Nurr1 modulators

Abstract

The present invention relates to novel imidazopyridine compounds as modulators of the transcription factor Nuclear receptor related 1 (Nurr1, NR4A2) and related NR4A receptors in medicine, particularly in the prevention and / or treatment of a degenerative and / or inflammatory disease.

Description

[0001] Nurr1 modulators Specification The present invention relates to novel imidazopyridine compounds as modulators of the transcription factor Nuclear receptor related 1 (Nurr1, NR4A2) and related NR4A receptors in medicine, particularly in the prevention and / or treatment of a degenerative disease or an inflammatory disease and / or a hyperproliferative disease such as cancer. BACKGROUND Nurr1 is a ligand-activated transcription factor mainly expressed in neurons and immune cells of the brain1-3. The receptor is critically involved in the regulation of (dopaminergic) neuron development and maintenance as well as inflammatory processes3-6. Observations of diminished Nurr1 levels in patients7and animal models8-10of Alzheimer's (AD) and Parkinson's disease (PD) underline therapeutic potential of Nurr1 modulation in neurodegenerative diseases. Moreover, recent findings suggest a protective and anti-inflammatory role of Nurr1 in retinal pigment epithelial cells in the eye with possible therapeutic relevance in age-related macular degeneration11. Pharmacological modulation of Nurr1 activity may therefore offer new therapeutic options in various degenerative diseases and potent Nurr1 modulators are needed12. Nurr1 acts as a monomer, homodimer or heterodimer and has constitutive transcriptional activator activity also in absence of ligands but can be modulated by agonists and inverse agonists in a bidirectional fashion13-15. The dopamine metabolite 5,6-dihydroxyindole (DHI)16, poly-unsaturated fatty acids17and the prostaglandins A and E18have been identified as natural Nurr1 ligands. A few synthetic Nurr1 ligand chemotypes have been recently identified19-23among which the antimalarial amodiaquine (AQ, 1; EC50~20 µM)24was the first validated Nurr1 agonist and emerged as a valuable early tool to study therapeutic effects of Nurr1 activation. AQ treatment counteracted neuroinflammation and ameliorated behavioral deficits in a PD model24and reduced neuronal loss and amyloid beta deposition in an AD model25. Structural optimization efforts have recently yielded the AQ descendant 2 which exhibits improved Nurr1 agonist potency and mediated protective effects in a PD model26. These promising observations suggest Nurr1 ligands derived from AQ (1) as attractive tools and eventually drug candidates (Fig. 1). We have previously discovered that AQ (1) can be simplified to its fragment-like 7-chloroquinolin-4-amine (3) substructure without fully losingNurr1 agonism (EC50259 µM) 27. Notably, the Nurr1 agonism of the fragment 3 could be tunedby minor structural modifications to the substantially more potent Nurr1 agonist 8-chloro-2- methylquinolin-4-amine (4, EC5017 µM)27. Additionally, we identified a 5-(4-chlorophenyl) furan-2-carboxamide motif (5, EC50 3.0 µM)28as a replacement for the unfavorable 4- aminophenol residue of AQ (1). Compounds (1) – (5) are depicted in the following Chart 1: It was an object of the present invention to provide novel and more active NR4A modulators, e.g., Nurr1 modulators. SUMMARY OF THE INVENTION A first aspect of the present invention relates to a compound of formula (I) or a salt or solvate thereof: wherein R1is selected from -H, -OH, -C1-C4 alkyl optionally substituted, -C2- C4alkenyl optionally substituted, -C2-C4alkynyl optionallysubstituted, -C3-C8cycloalkyl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4 alkynyl optionally substituted, -OC3-C8 cycloalkyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, heteroaryl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted or -O-heteroaryl optionally substituted; R2is selected from halo, -C1-C4alkyl optionally substituted, -C2-C4alkenyl optionally substituted, C2-C4alkynyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, -heteroaryl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted, or -O-heteroaryl optionally substituted; R3is selected from H or -CH3 optionally substituted; R4is selected from H, -CH3 optionally substituted or -R5, R5is -Y-A-R6; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene, R6is selected from aryl, e.g., phenyl or naphthyl, heteroaryl, -C3-C8 cycloalkyl, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, wherein each of said residues is optionally substituted with -R7, -OR8, - NR9R10and / or halo; R7is selected from -H, halo, -C1-C6 alkyl optionally substituted, -C2- C6alkenyl optionally substituted, -C2-C6alkynyl optionallysubstituted, or -C3-C8cycloalkyl optionally substituted; R8is selected from H, C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted; and R9and R10are independently selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system. In particular embodiments, R5is wherein X is selected from O, S or NR11, R11is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8 cycloalkyl optionally substituted, and Y and R6are as herein defined above. A further aspect of the present invention relates to a compound of formula (Ia) or a salt or solvate thereof: wherein R1is selected from -H, -OH, -C1-C4alkyl optionally substituted, -C2- C4alkenyl optionally substituted, -C2-C4alkynyl optionally substituted, -C3-C8 cycloalkyl optionally substituted, -OC1-C4 alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, aryl, e.g., phenyl or naphthyl optionally substituted, heteroaryl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted or -O-heteroaryl optionally substituted; R2is selected from halo, -C1-C4alkyl optionally substituted, -C2-C4alkenyl optionally substituted, C2-C4alkynyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, -heteroaryl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted, or -O-heteroaryl optionally substituted; R3is selected from H or -CH3optionally substituted; R4is -R5; R5is -Y-A-R6; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene; R6is selected from aryl, e.g., phenyl or naphthyl, heteroaryl, -C3-C8 cycloalkyl, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, wherein each of said residues is optionally substituted with -R7, -OR8, - NR9R10and / or halo;R7 is selected from -H, halo, -C1-C6alkyl optionally substituted, -C2- C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted, or -C3-C8cycloalkyl optionally substituted; R8is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted; and C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system, and R9and R10are independently selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system. A further aspect of the present invention relates to a compound of formula (Ib) or a salt or solvate thereof: wherein R1is CH3 optionally substituted; R2is Cl; R3is selected from H or -CH3 optionally substituted; R4is selected from H or -CH3 optionally substituted or -R5; R5is -Y-A-R6; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene, R6is selected from aryl, e.g., phenyl or naphthyl, heteroaryl, -C3-C8cycloalkyl, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, wherein each of said residues is optionally substituted with -R7, -OR8, - NR9R10and / or halo; R7is selected from -H, halo, -C1-C6alkyl optionally substituted, -C2- C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted, or -C3-C8cycloalkyl optionally substituted; R8is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted or C3-C8 cycloalkyl optionally substituted; and R9and R10are independently selected from H, C1-C6alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted or C3-C8 cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in medicine, e.g., in human or veterinary medicine. A further aspect of the present invention relates to a pharmaceutical composition comprising the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof as an active agent and a pharmaceutically acceptable carrier. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in in the prevention and / or treatment of a disease caused by and / or associated with insufficient NR4A activity. The term “insufficient NR4A activity” particularly relates to “insufficient Nurr1 activity”. In some embodiments, however, the term “insufficient NR4A activity” relates to insufficient activity of related NR4A receptors including “insufficient Nurr77 / NR4A1 activity” and / or insufficient “NOR1 / NR4A3 activity”. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in in the prevention and / or treatment of a disease caused by and / or associated with insufficient NR4A activity, e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in in the prevention and / or treatment of a degenerative disease, an inflammatory disease and / or a hyperproliferative disease such as cancer. A further aspect relates to a method of preventing and / or treating a disease caused by and / or associated with insufficient NR4A activity, e.g., insufficient Nurr1 activity comprising administering to a subject, e.g., a human subject, in need thereof an effective amount of a compound of formula (I), (Ia) or (Ib). A further aspect relates to method of preventing and / or treating a degenerative disease, an inflammatory disease and / or a hyperproliferative disease such as cancer comprising administering to a subject, e.g., a human subject, in need thereof an effective amount of a compound of formula (I), (Ia) or (Ib). DETAILED DESCRIPTION The present invention relates to a novel class of NR4A modulators, e.g., Nurr1 modulators, with substantially enhanced potency. These compounds are useful as medicaments and high- quality chemical tools. In certain embodiments, the compounds are universal NR4A modulators, i.e., they modulate Nurr1 activity and further modulate Nur77 / NR4A1 activity and / or NOR1 / NR4A3 activity. In further embodiments, the compounds are selective Nurr1 modulators, i.e., they modulate Nurr1 activity and do not modulate Nur77 / NR4A1 activity and NOR1 / NR4A3 activity. In certain embodiments, the compounds are NR4A agonists, e.g., Nurr1 agonists, i.e. the compounds are activators of an NR4A receptor, e.g., Nurr1. Activation of an NR4A receptor, e.g., Nurr1 may be determined quantitatively in a Gal4-NR4A hybrid reporter assay, e.g., a Gal4-Nurr1 hybrid reporter assay, in a reporter gene assay for a full-length NR4A, e.g., Nurr1 and the respective response elements, e.g., NurRE, NBRE and DR5, or by evaluation of NR4A-regulated gene expression, e.g., Nurr1-regulated gene expression by qPCR as described herein. In certain embodiments, a compound of the present invention has an EC50for Nurr1 activation of about 10 µM or less, particularly 1 µM or less, more particularly of about 0.5 µM or less and even more particularly of about 0.01 µM or less. In certain embodiments, the compound is a universal NR4A agonist having an EC50for Nurr1 activation, Nur77 / NR4A1 activation and NOR1 / NR4A3 activation of about 10 µM or less, particularly 1 µM or less, more particularly of about 0.5 µM or less. In particular embodiments, a compound of the present invention selectively activates a Nurr1 dimer, e.g., a Nurr1 homodimer and a Nurr1-RXR heterodimer but is inactive on a Nurr1 monomer. In further embodiments, the compounds are inverse NR4A agonists, e.g., inverse Nurr1 agonists, i.e. the compounds are inhibitors of NR4A activity, e.g.,. inhibitors of Nurr1 activity. Inhibition of an NR4A receptor, e.g., Nurr1, may be determined quantitatively in a Gal4-NR4A hybrid reporter assay, e.g., in a Gal4-Nurr1 hybrid reporter assay or in a reporter gene assay for a full-length NR4A, e.g., full-length Nurr1 and the respective response elements, e.g., NurRE, NBRE and DR5 or by evaluation of NR4A-regulated gene expression, e.g., Nurr1- regulated gene expression by qPCR as described herein. In further embodiments, a compound of the present invention has an IC50 for Nurr1 inhibition of about 10 µM or less, particularly 1 µM or less, more particularly of about 0.5 µM or less and even more particularly of about 0.01 µM or less. In certain embodiments, the compound is an inverse universal NR4A agonist having an for Nurr1 inhibition, and an IC50 for Nur77 / NR4A1 inhibition and / or NOR1 / NR4A3 inhibition of about 10 µM or less, particularly 1 µM or less, more particularly of about 0.5 µM or less. The present invention relates to compounds of formula (I), (Ia) or (Ib) and salts or solvates thereof: as described herein. The definitions of atoms in the compounds of formula (I), (Ia) or (Ib) encompasses all possible isotopes including stable and unstable isotopes. For example, the term “H” encompasses hydrogen isotopes including deuterium. In individual residues of compounds of formula (I), (Ia) or (Ib) the following general definitions apply: The term “optionally substituted” includes “unsubstituted” and “substituted”, e.g., “mono- and polysubstituted”. The term “substituted” means that a H atom is replaced by an atom or moiety different from H. For example, the term “CH3optionally substituted” means that at least one H atom of a CH3 residue may be replaced by an atom or moiety different from H. The terms “alkyl”, “alkenyl” and “alkynyl” include linear and branched alkyl, alkenyl and alkynyl residues which are optionally substituted. The term “cyclic system” relates to mono- or polycyclic ring system, particularly a 3- to 8- membered ring, e.g., a saturated, unsaturated, spiro- or aromatic ring which is optionally substituted. Preferred substituents of ring systems include -OH, halo, -C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted, -C3-C8 cycloalkyl optionally substituted, -OC1-C6 alkyl optionally substituted, -OC2-C6 alkenyl optionally substituted, -OC2-C6 alkynyl optionally substituted, -OC3-C8 cycloalkyl optionally substituted, -NH2, -NH(C1-C4 alkyl), N(C1-C4 alkyl)2 or deuterium. Preferred substituents of alkyl, alkenyl and alkynyl residues include -OH, halo, -O(C1-C4 alkyl), -NH2,-NH(C1-C4alkyl), -N(C1-C4alkyl)2, and deuterium. The term “aryl” includes 6-14 membered mono- or polycyclic and at least partially aromatic residues, e.g., phenyl or naphthyl residues, which are optionally substituted. Preferred substituents of aryl, e.g., phenyl or naphthyl, include -OH, halo, -C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC1-C6 alkyl optionally substituted, -OC2-C6 alkenyl optionally substituted, -OC2-C6alkynyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, -NH2, -NH(C1-C4alkyl), N(C1-C4alkyl)2or deuterium. The term “heteroaryl” includes 5-14 membered mono- or polycyclic and at least partially heteroaromatic residues, and particularly 5- or 6-membered heteroaromatic residues, e.g., heteroaromatic residues comprising at least one N-, O- or S- atom in the ring which are optionally substituted. In certain embodiments, heteroaryl is furyl. Preferred substituents of heteroaryl include -OH, halo, -C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC1- C6alkyl optionally substituted, -OC2-C6alkenyl optionally substituted, -OC2-C6alkynyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, -NH2, -NH(C1-C4alkyl), N(C1- C4alkyl)2or deuterium. The term “cycloalkyl” includes 3- to 8-membered cyclic non-aromatic and particularly saturated rings which are optionally substituted. Preferred substituents of cycloalkyl include -OH, halo, - C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted, -C3-C8 cycloalkyl optionally substituted, -OC1-C6 alkyl optionally substituted, -OC2-C6alkenyl optionally substituted, -OC2-C6alkynyl optionally substituted, - OC3-C8 cycloalkyl optionally substituted, -NH2, -NH(C1-C4 alkyl), N(C1-C4 alkyl)2 or deuterium. The term “halo” as used herein includes -F, -Cl, -Br and -I if not indicated differently. In certain embodiments, R1is selected from -H, -OH, -CH3 optionally substituted with -OH and / or halo, -OCH3 optionally substituted with -OH and / or halo, phenyl or heteroaryl optionally substituted with -OH, halo, -NH2, -NH(alkyl), N(alkyl)2, and / or -CH3 optionally halogenated, and -O-phenyl or -O-heteroaryl optionally substituted with -OH, halo, -NH2, -NH(alkyl), N(alkyl)2 and / or -CH3 optionally halogenated. In particular embodiments, R1is -CH3, -furyl, -phenyl, -3-methylphenyl, -3- (trifluoromethyl)phenyl, -4-methylphenyl, -4-trifluoromethylphenyl, -2-chlorophenyl, -3- chlorophenyl, -4-chlorophenyl, -3,4-dimethylphenyl, -3,4-dichlorophenyl or -isopropyl. In more particular embodiments, R1is -CH3.In certain embodiments, R2 is halo. In particular embodiments, R2 is -Cl.In certain embodiments, R3is selected from -H or -CH3, optionally substituted with halo. In particular embodiments,R3is H.In certain embodiments, R4is H, -CH3optionally substituted with halo, or -R5. In certain embodiments, R4is -R5which is a group -Y-A-R6. A is a 5-, 6-, 7- or 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S. A may be a saturated, unsaturated or aromatic monocyclic, bicyclic or spiro ring system, particularly a monocyclic ring system and more particularly an aromatic or heteroaromatic monocyclic ring system. In particular embodiments, R3is H and R4is -R5. In certain embodiments, Y is C(O)-. In certain embodiments, A is a heterocyclic ring system, particularly a 5-membered heterocyclic ring system and more particularly a 5-membered heterocyclic ring system comprising at least one hetero ring atom which is O. In particular embodiments, R5is , wherein X is selected from O, S or NR11. In more particular embodiments, X is O. In even more particular embodiments, -R5is . In certain embodiments, R6is aryl, e.g., phenyl or naphthyl, or heteroaryl optionally substituted.In certain embodiments, R6 is phenyl substituted at position 4 (p-position) relative to theposition of attachment to the basic structure. In certain embodiments, R6is phenyl or naphthyl unsubstituted or substituted with -R7, -OR8, - NR9R10and / or halo, particularly Cl. In even more particular embodiments, R6is phenyl or naphthyl substituted with -NR9R10or Cl. In certain embodiments, R7is -H, halo, particularly -Cl, -C1-C6alkyl or cycloalkyl, particularly - C1-C5alkyl, and more particularly -CH3optionally substituted with halo, particularly F. In particular embodiments, R7is H, -CH3or -CF3. In certain embodiments, R8is H, -C1-C6alkyl, particularly -C1-C3alkyl, and more particularly - CH3optionally substituted with halo, particularly F. In particular embodiments, R8is -CH3or - CF3. In certain embodiments, R9and R10are independently selected from H, -C1-C6alkyl and -C3- C8cycloalkyl, particularly -C1-C3alkyl, and more particularly -CH3optionally substituted with halo CH3or R9and R10form a cyclic system. In particular embodiments, R9and R10are independently selected from -H and -CH3. In even more particular embodiments, R9and R10are -CH3 or R9and R10form a 5-membered ring. Particularly preferred compounds of formula (I), (Ia) or (Ib) are or salts or solvates thereof. The present invention also encompasses salts of the compounds of formula (I), (Ia) or (Ib), in particular pharmaceutically acceptable salts. The compounds of the present invention are capable of forming acid and / or base salts by means of the presence of basic and / or acidic groups. 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. 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. Also included are solvates, e.g. hydrates, of the compounds of formula (I), (Ia) or (Ib) and solvates of their salts. A further aspect of the present invention relates to the use of a compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in medicine, e.g., in human or veterinary medicine. The compounds of formula (I) may be administered to a subject, e.g., a human subject, in need thereof for preventing a disease (particularly to a subject being at risk of acquiring a disease) or for treating a disease (particularly to a subject already suffering from a disease). A further aspect of the present invention relates to a pharmaceutical composition comprising the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof as an active agent and a pharmaceutically acceptable carrier. 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, by 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 is administered in a therapeutically effective dose which may be determined by the skilled practitioner based on the subject and the disorder to be treated. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of a disease caused by and / or associated with insufficient NR4A activity, e.g., Nurr1 activity. The term “insufficient NR4A activity e.g., Nurr1 activity” is understood that the disease may be prevented, ameliorated and / or cured by increasing the NR4A activity, e.g., the Nurr1 activity, in a subject in need thereof, e.g., a human subject. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of a degenerative disease, an inflammatory disease and / or a hyperproliferative disease such as cancer, e.g., a degenerative disease, an inflammatory disease, and / or a hyperproliferative disease such as cancer caused by and / or associated with insufficient NR4A activity, e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of a neurodegenerative disease caused by and / or associated with insufficient NR4A activity , e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of an ocular disease caused by and / or associated with insufficient NR4A activity , e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of a gastro-intestinal disease caused by and / or associated with insufficient NR4A activity , e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of cancer caused by and / or associated with insufficient NR4A activity , e.g., insufficient Nurr1 activity. A further aspect of the present invention relates to the use of the compound of formula (I), (Ia) or (Ib) or a salt or solvate thereof in the prevention and / or treatment of a disease selected from Morbus Alzheimer including memory loss and / or neuroinflammation associated with Alzheimer, Morbus Parkinson including familial Parkinson, dementia, multiple sclerosis, progressive supranuclear palsy (PSP), stroke including ischemic stroke, schizophrenia including dysfunction in auditory working memory in schizophrenic patients and multiple schizophrenia, depression including manic depression, anxiety disorder, psychosis including hallucinations, neuroinflammation, brain aging, ADHD particularly in male patients, circadian rhythm disorder, obesity, inflammation associated with metabolic syndrome, chronic inflammation and / or insulin resistance in patients with type 2 diabetes, alcohol dependence, rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, macular degeneration including age-related macular degeneration, cancer including gastric cancer, B-cell lymphoma, e.g., diffuse large B-cell lymphoma, cholangiocarcinoma, pheochromocytoma, paraganglioma, skin cutaneous melanoma, bladder urothelial carcinoma, ovarian serous cystadenocarcinoma, kidney renal papillary cell carcinoma, kidney renal clear cell carcinoma, adrenocortical carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, thymoma, glioblastoma multiforme, glioma, e.g., brain lower grade glioma, head and neck squamous cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma., lung squamous cell carcinoma, mesothelioma, prostate adenocarcinoma, sarcoma, testicular germ cell tumor and thyroid carcinoma, and increased sensitivity to chemotherapeutics. A further aspect relates to method of preventing and / or treating a degenerative or inflammatory disease comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (Ia) or (Ib). A compound of formula (I) may be administered as a monotherapy or as a combination therapy, i.e., in combination with at least one further medicament different from a compound of formula (I), (Ia) or (Ib), particularly at least one further medicament suitable for the treatment of a degenerative and / or inflammatory disease as described above. More particularly a compound of formula (I), (Ia) or (Ib) may be used in combination therapy with levodopa, benserazide, opicapone, entacapone, tolcapone, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, safinamide, selegiline, rasagiline, lisuride, amantadine, donzepezil, rivastigmine, galantamine, memantine, glucocorticoids, glatiramer acetate, interferon beta, teriflunomide, dimethyl fumarate, fingolimod, ozanimod, ofatumumab, alemtuzumab, ocrelizumab, azathioprine, or methotrexate. Further, the compounds of formula (I) (Ia) or (Ib) are also useful for non-medical applications, e.g., in the fields of basic research, diagnostics and / or drug screening. The compounds of formula (I) (Ia) or (Ib) may be prepared by synthesis procedures as described herein. Compounds 7, 8, 12 and 14-24 were prepared by a Groebke-Blackburn reaction according to Scheme 1.3-Chloropyridin-2-amine (39) and 4-chloropyridin-2-amine (40) were cyclized with the aldehydes 41-53 and 1,1,3,3-tetramethylbutylisocyanide followed by acid-mediated cleavage to 7, 8 and 14-24 using 4 N HCl in dioxane or TFA / CH2Cl2 (1:1). 1,1,3,3- Tetramethylbutylisocyanide 59 was commercially available. 3-Amino-8-chloroimidazo[1,2- a]pyridine 12 was prepared by nitration of 8-chloroimidazo[1,2-a]pyridine 60 followed by reduction with iron. Scheme 1. Synthesis of 7, 8, 12, 14-24, 26 and 27.a a: Reagents & Conditions: (a) AcOH, MeOH, rt, 24-48 h; (b) TFA / DCM, rt, 30 min to overnight, 3-30% over two steps; (c) nitric acid, sulfuric acid, 0°C – rt, 1 h, 93%; (d) iron, ammonium chloride, MeOH / water, reflux, overnight, 57%. Compounds 26-36 were obtained by amide coupling of 3-amino-8-chloro-2-methylimidazo[1,2- a]pyridine (8) and the carboxylic acids 68-77 using HATU or thionyl chloride (Scheme 2). The carboxylic acids 68 and 69 were prepared by Suzuki coupling of aryl bromide 63 with the boronates 64, 65 to 66, 67 followed by alkaline ester hydrolysis. 70-77 were commercially available. Scheme 2. Synthesis of 26-36.aa: Reagents & Conditions: (a) XPhos Pd G2, K3PO4, water / dioxane, reflux, overnight, 86- 97%; (b) LiOH, water / THF, rt, overnight, 67-73%; (c) HATU, DIPEA, DMF, rt, overnight, 33- 100% or SOCl2, CHCl3 reflux, 3 h, 11%. Scheme 3: Synthesis of 90-158a. Compounds 90-158 were synthesized as described in Scheme 3. a: Reagents and conditions were as follows: (a) HATU, DIPEA, DMF, rt, overnight, 61%; (b) Pd(PPh3)4, Na2CO3, water / dioxane, reflux, overnight, 21-77%; (c) F3CCOOH, DMF, rt, 2 h, 89%.

[0002] 220004PWO In the following, the present invention shall be explained in more detail by the Figures and Examples. FIGURE LEGENDS Figure 1. Orthogonal validation of 8 (a), 24 (b) and 26 (c) as direct Nurr1 ligands by isothermal titration calorimetry (ITC). The fittings of the heat of binding are shown and the isotherms at 25°C are shown as insets. Figure 2. Orthogonal validation and profiling of 36. (a) 36 robustly activated the human full- length Nurr1 homodimer (NurRE) but not the monomer (NBRE). Data are the mean ± S.E.M. fold activation vs. DMSO ctrl; n≥3. (b) 36 activated the Nurr1-RXR heterodimer (DR5) and synergized with bexarotene (0.1 µM). Data are the mean ± S.E.M. fold activation vs. DMSO ctrl or vs.0.1 µM BEX; n≥3. (c) ITC confirmed binding of 36 to the Nurr1 LBD (Kd0.17 µM, n=1.0). The fitting of the heat of binding is shown and the isotherm at 25°C is shown as inset. (d) Effects of 36 on the expression of the Nurr1-regulated tyrosine hydroxylase (TH), vesicular amino acid transporter 2 (VMAT2) and superoxide dismutase 2 (SOD2) in astrocytes (T98G). 29 had no effect. Data are the mean ± S.E.M. fold mRNA induction vs. DMSO control; n=3;#p<0.1, * p<0.05 (t-test vs. DMSO ctrl). (e) Selectivity screening of 36 revealed no off-target activity on nuclear receptors. Heatmap shows the mean relative activation compared to reference ligands (listed in methods section); n=3. EXAMPLES 1. Experimental 1.1 Chemistry General. All chemicals were of reagent grade, purchased from commercial sources (e.g., Sigma-Aldrich, TCI, BLDpharm) and used without further purification unless otherwise specified. All reactions were conducted under nitrogen or argon atmosphere and in absolute solvents purchased from Sigma-Aldrich. Other solvents, especially for work-up procedures, were of reagent grade or purified by distillation (cyclohexane, ethyl acetate, EtOH). Reactions were monitored by thin layer chromatography (TLC) on TLC Silica gel 60 F254 coated aluminum sheets by Merck and visualized under ultraviolet light (254 nm) or by using ninhydrin or Ehrlichs reagent stains. Purification by column chromatography was performed on a puriFlash® XS520Plus system (Advion, Ithaca, NY, USA) using high performance spherical silica columns (SIHP, 50 µM) by Interchim and a gradient of i-hexane or cyclohexane to ethyl acetate, Reversed-phase column chromatography was performed on a puriFlash® 5.250 system (Advion) using C18HP columns (SIHP, 15 µM) by Interchim and a gradient of H2O with 10% MeCN to 100% MeCN (HPLC gradient grade). Mass spectra were obtained on a puriFlash®-CMS system (Advion) using atmospheric pressure chemical ionization (APCI). HRMS were obtained with a Thermo Finnigan LTQ FT instrument for electron impact ionization (EI) or electrospray ionization (ESI). NMR spectra were recorded on Bruker Avance III HD 400 MHz or 500 MHz spectrometers equipped with a CryoProbeTM Prodigy broadband probe (Bruker).Chemical shifts are reported in δ values (ppm), coupling constants (J) in hertz (Hz). The purity of the compounds was determined by 1H NMR (qHNMR) according to the method described by Pauli et al.1 with internal calibration. To ensure accurate determination of peak area ratio, the qHNMR measurements were conducted under conditions allowing for complete relaxation. Ethyl 4- (dimethylamino)benzoate (LOT#BCCC6657, purity 99.63%), dimethyl terephthalate (LOT#BCBT9974, purity 99.95%) and maleic acid (LOT#BCBM8127V, purity 99.94%) were used as internal standards in MeOD-d4, DMSO-d6, or acetone-d6. All compounds for biological testing had a purity >95% according to quantitative NMR. General procedure A for Groebke-Blackburn-Bienaymé reaction and hydrolysis. 2-Amino-3- chloropyridine (39, 1.0 eq.) or 2-amino-4-chloropyridine (40, 1.0 eq.), aldehyde (41-53, 1.0-1.1 eq.) and glacial acetic acid (1.5 eq.) were dissolved in dry methanol (0.7 M) under nitrogen atmosphere. The mixture was stirred for 30 – 45 min. at room temperature (rt) for imine formation.1,1,3,3-tetramethylbutylisocyanide (59, 1.5 eq.) was subsequently added, and the mixture was stirred at rt for 17-48 h. When TLC monitoring indicated completion, the isocyanide was quenched by addition of 2 N HCl (2 mL) and further stirring for 30 min.2 N NaOH and ethyl acetate (10 mL) were then added, and the phases were separated. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was dissolved in a mixture of CH2Cl2 and trifluoroacetic acid (10 mL, 1:1) or 4N HCl in dioxane (10 mL) and the mixture was stirred for 30-60 min. at rt. When TLC monitoring indicated completion, 2 N NaOH was added, phases were separated, and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over MgSO4 and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of iso-hexane or cyclohexane / ethyl acetate as mobile phase, and potentially by reverse phase chromatography using a gradient of H2O with 10% MeCN to 100% MeCN (HPLC gradient grade). General procedure B for amide coupling with HATU. The corresponding carboxylic acid (68- 76, 1.2 eq.) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.2 eq.) were dissolved in DMF (0.13 M). Ethyldiisopropylamine (DIPEA, 0.13 M, 1.2 eq) was added and the mixture was stirred at rt for 40 min. The corresponding 3-aminoimidazo[1,2-a]pyridine (8, 1.0 eq.) was dissolved in DMF (0.11 M) and added to the activated carboxylic acid. The mixture was stirred at rt overnight. When TLC monitoring indicated completion, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and treated with 5% HCl (0.13 M). Phases were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with 1 N NaOH and dried over MgSO4. The solvents were evaporated under reduced pressure and the crude product was purified by flash chromatography using a gradient of iso-hexane / ethyl acetate as mobile phase, and potentially by reverse phase chromatography using a gradient of H2O with 10% MeCN to 100% MeCN (HPLC gradient grade). General procedure C for Suzuki reaction. The respective boronic acid or pinacol ester (1.0 eq), 5-bromo-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (1.00 eq) and sodium carbonate (3.00 eq) were dissolved in dioxane / H2O (0.017 M, 9:1). The solution was degassed by freeze-pump-thaw cycles (3x). Pd(PPh3)4(0.05 eq) was added and the mixture was refluxed for 3 h under argon atmosphere. The resulting suspension was filtered through Celite, and the solvents were removed under reduced pressure. The residue was dissolved in 2 N aqueous NaOH solution and extracted with ethyl acetate (3x). The combined organic layers were dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography and reverse column chromatography using a gradient of H2O with 10% MeCN to 100% MeCN (HPLC gradient grade). 8-Chloro-2-methylimidazo[1,2-a]pyridine-3-amine (8). Preparation according to general procedure A, using 2-amino-3-chloropyridine (39, 821 mg, 6.39 mmol, 1.00 eq) and acetaldehyde (41, 39 µL, 7.03 mmol, 1.10 eq).8 was obtained as a colorless solid (344 mg, 30%).1H-NMR (400 MHz, acetone-d6): δ = 8.05 (dd, J = 6.8, 1.1 Hz, 1H), 7.11 (dd, J = 7.3, 1.0 Hz, 1H), 6.76 (t, J = 7.0 Hz, 1H), 4.17 (s, 2H), 2.33 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 136.11, 130.11, 126.33, 121.50, 121.00, 119.83, 110.01, 11.89. MS (APCI+): m / z 181.9 ([M+H]+). HRMS (EI+): m / z calculated 181.0407 for C8H8ClN3, found 181.0400 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 97.5%. 8-Chloro-2-(3,4-dichlorophenyl)imidazo[1,2-a]pyridine-3-amine (24). Preparation according to general procedure A, using 2-amino-4-chlorpyridine (39, 1.29 g, 10.0 mmol, 1.00 eq) and 3,4- dichlorobenzaldehyde (52, 1.93 g, 11.0 mmol, 1.01 eq).24 was obtained as a yellow solid (197 mg, 6%).1H-NMR (400 MHz, acetone-d6): δ = 8.41 – 8.35 (m, 1H), 8.30 – 8.23 (m, 1H), 8.20 – 8.12 (m, 1H), 7.63 – 7.56 (m, 1H), 7.27 (dd, J = 7.3, 1.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 4.83 (s, 2H).13C-NMR (101 MHz, MeOD-d4): δ = 137.16, 134.44, 132.08, 130.14, 130.03, 128.55, 127.99, 127.52, 126.32, 122.59, 121.74, 121.32, 111.34. MS (APCI+): m / z 311.9 ([M+H]+). HRMS (EI+): m / z calculated 310.9784 for C13H8Cl3N3, found 310.9778 ([M]•+). qHNMR (400 MHz, acetone-d6, ethyl-4-(dimethylamino)benzoate as reference) purity = 95.7%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(dimethylamino)phenyl)furan-2- carboxamide (36). Preparation according to general procedure B using 8-chloro-2- methylimidazo[1,2-a]pyridine-3-amine (8, 50 mg, 0.28 mmol, 1.00 eq) and 5-(4- (dimethylamino)phenyl)furan-2-carboxylic acid (69, 76 mg, 0.33 mmol, 1.20 eq). 36 was obtained as a yellow solid (69 mg, 64%).1H-NMR (400 MHz, acetone-d6): δ = 9.68 (s, 1H), 8.11 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.40 – 7.27 (m, 2H), 6.94 – 6.73 (m, 4H), 3.00 (s, 6H), 2.36 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 157.70, 157.19, 151.01, 145.08, 139.07, 138.69, 125.87, 122.80, 122.61, 121.82, 117.98, 117.58, 117.02, 111.99, 110.99, 104.28, 39.38, 12.36. MS (APCI+): m / z 394.7 ([M+H]+). HRMS (EI+): m / z calculated 394.1197 for C21H19ClN4O2, found 394.1194 ([M]•+). qHNMR (400 MHz, acetone-d6, maleic acid as reference) purity = 95.1%. 5-Bromo-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (79). Preparation according to general procedure B using 8-chloro-2-methylimidazol[1,2-a]pyridine- 3-amine (8, 896 mg, 4.93 mmol, 1.00 eq) and 5-bromofuran-2-carboxylic acid (78, 1130 mg, 5.92 mmol, 1.20 eq) yielded compound 79 as a yellow solid (1065 mg, 61 %).1H-NMR (400 MHz, MeOD-d4): δ = 8.00 (d, J = 1.0 Hz, 1H), 7.43 (d, J = 1.0 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 6.73 (d, J = 3.7 Hz, 1H), 2.39 (s, 3H).13C-NMR (101 MHz, MeOD-d4): δ = 157.5, 148.5, 139.5, 138.1, 126.6, 124.2, 122.2, 121.4, 118.5, 116.3, 114.4, 111.9, 11.2. MS (APCI+): m / z 355.4 ([M+H]+). N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(dimethylamino)-3-fluorophenyl)furan-2- carboxamide (90). Preparation according to general procedure C using 5-bromo-N-(8-chloro- 2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (79, 80.0 mg, 226 mmol, 1.00 eq) and 2-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (80, 60.0 mg, 226 mmol, 1.00 eq) yielded compound 90 as a colorless solid (37 mg, 40%).1H-NMR (400 MHz, acetone-d6): δ = 9.79 (s, 1H), 8.13 (dd, J = 6.8, 1.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.41 – 7.31 (m, 2H), 7.07 – 6.96 (m, 2H), 6.88 (t, J = 6.8 Hz, 1H), 2.92 (d, J = 1.2 Hz, 6H), 2.36 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 157.0, 155.6, 154.3 (d, J = 243.0 Hz), 146.0, 141.0 (d, J = 8.5 Hz), 139.1, 138.7, 122.9, 122.6, 121.9, 121.2, 118.1, 117.8, 112.7 (d, J = 24.1 Hz), 111.1, 106.4, 41.6, 12.4. MS (APCI+): m / z 412.6 ([M+H]+). HRMS (ESI+): m / z calculated 412.1102 for C21H18ClFN4O2, found 413.1169 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl- 4(dimethylamino)benzoate as reference): purity = 100%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(dimethylamino)-3-methylphenyl)furan- 2-carboxamide (91). Preparation according to general procedure C using (79) ( 60.0 mg, 169 mmol, 1.00 eq) and (4-(dimethylamino)-3-methylphenyl)boronic acid (81, 30.3 mg, 169 mmol, 1.00 eq) yielded compound 91 as a colorless solid (30 mg, 43%).1H-NMR (400 MHz, acetone- d6): δ = 9.72 (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.77 – 7.67 (m, 2H), 7.38 – 7.33 (m, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 2.73 (s, 6H), 2.37 – 2.33 (m, 6H).13C-NMR (101 MHz, acetone-d6): δ = 157.1, 156.9, 153.7, 145.8, 139.1, 138.8, 131.9, 127.4, 123.5, 123.1, 122.9, 122.6, 121.9, 118.4, 117.8, 116.9, 111.0, 106.1, 43.2, 18.0, 12.4. MS (APCI+): m / z 408.6 ([M+H]+). HRMS (ESI+): m / z calculated 408.1353 for C22H21ClN4O2, found 409.14.19 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 98.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)furan-2-carboxamide (92). Preparation according to general procedure C using (79) (60.0 mg, 169 mmol, 1.00 eq) and 4-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (82, 46.5 mg, 169 mmol, 1.00 eq) yielded compound 92 as a colorless solid (31 mg, 43%).1H-NMR (400 MHz, acetone-d6): δ = 9.74 (s, 1H), 8.16 – 8.06 (m, 1H), 7.42 – 7.31 (m, 2H), 7.34 – 7.23 (m, 2H), 6.90 – 6.81 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 4.33 – 4.25 (m, 2H), 3.40 – 3.34 (m, 2H), 2.95 (s, 3H), 2.36 (s, 3H).13C-NMR (126 MHz, acetone-d6): δ = 157.2, 157.1, 145.3, 144.3, 139.1, 138.7, 137.7, 122.8, 122.6, 121.8, 119.1, 118.5, 117.9, 117.0, 112.0, 111.9, 111.0, 104.9, 64.6, 48.6, 37.6, 12.4. MS (APCI+): m / z 422.5 ([M+H]+). HRMS (ESI+): m / z calculated 422.1146 for C22H19ClN4O3, found 423.1212 ([M+H]+). qHNMR (400 MHz, acetone-d6, maleic acid as reference): purity = 95.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)furan-2-carboxamide (93). Preparation according to general procedure C using (79) (60.0 mg, 169 mmol, 1.00 eq) and 3-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (83, 46.5 mg, 169 mmol, 1.00 eq) yielded compound 93 as an orange solid (15 mg, 21%).1H-NMR (400 MHz, acetone-d6): δ = 9.83 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.94 – 7.84 (m, 2H), 7.43 – 7.29 (m, 3H), 7.12 (d, J = 3.7 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 3.45 (s, 3H), 2.36 (s, 3H).13C-NMR (126 MHz, acetone-d6): δ = 157.0, 155.8, 154.1, 146.3, 143.1, 139.2132.8, 131.9, 128.5, 124.4, 122.9, 122.6, 121.9, 120.8, 117.8, 111.1, 109.0, 107.1, 105.8, 27.7, 12.4. MS (APCI+): m / z 422.4 ([M+H]+). HRMS (ESI+): m / z calculated 422.0782 for C21H15ClN4O4, found 423.0850 ([M+H]+). qHNMR (400 MHz, DMSO-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 96.0%. 5-(Benzo[d][1,3]dioxol-5-yl)-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2- carboxamide (94). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 3,4-Methylenedioxyphenyl boronic acid (84, 33 mg, 0.2 mmol, 1 eq) yielded compound 94 as a yellow solid (49 mg, 62%).1H-NMR (500 MHz, DMSO-d6): δ = 10.44 (s, 1H), 8.10 (d, J = 6.7 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.2, 1.7 Hz, 1H), 7.45 (dd, J = 7.3, 1.0 Hz, 1H), 7.40 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 6.10 (s, 2H), 2.32 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.0, 155.5, 148.0, 147.9, 145.1, 138.4, 137.9, 125.5, 123.2, 123.0, 120.8, 119.0, 118.1, 116.9, 111.4, 108.8, 106.9, 105.1, 101.5, 13.0. HRMS (ESI): m / z calculated 396.0751 for C20H15ClN3O4, found 396.0740 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 98.9%. 5-(Benzofuran-6-yl)-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (95). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 2- (Benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85, 50 mg, 0.2 mmol, 1 eq) yielded compound 95 as a yellow solid (42 mg, 54%).1H-NMR (400 MHz, Chloroform-d): δ = 8.26 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 7.1 Hz, 1H), 6.83-6.81 (m, 2H), 6.79 (t, J = 7.1 Hz, 1H), 2.47 (s, 3H).13C-NMR (101 MHz, Chloroform-d): δ = 157.5, 157.4, 155.3, 146.2, 145.2, 144.4, 139.5, 139.5, 128.1, 124.4, 124.3, 122.3, 121.9, 121.6, 119.3, 117.9, 112.1, 112.1, 107.1, 106.8, 12.8. HRMS (ESI): m / z calculated 392.0802 for C21H15ClN3O3, found 392.0791 ([M+H]+). qHNMR (400 MHz, Chloroform-d, maleic acid as reference): purity = 95.6%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(1-methyl-1H-indol-5-yl)furan-2- carboxamide (96). Preparation according to general procedure C using (79) (60.0 mg, 169 mmol, 1.00 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (86, 43.5 mg, 169 mmol, 1.00 eq) yielded compound 96 as a colorless solid (14 mg, 21%).1H-NMR (400 MHz, acetone-d6): δ = 9.78 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.31 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 6.51 (dd, J = 3.1, 0.9 Hz, 1H), 3.88 (s, 4H), 2.38 (s, 3H).13C- NMR (126 MHz, acetone-d6): δ = 159.0, 157.9, 146.3, 139.8, 139.5, 137.8, 131.3, 129.5, 123.5, 123.3, 122.6, 121.9, 119.3, 118.6, 118.0, 117.7, 111.7, 110.7, 106.2, 102.0, 32.9, 13.1. MS (APCI+): m / z 404.5 ([M+H]+). HRMS (ESI+): m / z calculated 404.1040 for C22H17ClN4O2, found 405.1106 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 97.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(1-methyl-1H-benzo[d]imidazol-5-yl)furan- 2-carboxamide (97). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole (87, 43.6 mg, 0.169 mmol, 1.00 eq) yielded compound 97 as a colorless solid (33 mg, 48 %).1H-NMR (400 MHz, acetone-d6): δ = 9.95 (s, 1H), 8.27 (s, 1H), 8.17 (dd, J = 6.8, 1.0 Hz, 1H), 8.12 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.42 – 7.31 (m, 2H), 7.10 (d, J = 3.6 Hz, 1H), 6.94 – 6.83 (m, 1H), 3.96 (s, 3H), 2.39 (s, 3H).13C-NMR (126 MHz, acetone-d6): δ = 157.3, 157.1, 146.1, 145.6, 144.5, 139.1, 138.7, 135.6, 123.7, 122.8, 122.7, 121.8, 119.7, 117.9, 117.0, 116.1, 111.0, 110.5, 106.4, 30.4, 12.4. MS (APCI+): m / z 405.5 ([M+H]+). HRMS (ESI+): m / z calculated 405.0993 for C21H16ClN5O2, found 406.1059 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 95.0%. 5-(1-Acetylindolin-5-yl)-N-(8-chlor-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (98). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (88, 48.5 mg, 0.169 mmol, 1.00 eq) yielded compound 98 as a colorless solid (47 mg, 64%).1H-NMR (400 MHz, acetone-d6): δ = 9.77 (s, 1H), 8.17 (dd, J = 29.2, 7.6 Hz, 2H), 7.85 – 7.70 (m, 2H), 7.40 – 7.30 (m, 2H), 7.01 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 4.21 (t, J = 8.6 Hz, 2H), 3.26 (t, J = 8.5 Hz, 2H), 2.36 (s, 3H), 2.20 (s, 3H). MS (APCI+): m / z 434.5 ([M+H]+). HRMS (ESI+): m / z calculated 434.1146 for C23H19ClN4O3, found 435.1214 ([M+H]+). N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(quinolin-6-yl)furan-2-carboxamide (99). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and quinolin-6-ylboronic acid (89, 35 mg, 0.2 mmol, 1 eq) yielded compound 99 as a yellow solid (62 mg, 77%).1H-NMR (500 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.38 (dd, J = 8.9, 2.0 Hz, 1H), 8.17 (d, J = 6.7 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.3, 4.2 Hz, 1H), 7.54 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 3.5 Hz, 1H), 6.92 (t, J = 7.1 Hz, 1H), 2.36 (s, 3H);.13C- NMR (126 MHz, DMSO-d6): δ = 157.1, 155.0, 151.1, 147.6, 146.4, 138.5, 138.0, 136.3, 129.8, 128.0, 127.1, 126.1, 123.4, 123.3, 123.0, 122.4, 120.8, 118.0, 116.8, 111.5, 109.3, 13.0. HRMS (ESI): m / z calculated 403.0962 for C22H16ClN4O2, found 403.0950 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 95.2%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(naphthalen-2-yl)furan-2-carboxamide (110). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 2-naphthaleneboronic acid (100, 34 mg, 0.2 mmol, 1 eq) yielded compound 110 as a yellow solid (62 mg, 77%).1H-NMR (400 MHz, acetone-d6): δ = 9.87 (s, 1H), 8.51 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.08 (d, J = 8.5Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.96-7.94 (m, 2H), 7.59- 7.53 (m, 2H), 7.44 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 3.7 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 2.38 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 158.1, 157.3, 147.8, 140.2, 139.9, 134.5, 134.5, 129.8, 129.3, 128.9, 128.1, 127.9, 127.8, 124.6, 124.0, 123.7, 123.4, 122.9, 118.8, 117.8, 112.1, 109.3, 13.4. HRMS (ESI): m / z calculated 402.1009 for C23H17ClN3O2, found 402.0998 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic as reference): purity = 95.7%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-chloronaphthalen-2-yl)furan-2- carboxamide (111). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (6-chloronaphthalen-2-yl)boronic acid (101, 42 mg, 0.2 mmol, 1 eq) yielded compound 111 as a colorless solid (55 mg, 63%).1H-NMR (500 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.59 (s, 1H), 8.19-8.15 (m, 2H), 8.11 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 3.7 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 2.35 (s, 3H).13C-NMR (126 MHz, DMSO- d6): δ = 157.1, 155.3, 146.2, 138.5, 137.9, 133.5, 131.4, 131.3, 130.4, 128.1, 127.6, 127.1, 126.6, 123.8, 123.5, 123.2, 123.1, 120.8, 118.1, 116.9, 111.6, 109.1, 13.0. HRMS (ESI): m / z calculated 436.0620 for C23H16Cl2N3O2, found 436.0583 ([M+H]+). qHNMR (400 MHz, DMSO- d6, maleic acid as reference): purity = 95.4%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-fluoronaphthalen-2-yl)furan-2- carboxamide (112). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (6-fluoronaphthalen-2-yl)boronic acid (102, 39 mg, 0.2 mmol, 1 eq) yielded compound 112 as a colorless solid (58 mg, 69%).1H-NMR (500 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.59 (s, 1H), 8.16 (t, J = 7.5 Hz, 2H), 8.11 – 8.02 (m, 2H), 7.77 (dd, J = 10.1, 2.6 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 3.7 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 2.35 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 160.5 (d, J = 245.1 Hz), 157.1, 155.4, 146.1, 138.5, 138.0, 133.7 (d, J = 9.8 Hz), 131.1 (d, J = 9.4 Hz), 130.1, 128.1 (d, J = 5.3 Hz), 126.2, 123.7, 123.4, 123.3, 123.0, 120.8, 118.0, 117.2 (d, J = 25.5 Hz), 116.8, 111.5, 111.1 (d, J = 20.7 Hz), 108.6, 13.0. MS (APCI+): m / z 420.6 ([M+H]+) HRMS (ESI): m / z calculated 420.0910 for C23H16ClFN3O2, found 420.0895 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 96.8%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-hydroxynaphthalen-2-yl)furan-2- carboxamide (113). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (6-hydroxynaphthalen-2-yl)boronic acid (103, 38 mg, 0.2 mmol, 1 eq) yielded compound 113 as a colorless solid (34 mg, 41%).1H-NMR (500 MHz, DMSO-d6): δ = 10.52 (s, 1H), 8.42 – 8.38 (m, 2H), 8.14 (dd, J = 6.7, 1.0 Hz, 1H), 7.98 (dd, J = 8.5, 1.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.46 (dd, J = 7.3, 1.0 Hz, 1H), 7.24 (d, J = 3.7 Hz, 1H), 7.18 – 7.14 (m, 2H), 6.90 (t, J = 7.0 Hz, 1H), 2.34 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.2, 156.4, 156.3, 145.5, 138.4, 138.0, 134.7, 129.9, 127.4, 126.8, 123.6, 123.4, 123.3, 123.0, 122.8, 120.8, 119.6, 118.1, 117.0, 111.4, 109.0, 107.4, 13.0. MS (APCI+): m / z 418.2 ([M+H]+) HRMS (ESI): m / z calculated 418.0953 for C23H17ClN3O3, found 418.0939 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 97.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-methoxynaphthalen-2-yl)furan-2- carboxamide (114). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (6-methoxynaphthalen-2-yl)boronic acid (104, 42 mg, 0.2 mmol, 1 eq) yielded compound 114 as a colorless solid (20 mg, 23%).1H-NMR (500 MHz, DMSO-d6): δ = 10.54 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.14 (dd, J = 6.7, 1.0 Hz, 1H), 8.06 (dd, J = 8.6, 1.8 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 3.7 Hz, 1H), 7.46 (dd, J = 7.5, 1.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 7.23 (dd, J = 9.0, 2.5 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 3.90 (s, 3H), 2.34 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 158.0, 157.2, 156.0, 145.7, 138.4, 138.0, 134.4, 129.7, 128.3, 127.5, 124.5, 123.3, 123.3, 123.1, 123.0, 120.8, 119.5, 118.1, 116.9, 111.4, 107.8, 106.3, 55.3, 13.0. MS (APCI+): m / z 432.3 ([M+H]+) HRMS (ESI): m / z calculated 432.1109 for C24H19ClN3O3, found 432.1095 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 95.4%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-(hydroxymethyl)naphthalen-2-yl)furan-2- carboxamide (115). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanol (105, 57 mg, 0.2 mmol, 1 eq) yielded compound 115 as a colorless solid (46 mg, 53%).1H- NMR (500 MHz, DMSO-d6): δ = 10.58 (s, 1H), 8.55 – 8.51 (m, 1H), 8.15 (dd, J = 6.7, 1.0 Hz, 1H), 8.09 (dd, J = 8.6, 1.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.56 – 7.49 (m, 2H), 7.46 (dd, J = 7.3, 1.0 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 4.68 (s, 2H), 2.35 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.1, 155.8, 146.0, 141.3, 138.4, 138.0, 132.9, 132.1, 128.5, 128.0, 126.3, 126.2, 124.4, 123.3, 123.2, 123.0, 122.7, 120.8, 118.1, 116.9, 111.4, 108.4, 62.9, 13.0. MS (APCI+): m / z 432.8 ([M+H]+) HRMS (ESI): m / z calculated 432.1109 for C24H19ClN3O3, found 432.1094 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 98.2%. Methyl 6-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)carbamoyl)furan-2-yl)-2-naphthoate (116). Preparation according to general procedure C using (79) (106 mg, 0.3 mmol, 1.00 eq) and (6-(methoxycarbonyl)naphthalen-2-yl)boronic acid (106, 73 mg, 0.3 mmol, 1 eq) yielded compound 116 as a colorless solid (88 mg, 64%).1H-NMR (500 MHz, DMSO-d6): δ = 10.62 (s, 1H), 8.65 (dd, J = 17.3, 1.7 Hz, 2H), 8.27 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (dd, J = 6.8, 0.9 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.04 (dd, J = 8.7, 1.7 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.49 – 7.43 (m, 2H), 6.91 (t, J = 7.1 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H).13C- NMR (126 MHz, DMSO-d6): δ = 166.3, 157.1, 155.1, 146.5, 138.6, 138.1, 135.2, 132.0, 130.5, 130.3, 128.9, 128.8, 127.5, 125.9, 123.5, 123.4, 123.1, 123.0, 120.9, 118.1, 116.8, 111.5, 109.8, 52.4, 13.0. MS (APCI+): m / z 460.3 ([M+H]+) HRMS (ESI): m / z calculated 460.1059 for C25H19ClN3O4, found 460.1044 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 98.6%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-cyanonaphthalen-2-yl)furan-2- carboxamide (117). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthonitrile (107, 59 mg, 0.2 mmol, 1 eq) yielded compound 117 as a colorless solid (25 mg, 30%).1H-NMR (500 MHz, DMSO-d6): δ = 10.65 (s, 1H), 8.68 – 8.64 (m, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.28 (dd, J = 8.6, 1.7 Hz, 1H), 8.22 – 8.13 (m, 3H), 7.85 (dd, J = 8.5, 1.6 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.46 (dd, J = 7.3, 1.0 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 2.35 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.0, 154.7, 146.7, 138.5, 138.0, 134.4, 134.3, 131.7, 129.6, 129.5, 129.4, 127.4, 124.2, 123.3, 123.1, 123.0, 120.9, 119.1, 118.0, 116.8, 111.5, 110.2, 108.8, 13.0. MS (APCI+): m / z 427.6 ([M+H]+) HRMS (ESI): m / z calculated 427.0956 for C24H16ClN4O2, found 427.0938 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 96.3%. tert-Butyl (6-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)carbamoyl)furan-2- yl)naphthalen-2-yl)carbamate (118). Preparation according to general procedure C using (79) (106 mg, 0.3 mmol, 1.00 eq) and tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)carbamate (108, 114 mg, 0.3 mmol, 1 eq) yielded compound 118 as a colorless solid (101 mg, 65%).1H-NMR (500 MHz, DMSO-d6): δ = 10.51 (s, 1H), 9.68 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.17 – 8.11 (m, 2H), 8.03 (dd, J = 8.6, 1.8 Hz, 1H), 7.88 (t, J = 9.4 Hz, 2H), 7.56 (dd, J = 8.9, 2.1 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 2.34 (s, 3H), 1.52 (s, 9H).13C-NMR (126 MHz, DMSO-d6): δ = 157.1, 156.0, 152.8, 145.7, 138.4, 138.1, 138.0, 133.6, 128.9, 128.8, 127.9, 124.8, 123.3, 123.1, 123.0, 123.0, 120.8, 120.4, 118.1, 116.9, 113.4, 111.4, 107.9, 79.4, 28.1, 13.0. MS (APCI+): m / z 517.4 ([M+H]+) HRMS (ESI): m / z calculated 517.1637 for C28H26ClN4O4, found 517.1620 ([M+H]+). N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(6-(methylsulfonamido)naphthalen-2- yl)furan-2-carboxamide (119). Preparation according to general procedure C using (79) 71 mg, 0.2 mmol, 1.00 eq) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2- yl)methanesulfonamide (109, 73 mg, 0.2 mmol, 1 eq) yielded compound 119 as a colorless solid (23 mg, 23%).1H-NMR (500 MHz, DMSO-d6): δ = 10.56 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.14 (dd, J = 6.8, 1.0 Hz, 1H), 8.07 (dd, J = 8.7, 1.8 Hz, 1H), 7.93 (dd, J = 8.9, 2.9 Hz, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.46 (dd, J = 7.3, 1.0 Hz, 1H), 7.40 (dd, J = 8.8, 2.3 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 3.06 (s, 3H), 2.34 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.1, 155.8, 145.8, 138.4, 138.2, 138.0, 133.7, 129.5, 129.3, 127.9, 125.2, 123.3, 123.1, 123.0, 121.5, 120.8, 118.1, 116.9, 114.5, 111.4, 108.1, 13.0. MS (APCI+): m / z 495.7 ([M+H]+) HRMS (ESI): m / z calculated 495.0888 for C24H20ClN4O4S, found 495.0873 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 99.2%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-isopropylphenyl)furan-2-carboxamide (139). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and 4-isopropylphenylboronic acid (120, 27.7 mg, 0.169 mmol, 1.00 eq) yielded compound 139 as a colorless solid (36 mg, 54%).1H-NMR (400 MHz, acetone-d6): δ = 9.78 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.44 – 7.31 (m, 4H), 7.10 – 7.03 (m, 1H), 6.88 (t, J = 7.1 Hz, 1H), 3.02 – 2.93 (m, 1H), 2.36 (s, 3H), 1.27 (dd, J = 7.0, 1.3 Hz, 6H).13C-NMR (126 MHz, acetone-d6): δ = 158.0, 157.4, 150.8, 147.1, 140.0, 139.6, 128.3, 127.8, 125.7, 123.8, 123.5, 122.8, 118.5, 117.7, 111.9, 107.9, 34.7, 24.1, 13.3. MS (APCI+): m / z 393.7 ([M+H]+). HRMS (ESI+): m / z calculated 393.1244 for C22H20ClN3O2, found 394.1312 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 96.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-isopropoxyphenyl)furan-2-carboxamide (140). Preparation according to general procedure C using (79) 60.0 mg, 0.169 mmol, 1.00 eq) and 4-isopropoxyphenylboronic acid (121, 30.4 mg, 169 mmol, 1.00 eq) yielded compound 140 as a colorless solid (47 mg, 68%).1H-NMR (500 MHz, acetone-d6): δ = 9.76 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.39 – 7.32 (m, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.98 – 6.94 (m, 1H), 6.88 (t, J = 7.0 Hz, 1H), 4.77 – 4.66 (m, 1H), 2.36 (s, 3H), 1.35 – 1.30 (m, 6H).13C-NMR (126 MHz, acetone-d6): δ = 158.8, 157.1, 156.6, 145.8, 139.1, 138.7, 126.3, 122.8, 122.6, 122.2, 121.9, 117.8, 116.9, 116.0, 111.0, 105.9, 69.6, 21.3, 12.4. MS (APCI+): m / z 409.7 ([M+H]+). HRMS (ESI+): m / z calculated 409.1193 for C22H20ClN3O3, found 410.1260 ([M+H]+). qHNMR (400 MHz, acetone-d6,ethyl-4(dimethylamino)benzoate as reference): purity = 100%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-cyclopropoxyphenyl)furan-2- carboxamide (141). Preparation according to general procedure C, using (79) 60.0 mg, 0.169 mmol, 1.00 eq) and 4-cyclopropoxyphenylboronic acid (122, 30.1 mg, 169 mmol, 1.00 eq) yielded compound 141 as a colorless solid (45 mg, 65%).1H-NMR (400 MHz, acetone-d6): δ = 9.76 (s, 1H), 8.13 (d, J = 1.0 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.41–7.29 (m, 2H), 7.22–7.09 (m, 2H), 6.98 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 6.8 Hz, 1H), 3.93–3.85 (m, 1H), 2.36 (s, 3H), 0.89–0.67 (m, 4H).13C-NMR (126 MHz, acetone-d6): δ = 159.8, 157.1, 156.5, 145.9, 139.1, 138.7, 126.1, 122.9, 122.8, 122.6, 121.9, 117.8, 116.9, 115.4, 111.0, 106.0, 50.8, 12.4, 5.7. MS (APCI+): m / z 407.7 ([M+H]+). HRMS (ESI+): m / z calculated 408.1109 for C22H19ClN3O3+, found 408.1103 ([M+H]+). qHNMR (400 MHz, acetone-d6,ethyl-4(dimethylamino)benzoate as reference): purity = 97.5%. Methyl 4-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)carbamoyl)furan-2-yl)benzoate (142). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 4-methoxycarbonylphenylboronic acid (123, 37 mg, 0.2 mmol, 1 eq) yielded compound 142 as a yellow solid (43 mg, 53%).1H-NMR (500 MHz, DMSO-d6): δ = 10.62 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 8.13 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.51-7.50 (m, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 3.7 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 3.88 (s, 3H) 2.33 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 165.8, 156.9, 154.2, 146.7, 138.4, 137.8, 133.2, 129.8, 129.3, 124.7, 123.3, 123.0, 120.8, 118.0, 116.8, 111.5, 110.3, 52.3, 13.0. HRMS (ESI): m / z calculated 410.0908 for C21H17ClN3O4, found 410.0896 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 97.2%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(methylsulfonyl)phenyl)furan-2- carboxamide (143). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 4-(methylsulfonyl)phenylboronic acid (124, 40 mg, 0.2 mmol, 1 eq) yielded compound 143 as a yellow solid (60 mg, 70%).1H-NMR (500 MHz, DMSO-d6): δ = 10.63 (s, 1H), 8.26 (d, J = 8.6 Hz, 2H), 8.14 (dd, J = 6.8, 1.1 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.52-7.48 (m, 2H), 7.46 (dd, J = 7.4, 1.0 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 3.28 (s, 3H), 2.34 (s, 3H).13C- NMR (126 MHz, DMSO-d6): δ = 156.9, 153.7, 147.0, 140.3, 138.5, 137.9, 133.5, 127.8, 125.1, 123.3, 123.1, 120.8, 117.9, 116.7, 111.5, 110.9, 43.4, 13.0. HRMS (ESI): m / z calculated 430.0628 for C20H17ClN3O4S, found 430.0617 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 98.4%. 5-(4-Aminophenyl)-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (144). Preparation according to general procedure C using 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (125, 37 mg, 0.169 mmol, 1.00 eq) and (79) (60.0 mg, 0.169 mmol, 1.00 eq) yielded compound 144 as a yellow solid (25 mg, 40%).1H-NMR (400 MHz, DMSO- d6) δ = 10.30 (s, 1H), 8.07 (d, J = 6.7 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.82 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 8.3 Hz, 2H), 5.54 (s, 2H), 2.31 (s, 3H).13C-NMR (101 MHz, DMSO-d6) δ = 158.0, 157.7, 150.3, 144.4, 138.8, 138.3, 126.5, 123.7, 123.4, 121.3, 118.8, 117.6, 117.3, 114.1, 111.9, 104.4, 13.4. qHNMR (400 MHz, DMSO-d6, maleic acid as reference) purity = 99.1%. HRMS (ESI): m / z calculated 367.0956 for C19H16ClN4O2+, found 367.0956 ([M+H]+). 5-(4-Acetamidophenyl)-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (145). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 4-acetamidophenylboronic acid (126, 37 mg, 0.2 mmol, 1 eq) yielded compound 145 as a yellow solid (70 mg, 86%).1H-NMR (500 MHz, DMSO-d6): δ = 10.42 (s, 1H), 10.12 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 7.3, 0.6 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 2.32 (s, 3H), 2.07 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 168.5, 157.1, 155.7, 145.3, 140.0, 138.4, 137.9, 125.3, 123.9, 123.2, 123.0, 120.8, 119.0, 118.0, 116.9, 111.4, 106.8, 24.1, 13.0. HRMS (ESI): m / z calculated 409.1067 for C21H18ClN4O3, found 409.1057 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 99.3%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(diethylamino)phenyl)furan-2- carboxamide (146). Preparation according to general procedure C using (79) (60.0 mg, 169 mmol, 1.00 eq) and N,N-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (127, 55.8 mg, 203 mmol, 1.20 eq) yielded compound 146 as a colorless solid (35.8 mg, 50%).1H- NMR (400 MHz, acetone-d6): δ = 9.64 (s, 1H), 8.11 (d, J = 1.0 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.39 – 7.28 (m, 2H), 6.87 (t, J = 7.1 Hz, 1H), 6.83 – 6.72 (m, 3H), 3.46 (q, J = 7.1 Hz, 4H), 2.36 (s, 3H), 1.18 (t, J = 7.0 Hz, 6H).13C-NMR (101 MHz, acetone-d6): δ = 158.8, 149.2, 145.8, 140.0, 139.6, 127.1, 123.7, 123.5, 122.7, 121.9, 118.9, 118.1, 117.6, 112.3, 111.9, 104.8, 44.9, 13.3, 12.8. MS (APCI+): m / z 422.4 ([M+H]+). HRMS (ESI-): m / z calculated 422.1510 for C23H23ClN4O2, found 421.3 ([M-H]-). qHNMR (400 MHz, acetone-d6, ethyl- 4(dimethylamino)benzoate as reference): purity = 95.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(methylsulfonamido)phenyl)furan-2- carboxamide (147). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and N-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenylmethanesulfonamide (128, 61 mg, 0.2 mmol, 1 eq) yielded compound 147 as a yellow solid (52 mg, 58%).1H-NMR (500 MHz, acetone-d6): δ = 9.78 (s, 1H), 8.13 (d, J = 6.7 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.38-7.35 (m, 2H), 7.07 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 3.06 (s, 3H), 2.36 (s, 3H);13C-NMR (126 MHz, acetone-d6): δ = 158.0, 156.8, 147.2, 140.2, 140.0, 139.7, 126.7, 126.4, 123.8, 123.4, 122.8, 120.8, 118.6, 117.7, 112.0, 107.9, 39.7, 13.3. HRMS (ESI): m / z calculated 445.0737 for C20H18ClN4O4S, found 445.0727 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 95.8%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(pyrrolidin-1-yl)phenyl)furan-2- carboxamide (148). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and (4-(pyrrolidin-1-yl)phenyl)boronic acid (129, 32.3 mg, 0.169 mmol, 1.00 eq) yielded compound 148 as a yellow solid (41 mg, 58%).1H-NMR (400 MHz, DMSO-d6): δ = 9.65 (s, 1H), 8.11 (dd, J = 6.8, 1.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.35 (dd, J = 7.3, 1.1 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.87 (dd, J = 7.3, 6.8 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H), 3.37 – 3.29 (m, 4H), 2.36 (d, J = 0.6 Hz, 3H), 2.04 – 2.01 (m, 4H).13C- NMR (101 MHz, DMSO-d6): δ = 158.9, 158.1, 149.4, 145.8, 140.0, 139.6, 126.9, 123.7, 123.5, 122.7, 118.9, 118.0, 117.7, 112.5, 111.9, 104.8, 48.2, 26.0, 13.3. MS (APCI+): m / z 420.2 ([M+H]+). HRMS (ESI): m / z calculated 421.1426 for C23H22ClN4O2, found 421.1412 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 95.7%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(piperidin-1-yl)phenyl)furan-2- carboxamide (149). Preparation according to general procedure C, using 5-bromo-N-(8-chloro- 2-methylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxamide (79, 106 mg, 0.3 mmol, 1.00 eq) and (4-(piperidin-1-yl)phenyl)boronic acid (130, 63 mg, 0.3 mmol, 1 eq) yielded compound 149 as a colorless solid (46 mg, 35%).1H-NMR (400 MHz, DMSO-d6): δ = 10.36 (s, 1H), 8.08 (dd, J = 6.8, 1.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 7.3, 1.0 Hz, 1H), 7.40 (d, J = 3.7 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.88 (dd, J = 7.3, 6.8 Hz, 1H), 3.26 (t, J = 5.2 Hz, 4H), 2.32 (s, 3H), 1.61 (d, J = 6.5 Hz, 6H).13C-NMR (101 MHz, DMSO-d6): δ = 157.2, 156.7, 151.6, 144.5, 138.4, 137.9, 125.8, 123.2, 123.0, 120.8, 118.7, 118.2, 117.1, 114.9, 111.4, 105.2, 48.6, 25.1, 23.9, 13.0. MS (APCI+): m / z 434.9 ([M+H]+) HRMS (ESI): m / z calculated 435.1582 for C24H24ClN4O2, found 435.1568 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 96.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(4-methylpiperazin-1-yl)phenyl)furan-2- carboxamide (150). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (131, 51.1 mg, 0.169 mmol, 1.00 eq) yielded compound 150 as a yellow solid (30 mg, 40%).1H-NMR (400 MHz, acetone-d6): δ = 9.71 (s, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.39–7.30 (m, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.92–6.83 (m, 2H), 3.31– 3.24 (m, 4H), 2.53–2.46 (m, 4H), 2.35 (s, 3H), 2.26 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 157.1, 151.8, 145.5, 139.1, 138.7, 125.8, 122.8, 122.6, 121.8, 120.0, 117.9, 117.0, 115.0, 111.0, 105.1, 54.8, 47.8, 45.5, 12.4. MS (APCI+): m / z 449.5 ([M+H]+). HRMS (ESI+): m / z calculated 450.1691 for C24H25ClN5O2+, found 450.1686 ([M+H]+). qHNMR (400 MHz, acetone- d6, ethyl-4(dimethylamino)benzoate as reference): purity = 96.5%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-morpholinophenyl)furan-2-carboxamide (151). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (132, 48.9 mg, 0.169 mmol, 1.00 eq) yielded compound 151 as a yellow solid (33 mg, 45%).1H-NMR (400 MHz, acetone-d6): δ = 9.72 (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.40– 7.31 (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.95–6.84 (m, 2H), 3.81–3.76 (m, 4H), 3.27–3.21 (m, 4H), 2.36 (s, 3H).13C-NMR (101 MHz, acetone-d6): δ = 157.9, 152.8. 152.5, 146.4, 140.0, 139.6, 126.7, 123.7, 123.5, 122.7, 121.4, 118.8, 117.8, 115.8, 111.9, 106.2, 67.2, 49.1, 13.3. MS (APCI+): m / z 436.2 ([M]•+). HRMS (ESI+): m / z calculated 437.1375 for C23H22ClN4O3+, found 437.1369 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 95.2%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)furan-2- carboxamide (152). Preparation according to general procedure C using (79) 60.0 mg, 0.169 mmol, 1.00 eq) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (133, 48.5 mg, 0.169 mmol, 1.00 eq) yielded compound 152 as a colorless solid (28 mg, 38%).1H-NMR (400 MHz, acetone-d6): δ = 9.77 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.45 – 7.32 (m, 2H), 7.07 (d, J = 3.6 Hz, 1H), 6.88 (t, J = 6.8 Hz, 1H), 3.94 (t, J = 7.0 Hz, 2H), 2.58 – 2.51 (m, 2H), 2.36 (s, 3H), 2.24 – 2.13 (m, 2H).13C-NMR (126 MHz, acetone-d6): δ = 173.9, 157.1, 156.1, 146.2, 140.8, 139.1, 138.8, 125.0, 124.8, 122.9, 122.6, 121.9, 119.1, 117.7, 116.8, 111.0, 106.9, 48.0, 32.4, 17.6, 12.4. MS (APCI+): m / z 434.4 ([M+H]+). HRMS (ESI+): m / z calculated 434.1146 for C23H19ClN4O3, found 435.1212 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 96.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(1,1-dioxidoisothiazolidin-2- yl)phenyl)furan-2-carboxamide (153). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (4-(1,1-Dioxidoisothiazolidin-2-yl)phenyl)boronic acid (134, 50 mg, 0.2 mmol, 1 eq) yielded compound 153 as a yellow solid (58 mg, 62%).1H-NMR (500 MHz, DMSO-d6): δ = 10.45 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 3.6 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 3.82 (t, J = 6.5 Hz, 2H), 3.56 (t, J = 7.3 Hz, 2H), 2.43 (quint, J = 6.9 Hz, 2H), 2.33 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.1, 155.4, 145.4, 138.8, 138.4, 137.9, 125.8, 125.6, 123.9, 123.3, 123.0, 120.8, 119.4, 118.0, 117.6, 116.9, 111.4, 107.2, 48.4, 46.5, 18.5, 13.0. HRMS (ESI): m / z calculated 471.0894 for C22H20ClN4O4S, found 471.0883 ([M+H]+). qHNMR (400 MHz, DMSO- d6, maleic acid as reference): purity = 99.2%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-((dimethylamino)methyl)phenyl)furan-2- carboxamide (154). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and (4-[(dimethylamino)methyl]phenyl)boronic acid (135, 30.3 mg, 0.169 mmol, 1.00 eq) yielded compound 154 as a colorless solid (28 mg, 41%).1H-NMR (400 MHz, acetone-d6): δ = 9.79 (s, 1H), 8.19 – 8.10 (m, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.49 – 7.30 (m, 4H), 7.10 (d, J = 3.7 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 3.44 (s, 2H), 2.36 (s, 3H), 2.20 (s, 6H).13C-NMR (126 MHz, acetone-d6): δ = 157.1, 156.3, 146.4, 140.7, 139.1, 138.8, 129.3, 128.4, 124.5, 122.9, 122.6, 121.9, 117.6, 116.8, 111.0, 107.3, 63.5, 44.7, 12.4. MS (APCI+): m / z 408.5 ([M+H]+). HRMS (ESI+): m / z calculated 408.1353 for C22H21ClN4O2, found 409.1419 ([M+H]+). qHNMR (400 MHz, acetone-d6, ethyl-4(dimethylamino)benzoate as reference): purity = 95.0%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(pyrrolidin-1-ylmethyl)phenyl)furan-2- carboxamide (155). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine (136, 67 mg, 0.2 mmol, 1 eq) yielded compound 155 as a colorless solid (32 mg, 37%).1H-NMR (500 MHz, DMSO-d6): δ = 10.47 (s, 1H), 8.11 (dd, J = 6.7, 1.0 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.48 – 7.40 (m, 4H), 7.19 (d, J = 3.6 Hz, 1H), 6.89 (t, J = 7.0 Hz, 1H), 3.61 (s, 2H), 2.44 (td, J = 4.8, 2.1 Hz, 4H), 2.32 (s, 3H), 1.70 (p, J = 3.0 Hz, 4H).13C-NMR (126 MHz, DMSO-d6): δ = 157.1, 155.8, 145.6, 140.6, 138.4, 137.9, 129.0, 127.7, 124.5, 123.2, 123.0, 120.8, 118.0, 116.9, 111.4, 107.6, 59.3, 53.5, 23.2, 13.0. MS (APCI+): m / z 434.5 ([M+H]+) HRMS (ESI): m / z calculated 435.1582 for C24H24ClN4O2, found 435.1567 ([M+H]+). qHNMR (400 MHz, DMSO- d6, maleic acid as reference): purity = 95.9%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(pyrrolidine-1-carbonyl)phenyl)furan-2- carboxamide (156). Preparation according to general procedure C using (79) (71 mg, 0.2 mmol, 1.00 eq) and (4-(pyrrolidine-1-carbonyl)phenyl)boronic acid (137, 45 mg, 0.2 mmol, 1 eq) yielded compound 156 as a colorless solid (49 mg, 54%).1H-NMR (500 MHz, DMSO-d6): δ = 10.54 (s, 1H), 8.12 (dd, J = 6.8, 1.0 Hz, 1H), 8.08 – 8.03 (m, 2H), 7.67 – 7.60 (m, 2H), 7.50 – 7.43 (m, 2H), 7.32 (d, J = 3.6 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H), 3.45 (dt, J = 28.0, 6.6 Hz, 4H), 2.33 (s, 3H), 1.86 (dp, J = 20.1, 6.8 Hz, 4H).13C-NMR (126 MHz, DMSO-d6): δ = 167.6, 157.0, 154.8, 146.2, 138.4, 137.9, 137.2, 130.2, 127.8, 124.3, 123.3, 123.0, 120.8, 117.9, 116.9, 111.4, 109.0, 48.8, 46.0, 26.0, 23.9, 13.0. MS (APCI+): m / z 448.5 ([M+H]+) HRMS (ESI): m / z calculated 449.1375 for C24H22ClN4O3, found 449.1362 ([M+H]+). qHNMR (400 MHz, DMSO- d6, maleic acid as reference): purity = 96.7%. N-(8-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-(dimethylcarbamoyl)phenyl)furan-2- carboxamide (157). Preparation according to general procedure C using (79) (60.0 mg, 0.169 mmol, 1.00 eq) and N,N-dimethyl-4-boronobenzamide (138, 32.6 mg, 0.169 mmol, 1.00 eq) yielded compound 157 as a colorless solid (33 mg, 46%).1H-NMR (400 MHz, MeOD-d4): δ = 8.10 – 8.01 (m, 3H), 7.60 – 7.53 (m, 2H), 7.49 – 7.42 (m, 2H), 7.16 (d, J = 3.7 Hz, 1H), 6.93 (t, J = 7.1 Hz, 1H), 3.09 (d, J = 30.5 Hz, 6H), 2.43 (s, 3H).13C-NMR (101 MHz, MeOD-d4): δ = 173.1, 160.0, 157.5, 147.5, 140.9, 139.6, 137.6, 132.1, 128.9, 125.9, 125.6, 123.6, 122.8, 119.7, 117.9, 113.3, 109.8, 35.7, 12.6. MS (APCI+): m / z 422.4 ([M+H]+). HRMS (ESI+): m / z calculated 422.1146 for C22H19ClN4O3, found 423.1212 ([M+H]+). qHNMR (400 MHz, MeOD- d4, ethyl-4(dimethylamino)benzoate as reference): purity = 99.0%. 5-(6-Aminonaphthalen-2-yl)-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)furan-2- carboxamide (158). tert-Butyl (6-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-3- yl)carbamoyl)furan-2-yl)naphthalen-2-yl)carbamate (118, 52 mg, 0.1 mmol, 1 eq). was dissolved in DCM (2 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at rt for 2 h. The solvent mixture was removed under reduced pressure, the residue was dissolved in ethyl acetate and treated with saturated aqueous NaHCO3-solution. Phases were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with Brine and dried over MgSO4. The solvent was evaporated under reduced pressure and the crude product was purified by reverse phase chromatography using a gradient of H2O with 10% MeCN to 100% MeCN (HPLC gradient grade). Compound 158 was obtained as a yellow solid (37 mg, 89%).1H-NMR (500 MHz, DMSO-d6): δ = 10.44 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.12 (dd, J = 6.7, 1.0 Hz, 1H), 7.85 (dd, J = 8.7, 1.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.14 (d, J = 3.6 Hz, 1H), 6.99 (dd, J = 8.8, 2.2 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 5.62 (s, 2H), 2.34 (s, 3H).13C-NMR (126 MHz, DMSO-d6): δ = 157.2, 156.7, 147.8, 145.2, 138.4, 137.9, 135.2, 129.2, 125.8, 125.7, 123.6, 123.2, 123.0, 122.6, 121.7, 120.8, 119.2, 118.1, 117.2, 111.4, 106.6, 105.7, 13.0. MS (APCI+): m / z 417.6 ([M+H]+) HRMS (ESI): m / z calculated 417.1113 for C23H18ClN4O2, found 417.1097 ([M+H]+). qHNMR (400 MHz, DMSO-d6, maleic acid as reference): purity = 98.9% 1.2 In vitro Characterization Hybrid reporter gene assays. Nurr1 modulation was determined in a Gal4 hybrid reporter gene assay in HEK293T cells (German Collection of Microorganisms and Cell Culture GmbH, DSMZ) using pFR-Luc (Stratagene, La Jolla, CA, USA; reporter), pRL-SV40 (Promega, Madison, WI, USA; internal control) and pFA-CMV-hNurr1-LBD14, coding for the hinge region and ligand binding domain of the canonical isoform of human Nurr1. 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), and streptomycin (100 μg / mL) at 37 °C and 5% CO2and 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 supplemented with penicillin (100 U / mL), streptomycin (100 μg / mL) and 0.1% DMSO for 16 h before luciferase 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) 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 EC50 values, the equation “[Agonist] vs. response -- Variable slope (four parameters)" was used in GraphPad Prism (version 7.00, GraphPad Software, La Jolla, CA, USA). Selectivity profiling was performed with identical procedures using pFA-CMV-Nur77-LBD14, pFA-CMV-NOR-1-LBD14, pFA-CMV-THRα-LBD39, pFA-CMV-RARα-LBD40, pFA-CMV-PPARα-LBD41, pFA-CMV-PPARγ-LBD41, pFA-CMV-PPARδ-LBD41, pFA-CMV-LXRα-LBD37, pFA-CMV-FXR-LBD42and pFA-CMV-hRXRα-LBD43. Full-length Nurr1 reporter gene assays. Activation of full length human Nurr1 was studied in transiently transfected HEK293T cells using the reporter plasmids pFR-Luc-NBRE14, pFR-Luc- POMC14or pFR-Luc-DR514each containing one copy of the respective human Nurr1 response element NBRE Nl3, NurRE, or DR5. The full length human nuclear receptor Nurr1 (pcDNA3.1- hNurr1-NE; Addgene plasmid #102363) and, for DR5, RXRα (pSG5-hRXR)44were overexpressed. pRL-SV40 (Promega) was used for normalization of transfection efficacy and to observe test compound toxicity. 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), and streptomycin (100 μg / mL) at 37 °C and 5 % CO2and 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) according to the manufacturer’s protocol. Five hours after transfection, cells were incubated with the test compounds in Opti-MEM supplemented with penicillin (100 U / mL), streptomycin (100 μg / mL) and 0.1% DMSO for 16 h before luciferase 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). Firefly luminescence was divided by Renilla luminescence and multiplied by 1000 resulting in relative light units (RLU) 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 EC50 values, the equation “[Agonist] vs. response -- Variable slope (four parameters)" was used in GraphPad Prism (version 7.00, GraphPad Software). Isothermal Titration Calorimetry (ITC). ITC experiments were conducted on an Affinity ITC instrument (TA Instruments, New Castle, DE) at 25°C with a stirring rate of 75 rpm. Nurr1 LBD protein (10-30 µM, expressed as described previously21) in buffer (20 mM Tris pH 7.5, 100 mM NaCl, 5% glycerol) containing 1-4% DMSO was titrated with the test compounds (60-150 μM in the same buffer containing 1-4% DMSO) in 26 injections (1x 1 µL, 25x 3-4 μL) with an injection interval of 150 s. As control experiments, the test compounds were titrated to the buffer, and the buffer was titrated to the Nurr1 LBD protein under otherwise identical conditions. Results were analyzed using NanoAnalyze software (version 3.11.0, TA Instruments, New Castle, DE) with independent binding models. Evaluation of Nurr1-regulated VMAT2 expression in T98G cells. T98G (ATCC CRL-1690™) were grown in DMEM, high glucose supplemented with 10% FCS, sodium pyruvate (1 mM), penicillin (100 U / mL), and streptomycin (100 μg / mL) at 37°C and 5% CO2and seeded at a density of 250,000 cells per well in 12-well plates. After 24 h, medium was changed to DMEM, high glucose supplemented with 0.2% fetal calf serum (FCS), penicillin (100 U / mL) and streptomycin (100 µg / mL) and the cells were incubated for another 24 h before stimulation with the test compounds (36 (0.3 µM), 29 (10 µM)) solubilized with 0.1% DMSO or with 0.1% DMSO as negative control. After 16 h of incubation the medium was removed, cells were washed with phosphate buffered saline (PBS) and after full aspiration of residual liquids immediately frozen at -80 °C until further processing. Total RNA was isolated using the E.Z.N.A.® Total RNA Kit I (Omega Bio-tek, Norcross, USA) following the manufacturer’s instructions. RNA concentration and purity was assessed using a NanoDrop™ One UV / VIS spectrophotometer (Thermo Fisher Scientific, Waltham, USA) at 260 / 280 nm. Right before reverse transcription (RT), RNA was linearized at 65 °C for 10 min and then immediately incubated on ice for at least 1 min. Reverse transcription was performed using 2 µg total RNA, 20 U Recombinant RNasin® Ribonuclease Inhibitor (Promega, Mannheim, Germany), 100 U SuperScript ® IV Reverse Transcriptase including 5x First Strand Buffer and 0.1 M dithiothreitol (Thermo Fisher Scientific, Waltham, USA), 3.75 ng linear acrylamide, 625 ng random hexamere primers (#11277081001, Merck, Darmstadt, Germany) and 11.25 nmol deoxynucleoside triphosphate mix (2.8 nmol each ATP, TTP, CTP, GTP; #R0186, Thermo Fisher Scientific, Waltham, USA) at a volume of 22.45 µL at 50 °C for 10 min and 80 °C for 10 min using a Thermal cycler XT⁹⁶ (VWR International, Darmstadt, Germany). Quantitative polymerase chain reaction (qPCR) was conducted using an Applied Biosystems™ QuantStudio 1 (Waltham, USA) and a SYBR green based detection method. Appropriately diluted cDNA was added to 6 pmol of forward and reverse primer, respectively, 0.8 U Taq DNA Polymerase (#M0267, New England Biolabs, Ipswich, USA), 40 ppm SYBR® Green I (#S9430, Sigma Aldrich, St. Louis, USA), 15 nmol deoxynucleoside triphosphate mix (as indicated above), 60 nmol MgCl2, 4 µg bovine serum albumin (#B14, Thermo Fisher Scientific, Waltham, USA), 20% BioStab PCR Optimizer II (#53833, Merck, Darmstadt, Germany), and 10% Taq buffer without detergents (#B55, Thermo Fisher Scientific, Waltham, USA) topped up at a final volume of 20 µL with ddH2O. Samples underwent 40 cycles of 15 s denaturation at 95 °C, 15 s of primer annealing at 59.4 or 62.4 °C (depending on the primer), and 20 s of elongation at 68 °C. PCR product specificity was evaluated using a melting curve analysis ranging from 65 to 95 °C. VMAT2 mRNA expression was normalized to GAPDH mRNA expression per each sample using the ΔCt-method. The following primers for the human genes were used: hSOD2 (60°C): 5’-CCA AAG GGG AGT TGC TGG AA-3’ (fw) (SEQ ID NO. 1) and 5’-GAA ACC AAG CCA ACC CCA AC-3’ (rev) (SEQ ID NO.2); hTH (62.4°C): 5’-GCT GGA CAA GTG TCA TCA CCT G-3’ (fw) ) (SEQ ID NO.3) and 5’-CCT GTA CTG GAA GGC GAT CTC A-3’ (rev) (SEQ ID NO.4); hVMAT2 (SLC18A2, 62.4°C): 5’-GCT ATG CCT TCC TGC TGA TTG C-3’ (fw) (SEQ ID NO.5) and 5’-CCA AGG CGA TTC CCA TGA CGT T-3’ (rev) (SEQ ID NO.6); hGAPDH (59.4°C): 5’-AGG TCG GAG TCA ACG GAT TT-3’ (fw) (SEQ ID NO.7) and 5’-TTC CCG TTC TCA GCC TTG AC-3’ (rev) (SEQ ID NO.8). Determination of aqueous solubility. The aqueous solubility of 29 and 36 was assessed by mixing 1 mg of each test compound with an appropriate volume of water for a theoretical concentration of 4 mM to obtain an oversaturated mixture. The mixture was agitated in a VWR Thermal Shake lite (VWR International GmbH, Darmstadt, Germany) for 24 h at 600 rpm and constant temperature of 25°C. The supersaturated mixtures were subsequently centrifuged at 23.300 rpm for 15 min (25 °C). Part of the supernatant was taken off for quantification by UV absorbance at 312 nm with external calibration. The external calibration samples contained 1% DMSO and the test samples were spiked with DMSO to 1% concentration right before the measurement. Absorbance was measured with a Tecan Spark luminometer (Tecan Deutschland GmbH, Crailsheim, Germany). The solubility test was repeated in three independent experiments. 2. Results We commenced the development of AQ-derived Nurr1 modulators by probing replacement of the quinoline scaffold of the optimized AQ fragment 4 by alternative heterocycles (Table 1). The corresponding quinazoline 5 was inactive and 7-chloro-2-methyl-1H-indol-3-amine (6) was not stable.4-Chloro-2-methyl-benzimidazole (7) also failed to activate Nurr1 suggesting that the amino substituent was required and could not be replaced by the ring NH. Table 1. Optimization of the chloroquinoline fragment EC50(Nurr1) (max. activation) 17±6 µM (1.7±0.1-fold) inactive (100 µM) unstable aNurr1 modulation was determined in a Gal4-Nurr1 hybrid reporter gene assay. Max. activation refers to the maximum effect vs.0.1% DMSO control. Data are the mean±SD; n≥3. The alternative imidazo[1,2-a]pyridine scaffold (8), in contrast, retained Nurr1 agonism and achieved a notable improvement in potency and efficacy compared to 4. The smaller skeleton was not compatible with the original regiochemistry of the chloro substituent (9) and systematic deconstruction of 8 highlighted importance of all substituents (10-13). With single-digit micromolar potency and affinity (Kd 2.7 µM, Figure 1a), the imidazo[1,2-a]pyridine 8 hence emerged as an improved fragment-like Nurr1 agonist which was also evident from enhanced ligand efficiency (LE), lipophilic ligand efficiency (LLE), and size-independent ligand efficiency (SILE) compared to AQ (1) and the lead fragment 4 (Table 2). Table 2. Ligand efficiency metrics of 1, 4 and 8.a1 4 8 ligand efficiency (LE) 0.26 0.50 0.59 lipophilic ligand efficiency - 1.99 3.28 (LLE) 0.48 size-independent ligand eff. 1.79 2.21 2.45 (SILE) a Efficiency metrics were computed according to29. Aiming to enhance potency by fragment growing, we next evaluated a potential optimization of the 2-methyl substituent of 8 (Table 3). Extension in this region caused a general reduction in Nurr1 activation efficacy. In a rough exploration of aliphatic (14) and aromatic (15, 16) extensions, only the phenyl substituent (15) retained sufficient efficacy and provided a slight improvement over 8 in terms of potency (EC504 µM). Chloro substituents in 4- (17) and 3- (18) positions of the phenyl motif enhanced activation efficacy but diminished potency. 2-Chloro substitution (19) disrupted activity on Nurr1. Replacement of the chloro substituents (17, 18) by a methyl group was tolerated in 4-position (20) but not in 3-position (21), and trifluoromethyl substituents (22, 23) also caused a marked drop in efficacy. Double 3,4-chloro substitution (24), in contrast, was additive and resulted in enhanced potency (EC500.4 µM) and efficacy (1.8-fold activation). The corresponding dimethyl analogue 25 was less active. Although structural extension of the 2-methyl substituent in 8 provided no major improvement in Nurr1 agonist activity, the 3,4-dichlorophenyl derivative 24 was favored and achieved a 7- fold increase in potency over 8. which was in line with results from ITC showing enhanced affinity of 24 (Kd0.7 µM, Figure 1b). The 2-(3,4-dichlorophenyl) substituent of 24 may thus be a valuable potency driving extension in fused derivatives. Table 3. Extension of the imidazo[1,2-a]pyridine 8 12±2 µM (2.0±0.2-fold) < 1.2-fold act. < 1.2-fold act. < 1.2-fold act. 0.4±0.2 µM (1.8±0.1-fold) 14±2 µM (1.6±0.1-fold) a Nurr1 modulation was determined in a Gal4-Nurr1 hybrid reporter gene assay. Max. activation refers to the maximum effect vs.0.1% DMSO control. Data are the mean±SD; n≥3. The optimized fragment Nurr1 agonist 8 obtained by fragment hopping from the chloroquinoline motif of AQ also appeared suitable for fragment growing by fusion with N- substituents. Our previous studies30have revealed a 5-(4-chlorophenyl)furan-2-carboxamide residue as alternative motif to replace the aminophenol of AQ (1). Transfer of this SAR knowledge to the new imidazo[1,2-a]pyridine scaffold of 8 in the fused 5-(4-chlorophenyl)furan- 2-carboxamide derivative 26 provided a notable improvement in Nurr1 agonist potency (Table 4). Simplification of 26 by removal of the chloro substituent (27) was tolerated but among alternative central aromatic systems only thiophen (28) retained Nurr1 agonism while replacement of furan (27) by pyrrole (29) or benzene (30) disrupted activity thus suggesting 26 as lead for further optimization. Table 4. Fusion of 8 with N-substituents 4±1 µM (2.1±0.1-fold) 3.2±0.4 µM (2.1±0.1-fold) >10 µM >10 µMaNurr1 modulation was determined in a Gal4-Nurr1 hybrid reporter gene assay. Max. activa- tion refers to the maximum effect vs.0.1% DMSO control. Data are the mean±SD; n≥3. Favorable Nurr1 agonist potency and improved binding affinity (Kd0.7 µM, Figure 1c) highlighted 26 as attractive Nurr1 agonist scaffold derived from AQ (1) but further improvement of potency was required. The imidazo[1,2-a]pyridine and phenylfuran-2-carboxamide skeletons already appeared highly favored according to the SAR evaluation, but optimization potential seemed to rest in the 4-chloro substituent as its removal (27) hardly diminished potency. This suggested that space to accommodate substituents was available in this region but alternative motifs to replace the chlorine atom were needed. Hence, we focused our attention on varying the 4-substituent of the phenylfuran-2-carboxamide residue (Table 5). The 4-trifluoromethyl derivative 31 exhibited similar activity as 26 while the corresponding 4- methyl analogue 32 was substantially more potent. A similar trend was observed for the 4- trifluoromethoxy (33) and 4-methoxy (34) pair, which indicated potential relevance of inductive effects. Like 4-methyl (32) and 4-methoxy (34), a 4-methylamino substituent (35) was highly favored and enhanced Nurr1 agonist potency to a sub-micromolar range. A 4-dimethylamino group (36) provided further improvement to a double-digit nanomolar EC50 value. Table 5. Optimization of the fused derivative 26 aNurr1 modulation was determined in a Gal4-Nurr1 hybrid reporter gene assay. Max. activa- tion refers to the maximum effect vs.0.1% DMSO control. Data are the mean±SD; n≥3. Potent Nurr1 agonism of 36 was also evident on full-length human Nurr1 (Figure 2a,b).36 robustly activated the Nurr1 homodimer (NurRE, EC50 = 0.094 µM; Figure 2a) and the Nurr1- RXR heterodimer (DR5, EC50= 0.165 µM; Figure 2b) but interestingly was inactive on the Nurr1 monomer (NBRE; Figure 2a) indicating an unprecedented Nurr1 dimer preference. The RXR agonist bexarotene caused generally reduced activity of DR5 but enhanced the potency of 36 by a factor of >5 (EC50= 0.033 µM (DR5 w. 0.1 µM BEX)) suggesting potentially cooperative binding31to and activation of the Nurr1-RXR heterodimer. 36 exhibited high affinity binding (Kd0.17 µM) to the Nurr1 LBD in ITC (Figure 2c) orthogonally validating its potent Nurr1 agonism. Moreover, 36 induced expression of the Nurr1-regulated tyrosine hydroxylase (TH), vesicular amino acid transporter 2 (VMAT2), and superoxide dismutase 2 (SOD2) in astrocytes (T98G) at low concentrations (0.1 µM, 0.3 µM) supporting cellular target engagement. Selectivity profiling revealed a preference of 36 for Nurr1 over Nur77 (Table 6) and no activity outside the NR4A family at 3 µM corresponding to >30-fold selectivity (Figure 2e) and emphasizing 36 as a highly optimized Nurr1 agonist also fulfilling community agreed quality criteria for chemical tools32,33. With this favorable profile,36emerges as next-generation tool to study the effects of Nurr1 modulation by AQ-type ligands. To boost the value of 36 as a chemical tool, we aimed to complement it with a structurally matched negative control compound for which 29 appeared suitable.29 strongly resembles 36 in its chemical structure and physicochemical characteristics but exhibited no Nurr1 agonism in cellular setting at 10 µM and revealed no detectable binding to Nurr1 in ITC (Table 6). Further profiling of 29 revealed no effect on Nur77 and NOR-1, no activation of full-length Nurr1, and no induction of Nurr1-regulated gene expression (Figure 2d). Thus, 29 is more than 100-fold less active than 36 as Nurr1 modulator and suitable as negative control. Table 6. Characterization of NR4A agonist 36 and negative control 29 EC50(NOR-1) 0.11±0.03 µM no activation (10 µM) no activation no activation (1 µM) (10 µM) EC50(NurRE) 0.094±0.003 µM no activation (10 µM) µM no activation (10 µM) µM no bindingbmg / L 4.1 mg / L 4.54aNurr1 modulation was determined in a Gal4-Nurr1 hybrid reporter gene assay. Max. activation refers to the maximum effect vs.0.1% DMSO control. Data are the mean±SD; n≥3.bNo binding observable in ITC with 100 µM 29 and 30 µM protein (Figure S2).cSlogP was computed with RDKit34software. Table 7. Nurr1 modulation data for 90-158. Data are from Gal4-Nurr1 hybrid reporter gene assays and represent the mean ± S.E.M., n≥3. The maximum effect (max. eff.) is indicated in µM refers to the maximum activation (agonists) or maximum repression (inverse agonists). 110 ± 0.11 141 0.12 ± 0.06 ± 0.07) ± 0.2) 142 >10 151 >10 143 >10 152 >3 144 fold act. 153 >10 145 >10 154 >3 146 ± 0.011 ± 0.02) 155 >3 147 >10 156 >3 148 ± 0.024 ± 0.02) 157 >3 149 ± 0.03 ± 0.04) 158 >3 150 >10 3. Conclusion Nurr1 is attracting remarkable interest as candidate target for neurodegenerative disease treatment12. Therapeutic potential of the nuclear receptor is strongly supported by knockout studies and observations from patients12. AQ (1) was discovered as direct Nurr1 modulator and used in pharmacological studies24,35but is a weak Nurr1 agonist and exhibits non-specific effects19disqualifying the antimalarial as Nurr1 agonist drug. We have developed potent and fully validated Nurr1 ligands from AQ (1). Scaffold-hopping from the chloroquinoline to chloroimidazopyridine and replacement of the aminophenol motif of AQ which has PAINS36character generated potent Nurr1 agonists with favorable properties and validated high-affinity binding to advance Nurr1 modulation as therapeutic strategy in neurodegeneration and beyond.

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Claims

CLAIMS 1. A compound of formula (Ia) or a salt or solvate thereof:wherein R1is selected from -H, -OH, -C1-C4alkyl optionally substituted, -C2- C4alkenyl optionally substituted, -C2-C4alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, heteroaryl optionally substituted, -O-aryl, e.g., -O-phenyl optionally substituted or -O-heteroaryl optionally substituted; R2is selected from halo, -C1-C4 alkyl optionally substituted, -C2-C4 alkenyl optionally substituted, C2-C4alkynyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, -heteroaryl optionally substituted, -OC1-C4 alkyl optionally substituted, -OC2-C4 alkenyl optionally substituted, -OC2-C4 alkynyl optionally substituted, -C3-C8 cycloalkyl optionally substituted, -OC3-C8 cycloalkyl optionally substituted, -O-aryl, e.g., -O-phenyl optionally substituted, or -O-heteroaryl optionally substituted; R3is selected from H or -CH3 optionally substituted; R4is -R5;R5is -Y-A-R6; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene; R6is selected from aryl, e.g., phenyl or naphthyl, heteroaryl, C3-C8cycloalkyl, C1-C6alkyl, -C2-C6alkenyl optionally substituted, -C2- C6alkynyl optionally substituted, wherein each of said residues is optionally substituted with -R7, -OR8, -NR9R10and / or halo; R7is selected from -H, halo, -C1-C6alkyl optionally substituted, -C2- C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted, or -C3-C8cycloalkyl optionally substituted; R8is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted; and R9and R10are independently selected from H, C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system.

2. A compound of formula (Ib) or a salt or solvate thereof:whereinR1is CH3 optionally substituted; R2is Cl; R3is selected from H or -CH3 optionally substituted; R4is selected from H or -CH3optionally substituted or -R5; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene, R6is selected from aryl, e.g., phenyl or naphthyl, heteroaryl, -C3-C8cycloalkyl, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, wherein each of said residues is optionally substituted with -R7, -OR8, - NR9R10and / or halo; R7is selected from -H, halo, -C1-C6alkyl optionally substituted, -C2- C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted, or -C3-C8 cycloalkyl optionally substituted; R8is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted or C3-C8 cycloalkyl optionally substituted; and R9and R10are independently selected from H, C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted or C3-C8 cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system.

3. The compound of claim 1 or 2 wherein (i) R1is -CH3, (ii) R2is Cl, and / or (iii) R3is H.

4. The compound of any one of claims 1-3 wherein R5isX is selected from O, S or NR11, and R11is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted.

5. The compound of any one of claims 1-4 wherein R5is.

6. The compound of any one of claims 1-5 wherein R6is phenyl substituted at position 4 relative to the position of attachment to the basic structure.

7. The compound of any one of claims 1-6 wherein R6is phenyl or naphthyl substituted with -R7, -OR8, -NR9R10and / or halo, wherein R7is -CH3 optionally substituted with -F, particularly -CH3 or -CF3; wherein R8is -CH3 optionally substituted with -F, particularly -CH3 or -CF3, and wherein R9and R10are independently selected from H and -CH3 optionally substituted with -F or wherein R9and R10form a cyclic system.

8. The compound of any one of claims 1-7 wherein R9and R10are -CH3.

9. The compound of any one of claims 1-8 which isor a salt or solvate thereof.

10. A pharmaceutical composition comprising the compound of formula (Ia) or (Ib) or a salt or solvate thereof of any one of claims 1-9 as an active agent and a pharmaceutically acceptable carrier.

11. A compound of formula (Ia) or (Ib) or a salt or solvate of any one of claims 1-9 or a pharmaceutical composition of claim 10 for use in medicine.

12. A compound of formula (I) or a salt or solvate thereof:wherein R1is selected from -H, -OH, -C1-C4alkyl optionally substituted, -C2- C4alkenyl optionally substituted, -C2-C4alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, heteroaryl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted or -O-heteroaryl optionally substituted; R2is selected from halo, -C1-C4alkyl optionally substituted, -C2-C4alkenyl optionally substituted, C2-C4alkynyl optionally substituted, aryl, e.g., phenyl or naphthyl, optionally substituted, -heteroaryl optionally substituted, -OC1-C4alkyl optionally substituted, -OC2-C4alkenyl optionally substituted, -OC2-C4alkynyl optionally substituted, -C3-C8cycloalkyl optionally substituted, -OC3-C8cycloalkyl optionally substituted, -O-aryl, e.g., -O-phenyl, optionally substituted, or -O-heteroaryl optionally substituted; R3is selected from H or -CH3optionally substituted; R4is selected from H, -CH3optionally substituted or -R5; R5is -Y-A-R6; A is a 5- to 8-membered ring system optionally comprising at least one hetero ring atom selected from N, O and S; Y is selected from -C(O)- or C1-C3- alkylene; R6is selected from phenyl or naphthyl, heteroaryl, C3-C8 cycloalkyl, C1-C6 alkyl, -C2-C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted, wherein each of said residues is optionally substituted with -R7, -OR8, -NR9R10and / or halo; R7is selected from -H, halo, -C1-C6 alkyl optionally substituted, -C2- C6 alkenyl optionally substituted, -C2-C6 alkynyl optionally substituted, or -C3-C8 cycloalkyl optionally substituted;R8is selected from H, C1-C6 alkyl optionally substituted, -C2-C6 alkenyl optionally substituted, -C2-C6alkynyl optionallysubstituted or C3-C8cycloalkyl optionally substituted; and R9and R10are independently selected from H, C1-C6 alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted or wherein R9and R10may form a cyclic system; for use in the prevention and / or treatment of a disease caused by and / or associated with insufficient Nurr1 activity.

13. The compound of claim 12, which is a compound of formula (Ia) according to claim 1 for the use of claim 12.

14. The compound of claim 12, which is a compound of formula (Ib) according to claim 2 for the use of claim 12.

15. The compound of any one of claims 12-14 for the use of claim 12 wherein (i) R1is - CH3, (ii) R2is Cl, and / or (iii) R3is H.

16. The compound of any one of claims 12-15 for the use of claim 12 wherein R5isX is selected from O, S or NR11, and R11is selected from H, C1-C6alkyl optionally substituted, -C2-C6alkenyl optionally substituted, -C2-C6alkynyl optionally substituted or C3-C8cycloalkyl optionally substituted.

17. The compound of any one of claims 12-16 for the use of claim 12 wherein R5is.

18. The compound of any one of claims 12-17 for the use of claim 12 wherein R6is phenyl substituted at position 4 relative to the position of attachment to the basic structure.

19. The compound of any one of claims 12-18 for the use of claim 12 wherein R6is phenyl or naphthyl substituted with -R7, -OR8, -NR9R10and / or halo, wherein R7is -CH3optionally substituted with -F, particularly -CH3or -CF3; wherein R8is -CH3optionally substituted with -F, particularly -CH3or -CF3, and wherein R9and R10are independently selected from H and -CH3optionally substituted with -F or wherein R9and R10form a cyclic system.

20. The compound of any one of claims 12-19 for the use of claim 12 wherein R9and R10are -CH3.

21. The compound of any one of claims 12-20 for the use of claim 12 which isor a salt or solvate thereof.

22. The compound of formula (Ia) or (Ib) or a salt or solvate of any one of claims 1-9, a pharmaceutical composition of claim 10 or a compound of formula (I) or a salt or solvate of any one of claims 12-21 for use in the prevention and / or treatment of a degenerative disease, an inflammatory disease and / or a hyperproliferative disease.

23. The compound of formula (Ia) or (Ib) or a salt or solvate of any one of claims 1-9, a pharmaceutical composition of claim 10 or a compound of formula (I) or a salt or solvate of any one of claims 12-21 for use in the prevention and / or treatment of a neurodegenerative disease, an ocular disease, a gastro-intestinal disease, or cancer caused by and / or associated with insufficient Nurr1 activity.

24. The compound of formula (Ia) or (Ib) or a salt or solvate of any one of claims 1-9, a pharmaceutical composition of claim 10 or a compound of formula (I) or a salt or solvate of any one of claims 12-21 for use in the prevention and / or treatment of a disease selected from Morbus Alzheimer, Morbus Parkinson, dementia, multiple sclerosis, progressive supranuclear palsy (PSP), stroke including ischemic stroke, schizophrenia, depression, psychosis, neuroinflammation, brain aging, ADHD, circadian rhythm disorder, obesity, inflammation associated with metabolic syndrome, chronic inflammation and / or insulin resistance in patients with type 2 diabetes, alcohol dependence, rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, macular degeneration including age-related macular degeneration, cancer and increased sensitivity to chemotherapeutics.

25. The compound of (Ia) or (Ib) or a salt or solvate of any one of claims 1-9, a pharmaceutical composition of claim 10 or a compound of formula (I) or a salt or solvate of any one of claims 12-21 for use of any one of claims 11 or 12-24 as a monotherapy or as a combination therapy with at least one further medicament.

26. A method of preventing and / or treating disease caused by and / or associated with insufficient Nurr1 activity comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (Ia) or (Ib).

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