (18 mg, 14%). 1H NMR (400 MHz, MeOD) δ8.44 (d, J = 5.3 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.24 (dd, J = 5.3, 1.7 Hz, 1H), 6.88 (d, J= 2.6 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 2.58 (s, 3H). 13C NMR (101 MHz, MeOD) δ159.26, 150.62, 149.45, 149.14, 141.33, 134.80, 125.35, 123.03, 117.65, 116.94,10 116.33, 23.80. HRMS (GC / EI+): m / z calculated 252.0216 for C12H10Cl2N2, found252.0216 ([M]+).167: 1-bromo-3-phenethoxy-5-(trifluoromethyl)benzene. To a solution of 3-bromo-5-(trifluoromethyl)phenol (690 µL, 5.00 mmol, 1 eq.) in acetonitrile (25 mL) was added 2-phenylethylbromide (1000 µL, 7.40 mmol, 1.5 eq.) and K2CO3 (1385 mg, 10.02 mmol,15 2 eq.). The reaction mixture was stirred at 80°C overnight, then concentrated under reduced pressure. The residue was taken up in EtOAc, filtered and washed with 5% HCl solution (2x) and brine. The organic layer was dried over Na2SO4, concentrated and purified by flash column chromatography to yield a colorless crystalline solid (694 mg, 40%). 1H NMR (400 MHz, DMSO) δ 7.49 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 7.36 –20 7.19 (m, 6H), 4.32 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H). 13C NMR (101 MHz,DMSO) δ 159.68, 137.92, 131.78 (q, J = 32.6 Hz), 128.97, 128.31, 126.35, 123.01 (q,J = 272.4 Hz), 122.95, 121.48, 119.86 (q, J = 4.2 Hz), 111.02 (q, J = 3.8 Hz), 69.11,34.64. 168: N-(3-bromo-5-(trifluoromethyl)phenyl)-N-methyl-2-phenylacetamide. To a stirred25 solution of 161 (378 mg, 1.06 mmol, 1 eq.) in dry DMF (2.5 mL) at 0°C was added NaH(63 mg, 1.58 mmol, 1.5 eq.) and the mixture was stirred for 10 minutes. Methyl iodide (131 µL, 2.11 mmol, 2 eq.) was added and the solution was allowed to warm up to rt and stirred for 6h. After quenching with aq. sat. NH4Cl, the mixture was extracted with EtOAc and washed three more times with aq. sat. NH4Cl. The organic layer was dried30 over Na2SO4and concentrated. After purification by flash column chromatography and lyophilization, the product was yielded as a yellow oil (106 mg, 27%). 1H NMR (400MHz, Acetone) δ 7.85 (s, 1H), 7.82 – 7.78 (m, 1H), 7.68 – 7.63 (m, 1H), 7.30 – 7.16 107 220860PWO (m, 3H), 7.16 – 7.04 (m, 2H), 3.62 (s, 2H), 3.32 (s, 3H). 13C NMR (101 MHz, Acetone)δ 147.43, 136.45, 135.88 – 135.28 (m), 130.24, 130.01, 129.40, 129.21, 127.47,125.38, 123.61, 122.67, 41.97, 37.76. 154: N-(3-(2,6-dimethylpyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-methyl-2-5 phenylacetamide. Preparation according to general procedure A from 168 (53 mg, 0.14mmol, 1 eq.) and (2,6-dimethylpyridin-4-yl)boronic acid (30 mg, 0.19 mmol, 1.3 eq.).Further purification by RP column chromatography yielded a white solid (26 mg, 46%).1H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 8.03 – 7.97 (m, 1H), 7.77 – 7.71 (m, 1H),7.45 (s, 2H), 7.29 – 7.15 (m, 3H), 7.12 – 6.95 (m, 2H), 3.53 (s, 2H), 3.29 (s, 3H), 2.4910 (s, 6H).13C NMR (126 MHz, DMSO) δ 169.77, 158.09, 145.20, 140.20, 135.46, 130.23,129.00, 128.15, 128.10 – 127.65 (m), 126.85, 126.36, 123.60 (q, J = 273.2 Hz), 120.34,118.14 – 117.49 (m), 117.83, 40.70, 37.08, 24.00.155: N-methyl-N-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-2-phenylacetamide. Preparation according to general procedure A from 168 (53 mg,15 0.14 mmol, 1 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (53 mg, 0.20 mmol, 1.4 eq.). Further purification by RPcolumn chromatography yielded a white solid (43 mg, 73%). 1H NMR (400 MHz,DMSO) δ 8.63 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.01 (s, 1H), 7.98 – 7.96(m, 1H), 7.66 – 7.63 (m, 1H), 7.60 (d, J = 3.4 Hz, 1H), 7.28 – 7.15 (m, 3H), 7.06 (s,20 2H), 6.55 (d, J = 3.4 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 2H), 3.30 (s, 3H). 13C NMR (126MHz, DMSO) δ 169.81, 147.37, 145.12, 141.50, 135.56, 131.31, 130.54 – 129.55 (m),129.22, 129.05, 128.35, 128.13, 127.13, 127.03 – 126.54 (m), 126.33, 125.77, 123.75(q, J = 273.2 Hz), 122.34 – 122.05 (m), 119.92, 99.43, 40.65, 37.10, 30.99.169: N-benzyl-3-bromo-5-(trifluoromethyl)benzamide. Preparation according to25 general procedure D from 3-bromo-5-(trifluoromethyl)benzoic acid (1.36 g, 5.04 mmol, 1eq.) and benzylamine (667 µL, 6.04 mmol, 1.2 eq.) to yield a white solid (1.27 g,70%). 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.42 – 8.36 (m, 1H), 8.26 – 8.22 (m,1H), 8.20 – 8.16 (m, 1H), 7.34 (d, J = 4.5 Hz, 4H), 7.29 – 7.23 (m, 1H), 4.50 (s, 2H).13C NMR (101 MHz, DMSO) δ 163.25, 138.93, 137.05, 134.20, 131.10 (q, J = 32.830 Hz), 130.62 (q, J = 3.6 Hz), 128.35, 127.43, 126.94, 123.16 (q, J = 4.1 Hz), 122.97 (q, 108 220860PWO Measurement of biological activity Hybrid reporter gene assays. TLX modulation was determined in a Gal4 hybridreporter gene assay in HEK293T cells (German Collection of Microorganisms and Cell Culture GmbH, DSMZ) using pFR-Luc (Stratagene, La Jolla, CA, USA; reporter), pRL- 5 SV40 (Promega, Madison, WI, USA; internal control), pECE-SV40-Gal4-VP16 (#71728, Addgene, Watertown, MA), and pFA-CMV-hTLX-LBD, coding for the hinge region and ligand binding domain of the canonical isoform of human TLX. Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM), high glucose supplemented with 10% fetal calf serum (FCS), sodium pyruvate (1 mM), penicillin (100 U / mL), and10 streptomycin (100 μg / mL) at 37 °C and 5% CO2 and seeded in 96-well plates (3×104cells / well). After 24 h, medium was changed to Opti-MEM without supplements and cells were transiently transfected using Lipofectamine LTX reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s protocol. Five hours after transfection, cells were incubated with the test compounds in Opti-MEM supplemented15 with penicillin (100 U / mL), streptomycin (100 μg / mL) and 0.1% DMSO for 16 h beforeluciferase activity was measured using the Dual-Glo Luciferase Assay System (Promega) according to the manufacturer’s protocol on a Tecan Spark luminometer (Tecan Deutschland GmbH, Crailsheim, Germany). Firefly luminescence was divided by Renilla luminescence and multiplied by 1000 resulting in relative light units (RLU)20 to normalize for transfection efficiency and cell growth. Fold activation was obtained by dividing the mean RLU of test compound by the mean RLU of the untreated control. All samples were tested in at least three biologically independent experiments in duplicates. For dose-response curve fitting and calculation of EC50values, the equation “[Agonist] vs. response -- Variable slope (four parameters)" was used in GraphPad25 Prism (version 7.00, GraphPad Software, La Jolla, CA, USA). Isothermal Titration Calorimetry (ITC). ITC experiments were conducted on anAffinity ITC instrument (TA Instruments, New Castle, DE) at 25°C with a stirring rate of 75 rpm. TLX LBD protein (10-20 µM) in buffer (20 mM Tris pH 7.5, 150 mM NaCl, 0.2 mM TCEP, 5% glycerol) containing 1-4% DMSO was titrated with the test compounds30 (60-100 μM in the same buffer containing 1-4% DMSO) in 26 injections (1x 1 µL, 25x4 μL) with an injection interval of 150 s. As control experiments, the test compoundswere titrated to the buffer, and the buffer was titrated to the TLX LBD protein under 109 220860PWO otherwise identical conditions. Results were analyzed using NanoAnalyze software (version 3.11.0, TA Instruments, New Castle, DE) with independent binding models.

[0002] 110 220860PWO References 1. Shi, Y. et al. Expression and function of orphan nuclear receptor TLX in adultneural stem cells. Nature 427, 78–83 (2004).5 2. Miyawaki, T. et al. Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbersand Astrocyte Development in the Developing Retina. J. Neurosci.24, 8124–8134 (2004).10 3. Willems, S., Zaienne, D. & Merk, D. Targeting Nuclear Receptors inNeurodegeneration and Neuroinflammation. J. Med. Chem.64, 9592–9638(2021).4. Zhang, C.-L., Zou, Y., Yu, R. T., Gage, F. H. & Evans, R. M. Nuclear receptor15 TLX prevents retinal dystrophy and recruits the corepressor atrophin1. GenesDev.20, 1308–1320 (2006).5. Nelson, A. T., Wang, Y. & Nelson, E. R. TLX, an Orphan Nuclear Receptor withEmerging Roles in Physiology and Disease. Endocrinol. (United States) 162,20 bqab184 (2021).6. Liu, H. K. et al. The nuclear receptor tailless is required for neurogenesis in theadult subventricular zone. Genes Dev.22, 2473–2478 (2008).25 7. Islam, M. M. & Zhang, C.-L. TLX: A master regulator for neural stem cellmaintenance and neurogenesis. Biochim. Biophys. Acta - Gene Regul. Mech.1849, 210–216 (2015).8. Sun, G., Yu, R. T., Evans, R. M. & Shi, Y. Orphan nuclear receptor TLX recruits30 histone deacetylases to repress transcription and regulate neural stem cellproliferation. Proc. Natl. Acad. Sci. U. S. A.104, 15282–7 (2007).9. Kozareva, D. A., O’Leary, O. F., Cryan, J. F. & Nolan, Y. M. Deletion of TLXand social isolation impairs exercise-induced neurogenesis in the adolescent35 hippocampus. Hippocampus 28, 3–11 (2018).10. O’Leary, J. D., O’Leary, O. F., Cryan, J. F. & Nolan, Y. M. Regulation ofbehaviour by the nuclear receptor TLX. Genes, Brain Behav.17, 1–11 (2018).40 11. Kumar, R. A. et al. Initial association of NR2E1 with bipolar disorder andidentification of candidate mutations in bipolar disorder, schizophrenia, andaggression through resequencing. Am. J. Med. Genet. Part B Neuropsychiatr.Genet.147B, 880–889 (2008). 111 220860PWO 12. O’Leary, J. D. et al. The nuclear receptor Tlx regulates motor, cognitive andanxiety-related behaviours during adolescence and adulthood. Behav. BrainRes.306, 36–47 (2016).5 13. Abrahams, B. S. et al. Pathological aggression in ‘Fierce’ mice corrected byhuman nuclear receptor 2E1. J. Neurosci.25, 6263–6270 (2005).14. Griffett, K. et al. The Orphan Nuclear Receptor TLX Is a Receptor for Syntheticand Natural Retinoids. Cell Chem. Biol.27, 1272-1284.e4 (2020).10 15. Benod, C. et al. The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1)is Druggable. PLoS One 9, e99440 (2014).16. Faudone, G. et al. Propranolol Activates the Orphan Nuclear Receptor TLX to15 Counteract Proliferation and Migration of Glioblastoma Cells. J. Med. Chem.64, 8727–8738 (2021).17. Kandel, P. et al. Oleic acid is an endogenous ligand of TLX / NR2E1 thattriggers hippocampal neurogenesis. Proc. Natl. Acad. Sci. U. S. A.119,20 e2023784119 (2022).18. Dueva, E. et al. Computer-aided discovery of small molecule inhibitors oftranscriptional activity of TLX (NR2E1) nuclear receptor. Molecules 23, 2967(2018).25 19. Faudone, G. et al. Design of a Potent TLX Agonist by Rational FragmentFusion. J. Med. Chem.65, 2288–2296 (2022).20. Wu, D. et al., Knockdown of TLX has been shown to enhance sensitivity to30 prostate cancer therapies. J. Pathol. 2015, 236(1): 103-115.21. Jia, L. et al., LX overexpression is also involved in glioblastoma stem cell(GSC) self-renewal and tumorigenesis, and TLX knockdown inhibits GSCgrowth. Oncogene 2018, 37: 3340-3355.35 22. Cui, Q. et al., Downregulation of TLX induces TET3 expression and inhibitsglioblastoma stem cell self-renewal and tumorigenesis. Nat. Commun. 2016,7(10637): 1-15.40 23. Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418.24. Journal of Pharmaceutical Science 1977, 66 (2).

Claims

1. 112 220860PWO Claims 5 1. A compound of formula (I) or a salt or solvate thereof: wherein R1 is -R1a or -NH-CO-R1a,10 R1ais an aromatic or heteroaromatic ring system optionally comprising at least one heteroatom selected from N, O and S which is optionally substituted; R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6-alkynyl-R2a or -C1-C615 alkyl, wherein alkyl and alkynyl is optionally substituted; R3and R4are independently selected from H, OH, C1-C6alkyl, C2-C6alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted;20 n is 0, 1 or 2,R2a is a saturated, unsaturated or aromatic monocyclic orbicyclic ring system optionally comprising at least oneheteroatom selected from N, O and S which is optionally substituted; 25 R5is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or R5and R2together form a ring which is optionally substituted; R6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8cycloalkyl, OC3-C8cycloalkyl, cyano, CO-C1-C6alkyl and 113 220860PWO halo, wherein alkyl, alkenyl, alkynyl and cycloalkyl areoptionally substituted, e.g. by halo; and mis 1, 2 or 3;5 with the proviso that compound (I) is not 10 15 2. A compound of formula (II) or a salt or solvate thereof:20 wherein R1, R2, R5 and R6 are defined as in claim 1,with the proviso that compound (I) is not 25 30 3. The compound of claim 1 or 2 wherein R1a is 114 220860PWO a monocyclic ring, e.g., a 5-membered or 6-membered ring which is optionally substituted, and / or selected from pyrrolyl, e.g., pyrrol-1-yl, furyl, thiophenyl, e.g. thiophen-2-yl, orthiophen-3-yl, imidazolyl, e.g. imidazol-1-yl, imidazol-4-yl or imidazol-5-yl, pyrazolyl, 5 e.g. pyrazol-1-yl, pyrazol-3-yl or pyrazol-4-yl, oxazolyl, isoxazolyl, e.g., isoxazol-4-yl, thiazolyl, e.g., thiazol-2-yl or thiazol-4-yl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, e.g., 1,2,4-triazol-3-yl, which are optionally substituted, and / or selected from phenyl, pyridinyl, e.g., pyridin-3-yl, or pyridin-4-yl, pyrimidinyl, e.g. pyrimidin-5-yl, or pyrazidinyl which are optionally substituted, and / or 10 a bicyclic ring, e.g., a 7-membered, 8-membered, 9-membered or 10-membered ring which is optionally substituted, and / or selected from indolyl, e.g., indol-1-yl, indol-3-yl, or indol-5-yl, indolinyl, e.g., indolin-5-yl, indazolyl, e.g., indazol-5-yl, pyrrolopyridinyl, e.g., pyrrolopyridin-5-yl, pyrazolopyridinyl, benzoimidazolyl, e.g., benzoimidazol-1-yl, benzofuranyl, e.g.,15 benzofuran-5-yl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, e.g., imidazopyridine- 7-yl, or benzothiophenyl, e.g. benzothiophen-5-yl, benzothiazolyl, benzoisothiazolyl which are optionally substituted, and / or substituted with one or more substituents independently selected from OH, CN, NO2, halo, e.g., F, Cl, Br, or I, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, OC1-C6alkyl,20 OC2-C6alkenyl, OC2-C6alkynyl, SC1-C6alkyl, SC2-C6alkenyl, SC2-C6alkynyl, CO-C1- C6 alkyl, COOH, COOC1-C6 alkyl, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, wherein each alkyl, alkenyl or alkenyl substituent on R1amay be substituted with OH, CN, halo, OC1-C3alkyl, COOH, COOC1-C3alkyl, NH2, NH(C1-C3alkyl), (C1-C3alkyl)2, or any combination thereof. 25 4. The compound of any one of claims 1-3, wherein R1 is selected from: 115 220860PWO 5 or wherein R1is selected from:10 or wherein R1 is selected from:15 116 220860PWO 5 5. The compound of any one of claims 1-4, whereinR2 is -CO-R2a or -CO-(C(R3R4))n-R2a,R3and R4are independently selected from H, OH, C1-C4alkyl,10 trifluoromethyl, fluoro and cyclopentyl, R2ais a monocyclic ring, e.g., a 3-membered, 4-membered, 5-membered or 6-membered ring which is optionally substituted, preferably wherein R2a isselected from cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, pyrazolyl, e.g. pyrazol-3-yl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,15 1,2,4-triazolyl, 1,2,3-triazolyl, cyclohexyl, piperidinyl, e.g., piperidin-3-yl, morpholinyl, phenyl, and pyridinyl, e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, which are optionally substituted, and / or R2ais a bicyclic ring, e.g. an 8-membered, 9-membered, or 10-membered bicyclic ring which is optionally substituted, preferably wherein R2a is selected20 from naphthyl, e.g., naphth-1-yl or naphth-2-yl, quinolinyl, e.g., quinon-4-yl, isoquinolinyl, quinazolinyl, tetrahydroquinolinyl, indolyl, e.g., indol-3-yl, indazolyl, benzoimidazolyl, benzofuranyl, benzoxazolyl, benzodioxolyl, pyrrolopyridinyl, imidazopyridinyl, e.g., imidazopyridine-7-yl, or benzothiophenyl, e.g. benzothiophen-2-yl, benzothiazolyl which are optionally25 substituted, and / or R2ais substituted with one or more substituents independently from OH, CN, NO2, halo, e.g., F, Cl, Br or I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OC1- C6 alkyl, OC2-C6 alkenyl, OC2-C6 alkynyl, SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 117 220860PWO alkynyl, CO-C1-C6 alkyl, COOH, COOC1-C6 alkyl, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, wherein each alkyl, alkenyl or alkynyl substituent on R2a may besubstituted with OH, CN, halo, OC1-C3alkyl, COOH, COOC1-C3alkyl, NH2, NH(C1-C3 alkyl), (C1-C3 alkyl)2, or any combination thereof. 5 6. The compound of any one of claims 1-5, wherein R2a is not substituted with NH2.

7. The compound of any one of claims 1-6, wherein R2 is selected from:10 15 118 220860PWO 5 10 15 8. The compound of any one of claims 1-7, 119 220860PWO wherein R5is H, and / or wherein R6 is selected from H, halo, e.g., Cl, CN, C1-C4 alkyl, e.g. CF3,C1-C4 alkoxy, e.g., OCF3, CO-CH3, or OH.5 9. The compound of any one of claims 1-8 wherein:R1 is imidazolyl, pyridyl or pyrrolopyridinyl, particularly , R2 is -CO-(C(R3R4))n-R2a or -SO2-(C(R3R4))n-R2a, wherein R3 and R410 are particularly H, and n is particularly 0 or 1,R2ais phenyl optionally substituted, particularly phenyl substituted with one or more substituents selected from halo, e.g., Cl, C1-C6 alkyl, e.g., CF3, CN, O(C1-C6alkyl), NH(C1-C6 alkyl) and N(C1-C6 alkyl)2, e.g., N(CH3)2, and15 ,, R5is H, and R6 is H, CF3, Cl or OCF3 .20 10. The compound of any one of claims 1-9, wherein n is 0. 120 220860PWO 11. The compound of any one of claims 1-9, wherein n is 1.12.A pharmaceutical composition comprising the compound of formula (I) or (II) ora salt or solvate thereof of any one of claims 1-11 as an active agent and a5 pharmaceutically acceptable carrier. 13.A compound of formula (I) or (II) or a salt or solvate of any one of claims 1-11 ora pharmaceutical composition of claim 12 for use in medicine.10 14.A compound of formula (I) or (II) or a salt or solvate thereof for use in theprevention and / or treatment of a disease caused by and / or associated with insufficient TLX activity 15.A compound of formula (Ia) or a salt or solvate thereof for use in the prevention15 and / or treatment of a disease caused by and / or associated with insufficient TLX activity: wherein R1 is -R1a or -NH-CO-R1a,20 R1ais an aromatic or heteroaromatic ring system optionally comprising at least one heteroatom selected from N, O and Swhich is optionally substituted;R2 is -CO-(C(R3R4))n-R2a, -SO2-(C(R3R4))n-R2a, -CO-NH-R2a, -CO-O-R2a, -(C(R3R4))n-R2a, -C2-C6-alkynyl-R2a , -C1-C6 alkyl25 or -H, wherein alkyl and alkynyl is optionally substituted;R3and R4are independently selected from H, OH, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C3-C8 cycloalkyl, whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionallysubstituted;30 n is 0, 1 or 2; 121 220860PWO R2ais a saturated, unsaturated or aromatic ring system optionally comprising at least one heteroatom selected from N, O and S which is optionally substituted; R5is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, or R5and 5 R2together form a ring which is optionally substituted; R6 is selected from H, OH, C1-C6 alkyl, OC1-C6 alkyl, C2-C6alkenyl, OC2-C6 alkenyl, C2-C6 alkynyl, OC2-C6 alkynyl, C3-C8 cycloalkyl, OC3-C8 cycloalkyl, cyano, CO-C1-C6 alkyl andhalo, wherein alkyl, alkenyl, alkynyl and cycloalkyl are10 optionally substituted, e.g. by halo; and mis 1, 2 or 3;with the proviso that compound (Ia) is not 15 20 16.A compound of formula (IIa) or a salt or solvate thereof for use in the preventionand / or treatment of a disease caused by and / or associated with insufficient TLX activity: 25 30 wherein R1, R2, R5 and R6 are defined as in claim 12. 122 220860PWO 17.A compound of formula (I), (II), (Ia) or (IIa) or a salt or solvate of any one ofclaims 1-11 or 15-16 or a pharmaceutical composition of claim 12 for use in theprevention and / or treatment of a neurodegenerative disease, a disease linked to a defect in neurogenesis, a mental disorder e.g. bipolar disorders or 5 schizophrenia, a retinal dysfunction e.g. retinopathy, a retinal dystrophy or an age-related macular degeneration, a retinoblastoma or a central nervous system tumor, e.g. glioblastoma, neuroblastoma or astrocytoma. 18.A compound of formula (I), (II), (Ia) or (IIa) or a salt or solvate of any one of10 claims 1-11 or 15-16 or a pharmaceutical composition of claim 12 or a salt orsolvate thereof for use in the prevention and / or treatment of aneurodegenerative disease caused by and / or associated with insufficient TLX activity.15 19.A compound of formula (I), (II), (Ia) or (IIa) or a salt or solvate of any one ofclaims 1-11 or 15-16 or a pharmaceutical composition of claim 12 for use in theprevention and / or treatment of a disease selected from Morbus Alzheimer, Morbus Parkinson, dementia, multiple sclerosis, amyotrophic lateral sclerosis or Huntington’s disease.2020.A compound of formula (I), (II), (Ia) or (IIa) or a salt or solvate of any one ofclaims 1-11 or 15-16 or a pharmaceutical composition of claim 12 for use of anyone of claims 13-19 as a monotherapy or as a combination therapy with at leastone further medicament.2521.A method of preventing and / or treating a disease caused by and / or associatedwith insufficient TLX activity comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (Ia) or (IIa). 30

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