WO2019106087A1

WO2019106087A1 - Ampk inhibitors

Info

Publication number: WO2019106087A1
Application number: PCT/EP2018/083001
Authority: WO
Inventors: Jan LANZ; Trond Ulven
Original assignee: Syddansk Universitet
Priority date: 2017-11-29
Filing date: 2018-11-29
Publication date: 2019-06-06

Abstract

The 5'-AMP-activated protein kinase AMPK functions as a master switch to maintain cellular and whole-body energy homeostasis and abnormal activity profiles of AMPK may cause pathological disorders. The present invention relates to a series of compounds (I) based on a pyrrolo[2,3-c]pyridine and a thieno[2,3- c]pyridine scaffold as AMPK inhibitors. In particular, the present invention relates to the synthesis of such compounds and the medical use of such compounds.

Description

AMPK inhibitors

Technical field of the invention

The present invention relates to a series of compounds based on a pyrrolo[2,3- c]pyridine and a thieno[2,3-c]pyridine scaffold. In particular, the present invention relates to the synthesis of such compounds and the medical use of such compounds.

Background of the invention

The 5'-AMP-activated protein kinase AMPK functions as a master switch to maintain cellular and whole-body energy homeostasis. Abnormal activity profiles of AMPK may cause pathological disorders, and growing evidence supports pharmacological targeting of AMPK as a promising approach to treat human diseases, such as metabolic disorders, cancer and neurodegenerative diseases. However, isoform-dependent signaling of AMPK in health and disease remains largely elusive. Therefore, continuous investigations are required as well as new tools to study the physiological functions of AMPK. Previously, the focus has been directed towards development of allosteric AMPK activators whereas only few attempts have been reported describing AMPK inhibitors. One such attempt is W02010/036629, which describes the synthesis of a series of heterocyclic AMPK inhibitors.

AMPK acts as a multifaceted guard that maintains cellular energy balance, namely via sensing and regulating cellular levels of ATP, and also takes a key part in the whole-body energy homeostasis. By switching between anabolic and catabolic pathways, AMPK orchestrates the consumption and production of ATP in cells during metabolically stressful situations, such as exercise, hypoxia, rapid cell growth, and starvation.^{1 4} This omnipresent energy regulator can be found in essentially all eukaryotic cells as a heterotrimeric complex comprising the catalytic subunit a and the two regulatory subunits b and y.

Abnormal AMPK activity has been linked to various human pathological conditions, such as metabolic disorders, cancer, neurodegenerative diseases, inflammation and cardiovascular diseases.⁴ _' ⁵ _' ⁶ AMPK can protect cancer cells when nutrients are scarce and in addition, AMPK was found to stimulate expression of vascular endothelial growth factor (VEGF) and angiogenesis in skeletal muscle.⁷' ⁸ Other examples demonstrate that that activity of AMPK in hypoxic tumor microenvironments is important for tumor growth,⁹ and that AMPK promotes tumor cell survival via regulation of NADPH homeostasis during energetic stress.¹⁰

The first described AMPK inhibitor Compound C was identified in 2001.¹¹ Initially, Compound C was claimed to be a selective AMPK inhibitor and is still widely used as a tool compound for the investigation of AMPK-dependent physiological functions. However, subsequent selectivity screens and cell-based assays revealed numerous off-targets. For instance, multiple protein kinases are inhibited by Compound C with greater potency than AMPK in direct comparison including Src, Lck, EPHA2, VEGFR1, VEGFR2, Flt3 and MNK1.¹² Similarly, the AMPK inhibitors of W02010/036629 target multiple protein kinases, such as C-ABL, EGFR, Flt3, RET, RAF, Src, TIE2, ABL1 T315I, ALK, AMPK, CHEK2, VEGFR2, MST1R, NTRK1 or RAF1 Y340D Y341D. Hence, an improved AMPK inhibitor would be advantageous, and in particular a more selective and potent AMPK inhibitor.

Summary of the invention

Thus, an object of the present invention relates to synthesis of AMPK inhibitors and the use of such inhibitors in the treatment of cancer, neurological- and metabolic diseases. In particular, it is an object of the present invention to provide an AMPK inhibitor that solves the above mentioned problems of the prior art and improves selectivity towards AMPK.

Thus, a first aspect of the invention relates to compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or O, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), -CONH2, -CONH(Ci-Ci0 alkyl), -CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), Ci- Cio alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), C1-C10 alkyl sulfonate (-S03-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHSC>2(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl)), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

wherein A is NH, S or 0; a is the integer 1-3; b is 2 or 3 and c is the integer 1-4; R2 is H or C1-C5 alkyl;

R3 is C1-C10 alkyl, C3-C6 cycloalkyl or a 5 or 6 membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said C3-C6 cycloalkyl, aryl or heteroaryl may independently be substituted with one or more substituents which can be the same or different and are independently selected from halogens, Ci- C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Ci-Cio alkoxy (-O-alkyl) or C1-C10 thioalkyl (-S-alkyl);

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHC0CH₃, -NCH3COCH3, - NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, -NHCONHCHs, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH3CSNH2, -NHCSNHCHs, - NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, -OCHS, -OAc, -SH, - SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)2, -CSNH2, -CSNHCHs, - CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFs, -COOH, -COOCHs, -CSOH, -CSOCH3, -SOsH, -SO3CH3, -CONHOH, - CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)2, -PO(OH)₂, -PO(OCH₃)2, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

W is CH2, NH, 0, S or a bond; and further wherein, R² may optionally be linked via a carbon chain (-CH2-)m to Z, wherein m is 2 or 3, to form a 5 or 6 membered heterocyclic ring

with the proviso that:

when X is S and R1 is a 6 membered aryl para-substituted with a halogene then W is not 0,

when X is N, W is a bond, Ri is H, R2 is H, and Z is CH3 then R3 is not phenyl, or when X is N, R2 and Z are H, and R3 is a 6 membered heteroaryl with the heteroatom of said heteroaryl numbers 1 then the hetero atom is not N. A second aspect of the present invention relates to a method for producing a compound according to the first aspect, wherein said method comprises: contacting a compound of Formula (IV)

with a compound of Formula (V)

in the presence of a transition metal catalyst, at least one solvent, optionally a ligand and optionally a base;

wherein Ri, R2, R3, X, and Y are defined as in the first aspect

Z is H, -(CH2)nU, -(CH2)NP(CH₂)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1- 3 and U is -H, -NH2, NHP, -NHCHs, NPCHs, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCHs, -NCH3COCH3, -NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, - NHCONHCHs, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, - NCH3CSNH2, -NHCSNHCHs, -NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, - CON(CH₃)₂, -CSNH2, -CSNHCHs, -CSN(CH₃)₂, -S0₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂, -NHS0₂CH₃, -NCH₃S0₂CH₃, -CH₂F, -CHF₂, -CFS, -COOH, -COOCHS, -CSOH, - CSOCHs, -SOsH, -SOsCHs, -CONHOH, -CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, -P(0)(H)0CH₃, B(OH)₂, or B(OCH₃)₂;

further wherein P is a protecting group;

E is Cl, Br, I or OTf;

T is CH₂Zn(halogen), CH₂B(OH)₂, CH₂B(pin), CH₂(9-BBN), CH₂BF₃K, NH, OH, SH, B(OH)₂, B(pin), (9-BBN), BF₃K, Zn(halogen), SnBu₃ or Si(0-alkyl)₃.

A third aspect of the present invention is the use of a compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C₂-Cio alkenyl, C₂-Cio alkynyl, amino (-NH₂), -CH₂NH(CI-CIO alkyl), - CH₂N(CI-CIO alkyl)₂, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)₂, cyano (- CN), CONH₂, CONH(CI-CIO alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), Ci-Cio alkyl hydroxyl (-alkyl-OH), Ci-Cio alkoxy(-O-alkyl), carboxylic acid (-COOH), Ci-Cio alkyl esters (-COO-alkyl), Ci-Cio alkyl acyl (-CO-alkyl), sulfonic acid (-S0₃H), Ci- Cio alkyl sulfonate (-S0₃-alkyl), phosphonic acid (-PO(OH)₂), Ci-Cio alkyl phosphonate (-P0(0-alkyl)₂), phosphinic acid (-P(0)(H)0H), S0₂NH₂, hydroxamic acid (-CONHOH), Ci-Cio alkyl sulfonylureas (-NHC0NHS0₂(alkyl)), Ci-Cio acylsulfonamides (-S0₂-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-N0₂), halogens,

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHCOCH3, -NCH3COCH3, - NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, -NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH3CSNH2, -NHCSNHCHs, - NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, -OCHS, -OAc, -SH, - SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)2, -CSNH2, -CSNHCHs, - CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFs, -COOH, -COOCHs, -CSOH, -CSOCH3, -SOsH, -SO3CH3, -CONHOH, - CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)2, -PO(OH)₂, -PO(OCH₃)2, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

W is CH2, NH, 0, S or a bond; and

further wherein, R² may optionally be linked via a carbon chain (-CH2-)m to Z, wherein m is 2 or 3, to form a 5 or 6 membered heterocyclic ring;

as a pharmacological tool to study physiological and pathological processes that can be influenced by the modulation of the function of AMPK, particularly, for the use in methods to study physiological processes, such as cellular metabolism, in particular glucose, lipid and protein metabolism, cell cycle regulation, proliferation and associated conditions with impaired physiological processes.

A fourth aspect of the present invention relates to a compound according to the third aspect for use as a medicament. A fifth aspect of the present invention relates to a compound according to the third aspect for use in the prevention or treatment of cancer, neurological diseases or metabolic diseases.

Brief description of the figures

Figure 1 shows dose-response curves from compounds Compound C (A), compound 31 (B) and compound 44 (C) in the presence of 200 mM AMP. Figure 2 shows evaluation of compound 62 in an ICKP express kinase panel screen.

Figure 3A-C shows evaluation of compound 62 and Compound C in HepG2 liver cells. Phosphorylated ACC (P-ACC) was measured via immunoblotting as marker for AMPK activity in comparison with non-phosphorylated ACC. Three experiments are shown (A, B and C). ^compound 62, ^§Compound C, combo = 250 pM AICAR + 20 pM test compound, C = control. Incubation time after addition of the test compound is given in the figure labels. Incubation time for the combinations is equal to non-combination samples in starved cells.

The present invention will now be described in more detail in the following.

Detailed description of the invention

In one aspect, the invention relates to a compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or O, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), Ci- C10 alkyl sulfonate (-SC>3-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHC0NHS02(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -N HCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHCOCH₃, -NCH3COCH3, -

NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, -NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH3CSNH2, -NHCSNHCHs, - NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, -OCHS, -OAc, -SH, - SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)2, -CSNH2, -CSNHCHs, - CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFS, -COOH, -COOCHS, -CSOH, -CSOCH3, -SOsH, -SO3CH3, -CONHOH, - CONCHsOH, -OPO(OH)2, -OPO(OCH₃)₂, -PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)₂, or B(OCH₃)₂;

W is CH₂, NH, 0, S or a bond; and

further wherein, R² may optionally be linked via a carbon chain (-CH₂-)_m to Z, wherein m is 2 or 3, to form a 5 or 6 membered heterocyclic ring.

In the present context Ci-Cio alkyl is to be understood as univalent groups derived from alkanes (CH^z) by removal of a hydrogen atom from any carbon atom (-CH_2n+i) or (-Ch - ) where n is 1-10, i.e. 1-10 carbon atoms are comprised. Ci-Cio alkyls may be linear (-CH₂„_+I), branched (-CH₂„_+I) or cyclic (-CH₂„._I). The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups (H(CH₂)„-) The groups RCH₂- R₂CH- (R ¹ H), and R₃C- (R ¹ H) are primary, secondary and tertiary alkyl groups, respectively. Cx-Cy, such as Ci-Cio generally refers to the total number of carbon atoms also for alkenyls, alkynyls, etc., which all have their usual meaning. C₂-Cio alkenyls and alkynyls may be linear or branched and C₂-Cio alkenyls may be cyclic. Furthermore, C₂-Cio alkenyls and alkynyls may contain one or more alkene(s) or alkyne(s).

Aryl and heteroaryl has the usual meaning in the art as groups derived from arenes or heteroarenes by removal of a hydrogen atom from any ring carbon atom. Thus, 5 or 6 membered heteroaryls, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or O, include but are not limited to heteroaryls derived from pyrrole, furane, thiophene, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4- triazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine.

In the present context 9 or 10 membered aryl or heteroaryls refers to bicyclic fused ringsystems. Likewise 9 or 10 membered heteroaryls, wherein the

heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, include but are not limited to heteroaryls derived from lFHndole, indolizine, lFHndazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7- azaindole, 7-azaindazole, pyrazolo[l,5-a]pyrimidine, benzofuran, isobenzofuran, benzo[b]thiophene, benzo[c]thiophene, benzo[c/]isoxazole, benzo[c]isoxazole, benzo[c/]oxazole, benzo[c]isothiazole, benzo[c/]thiazole, benzo[c][l,2,5]thiaciazole, lH-benzotriazole, quinolone, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, 1,8-naphthyridine, pyrido[3,2-c/]pyrimidine, pyrido[4,3-c/] pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine.

Furthermore, arenes has the usual meaning in the art as being mono- or polycyclic aromatic hydrocarbons. Likewise, heteroarenes are heterocyclic compounds formally derived from arenes by replacement of one or more methine (-C=) and/or vinylene (-CH=CH-) groups by trivalent or divalent heteroatoms, respectively, in such a way as to maintain the continuous n-electron system characteristic of aromatic systems and a number of out-of-plane n-electrons corresponding to the Huckel rule (4 n + 2). A heteroatom has the usual meaning in the art as being an atom that is not carbon (C) or hydrogen (H). Typical examples of heteroatoms include but are not limited to nitrogen (N), sulfur (S), oxygen (O), phosphorus (P) and halogens.

In an embodiment of the invention the compound of formula I defined above is with the proviso that: when X is S and Ri is a 6 membered aryl para-substituted with a halogene then W is not O, when X is N, W is a bond, Ri is H, R2 is H, and Z is CH3 then R3 is not phenyl, or

when X is N, R2 and Z are H, and R3 is a 6 membered heteroaryl with the heteroatom of said heteroaryl numbers 1 then the hetero atom is not N.

In another embodiment of the invention, Ri is a 5- or 6-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1; and

R3 is C1-C10 alkyl, C3-C6 cycloalkyl or a 6-membered aryl. Examples of heteroaryls with one heteroatom include but are not limited to pyridinyl (pyridine), pyrrolyl (pyrrole), thiophenyl (thiophene) and furanyl (furane).

In a preferred embodiment of the invention, Ri is a 6-membered aryl; and R3 is a 6-membered aryl.

In another preferred embodiment of the invention W is NH or a bond.

In an embodiment of the invention, R3 is a 6-membered aryl, wherein said aryl is substituted with one or more substituents, which are the same or different and are independently selected from halogens and C1-C10 alkyl. In a preferred embodiment of the invention, R3 is a 6-membered aryl, wherein said aryl is substituted with one or more substituents, which are the same or different and are independently selected from halogens. In a more preferred embodiment of the invention, R3 is a 6-membered aryl, wherein said aryl is substituted with a substituent, which is independently selected from chlorine or fluorine.

In another embodiment of the invention, Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is 1 or 2. In a preferred embodiment of the invention, Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is 1. In an even more preferred embodiment of the invention Z is H or -(CH2)nU. In the most preferred embodiment of the invention Z is -(CH2)nU.

In yet another embodiment of the invention U is H, NH2, NHCH3, N(CH3)2,

NHCOCHs, NHCONH2, OH, OCHs, OAc, CONH2, CONHCHs or SO2NH2. U may (except when being H) function as a hydrogen bond donor and/or a hydrogen bond acceptor in the binding pocket, by interaction with the backbone and/or amino acid side chains of AMPK. Thus, in principle other groups capable of forming a hydrogen bond with the AMPK backbone and/or amino acid side chains may be suitable. In a preferred embodiment of the invention, U is H, NH2, NHCH3, NHCONH2, OH, OCH3, OAc, CONH2, or SO2NH2. In a more preferred embodiment of the invention, U is H, OH, OCH3, OAc, or CONH2. In an even further preferred embodiment of the invention, U is H or OH. In the most preferred embodiment of the invention, U is OH. In a further embodiment of the invention, Ri is halogen or a 6-membered aryl, wherein said aryl is meta and/or para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2NH(CI-CIO alkyl), -CH2N(CI-CIO alkyl)2, -NH(Ci-Cio alkyl), -N(Ci-Cio alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH, S or O; a is the integer 1-3; b is 2 or 3 and c is 3 or 4. In a further embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CIO alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH, S or 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4;

and R3 is a 6-membered aryl, wherein said aryl is meta substituted with a chlorine or fluorine. In a preferred embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N (CI-CIO alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH or 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4;

and R3 is a 6-membered aryl, wherein said aryl is meta substituted with a chlorine. In an more preferred embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with a substituent, which is

independently selected from the group consisting of amino (-NH2), -CH2N (CI-CS alkyl)2, -CONH2, hydroxyl (-OH), C1-C5 alkyl hydroxyl (-alkyl-OH),

wherein A is 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4. In an even more preferred embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CS alkyl)2, -CONH2, hydroxyl (-OH), C1-C5 alkyl hydroxyl (-alkyl-OH),

wherein A is 0; a is 1 or 2; b is 2 and c is 3. In the most preferred embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with -CH₂N(CH₂)₄; and

R3 is aryl, wherein said aryl is meta substituted with chlorine.

In another embodiment of the invention, Ri is H, halogen, a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; R₂ is hydrogen or methyl; R3 is methyl, cyclo propyl or a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; X is selected from NMe, NEt or S; and W is NH or a bond. The aryl and heteroaryl groups may of course be substituted as defined above.

In an embodiment of the invention, X is NMe or S. In a preferred embodiment of the invention X is S.

In another embodiment of the invention, X is S; and W is NH or a bond; and Z is CH₂OH. In a preferred embodiment of the invention, X is S; and W is a bond; and Z is CH₂OH.

In yet another embodiment of the invention, X is NMe; and W is NH or a bond; and Z is CH₂OH. In a preferred embodiment of the invention, X is NMe; and W a bond; and Z is CH₂OH.

In yet a further embodiment of the invention, Ri is a 6-membered aryl, wherein said aryl is para substituted with -CH₂N(CH₂)₄; R3 is aryl, wherein said aryl is meta substituted with chlorine; X is S; W is a bond and Z is CH₂OH.

In an embodiment of the invention, the compound is a racemate. Racemate or racemic mixture has the usual meaning in the art being an equimolar mixture of a pair of enantiomers and hence does not exhibit optical activity. The skilled person may synthesize the compounds as single enantiomers, enantiomerically enriched or as racemic mixtures. By enantiomerically enriched, is to be understood a sample of a chiral substance whose enantiomeric ratio is greater than 50: 50 but less than 100: 0. If a single enantiomer or an more enantiomerically enriched compound is needed from an mixture of enantiomers, the skilled person is aware of a large amount of chiral resolution methods for separating the enantiomers. Examples of such methods include but not limited to chiral SFC, chiral HPLC, using chiral derivatizing agents or resolution by crystallization. In another embodiment of the invention, the compound is the enantiomer of Formula (II).

In yet another embodiment of the invention the compound is the enantiomer of Formula (III).

In an embodiment of the invention, the compound is a crystalline solid. In another embodiment of the invention, the compound is an amorphous solid. Crystalline and amorphous solid has the usual meaning in the art. A crystalline solid thus means any solid material whose constituents are arranged in a highly ordered microscopic structure forming a crystal lattice, i.e. it is the presence of three- dimensional order on the level of atomic dimensions. Crystalline solid may either be single crystals or polycrystals composed of many microscopic crystals also known as crystallites. Several techniques known to the skilled person can be used for the detection of crystallinity such as but not limited to Powder X-Ray

Diffraction (PXRD) and Single-crystal X-Ray Diffraction.

In an embodiment of the invention, a pharmaceutically acceptable salt of a compound is made. Several reasons may prompt the skilled person to make a pharmaceutically acceptable salt of a compound. Such reasons may include but are not limited to improving solubility and/or permeability and/or stability and/or ease of purification. In another embodiment of the invention, a prodrug, such as an ester, of a compound is made. A prodrug has the usual meaning in the art being a medication or compound that, after administration, is metabolized into a pharmacologically active drug. Prodrugs a typical used to improve ADME properties such as poor bioavailability e.g. a drug being poorly absorbed in the gastrointestinal tract. In an embodiment of the invention, the pharmaceutically acceptable salt is selected from the group consisting of a chloride salt, bromide salt, iodide salt, fumarate salt, maleate salt, citrate salt, tartrate salt, acetate salt, gluconate salt, sulfate salt, mesylate salt, nitrate salt and phosphate salt. The compounds according to the invention contains a basic pyridine and thus any acid capable of protonating the pyridine may in principle be used in salt formation.

In a second aspect the invention relates to a method for producing a compound according to the first aspect, wherein said method comprises: contacting a compound of Formula (IV)

with a compound of Formula (V)

wherein Ri, R2, R3, X, and Y are defined as in the first aspect Z is H, -(CH2)nU, -(CH₂)NP(CH₂)nU or -(CH₂)NH(CH₂)_nU, wherein n is an integer 1- 3 and U is -H, -NH₂, NHP, -NHCHs, NPCHs, -N(CH₃)₂, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCHs, -NCH3COCH3, -NHCSCHs, -NCH3CSCH3, -NHCONH₂, -NCH₃CONH₂, - NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH2, - NCH₃CSNH₂, -NHCSNHCHS, -NCH3CSNHCH3, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -S0₂CH₃, -CONH₂, -CONHCH3, - CON(CH₃)₂, -CSNH₂, -CSNHCHS, -CSN(CH₃)₂, -SO₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CFS, -COOH, -COOCHS, -CSOH, - CSOCH3, -SOsH, -SO3CH3, -CONHOH, -CONCH3OH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)OH, -P(0)(H)OCH₃, B(OH)₂, or B(OCH₃)₂;

further wherein P is a protecting group; E is Cl, Br, I or OTf;

T is CH₂Zn(halogen), CH₂B(OH)₂, CH₂B(pin), CH₂(9-BBN), CH₂BF₃K, NH, OH, SH,B(OH)₂, B(pin), (9-BBN), BF3K, Zn(halogen), SnBu₃ or Si(0-alkyl)3.

The skilled person is aware of a large number of suitable protecting groups for amines, alcohols and thiols if needed. In the case Z contains an amine (primary or secondary), an alcohol (-OH) or a thiol (-SH) group it might be desired to protect the group to achieve chemoselectivity for example to avoid competing cross- coupling reactions. Furthermore, the acidic character of the protons in these groups may require their protection if using organometallic reagents, such as Negishi (CH₂Zn(halogen)) reagents in order to avoid quenching of the

organometallic reagent.

The skilled person is aware of a number of suitable protecting groups for alcohols (P¹) including but not limited to ethers, esters and silyl ethers. Suitable ethers may include but are not limited to methoxymethyl ether (MOM-O-),

benzyloxymethyl ether (BOM-O-), allyl ether, tert-butyl ether, benzyl ether (Bn-O- ), p-methoxybenzyl ether (PMB-O-) or tetrahydropyranyl ether (THP-O-). Suitable esters may include but are not limited to acetic acid ester (Ac-O-), benzoic acid ester (Bz-O-) or pivalic acid ester. Suitable alkylsilyl ethers may include but are not limited to trimethylsilyl ether (TMS-O-), tert-buthyldimethylsilyl (TBDMS-O-) or tert-butyldiphenylsilyl ether (TBDPS-O-). Furthermore, the skilled person is aware of a large number of conditions for introduction and removal of such protecting groups. Suitable protecting groups for amines (P) may include, but are not limited to, t-Butyl carbamate (Boc-NH-), 9-Fluorenylmethyl carbamate (Fmoc- NH-), Benzyl carbamate (Cbz-NH-), Acetamide (Ac-NH-), Trifluoroacetamide, Phthalimide, Benzylamine (Bn-NH-), Triphenylmethylamine (Tr-NH-),

Benzylideneamine, p-Toluenesulfonamide (Ts-NH-). Primary amines may be mono- or bis protected. Suitable protecting groups for thiols (P²) include, but are not limited to, ethers, thioesters, thiocarbonate derivatives and thiocarbamate derivatives. Suitable ethers may include, but are not limited to, benzyl thioether (Bn-S-), p-methoxybenzyl thioether (PMB-S-), 9-Fluorenylmethyl thioether (Fm- S-), Triphenylmethyl thioether (Tr-S-), tert-butyl thioether, benzyloxymethyl thioether (BOM-S-) and silyl thioethers such as trimethylsilyl ether (TMS-S-), tert- buthyld imethylsilyl (TBDMS-S-) or tert-butyldiphenylsilyl ether (TBDPS-S-).

Suitable thioesters may include but are not limited to acetic acid ester (Ac-S-) and benzoic acid ester (Bz-S-). Suitable thiocarbonates derivatives may include, but are not limited to, t-Butoxycarbonyl derivative (Boc-S-), Benzyloxycarbonyl derivative (Cbz-S-) and 9-Fluorenylmethyl carbonyl derivative (Fmoc-S-).

Preferably, a protecting group is chosen that is stable under the conditions used in the cross-coupling.

Cross-couplings has the usual meaning in the art and should be understood in the broadest sense as a coupling reaction where two hydrocarbon fragments are coupled with the aid of a metal catalyst. Several cross-couplings types can be employed to install R¹, depending on the nature of the substrate (V). One of the reactants used in cross-couplings is an organohalide or -triflate (RCI, RBr, RI, ROTf). In a preferred embodiment of the invention, the organohalide is a bromide (E = Br). In the case that (V) is a boronic acid or a boronic acid derivative, the cross-coupling is referred to as a Suzuki-Miyaura cross-coupling. One advantage of the Suzuki-Miyaura cross-coupling is the large number of commercially available building blocks. Other cross-couplings suitable to install R¹ may include but are not limited to the Negishi-, Buchwald-Hartwig-, Hiyama-, Stille- or Ullmann type cross-couplings. The Negishi reagents may be prepared easily from the corresponding halides using zinc, such as zinc dust in the presence of iodine or highly reactive Rieke zinc. Other methods include transmetallation of Grignard reagents or organolithium reagents with anhydrous zinc salts (e.g. ZnBr2). In a preferred embodiment, the cross-coupling used is a Suzuki-Miyaura or Buchwald- Hartwig cross-coupling. The Buchwald-Hartwig cross-coupling also known as Buchwald-Hartwig amination can be used for coupling of other nucleophiles than amines such as alcohols and thiols.

In an embodiment of the invention, the transition metal catalyst is selected from Pd(CI)2, Pd(OAc)₂, Pd(PPh3)₄, Pd₂(dba)₃, PdCI₂(MeCN)₂, Pd(CI)₂(PPh₃)₂,

Pd(dppf)CI₂, Pd₂(dba)₃, Ni(OAc)₂, Ni(Br)₂, Ni(CI)₂, Ni(OTf)₂, Cu(I), Cu(Br), Cu(CI), Cu(OAc). In principle any Pd(0)/(II) or Ni(0)/(II) source may be used. Without being bound to theory, when a Pd(II) or Ni(II) source is used the active catalyst is generated in situ by reduction of Pd(II)/Ni(II) to Pd(0)/Ni(0). The active catalyst (ligand - transition metal complex) may be formed in situ by mixing a transition metal catalyst with a desired ligand. Otherwise, a preformed catalyst may be synthesized or purchased, such as Pd(PPh₃)₄ and used directly. In an embodiment of the invention, the transition metal catalyst is present in catalytic amounts such as less than 10 mol %, such as less than 5 mol %, such as less than 4 mol %, such as less than 3 mol %, such as less than 2 mol %, such as less than 1 mol %, such as at least 0.5 mol %. In a preferred embodiment, the transition metal catalyst is present at 3 mol %.

A huge number of ligands have been developed for tuning the reactivity of the catalyst, depending on the type of cross-coupling employed, the specific reaction conditions used and the nature of the substrate. One feature influencing the catalyst is the size (bulk) of the ligand, often characterized by the ligand cone angle. Without being bound to theory bulky ligands may increase reaction rate by favoring displacement of the ligand from Pd(0) to generate the active 14-electron Pd(0) species as well as favoring reductive elimination. In an embodiment of the invention, the ligand is selected from 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos), triphenylphoshine (PPh₃), tri(o-tolyl)phosphine (P(o-tolyl)₃), ethylenebis(diphenylphosphine) (dppe), l,3-bis(diphenylphosphino)- propane (dppp), l,4-Bis(diphenylphosphino)butane (dppb), l,l '-ferrocenediyl- bis(diphenylphosphine) (dppf), BINAP, 2,3-0-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane (DIOP), bis(diphenylphosphino)-methane (dppm), l,2-bis(dicyclohexylphosphino)ethane (dcpe), 2,3-bis(diphenylphosphino)butane (Chiraphos), transJrans- dibenzylideneacetone (dba), tri-tert-butylphosphine (P(t- BU)₃), tert-butyldiphenylphosphine ((Ph)₂PtBu)), bis[(2- diphenylphosphino)phenyl] ether (DPEPhos), l,l'-bis(di-tert- butylphosphino)ferrocene (DTBPF), (2-Biphenyl)dicyclohexylphosphine (cyclohexyl JohnPhos), 2-dicyclohexylphosphino-2'-(/V,/V-dimethylamino)biphenyl (DavePhos), 2-Dicyclohexylphosphino-2^,,4^,,6'-triisopropylbiphenyl (XPhos), 2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2- Dicyclohexylphosphino-2'-methylbiphenyl (MePhos), 2-Dicyclohexylphosphino- 2',6'-diisopropoxybiphenyl (RuPhos), (2-Biphenyl)di-tert-butylphosphine

(JohnPhos), l,2,3,4,5-Pentaphenyl-l'-(di-tert-butylphosphino)ferrocene (QPhos), and Tris(dimethylamino)phosphine (HMPT). In a preferred embodiment, the ligand is selected from triphenylphosphine and XantPhos. In an embodiment of the invention, the ligand is present in amounts such as less than 10 mol %, such as less than 5 mol %, such as less than 4 mol %, such as less than 3 mol %, such as less than 2 mol %, such as less than 1 mol %, such as at least 0.5 mol %.

Typically, the ligand is employed in excess of the transition metal catalyst as e.g. Pd(0) is capable of coordinating four monodentate ligands.

In an embodiment of the invention, the reaction mixture is degassed. The skilled person is aware that oxygen may be detrimental to cross-couplings due to oxidation of e.g. phosphine ligands. If to much ligand is oxidized during the reaction, it might slow- or completely shut down the reaction. This may be particular pronounced if the reaction is run a low catalyst loading. The skilled person is aware of several methods for degassing a reaction mixture to remove dissolved oxygen. One such method include bubbling inert gas (e.g. argon) through the mixture while subjecting it to ultrasound waves. In an embodiment of the invention, the reaction mixture is not degassed. In a preferred embodiment of the invention, the reaction mixture is degassed.

Suzuki cross-couplings protocols employ base, which assists in forming a more reactive ate complex (borate). Buchwald Hartwig cross-couplings protocols also employ base, having the dual role of deprotonating the nucleophile (amine, alcohol or thiol) and quenching the acid generated during the course of the reaction. In an embodiment of the invention, the base is selected from the group consisting of NaOAc, KOAc, LiOAc, Et3N, pyridine, collidine, TMP, DBU, CaCC>3, CS2CO3, U2CO3, l\la₂C03, K2CO3, LiHCOs, NaHCOs, KHCOs, U3PO4, Na₃P0₄, K3PO4, U2HPO4, Na₂HP0₄, K2HPO4, Ca(OH)2, LiOH, NaOH, KOH, Ba(OH)₂, NaOtBu, KOtBu and LiOtBu. A range of different solvents or combinations thereof are employed in cross- coupling reactions. Some cross-coupling reactions are water sensitive, such as the Negishi cross-coupling and requires anhydrous solvents. The skilled person is aware of several methods for generating anhydrous solvents. Such Examples include, but are not limited to, drying the solvent in the presence of activated sieves, distillation of the solvent after drying with sodium (Na) or by drying the solvents using commercial SPS-systems. Other cross-couplings, such as Suzuki cross-couplings often are run in the presence of water and can be run as a biphasic system (e.g. water and toluene) or in a single phase (e.g. water and dioxane). In an embodiment of the invention, the solvent(s) is selected from the group consisting of water, THF, 2-MeTHF, DMF, toluene, MeCN, t-BuOH, MTBE, NMP, 2-propanol, 1,4-dioxane and DMSO. Cross-couplings are usually run under heating. However, heating is not a prerequisite as some cross-couplings protocols have be shown to proceed effectively at room temperature. In an embodiment of the invention, the reaction is run at 30 to 160 °C, such as 35 to 155 °C, such as 40 to 150 °C, such as 45 to 145 °C, such as 50 to 140 °C, such as 55 to 135 °C, such as 55 to 130 °C, such as 60 to 125 °C, preferably 65 to 120 °C, more preferably 70 to 115 °C, most preferably 75- 110 °C. Heating may be performed by any methods known to the skilled person such as conventional heating using heating plates or using microwave heating.

The reaction time needed to complete the cross-coupling is highly dependent on the substrates, base, solvent, ligand and temperature used in the reaction mixture. Thus, in an embodiment of the invention, the reaction time is less than 48 h., such as less than 24 h., such as less than 16 h., such as less than 12 h., such as less than 10 h., such as less than 8 h., such as less than 6 h., such as less than 4 h., such as less than 2 h, such as at least 30 min. In an embodiment of the invention, the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (VI)

with a compound of Formula (VII)

in the presence of at least one solvent, optionally a coupling reagent and optionally a base;

wherein R₂, R₃, X, and Y are defined as in the first aspect;

Z is H, -(CH₂)_nU, -(CH₂)NP(CH₂)nU or -(CH₂)NH(CH₂)_nU, wherein n is an integer 1-

3 and U is -H, -NH₂, NHP, -NHCHs, NPCHs, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH₂

NHCOCHs, -NCHsCOCHs, -NHCSCHs, -NCHsCSCHs, -NHCONH₂, -NCH₃CONH₂, - NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH₂, - NCH₃CSNH₂, -NHCSNHCHS, -NCHSCSNHCHS, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, OP¹, -OCHs, -OAC, -SH, SP², -SCHS, -SOCHS, -S0₂CH₃, -CONH₂, -CONHCHS, - CON(CH₃)₂, -CSNH₂, -CSNHCHS, -CSN(CH₃)₂, -S0₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂,

-NHS0₂CH₃, -NCH₃S0₂CH₃, -CH₂F, -CHF₂, -CF₃, -COOH, -COOCHS, -CSOH, - CSOCHs, -SOsH, -SOsCHs, -CONHOH, -CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, -P(0)(H)0CH₃, B(OH)₂, or B(OCH₃)₂;

further wherein P is a protecting group;

W is Cl, Br, I or OTf; and

L is OH, OMe or Cl.

The synthesis of compounds of structure (VI) may be performed as described in the literature.¹³ _' ¹⁴ _' ¹⁵

In an embodiment of the invention, the solvent(s) is selected from the group consisting of THF, 2-MeTHF, DCM, toluene, DMF, MeCN, MTBE, 1,4-dioxane and DMSO. The reaction is usually conducted in the presence of anhydrous solvents to avoid competing reactions with water. Furthermore, in some cases compound (VII) may act as both nucleophile and as the sole solvent itself.

Different reactions protocols for synthesizing amides, esters or thioesters are well known to the skilled person and may be employed for reacting compound (VI) with compound (VII) depending on the nature of L. In an embodiment, if compound (VI) is an acid chloride (L is Cl) compound (VI) can be reacted with compound (VII) without a coupling reagent but in the presence of a base. If compound (VII) is a base itself (e.g. amine) the reaction may be carried out in excess of compound (VII) without the need of any additional base. In a further embodiment, if compound (VI) is an ester (L = OMe) it may be reacted with a thiol or amine with or without the need of an additional base. In yet another embodiment, if (VI) is an ester and (VII) is an alcohol the reaction (ester formation) may be pushed to completion by an excess of (VII) with or without addition of an acid or base. In an embodiment of the invention, compound (VII) may be converted into an alkoxide by a reducing metal such as sodium (Na) before contacting with compound (VI). In yet another embodiment of the invention, where compound (VI) is an acid (L is OH) the acid need to be activated into a better leaving group. The skilled person is aware of several methods for this purpose such as but not limited to formation of acyl halides, acyl azides, acylimidazoles with CDI, anhydrides (symmetric or mixed), esters or one-pot coupling reagents such as carbodiimide/HOBt, phosphonium coupling reagents and Uronium/Guanidinum coupling reagents.

In an embodiment of the invention, the coupling reagent is selected from the group consisting of a carbodiimide coupling reagents, a phosphonium coupling reagents and an uronium coupling reagents. In an embodiment of the invention, the carbodiimide coupling reagent is selected from EDC-HCI, DCC and DIC in the presence of HOBt. In another embodiment of the invention, the phosphonium coupling reagent is selected from BOP, PyBOP, PyAOP and PyBrOP. In yet another embodiment of the invention, the uronium coupling reagent is selected from TBTU, HBTU, HCTU, HATU, COMU, TNTU, TSTU and TFFH. In a preferred embodiment of the invention, EDC-HCI/HOBt is the coupling reagent. In an embodiment of the invention, the base is selected from the group consisting of Et3N, DIPEA, pyridine, alkali metal alkoxides (e.g. tBuONa) and alkali metal hydroxides (e.g. NaOH). Alkali metal alkoxides may be purchased or produced from alcohols in the presence of reducing metals such as sodium (Na). In a preferred embodiment of the invention, the base is Et3l\l or DIPEA.

Depending on substrates, solvent, optionally coupling reagent and optionally base used, the reaction may be run at different temperatures and reaction times. In an embodiment of the invention, the reaction is run at less than 80 °C, such as less than 75 °C, such as less than 70 °C, such as less than 65 °C, such as less than 60 °C, such as less than 55 °C, such as less than 50 °C, such as less than 45 °C, such as less than 40 °C, such as less than 35 °C, such as at least 0 °C, preferably at room temperature. When using coupling reagents or acid chlorides the reaction is often instantaneous. In an embodiment of the invention, the reaction time is less than 24 h., such as less than 16 h., such as less than 12 h., such as less than 10 h., such as less than 8 h., such as less than 6 h., such as less than 4 h., preferably less than 2 h, such as at less than 1 h, such as less than 30 min, such as at least 5 min, such as at least 1 min. In an embodiment of the invention, the reaction is run under ambient

atmosphere. In a preferred embodiment of the invention, the reaction is run under an artificial atmosphere to exclude moisture from the air. The artificial atmosphere may be any inert gas, preferably argon or nitrogen. In an embodiment of the invention, the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (XIII)

with a base and a compound of Formula (IX) R² - V

(IX)

in the presence of at least one solvent; wherein R3 and X are defined as in aspect one;

Z is H, -(CH2)nU, -(CH₂)NP(CH₂)nU or -(CH₂)NH(CH₂)_nU, wherein n is an integer 1- 3 and U is -H, -NH₂, NHP, -NHCHs, NPCHs, -N(CH₃)₂, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCH3, -NCHsCOCHs, -NHCSCHs, -NCHsCSCHs, -NHCONH₂, -NCH₃CONH₂, - NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH₂, - NCH₃CSNH₂, -NHCSNHCHS, -NCHSCSNHCHS, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -S0₂CH₃, -CONH₂, -CONHCHs, - CON(CH₃)₂, -CSNH₂, -CSNHCHS, -CSN(CH₃)₂, -S0₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CFS, -COOH, -COOCHS, -CSOH, - CSOCHs, -SOsH, -SOsCHs, -CONHOH, -CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)OH, -P(0)(H)OCH₃, B(OH)₂, or B(OCH₃)₂;

further wherein P is a protecting group;

R₂ is alkyl;

E is Cl, Br, I or OTf; and

V is a leaving group such as Br, I, OTf and OMs.

The skilled person is well known with methods for alkylating amides. In an embodiment of the invention, the at least one solvent is selected from the group consisting of THF, 2-MeTHF, DMF, DMA, MeCN, NMP, 1,4-dioxane, HMPA, DMPU and DMSO. In a preferred embodiment, the solvent is DMF.

The skilled person is familiar with a range of suitable bases for alkylation of amides. In an embodiment of the invention, the base is selected from the group consisting of NaH, Cs₂C0₃, n-BuLi, LiHMDS, NaHMDS.

In an third aspect of the invention, the compounds according to the first aspect can be used as pharmacological tools to study physiological and pathological processes that can be influenced by the modulation of the function of AMPK, particularly, for the use in methods to study physiological processes, such as cellular metabolism, in particular glucose, lipid and protein metabolism, cell cycle regulation, proliferation and associated conditions with impaired physiological processes. In one embodiment, the use as pharmacological tools is carried out in vitro. In a further embodiment the use as pharmaceutical tools is carried out in vitro on a sample of body fluid or on a tissue sample.

In a fourth aspect of the invention, the compounds according to the first aspect can be used as a medicament. In a preferred embodiment of the invention, the compounds can be used in the treatment of cancer, neurological diseases or metabolic diseases.

In a preferred embodiment of the invention, the cancer is selected from the group consisting of glioblastoma and melanoma. In a preferred embodiment of the invention, the neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease. In a preferred embodiment of the invention, the metabolic disease is selected from the group consisting of diabetes or conditions associated with diabetes. In a more preferred embodiment of the invention, the diabetes is type 2 diabetes.

In a more preferred embodiment of the invention, the conditions associated with diabetes is selected from the group consisting of insulin resistance, obesity, cardiovascular disease and inflammation.

It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention. All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples.

Examples

AMPK enzymatic assay - Luminometric assay:

Human recombinant M5-rTIΐGΐ72-AMRKa2b1g1 (MRC PPU Reagents and Services, University of Dundee, UK; DU# DU46962) was used in a luminometric assay format (Kinase-Glo® Luminescent Kinase Assay - Promega Corp.). Assay conditions are as follows: AMPK 1.25 ng/pL, ATP 10 mM, SAMS peptide (Innovagen AB #SP-SAMS; sequence: HMRSAMSGLHLVKRR) 25 pM, 0.25-1% final DMSO in buffer (40 mM Tris/HCI pH 7.5, 20 mM MgCI2, 1 mM DTT, 0.1 g/L BSA). Samples and AMPK stock solutions were diluted into buffer to afford 4x and 2x assay concentration, respectively. ATP and SAMS peptide stock solutions were mixed together in buffer to afford 4x assay concentration. 10 pL sample solution (4x) was mixed with 20 pL AMPK solution (2x) and incubated for 10 min at 21 °C. The kinase reaction was initiated by addition of 10 pL ATP/SAMS solution (4x) and incubated for 2 h at 21 °C. The kinase reaction was stopped by addition of 40 pL Kinase-Glo® Reagent, which also initiated the luminescent reaction. The luminescent reaction was incubated for 10 min at 21 °C to stabilize the

luminescent signal. The luminescent signal was then measured and converted into % relative enzyme activity (EA) in respect to control signals (no enzyme: 0% EA; basal activity: 100% EA). Alternatively, ICso is obtained through fitting of the concentration-response curves.

AMPK enzymatic assay - Radiometric assay:

[gamma-³²P]ATP (Biotech IgG A/S, #FP-301, 10 mCi/mL) and scintillation cocktail Optiphase HiSafe 3 (PerkinElmer Inc., #1200.437) were used in the assay. AMPK and SAMS peptide are the same as used in the luminometric assay. Assay conditions are as follows: AMPK 1.25 ng/pL, ATP 10 or 100 pM, SAMS peptide 25 pM, AMP 0 or 200 pM, 0.25-0.4% final DMSO in buffer (40 mM Tris/HCI pH 7.5, 20 mM MgCI2, 1 mM DTT, 0.1 g/L BSA). Sample solutions (lOx assay cone in water) were prepared from DMSO stock solutions and mixed in 1.5 mL tubes with a cocktail prepared from the following solutions: AMPK 2.5 ng/pL in 2x cone buffer, SAMS peptide 250 pM in water, AMP 0 or 2 mM in water. Non-labeled ATP (lOx assay cone in water) was 'spiked' with [gamma-³²P]ATP to afford a radioactivity of lxlO⁵ to lxlO⁶ c.p.m./nmol.

The radiometric assay was then peformed according to a published procedure.¹⁹ Assay tubes were put on ice to stop the kinase reaction. Then, 10 or 40 pL assay mixture was 'spotted' on Whatman P81 phosphocellulose filter paper on marked 2x2 cm squares (per assay point). The filter paper was washed three times with 75 mM phosphoric acid and once with acetone before air-drying under IR irradiation. Then, the filter paper was cut according to the marked squares. Each square was transferred into a 4 mL MicroBeta vial (PerkinElmer Inc. #1200.421) and suspended in 3 mL scintillation cocktail. Each vial was measured in a

PerkinElmer 2450 microplate scintillation counter for 1 min using the ³²P program. The signal was converted into kinase activity in U/mL and expressed as % relative enzyme activity (EA) in respect to control signals (no SAMS peptide: 0% EA; basal activity: 100% EA). Alternatively, ICso is obtained through fitting of the

concentration-response curves.

HepG2 assay:

HepG2 cells were purchased from ATCC (Rockville, MD, USA). Cells were treated when 70% confluent, 24 h after seeding. The antibodies used were the following : Rabbit polyclonal anti-ACC and rabbit polyclonal anti-phospho-ACC (S79) (from Cell Signaling Biotechnology). Anti-beta actin was from Sigma. Phosphorylated ACC (P-ACC) was measured with Western blot analysis, as marker for AMPK activity in comparison with non-phosphorylated ACC (Figure 3A-C).

Preparation of cell extract and Western blot analysis:

Cell pellets were re-suspended in cold lysis buffer (50 mM Tris/HCI pH 7.5, 150 mM NaCI, 1% Triton X-100, 10% glycerol, 1 mM DTT, 1 mM Na₃V0₄, 30 mM B- glycerophosphate 10 mM NaF and 100 nM okadaic acid) containing the AMPK inhibitor(s). Cells were sonicated and subsequently centrifuged at 4°C for 30 min at 10,000 g. Whole extracts were subjected to SDS-PAGE and subsequently transferred to a PVDF membrane (Bio-Rad). Protein-antibody complexes were visualized by a chemiluminescence detection system following the manufacturer's guidelines (CDP Star, Applied Biosytems).

General remarks

Commercially available starting materials and solvents were used without further purification unless stated otherwise. CS2CO3 and K2CO3 for dry reactions were dried in an oven. Solvents for dry reactions were stored over 4 A sieves. THF was freshly distilled from sodium/benzophenone. Petroleum ether (PE) refers to alkanes with bp 60-80 °C. Water used for reactions was de-ionized. TLC was performed on TLC Silica gel 60 F254 plates (Merck). Microwave assisted reaction were carried out with a Biotage Initiator. Purification by flash chromatography was carried out using glass columns with silica gel 60 (0.040-0.063 mm, Merck) or using the Reveleris X2 flash chromatography system equipped with GraceResolv silica flash cartridges. Freeze-drying was carried out on a Heto Drywinner Freeze- dryer. ¹³C and ¹⁹F NMR spectra were recorded at 400, 101 and 376 MHz, respectively; on a Bruker Avance III 400 NMR spectrometer at 300 K with chemical shifts reported in ppm relative the internal standard TMS or the residual solvent peak (CDCIs, ^ NMR d = 7.26 ppm, ¹³C NMR d = 77.16 ppm; DMSO -c/6, ^!H NMR d = 2.50 ppm, ¹³C NMR d = 39.52 ppm; CDsOD, H NMR d = 3.31 ppm, ¹³C NMR d = 49.00 ppm). Rotamer peaks in NMR spectra are marked with an asterisk (*) and have been assigned where possible. Rotamer peaks are labeled with an integral equal to its main partner. Purity of test compounds was determined by HPLC and confirmed by inspection of the NMR spectra. HPLC analysis was performed on a Dionex Ultimate 3000 system equipped with a Dionex 120 C18 column (5 pm, 4.6x150 mm); column temperature: 30 °C; flow:

1 mL/min; 10% MeCN in water (0-1 min), 10-100% MeCN in water (1-10 min), 100% MeCN (11-15 min), with both solvents containing 0.1% formic acid as modifier; UV detection at 254 nm. lF/-Pyrrolo[2,3-c]pyridine containing compounds were often detected as double peaks, a broader peak with a slightly shorter tR than the following sharp peak, due to formation of formate salts. High- resolution mass spectra (HRMS) were recorded on a Bruker ESI-micrOTOF-Q II. Specific optical rotation was recorded on an Anton Paar MCP 100 polarimeter. All test compounds were of >95% purity unless stated otherwise.

General procedure A - /V-alkylation

A mixture of lF/-pyrrolo[2,3-c]pyridine (1 equiv., 0.25-0.5 M) and anhydrous CS2CO3 (1.1-2.0 equiv.) in anhydrous DMF under argon was stirred at 80 °C for 1 h. The reaction mixture was allowed to cool down to ambient temperature. Liquid alkyl halide (1.05-2 equiv.) was added dropwise to the reaction at rt over 0.5-1 h (preferably with a syringe pump). The reaction mixture was stirred for another 10 min, mixed with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography. General procedure B1 - Ester hydrolysis

6 M NaOH (4 equiv.) was added to a stirred solution of methyl carboxylate (1 equiv.) in EtOH (EtOH:water 3 : 1) at rt. The reaction progress was monitored by TLC. The reaction mixture was neutralized with 1 M HCI. The precipitated product was filtered off, washed with water and dried in vacuo.

General procedure B2 - Ester hydrolysis

LiOH monohydrate (4 equiv.) was added to a stirred solution of methyl carboxylate (1 equiv.) in THF/water (1 : 1) at rt for 1 h. The reaction mixture was acidified with 1 M HCI to pH 4-5. The precipitated product was filtered off and washed with water or separated from the liquid phase by centrifugation, re- suspended in water and separated again (3x). The wet product was dried via freeze-drying to give the desired carboxylic acid.

General procedure Cl - Amide coupling

Oxalyl chloride (1.1 equiv.) was added dropwise to a suspension of carboxylic acid in DCM at rt under argon. Catalytic amount of DMF was added and the reaction was stirred at 80 °C under argon for 4 h. The reaction mixture was concentrated in vacuo and re-suspended in DCM at rt under argon. Et3l\l (5 equiv.) and amine (1.0-1.1 equiv.) were added dropwise and the reaction mixture was stirred overnight at rt under argon. The reaction mixture was mixed with water and extracted with DCM (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography.

General procedure C2 - Amide coupling

iPr2EtN (4 equiv.) was added to a stirred suspension of carboxylic acid (1 equiv.), HOBt monohydrate (1.5 equiv.) and EDC HCI (1.5 equiv.) in anhydrous DMF (0.2- 0.5 mmol carboxylic acid/mL) at rt under argon. The reaction mixture was stirred at rt for 1-2 h under argon. Then, amine or hydrochloride salt of an amine (0.8-2 equiv.) was added and the reaction mixture was heated to 80 °C for 1-12 h under argon. The reaction mixture was mixed with water and extracted with DCM or EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography.

General procedure D - Suzuki cross-coupling

A mixture of aryl bromide (1 equiv.), aryl boronic acid or boronic acid analogue (1.1 equiv.), K3PC (1.5 equiv.) and Pd(PPti3)₄ (0.03 equiv.) was flushed with argon for 10 min. Degassed solvent (1,4-dioxane: water 1 : 1, lmL/30-50 mg aryl halide) was added. The capped reaction was stirred at 90 °C under argon until full conversion of the aryl halide (typically 1-4 h). The reaction progress was monitored by TLC. The reaction mixture was mixed with EtOAc and the organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography. Only pure fractions were collected. Therefore, the yield was lower for some compounds. Example 1 : Synthesis of Ethyl lH-pyrrolo[2,3-c]pyridine-2-carboxylate (1)

The title compound was prepared according to the published procedure.¹³ Notes: Purification of the starting material 3-amino-4-chloropyridine was necessary prior to the reaction by trituration from DCM/MeOH. Freshly purified 3-amino-4- chloropyiridine (colorless crystals) can be stored at 4 °C, sealed from light and under argon for more than a year and used for reactions without further purification. The highest yield was achieved by starting from 0.29 g (2.24 mmol) 3-amino-4-chioropyridine. The yield was decreased for larger scale reactions! In order to produce more of the title compound, the reaction was carried out in 10 equally sized, small batches in parallel. The reaction mixtures were combined for work-up and purification. To a mixture of 3-amino-4-chloropyridine (0.29 g, 2.24 mmol) and PPTS (0.14 g, 0.56 mmol) in a capped microwave vial under argon equipped with a stirring bar were added anhydrous pyridine (0.75 ml_), tetraethyl orthosilicate (0.50 ml_, 2.24 mmol) and ethyl pyruvate (0.51 ml_, 4.48 mmol). The reaction mixture was stirred protected from light, at rt for 48 h. Formation of the enamine intermediate was followed by TLC (staining with ninhydrin). The reaction mixture was treated with Pd(PPti3)₄ (0.13 g, 0.11 mmol), re-capped and flushed with argon. TEA (0.51 ml_, 2.91 mmol) was added and the reaction was heated by microwave irradiation at 160 °C for 40 min. After cooling to rt, precipitated product was filtered off and washed with DCM. The filtrate was mixed with water and extracted with DCM (3x). The combined organic phase was washed with brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo. The crude product was separated from major impurities by flash chromatography (0-5% MeOH in DCM), combined with the filtered crude product, dissolved in DCM, treated with activated charcoal, filtered through celite and concentrated in vacuo. The pure product was obtained after recrystallization from toluene as colorless crystals (2.52 g, 59% yield), mp 210-212 °C (toluene) {Lit. mp 212-214 °C}; Rf = 0.35 (DCM : MeOH 9: 1); ^ NMR (400 MHz, CDCIs) d 9.56 (br s, 1H), 8.95 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 5.6, 1.2 Hz, 1H), 7.21 (d, J = 0.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.6, 139.5, 136.0, 133.6, 132.1, 131.0, 116.6, 107.3, 61.8, 14.5; ESI-HRMS calcd for C10H11N2O2 (M + H⁺) 191.0815, found 191.0816. Example 2: Ethyl l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (2)

The title compound was prepared from ethyl lH-pyrrolo[2,3-c]pyridine-2- carboxylate (1) (0.85 g, 4.47 mmol) and methyl iodide (0.29 ml_, 4.69 mmol) according to general procedure A. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white solid (0.69 g, 76% yield). Rf = 0.50

(DCM : MeOH 9: 1); ^ NMR (400 MHz, CDCIs) d 8.89 (s, 1H), 8.30 (d, J = 5.5 Hz, 1H), 7.54 (dd, J = 5.5, 1.1 Hz, 1H), 7.24 (d, J = 0.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.17 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.7, 139.2, 136.0, 134.6, 131.0, 130.2, 116.1, 108.5, 61.1, 32.0, 14.3; ESI-HRMS calcd for C11H13N2O2 (M + H⁺) 205.0972, found 205.0968.

Example 3: l-Methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (3)

The title compound was prepared from ethyl l-methyl-lH-pyrrolo[2,3-c]pyridine- 2-carboxylate (2) (1.3 g, 6.4 mmol) according to general procedure Bl. The product was obtained as a white solid (0.81 g, 72% yield). ¹ NMR (400 MHz, DMSO) d 9.04 (t, J = 0.9 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 7.64 (dd, J = 5.5, 1.1 Hz, 1H), 7.20 (d, J = 0.9 Hz, 1H), 4.13 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 162.5, 138.1, 135.5, 134.8, 132.3, 129.5, 115.8, 107.6, 31.8; ESI-HRMS calcd for C9H9N2O2 (M + H⁺) 177.0659, found 177.0651.

Example 4: N-(3-Chlorobenzyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (4)

The title compound was prepared from l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxylic acid (3) (200 mg, 1.14 mmol) and (3-chlorophenyl)methanamine (0.28 ml_, 2.27 mmol) according to general procedure C2. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white solid (0.30 g, 88% yield). Rf = 0.48 (DCM: MeOH 9: 1); NMR (400 MHz, CDCIs) d 8.78 (t, J = 0.9 Hz, 1H), 8.23 (d, J = 5.5 Hz, 1H), 7.45 (dd, J = 5.5, 1.1 Hz, 1H), 7.34 - 7.32 (m, 1H), 7.28 - 7.21 (m, 4H), 6.86 (d, J = 0.8 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.11 (s, 3H); ¹³C NMR (101 MHz, CDC ) d 162.0, 140.1, 139.3, 135.6, 134.9, 134.8, 134.3, 130.8, 130.2, 128.0, 127.9, 126.0, 115.8, 102.9, 43.2, 32.0; ESI-HRMS calcd for CieHisCINsO (M + H⁺) 300.0898, found 300.0893; HPLC t_R = 6.87 and 7.05 min, >99.9% pure.

Example 5: (R)-N-(l-(3-Chlorophenyl)ethyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (5)

The title compound was prepared from l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxylic acid (3) (30 mg, 0.17 mmol) and (R)-l-(3-chlorophenyl)ethan-l-amine (24 pL, 0.17 mmol) according to general procedure Cl. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an amorphous, off-white solid (28 mg, 53% yield). Rf = 0.26 (EtOAc); ^ NMR (400 MHz, CDCb) d 8.79 (s, 1H), 8.25 (d, J = 5.5 Hz, 1H), 7.45 (dd, J = 5.5, 1.0 Hz, 1H), 7.38 - 7.36 (m, 1H),

7.29 - 7.23 (m, 3H), 6.92 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 5.27 (p, J = 7.1 Hz, 1H), 4.08 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCb) d 161.2, 145.1, 139.3, 135.6, 135.0, 134.8, 134.3, 130.7, 130.2, 127.8, 126.4, 124.6, 115.7, 102.7, 48.9, 32.0, 21.9; ESI-HRMS calcd for C17H17CIN3O (M + H⁺)

314.1055, found 314.1045; HPLC t_R = 7.18 and 7.29 min, >99.9% pure; [a]²⁰o = -72° (c = 0.52, MeOH).

Example 6: (S)-N-(l-(3-Chlorophenyl)ethyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (6)

The title compound was prepared from l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxylic acid (3) (30 mg, 0.17 mmol) and (S)-l-(3-chlorophenyl)ethan-l-amine (24 pL, 0.17 mmol) according to general procedure Cl. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an amorphous, off-white solid (13 mg, 25% yield). Rf = 0.26 (EtOAc); ^ NMR (400 MHz, CDCb) d 8.83 (s, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 5.3 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.33 - 7.24 (m, 3H), 6.84 (s, 1H), 6.72 (d, J = 7.4 Hz, 1H), 5.28 (p, J = 7.1 Hz, 1H), 4.10 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCb) d 161.2, 145.1, 139.4, 135.7, 134.9, 134.8, 134.4, 130.7, 130.3, 127.9, 126.4, 124.6, 115.7, 102.7, 48.9, 32.0, 22.0; ESI-HRMS calcd for C17H17CIN3O (M + H⁺) 314.1055, found 314.1051; HPLC tR = 7.20 and 7.29 min, >99.9% pure; [O ]²⁰D = +73° (c = 0.54, MeOH).

Example 7: Methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(3,5-dibromopyridin- 4-yl)acrylate (7)

The title compound was prepared according to a published procedure.¹⁴ N- (Benzyloxycarbonyl)-o-phosphonoglycine trimethyl ester (4.04 g, 11.83 mmol) was dissolved in DCM (20 ml_) at rt under argon. A solution of DBU (2.46 ml_,

16.14 mmol) in DCM (20 ml_) was added dropwise and the reaction was stirred for another 20 min at rt. Then, a solution of 3,5-dibromopyridine-4-carboxaldehyde (3.00 g, 10.76 mmol) in DCM (20 ml_) was added dropwise at rt and the reaction was stirred for 1 h. The reaction mixture was washed with 1 M HCI (2x) and water (2x). The organic phase was dried over Na2S0₄, filtered and concentrated in vacuo. The crude material was triturated from DCM/PE to give the intermediate methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(3,5-dibromopyridin-4-yl)acrylate as a white solid (3.50 g, 73% yield) which was used for the next reaction without further purification. R_f = 0.47 (PE: EtOAc 1 : 1); ^ NMR (400 MHz, CDCb) d 8.57 (s, 2H), 7.43 - 7.31 (m, 3H), 7.25 - 7.21 (m, 2H), 7.08 (br s, 1H), 7.00 (s, 1H), 4.96 (s, 2H), 3.92 (s, 3H).

Example 8: 4-Bromo-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (8)

The title compound was prepared according to published a procedure.¹⁴ Methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(3,5-dibromopyridin-4-yl)acrylate (7)

(2.80 g, 5.96 mmol), /.-proline (140 mg, 1.19 mmol), anhydrous K2CO3 (2.47g, 17.87 mmol) and Cul (99.999%, 113 mg, 0.60 mmol) were mixed and flushed with argon for 10 min. Anhydrous, degassed 1,4-dioxane (50 ml_) was added and the reaction was refluxed for 4 h under argon. The reaction was cooled to rt and diluted into EtOAc and water. The mixture was acidified with 1 M HCI to pH 2. The aqueous phase was collected and the organic phase was extracted with water (2x). The organic phase was discarded. The combined aqueous phase was treated with sat. NaHCC>3 to pH 8 and extracted with EtOAc (3x). The combined organic phase was washed with sat. NaHCC>3 (lx) and brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo. Purification by flash chromatography (EtOAc) afforded an off-white solid (1.12 g, 74% yield). Rf = 0.47 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 12.90 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 7.07 (s, 1H), 3.93 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 160.8, 138.9, 135.4, 131.4, 131.1, 105.5, 52.4; ESI-HRMS calcd for CgH₈BrN₂0₂ (M + H⁺) 254.9764, found

254.9772.

Example 9: Methyl 4-bromo-l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylate

The title compound was prepared from methyl 4-bromo-lH-pyrrolo[2,3- c]pyridine-2-carboxylate (8) (0.86 mg, 3.37 mmol) and methyl iodide (0.22 ml_, 3.54 mmol) according to general procedure A. Purification by flash

chromatography (EtOAc in PE, 0-100%) afforded an off-white solid (0.73 g, 80% yield). Rf = 0.60 (DCM: MeOH 9: 1); H NMR (400 MHz, CDCIs) d 8.80 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 0.6 Hz, 1H), 4.18 (s, 3H), 3.97 (s, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.9, 140.3, 136.0, 133.3, 131.4, 131.2, 113.8, 108.9, 52.4, 32.7; ESI-HRMS calcd for CioHioBrN₂0₂ (M + H⁺) 268.9920, found 268.9928; HPLC t_R = 8.86 min.

Example 10: 4-Bromo-l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid

The title compound was prepared from methyl 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylate (9) (0.72 g, 2.68 mmol) according to general procedure B2. The product was obtained as white solid (0.64 g, 94% yield). ^ NMR (400 MHz, DMSO) d 13.77 (br s, 1H), 9.05 (s, 1H), 8.35 (s, 1H), 7.07 (s, 1H), 4.15 (s, 3H); ESI-HRMS calcd for CgH₈BrN₂0₂ (M + H⁺) 254.9764, found 254.9772. Example 11 : (R)-4-Bromo-l-methyl-N-(l-phenylethyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (11)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and (R)-l-phenylethan-l- amine (51 pL, 0.39 mmol) according to general procedure C2. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (48 mg, 68% yield). R_f = 0.53

9.22 (d, J = 8.0 Hz, 1H), 8.98 (s, 1H), 8.34 (s, 1H), 7.44 - 7.40 (m, 2H), 7.37 - 7.22 (m, 4H), 5.18 (p, J = 7.1 Hz, 1H), 4.07 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 159.8, 144.4, 139.0, 135.7, 135.0, 133.8, 130.4, 128.3, 126.7, 126.0, 112.0, 102.9, 48.3, 32.4, 22.0; ESI-HRMS calcd for CiyHiyBrNsO (M + H⁺) 358.0550, found 358.0560; HPLC t_R = 8.89 min, 95.1% pure; [a]²⁰o = -107° (c = 0.60, DCM).

Example 12: 4-Bromo-l-methyl-N-(pyridin-2-ylmethyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (12)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and pyridin-2- ylmethanamine (43 mI_, 0.39 mmol) according to general procedure C2.

Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (33 mg, 49% yield). R_f = 0.52 (DCM : MeOH 9: 1); NMR (400 MHz, DMSO) d 9.48 (t, J = 6.0 Hz, 1H), 9.01 - 9.00 (m, 1H), 8.53 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.35 (d, J = 0.5 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.41 - 7.38 (m, 1H), 7.31 - 7.26 (m, 1H), 7.26 (d, J = 0.8 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.12 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 160.8, 158.2, 148.9, 139.0, 136.7, 135.5, 135.1, 133.9, 130.4, 122.2, 121.0, 112.0, 103.0, 44.4, 32.4; ESI-HRMS calcd for Ci₅Hi₄BrN₄0 (M + H⁺) 345.0346, found 345.0358; HPLC t_R = 2.11 and 3.84 min, 97.7% pure. Example 13 : 4-Bromo-l-methyl-N-(pyridin-3-ylmethyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (13)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and pyridin-3- ylmethanamine (42 pL, 0.39 mmol) according to general procedure C2.

Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (22 mg, 32% yield). R_f = 0.37 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.45 (t, J = 5.9 Hz, 1H), 9.01 - 8.99 (m, 1H), 8.60 - 8.58 (m, 1H), 8.48 (dd, J = 4.8, 1.7 Hz, 1H), 8.34 (d, J = 0.5 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.38 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.20 (d, J = 0.8 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 4.12 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 160.7, 148.9, 148.2, 139.0, 135.4, 135.2, 135.1, 134.5, 133.9, 130.4, 123.5, 112.0, 102.9, 40.2, 32.4; ESI-HRMS calcd for Ci₅Hi₄BrN₄0 (M + H⁺) 345.0346, found 345.0356; HPLC t_R = 1.91 min, 96.4% pure.

Example 14: 4-Bromo-l-methyl-N-(pyridin-4-ylmethyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (14)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and pyridin-4- ylmethanamine (42 mI_, 0.39 mmol) according to general procedure C2.

Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off- white solid (44 mg, 65% yield). Rf = 0.38 (DCM : MeOH 9: 1); NMR (400 MHz, DMSO) d 9.50 (t, J = 6.0 Hz, 1H), 9.02 - 9.01 (m, 1H), 8.54 - 8.52 (m, 2H), 8.35 (d, J = 0.5 Hz, 1H), 7.37 - 7.35 (m, 2H), 7.25 (d, J = 0.8 Hz, 1H), 4.52 (d, J =

6.0 Hz, 2H), 4.12 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 160.9, 149.5, 148.0, 139.0, 135.3, 135.1, 133.9, 130.4, 122.2, 112.0, 103.0, 41.4, 32.4; ESI-HRMS calcd for CisHi₄BrN₄0 (M + H⁺) 345.0346, found 345.0358; HPLC t_R = 1.72 min, 96.9% pure. Example 15 : 4-Bromo-N-isopropyl-l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (15)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and propan-2-amine (34 pL, 0.39 mmol) according to general procedure C2. Purification by flash

chromatography (MeOH in DCM, 0-10%) afforded a white solid (45 mg, 77% yield). R_f = 0.47 (DCM: MeOH 9: 1); NMR (400 MHz, DMSO) d 8.97 (s, 1H), 8.64 (d, J = 7.7 Hz, 1H), 8.32 (s, 1H), 7.13 (d, J = 0.6 Hz, 1H), 4.16 - 4.04 (m, 4H), 1.19 (d, J = 6.6 Hz, 6H); ¹³C NMR (101 MHz, DMSO) d 159.7, 138.9, 136.2, 135.0, 133.7, 130.4, 111.9, 102.5, 40.9, 32.3, 22.1; ESI-HRMS calcd for

CizHisBrNsO (M + H⁺) 296.0393, found 296.0405; HPLC t_R = 6.78 and 6.99 min, 98.9% pure.

Example 16: 4-Bromo-N-(cyclopropylmethyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (16)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and

cyclopropylmethanamine (35 mI_, 0.39 mmol) according to general procedure C2. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (30 mg, 49% yield). Rr = 0.47 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 8.98 (s, 1H), 8.95 (t, J = 5.6 Hz, 1H), 8.33 (s, 1H), 7.13 (d, J = 0.7 Hz, 1H), 4.11 (s, 3H), 3.16 (dd, J = 6.5, 6.0 Hz, 2H), 1.10 - 1.00 (m, 1H), 0.49 - 0.43 (m, 2H), 0.28 - 0.23 (m, 2H); ¹³C NMR (101 MHz, DMSO) d 160.5, 139.0, 136.0, 135.0, 133.8, 130.4, 111.9, 102.5, 43.3, 32.3, 10.7, 3.3; ESI-HRMS calcd for CisHisBrNsO (M + H⁺) 308.0393, found 308.0402; HPLC t_R = 7.43 min, 99.7% pure. Example 17 : 4-Bromo-N-(2-hydroxyethyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide (17)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (50 mg, 0.20 mmol) and 2-aminoethan-l-ol (25 pL, 0.39 mmol) according to general procedure C2. Purification by flash

chromatography (MeOH in DCM, 0-10%) afforded a white solid (11 mg, 18% yield). R_f = 0.38 (DCM: MeOH 9: 1); NMR (400 MHz, DMSO) d 8.98 (s, 1H),

8.80 (t, J = 5.5 Hz, 1H), 8.33 (s, 1H), 7.14 (d, J = 0.7 Hz, 1H), 4.76 (t, J = 5.3 Hz, 1H), 4.10 (s, 3H), 3.57 - 3.51 (m, 2H), 3.38 - 3.31 (m, 2H); ¹³C NMR (101 MHz, DMSO) d 160.7, 138.9, 136.1, 135.0, 133.8, 130.5, 111.9, 102.6, 59.5, 41.9, 32.3; ESI-HRMS calcd for CuHis BrNsOz (M + H⁺) 298.0186, found

298.0193; HPLC t_R = 2.10 min, 95.1% pure.

Example 18: 4-Bromo-N-(3-chlorobenzyl)-l-methyl-lH-pyrrolo[2,3-c] pyridine-2- carboxamide (18)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (490 mg, 1.92 mmol) and (3- chlorophenyl)methanamine (0.48 ml_, 3.84 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 0-100%) afforded a white solid (0.70 g, 96% yield). R_f = 0.33 (EtOAc); ^ NMR (400 MHz, CDCIs) d 8.76 (s, 1H), 8.37 (s, 1H), 7.37 - 7.35 (m, 1H), 7.32 - 7.24 (m, 3H), 6.92 - 6.85 (m,

2H), 4.63 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.4, 140.4, 139.7, 135.7, 135.2, 134.9, 133.0, 131.7, 130.3, 128.2, 128.1, 126.1, 113.2, 103.0, 43.4, 32.7; ESI-HRMS calcd for Ci6Hi₄BrCINsO (M + H⁺) 378.0003, found 378.0017; HPLC tR = 9.53 min, 97.5% pure. Example 19 : 4-Bromo-N-(3-chlorobenzyl)-N,l-dimethyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (19)

To a solution of 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lF/-pyrrolo[2,3-c]pyridine- 2-carboxamide (18) (30 mg, 79 pmol) in anhydrous THF (0.4 ml_) at 0 °C was added NaH 60% in mineral oil (3.8 mg, 95 pmol). The reaction was allowed to warm to rt and stirred for 1 h. Methyl iodide (5.2 pL, 83 pmol) was added and the reaction was stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc in PE, 0-100%) to give a colorless, amorphous solid (17 mg, 53% yield). Rf = 0.14 (EtOAc); ^ NMR (400 MHz, CDCIs) d 8.75 (s, 1H), 8.39 (s, 1H), 7.39 - 7.00 (m, 4H), 6.72 - 6.57 (m, 1H), 4.77 (br s, 2H), 3.96 (br s, 3H), 3.12 (s, 3H); ESI-HRMS calcd for

CiyHieBrCINsO (M + H⁺) 392.0160, found 392.0146; HPLC t_R = 9.32 min, 98.1% pure.

Example 20: N-(3-Chlorobenzyl)-l-methyl-4-phenyl-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide (20)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lF/- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (50 mg, 0.132 mmol) and

phenylboronic acid (19 mg, 0.145 mmol) according to general procedure D.

Purification by flash chromatography (EtOAc in PE, 30-100%) afforded a white solid (42 mg, 85% yield). Rf = 0.48 (DCM : MeOH 9: 1); NMR (400 MHz, CDCIs) d 8.74 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 7.57 - 7.49 (m, 3H), 7.42 - 7.30 (m, 4H), 7.25 - 7.18 (m, 3H), 7.09 (d, J = 0.8 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.14 (s, 3H); ESI-HRMS calcd for C22H19CIN3O (M + H⁺) 376.1211, found 376.1200; HPLC t_R = 8.12 min, 93.8% pure. Example 21 : N-(3-Chlorobenzyl)-l-methyl-4-(pyridin-3-yl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (21)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and pyridin-3- ylboronic acid pinacol ester (18 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded white solid (14 mg, 46% yield). R_f = 0.41 (DCM : MeOH 9: 1); NMR (400 MHz, DMSO) d 9.34 (t, J = 6.0 Hz, 1H), 9.06 - 9.05 (m, 1H), 8.98 (dd, J = 2.3, 0.9 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (ddd, J = 7.9, 2.4, 1.7 Hz, 1H), 7.60 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.43 (d, J = 0.9 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.34 - 7.30 (m, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.17 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.0, 148.8, 148.8, 141.6, 137.5, 135.6, 135.2, 135.0, 134.4, 132.9, 132.8, 130.2, 127.9, 127.1, 126.8, 125.9, 125.2, 124.0, 102.4, 41.8, 32.0; ESI-HRMS calcd for C21H18CIN4O (M + H⁺) 377.1164, found 377.1148; HPLC tR = 7.23 and 7.33 min, >99.9% pure.

Example 22: N-(3-Chlorobenzyl)-l-methyl-4-(pyridin-4-yl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (22)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and pyridin-4- ylboronic acid (18 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded white solid (11 mg, 38% yield). Rf = 0.36 (DCM: MeOH 9: 1); NMR (400 MHz, DMSO) d 9.34 (t, J = 6.0 Hz, 1H), 9.09 (s, 1H), 8.75 - 8.73 (m, 2H), 8.45 (s, 1H), 7.79 - 7.77 (m, 2H), 7.45 (d, J = 0.7 Hz, 1H), 7.42 - 7.31 (m, 4H), 4.51 (d, J = 6.0 Hz, 2H), 4.17 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.0, 150.2, 144.6, 141.7, 137.6, 135.5, 135.2, 135.1, 133.0, 130.3, 127.6, 127.2, 126.9, 126.0, 125.7, 123.0, 102.3, 41.8, 32.1; ESI-HRMS calcd for C21H18CIN4O (M + H⁺) 377.1164, found 377.1170; HPLC tR = 6.88 and 7.04 min, 97.4% pure.

Example 23 : N-(3-Chlorobenzyl)-l-methyl-4-(o-tolyl)-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide (23)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and o-tolylboronic acid (12 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white, amorphous solid (23 mg, 74% yield). R_f = 0.50

9.24 (t, J = 6.0 Hz, 1H), 9.02 (s, 1H), 8.10 (s, 1H), 7.42 - 7.24 (m, 8H), 6.93 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H), 2.14 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.0, 141.7, 137.7, 136.4, 135.8, 134.9, 134.7, 133.3, 132.9, 130.3, 130.2, 130.0, 129.4, 129.0, 127.9, 127.1, 126.8, 126.0, 125.9, 102.8, 41.8, 32.1, 19.9; ESI-HRMS calcd for C23H21CIN3O (M + H⁺) 390.1368, found 390.1383; HPLC tR = 8.31 min, 95.8% pure.

Example 24: N-(3-Chlorobenzyl)-l-methyl-4-(m-tolyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (24)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and m-tolylboronic acid (12 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white, amorphous solid (30 mg, 94% yield). R_f = 0.21

9.32 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 7.54 - 7.19 (m, 9H), 4.49 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 2.43 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 141.8,

138.2, 137.0, 137.0, 135.1, 133.4, 132.9, 130.2, 128.9, 128.8, 128.7, 128.5, 128.1, 127.1, 127.0, 126.8, 126.0, 125.5, 102.7, 41.8, 32.0, 21.1; ESI-HRMS calcd for C23H21CIN3O (M + H⁺) 390.1368, found 390.1374; HPLC t_R = 8.41 min, 96.7% pure.

Example 25 : N-(3-Chlorobenzyl)-l-methyl-4-(p-tolyl)-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide (25)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and p-tolylboronic acid (12 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white, amorphous solid (30 mg, 94% yield). Rf = 0.54 (DCM : MeOH 9: 1); NMR spectra are difficult to interpret due to signals that may originate from amide rotamers and/or impurities. ESI-HRMS calcd for C23H21CIN3O (M + H⁺) 390.1368, found 390.1354; HPLC t_R = 8.41 min, 95.1% pure.

Example 26: N-(3-Chlorobenzyl)-4-(4-cyanophenyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (26)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4- cyanophenyl)boronic acid (13 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (20 mg, 63% yield). Rf = 0.45 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.34 (t, J = 5.9 Hz, 1H), 9.07 (s, 1H), 8.40 (s, 1H), 8.05 - 8.01 (m, 2H), 7.98 - 7.94 (m, 2H), 7.42 - 7.29 (m, 5H), 4.50 (d, J = 4.1 Hz, 2H), 4.17 (s, 3H); ESI- HRMS calcd for C23H18CIN4O (M + H⁺) 401.1164, found 401.1152; HPLC t_R = 8.31 min, 97.4% pure. Example 27 : N-(3-Chlorobenzyl)-4-(2-methoxyphenyl)-l -methyl- lH-pyrrolo[2, 3- c]pyridine-2-carboxamide (27)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (2- methoxyphenyl)boronic acid (14 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off- white, amorphous solid (16 mg, 50% yield). Rf = 0.14 (EtOAc); ^ NMR (400 MHz, DMSO) d 9.21 (t, J = 6.0 Hz, 1H), 8.94 (s, 1H), 8.17 (s, 1H), 7.47 - 7.42 (m, 1H), 7.39 - 7.19 (m, 6H), 7.12 - 7.07 (m, 1H), 7.01 (d, J = 0.7 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.13 (s, 3H), 3.74 (s, 3H); ¹³C NMR (101 MHz, DMSO) d

161.3, 156.7, 141.8, 138.6, 134.9, 134.4, 133.2, 132.9, 131.0, 130.2, 129.5,

129.4, 127.0, 126.8, 126.2, 125.9, 125.6, 120.6, 111.8, 103.4, 55.4, 41.7, 31.9; ESI-HRMS calcd for C23H21CIN3O2 (M + H⁺) 406.1317, found 406.1303; HPLC t_R = 8.10 min, 98.2% pure.

Example 28: N-(3-Chlorobenzyl)-4-(4-methoxyphenyl)-l -methyl- lH-pyrrolo[2, 3- c]pyridine-2-carboxamide (28)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4- methoxyphenyl)boronic acid (14 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off- white, amorphous solid (25 mg, 78% yield). Rf = 0.47 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.31 (t, J = 6.0 Hz, 1H), 8.94 (s, 1H), 8.27 (s, 1H), 7.70 - 7.66 (m, 2H), 7.41 - 7.30 (m, 5H), 7.14 - 7.10 (m, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.14 (s, 3H), 3.83 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 159.1, 141.8, 136.9, 135.2, 134.8, 133.1, 132.9, 130.2, 129.5, 128.3, 127.9, 127.2, 126.8, 126.0, 114.5, 102.8, 55.2, 41.8, 32.0; ESI-HRMS calcd for C23H21CIN3O2 (M + H⁺)

406.1317, found 406.1302; HPLC t_R = 8.09 min, 98.1% pure.

Example 29 : N-(3-Chlorobenzyl)-4-(2-hydroxyphenyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (29)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and potassium trifluoro(2-hydroxyphenyl)borate (18 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (18 mg, 58% yield). Rf = 0.38 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.53 (s, 1H), 9.24 (t, J = 5.9 Hz, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 7.39 - 7.23 (m, 6H), 7.08 (d, J = 0.7 Hz, 1H), 7.01 (dd, J = 8.2, 1.1 Hz,

1H), 6.94 (td, J = 7.4, 1.1 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.13 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.3, 154.8, 141.8, 138.7, 135.0, 134.2, 132.9, 132.8, 131.0, 130.2, 129.4, 129.0, 127.2, 126.8, 126.6, 126.0, 123.9, 119.1, 116.0, 103.7, 41.8, 31.9; ESI-HRMS calcd for C22H19CIN3O2 (M + H⁺) 392.1160, found 392.1158; HPLC t_R = 7.83 min, 97.3% pure.

Example 30: N-(3-Chlorobenzyl)-4-(3-hydroxyphenyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (30)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (3- hydroxyphenyl)boronic acid (13 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (25 mg, 81% yield). Rf = 0.34 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.63 (s, 1H), 9.35 (t, J = 6.0 Hz, 1H), 8.97 (s, 1H), 8.26 (s, 1H), 7.43 - 7.28 (m, 6H), 7.16 - 7.09 (m, 2H), 6.88 - 6.84 (m, 1H), 4.48 (d, J = 5.4 Hz, 2H), 4.15 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 157.8, 141.8, 138.4, 137.0, 135.1, 134.9, 133.6, 132.9, 130.2, 129.9, 128.7, 128.0, 127.2, 126.8, 126.0, 119.1, 115.1, 114.8, 102.7, 41.8, 32.0; ESI-HRMS calcd for C22H19CIN3O2 (M + H⁺) 392.1160, found 392.1178; HPLC t_R = 7.79 min, 99.6% pure.

Example 31 : N-(3-Chlorobenzyl)-4-(4-hydroxyphenyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (31)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4- hydroxyphenyl)boronic acid (13 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (21 mg, 68% yield). R_f = 0.37 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.67 (s, 1H), 9.31 (t, J = 6.0 Hz, 1H), 8.91 (s, 1H), 8.24 (s, 1H), 7.59 - 7.53 (m, 2H), 7.41 - 7.29 (m, 5H), 6.97 - 6.92 (m, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.14 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 157.4, 141.8, 136.6, 135.2, 134.7, 132.9, 132.7, 130.2, 129.5, 128.7, 127.9, 127.6, 127.1, 126.8, 126.0, 115.8, 102.9, 41.8, 32.0; ESI-HRMS calcd for C22H19CIN3O2 (M + H⁺) 392.1160, found 392.1153; HPLC t_R = 7.71 min, 99.8% pure.

Example 32: N-(3-Chlorobenzyl)-4-(3-(hydroxymethyl)phenyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (32)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (3- (hydroxymethyl)phenyl)boronic acid (14 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (25 mg, 78% yield). Rf = 0.38 (DCM : MeOH 9: 1); ^ NMR (400 MHz, CDCI3) d 8.54 (s, 1H), 8.05 (s, 1H), 7.66 (t, J = 5.7 Hz, 1H), 7.50 (s, 1H), 7.37 - 7.11 (m, 8H), 6.97 (s, 1H), 4.65 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.01 (s, 3H); ¹³C NMR (101 MHz, CDCb) d 161.9, 142.1, 140.1, 137.6, 137.5, 135.6, 135.5, 134.7, 132.7, 130.1, 129.8, 129.4, 129.0, 127.9, 127.9, 127.6, 127.1, 126.6, 126.0, 102.7, 64.8, 43.2, 32.2; ESI-HRMS calcd for C23H21CIN3O2

(M + H⁺) 406.1317, found 406.1326; HPLC t_R = 7.67 min, 98.9% pure.

Example 33 : N-(3-Chlorobenzyl)-4-(4-(hydroxymethyl)phenyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (33)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and potassium trifluoro(4-(hydroxymethyl)phenyl)borate (19 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (22 mg, 68% yield). Rf = 0.35 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.31 (t, J = 6.0 Hz, 1H), 8.97 (s, 1H), 8.31 (s, 1H), 7.72 - 7.67 (m, 2H), 7.52 - 7.48 (m, 2H), 7.42 - 7.28 (m, 5H), 5.26 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 142.3, 141.8, 137.1, 135.4, 135.1, 135.0, 133.5, 132.9, 130.2, 128.5, 128.1, 127.1, 127.0, 126.8, 126.0, 102.7, 62.6, 41.8, 32.0; ESI- HRMS calcd for C23H21CIN3O2 (M + H⁺) 406.1317, found 406.1297; HPLC t_R = 7.57 and 7.61 min, 99.6% pure.

Example 34: 4-(3-Aminophenyl)-N-(3-chlorobenzyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (34)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (3- aminophenyl)boronic acid monohydrate (14 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off-white solid (10 mg, 32% yield). Rf = 0.40 (DCM : MeOH 9: 1); ^

NMR (400 MHz, DMSO) d 9.32 (t, J = 6.0 Hz, 1H), 8.94 (s, 1H), 8.22 (s, 1H), 7.41

7.29 (m, 5H), 7.18 (t, J = 7.8 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.86 - 6.82 (m,

1H), 6.67 - 6.63 (m, 1H), 5.24 (br s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.14 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.2, 149.2, 141.8, 137.7, 136.8, 135.1, 134.8, 133.2, 132.9, 130.2, 129.5, 129.3, 128.1, 127.2, 126.8, 126.0, 116.0, 113.6, 113.4, 103.0, 41.8, 32.0; ESI-HRMS calcd for C22H20CIN4O (M + H⁺) 391.1320, found 391.1307; HPLC tR = 7.46 and 7.54 min, >99.9% pure.

Example 35 : 4-(4-Aminophenyl)-N-(3-chlorobenzyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (35)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4- aminophenyl)boronic acid pinacol ester (19 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded yellow, amorphous solid (14 mg, 45% yield). Rf = 0.41 (DCM : MeOH 9: 1); ^!H NMR (400 MHz, DMSO) d 9.30 (t, J = 6.0 Hz, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.45 - 7.30 (m, 7H), 6.77 - 6.71 (m, 2H), 5.33 (br s, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.12 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 161.3, 148.7, 141.8, 136.2, 135.2, 134.4, 132.9, 131.9, 130.2, 129.3, 129.0, 127.7, 127.1, 126.8, 125.9, 124.1, 114.2, 103.2, 41.8, 31.9; ESI-HRMS calcd for C22H20CIN4O (M + H⁺) 391.1320, found 391.1309; HPLC t_R = 7.51 min, 99.8% pure.

Example 36: 4-(2-Carbamoylphenyl)-N-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (36)

The title compound was isolated from the reaction of 4-bromo-/V-(3-chlorobenzyl)- l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (2-cyanophenyl)boronic acid (13 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (17 mg, 51% yield). Rf = 0.29 (DCM : MeOH 9: 1); H NMR (400 MHz, DMSO) d 9.23 (t, J = 6.0 Hz, 1H), 8.94 (s, 1H), 8.15 (s, 1H), 7.62 - 7.47 (m, 5H), 7.39 - 7.26 (m, 4H), 7.23 (s, 1H), 7.08 (s, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.13 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 170.4, 161.2, 141.8, 137.9, 137.5, 134.8, 134.7 134.7, 133.2, 132.9, 130.6, 130.2, 129.3, 129.2, 128.4, 127.8, 127.5, 127.1,

126.8, 125.9, 102.9, 41.8, 31.9; ESI-HRMS calcd for C23H20CI N4O2 (M + H⁺) 419.1269, found 419.1285; HPLC t_R = 7.40 and 7.45 min, 99.8% pure.

Example 37 : 4-(3-Carbamoylphenyl)-N-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (37)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (3- carbamoylphenyl)boronic acid (15 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (22 mg, 67% yield). R_f = 0.35 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.33 (t, J = 6.0 Hz, 1H), 9.02 (s, 1H), 8.38 (s, 1H), 8.21 - 8.19 (m, 1H), 8.11 (s, 1H), 7.97 - 7.94 (m, 1H), 7.90 - 7.87 (m, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.41 - 7.29 (m, 5H), 4.49 (d, J = 6.0 Hz, 2H), 4.17 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 167.6, 161.1, 141.7, 137.5, 137.1, 135.2, 135.1, 135.1, 133.9, 133.0, 131.1, 130.2, 128.9, 128.1, 128.0, 127.2, 127.2, 127.0, 126.8, 126.0, 102.5, 41.8, 32.1; ESI-HRMS calcd for C23H20CIN4O2 (M + H⁺) 419.1269, found 419.1278; HPLC tR = 7.40 and 7.49 min, 99.3% pure.

Example 38: 4-(4-Carbamoylphenyl)-N-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (38)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4- carbamoylphenyl)boronic acid (15 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (7.5 mg, 23% yield). R_f = 0.32 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.33 (t, J = 6.0 Hz, 1H), 9.03 (s, 1H), 8.38 (s, 1H), 8.11 - 8.04 (m, 3H), 7.84 -

7.80 (m, 2H), 7.45 (s, 1H), 7.41 - 7.30 (m, 5H), 4.50 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H); ¹³C NMR (101 MHz, DMSO) d 167.4, 161.1, 141.7, 139.8, 137.3, 135.3, 135.1, 134.1, 133.5, 133.0, 130.2, 128.1, 128.1, 128.0, 127.7, 127.2, 126.8, 126.0, 102.6, 41.8, 32.0; ESI-HRMS calcd for C23H20CIN4O2 (M + H⁺) 419.1269, found 419.1290; HPLC tR = 7.24 and 7.32 min, 99.6% pure.

Example 39 : (3-(Pyrrolidin-l-ylmethyl)phenyl)boronic acid pinacol ester (39)

(3-(Bromomethyl)phenyl)boronic acid pinacol ester (200 mg, 0.67 mmol), pyrrolidine (67 pL, 0.81 mmol), KI (5.6 mg, 34 pmol) and anhydrous K2CO3 (279 mg, 2.02 mmol) were mixed in MeCN (5 ml_) under argon and heated to 50 °C for 2 h. The reaction was cooled to rt, filtered and concentrated in vacuo. The crude orange solid (quant, yield) was used for the next reaction without further purification. ESI-HRMS calcd for C17H27BNO2 (M + H⁺) 287.2166, found 287.2152. Example 40: N-(3-Chlorobenzyl)-l-methyl-4-(3-(pyrrolidin-l-ylmethyl)phenyl)- lH-pyrrolo[2,3-c]pyridine-2-carboxamide (40)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (3-(pyrrolidin- l-ylmethyl)phenyl)boronic acid pinacol ester (39) (26 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0- 20%) afforded a yellow, amorphous solid (11 mg, 29% yield). Rf = 0.12

(DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.36 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 8.32 (s, 1H), 7.72 - 7.29 (m, 9H), 4.49 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 3.85 (br s, 2H), 2.63 (br s, 4H), 1.75 (br s, 4H); ESI-HRMS calcd for C27H28CIN4O (M + H⁺) 459.1946, found 459.1952; HPLC t_R = 2.10 and 6.48 min, 99.1% pure. Example 41 : (4-(pyrrolidin-l-ylmethyl)phenyl)boronic acid (41)

(4-(Bromomethyl)phenyl)boronic acid (200 mg, 0.93 mmol), pyrrolidine (93 pL, 1.12 mmol), KI (7.7 mg, 47 pmol) and anhydrous K2CO3 (386 mg, 2.79 mmol) were mixed in MeCN (5 ml_) under argon and heated to 50 °C for 2 h. The reaction was cooled to rt, filtered and concentrated in vacuo. The crude white solid (quant, yield) was used for the next reaction without further purification. ESI-HRMS calcd for C11H17BNO2 (M + H⁺) 205.1383, found 205.1374.

Example 42: N-(3-Chlorobenzyl)-l-methyl-4-(4-(pyrrolidin-l-ylmethyl)phenyl)- lH-pyrrolo[2,3-c]pyridine-2-carboxamide (42)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4-(pyrrolidin- l-ylmethyl)phenyl)boronic acid (41) (19 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 5-20%) afforded a yellow, amorphous solid (2.6 mg, 7.2% yield). Rf = 0.09 (DCM : MeOH 9: 1); ^!H NMR (400 MHz, DMSO) d 9.34 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 8.33 (s, 1H), 7.77 - 7.71 (m, 2H), 7.61 - 7.54 (m, 2H), 7.41 - 7.30 (m, 5H), 4.49 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 3.93 (br s, 2H), 2.74 (br s, 4H), 1.81 (br s, 4H); ESI- HRMS calcd for C27H28CIN4O (M + H⁺) 459.1946, found 459.1941; HPLC t_R = 2.10 and 6.42 min, 98.4% pure.

Example 43: (4-((2-Morpholinoethyl)amino)phenyl)boronic acid pinacol ester

The synthesis of the title compound was adapted from published procedures.²⁸¹ (4-aminophenyl)boronic acid pinacol ester (100 mg, 0.46 mmol), 4-(2- chloroethyl)morpholine hydrochloride (85 mg, 0.46 mmol), KI (19 mg, 0.46 mmol) and K2CO3 (126 mg, 0.91 mmol) were mixed in MeCN (1 ml_) under argon and heated by microwave irradiation at 110 °C for 5 min. The crude reaction mixture was concentrated in vacuo and purification by flash chromatography (EtOAc in PE, 50-100%) afforded an off-white solid (51 mg, 34% yield). ^ NMR (400 MHz, CDCI3) d 7.66 - 7.62 (m, 2H), 6.62 - 6.58 (m, 2H), 4.53 (br s, 1H), 3.74 - 3.70 (m, 4H), 3.20 (t, J = 5.6 Hz, 2H), 2.66 - 2.61 (m, 2H), 2.50 - 2.44 (m, 4H), 1.32 (s, 12H); ¹³C NMR (101 MHz, CDCIs) d 151.1, 136.5, 112.1, 83.4, 67.1, 57.2, 53.5, 39.6, 25.0; ESI-HRMS calcd for C18H30BN2O2 (M + H⁺)

333.2347, found 333.2363.

Example 44: N-(3-Chlorobenzyl)-l-methyl-4-(4-((2- morpholinoethyl)amino)phenyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (44)

The title compound was prepared from 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol) and (4-((2- morpholinoethyl)amino)phenyl)boronic acid pinacol ester (43) (23 mg, 87 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded yellow, amorphous solid (17 mg, 42% yield). Rf = 0.40 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.30 (t, J = 6.0 Hz, 1H), 8.85 (s, 1H), 8.22 (s, 1H), 7.51 - 7.47 (m, 2H), 7.41 - 7.29 (m, 5H), 6.79 - 6.74 (m,

2H), 5.74 (br s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 4.12 (s, 3H), 3.63 - 3.58 (m, 4H), 3.24 - 3.18 (m, 2H), 2.57 - 2.52 (m, 2H), 2.48 - 2.43 (m, 4H); ¹³C NMR (101 MHz, DMSO) d 161.3, 148.7, 141.8, 136.2, 135.2, 134.5, 132.9, 132.0, 130.2, 129.2, 129.0, 127.7, 127.1, 126.8, 125.9, 124.2, 112.4, 103.2, 66.1, 57.0, 53.3, 41.8, 40.2, 31.9; ESI-HRMS calcd for C28H31CIN5O2 (M + H⁺) 504.2161, found 504.2146; HPLC t_R = 2.10 and 6.52 min, 98.4% pure. Example 45: N-(3-Chlorobenzyl)-l-methyl-4-(pyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (45)

The synthesis of the title compound was adapted from published procedures.²⁸² 4- Bromo-/V-(3-chlorobenzyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (18) (30 mg, 79 pmol), pyridine-2-boronic acid /V-phenyldiethanolamine ester (42 mg, 158 pmol), anhydrous K2CO3 (22 mg, 158 pmol), Pd(PPh3)₄ (4.6 mg, 3.96 pmol) and Cul (6.0 mg, 31.7 pmol) were mixed and flushed with argon for 10 min. Degassed, anhydrous 1,4-dioxane (0.4 ml_) was added and the reaction was heated overnight at 90 °C. The reaction was cooled to rt, diluted in EtOAc, mixed with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc in PE, 50- 100%) to give an off-white, amorphous solid (3.4 mg, 11%). Rf = 0.41

(DCM : MeOH 9: 1); ESI-HRMS calcd for C2iHi₈CIN₄0 (M + H⁺) 377.1164, found 377.1169.

Example 46: N-(3-Chlorobenzyl)-l-methyl-4-(phenylamino)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (46)

A mixture of 4-bromo-/V-(3-chlorobenzyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (18) (50 mg, 0.13 mmol), Pd2(dba)3 (4 mg, 4.3 pmol), Xantphos (5 mg, 8.6 pmol) and anhydrous CS2CO3 (48 mg, 145 pmol) were flushed with argon for 10 min. Degassed, anhydrous 1,4-dioxane (1 ml_) and aniline (14 pL, 145 pmol) were added. The capped reaction was stirred for 5 h 40 min until full conversion of the starting material at 100 °C under argon. The reaction progress was followed by TLC. The reaction was cooled to rt, filtered through a pad of celite and concentrated in vacuo. The pure product was obtained from purification by flash chromatography (MeOH in DCM, 0-10%) as a yellow solid (43 mg, 83% yield). R_f = 0.42 (DCM: MeOH 9: 1); NMR (400 MHz, CDCIs) d 8.40 (s, 1H), 8.08 (s, 1H), 7.29 - 7.27 (m, 1H), 7.25 - 7.14 (m, 6H), 6.98 - 6.94 (m, 2H), 6.93 - 6.88 (m, 1H), 6.72 (s, 1H), 6.05 (s, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.06 (s, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.9, 142.9, 140.1, 136.6, 134.7, 133.5, 132.5, 130.2, 129.4, 128.2, 127.9, 127.9, 125.9, 123.4, 121.6, 118.1, 101.3, 43.1, 32.3; ESI-HRMS calcd for C22H20CIN4O (M + H⁺) 391.1320, found 391.1318; HPLC t_R = 7.93 min, 99.4% pure.

Example 47: (R)-4-Bromo-N-(l-(3-chlorophenyl)ethyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (47)

The title compound was prepared from 4-bromo-l-methyl-lF/-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (300 mg, 1.18 mmol) and (R)-l-(3- chlorophenyl)ethan-l-amine (0.37 ml_, 2.35 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 10-100%) afforded an off-white solid (0.33 g, 72% yield). Rf = 0.35 (EtOAc); ^ NMR (400 MHz, DMSO) d 9.24 (d, J = 7.9 Hz, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 7.49 (s, 1H), 7.41 - 7.26 (m, 4H), 5.17 (p, J = 7.1 Hz, 1H), 4.07 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 159.9, 147.0, 139.0, 135.5, 135.1, 133.9, 133.0, 130.4, 130.2, 126.7, 126.0, 124.8, 112.0, 103.0, 48.1, 32.4, 21.9; ESI- HRMS calcd for CiyHieBrCINsO (M + H⁺) 392.0160, found 392.0179; HPLC t_R = 9.84 min, 97.8% pure; [O ]²⁰D = -126° (c = 0.60, DCM).

Example 48: (R)-4-Bromo-N-(l-(3-chlorophenyl)ethyl)-N,l-dimethyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (48)

To solution of (R)-4-bromo-/V-(l-(3-chlorophenyl)ethyl)-l-methyl-lF/-pyrrolo[2,3- c]pyridine-2-carboxamide (47) (30 mg, 76 pmol) in anhydrous THF (0.4 mL) at 0 °C was added NaH 60% in mineral oil (3.7 mg, 92 pmol). The reaction was allowed to warm to rt and stirred for 1 h. Methyl iodide (5 pL, 80 pmol) was added and the reaction was stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc in PE, 50-100%) to give a colorless, amorphous solid (20 mg, 49% yield). Rf = 0.28 (EtOAc); ^ NMR (400 MHz, CDCIs) d 8.74 (s, 1H), 8.39 (s, 1H), 7.43 - 7.07 (m, 4H), 6.64 (s, 1H), 6.16* (s, 1H), 5.43* (s, 1H), 3.95 (s, 3H), 2.86 (br s, 3H), 1.67 (d, J = 7.0 Hz, 3H); ESI-HRMS calcd for CisHisBrCINsO (M + H⁺) 406.0316, found 406.0317; HPLC t_R = 9.85 min, 98.4% pure; [a]²⁰o = +104° (c = 0.60, DCM).

Example 49: (R)-N-(l-(3-Chlorophenyl)ethyl)-4-(4-hydroxyphenyl)-l-methyl- lH-pyrrolo[2,3-c]pyridine-2-carboxamide (49)

The title compound was prepared from (R)-4-bromo-/V-(l-(3-chlorophenyl)ethyl)- l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (47) (50 mg, 127 pmol) and (4-hydroxyphenyl)boronic acid (20 mg, 141 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-20%) afforded a white solid (21 mg, 41% yield). Rf = 0.43 (DCM : MeOH 9: 1); NMR (400 MHz, DMSO) d 9.69 (s, 1H), 9.08 (d, J = 7.9 Hz, 1H), 8.89 (s, 1H), 8.23 (s, 1H), 7.59 - 7.54 (m, 2H), 7.47 - 7.45 (m, 1H), 7.42 - 7.35 (m, 3H), 7.33 - 7.28 (m, 1H), 7.00 - 6.95 (m, 2H), 5.17 (p, J = 7.1 Hz, 1H), 4.08 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 160.5, 157.4, 147.1, 136.7, 135.1, 134.8, 133.0, 132.7, 130.2, 129.5, 128.8, 127.9, 127.8, 126.7, 125.9, 124.8, 115.8, 102.9, 48.0, 31.9, 21.9; ESI-HRMS calcd for C23H21CIN3O2 (M + H⁺) 406.1317, found

406.1337; HPLC t_R = 7.84 and 7.88 min, 96.9% pure; [a]²⁰o = -281° (c = 0.50, DMSO).

Example 50: (S)-4-Bromo-N-(l-(3-chlorophenyl)-2-hydroxyethyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (50)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (254 mg, 1.0 mmol) and (S)-2-amino-2-(3- chlorophenyl)ethan-l-ol (150 mg, 0.83 mmol) according to general procedure C2. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded a white solid (298 mg, 88% yield). Rf = 0.39 (EtOAc); H NMR (400 MHz, DMSO) d 9.15 (d, J = 8.1 Hz, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 7.51 - 7.49 (m, 1H), 7.41 - 7.26 (m, 4H), 5.11 - 5.05 (m, 2H), 4.07 (s, 3H), 3.77 - 3.63 (m, 2H); ¹³C NMR (101 MHz, DMSO) d 160.5, 143.3, 139.0, 135.6, 135.1, 133.9, 132.9, 130.4, 130.1, 127.0, 126.8, 125.9, 112.0, 103.2, 64.0, 55.3, 32.3; ESI-HRMS calcd for

CiyHieBrCINsOz (M + H⁺) 408.0109, found 408.0117; HPLC t_R = 8.28 min, 98.1% pure; [a]²⁰o = -105° (c = 0.50, DMSO).

Example 51: (S)-4-Bromo-N-(l-(3-chlorophenyl)-2-methoxyethyl)-l-methyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (51)

To a solution of (S)-4-bromo-/V-(l-(3-chlorophenyl)-2-hydroxyethyl)-l-methyl- lF/-pyrrolo[2,3-c]pyridine-2-carboxamide (50) (16 mg, 39 pmol) in anhydrous THF (0.4 ml_) at 0 °C was added NaH 60% in mineral oil (1.6 mg, 41 pmol). The reaction was allowed to warm to rt and stirred for 1 h. Methyl iodide (2.6 pL, 41 pmol) was added and the reaction was stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc in PE, 50-100%) to give a colorless, amorphous solid (1.3 mg, 8.1% yield). Rf = 0.42 (EtOAc); ^!H NMR (400 MHz, CDCIs) d 8.78 (s, 1H), 8.42 (s, 1H), 7.42 - 7.39 (m, 1H), 7.34 - 7.26 (m, 3H), 7.11 - 7.06 (m, 1H), 6.95 (s, 1H), 5.29 - 5.24 (m,

1H), 4.12 (s, 3H), 3.78 (dd, J = 9.8, 4.3 Hz, 1H), 3.72 (dd, J = 9.8, 5.1 Hz, 1H), 3.43 (s, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.1, 141.7, 140.5, 135.1, 134.8, 133.1, 133.1, 131.7, 130.2, 128.2, 127.1, 125.2, 103.1, 74.7, 59.4, 53.1, 32.7; ESI-HRMS calcd for CisHisBrCINsOz (M + H⁺) 422.0265, found 422.0248;

Example 52: (S)-2-(4-Bromo-l-methyl-lH-pyrrolo[2,3-c]pyridine-2- carboxamido)-2-(3-chlorophenyl)ethyl acetate (52)

The title compound was isolated from the following reaction. The title compound may have formed during the work-up from unreacted, deprotonated starting material. The desired compound (S)-4-bromo-/V-(l-(3-chlorophenyl)-2- isopropoxyethyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide was not observed.

To a solution of (S)-4-bromo-/V-(l-(3-chlorophenyl)-2-hydroxyethyl)-l-methyl- lH-pyrrolo[2,3-c]pyridine-2-carboxamide (50) (30 mg, 73 pmol) in anhydrous THF (0.4 ml_) at 0 °C was added NaHMDS 1 M in THF (73 pL, 73 pmol). The reaction was allowed to warm to rt and stirred for 30 min. Isopropyl bromide (6.9 pL, 73 pmol) was added and the reaction was stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄ and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc in PE, 10-100%) to give a colorless, amorphous solid (18 mg, 54% yield). Rf = 0.41 (EtOAc);

NMR (400 MHz, CDCIs) d 8.77 (s, 1H), 8.41 (s, 1H), 7.40 - 7.27 (m, 4H), 7.24 (d, J = 7.0 Hz, 1H), 6.94 (s, 1H), 5.39 (td, J = 7.6, 4.0 Hz, 1H), 4.58 (dd, J = 11.9, 7.9 Hz, 1H), 4.35 (dd, J = 11.9, 4.1 Hz, 1H), 4.12 (s,

3H), 2.12 (s, 3H); ¹³C NMR (101 MHz, CDCIs) d 171.9, 161.1, 140.5, 140.0,

135.8, 135.2, 134.7, 133.1, 131.7, 130.5, 128.7, 127.0, 125.0, 113.3, 103.3, 66.1, 53.5, 32.7, 21.0; ESI-HRMS calcd for CigHisBrCINsOs (M + H⁺) 450.0215, found 450.0206; HPLC tR = 9.80 min, 98.6% pure; [O ] ²⁰D = -116° (c = 0.50, DCM).

Example 53: (S)-N-(l-(3-Chlorophenyl)-2-hydroxyethyl)-4-(4-hydroxyphenyl)-l- methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (53)

The title compound was prepared from (S)-4-bromo-/V-(l-(3-chlorophenyl)-2- hydroxyethyl)-l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (50) (20 mg, 49 pmol) and (4-hydroxyphenyl)boronic acid (8 mg, 54 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 5- 10%) afforded a white solid (12 mg, 58% yield). Rf = 0.29 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.69 (s, 1H), 8.99 (d, J = 8.1 Hz, 1H), 8.89 (s, 1H), 8.23 (s, 1H), 7.61 - 7.55 (m, 2H), 7.47 (s, 1H), 7.43 (s, 1H), 7.39 - 7.30 (m, 3H), 7.00 - 6.95 (m, 2H), 5.12 - 5.03 (m, 2H), 4.07 (s, 3H), 3.76 - 3.61 (m, 2H); ¹³C NMR (101 MHz, DMSO) d 161.0, 157.4, 143.5, 136.8, 135.1, 134.9, 132.8, 132.7, 130.1, 129.5, 128.8, 127.9, 127.8, 126.9, 126.8, 125.9, 115.8, 103.0, 64.0, 55.2, 31.9; ESI-HRMS calcd for C23H21CIN3O3 (M + H⁺) 422.1266, found 422.1286; [O ]²⁰D = -277° (c = 0.25, DMSO).

Example 54: (S)-4-Bromo-N-(l-(3-chlorophenyl)ethyl)-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (54)

The title compound was prepared from 4-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (10) (100 mg, 0.39 mmol) and (S)-l-(3- chlorophenyl)ethan-l-amine (0.11 ml_, 0.78 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 10-100%) afforded an off-white solid (0.141 g, 92% yield). Rf = 0.35 (EtOAc); ^ NMR (400 MHz, DMSO) d 9.24 (d, J = 7.8 Hz, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 7.49 (s, 1H), 7.41 - 7.27 (m, 4H), 5.17 (p, J = 7.0 Hz, 1H), 4.07 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 159.9, 147.0, 139.0, 135.5, 135.1, 133.9, 133.0, 130.4, 130.2, 126.7, 126.0, 124.8, 112.0, 103.0, 48.1, 32.3, 21.9; ESI- HRMS calcd for CiyHieBrCINsO (M + H⁺) 392.0160, found 392.0147; HPLC t_R = 9.86 min, 97.8% pure; [a]²⁰o = +135° (c = 0.55, DCM).

Example 55: (S)-N-(l-(3-Chlorophenyl)ethyl)-4-(4-hydroxyphenyl)-l-methyl- lH-pyrrolo[2,3-c]pyridine-2-carboxamide (55)

The title compound was prepared from (S)-4-bromo-/V-(l-(3-chlorophenyl)ethyl)- l-methyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (54) (50 mg, 127 pmol) and (4-hydroxyphenyl)boronic acid (20 mg, 141 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-20%) afforded a white solid (21 mg, 40% yield). Rf = 0.43 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.68 (s, 1H), 9.08 (d, J = 7.9 Hz, 1H), 8.89 (s, 1H), 8.23 (s, 1H), 7.59 - 7.54 (m, 2H), 7.47 - 7.45 (m, 1H), 7.41 - 7.35 (m, 3H), 7.33 - 7.28 (m, 1H), 6.99 - 6.95 (m, 2H), 5.17 (p, J = 7.0 Hz, 1H), 4.08 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 160.5, 157.4, 147.1, 136.8, 135.1, 134.8, 133.0, 132.7, 130.2, 129.5, 128.8, 127.9, 127.8, 126.7, 125.9, 124.8, 115.8, 102.9, 47.9,

31.9, 21.9; ESI-HRMS calcd for C23H21CIN3O2 (M + H⁺) 406.1317, found

406.1322; HPLC t_R = 7.85 and 7.88 min, 97.6% pure; [a]²⁰o = +261° (c = 0.30, DMSO).

Example 56: Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (56)

The title compound was prepared according to published literature.²²³ To as suspension of 3,5-dibromopyridine-4-carboxaldehyde (1.00 g, 3.59 mmol) and anhydrous CS2CO3 (1.29 g, 3.94 mmol) in anhydrous THF (17 ml_) in a 20 ml_ microwave vial under argon was added methyl thioglycolate (0.34 ml_, 3.59 mmol). The capped reaction was heated to 60 °C for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude product was diluted in EtOAc, mixed with water and extracted with EtOAc (3x). The combined organic phase was washed with water (lx) and brine (2x), dried over Na2S0₄, filtered and concentrated in vacuo to give a white solid (0.75 g, 77%) that was used for the next reaction without further purification. ^ NMR (400 MHz, CDCb) d 9.08 (s, 1H), 8.65 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 4.01 (s, 3H); ¹³C NMR (101 MHz, CDCb) d 162.3, 145.0, 144.1, 139.7, 138.4, 129.2, 116.3, 53.3; ESI-HRMS calcd for CgHyBrNC S (M + H⁺) 271.9375, found 271.9377; HPLC t_R = 11.57 min.

Example 57: 4-Bromothieno[2,3-c]pyridine-2-carboxylic acid (57)

The title compound was prepared from methyl 4-bromothieno[2,3-c]pyridine-2- carboxylate (56) (0.70 g, 2.57 mmol) according to general procedure B2. The product was obtained as white solid (0.64 g, 96% yield). Rf = 0.25 (DCM : MeOH 9: 1); ^!H NMR (400 MHz, DMSO) d 14.21 (br s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 7.95 (s, 1H); ¹³C NMR (101 MHz, DMSO) d 162.5, 145.0, 144.3, 143.3, 142.1, 137.7, 127.1, 115.0; ESI-HRMS calcd for C8H₅BrN0₂S (M + H⁺) 257.9219, found 257.9228; HPLC t_R = 9.70 min, 99.0% pure. Example 58: (R)-4-Bromo-N-(l-(3-chlorophenyl)ethyl)thieno[2,3-c] pyridine-2- carboxamide (58)

The title compound was prepared from 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (58) (300 mg, 1.16 mmol) and (R)-l-(3-chlorophenyl)ethan-l-amine (0.33 ml_, 2.32 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 0-50%) afforded a yellow solid (296 mg, 64% yield). R_f = 0.53 (DCM: MeOH 9: 1); NMR (400 MHz, DMSO) d 9.51 (d, J = 7.7 Hz, 1H), 9.29 (s, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 7.49 - 7.20 (m, 4H), 5.16 (p, J = 7.1 Hz, 1H), 1.53 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 159.7, 147.0, 146.6, 144.5, 144.2, 144.2, 136.9, 133.0, 130.3, 126.9, 126.0, 124.9, 123.0, 114.9, 48.7, 21.8; ESI-HRMS calcd for CieHisBrCINzOS (M + H⁺)

394.9615, found 394.9630; HPLC t_R = 12.63 min, 99.3% pure; [a]²⁰o = -101° (c = 0.60, DCM).

Example 59: (R)-N-(l-(3-Chlorophenyl)ethyl)-4-(4-hydroxyphenyl)thieno[2,3- c]pyridine-2-carboxamide (59)

The title compound was prepared from (R)-4-bromo-/V-(l-(3- chlorophenyl)ethyl)thieno[2,3-c]pyridine-2-carboxamide (58) (30 mg, 76 pmol) and (4-hydroxyphenyl)boronic acid (12 mg, 83 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded yellow solid (24 mg, 76% yield). Rf = 0.47 (DCM: MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.80 (s, 1H), 9.35 (d, J = 7.7 Hz, 1H), 9.23 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.52 - 7.28 (m, 6H), 7.03 - 6.97 (m, 2H), 5.14 (p, J = 7.1 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 160.3, 157.8, 146.7, 145.3, 143.3, 142.6, 142.2, 136.6, 133.0, 132.7, 130.3, 130.2, 127.1, 126.8, 126.0, 124.9, 122.7, 115.9, 48.6, 21.7; ESI-HRMS calcd for C22H18CIN2O2S (M + H⁺) 409.0772, found 409.0759; HPLC t_R = 10.21 min, 99.1% pure; [a]²⁰o = - 225° (c = 0.60, DMSO). Example 60: (S)-4-Bromo-N-(l-(3-chlorophenyl)-2-hydroxyethyl)thieno[2,3- c]pyridine-2-carboxamide (60)

The title compound was prepared from 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (57) (86 mg, 0.33 mmol) and (S)-2-amino-2-(3-chlorophenyl)ethan-l-ol (50 mg, 0.28 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 5-100%) afforded a yellow solid (45 mg, 40% yield). Rf = 0.42 (EtOAc); NMR (400 MHz, DMSO) d 9.45 (d, J = 8.0 Hz, 1H), 9.30 (s, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.44 (s, 1H), 7.51 - 7.48 (m, 1H), 7.40 - 7.31 (m, 3H), 5.15 - 5.05 (m, 2H), 3.79 - 3.67 (m, 2H); ¹³C NMR (101 MHz, DMSO) d 160.3, 147.0, 144.5, 144.2, 144.2, 143.0, 136.9, 132.9, 130.1, 127.1, 126.8, 125.9, 123.1, 114.9, 63.9, 55.8; ESI-HRMS calcd for Ci6Hi3BrCIN₂02S (M + H⁺) 410.9564, found 410.9555; [a]²⁰o = -116° (c = 0.25, DMSO).

Example 61: (S)-N-(l-(3-Chlorophenyl)-2-hydroxyethyl)-4-(4-(pyrrolidin-l- ylmethyl)phenyl)thieno[2,3-c]pyridine-2-carboxamide (61)

The title compound was prepared from (S)-4-bromo-/V-(l-(3-chlorophenyl)-2- hydroxyethyl)thieno[2,3-c]pyridine-2-carboxamide (60) (30 mg, 73 pmol) and (4-(pyrrolidin-l-ylmethyl)phenyl)boronic acid (16 mg, 80 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 5- 20%) afforded a yellow solid (14 mg, 38% yield). Rf = 0.12 (DCM : MeOH 9: 1); ^ NMR (400 MHz, DMSO) d 9.32 (d, J = 8.0 Hz, 1H), 9.29 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.68 - 7.64 (m, 2H), 7.59 - 7.55 (m, 2H), 7.46 - 7.44 (m, 1H), 7.40 - 7.30 (m, 3H), 5.11 - 5.03 (m, 2H), 3.80 - 3.64 (m, 4H), 2.59 (br s, 4H), 1.80 - 1.73 (m, 4H); ¹³C NMR (101 MHz, DMSO) d 160.8, 145.7, 144.1, 143.1, 142.6, 142.4, 136.6, 135.2, 132.9, 132.3, 130.1, 129.2, 128.9, 127.0, 126.8, 125.9, 122.6, 63.8, 58.9, 55.8, 53.6, 23.1; ESI-HRMS calcd for C27H27CIN3O2S 492.1507 (M + H⁺), found 492.1508; [O ]²⁰D = -122° (c = 0.20, DCM). Example 62: Ethyl l-ethyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (62)

The title compound was prepared from ethyl lH-pyrrolo[2,3-c]pyridine-2- carboxylate (1) (100 mg, 0.53 mmol) and ethyl iodide (44 pL, 0.55 mmol) according to general procedure A. Purification by flash chromatography (MeOH in DCM, 0-20%) afforded a white solid (81 mg, 71% yield). Rf = 0.50 (DCM : MeOH 9: 1); ^!H NMR (400 MHz, CDCIs) d 8.91 (s, 1H), 8.30 (d, J = 5.4 Hz, 1H), 7.55 (d, J = 5.5 Hz, 1H), 7.25 (s, 1H), 4.71 (q, J = 7.1 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.6, 139.3, 135.1, 134.7, 130.5, 130.3, 116.4, 108.9, 61.2, 40.3, 16.1, 14.4. Example 63: l-Ethyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (63)

The title compound was prepared from ethyl l-ethyl-lff-pyrrolo[2,3-c]pyridine-2- carboxylate (62) (80 mg, 0.37 mmol) according to general procedure Bl. The crude product was obtained as white solid (70 mg, quant, yield) and used directly without further purification. ESI-HRMS calcd for C10H11N2O2 (M + H⁺) 191.0815, found 191.0824.

Example 64: N-(3-Chlorobenzyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (64)

The title compound was prepared from l-ethyl-lff-indole-2-carboxylic acid (63) (50 mg, 0.26 mmol) and (3-chlorophenyl)methanamine (32 mI_, 0.26 mmol) according to general procedure Cl. Purification by flash chromatography (EtOAc) afforded an off-white solid (14 mg, 17% yield). Rf = 0.21 (EtOAc); ^ NMR (400 MHz, CDCIs) d 8.85 (s, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.49 (dd, J = 5.4, 1.0 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.30 - 7.22 (m, 3H), 6.92 (br t, J = 6.4 Hz, 1H), 6.84 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.63 (d, J = 6.0 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) d 161.9, 140.1, 139.3, 134.9, 134.7, 134.4, 134.3, 131.0, 130.3, 128.1, 127.9, 126.0, 115.9, 102.9, 43.3, 40.3, 16.3; ESI- HRMS calcd for C17H17CIN3O (M + H⁺) 314.1055, found 314.1050; t_R = 7.21 and 7.31 min, 99.4% pure.

Example 65: Methyl 4-bromo-l-ethyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylate

The title compound was prepared from methyl 4-bromo-lH-pyrrolo[2,3- c]pyridine-2-carboxylate (8) (200 mg, 0.78 mmol) and ethyl iodide (66 pL, 0.82 mmol) according to general procedure A. Purification by flash chromatography (EtOAc in PE, 0-100%) afforded an off-white solid (0.146 g, 66% yield). Rf = 0.50 (EtOAc); ^!H NMR (400 MHz, CDCIs) d 8.81 (s, 1H), 8.43 - 8.38 (m, 1H), 7.28 (d, J = 0.8 Hz, 1H), 4.70 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H);

¹³C NMR (101 MHz, CDCIs) d 161.6, 140.2, 135.1, 133.3, 131.5, 130.4, 113.9, 109.2, 52.4, 40.9, 16.1; ESI-HRMS calcd for CiiHi₂BrN₂02 (M + H⁺) 283.0077, found 283.0074; HPLC t_R = 10.11 min.

Example 66: 4-Bromo-l-ethyl-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (66)

The title compound was prepared from methyl 4-bromo-l-ethyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylate (65) (126 mg, 0.45 mmol) according to general procedure B2. The product was obtained as white solid (119 mg, quant yield). ^ NMR (400 MHz, DMSO) d 13.72 (br s, 1H), 9.09 (s, 1H), 8.36 (s, 1H), 7.10 (s, 1H), 4.72 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 161.8, 139.1, 134.6, 134.3, 131.9, 130.1, 112.4, 107.2, 40.2, 15.9; ESI-HRMS calcd for CioHioBrN₂0₂ (M + H⁺) 268.9920, found 268.9920.

Example 67: (R)-4-Bromo-N-(l-(3-chlorophenyl)ethyl)-l-ethyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide (67)

The title compound was prepared from 4-bromo-l-ethyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (66) (86 mg, 0.32 mmol) and (R)-l-(3- chlorophenyl)ethan-l-amine (90 pL, 0.64 mmol) according to general procedure C2. Purification by flash chromatography (EtOAc in PE, 0-100%) afforded an off- white solid (98 mg, 75% yield). ^ NMR (400 MHz, CDCIs) d 8.78 (s, 1H), 8.39 (s, 1H), 7.39 - 7.37 (m, 1H), 7.35 - 7.27 (m, 3H), 6.86 (d, J = 0.6 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 5.28 (p, J = 7.1 Hz, 1H), 4.63 (q, J = 7.2 Hz, 2H), 1.63 (d, J = 7.0 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) d 160.6, 144.9, 140.3, 135.0, 134.8, 134.7, 133.0, 131.9, 130.4, 128.0, 126.4, 124.5, 113.3, 102.9, 49.2, 41.0, 22.0, 16.3; ESI-HRMS calcd for CisHisBrCINsO (M + H⁺)

406.0316, found 406.0317; HPLC t_R = 10.53 min, 98.8% pure; [a]²⁰o = -132° (c = 0.50, DCM).

Example 68: (R)-N-(l-(3-Chlorophenyl)ethyl)-l-ethyl-4-(4-hydroxyphenyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (68)

The title compound was prepared from (R)-4-bromo-/V-(l-(3-chlorophenyl)ethyl)- l-ethyl-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (67) (30 mg, 74 pmol) and (4- hydroxyphenyl)boronic acid (12 mg, 81 pmol) according to general procedure D. Purification by flash chromatography (MeOH in DCM, 0-10%) afforded an off- white solid (13 mg, 42% yield). Rf = 0.42 (DCM : MeOH 9: 1);

NMR (400 MHz, DMSO) d 9.69 (s, 1H), 9.10 (d, J = 7.9 Hz, 1H), 8.93 (s, 1H), 8.23 (s, 1H), 7.58 - 7.54 (m, 2H), 7.46 - 7.44 (m, 1H), 7.41 - 7.28 (m, 4H), 6.99 - 6.95 (m, 2H), 5.17 (p, J = 6.9 Hz, 1H), 4.63 (q, J = 6.9 Hz, 2H), 1.48 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, DMSO) d 160.5, 157.4, 147.2, 136.7, 134.3, 134.0, 133.0, 132.5, 130.2, 129.5, 129.0, 128.1, 127.8, 126.7, 125.9, 124.8, 115.8, 103.1, 48.0, 39.5, 21.9, 16.0; ESI-HRMS calcd for C24H23CIN3O2 (M + H⁺) 420.1473, found 420.1462; HPLC t_R = 8.03 min, 99.6% pure; [O ]²⁰D = - 246° (c = 0.25, DMSO).

Example 69: Potency determination using the luminometric assay.

Table 1 : Potency (IC50) and relative enzymatic activity (EA) at 10 pM for selected compounds of the invention using the luminometric assay.

Table 1 shows selected compounds according to the invention. As can be seen from the Table 1, the compounds according to the invention possess potencies in the low micro-molar range.

Example 70: Potency determination with the [³²P]ATP assay.

Table 2: Potency (ICso) and relative enzymatic activity (EA) at 10 mM for selected compounds of the invention using the [³²P]ATP assay. ^a

When keeping the ATP concentration the same as used for the primary screens (10 pM), an obvious difference between Compound C and the pyrrolo[2,3- c]pyridines becomes visible as represented in Table 2. At 10 pM ATP, Compound C suffered from a drastic decrease in potency in the presence of AMP (200 pM), whereas the pyrrolo[2,3-c]pyridines merely showed a minor deviation in potency from the assay without AMP. Furthermore, when tested at 10-fold increased ATP concentration (100 mM) and addition of AMP (200 mM), Compound C, 31, and 44 all showed erosion of potency (Table 2 and Figure 1) as is expected from ATP- competitive kinase inhibitors. Then again, the overall change in potency for Compound C was more pronounced with about 20-fold decrease in potency (data from measurements at 10 mM ATP and 100 mM ATP + 200 mM AMP) compared to an approximately 4-fold lower potency for 31 and 44. Thus, the data indicated stronger binding of the pyrrolo[2,3-c]pyridines to the active enzyme when compared to Compound C.

Example 71: Biological evaluation of compound 61

Compound 61 was evaluated in a RBC atypical kinase panel screen. The kinase HotSpot radiometric assay was performed by the CRO RBC as previously reported.¹⁷ Data from one experiment measured in duplicates is shown (Table 3). Besides the listed eight AMPK complexes, the RBC atypical kinase panel further includes the following 12 kinases:

DNA-PK DNA-dependent protein kinase

eEF2 Eukaryotic elongation factor 2 kinase

EIF2AK1/2/3/4 Eukaryotic translation initiation factor 2-alpha kinase 1, 2, 3, and 4

mTOR/FRAPl Mechanistic target of rapamycin

PDHK1/2/3/4 Pyruvate dehydrogenase kinase 1, 2, 3, and 4

TRPM7/CHAK1 Transient receptor potential cation channel subfamily M

member 7/channel-kinase 1

Table 3: RBC's atypical kinase panel screen for compound 61. ^£

The panel screen carried out by the CRO Reaction Biology Corp. (RBC), Malvern, PA, USA, included, besides the herein studied heterotrimeric AMPK complex a2b1g1, seven additional human AMPK complexes along with 12 other kinases. All AMPK complexes were inhibited to a similar extend as the complex a2b1g1 whereas 62 did not cause any reasonable inhibition of the other 12 kinases.

Example 72: Biological evaluation of compound 61

Compound 61 was evaluated in an ICKP express kinase panel screen. The radiometric assay was performed by the CRO ICKP as previously reported.¹⁸ _' ¹⁹ Data from one experiment measured in duplicates is shown (Figure 2 & Table 4). Besides the AMPK complex a1b2g1, the ICKP express panel includes another 49 kinases listed below:

Aurora B Aurora kinase B

BTK Bruton agammaglobulinemia tyrosine kinase

CaMKl (CAMK1) Ca2+/calmodulin-dependent protein kinase 1

CaMK^ (CAMKKb) Ca2+/calmodulin-dependent protein kinase kinase 2

CHK2 Checkpoint kinase 2

CK16 Casein kinase 1

CK2al (CK2) Casein kinase 2

DYRK1A Dual specificity tyrosine-phosphorylation-regulated kinase 1A eEF2 (EF2K) Eukaryotic elongation factor 2 kinase EPHA2 Ephrin receptor A2

GSk^ Glycogen synthase kinase 3 beta

HER4 V-erb a erythroblastic leukemia viral oncogene homolog 1

HIPK2 Homeodomain-interacting protein kinase 2

IGF1R Insulin-like growth factor 1 receptor

IRAK4 Interleukin-1 receptor-associated kinase 4

JAK3 Janus kinase 3

JNK1 c-Jun N-terminal kinase

Lck Lymphocyte kinase

LKB1 Liver kinase B1

MAPKAP-Kla/RSKl/p90RSK (RSK1) MAPK-activated protein kinase la MARK3 MAP/microtubule affinity-regulating kinase 3

MKK1 Dual specificity mitogen-activated protein kinase kinase 1

MLK3 Mixed lineage kinase 3

MSK1 Mitogen- and stress-activated protein kinase 1

MST2 Mammalian STE20-like protein kinase 2

NEK6 NIMA related protein kinase 6

r38a MAPK Stress-activated protein kinase 2a

PAK4 p21-activated kinase 4

PDK1 3-Phosphoinositide-dependent protein kinase 1

PIM 1 Serine/threonine-protein kinase pirn 1

RKAa (PKA) Protein kinase A

RKBa/Akt Protein kinase B

PKCa Protein kinase C

PKD1 Protein kinase D 1

PLK1 Polo like kinase 1

PRK2 PKC-like kinase 2

RIPK2 Receptor-interacting protein kinase 2

ROCK2 Rho-associated protein kinase 2

S6K1 p70 ribosomal protein S6 kinase

SGK1 Serum/glucocorticoid-regulated kinase 1

SmMLCK Smooth muscle myosin light chain kinase

Src Sarcoma kinase

SRPK1 Serine/arginine-rich protein-specific kinase 1

SYK Spleen tyrosine kinase TAK1 Transforming growth factor-beta-activated kinase 1

TBK1 TANK-binding kinase 1

TrkA Neurotrophic tyrosine kinase receptor type 1

TTK Phosphotyrosine picked threonine-protein kinase VEGFRl/Ftll Vascular endothelial growth factor receptor 1

Table 4: ICKP express panel screen for compound 61. ^a

The kinase panel screen performed by the CRO International Center for Kinase Profiling (ICKP), Dundee, UK, comprises a selection of 50 representative kinases from the human kinome including the human AMPK complex a1b2g1. Although this AMPK complex still showed 58 ± 9% remaining activity after repeated measurements, only five more kinases including CK2, PDK1, PKA, Akt and PRK2 were found to be inhibited to a similar extent. The remaining 44 kinases in the ICKP panel were not inhibited (remaining activity >85%) by compound 61 at the test concentration of 1 mM.

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Items according to the invention

1. A compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), Ci- C10 alkyl sulfonate (-S03-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHSC>2(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

X is selected from NMe, NEt or S;

W is CH2, NH, 0, S or a bond; and

further wherein, R² may optionally be linked via a carbon chain (-CH2-)m to Z, wherein m is 2 or 3, to form a 5 or 6 membered heterocyclic ring.

2. The compound according to item 1, with the proviso that:

when X is S and Ri is a 6 membered aryl para-substituted with a halogene then

W is not 0,

when X is N, W is a bond, Ri is H, R2 is H, and Z is CH3 then R3 is not phenyl, or when X is N, R2 and Z are H, and R3 is a 6 membered heteroaryl with the heteroatom of said heteroaryl numbers 1 then the hetero atom is not N. 3. A compound of according to item 1 or 2, wherein Ri is a 5- or 6-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1; and

R3 is Ci-Cio alkyl, C3-C6 cycloalkyl or a 6-membered aryl.

4. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl; and R3 is a 6-membered aryl.

5. A compound according to any one of the preceding items, wherein W is NH or a bond.

6. A compound according to any one of the preceding items, wherein R3 is a 6- membered aryl, wherein said aryl is substituted with one or more substituents, which are the same or different and are independently selected from halogens and C1-C10 alkyl.

7. A compound according to any one of the preceding items, wherein R3 is a 6- membered aryl, wherein said aryl is substituted with one or more substituents, which are the same or different and are independently selected from halogens.

8. A compound according to any one of the preceding items, wherein R3 is a 6- membered aryl, wherein said aryl is substituted with a substituent, which is independently selected from chlorine or fluorine. 9. A compound according to any one of the preceding items, wherein Z is H, - (CH2)nU or -(CH2)NH(CH2)nU, wherein n is 1 or 2.

10. A compound according to any one of the preceding items, wherein Z is H, - (CH2)nU or -(CH2)NH(CH2)nU, wherein n is 1.

11. A compound according to any one of the preceding items, wherein Z is H or - (CH₂)nU . 12. A compound according to any one of the preceding items, wherein U is H,

NH2, N HCHS, N (CH₃)2, NHCOCHs, NHCONH2, OH, OCHs, OAc, CONH2, CONHCH3 or SO2NH2; 13. A compound according to any one of the preceding items, wherein U is H,

NH₂, NHCHS, NHCONH2, OH, OCHs, OAc, CONH2, or SO2NH2;

14. A compound according to any one of the preceding items, wherein U is H, OH, OCHs, OAc, or CONH2;

15. A compound according to any one of the preceding items, wherein

U is H or OH.

16. A compound according to any one of the preceding items, wherein

U is OH.

17. A compound according to any one of the preceding items, wherein Ri is halogen or a 6-membered aryl, wherein said aryl is meta and/or para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH₂NH(CI-CIO alkyl), -CH₂N(CI-CIO alkyl)₂, -NH(Ci-Cio alkyl), - N(Ci-Cio al ky 1)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH, S or O; a is the integer 1-3; b is 2 or 3 and c is 3 or 4. 18. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CIO alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH, S or 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4; and R3 is a 6-membered aryl, wherein said aryl is meta substituted with a chlorine or fluorine.

19. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CIO alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH or 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4;

and R3 is a 6-membered aryl, wherein said aryl is meta substituted with a chlorine.

20. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CS alkyl)2, -CONH2, hydroxyl (-OH), C1-C5 alkyl hydroxyl (-alkyl-OH),

wherein A is O; a is 1 or 2; b is 2 or 3 and c is 3 or 4. 21. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CS alkyl)2, -CONH2, hydroxyl (-OH), C1-C5 alkyl hydroxyl (-alkyl-OH),

wherein A is 0; a is 1 or 2; b is 2 and c is 3. 22. A compound according to any one of the preceding items, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with -CH2N(CH2)₄; and R3 is aryl, wherein said aryl is meta substituted with chlorine. 23. A compound according to any one of the preceding items, wherein Ri is H, halogen, or a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; R2 is hydrogen or methyl; R3 is methyl, cyclo propyl or a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; X is selected from NMe, NEt or S; and W is NH or a bond.

24. A compound according to any one of the preceding claims, wherein X is NMe or S.

25. A compound according to any one of the preceding items, wherein X is S; and W is NH or a bond; and Z is CH2OH.

26. A compound according to any one of the preceding items, wherein X is NMe; and W is NH or a bond; and Z is CH2OH. 27. A compound according to any one of the preceding items, wherein the compound is a racemate.

28. A compound according to any one of items 1-26, wherein the compound is the enantiomer of Formula (II).

29. A compound according to any one of items 1-26, wherein the compound is the enantiomer of Formula (III).

30. A compound according to any one of the preceding items, wherein the compound is a crystalline solid.

31. A compound according to any one of the preceding items, wherein the compound is an amorphous solid. 32. A pharmaceutically acceptable salt of a compound according to any one of the preceding items.

33. A prodrug, such as an ester, of a compound according to any one of the preceding items.

34. A pharmaceutically acceptable salt according to item 30, wherein the salt is selected from the group consisting of a chloride salt, bromide salt, iodide salt, fumarate salt, maleate salt, citrate salt, tartrate salt, acetate salt, gluconate salt, sulfate salt, mesylate salt, nitrate salt and phosphate salt.

35. A method for producing a compound according to item 1, wherein said method comprises:

contacting a compound of Formula (IV)

with a compound of Formula (V)

wherein Ri, R2, R3, X, and Y are defined as in item 1;

Z is H, -(CH2)nU, -(CH2)NP(CH₂)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1- 3 and U is -H, -NH2, NHP, -NHCHs, NPCHs, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCH3, -NCHsCOCHs, -NHCSCHs, -NCHsCSCHs, -NHCONH2, -NCH₃CONH₂, - NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH2, - NCH₃CSNH₂, -NHCSNHCHS, -NCHSCSNHCHS, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -S0₂CH₃, -CONH2, -CONHCHs, - CON(CH₃)₂, -CSNH2, -CSNHCHs, -CSN(CH₃)₂, -SO2NH2, -S0₂NHCH₃, -S0₂N(CH₃)2, -NHS0₂CH₃, -NCH₃S0₂CH₃, -CH2F, -CHF2, -CFS, -COOH, -COOCHS, -CSOH, - CSOCHs, -SOsH, -SOsCHs, -CONHOH, -CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)2, -PO(OCH₃)₂, -P(0)(H)0H, -P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

further wherein P is a protecting group;

E is Cl, Br, I or OTf;

T is CH₂Zn(halogen), CH₂B(OH)₂, CH₂B(pin), CH₂(9-BBN), CH₂BF₃K, NH, OH, SH,B(OH)2, B(pin), (9-BBN), BF₃K, Zn(halogen), SnBus or Si(0-alkyl)₃.

36. A method according to item 35, wherein the transition metal catalyst is selected from Pd(CI)2, Pd(OAc)2, Pd(PPh₃)₄, Pd2(dba)₃, PdCl2(MeCN)2,

Pd(CI)₂(PPh₃)2, Pd(dppf)CI₂, Pd₂(dba)₃, Ni(OAc)₂, Ni(Br)₂, Ni(CI)₂, Ni(OTf)₂.

37. A method according to items 35-36, wherein the transition metal catalyst is present in catalytic amounts such as less than 10 mol %, such as less than 5 mol %, such as less than 4 mol %, such as less than 3 mol %, such as less than 2 mol %, such as less than 1 mol %, such as at least 0.5 mol %.

38. A method according to any of the preceding items 35-37, wherein the ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), triphenylphoshine (PPh₃), tri(o-tolyl)phosphine (P(o-tolyl)₃), ethylenebis(diphenylphosphine) (dppe), l,3-bis(diphenylphosphino)-propane (dppp), l,4-Bis(diphenylphosphino)butane (dppb), I,I '-ferrocenediyl- bis(diphenylphosphine) (dppf), BINAP, 2,3-0-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane (DIOP), bis(diphenylphosphino)-methane (dppm), l,2-bis(dicyclohexylphosphino)ethane (dcpe), 2,3-bis(diphenylphosphino)butane (Chiraphos), transJrans- dibenzylideneacetone (dba), tri-tert-butylphosphine (P(t- BU)3), tert-butyldiphenylphosphine ((Ph)2PtBu)), bis[(2- diphenylphosphino)phenyl] ether (DPEPhos), l,l'-bis(di-tert- butylphosphino)ferrocene (DTBPF), (2-Biphenyl)dicyclohexylphosphine (cyclohexyl JohnPhos), 2-dicyclohexylphosphino-2'-(A/,A/-dimethylamino)biphenyl (DavePhos), 2-Dicyclohexylphosphino-2^,,4',6^,-triisopropylbiphenyl (XPhos), 2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2- Dicyclohexylphosphino-2'-methylbiphenyl (MePhos), 2-Dicyclohexylphosphino- 2',6'-diisopropoxybiphenyl (RuPhos), (2-Biphenyl)di-tert-butylphosphine

(JohnPhos), l,2,3,4,5-Pentaphenyl-l'-(di-tert-butylphosphino)ferrocene (QPhos), and Tris(dimethylamino)phosphine (HMPT).

39. A method according to any of the preceding items 35-38, wherein the reaction is degassed.

40. A method according to any of the preceding items 35-39, wherein the reaction is not degassed.

41. A method according to item 35-40, wherein the ligand is present in amounts such as less than 10 mol %, such as less than 5 mol %, such as less than 4 mol %, such as less than 3 mol %, such as less than 2 mol %, such as less than 1 mol %, such as at least 0.5 mol %.

42. A method according to any of the preceding items 35-41, wherein the base is selected from the group consisting of NaOAc, KOAc, LiOAc, Et3N, pyridine, collidine, TMP, DBU, CaC03, CS2CO3, U2CO3, Na2C03, K2CO3, UHCO3, NaHC03, KHCOs, U3PO4, Na₃P0₄, K3PO4, U2HPO4, Na₂HP0₄, K2HPO4, CaOH₂, LiOH, NaOH, KOH, Ba(OH)2, NaOf-Bu, KOtBu and LiOtBu. 43. A method according to any of the preceding items 35-42, wherein the solvent(s) is selected from the group consisting of water, THF, 2-MeTHF, DMF, toluene, MeCN, t-BuOH, MTBE, NMP, 2-propanol, 1,4-dioxane and DMSO. 44. A method according to any of the preceding items 35-43, wherein the reaction is run at 30 to 160 °C, such as 35 to 155 °C, such as 40 to 150 °C, such as 45 to 145 °C, such as 50 to 140 °C, such as 55 to 135 °C, such as 55 to 130 °C, such as 60 to 125 °C, preferably 65 to 120 °C, more preferably 70 to 115 °C, most preferably 75- 110 1C.

45. A method according to any of the preceding items 35-44, wherein the reaction time is less than 48 h., such as less than 24 h., such as less than 16 h., such as less than 12 h., such as less than 10 h., such as less than 8 h., such as less than 6 h., such as less than 4 h., such as less than 2 h, such as at least 30 min.

46. The method according to items 35-45, wherein the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (VI)

with a compound of Formula (VII)

wherein R2, R3, and X are defined as in item 1;

Z is H, -(CH2)nU, -(CH2)NP(CH₂)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1- 3 and U is -H, -NH 2, NHP, -NHCHs, NPCHs, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCHs, -NCH3COCH3, -NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, - NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, - NCH3CSNH2, -NHCSNHCHs, -NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, - CON(CH₃)2, -CSNH2, -CSNHCHs, -CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFs, -COOH, -COOCHs, -CSOH, - CSOCH3, -SOsH, -SO3CH3, -CONHOH, -CONCH3OH, -OPO(OH)₂, -ORO(OOH₃)₂, - PO(OH)2, -PO(OCH₃)2, -P(0)(H)OH, -P(0)(H)OCH₃, B(OH)2, or B(OCH₃)₂;

further wherein P is a protecting group;

E is Cl, Br, I or OTf; and

L is OH, OMe or Cl.

47. A method according to item 46, wherein the solvent(s) is selected from the group consisting of H2O, THF, 2-MeTHF, DCM, toluene, DMF, MeCN, MTBE, 1,4- dioxane and DMSO.

48. A method according to any one of the preceding items 46-47, wherein the coupling reagent is selected from the group consisting of a carbodiimide coupling reagent, a phosphonium coupling reagent and an imonium coupling reagent.

49. A method according to any one of the preceding items 46-48, wherein the carbodiimide coupling reagent is selected from EDC-HCI, DCC and DIC.

50. A method according to any one of the preceding items 46-49, wherein the phosphonium coupling reagent is selected from BOP, PyBOP, PyAOP and PyBrOP.

51. A method according to any one of the preceding items 46-50, wherein the imonium coupling reagent is selected from TBTU, HBTU, HATU, HOBt, COMU and TFFH.

52. A method according to any one of the preceding items 46-51, wherein the base is selected from the group consisting of Et3N, DIPEA, pyridine and NaOH.

53. A method according to any of the preceding items 46-52, wherein the reaction is run at less than 80 °C, such as less than 75 °C, such as less than 70 °C, such as less than 65 °C, such as less than 60 °C, such as less than 55 °C, such as less than 50 °C, such as less than 45 °C, such as less than 40 °C, such as less than 35 °C, such as at least above 0 °C, preferably at room temperature. 54. A method according to any of the preceding items 46-53, wherein the reaction time is less than 24 h., such as less than 16 h., such as less than 12 h., such as less than 10 h., such as less than 8 h., such as less than 6 h., such as less than 4 h., preferably less than 2 h, such as at least 5 min 55. A method according to any of the preceding items 46-54, wherein the reaction is run under ambient atmosphere.

56. A method according to any of the preceding items 46-55, wherein the reaction is run under an artificial atmosphere.

57. The method according to items 35-45, wherein the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (XIII)

with a base and a compound of Formula (IX)

R² - V

(IX)

in the presence of at least one solvent;

wherein R3 and X are defined as in claim 1;

Z is H, -(CH2)nU, -(CH₂)NP(CH₂)nU or -(CH₂)NH(CH₂)_nU, wherein n is an integer 1- 3 and U is -H, -NH₂, NHP, -NHCHs, NPCHs, -N(CH₃)₂, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCH3, -NCHsCOCHs, -NHCSCHs, -NCHsCSCHs, -NHCONH₂, -NCH₃CONH₂, - NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH₂, - NCH3CSNH2, -NHCSNHCHs, -NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, - CON(CH₃)2, -CSNH2, -CSNHCHs, -CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFs, -COOH, -COOCHs, -CSOH, - CSOCH3, -SOsH, -SO3CH3, -CONHOH, -CONCH3OH, -OPO(OH)₂, -ORO(OOH₃)₂, - PO(OH)2, -PO(OCH₃)2, -P(0)(H)OH, -P(0)(H)OCH₃, B(OH)2, or B(OCH₃)₂;

further wherein P is a protecting group;

R2 is alkyl;

E is Cl, Br, I or OTf; and

V is a leaving group such as Br, I, OTf and OMs.

58. Use of a compound according to anyone of items 1-34 as a pharmacological tool to study physiological and pathological processes that can be influenced by the modulation of the function of AMPK, particularly, for the use in methods to study physiological processes, such as cellular metabolism, in particular glucose, lipid and protein metabolism, cell cycle regulation, proliferation and associated conditions with impaired physiological processes.

59. A use according to claim 58, which is carried out in vitro on a sample of body fluid.

60. A compound according to anyone of items 1-34 for use as a medicament.

61. A compound according to anyone of items 1-34 for use in the prevention or treatment of cancer, neurological diseases or metabolic diseases.

62. A compound according to item 61, wherein the cancer is selected from the group consisting of glioblastoma and melanoma.

63. A compound according to item 61, wherein the neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

64. A compound according to item 61, wherein the metabolic disease is selected from the group consisting of diabetes or conditions associated with diabetes. 65. A compound according to item 64, wherein the diabetes is type 2 diabetes.

66. A compound according to item 64, wherein the conditions associated with diabetes is selected from the group consisting of insulin resistance, obesity, cardiovascular disease and inflammation.

67. Method for the prevention or treatment of a disease using a compound according to item 1-34. 68. A method according to item 67, wherein the disease is selected from cancer, neurological diseases or metabolic diseases.

69. A method according to item 68, wherein the cancer is selected from the group consisting of glioblastoma and melanoma.

70. A method according to item 68, wherein the neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

71. A method according to item 68, wherein the metabolic disease is selected from the group consisting of diabetes or conditions associated with diabetes.

72. A method according to item 71, wherein the diabetes is type 2 diabetes.

73. A method according to item 71, wherein the conditions associated with diabetes is selected from the group consisting of insulin resistance, obesity, cardiovascular disease and inflammation.

Claims

1. A compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Ci0 alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), Ci- Cio alkyl sulfonate (-SC>3-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHC0NHS02(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

R3 is C1-C10 alkyl, C3-C6 cycloalkyl or a 5 or 6 membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said C3-C6 cycloalkyl, aryl or heteroaryl may independently be substituted with one or more substituents which can be the same or different and are independently selected from halogens, Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Ci-Cio alkoxy (-O-alkyl) or C1-C10 thioalkyl (-S-alkyl);

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHC0CH₃, -NCHSCOCHS, - NHCSCHs, -NCHsCSCHs, -NHCONH2, -NCH₃CONH₂, -NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH₃CSNH₂, -N HCSNHCHS, - NCHsCSNHCHs, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, -OCHs, -OAc, -SH, - SCHs, -SOCHS, -S0₂CH₃, -CONH2, -CONHCHs, -CON(CH₃)₂, -CSNH2, -CSNHCHs, - CSN(CH₃)₂, -SO2NH2, -S0₂NHCH₃, -S0₂N(CH₃)2, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CF₃, -COOH, -COOCHS, -CSOH, -CSOCHS, -SOSH, -SOSCHS, -CONHOH, - CONCHsOH, -OPO(OH)2, -OPO(OCH₃)₂, -PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)OH, - P(0)(H)OCH₃, B(OH)2, or B(OCH₃)₂;

W is CH2, NH, O, S or a bond; and

With the proviso that when X is S and Ri is a 6 membered aryl para-substituted with a halogene then W is not 0,

when X is N, W is a bond, Ri is H, R2 is H, and Z is CH₃ then R₃ is not phenyl, or when X is N, R2 and Z are H, and R₃ is a 6 membered heteroaryl with the heteroatom of said heteroaryl numbers 1 then the hetero atom is not N.

2. A compound of according to claim 1, wherein Ri is a 5- or 6-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1; and

R₃ is C1-C10 alkyl, C₃-Ce cycloalkyl or a 6-membered aryl.

3. A compound according to any one of the preceding claims, wherein W is NH or a bond.

4. A compound according to any one of the preceding claims, wherein Z is H, - (CH2)nU or -(CH2)NH(CH2)nU, wherein n is 1 or 2.

5. A compound according to any one of the preceding claims, wherein Ri is a 6- membered aryl, wherein said aryl is para substituted with a substituent, which is independently selected from the group consisting of amino (-NH2), -CH2N(CI-CIO alkyl)2, -CONH2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH),

wherein A is NH, S or 0; a is 1 or 2; b is 2 or 3 and c is 3 or 4;

and R3 is a 6-membered aryl, wherein said aryl is meta substituted with a chlorine or fluorine.

6. A compound according to any one of the preceding claims, wherein Ri is H, halogen, or a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; R2 is hydrogen or methyl; R3 is methyl, cyclo propyl or a 6 membered aryl or heteroaryl with the heteroatom of said heteroaryl numbers 1 and is N; X is selected from NMe, NEt or S; and W is NH or a bond.

7. A compound according to any one of the preceding claims, wherein the compound is the enantiomer of Formula (II).

8. A compound according to any one of the preceding claims, wherein the compound is a crystalline solid.

9. A pharmaceutically acceptable salt of a compound according to any one of the preceding claims.

10. A method for producing a compound according to claim 1, wherein said method comprises:

contacting a compound of Formula (IV)

with a compound of Formula (V)

wherein Ri, R2, R3, and X are defined as in claim 1;

further wherein P is a protecting group;

E is Cl, Br, I or OTf; and

T is CH₂Zn(halogen), CH₂B(OH)₂, CH₂B(pin), CH₂(9-BBN), CH₂BF₃K, NH, OH, SH,B(OH)2, B(pin), (9-BBN), BF₃K, Zn(halogen), SnBu₃ or Si(0-alkyl)₃.

11. The method according to claim 10, wherein the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (VI)

with a compound of Formula (VII)

wherein R2, R3, and X are defined as in claim 1;

Z is H, -(CH2)nU, -(CH2)NP(CH₂)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-

3 and U is -H, -NH2, NHP, -NHCHs, NPCHs, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2_, NHCOCHs, -NCH₃COCH₃, -NHCSCHS, -NCH₃CSCH₃, -NHCONH2, -NCH₃CONH₂, - NHCONHCHs, -NCH₃CONHCH₃, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, - NCH₃CSNH₂, -NHCSNHCHS, -NCH₃CSNHCH₃, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN,

-OH, OP¹, -OCH₃, -OAC, -SH, SP², -SCH₃, -SOCH₃, -S0₂CH₃, -CONH2, -CONHCHs, CON(CH₃)₂, -CSNH2, -CSNHCHs, -CSN(CH₃)₂, -SO2NH2, -S0₂NHCH₃, -S0₂N(CH₃)2_, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CF₃, -COOH, -COOCH₃, -CSOH, -

CSOCH₃, -SOSH, -S0₃CH₃, -CONHOH, -CONCHSOH, -OPO(OH)2, -OPO(OCH₃)2, - PO(OH)2, -PO(OCH₃)2, -P(0)(H)0H, -P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

further wherein P is a protecting group;

E is Cl, Br, I or OTf; and

L is OH, OMe or Cl.

12. The method according to claim 10, wherein the compound of Formula (IV) is produced by a method comprising contacting a compound of Formula (XIII)

with a base and a compound of Formula (IX)

R² - V

(IX)

in the presence of at least one solvent;

wherein R3 and X are defined as in claim 1 ;

Z is H, -(CH2)nU, -(CH₂)NP(CH₂)nU or -(CH₂)NH(CH₂)_nU, wherein n is an integer 1- 3 and U is -H, -NH₂, NHP, -NHCHs, NPCHs, -N(CH₃)₂, -C(NH)NH₂, -C(NCH₃)NH₂,- NHCOCHs, -NCHsCOCHs, -NHCSCHs, -NCHsCSCHs, -NHCONH₂, -NCH₃CONH₂, - NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)₂, -NCH₃CON(CH₃)₂, -NHCSNH₂, - NCH₃CSNH₂, -NHCSNHCHS, -NCHSCSNHCHS, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, OP¹, -OCHs, -OAc, -SH, SP², -SCHs, -SOCHs, -S0₂CH₃, -CONH₂, -CONHCHs, - CON(CH₃)₂, -CSNH₂, -CSNHCHS, -CSN(CH₃)₂, -S0₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CFS, -COOH, -COOCHS, -CSOH, - CSOCHs, -SOsH, -SOsCHs, -CONHOH, -CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, - PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, -P(0)(H)0CH₃, B(OH)₂, or B(OCH₃)₂;

further wherein P is a protecting group;

R₂ is alkyl;

E is Cl, Br, I or OTf; and

V is a leaving group such as Br, I, OTf and OMs.

13. Use of a compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C₁₀ alkenyl, C2-C₁₀ alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C₁-C₁₀ alkyl hydroxyl (-alkyl-OH), C₁-C₁₀ alkoxy(-O-alkyl), carboxylic acid (-COOH), C₁-C₁₀ alkyl esters (-COO-alkyl), C₁-C₁₀ alkyl acyl (-CO-alkyl), sulfonic acid (-SO₃H), Ci- C₁₀ alkyl sulfonate (-S03-alkyl), phosphonic acid (-PO(OH)2), C₁-C₁₀ alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C₁-C₁₀ alkyl sulfonylureas (-NHCONHSC>2(alkyl)), C₁-C₁₀ acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

R3 is C1-C10 alkyl, C3-C₆ cycloalkyl or a 5 or 6 membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said C3-C₆ cycloalkyl, aryl or heteroaryl may independently be substituted with one or more substituents which can be the same or different and are independently selected from halogens, Ci- C₁₀ alkyl, C2-C₁₀ alkenyl, C2-C₁₀ alkynyl, Ci-Cio alkoxy (-O-alkyl) or C₁-C₁₀ thioalkyl (-S-alkyl);

X is selected from NMe, NEt or S; Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHC0CH₃, -NCHSCOCHS, - NHCSCHs, -NCHsCSCHs, -NHCONH2, -NCHsCONhh, -NHCONHCHs, -NCHsCONHCHs, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH₃CSNH₂, -N HCSNHCHS, - NCHsCSNHCHs, -NHCSN(CH₃)₂, -NCH₃CSN(CH₃)₂,-CN, -OH, -OCHs, -OAc, -SH, - SCHs, -SOCHS, -S0₂CH₃, -CONH2, -CONHCHs, -CON(CH₃)₂, -CSNH2, -CSNHCHs, - CSN(CH₃)₂, -SO2NH2, -S0₂NHCH₃, -S0₂N(CH₃)2, -NHSO₂CH₃, -NCH₃SO₂CH₃, -CH₂F, -CHF₂, -CF₃, -COOH, -COOCHS, -CSOH, -CSOCHS, -SOSH, -SOSCHS, -CONHOH, - CONCHsOH, -OPO(OH)2, -OPO(OCH₃)₂, -PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

W is CH2, NH, 0, S or a bond; and

14. A use according to claim 13, which is carried out in vitro.

15. A compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or O, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), Ci- C10 alkyl sulfonate (-S03-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHSC>2(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHC0CH₃, -NCH3COCH3, - NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, -NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH3CSNH2, -NHCSNHCHs, - NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, -OCHS, -OAc, -SH, - SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)2, -CSNH2, -CSNHCHs, - CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFs, -COOH, -COOCHs, -CSOH, -CSOCH3, -SOsH, -SO3CH3, -CONHOH, - CONCHsOH, -OPO(OH)₂, -OPO(OCH₃)₂, -PO(OH)₂, -PO(OCH₃)2, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

for use as a medicament.

16. A compound according to claim 15 for use in the prevention or treatment of cancer, neurological diseases or metabolic diseases.

17. A compound according to claim 16, wherein the cancer is selected from the group consisting of glioblastoma and melanoma.

18. A compound according to claim 16, wherein the neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

19. A compound according to claim 16, wherein the metabolic disease is selected from the group consisting of diabetes or conditions associated with diabetes.

20. Method for the prevention or treatment of a disease using a compound of formula I:

wherein Ri is H, halogen or a 5-, 6-, 9- or 10-membered aryl or heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or 3 and is independently selected from N, S or 0, further wherein each of said aryl or heteroaryl may independently be substituted with one or more substituents, which can be the same or different and are independently selected from the group consisting of Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), - CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2, cyano (- CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), Ci- C10 alkyl sulfonate (-SC>3-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-PO(0-alkyl)2), phosphinic acid (-P(0)(H)OH), SO2NH2, hydroxamic acid (-CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHS02(alkyl)), C1-C10 acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), halogens,

wherein A is NH, S or O; a is the integer 1-3; b is 2 or 3 and c is the integer 1-4; R2 is H, C1-C5 alkyl or not present;

X is selected from NMe, NEt or S;

Z is H, -(CH2)nU or -(CH2)NH(CH2)nU, wherein n is an integer 1-3 and U is -H, - NH₂, -NHCHS, -N(CH₃)2, -C(NH)NH₂, -C(NCH₃)NH2,-NHCOCH3, -NCH3COCH3, - NHCSCHs, -NCH3CSCH3, -NHCONH2, -NCH3CONH2, -NHCONHCH3, -NCH3CONHCH3, -NHCON(CH₃)2, -NCH₃CON(CH₃)2, -NHCSNH2, -NCH3CSNH2, -NHCSNHCHs, - NCH3CSNHCH3, -NHCSN(CH₃)2, -NCH₃CSN(CH₃)2,-CN, -OH, -OCHS, -OAc, -SH, - SCHs, -SOCHs, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)2, -CSNH2, -CSNHCHs, - CSN(CH₃)2, -SO2NH2, -SO2NHCH3, -S0₂N(CH₃)2, -NHSO2CH3, -NCH3SO2CH3, -CH2F, -CHF2, -CFS, -COOH, -COOCHS, -CSOH, -CSOCH3, -SOsH, -SO3CH3, -CONHOH, - CONCHsOH, -OPO(OH)2, -OPO(OCH₃)2, -PO(OH)₂, -PO(OCH₃)₂, -P(0)(H)0H, - P(0)(H)0CH₃, B(OH)2, or B(OCH₃)₂;

W is CH2, NH, 0, S or a bond; and

21. A method according to claim 20, wherein the disease is selectee from cancer, neurological diseases or metabolic diseases.

22. A method according to claim 21, wherein the cancer is selected from the group consisting of glioblastoma and melanoma.

23. A method according to claim 21, wherein the neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

24. A method according to claim 21, wherein the metabolic disease is selected from the group consisting of diabetes or conditions associated with diabetes.