PYRROLO[2,3-C]PYRIDINES AS IMAGING AGENTS FOR

NEUROFIBRILARY TANGLES

FIELD OF THE INVENTION

The invention is directed to novel pyrrolopyridine compounds, their salts, pharmaceutical compositions comprising them, and therapeutic uses and processes for making such compounds. This invention is further directed to 2H, 3H, HC, 13C, 1 C, 13N, 15N, 150, 1?0, 180, 18F, 35s, 36ci, 82Br, 76β _Γ , 77β _Γ , 123^ 124i and 13 ll isotopically labeled substituted

pyrrolopyridine derivative compounds of this invention. In particular, the present invention is directed to ^U C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹⁵ 0, ¹³ N, ³⁵ S, ² H, and ³ H isotopes of novel pyrrolopyridine compounds and methods of their preparation.

The present invention also relates to novel pyrrolopyridine compounds which may be suitable for imaging tau aggregates, B-sheet aggregates, B-amyloid aggregates, a-synuclein aggregates or trans-active response DNA binding protein 43kDa and hence are useful in binding and imaging tau aggregates in Alzheimer's patients. More specifically, this invention relates to a method of using the compounds of this invention as tracers in positron emission tomography (PET) imaging to study tau deposits in brain in vivo to allow diagnosis of Alzheimer's disease. The invention further relates to a method of measuring clinical efficacy of therapeutic agents targeting tau pathology.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid B peptide (AB).

In Alzheimer's, two main proteins form abnormal polymers (aggregates) in the brain that are believed to result from misfolding during aggregation of one of twenty nonhomologous human proteins. The intracellular neurofibrillary tangles-NFT's are made from the microtubule- associated protein (tau protein) and the extracellular "amyloid" plaques consist mainly of polymerized AB-peptide. Both are toxic to the brain neurons and are the result of fibers formed from the subunit protein by stacking of beta strands. See B. Bulic, E. Mandelkow et al.

Angewandte Chemie International Edition, Vol. 48, Issue 10, pgs. 1740-1752, 2009 and B. Bulic, et al. J. Med. Chem 2013 June 13; 56(11):4135-55.

Tubulin-associated unit, or Tau, is a microtubule-associated protein that is thought to play a critical role in the etiology of Alzheimer's disease (AD) based on several lines of evidence. First, intracellular aggregates of hyperphosphorylated tau (NFTs) are invariably found in the brains of patients with AD and several other neurodegenerative diseases. Second, the extent of NFT pathology in the brain of AD patients is closely correlated with cognitive function. Finally, while mutations in tau have not been shown to cause AD, such mutations do cause another form of dementia known as frontotemporal dementia with parkinsonism (FTDP).

Therefore, approaches aimed at reducing NFTs and/or hyperphosphorylated tau represent disease modifying treatments for AD.

Currently histological analysis of autopsy materials is the primary means of detecting tau aggregates. A tau PET tracer would be a valuable non-invasive tool for spatial and temporal quantification of neurofibrillary tangles (NFTs) in human brain, since post-mortem studies have shown NFT burden to better correlate with cognitive decline. A tau PET tracer will be a critical disease-relevant tool for quantifying a stabilization or decrease of NFT formation for disease- modifying Alzheimer's disease therapeutics. Additionally, a tau PET tracer could be useful for patient selection for AD clinical trials. In this mode, a tau PET tracer could be developed as a companion diagnostic. In addition to AD, there are other neurodegenerative diseases

characterized by the deposition of tau aggregates (frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease, etc.).

Therefore, a need exists for neuroimaging radiotracers that would allow in vivo imaging of tau pathology thereby providing insight into the deposition of tau aggregates in the human brain. The successful neuroimaging radiotracer must cross the blood-brain barrier and posses high affinity and specificity for tau aggregates and therefore must have appropriate lipophilicity (logD 1-3) and low molecular weight (,<450), show rapid clearance from blood and low nonspecific binding. The neuroimaging radiotracer will play a role in diagnosis by identifying patients with excess tau aggregates in the brain and therefore at risk for developing AD as well as shed light on the degree of tau aggregation, effect on the brain over time, the correlation with cognition and aid in the analysis of the efficacy of a tau inhibitor.

In a typical PET study, a small amount of radiotracer is administered to the experimental animal, normal human or patient being tested. The radiotracer then circulates in the blood of the subject and may be absorbed in certain tissues. The radiotracer may be preferentially retained in some of these tissues because of specific enzymatic conversion or by specific binding to macromolecular structures such as proteins. Using sophisticated imaging instrumentation to detect positron emission, the amount of radiotracer is then non-invasively assessed in the various tissues in the body. The resulting data are analyzed to provide

quantitative spatial information of the in vivo biological process for which the tracer was designed. PET gives pharmaceutical research investigators the capability to assess biochemical changes or metabolic effects of a drug candidate in vivo for extended periods of time, and PET can be used to measure drug distribution, thus allowing the evaluation of the pharmacokinetics and pharmacodynamics of a particular drug candidate under study. Importantly, PET tracers can be designed and used to quantitate the presence of binding sites in tissues. Consequently, interest in PET tracers for drug development has been expanding based on the development of isotopically labeled biochemicals and appropriate detection devices to detect the radioactivity by external imaging.

While the primary use of the isotopically labeled compounds of this invention is in positron emission tomography, which is an in vivo analysis technique, certain of the isotopically labeled compounds can be used for methods other than PET analyses. In particular, ¹⁴ C and ³ H labeled compounds can be used in in vitro and in vivo methods for the determination of binding, receptor occupancy and metabolic studies including covalent labeling. In particular, various isotopically labeled compounds find utility in magnetic resonance imaging,

autoradiography and other similar analytical tools.

SUMMARY OF THE INVENTION

The invention is directed to a class of pyrrolopyridine compounds of formula I, their salts, pharmaceutical compositions comprising them, diagnostic and therapeutic uses and processes for making such compounds. In particular, the invention is directed to a class of pyrrolopyridine compounds of formula I which may be useful for binding and imaging tau aggregates, B-sheet aggregates, beta-amyloid aggregates or alpha-synuclein aggregates, and hence are useful in binding and imaging tau aggregates in Alzheimer's patients. This invention also relates to use of the compounds as an imaging tool to improve diagnosis of patients likely to develop Alzheimer's disease by determining if said patients present with excess of tau aggregates in the brain. This invention further relates to finding an imaging tool that will be used to diagnosis and monitor the progression of AD. This invention also relates use of the pyrrolopyridine compound to monitor and measure treatment when an anti-tau aggregate drug becomes available. This invention also may be useful for imaging and detecting for other neurodegenerative diseases characterized by the deposition of tau aggregates such as frontotemporal dementia (FTD), progressive

supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease, etc. This invention further relates to a pharmaceutical composition containing a compound of formula I and a pharmaceutically acceptable carrier.

Also included are isotopically labeled compounds of this invention. Another aspect of the invention relates to use of the isotopically labled compounds as neuroimaging radiotracers for in vivo imaging of the brain for tau aggregates in the diagnosis, monitoring, and/or treatment of AD. Another aspect of the invention is use of the isotopically labeled compounds in positron emission tomography, which is an in vivo analysis technique in the diagnosis, monitoring, and/or treatment of AD. The ¹⁴ C and ³ H labeled compounds can be used in in vitro and in vivo methods for the determination of binding, receptor occupancy and metabolic studies including covalent labeling. In particular, various isotopically labeled compounds find utility in magnetic resonance imaging, autoradiography and other similar analytical tools. Thus, another aspect of this invention is further directed to 2H, 3H, He, 13C, He, 13N, 15N, 150, 1?0, 180, 18F, 35s, 36ci, 82Br, 76β _Γ , 77β _Γ , 123^ 124i and 13 ll isotopically labeled substituted

pyrrolopyridine derivative compounds of formula I. In particular, the present invention is directed to ^U C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹⁵ 0, ¹³ N, ³⁵ S, ² H, and ³ H isotopes of substituted pyrrolopyridine derivative compounds, compositions and methods of their preparation and use as radiotracers or PET tracers in diagnosing and measuring the effects of a compound in the treatment of AD. The present invention also relates to non-toxic tau protein binding compounds that can rapidly cross the blood brain barrier, have low non-specific binding properties and are rapidly cleared from the system. This and other aspects of the invention will be realized upon review of the specification in its entirety.

FIGURES

Figure 1 : shows saturation binding of [ ³ H]-6 (Example 49) in AD brain homogenates

Figure 2: Displacement binding of [compound 6] in AD brain homogenates, shows compound 6 (unlabeled) self-displaced [ ³ H]-6 with Ki value of 0.43 nM DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to quinoline amide compounds of generic formula (I)

(I)

or a pharmaceutically acceptable salt thereof wherein; X represents CH, or N;

R represents hydrogen, or -C^alkyl, said alkyl optionally substituted with 1 to 3 groups of R ^a ;

R ¹ represents hydrogen, -C^alkyl, -CN, -(CH ₂ ) _n NH(CH ₂ ) _n N(R) ₂ , -C _2.6 alkenyl, -(CH ₂ ) _n OR, or - (CH ₂ ) _n halogen; R ² represents -C^alkyl, -OC^ alkyl, -C _2.6 alkenylR ³ , -C _2.6 alkynylR ³ , -(CH ₂ ) _n OR, - (CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, -C _6.10 aryl, -C _5.10 heterocyclyl, -N(R) ₂ , -0(CH ₂ ) _n R ^a , - N(CH ₃ )(CH ₂ ) _n OR, - RC(0)R, - H(CH ₂ ) _n halo, -NC(O)C ₆ _ ₁₀ aryl, -NC(O)C _5.10 heterocyclyl, - N(CH ₃ )(CH ₂ ) _n halogen, -C(O)NC ₆ _ ₁₀ aryl, said alkyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R ^a ; or an adjacent R ¹ can combine with R ² to form a nine to ten membered bicyclic ring together with the ring to which R ¹ and R ² are attached, optionally interrupted with N, S, and/or O, said ring optionally substituted with 1 to 3 groups of R ^a ;

R ³ represents hydrogen, -C^alkyl, -(CH ₂ ) _n halogen, -(CH ₂ ) _n N(R) ₂ , -(CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , -C ₆ _ ₁₀ aryl, -C ₅ _ ₁₀ heteroaryl, said alkyl, aryl, and heteroaryl optionally substituted with 1 to 3 groups of R ^a ;

R ^a represents -CN, CF ₃ , -Ci-6alkyl, -C ₂ _ ₆ alkenyl, -C ₂ _ ₆ alkynyl, C ₆ _ ₁₀ aryl, -C ₅ _ ₁₀ heterocyclyl, - CN, N0 ₂ , (CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, (CH ₂ ) _n OR, -O(CH ₂ ) _n C _6.10 aryl, -(CH ₂ ) _n N(R) ₂ , - C(0)N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, - RCOR, -COR, - H(CH ₂ ) _n halo, -NC(0)C C _6.10 aryl, - N(CH ₃ )(CH ₂ ) _n halogen, C(O)C _6.10 aryl, or -C0 ₂ R;

R represents -Ci-6alkyl, -OR, or halogen ; and

n represents 0-4.

One aspect of this invention is realized when X is CH and all other variables are as originally described.

Another aspect of this invention is realized when X is N and all other variables are as originally described.

Still another aspect of this invention is realized when R is hydrogen. Yet another aspect of this invention is realized when R is optionally substituted -C^alkyl.

Another aspect of this invention is realized when R is hydrogen.

Another aspect of this invention is realized when R -C _j.g alkyl, said alkyl optionally substituted with 1 to 3 groups of R ^a .

Another aspect of this invention is realized when R is CN.

Another aspect of this invention is realized when R is -C _2.6 alkenyl, said alkenyl optionally substituted with 1 to 3 groups of R ^a .

Another aspect of this invention is realized when R is (CH ₂ ) _n OR.

Another aspect of this invention is realized when R ¹ is -(CH ₂ ) _n N(CH ₂ ) _n N(R) ₂ . Still another aspect of this invention is realized when R ¹ is (CH ₂ ) _n halogen Yet another aspect of this invention is realized when R ² is selected from the group consisting of -C2-6alkenylR ³ , -C2-6alkynylR ³ , -NC(O)C6-10 aryl, -NC(0)C5-io heterocyclyl, - C6-10 aryl, and -C5-I0 heterocyclyl said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when R ² is -C2- 6alkenylR ³ . A subembodiment of this aspect of the invention is realized when R ² is -C2-

6alkynylR ³ . A subembodiment of this aspect of the invention is realized when R ² is -NC(O) C6- 10 aryl, said ary optionally substituted. A subembodiment of this aspect of the invention is realized when R ² is -NC(0)C5-io heterocyclyl, said heterocyclyl optionally substituted. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted -C ~ 10 aryl. A subembodiment of this aspect of the invention is realized when the aryl of R ² is optionally substituted phenyl or napthyl. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted -C5-10 heterocyclyl. A subembodiment of this aspect of the invention is realized when the heterocyclyl of R ² is selected from the group consisting of optionally substituted pyridyl, thiazolyl, pyrimidinyl, piperizinyl, pyrazolyl, pyrazinyl, imidazolyl, and triazolyl.

Another aspect of this invention is realized when R ³ is -C^alkyl, said alkyl optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when the alkyl is methyl, ethyl, or propyl.

Another aspect of this invention is realized when R ³ is -(CH ₂ ) _n halogen. A subembodiment of this aspect of the invention is realized when the halogen is fluorine or chlorine.

Another aspect of this invention is realized when R ³ is C ₆ _ ₁₀ aryl, said aryl optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this invention is realized when the aryl is optionally substituted phenyl or napthyl.

Another aspect of this invention is realized when R ³ is -C ₅ _ ₁₀ heteroaryl, said heteroaryl optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when the heteroaryl is selected from the group consisting of optionally substituted pyridyl and thiazolyl.

Another aspect of this invention is realized when R ³ is -(CH ₂ ) _n N(R) ₂ , or- (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ .

Still another aspect of this invention is realized when R ² is combined with an adjacent R ¹ and the ring to which R ¹ and R ² are attached, to form a 9 to 10 membered bicycle ring, said ring optionally interrupted with N, S, and/or O, and said ring optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when the ring is optionally interrupted with one of N, S and/or O. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted pyrrolopyridinyl, furopyridinyl, naphthryidinyl, tetrahydronaphthyridinyl, quinazolinyl, quinolinyl, or

isoquinolinyl. A subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted pyrrolopyridinyl. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted naphthryidinyl or tetrahydronaphthyridinyl. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted quinazolinyl. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted quinolinyl. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted isoquinolinyl. Another subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted furopyridinyl.

Still another subembodiment of this aspect of the invention is realized when X is CH and R ² is selected from the group consisting of -C2-6alkenylR ³ , -C2-6alkynylR ³ , -C6-10 aryl, and -C5-10 heterocyclyl said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R ^a .

Another subembodiment of this aspect of the invention is realized when X is CH and R ² is -C2-6alkenylR ³ . A subembodiment of this aspect of the invention is realized when R ³ is selected from the group consisting of methyl, ethyl, propyl, (CH ₂ ) _n F, -(CH ₂ ) _n N(R) ₂ , - (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , optionally substituted phenyl, pyridyl and thiazolyl.

Another subembodiment of this aspect of the invention is realized when X is CH and R ² is -C2-6alkynylR ³ . A subembodiment of this aspect of the invention is realized when R ³ is selected from the group consisting of methyl, ethyl, propyl, (CH ₂ ) _n F, -(CH ₂ ) _n N(R) ₂ , - (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , optionally substituted phenyl, pyridyl and thiazolyl.

Still another subembodiment of this aspect of the invention is realized when X is

CH and R ² is optionally substituted -C6-10 aryl. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted phenyl or naphthyl.

Yet another subembodiment of this aspect of the invention is realized when X is CH and R ² is optionally substituted -C5-10 heterocyclyl. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted 0(CH ₂ ) _n pyridyl, NC(0)phenyl,

C(0)phenyl, naphthyl, naphthyridinyl, pyridyl, triazolyl, pyrimidinyl, thiazolyl, pyrazinyl, or imidazolyl.

Another aspect of this invention is realized when X is CH and R ² is combined with an adjacent R ¹ to form a 9 to 10 membered bicycle ring optionally interrupted with N, S and/or O, said bicycle optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted

pyrrolopyridinyl, furopyridinyl, naphthryidinyl, tetrahydronaphthyridinyl, quinolinyl, or isoquinolinyl.

Still another subembodiment of this aspect of the invention is realized when X is N and R ² is selected from the group consisting of -C2-6alkenylR ³ , -C2-6alkynylR ³ , -C6-10 aryl, and -C5-I0 heterocyclyl said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R ^a .

Another subembodiment of this aspect of the invention is realized when X is N and R ² is -C2-6alkenylR ³ . A subembodiment of this aspect of the invention is realized when R ³ is selected from the group consisting of methyl, ethyl, propyl, (CH ₂ ) _n F, -(CH ₂ ) _n N(R) ₂ , - (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , optionally substituted phenyl, pyridyl and thiazolyl.

Another subembodiment of this aspect of the invention is realized when X is N and R ² is -C2-6alkynylR ³ . A subembodiment of this aspect of the invention is realized when R ³ is selected from the group consisting of methyl, ethyl, propyl, (CH ₂ ) _n F, -(CH ₂ ) _n N(R) ₂ , - (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , optionally substituted phenyl, pyridyl and thiazolyl.

Still another subembodiment of this aspect of the invention is realized when X is N and R ² is optionally substituted -C6-10 aryl. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted phenyl or naphthyl.

Yet another subembodiment of this aspect of the invention is realized when X is N and R ² is optionally substituted -C5-10 heterocyclyl. A subembodiment of this aspect of the invention is realized when R ² is optionally substituted 0(CH ₂ ) _n pyridyl, NC(0)phenyl,

C(0)phenyl, naphthyl, naphthyridinyl, pyridyl, triazolyl, pyrimidinyl, thiazolyl, pyrazinyl, or imidazolyl.

Another aspect of this invention is realized when X is N and R ² is combined with an adjacent R ¹ together with the ring to which R ¹ and R ² are attached, to form a 9 to 10 membered bicycle ring optionally interrupted with N, S and/or O, said bicycle optionally substituted with 1 to 3 groups of R ^a . A subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted quinazolinyl.

Another aspect of the invention is realized when the compounds of formula I are isotopically labeled 2¾ 3jH, HC, 13C, HC, 13N, 15N, 150, 170, I80, 18F, 35S, 36 _C L, 82 _BR , 76 _Br , 77 _Br , 123i, 124i and 13 .

Still another aspect of this invention is realized with the compound of structural formula la:

la

or a pharmaceutically acceptable salt thereof, wherein Rl, and R are as described herein. A subembodiment of formula la is realized when R ¹ is hydrogen, halogen, -(CH ₂ ) _n N(CH ₂ ) _n N(R) ₂ , or optionally substituted C _1-6 alkyl and C _2- 6 alkenyl.

Another subembodiment of formula la is realized when R ² is selected from the group consisting of -C ₂ _ ₆ alkenylR ³ , -C ₂ _ ₆ alkynylR ³ , (CH ₂ ) _n OR, -0(CH ₂ ) _n halogen, C ₆ _ ₁₀ aryl, -C ₅ _

₁₀ heterocyclyl, -N(R) ₂ , -0(CJ¾) _n R ^a , -N(CH ₃ )(CH ₂ ) _n OR, - H(CH ₂ ) _n halogen, -NC(O) C _6.10 aryl, -N(CH ₃ )(CH ₂ ) _n halogen, C(O)NC ₆ _ ₁₀ aryl, said alkyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R ^a , and R ³ is selected from the group consisting of hydrogen, - (CH ₂ ) _n halogen, -(CH ₂ ) _n N(R) ₂ , (CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , C _6.10 aryl, -C _5.10 heteroaryl, said aryl,and heteroaryl optionally substituted with 1 to 3 groups of R ^a .

Another subembodiment of this aspect of formula la is realized when R ² is selected from the group consisting of C ₂ alkenylR ³ , C ₂ alkynylR ³ , 0(CH ₂ ) _n F, N(CH ₂ ) _n F, N(R) ₂ , and optionally substituted 0(CH ₂ ) _n pyridyl, NC(0)phenyl, C(0)phenyl, naphthyl, naphthyridinyl, pyridyl, triazolyl, pyrimidinyl, thiazolyl, pyrazinyl, and imidazolyl and R ³ is selected from the group consisting of methyl, ethyl, propyl, (CH ₂ ) _n F, -(CH ₂ ) _n N(R) ₂ , -(CH ₂ ) _n R(CH ₂ ) _n N(R) ₂ , optionally substituted phenyl, pyridyl and thiazolyl and R ¹ is selected from the group consisting of hydrogen, fluorine, or chlorine, -(CH ₂ ) _n N(CH ₂ ) _n N(R) ₂ . or optionally substituted Ci_6 alkyl and C _2-6 alkenyl.

Still another aspect of the invention of formula I is realized when R ² combines with an adjacent R ¹ together with the ring to which R ¹ and R ² are attached, to form a 9 to 10 membered bicycle optionally interrupted by N, S, O, said bicycle optionally substituted by 1 to 3 groups of R ^a which is naphthyridinyl, tetrahydronaphthyridinyl, furopyridinyl, isoquinolinyl, or pyrrol opyridinyl. A subembodiment of this aspect of the invention is realized wherein an adjacent R ¹ and R ² when combined is represented by structural formula Ibl, Ib2, Ib3, Ib4, or Ib5:

wherein W, W ¹ , W ² , and W ³ are independently selected from -CH- or -N- and R and Ra are as originally described. A subembodiment of this aspect of the invention is realized when W, W ¹ , W ² , and W ³ are all -CH-. Another subembodiment of this aspect of the invention is realized when at least one of W, W ¹ , W ² , and W ³ is -N- and the other is -CH-. Still another

subembodiment of this aspect of the invention is realized when one of W, W ¹ , W ² , and W ³ is -N.

Another aspect of the invention of formula I is represented by structural formula II:

or a pharmaceutically acceptable salt there of wherein Ib= Ibl, Ib2, Ib3, Ib4, or Ib5, and W, W ¹ , W ² , W ³ , R and R ^a are as originally described. A subembodiment of this aspect of the invention is realized when W, W ¹ , W ² , and W ³ are all -CH-. Another subembodiment of this aspect of the invention is realized when at least one of W, W ¹ , W ² , and W ³ is -N- and the other is -N-. Still another subembodiment of this aspect of the invention is realized when one of W, W ¹ , W ² , and W ³ is -N. A subembodiment of this aspect of the invention is realized when R ^a is selected from the group consisting of -Ci_6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, (CH ₂ ) _n OR, - (CH ₂ ) _n N(R) ₂ , N0 ₂ , CN, -N(CH ₃ )(CH ₂ ) _n OR, - H(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen.

Another subembodiment of this aspect of the invention is realized when R ^a is selected from the group consisting of CH ₃ , CH ₂ CH ₃ , OCH ₃ , OH, -(CH ₂ ) _n HCH ₃ , - H ₂ , halogen, -(CH ₂ ) _n N(CH ₃ ) ₂ , N0 ₂ , CN, -N(CH ₃ )(CH ₂ ) _n OH, -N(CH ₃ )(CH ₂ ) _n F, and 0(CH ₂ ) _n F.

Another embodiment of the invention of formula II is realized when lb is Ibl, R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, -NH(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen, and

W, W ¹ , W ² , and W ³ are all -CH-. Another embodiment of the invention of formula II is realized when lb is Ibl, R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, - 0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, -NH(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen, and at least one of W, W ¹ , W ² , and W ³ is -N. Another embodiment of the invention of formula II is realized when lb is Ib2 and R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, - H(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen.

Another embodiment of the invention of formula II is realized when lb is Ib3 and R ^a is selected from the group consisting of R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, - NH(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen.

Another embodiment of the invention of formula II is realized when lb is Ib4 and R ^a is selected from the group consisting of R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, - NH(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen.

Another embodiment of the invention of formula II is realized when lb is Ib5 and R ^a is selected from the group consisting of R ^a is selected from the group consisting of -Ci-6alkyl, -(CH ₂ ) _n halogen, -0(CH ₂ ) _n halogen, CN, N0 ₂ , (CH ₂ ) _n OR, -(CH ₂ ) _n N(R) ₂ , -N(CH ₃ )(CH ₂ ) _n OR, - NH(CH ₂ ) _n halo, and -N(CH ₃ )(CH ₂ ) _n halogen.

Still another aspect of the invention of formula I is realized when X is N and R ² is combined with an adjacent R ¹ to form a 9 to 10 membered bicycle ring optionally interrupted with N, S and/or O, said bicycle optionally substituted with 1 to 3 groups of R ^a . A

subembodiment of this aspect of the invention is realized when the bicycle formed is optionally substituted quinazolinyl.

The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual

diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S.H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190)

When any variable (e.g. aryl, heterocycle, R^ ^a , R^ etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, alkenyl is C2-C6 alkenyl.

As used herein alkynyl is C2-C6 alkynyl.

As used herein, "cycloalkyl" is intended to include cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Preferably, cycloalkyl is C3- Cio cycloalkyl. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocyclyl, heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocyclyl, heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,

benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyly, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, furopyridinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrazolopyridinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuiyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, and triazolyl.

Preferably, heterocyclyl is selected from furopyridinyl, imidazolyl, indolyl, isoquinolinylisothiazolyl, morpholinyl, naphthyridinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrazolopyridinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuiyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, and triazolyl. .

"Heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl, triazolyl and the like. Examples of an "effective amount" include amounts that enable imaging of amyloid deposit(s) in vivo, that yield acceptable toxicity and bioavailability levels for

pharmaceutical use, and/or prevent cell degeneration and toxicity associated with fibril formation.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N^-dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al, "Pharmaceutical Salts," J. Pharm. Sci, 1977:66: 1-19.

As indicated herein the present invention includes isotopically labeled compounds of the invention. An "isotopically-labeled", "radio-labeled", "tracer", "radiotracer", "labeled tracer" or "radioligand" compound, is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides (i.e. "detectable isotopes") that may be incorporated in compounds of the present invention include but are not limited to 2¾ 3¾ H C, 13C, He, 13N, 15N, 150, 1?0, 180, 18F, 35S, 36 _C 1, 82 _Br , 76Br, 77Br, 123i ₅ 124i and 13 ll. The isotopically labeled compounds of the invention need only to be enriched with a detectable isotope to, or above, the degree which allows detection with a technique suitable for the particular application. The radionuclide that is incorporated in the instant radiolabeled compounds will depend on the specific application of that radiolabeled compound. In another embodiment of the invention the radionuclides are represented by ^U C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹⁵ 0, ¹³ N, ³⁵ S, ² H, and ³ H, preferably ^U C, and ¹⁸ F.

This invention further relates to a pharmaceutical composition comprising an effective amount of at least one compound of formula I and a pharmaceutically acceptable carrier. The composition may comprise, but is not limited to, one or more buffering agents, wetting agents, emulsifiers, suspending agents, lubricants, adsorbents, surfactants, preservatives and the like. The composition may be formulated as a solid, liquid, gel or suspension for oral administration (e.g., drench, bolus, tablet, powder, capsule, mouth spray, emulsion); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, epidural injection); topical application (e.g., cream, ointment, controlled-released patch, spray); intravaginal, intrarectal, transdermal, ocular, or nasal administration.

This invention provides radiolabeled pyrrolopyridinyl derivatives as tau imaging agents and synthetic precursor compounds from which they are prepared. The compounds of formula I are active against age-related diseases such as Alzheimer, as well as other tauopathies and neurodegenerative diseases, such as progressive supranuclear palsy, chronic traumatic encephalopathy, frontotemporal dementia, Pick's disease, corticobasal degeneration, etc. The compounds of this invention may also be used in combination with a broad range of cognition deficit enhancement agents. Thus, in another embodiment of this invention a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is

administered concurrently, simultaneously, sequentially or separately with another

pharmaceutically active compound or compounds used in Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

This invention further relates to a method of treating or preventing a tau- related pathology in a patient comprising administering a therapeutically effective amount of a compound of formula I. This invention also provides a method for treating

neurodegenerative disorders such as dementia, Cognitive Deficit in Schizophrenia, Mild

Cognitive Impairment, Age Associated Memory Impairment, Age-Related Cognitive Decline, and the like.

An ultimate objective of the present invention is to provide a radiopharmaceutical agent, useful in tau imaging that has high specific radioactivity and high target tissue selectivity by virtue of its high affinity for tau aggregates. The tissue selectivity is capable of further enhancement by coupling this highly selective radiopharmaceutical with targeting agents, such as microparticles. In another aspect of this invention the claimed compounds have an unexpectedly low binding potential in tau free cortical gray matter and adjacent white matter, which provides improved profiles with regard to binding potential in white matter.

In accordance with the present invention, the most preferred method for imaging tau deposits in a patient, wherein an isotopically labeled novel pyrrolopyridine derivative is employed as the imaging agent, comprises the following steps: the patient is placed in a supine position in the PET camera, and a sufficient amount (< 10 mCi) of an isotopically labeled pyrrolopyridine derivative is administered to the brain tissue of the patient. An emission scan of the cerebral region is performed. The technique for performing an emission scan of the head is well known to those of skilled in the art. PET techniques are described in Freeman et al.,

Freeman and Johnson's Clinical Radionuclide Imaging. 3rd. Ed. Vol. 1 (1984); Grune & Stratton, New York; Ennis et Q. Vascular Radionuclide Imaging: A Clinical Atlas, John Wiley & Sons, New York (1983).

The term "labeled tracer" refers to any molecule which can be used to follow or detect a defined activity in vivo, for example, a preferred tracer is one that accumulates in the regions where tau aggregates may be found. Preferably, the labeled tracer is one that can be viewed in a living experimental animal, healthy human or patient (referred to as a subject), for example, by positron emission tomograph (PET) scanning. Suitable labels include, but are not limited to radioisotopes, fluorochromes, chemiluminescent compounds, dyes, and proteins, including enzymes.

The present invention also provides methods of determining in vivo activity of an enzyme or other molecule. More specifically, a tracer, which specifically tracks the targeted activity, is selected and labeled. In a preferred embodiment, the tracer tracks binding activity of tau protein in the brain and central nervous system. The tracer provides the means to evaluate various neuronal processes, including, regulation of neurotransmitter release, and long-term potentiation. The present invention gives researchers the means to study the biochemical mechanisms of pain, anxiety/depression, drug addiction and withdrawal, disorders of the basal ganglia, eating disorders, obesity, long-term depression, learning and memory, developmental synaptic plasticity, hypoxic-ischemic damage and neuronal cell death, epileptic seizures, visual processing, as well as the pathogenesis of several neurodegenerative disorders.

Biomarkers of Alzheimer's disease state, prognosis and progression will all be useful for general diagnostic utilities as well as for clinical development plans for therapeutic agents for Alzheimer's disease. The present invention will provide biomarker information as patients are enrolled in clinical trials for new Alzheimer's treatments to assist in patient selection and assignment to cohorts. The present invention will serve as one of the biomarkers of disease state in order to get the correct patients into the proper Phllb trial cohort. In addition, the present invention can serve as one marker of disease prognosis as an entry inclusion criterion in order to enhance the probability that the disease will progress in the placebo treatment arm, an issue that has plagued recent AD clinical trials. Finally, the present invention can serve as one biomarker of disease progression to monitor the clinical course of patients on therapy and could provide an independent biomarker measure of treatment response by a therapeutic drug.

Compounds within this invention are inhibitors and/or binders of aggregated tau protein.

Compounds, and isotopically labeled variants thereof, may be useful for the diagnosis and/or treatment of Alzheimer's disease, depression, schizophrenia, or Parkinson's disease. Means of detecting labels are well known to those skilled in the art. For example, isotopic labels may be detected using imaging techniques, photographic film or scintillation counters. In a preferred embodiment, the label is detected in vivo in the brain of the subject by imaging techniques, for example positron emission tomography (PET).

The labeled compound of the invention preferably contains at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from ^U C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹⁵ 0, ¹³ N, ³⁵ S, ² H, and ³ H, more preferably from ^U C, and ¹⁸ F.

The tracer can be selected in accordance with the detection method chosen.

Before conducting the method of the present invention, a diagnostically effective amount of a labeled or unlabeled compound of the invention is administered to a living body, including a human.

The diagnostically effective amount of the labeled or unlabeled compound of the invention to be administered before conducting the in-vivo method for the present invention is within a range of from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.

The isotopically labeled compounds of this invention are prepared by incorporating an isotope such as ^U C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹⁵ 0, ¹³ N, ³⁵ S, ² H, and ³ H into the substrate molecule. This is accomplished by utilizing reagents that have had one or more of the atoms contained therein made radioactive by placing them in a source of radioactivity such as a nuclear reactor, a cyclotron and the like. Additionally many isotopically labeled reagents, such as ² H ₂ 0, ³ H ₃ CI, ¹⁴ C ₆ H ₅ Br, C1CH ₂ ¹⁴ C0C1 and the like, are commercially available. The isotopically labeled reagents are then used in standard organic chemistry synthetic techniques to incorporate the isotope atom, or atoms, into a compound of Formula I as described below. The following Schemes illustrate how to make the compounds of formula I.

The compounds of the present invention have utility in diagnosing, monitoring, and measuring Alzheimer's disease and other non-AD tauopathies such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease, etc. Other conditions that may be diagnosed by the compounds of the invention include Parkinson's Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, , head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention are useful in diagnosing, monitoring or measuring Alzheimer's Disease, non-AD tauopathies, neurodegenerative disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.

The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound, which is a compound of formulae (I) to (VIII), is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.

The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI). 1H MR spectra were recorded at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

List of Abbreviations

analytical

«-butyl lithium

broad

calculated

3-chloroperoxybenzoic acid

doublet

diethylamine

N,N-diisopropylethylamine

dimethylformamide

electrospray ionization

ethyl acetate

ethanol

high-pressure liquid chromatography

z ^' so-propyl alcohol

z ^' so-propyl acetate

Karl-Fischer titration (to determine water content) potassium tert-butoxide

liquid chromatography-mass spectrometry

lithum hexamethyl silazane

multiplet

acetonitrile

methyl alcohol

milipascal

mass spectroscopy MTBE = methyl fert-butyl ether

NHS = normal human serum

NMR = nuclear magnetic resonance spectroscopy

Piv = pivalate, 2,2-dimethylpropanoyl Pd/C = palladium on carbon

rt = room temperature

s = singlet

SFC = supercritical fluid chromatography t = triplet

TLC = thin-layer chromatography

p-TsOU = para-toluene sulfonic acid

THF = tetrahydrofuran

wt% = percentage by weight

The following examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any manner.

Table 1

36 36 257.2 4.96 18230

36

37 37 291.1 19.7 —

F

37

38 38 264.1 52.3 92.92

38

39 39 251.0 10.8 —

39

40 40 265.1 52.7 —

40

41 41 263.1 8.8 10000

41

42 42 295.1 71 .1 —

42

78 1 326.0 — —

78

79 1 297.0 — —

79

80 1 315.0 — —

80

81 3 303.0 — —

81

82 3 303.0 — —

82

— —

83 2 328.0

83

— —

84 2 299.0

84 Example 1

Synthesis of l-(5-(2-(2-methylthiazol-4-yl)ethynyl)pyridin-2-yl)-lH-pyrro lo[2,3-c]pyridine (1):

Scheme 1

Step 1

74% 1 -1

Synthesis of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (1-1). To a solution of 1H- pyrrolo[2,3-c]pyridine (20 g, 0.17 mol) in N,N-dimethylformamide (300 mL) were added 2- fluoro-5-iodopyridine (45 g, 0.20 mol) and cesium carbonate (110 g, 0.34 mol). The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (1 L) and extracted with dichloromethane (3 x 200 mL). The combined organic layers was washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-3% methanol in dichloromethane to afford l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine as a colorless solid: MS (ESI, m/z): 322.0 [M + 1] ⁺ ; 1H NMR (400 MHz, CDC1 ₃ ) δ 9.61 (s, 1H), 8.77 (d, J= 2.0 Hz, 1H), 8.38 (d, J= 5.6 Hz, 1H), 8.12-8.09 (m, 1H), 7.81 (d, J = 3.6 Hz, 1H), 7.56-7.55 (m, 1H), 7.34-7.28 (m, 1H), 6.72 (d, J= 3.6 Hz, 1H).

Step 2

80 °C/16 h

87%

Synthesis of l-(5-(2-(trimethylsilyl)ethynyl)pyridin-2-yl)-lH-pyrrolo[2,3 -c]pyridine (1-2).

To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (4.1 g, 12.5 mmol) in 1,4- dioxane (50 mL) and triethylamine (50 mL) were added ethynyltrimethylsilane (3.7 g, 37.4 mmol), copper(I) iodide (1.4 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol). The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and the organic layer was separated out. The aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford l-(5-(2- (trimethylsilyl)ethynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyrid ine as a yellow solid: MS (ESI, m/z): 292.0 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.93 (s, 1H), 8.97 (d, J= 2.4 Hz, 1H), 8.76 (d, J= 1.5 Hz, 1H), 8.51 (d, J= 6.3 Hz, 1H), 8.25-8.21 (m, 2H), 8.07 (d, J= 8.4 Hz, 1H), 7.24 (d, J = 3.3 Hz, 1H), 0.17 (s, 9H). Step 3

69%

Synthesis of l-(5-ethynylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (1-3). A solution of l-(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyri dine (4.5 g, 15.4 mmol) in methanol (50 mL) was treated with potassium carbonate (4.3 g, 30.9 mmol) for 2 hours at ambient temperature. The resulting mixture was neutralized with acetic acid and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford l-(5-ethynylpyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine as a yellow solid: MS (ESI, m/z): 220.0 [M + 1] ⁺¹ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.95 (s, 1H), 9.00 (d, J= 2.4 Hz, 1H), 8.79 (d, J= 1.5 Hz, 1H), 8.53 (d, J= 6.3 Hz, 1H), 8.28- 8.23 (m, 2H), 8.10 (d, J= 8.4 Hz, 1H), 7.28 (d, J= 3.3 Hz, 1H), 4.58 (s, 1H).

Step 4

Synthesis of l-(5-(2-(2-methylthiazol-4-yl)ethynyl)pyridin-2-yl)-lH-pyrro lo[2,3-c]pyridine (1). To a solution of l-(5-ethynylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (141 mg, 0.64 mmol) in triethylamine (10 mL) were added 4-bromo-2-methylthiazole (178 mg, 1 mmol), copper(I) iodide (48 mg, 0.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.043 mmol). The resulting mixture was stirred for 16 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford l-(5-(2-(2-methylthiazol-4-yl)ethynyl)pyridin-2-yl)-lH-pyrro lo[2,3- c]pyridine as a colorless solid: MS (ESI, m/z): 317.0 [M + 1] ⁺ ; 1H NMR (400 MHz, CD ₃ OD) δ 9.88 (br s, 1H), 8.79 (d, J= 1.6 Hz, 1H), 8.34-8.33 (m, 2H), 8.15-8.12 (m, 1H), 7.85-7.82 (m, 2H), 7.77 (s, 1H), 6.96 (d, J= 3.2 Hz, 1H), 2.76 (s, 3H). Example 2 Synthesis of (E)-l-(5-styrylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (2):

Scheme 2

1 ,4-dioxane/H ₂ 0

1-3 80 °C/16 h 2-1 66%

84%

Step 1

1 ,4-dioxane/H ₂ 0

80 °C/16 h

84%

Synthesis of l-(5-vinylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (2-1). To a solution of l-(5- iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (2 g, 6.23 mmol) in 1,4-dioxane (40 mL) and water (4 mL) were added potassium trifluoro(vinyl)borate (1.25 g, 9.34 mmol), potassium carbonate (1.72 g, 12.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.72 g, 0.62 mmol). The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and the organic layer was separated out. The aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-2% methanol in dichloromethane to afford l-(5-vinylpyridin- 2-yl)-lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 222.0 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO-i ) δ 9.79 (s, 1H), 8.70 (d, J= 2.4 Hz, 1H), 8.35 (d, J= 3.6 Hz, 1H), 8.31 (d, J= 5.2 Hz, 1H), 8.23 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.91 (d, J= 8.4 Hz, 1H), 7.68 (dd, J= 0.8 Hz, 4.4 Hz, 1H), 6.90-6.83 (m, 2H), 6.08 (d, J= 17.6 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H).

Step 2

Synthesis of (E)-l-(5-styrylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (2). To a solution of 1- (5-vinylpyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.4 mmol) in N,N-dimethylformamide (2.5 mL) were added bis(acetato)palladium(II) (10 mg, 0.045 mmol), 1-iodobenzene (138 mg, 0.68 mmol), triphenylphosphine (12 mg, 0.045 mmol) and triethylamine (91 mg, 0.9 mmol). The resulting mixture was irradiated by microwave (100 W) for 1 hour at 100 °C. After cooling down to ambient temperature, the resulting mixture was quenched with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-2% methanol in dichloromethane to afford (E)-l-(5-styrylpyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine as a yellow solid: MS (ESI, m/z): 298.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.71 (s, 1H), 8.79 (d, J= 2.1 Hz, 1H), 8.56-8.32 (m, 3H), 7.93 (d, J= 8.7 Hz, 1H), 7.67-7.64 (m, 3H), 7.48-7.29 (m, 5H), 6.83 (d, J= 4.2 Hz, 1H).

Example 3

Synthesis of l-(5-(pyridin-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (3):

3

Scheme 3

1 -1 3

82%

Synthesis of l-(5-(pyridin-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (3). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.31 mmol) in 1,4-dioxane (20 mL) and water (5 mL) were added 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (96 mg, 0.47 mmol), potassium carbonate (129 mg, 0.93 mmol) and

tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The resulting mixture was stirred for 3 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(pyridin- 3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 273.0 [M + 1] ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.85 (s, 1H), 9.05-9.01 (m, 2H), 8.66-8.64 (m, 1H), 8.44-8.39 (m, 2H), 8.27-8.23 (m, 2H), 8.04 (d, J = 8.7 Hz, 1H), 7.75-7.73 (m, 1H), 7.68-7.54 (m, 1H), 6.89 (d, J = 3.3 Hz, 1H).

Example 4

Synthesis of N-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-4-methoxyb enzamide (4):

Synthesis of l-(5-nitropyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (4-1). To a solution of 1H- pyrrolo[2,3-c]pyridine (2 g, 16.9 mmol) in N,N-dimethylformamide (100 mL) was added 2- fluoro-5-nitropyridine (2.9 g, 20.3 mmol) and cesium carbonate (11.0 g, 33.9 mmol). The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-2% methanol in dichloromethane to afford l-(5-nitropyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine as an orange solid: MS (ESI, m/z): 241.0 [M + 1] ⁺ ; 1H NMR (400 MHz, DMSO- ₆ ) δ 9.95 (s, 1H), 9.46 (d, J= 2.4 Hz, 1H), 8.79 (dd, J= 2.8 Hz, 6.4 Hz, 1H), 8.50 (d, J= 3.6 Hz, 1H), 8.39 (d, J= 5.2 Hz, 1H), 8.16 (d, J= 9.2 Hz, 1H), 7.72 (d, J= 5.2 Hz, 1H), 7.00 (d, J= 3.6 Hz, 1H).

Step 2

Synthesis of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine (4-2). To a stirred solution of l-(5-nitropyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (0.8 g, 3.33 mmol) in methanol (50 mL) was added palladium on charcoal (1.0 g, 10% w/w). The resulting mixture was kept under a hydrogen atmosphere (1 atm.) for 3 hours at ambient temperature. Then, the mixture was filtered through Celite and evaporation of the filtrate under reduced pressure to afford 6-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine as a yellow solid: MS (ESI, m/z): 211.0 [M + 1] ⁺ ; 1H NMR (400 MHz, DMSO- ₆ ) δ 9.39 (s, 1H), 8.25 (d, J= 2.4 Hz, 1H), 8.09 (dd, J= 2.8 Hz, 6.4 Hz, 1H), 7.96 (d, J= 3.6 Hz, 1H), 7.63 (d, J= 5.2 Hz, 1H), 7.48 (d, J= 9.2 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6.71 (d, J= 3.6 Hz, 1H), 5.49 (br s, 2H).

Step 3

Synthesis of N-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-4-methoxyb enzamide (4).

To a solution of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine (100 mg, 0.48 mmol) in N,N- dimethylformamide (15 mL) were added 4-methoxybenzoic acid (109 mg, 0.71 mmol), 0-{l- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (271 mg, 0.71 mmol) and tri ethyl amine (144 mg, 1.43 mmol). The resulting solution was stirred for 16 hours at ambient temperature under nitrogen atmosphere. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-2% methanol in dichloromethane to afford N-(6-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-4-methoxybenzamide as a light yellow solid: MS (ESI, m/z): 345.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 10.4 (s, 1H), 9.66 (s, 1H), 8.96 (d, J = 2.4 Hz, 1H), 8.42 (dd, J= 2.7 Hz, 3.3 Hz, 1H), 8.27-8.24 (m, 2H), 8.03-8.00 (m, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.66-7.64 (m, 1H), 7.12-7.09 (m, 2H), 6.82 (d, J= 3.0 Hz, 1H), 3.85 (s, 3H).

Example 5

Synthesis of l-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyr idine (5):

5

Scheme 5

Synthesis of 2-((6-bromopyridin-3-yloxy)methyl)pyridine (5-1). To a solution of 6- bromopyridin-3-ol (0.5 g, 2.87 mmol) in N,N-dimethylformamide (30 mL) were added 2- (bromomethyl)pyridine hydrobromide (0.73 g, 2.87 mmol) and potassium carbonate (1.19 g, 8.62 mmol). The resulting mixture was stirred for 8 hours at ambient temperature under nitrogen atmosphere. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 10-30% ethyl acetate in petroleum ether to afford 2-((6-bromopyridin-3- yloxy)methyl)pyridine as a red solid: MS (ESI, m/z): 265.0, 267.0 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 8.62 (d, J= 4.2 Hz, 1H), 8.16 (d, J= 3.0 Hz, 1H), 7.77-7.71 (m, 1H), 7.49 (d, J= 10.4 Hz, 1H), 7.38 (d, J= 11.7 Hz, 1H), 7.29-7.20 (m, 1H), 7.18-7.17 (m, 1H), 5.22 (s, 2H).

Ste 2

Synthesis of l-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyr idine (5). To a stirred solution of lH-pyrrolo[2,3-c]pyridine (0.150 g, 1.27 mmol) in dimethyl sulfoxide (50 mL) were added 2-bromo-5-(pyridin-2-ylmethoxy)pyridine (0.67 g, 2.54 mmol),

dimethylglycine (0.13 g, 1.27 mmol), copper (I) iodide (0.24 g, 1.27 mmol) and cesium carbonate (1.65 g, 5.08 mmol). The resulting mixture was stirred for 16 hours at 130 °C under nitrogen atmosphere. After cooling to ambient temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column, eluted with 0.3-2% methanol in dichloromethane to afford l-(5-(pyridin-2- ylmethoxy)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as an off-white solid: MS (ESI, m/z): 303.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.62 (br s, 1H), 8.62-8.60 (m, 1H), 8.43 (d, J= 2.7 Hz, 1H), 8.25 (br s, 1H), 8.17 (d, J= 5.7 Hz, 1H), 7.90-7.74 (m, 3H), 7.63-7.59 (m, 2H), 7.41-7.36 (m, 1H), 6.80 (d, J= 3.3 Hz, 1H), 5.35 (s, 2H).

Example 6

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (6):

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (6). To a stirred solution of 1H- pyrrolo[2,3-c]pyridine (0.13 g, 1.08 mmol) in dimethyl sulfoxide (15 mL) were added copper(I) iodide (0.055 g, 0.29 mmol), 3-bromoisoquinoline (0.150 g, 0.72 mmol), cesium carbonate (0.94 g, 2.88 mmol) and dimethylglycine (0.029 g, 0.29 mmol). The resulting mixture was stirred for 16 hours at 130 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtration was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-2% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline as an off-white solid: MS (ESI, m/z): 246.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.70 (s, 1H), 9.43 (s, 1H), 8.36 (d, J= 3.3 Hz, 1H), 8.30-8.28 (m, 2 H), 8.21 (d, J= 8.1 Hz, 1H), 8.07 (d, J= 8.4 Hz, 1H), 7.88- 7.82 (m, 1H), 7.71-7.66 (m, 2H), 6.87 (d, J= 3.3 Hz, 1H). Example 7

Synthesis of l-(5-(3-fluoroprop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyr idine (7):

Scheme 7

1 ,4-dioxan/ 60 °C/2 h

1-1 70% 7-1 30%

1 ,4-dioxan/ 60 °C/2 h

1-1 70% 7-1

Synthesis of 3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)prop-2-yn-l -ol (7-1). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (200 mg, 0.62 mmol) in 1,4- dioxane (20 mL) and triethylamine (5 mL) were added trimethyl(prop-2-ynyloxy)silane (96 mg, 0.77 mmol), copper (I) iodide (71 mg, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (0) (140 mg, 0.12 mmol). The resulting mixture was stirred for 2 hours at 60 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and the organic layer was separated out. The aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford 3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)prop-2-yn-l -ol as a colorless solid: MS (ESI, m/z): 250.0 [M + 1] ⁺ ; 1H NMR (300 MHz, OMSO-d ₆ ) δ 9.79 (br s, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.34-8.23 (m, 2H), 8.08-8.04 (m, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.67 (d, J= 5.1 Hz, 1H), 6.87 (d, J= 3.3 Hz, 1H), 5.45 (t, J= 6.0 Hz, 1H), 4.37 (d, J= 6.0 Hz, 2H).

30%

Synthesis of l-(5-(3-fluoroprop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyr idine (7). To a solution of 3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)prop-2-yn-l -ol (100 mg, 0.4 mmol) in dichloromethane (20 mL) was added diethylaminosulfurtrifluoride (DAST) (2 mL) at -78 °C. The resulting solution was stirred for 2 hours at ambient temperature and quenched with saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was separated out and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford l-(5-(3-fluoroprop-l-ynyl)pyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 252.0 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO-i ) δ 9.85 (br s, 1H), 8.76 (d, J= 2.1 Hz, 1H), 8.37 (d, J= 3.3 Hz, 1H), 8.32 (d, J= 5.1 Hz, 1H), 8.17-8.14 (m, 1H), 7.96 (d, J= 8.7 Hz, 1H), 7.68 (d, J= 5.4 Hz, 1H), 6.90 (d, J= 3.3 Hz, 1H), 5.49 (s, 1H), 5.33 (s, 1H).

Example 8 Synthesis of l-(lH-pyrrolo[2,3-c]pyridin-5-yl)-lH-pyrrolo[2,3-c]pyridine (8):

8 Scheme 8

41 %

8-1

Synthesis of l-(4-methyl-5-nitropyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (8-1).

To a solution of lH-pyrrolo[2,3-c]pyridine (1.0 g, 8.7 mmol) in N,N- dimethylformamide (30 mL) were added potassium carbonate (1.6 g, 11.6 mmol) and 2-chloro-4- methyl-5-nitropyridine(1.0 g, 5.8 mmol) at ambient temperature. The resulting mixture was stirred for 18 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction was diluted with brine (150 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 30-50% ethyl acetate in petroleum ether to afford l-(4-methyl-5-nitropyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 255.0 [M + 1] ⁺ .

Synthesis of (E)-N,N-dimethyl-2-(5-nitro-2-(lH-pyrrolo[2,3-c]pyridin-l-yl )pyridin-4- yl)ethenamine (8-2). A solution of l-(4-methyl-5-nitropyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (140 mg, 0.55 mmol) in Ν,Ν-dimethylformamide dimethyl acetal (20 mL) was stirred for 24 hours at 85 °C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 50-80% ethyl acetate in petroleum ether to afford (E)-N,N-dimethyl-2-(5-nitro-2-(lH-pyrrolo[2,3-c]pyridin-l-yl )pyridin-4-yl)ethenamine as a yellow solid: MS (ESI, m/z): 310.0 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 9.59 (s, 1H), 9.05 (s, 1H), 8.39-8.36 (m, 1H), 8.10 (d, J= 3.6 Hz, 1H), 7.69 (d, J= 7.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.43 (s, 1H), 6.83 (d, J= 3.6 Hz, 1H), 6.18 (d, J= 12.4 Hz, 1H), 3.12 (s, 6H).

Synthesis of l-(lH-pyrrolo[2,3-c]pyridin-5-yl)-lH-pyrrolo[2,3-c]pyridine (8). To a stirred solution of (E)-N,N-dimethyl-2-(5-nitro-2-(lH-pyrrolo[2,3-c]pyridin-l-yl )pyridin-4- yl)ethenamine (40 mg, 0.13 mmol) in methanol (10 mL) was added palladium on charcoal (5.0 mg, 10% w/w). The resulting mixture was kept under a hydrogen atmosphere (1 atm.) for 1 hour at ambient temperature. Then, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford l-(lH-pyrrolo[2,3- c]pyridin-5-yl)-lH-pyrrolo[2,3-c]pyridine as an off-white solid: MS (ESI, m/z): 235.0 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 1 1.80 (br s, 1H), 9.48 (s, 1H), 8.78 (s, 1H), 8.22-8.16 (m, 2H), 7.90 (s, 1H), 7.76-7.75 (m, 1H), 7.64-7.63 (m, 1H), 6.76 (d, J= 3.2 Hz, 1H), 6.62 (s, 1H). Example 9

Synthesis of 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (9):

9

Scheme 9

67% 9-1 82% 9-2

red phosphorous

AcOH/Hl (45%)/4 h/100 °C

2-amine mesylate

77%

t-BuONa/THF/50 °C/16 h

9-3

55%

Step 1

67% 9-1

Synthesis of (E)-5-fluoro-2-(hydroxyimino)-2,3-dihydroinden-l-one (9-1). To a stirred solution of 5-fluoro-2,3-dihydroinden-l-one (3 g, 20 mmol) in diethyl ether (50 mL) was bubbled with dry hydrochloride gas for 3 hours at 0 °C, then isopentyl nitrite (4.7 g, 40 mmol) was added over 5 min. After stirring for 3 hours at ambient temperature, the solid was collected by filtration and washed with diethyl ether (3 x 30 mL) to afford (E)-5-fluoro-2-(hydroxyimino)- 2,3-dihydroinden-l-one as an off-white solid: MS (ESI, m/z): 180.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 12.67 (s, 1H), 7.85-7.81 (m, 1H), 7.46-7.43 (m, 1H), 7.31-7.28 (m, 1H), 3.79 (s, 2H).

Step 2

Synthesis of l,3-dichloro-6-fluoroisoquinoline (9-2). To a stirred solution of (E)-5-fluoro- 2-(hydroxyimino)-2,3-dihydroinden-l-one (3 g, 13.4 mmol) in phosphorus oxy trichloride (50 mL) was added pentachlorophosphorane (3.2 g, 15.1 mmol) at 0 °C. Hydrochloride gas was bubbled into the resulting solution for 3 hours at 0 °C. The resulting mixture was stirred for 16 hours at 60 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the solid was washed with water (3 x 50 mL), dried in a vacuum oven to afford l,3-dichloro-6-fluoroisoquinoline as a dark grey solid: MS (ESI, m/z): 216.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 8.41-8.36 (m, 1H), 8.10 (s, 1H), 7.87-7.83 (m, 1H), 7.78-7.69 (m, 1H).

Step 3

Synthesis of 3-chloro-6-fluoroisoquinoline (9-3). To a stirred solution of 1,3 -dichloro-6- fluoroisoquinoline (2.5 g, 1 1.6 mmol) in acetic acid (40 mL) and hydriodic acid (20 mL, 45% aqueous solution) was added red phosphorus (0.9 g, 28.9 mmol) at ambient temperature. The resulting mixture was stirred for 4 hours at 100 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure. The residue was dissolved into dichloromethane (100 mL) and washed with saturated aqueous solution of sodium bicarbonate (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-chloro-6-fluoroisoquinoline as a dark grey solid: MS (ESI, m/z): 182.0 [M + 1] ⁺ ; 1H MR (400 MHz, OMSO-d ₆ ) δ 9.24 (s, 1H), 8.32-8.29 (m, 1H), 8.04 (s, 1H), 7.82-7.76 (m, 1H), 7.66-7.61 (m, 1H).

Synthesis of 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (9). To a stirred solution of lH-pyrrolo[2,3-c]pyridine (100 mg, 0.85 mmol) and 3-chloro-6-fluoroisoquinoline (231 mg, 1.27 mmol) in tetrahydrofuran (20 mL) were added sodium 2-methylpropan-2-olate (163 mg, 1.69 mmol) and 2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-l, l '-biphenyl)(2" '- amino-l ", "-biphenyl-2"-yl)palladium(II) mesylate (33.6 mg, 0.042 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichloromethane to afford 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline as a light yellow solid: MS (ESI, m/z): 264.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.69 (s, 1H), 9.43 (s, 1H), 8.40-8.25 (m, 4H), 8.01-7.95 (m, 1H), 7.71-7.68 (m, 1H), 7.58-7.51 (m, 1H), 6.89 (s, 1H).

Example 10

Synthesis of N,N-dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amin e (10):

10 Scheme 10

72% 10-1 35% 10

Stepl

72% 10-1

Synthesis of 6-bromo-N,N-dimethylpyridin-3-amine (10-1). To a solution of 6- bromopyridin-3 -amine (300 mg, 1.73 mmol) in tetrahydrofuran (30 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide (3.46 mL, 3.46 mmol) in tetrahydrofuran over 5 min at - 78 °C under nitrogen atmosphere. After stirring for 30 min at -78 °C, iodomethane (566 mg, 3.99 mmol) was added. The resulting mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% ethyl acetate in petroleum ether to afford 6-bromo- N,N-dimethylpyridin-3 -amine as a light yellow solid: MS (ESI, m/z): 201.0, 203.0 [M + 1] ⁺ .

Ste 2

10-1 35% 10 Synthesis of N,N-dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amin e (10). To a stirred solution of lH-pyrrolo[2,3-c]pyridine (100 mg, 0.84 mmol) in dimethyl sulfoxide (30 mL) were added 6-bromo-N,N-dimethylpyridin-3-amine (204 mg, 1.01 mmol), dimethylglycine (52 mg, 0.51 mmol), copper(I) iodide (97 mg, 0.51 mmol) and cesium carbonate (1.1 g, 3.39 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 130 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers was washed with brine (4 x 80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichlorom ethane to afford N,N- dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine as a light yellow solid: MS (ESI, m/z): 239.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.47 (s, 1H), 8.22 (d, J= 5.1 Hz, 1H), 8.11-8.09 (m, 2H), 7.66 (s, 1H), 7.62-7.61 (m, 1H), 7.40-7.35 (m, 1H), 6.75 (d, J= 3.3 Hz, 1H), 3.02 (s, 6H).

Example 11

Synthesis of 5-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (11):

11

90% 11 -1

Synthesis of 3-chloro-5-nitroisoquinoline (11-1). To a solution of 3-chloroisoquinoline (2.0 g, 12.2 mmol) in concentrated sulfuric acid (48 mL) was added potassium nitrate (1.48 g, 14.6 mmol) in portions at 0 °C. The resulting solution was stirred for 4 hours at ambient temperature and then poured onto ice-water (300 g). The precipitate wasd collected by filtration and dried to afford 3-chloro-5-nitroisoquinoline as a light yellow solid: MS (ESI, m/z): 209.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.46 (s, 1H), 8.75-8.72 (m, 1H), 8.66-8.63 (m, 1H), 8.45(s, 1H), 7.94-7.89 (m, 1H).

Step 2

Synthesis of 3-chloroisoquinolin-5-amine (11-2). To a solution of 3-chloro-5-nitroisoquinoline (2.3 g, 1 1.0 mmol) in acetic acid (100 mL) was added zinc dust (3.5 g, 55.1 mmol) in portions. The resulting mixture was stirred for 2 hours at ambient temperature. Then the resulting mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1% methanol in dichloromethane to afford 3-chloroisoquinolin-5-amine as an off-white solid: MS (ESI, m/z): 179.0 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 8.98 (s, 1H), 8.13 (s, 1H), 7.40-7.35 (m, 1H), 7.28-7.25 (m, 1H), 6.90-6.87 (m, 1H), 6.06

Synthesis of tert-butyl 3-chloroisoquinolin-5-ylcarbamate (11-3). To a solution of 3- chloroisoquinolin-5-amine (1.6 g, 8.96 mmol) in dichloromethane (50 mL) were added triethylamine (1.81 g, 17.92 mmol) and di-tert-butyl dicarbonate (2.34 g, 10.75 mmol). The resulting mixture was stirred for 3 hours at ambient temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to give tert-butyl (3-chloroisoquinolin-5-yl)carbamate as a light yellow solid: MS (ESI, m/z): 279.0 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 9.33 (s, 1H), 8.24-8.21 (m, 1H), 7.83-7.77 (m, 2H), 7.57 (s, 1H), 1.32 (s, 9H).

Ste 4

Synthesis of tert-butyl 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-ylcarbamate (11-4).

To a solution of lH-pyrrolo[2,3-c]pyridine (254 mg, 2.15 mmol) in tetrahydrofuran (25 mL) were added tert-butyl (3-chloroisoquinolin-5-yl)carbamate (400 mg, 1.43 mmol), sodium 2-methylpropan-2-olate (276 mg, 2.87 mmol) and 2-di-tert-butylphosphino- 2',4',6'-tri-iso-propyl-l, 1 '-biphenyl)(2' " -amino- 1 ", 1 "'-biphenyl-2"-yl)palladium(II) mesylate (114 mg, 0.14 mmol) under nitrogen atmosphere. The resulting solution was stirred for 16 hours at 50 °C. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford tert-butyl (3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin- 5-yl)carbamate as a colorless solid: MS (ESI, m/z): 361.0 [M + 1] ⁺ ; 1H NMR (400 MHz, DMSO- d ₆ ) δ 9.72 (s, 1H), 9.63 (s, 1H), 9.41 (s, 1H), 8.37-8.31 (m, 1H), 8.29 (s, 2H), 8.07 (d, J= 7.6 Hz, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.70 (d, J= 4.4 Hz, 1H), 7.68-7.62 (m, 1H), 6.90 (d, J= 4.8 Hz, 1H), 1.55 (s, 9 H).

Step 5

11-4 11 -5

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amine (11-5). To a solution of tert-butyl (3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-yl)carbamate (250 mg, 0.69 mmol) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (791 mg, 6.94 mmol). After stirring for 1 hour at ambient temperature, the resulting solution was washed with saturated aqueous solution of sodium bicarbonate (2 x 50 mL) and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5—1% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amine as an off- white solid: MS (ESI, m/z): 261.0 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 9.67 (s, 1H), 9.22 (s, 1H), 8.32-8.26 (m, 3H), 7.68-7.66 (m, 1H), 7.41-7.33 (m, 2H), 6.93-6.84 (m, 2H), 6.12 (br s, 2H). Step 6

37%

11-5 11

Synthesis of 5-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (11). To a solution of 3- (lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amine (100 mg, 0.38 mmol) in diluted sulfuric acid (10% aqueous solution) was added sodium nitrite (53.0 mg, 0.76 mmol) at 0 °C. After stirring for 20 min at 0 ° C, potassium iodide (128 mg, 0.76 mmol) was added in one portion. After additional 10 min, the resulting mixture was quenched by saturated sodium sulfite (10 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1.5% methanol in dichloromethane to afford 5-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline as a colorless solid: MS (ESI, m/z): 372.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.61 (s, 1H), 9.39 (s, 1H), 8.46-8.27 (m, 4H), 7.99 (s, 1H), 7.72-7.70 (m, 1H), 7.49-7.45 (m, 1H), 6.91 (d, J= 3.3 Hz,

1H).

Example 12

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-amine (12):

12

Synthesis of (E)-2-(hydroxyimino)-6-iodo-2,3-dihydroinden-l-one (12-1). To a solution of 6-iodo-2,3-dihydro-lH-inden-l-one (5 g, 19.4 mmol) in dichloromethane (300 mL) and methanol (15 mL, saturated with hydrochloride at 0 °C) was added a solution of isopentyl nitrite (4.5 g, 38.8 mmol) in dichloromethane (10 mL) over 30 min at 0 °C. The resulting solution was stirred for 3 hours at ambient temperature. The solvents were removed partially to about 50 mL followed by the dilution with ether (100 mL). Solid was collected by filtration to give (E)-2-

(hydroxyimino)-6-iodo-2,3-dihydroinden-l-one as a light yellow solid: MS (ESI, m/z): 288.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 12.75 (s, 1H), 8.06-8.01 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 3.72 (s, 2H). Step 2

Synthesis of l,3-dichloro-7-iodoisoquinoline (12-2). To a solution of (E)-2- (hydroxyimino)-6-iodo-2,3-dihydroinden-l-one (5.4 g, 18.81 mmol) in phosphoryl trichloride (80 mL) was added pentachlorophosphorane (5.9 g, 28.2 mmol). Then hydrochloride gas was bubbled into the solution for 3 hours at 0 °C. The resulting solution was stirred for 16 hours at 60 °C. After cooling down to ambient temperature, the mixture was concentrated under reduced pressure and the residue was taken up by dichloromethane (100 mL) and saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford l,3-dichloro-7-iodoisoquinoline as a brown solid: MS (ESI, m/z): 324.2 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 8.59 (s, 1H), 8.21 (dd, J= 1.2 Hz, 8.4 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J= 8.8 Hz, 1H).

Step 3 reflux/16 h

12-2 28% 12-3

Synthesis of 3-chloro-7-iodoisoquinoline (12-3). To a solution of l,3-dichloro-7- iodoisoquinoline (6 g, 18.52 mmol) in acetic acid (40 mL) were added hydriodic acid (20 mL, 55% w/w) and red phosphorus (1.43 g, 46.3 mmol). The resulting solution was refluxed for 16 hours, then concentrated under reduced pressure. The residue was taken up by dichloromethane (100 mL) and saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to afford 3-chloro-7-iodoisoquinoline as a light yellow solid: MS (ESI, m/z): 290.2 [M + 1] ⁺ ; 1H NMR (400 MHz, DMSO- ₆ ) δ 9.20 (s, 1H), 8.66 (s, 1H), 8.10 (dd, J= 1.2 Hz, 4.8 Hz, 1H), 8.06 (s, 1H), 7.78 (d, J= 8.8 Hz, 1H).

Step 4

Synthesis of 7-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (12-4). To a solution of 3-chloro-7-iodoisoquinoline (0.8 g, 2.76 mmol) in N,N-dimethylformamide (30 mL) were added lH-pyrrolo[2,3-c]pyridine (0.49 g, 4.15 mmol) and cesium carbonate (1.80 g, 5.53 mmol). The resulting mixture was stirred for 24 hours at 120 °C. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 7-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline as a light yellow solid: MS (ESI, m/z): 372.1 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 9.70 (s, 1H), 9.39 (s, 1H), 8.70 (s, 1H), 8.36 (d, J= 7.2 Hz, 1H), 8.30-8.29 (m, 2H), 8.10 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.69 (dd, J= 0.8 Hz, 5.2 Hz, 1H), 6.89 (d, J= 3.2 Hz, 1H).

Step 5

12-4 81%

12

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-amine (12). To a solution of 7-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (300 mg, 0.81 mmol) in toluene (30 mL) were added diphenylmethanimine (220 mg, 1.21 mmol), tris(dibenzylideneacetone)dipalladium (0) (41.8 mg, 0.04 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (46.7 mg, 0.081 mmol) and cesium carbonate (527 mg, 1.62 mmol). The resulting mixture was refluxed for 16 hours under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was diluted with methanol (30 mL). To the resulting solution was added hydrochloric acid (6 mL, 2 N) and the resulting solution was stirred for 3 hours at ambient temperature. The resulting solution was diluted with sodium bicarbonate (60 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 3-(lH- pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-amine as a light yellow solid: MS (ESI, m/z): 261.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.52 (s, 1H), 9.00 (s, 1H), 8.23-8.21 (m, 2H), 7.97 (s, 1H), 7.82 (d, J= 10.8 Hz, 1H), 7.66 (d, J= 5.1 Hz, 1H), 7.26 (d, J= 6.9 Hz, 1H), 7.03 (s, 1H), 6.78 (d, J= 3.0 Hz, 1H), 5.79 (br s, 2H).

Example 13

Synthesis of 7-methoxy-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (13):

13

Scheme 13

Step 1

Synthesis of (E)-2-(hydroxyimino)-6-methoxy-2,3-dihydroinden-l-one (13-1). To a stirred solution of 6-methoxy-2,3-dihydroinden-l-one (20 g, 123 mmol) in diethyl ether (300 mL) was bubbled with dry hydrochloride gas at 0 °C for 3 hours, then isopentyl nitrite (22 g, 185 mmol) was added. The resulting solution was stirred for 3 hours at ambient temperature. The solid was collected by filtration and washed with diethyl ether (3 x 100 mL) to afford (E)-2- (hydroxyimino)-6-methoxy-2,3-dihydroinden-l-one as an off-white solid: MS (ESI, m/z): 192.0 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 12.60 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 3.80 (s, 3H), 3.69 (s, 2H).

Synthesis of l,3-dichloro-7-methoxyisoquinoline (13-2). To a stirred solution of (E)-2- (hydroxyimino)-6-methoxy-2,3-dihydroinden-l-one (5.0 g, 26.2 mmol) in phosphorus oxytrichloride (80 mL) was added pentachlorophosphorane (6.0 g, 28.8 mmol) at 0 °C.

Hydrochloride gas was bubbled into the resulting solution for 3 hours. The resulting mixture was stirred for 16 hours at 60 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the solid was washed with water (3 x 50 mL), dried in a vacuum oven to afford l,3-dichloro-7-methoxyisoquinoline as a light yellow solid: MS (ESI, m/z): 228.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 8.06 (s, 1H), 8.00 (d, J= 9.0 Hz, 1H), 7.60 (dd, J= 2.4 Hz, 6.6 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 3.97 (s, 3H).

Step 3

Synthesis of 3-chloro-7-methoxyisoquinoline (13-3). To a stirred solution of 1,3-dichloro- 7-methoxyisoquinoline (4.0 g, 17.5 mmol) in acetic acid (60 mL) and hydriodic acid (30 mL, 45% aqueous solution) was added red phosphorus (1.3 g, 43.8 mmol) at ambient temperature. The resulting mixture was stirred for 4 hours at 100 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure. The residue was dissolved into dichloromethane (100 mL) and washed with saturated aqueous solution of sodium bicarbonate (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 5-10% ethyl acetate in petroleum to afford 3- chloro-7-methoxyisoquinoline as an off-white solid: MS (ESI, m/z): 194.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.00 (s, 1H), 8.00 (s, 1H), 7.89 (d, J= 9.0 Hz, 1H), 7.54 (dd, J= 2.4 Hz, 6.6 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 3.87 (s, 3H).

Synthesis of 7-methoxy-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (13): To a stirred solution of lH-pyrrolo[2,3-c]pyridine (79 mg, 0.52 mmol) and 3-chloro-7-methoxyisoquinoline (100 mg, 1.27 mmol) in tetrahydrofuran (20 mL) were added sodium 2-methylpropan-2-olate (163 mg, 1.69 mmol) and 2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-l, l '-biphenyl)(2"'- amino- l ", "-biphenyl-2"-yl)palladium(II) mesylate (33.6 mg, 0.042 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichloromethane to afford 7-methoxy-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline as a light yellow solid: MS (ESI, m/z): 276.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.64 (s, 1H), 9.30 (s, 1H), 8.31-8.27 (m, 2H), 8.22 (s, 1H), 8.00 (d, J= 6.0 Hz, 1H), 7.68 (d, J= 5.4 Hz, 1H), 7.61 (d, J= 2.4 Hz, 1H), 7.52-7.48 (m, 1H), 6.85 (d, J= 3.3 Hz, 1H), 3.95 (s, 3H).

Example 14

Synthesis of N-(2-fluoroethyl)-N-methyl-3-(lH-pyrrolo[2,3-c]pyridin-l-yl) isoquinolin-6- amine (14):

Synthesis of N-methyl-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6-amin e (14-1). To a sealed tube were added a solution of methanamine in ethanol (30 mL, 30% w/w) and 6-fluoro-3- (lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (150 mg, 0.57 mmol, 9). The resulting mixture was stirred for 48 hours at 100 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichlorom ethane to afford N-methyl-3 - (lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6-amine as a light yellow solid: MS (ESI, m/z): 275.1 [M + 1] ⁺ ; 1H NMR (300 MHz, OMSO-d ₆ ) δ 9.63 (s, 1H), 8.94 (s, 1H), 8.27-8.24 (m, 2H), 7.83 (s, 1H), 7.80 (d, J= 9.0 Hz, 1H), 7.64 (dd, J= 0.9 Hz, 4.5 Hz, 1H), 7.04 (dd, J= 5.1 Hz, 6.6 Hz, 1H), 6.82 (d, J= 3.0 Hz, 1H), 6.76-6.74 (m, 1H), 6.70 (d, 7= 1.8 Hz, 1H), 2.83 (d, 7= 4.8 Hz, 3H). Step 2

14-1 14

Synthesis of N-(2-fluoroethyl)-N-methyl-3-(lH-pyrrolo[2,3-c]pyridin-l-yl) isoquinolin-6- amine (14). To a stirred solution of N-methyl-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6- amine (50 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (14 mg, 0.36 mmol, 60% dispersed by mineral oil) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C followed by the addition of l-bromo-2-fluoroethane (46 mg, 0.36 mmol). The resulting mixture was stirred for 4 hours at ambient temperature and quenched with saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford N-(2-fluoroethyl)-N- methyl-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6-amine as a light yellow solid: MS (ESI, m/z): 321.2 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.68 (s, 1H), 9.04 (s, 1H), 8.38 (d, J = 3.3 Hz, 1H), 8.29 (d, J= 5.4 Hz, 1H), 7.96 (d, J= 9.0 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J= 5.4 Hz, 1H), 7.38 (d, J= 9.0 Hz, 1H), 7.01 (d, J= 1.8 Hz, 1H), 6.90 (d, J= 3.0 Hz, 1H), 4.75 (t, J= 4.8 Hz, 1H), 4.59 (t, J= 4.8 Hz, 1H), 3.93 (t, J= 5.1 Hz, 1H), 3.84 (t, J= 5.1 Hz, 1H), 3.14 (s, 3H).

Example 15

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-

15 Scheme 15

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-ol (15). To a stirred solution of 7-methoxy-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (70 mg, 0.25 mmol, 13) in dichloromethane (15 mL) was added tribromoborane (64 mg, 0.25 mmol) at -78 °C. The resulting mixture was stirred for 16 hours at ambient temperature then quenched by the addition of water (10 mL). The mixture was neutralized by the addition of potassium carbonate and extracted with dichloromethane (5 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-ol as a light-yellow solid: MS (ESI, m/z): 262.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 10.26 (s, 1H), 9.58 (s, 1H), 9.21 (s, 1H), 8.28-8.25 (m, 2H), 8.15 (s, 1H), 7.96 (d, J= 9.0 Hz, 1H), 7.66 (d, J= 5.1 Hz, 1H), 7.44-7.39 (m, 2H), 6.84 (d, J= 3.3 Hz, 1H).

Example 16

Synthesis of 7-(2-fluoroethoxy)-3- lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (16):

16

Scheme 16 Synthesis of 7-(2-fluoroethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquino line (16). To a stirred solution of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-ol (40 mg, 0.15 mmol, 15) in N,N-dimethylformamide (5 mL) were added potassium carbonate (42 mg, 0.31 mmol) and 1- bromo-2-fluoroethane (29 mg, 0.23 mmol). The resulting mixture was stirred for 16 hours at 30 °C then quenched with water (30 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford 7-(2-fluoroethoxy)-3- (lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline as a light-yellow solid: MS (ESI, m/z): 308.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.90 (s, 1H), 9.38 (s, 1H), 8.94 (d, J= 3.3 Hz, 1H), 8.47 (d, J= 6.3 Hz, 1H), 8.41 (s, 1H), 8.25 (d, J= 6.6 Hz, 1H), 8.05 (d, J= 9.0 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.64-7.60 (m, 1H), 7.26 (d, J= 3.3 Hz, 1H), 4.95 (t, J= 3.6 Hz, 1H), 4.79 (t, J= 3.6 Hz, 1H), 4.51 (t, J= 3.6 Hz, 1H), 4.41 (t, J= 3.6 Hz, 1H). Example 17

Synthesis of 7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinol ine (17):

Synthesis of 7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinol ine (17). A solution of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-ol (50 mg, 0.19 mmol, 15) in N,N- dimethylformamide (10 mL) was treated with sodium hydride (33 mg, 0.83 mmol, 60% w/w dispersed into mineral oil) at 0 °C for 10 min followed by the addition of bromofluoromethane (108 mg, 0.96 mmol). After additional 3 hours, the reaction was quenched with saturated aqueous solution of ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 7-(fluoromethoxy)-3-(lH-pyrrolo[2,3- c]pyridin-l-yl)isoquinoline as a light yellow solid: MS (ESI, m/z): 294.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.66 (s, 1H), 9.45 (s, 1H), 8.34 (d, J= 3.0 Hz, 1H), 8.30-8.27 (m, 2H), 8.12 (d, J= 9.0 Hz, 1H), 7.89 (s, 1H), 7.70-7.64 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 6.15 (s, 1H), 5.97 (s, 1H).

Example 18

Synthesis of 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amin e (18):

18

Scheme 18

Step 1

Synthesis of 3-chloro-6-fluoro-5-nitroisoquinoline (18-1). To a solution of 3-chloro-6- fluoroisoquinoline (2 g, 1 1.01 mmol, 9-3) in concentrated sulfuric acid (30 mL) was added potassium nitrate (1.17 g, 11.56 mmol) at 0 °C. The resulting mixture was stirred for 3 hours at ambient temperature then poured onto ice/water (200 g). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 10-20% ethyl acetate in petroleum ether to afford 3-chloro-6-fluoro-5-nitroisoquinoline as a light yellow solid: MS (ESI, m/z): 226 A [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.43 (s, 1H), 8.70-8.65 (m, 1H), 8.07 (s, 1H), 7.70-7.63 (m, 1H).

Step 2

Synthesis of 3-chloro-6-fluoroisoquinolin-5-amine (18-2). To a solution of 3-chloro-6- fluoro-5-nitroisoquinoline (1 g, 4.41 mmol) in acetic acid (100 mL) was added iron powder (1.27 g, 22.07 mmol). The resulting mixture was stirred for 2 hours at ambient temperature, then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to afford 3-chloro-6-fluoroisoquinolin-5-amine as a yellow solid: MS (ESI, m/z): 197.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.06 (s, 1H), 8.26 (s, 1H), 7.51-7.44 (m, 1H), 7.40-7.35 (m, 1H), 6.01 (br s, 2H).

Synthesis of tert-butyl 3-chloro-6-fluoroisoquinolin-5-ylcarbamate (18-3). To a solution of 3- chloro-6-fluoroisoquinolin-5-amine (150 mg, 0.76 mmol) in dichloromethane (30 mL) were added di-tert-butyl dicarbonate (216 mg, 0.99 mmol) and triethylamine (116 mg, 1.14 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. After that, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to afford tert-butyl 3- chloro-6-fluoroisoquinolin-5-ylcarbamate as a light yellow solid: MS (ESI, m/z): 297.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.03 (s, 1H), 7.93-7.88 (m, 1H), 7.83 (s, 1H), 7.41 (t, J= 9.3 Hz, 1H), 6.23 (br s, 1H), 1.52 (s, 9H).

Synthesis of tert-butyl 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-ylca rbamate (18-4). To a solution of lH-pyrrolo[2,3-c]pyridine (90 mg, 0.76 mmol) in tetrahydrofuran

(15 mL) were added tert-butyl (3-chloro-6-fluoroisoquinolin-5-yl)carbamate (150 mg, 0.51 mmol), sodium 2-methylpropan-2-olate (97 mg, 1.01 mmol) and 2-di-tert-butylphosphino- 2 ' ,4 ' , 6 ' -tri-i so-propy 1- 1, 1 ' -biphenyl)(2 " ' -amino- 1 " , 1 " ' -biphenyl-2 ' ' -yl)palladium(II) mesylate (40.2 mg, 0.051 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1% methanol in dichloromethane to afford tert-butyl 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-ylca rbamate as a yellow solid: MS (ESI, m/z): 379.2 [M + 1] ⁺ ; 1H MR (300 MHz, CD ₃ OD) δ 9.62 (s, 1H), 9.34 (s, 1H), 8.25-8.22 (m, 2H), 8.21-8.16 (m, 1H), 8.03 (s, 1H), 7.72 (d, J= 5.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 6.98 (d, J= 3.6 Hz, 1H), 1.55 (s, 9H).

Step 5

Synthesis of 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amin e (18). A solution of tert-butyl 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-ylca rbamate (65 mg, 0.17 mmol) in dichloromethane (15 mL) was treated with trifluoroacetic acid (3 mL) for 3 hours at ambient temperature. The resulting mixture was concentrated under reduced pressure and the residue was dissolved into dichloromethane (50 mL), washed with saturated aqueous solution of sodium bicarbonate (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 6-fluoro-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-5-amin e as a yellow solid: MS (ESI, m/z): 279.0 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.70 (s, 1H), 9.27 (s, 1H), 8.40 (s, 1H), 8.35-8.27 (m, 2H), 7.68-7.66 (m, 1H), 7.45-7.43 (m, 2H), 6.88 (d, J= 3.3 Hz, 1H), 6.03 (br s, 2H).

Example 19

Synthesis of l'-methyl-l,5'-bi(lH-p rrolo[2,3-c]pyridine) (19):

19 Scheme 19

65%

19-1

Synthesis of tert-butyl 6-bromo-4-methylpyridin-3-ylcarbamate (19-1). To a solution of 6-bromo-4-methylpyridin-3 -amine (2 g, 10.69 mmol) in dichloromethane (30 mL) were added tri ethyl amine (2.16 g, 21.39 mmol) and di-tert-butyl dicarbonate (3.03 g, 13.90 mmol). The resulting solution was stirred for 4 hours at ambient temperature, then concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 5-10% ethyl acetate in petroleum ether to afford tert-butyl 6-bromo-4-methylpyridin-3- ylcarbamate as a colorless solid: MS (ESI, m/z): 287.1, 289.1 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 8.72 (s, 1H), 7.30 (s, 1H), 6.18 (br s, 1H), 2.26 (s, 3H), 1.55 (s, 9H). Step 2

19-1 19-2

Synthesis of tert-butyl 6-bromo-4-methylpyridin-3-yl(methyl)carbamate (19-2). A solution of tert-butyl 6-bromo-4-methylpyridin-3-ylcarbamate (3.1 g, 10.8 mmol) in N,N- dimethylformamide (30 mL) was treated with sodium hydride (0.86 g, 21.6 mmol, 60% w/w dispersed into mineral oil) for 10 min at 0 °C followed by the addition of iodomethane (3.1 g, 21.6 mmol). The resulting mixture was stirred for 1 hour at ambient temperature and quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers was washed with brine (4 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 10-20% ethyl acetate in petroleum ether to afford tert-butyl 6-bromo-4-methylpyridin-3-yl(methyl)carbamate as a light yellow solid: MS (ESI, m/z): 301.2, 303.2 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 8.1 1 (s, 1H), 7.48 (s, 1H), 3.14 (s, 3H), 2.21 (s, 3H), 1.31 (s, 9H).

Step 3

19-2 19-3

Synthesis of 6-bromo-N,4-dimethylpyridin-3-amine (19-3). A solution of tert-butyl 6- bromo-4-methylpyridin-3-yl(methyl)carbamate (3.1 g, 10.3 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL) for 1 hour at ambient temperature. Then the resulting solution was concentrated under reduced pressure and the residue was dissolved into

dichloromethane (100 mL), washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtration was concentrated under reduced pressure to afford 6-bromo-N,4-dimethylpyridin-3 -amine as a light yellow solid: MS (ESI, m/z): 201.1, 203.1 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 7.66 (s, 1H), 7.11 (s, 1H), 3.48 (br s, 1H), 2.91 (s, 3H), 2.10 (s, 3H).

Step 4

19-3 19-4 Synthesis of 5-bromo-l-methyl-lH-pyrrolo[2,3-c]pyridine (19-4). A solution of 6- bromo-N,4-dimethylpyridin-3-amine (1 g, 4.97 mmol) in tetrahyrofuran (30 mL) was treated with 2.5 Mn-butyllithium (4.97 mL, 12.43 mmol) in hexane at -78 °C for 15 min under nitrogen atmosphere, followed by the addition of N,N-dimethylformamide (0.51 g, 6.96 mmol). The resulting solution was stirred for additional 1 hour at ambient temperature and quenched by the addition of saturated aqueous solution of sodium bicarbonate (60 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 10-20% ethyl acetate in petroleum ether to afford 5-bromo-l-methyl-lH-pyrrolo[2,3- c]pyridine as a yellow oil: MS (ESI, m/z): 211.1, 213.1 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 9.90 (s, 1H), 7.68 (s, 1H), 7.22 (d, J= 2.8 Hz, 1H), 6.44 (d, J= 2.4 Hz, 1H), 3.11 (s, 3H).

Synthesis of l'-methyl-l,5'-bi(lH-pyrrolo[2,3-c]pyridine) (19). To a solution of 5-bromo-l- methyl-lH-pyrrolo[2,3-c]pyridine (70 mg, 0.33 mmol) in tetrahydrofuran (20 mL) were added lH-pyrrolo[2,3-c]pyridine (59 mg, 0.49 mmol), sodium 2-methylpropan-2-olate (64 mg, 0.66 mmol) and 2-di-tert-butylphosphino-2 ' ,4' ,6' -tri-iso-propyl- 1 , 1 ' -biphenyl)(2' ' ' -amino- Γ ' , Γ " - biphenyl-2"-yl)palladium(II) mesylate (26 mg, 0.033 mmol). The resulting solution was stirred for 16 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford Γ- methyl-l,5'-bi(lH-pyrrolo[2,3-c]pyridine) as a light yellow solid: MS (ESI, m/z): 249.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 9.49 (s, 1H), 8.88 (s, 1H), 8.23-8.20 (m, 2H), 7.91 (s, 1H), 7.71 (d, J= 3.2 Hz, 1H), 7.66 (d, J= 5.6 Hz, 1H), 6.78 (d, J= 3.2 Hz, 1H), 6.60 (d, J= 2.8 Hz, 1H), 3.97 (s, 3H).

Example 20

Synthesis of 6-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (20):

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6-amine (20-1). To a sealed tube were added a saturated solution of ammonia in methanol (300 mL) and 6-fluoro-3-(lH- pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (2.5 g, 9.5 mmol, 9). The resulting mixture was stirred for 5 days at 120 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column

chromatography, eluted with 1-10% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3- c]pyridin-l-yl)isoquinolin-6-amine as a light yellow solid: MS (ESI, m/z): 261.1 [M + 1] ⁺ ; 1H NMR (300 MHz, OMSO-d ₆ ) δ 9.41 (s, 1H), 8.93 (s, 1H), 8.29-8.23 (m, 2H), 7.82 (d, J= 9.0 Hz, 1H), 7.80 (s, 1H), 7.64 (dd, J= 0.9 Hz, 4.5 Hz, 1H), 7.04 (dd, J= 5.1 Hz, 6.6 Hz, 1H), 6.83-6.78 (m, 2H), 6.19 (s, 2H).

Step 2

Synthesis of 6-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (20). To a suspension of 3- (lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-6-amine (0.15 g, 0.58 mmol) in water (20 mL) was added concentrated sulfuric acid (2 mL) at ambient temperature. The resulting mixture was heated to 70-80 °C until it gave a clear solution. The resulting solution was cooled down to 0 °C and sodium nitrite (80 mg, 1.15 mmol) was added in one portion. After stirring for 15 min at 0 °C, potassium iodide (0.19 g, 1.15 mmol) was added. The resulting mixture was stirred for additional 5 min and quenched with saturated aqueous solution of sodium sulfite (5 mL). The resulting mixture was extracted with dichloromethane (4 x 50 mL) and the combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1%) methanol in dichloromethane to afford 6-iodo-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline as an off-white solid: MS (ESI, m/z): 372.1 [M + 1] ⁺ ; 1H NMR (400 MHz,

DMSO-i ) δ 9.82 (s, 1H), 9.44 (s, 1H), 8.65 (d, J= 3.2 Hz, 1H), 8.56 (s, 1H), 8.41 (d, J= 5.6 Hz, 1H), 8.29 (s, 1H), 8.05-7.98 (m, 3H), 7.12 (d, J= 3.2 Hz, 1H).

Example 21 Synthesis of l-(4-(fluoromethyl)-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[ 2,3-c]pyridine (21):

S

Synthesis of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinic acid (21-1). To a stirred solution of lH-pyrrolo[2,3-c]pyridine (1.8 g, 15.2 mmol) in N,N-dimethylformamide (80 mL) were added cesium carbonate (14.9 g, 45.7 mmol) and methyl 5-bromo-2- chloroisonicotinate (5.0 g, 16.9 mmol). The resulting mixture was stirred for 3 hours at 100 °C. After cooling down to ambient temperature, the resulting mixture was filtered through Celite. The filtrate was diluted with water (200 mL) and acidified with concentrated aqueous hydrochloric acid (pH = 5-6). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers was washed with brine (2 x 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% methanol in ethyl acetate to afford 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinic acid as a light yellow solid: MS (ESI, m/z): 318.0, 320.0 [M + 1] ⁺ ; 1H MR (400 MHz, OMSO-d ₆ ) δ 14.3 (br s, 1H), 9.85 (s, 1H), 8.91 (s, 1H), 8.79 (s, 1H), 8.48-8.43 (m, 1H), 8.25 (s, 1H), 8.04 (d, J= 6.0 Hz, 1H), 7.13-7.11 (m, 1H).

Synthesis of (5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-yl)metha nol (21-3).

To a stirred solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinic acid (2.0 g, 6.29 mmol) in N,N-dimethylformamide (40 mL) were added sodium carbonate (2.0 g, 18.86 mmol) and isopropyl carbonochloridate (1.54 g, 12.57 mmol) at 0 °C. The resulting mixture was stirred for 16 hours at ambient temperature then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford crude 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l- yl)isonicotinic isobutyric anhydride (21-2, 2 g) as a yellow oil. The resulting crude yellow oil was dissolved into isopropanol (50 mL) at 0 °C and sodium borohydride (0.34 g, 9.02 mmol) was added. The resulting mixture was stirred for 16 hours at ambient temperature and quenched with saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column

chromatography, eluted with 1—10% methanol in dichloromethane to afford (5-bromo-2-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-yl)methanol as a light yellow solid: MS (ESI, m/z): 304.1, 306.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.65 (s, 1H), 8.68 (s, 1H), 8.29 (d, J= 5.4 Hz, 1H), 8.27 (d, J= 3.6 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J

1H), 5.85 (t, J= 5.7 Hz, 1H), 4.61 (d, J= 5.4 Hz, 2H).

Step 3

Synthesis of (5-(prop-l-ynyl)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4- yl)methanol (21-

4, . To a stirred solution of (5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4- yl)methanol (0.72 g, 2.37 mmol) and tributyl(prop-l-yn-l-yl)stannane (1.17 g, 3.55 mmol) in 1,4-dioxane (40 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.24 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (2 xlOO mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% methanol in dichl orom ethane to afford (5-(prop-l-yn-l-yl)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin -4-yl)methanol as a light yellow solid: MS (ESI, m/z): 264.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ + D ₂ 0) δ 9.94 (s, 1H), 8.93 (d, J= 3.3 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J= 6.3 Hz, 1H), 8.26 (d, J= 6.3 Hz, 1H), 7.96 (s, 1H), 7.26 (d, J= 3.3 Hz, 1H), 4.73 (s, 2H), 2.16 (s, 3H).

Step 4

Synthesis of l-(4-(fluoromethyl)-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[ 2,3-c]pyridine (21, . To a stirred solution of (5-(prop-l-yn-l-yl)-2-(lH-pyrrolo[2,3-c]pyridin-l- yl)pyridin-4-yl)methanol (50 mg, 0.19 mmol) in dry dichloromethane (20 mL) was added diethylaminosulfurtrifluoride (DAST, 92 mg, 0.57 mmol) at -78 °C under nitrogen atmosphere. The resulting solution was stirred for 4 hours at ambient temperature and quenched with saturated aqueous solution of sodium bicarbonate (50 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% methanol in dichloromethane to afford l-(4-(fluoromethyl)-5-(prop-l-yn-l- yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 266.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.95 (s, 1H), 8.95 (d, J= 3.6 Hz, 1H), 8.69 (s, 1H), 8.48

(d, J= 6.0 Hz, 1H), 8.21 (d, J= 6.0 Hz, 1H), 8.05 (s, 1H), 7.24 (d, J

5.62 (s, 1H), 2.17 (s, 3H).

Examples 22 & 23

Synthesis of l-(4-fluoro-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]py ridine (22) and 2- methyl-6-(lH-pyrr lo [2,3-c] pyridin-l-yl)furo [3,2-c] pyridine (23):

22 23

Scheme 22

21 -1 57% 22-1

Synthesis of tert-butyl (5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-ylcarbam ate (22-1). To a stirred solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinic acid (7.80 g, 8.09 mmol, 21-1) and triethylamine (2.46 g, 24.27 mmol) in tert-butyl alcohol (200 mL) was added diphenyl phosphorazidate (3.34 g, 12.14 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was dissolved into dichloromethane (200 mL), washed with water (200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford tert-butyl (5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l- yl)pyridin-4-yl)carbamate as a yellow solid: MS (ESI, m/z): 289.2, 291.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.72 (br s, 1H), 8.93 (s, 1H), 8.69 (s, 1H), 8.29 (d, J= 5.1 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J= 3.3 Hz, 1H), 7.68 (d, J= 0.9 Hz, 1H), 6.86 (d, J= 3.0 Hz, 1H), 1.48 (s, 9H).

Step 2

22-1 92% 22-2

Synthesis of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-amine (22-2). A solution of tert-butyl (5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-yl)carba mate (1.71 g, 4.39 mmol) in dichloromethane (50 mL) was treated with trifluoroacetic acid (5 mL) at ambient temperature for 6 hours. The resulting solution was concentrated under reduced pressure and the residue was dissolved into dichloromethane (100 mL), washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4- amine as a light yellow solid: MS (ESI, m/z): 289.2, 291.2 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO-i ) δ 9.53 (br s, 1H), 8.33 (s, 1H), 8.29-8.27 (m, 1H), 8.07 (d, J= 3.3 Hz, 1H), 7.66 (d, J = 5.1 Hz, 1H), 7.05 (s, 1H), 6.84 (d, J= 3.0 Hz, 1H), 6.61 (br s, 2H).

23-1

Synthesis of l-(5-bromo-4-fluoropyridin-2-yl)-lH-pyrrolo[2,3-c] pyridine (22-4) and 5- bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-ol (23-1). To a stirred solution of 5- bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-amine (0.5 g, 1.73 mmol) in hydrogen fluoride-pyridine (25 mL, 65-70% w/w) was added sodium nitrite (0.72 g, 10.38 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at 60 °C. After cooling down to ambient temperature, the resulting mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-bromo-4-fluoropyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 292.2, 294.2 [M + 1] ⁺ ; 1H NMR (300 MHz, CD ₃ OD) δ 10.08 (br s, 1H), 8.85-8.79 (m, 2H), 8.41 (d, J= 3.3 Hz, 1H), 8.23 (d, J = 6.3 Hz, 1H), 7.95 (d, J= 9.6 Hz, 1H), 7.21 (d, J= 3.6 Hz, 1H); and 5-bromo-2-(lH-pyrrolo[2,3- c]pyridin-l-yl)pyridin-4-ol as a light yellow solid (210 mg, 42%): MS (ESI, m/z): 290.1, 292.1 [M + 1] ⁺ ; 1H NMR (300 MHz, CD ₃ OD) δ 9.95 (br s, 1H), 8.62 (d, J= 2.7 Hz, 1H), 8.55 (s, 1H), 8.35 (d, J= 6.9 Hz, 1H), 8.20 (d, J= 6.0 Hz, 1H), 7.23 (s, 1H), 7.18 (s, 1H).

Step 4

22-4 22

Synthesis of l-(4-fluoro-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]py ridine (22).

To a stirred solution of l-(5-bromo-4-fluoropyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine (30 mg, 0.11 mmol) in 1,4-dioxane (15 mL) was bubbled with propyne for 10 min at ambient temperature followed by the addition of triethylamine (5 mL), copper (I) iodide (2 mg, 10 μπιοΐ) and bis(triphenylphosphine)palladium(II) dichloride (3.6 mg, 5.14 μπιοΐ). The resulting mixture was stirred for 4 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(4-fluoro-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]py ridine as a light yellow solid: MS (ESI, m/z): 252.1 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 9.81 (br s, 1H), 8.68 (d, J= 10.0 Hz, 1H), 8.40 (s, 1H), 8.32 (d, J= 5.2 Hz, 1H), 7.92 (d, J= 12.0 Hz, 1H), 7.84 (d, J= 5.6 Hz, 1H), 6.98 (s, 1H), 2.13 (s, 3H). Step 5

23-1 23

Synthesis of 2-methyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)furo[3,2-c]pyridin e (23). To a stirred solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-ol (30 mg, 0.11 mmol) in 1,4-dioxane (15 mL) was bubbled with propyne for 10 min at ambient temperature followed by the addition of triethylamine (5 mL), copper (I) iodide (2 mg, 10 μιηοΐ) and

bis(triphenylphosphine)palladium(II) dichloride (3.6 mg, 5.14 μιηοΐ). The resulting mixture was stirred for 4 hours at 50 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-methyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)furo[3,2-c]pyridin e as a colorless solid: MS (ESI, m/z): 250.1 [M + 1] ⁺ ; 1H MR (300 MHz, CD ₃ OD) δ 9.62 (br s, 1H), 8.77 (s, 1H), 8.22 (d, J= 5.4 Hz, 1H), 8.17 (d, J= 3.3 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J= 5.4 Hz, 1H), 6.86 (d, J= 3.3

Hz, 1H), 6.69 (s, 1H), 2.53 (s, 3H).

Example 24

Synthesis of 6-(fluoromethoxy)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoli ne (24):

Scheme 24

24-1

Synthesis of 6-methoxyquinazoline-2,4(lH,3H)-dione (24-1). A suspension of 2-amino-4- methoxybenzoic acid (5 g, 29.9 mmol) in water (35 mL) and acetic acid (0.7 mL, 29.7 mmol) was warmed to 35 °C followed by the addition of a solution of potassium cyanate (6.1 g, 74.8 mmol) in water (10 mL) over 5 min. After additional 1 hour, sodium hydroxide (12 g, 0.3 mol) was carefully added and the reaction system became a clear solution. The resulting solution was acidified by the addition of concentrated hydrochloric acid (27 mL) and solid was precipitated. A filtration was performed and the filter cake was washed with cold water (2 x 30 mL), dried in a vacuum oven to afford 6-methoxyquinazoline-2,4(lH,3H)-dione as a brown solid: MS (ESI, m/z): 193.1 [M + l] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 1 1.27 (s, 1H), 11.10 (s, 1H), 7.31 (s, 1H), 7.28 (d, J= 6.0 Hz, 1H), 7.13 (d, J= 5.4 Hz, 1H), 3.76 (s, 3H).

Step 2

24-1 24-2 Synthesis of 2,4-dichloro-6-methoxyquinazoline (24-2). A solution of 6-methoxyquinazoline- 2,4(lH,3H)-dione (5 g, 26.0 mmol) in trichloro phosphorus oxide (30 mL) was refluxed for 16 hours. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2,4-dichloro-6-methoxyquinazoline as a yellow solid: MS (ESI, m/z): 229 A [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 7.90 (d, J= 9.3 Hz, 1H), 7.61 (dd, J= 2.7 Hz, 6.6 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 4.00 (s, 3H).

Step 3

24-2

Synthesis of 2-chloro-6-methoxyquinazoline (24-3). To a solution of 2,4-dichloro-6- methoxyquinazoline (3 g, 13.1 mmol) in dichloromethane (50 mL) were added zinc dust (2.57 g, 39.3 mmol), aqueous solution of ammonia (50 mL, 34% w/w) and brine (10 mL). The resulting mixture was stirred for 4 hours at 40 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was filtered through Celite. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-chloro-6- methoxyquinazoline as a yellow solid: MS (ESI, m/z): 195.2 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 9.19 (s, 1H), 7.91 (d, J= 9.3 Hz, 1H), 7.61 (dd, J= 2.7 Hz, 6.6 Hz, 1H), 7.16 (d, J = 2.7 Hz, 1H), 3.96 (s, 3H).

24-3 24-4

Synthesis of 6-methoxy-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoline (24-4). To a solution of 2-chloro-6-methoxyquinazoline (198 mg, 1.02 mmol) in N,N-dimethylformamide (20 mL) were added lH-pyrrolo[2,3-c]pyridine (176 mg, 1.5 mmol) and cesium carbonate (552 mg, 1.69 mmol). The resulting mixture was stirred for 2 hours at 80 °C. After cooling down to ambient temperature, the resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 6-methoxy-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoline as a yellow solid: MS (ESI, m/z): 277 A [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 10.16 (s, 1H), 9.63 (s, 1H), 8.59 (d, J= 3.6 Hz, 1H), 8.35 (d, J= 5.1 Hz, 1H), 8.05 (d, J= 9.3 Hz, 1H), 7.74-7.69 (m, 2H), 7.62 (d, J= 2.7 Hz, 1H), 6.88 (d, J= 3.6 Hz, 1H), 3.95 (s, 3H).

Step 5

83%

24-4 24-5

Synthesis of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazolin-6-ol (24-5). To a solution of 6- methoxy-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoline (1 g, 3.62 mmol) in dichloromethane (50 mL) was added tribromoborane (4.53 g, 18.10 mmol) at -78 °C. After additional 2 hours at ambient temperature, the reaction was quenched with water (50 mL) and neutralized with sodium hydroxide (1.45 g, 36.25 mmol). The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazolin-6-ol as a yellow solid: MS (ESI, m/z): 263.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 10.46 (s, 1H), 10.41 (s, 1H), 9.56 (s, 1H), 8.58 (s, 1H), 8.34 (d, J= 5.1 Hz, 1H), 8.00 (d, J= 9.3 Hz, 1H), 7.73-7.57 (m, 2H), 7.38 (s, 1H), 6.86 (s, 1H).

Step 6

31 %

24-5 24

Synthesis of 6-(fluoromethoxy)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoli ne (24). A solution of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)quinazolin-6-ol (100 mg, 0.38 mmol) in N,N- dimethylformamide (15 mL) was treated with sodium hydride (76 mg, 1.91 mmol, 60% w/w dispersed by mineral oil) at 0 °C for 10 min followed by the addition of bromofluorom ethane (65 mg, 0.57 mmol). After additional 2 hours, the resulting mixture was quenched by water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 6-(fluoromethoxy)-2- (lH-pyrrolo[2,3-c]pyridin-l-yl)quinazoline as a colorless solid: MS (ESI, m/z): 295.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 10.23 (s, 1H), 9.72 (s, 1H), 8.61 (d, J= 3.6 Hz, 1H), 8.37 (d, J = 5.1 Hz, 1H), 8.16 (d, J= 8.7 Hz, 1H), 7.89-7.84 (m, 2H), 7.71 (d, J= 5.1 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.15 (s, 1H), 5.97 (s, 1H).

Example 25

Synthesis of l-fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (25):

Step 1

85%

25-1

Synthesis of 5-bromo-2-chloroisonicotinaldehyde (25-1). A solution of diisopropylamine (31.3 g, 0.31 mol) in tetrahydrofuran (600 mL) was treated with 2.5 n-butyllithium (109 mL, 0.27 mol) in hexane for 30 min at -78 °C, followed by the addition of a solution of 5-bromo-2- chloropyridine (35 g, 0.18 mol) in tetrahydrofuran (200 mL). The resulting solution was stirred for 30 min at -78 °C, then N,N-dimethylformamide (40.4 g, 0.55 mol) was added. After additional 30 min at -60 °C, The reaction mixture was quenched by saturated aqueous solution of ammonium chloride (1 L) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers was washed with brine (2 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% ethyl acetate in petroleum ether to afford 5-bromo-2-chloroisonicotinaldehyde as a light yellow solid: MS (ESI, m/z): 220.2, 222.1 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 10.31 (s, 1H), 8.70 (s, 1H), 7.74 (s, 1H).

Synthesis of 5-bromo-2-chloro-4-(l,3-dioxolan-2-yl)pyridine (25-2). To a solution of 5- bromo-2-chloroisonicotinaldehyde (15 g, 61.2 mmol) in toluene (500 mL) were added 4- methylbenzenesulfonic acid (1 1.6 g, 67.4 mmol) and ethane- 1,2-diol (7.6 g, 122 mmol). The resulting mixture was refluxed for 16 hours under nitrogen atmosphere. Water was removed by Dean-Stark trap. After cooling down to ambient temperature, the reaction mixture was quenched with water (300 mL) and neutralized by the addition of sodium hydroxide (2.9 g, 74.1 mmol). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers was washed with brine (2 x 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5-bromo-2-chloro-4-(l,3-dioxolan-2-yl)pyridine as a yellow solid: MS (ESI, m/z):

264.2, 266.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 8.69 (s, 1H), 7.59 (s, 1H), 5.93 (s, 1H), 4.13-3.98 (m, 4H).

St

25-2 25-3

Synthesis of l-(5-bromo-4-(l,3-dioxolan-2-yl)pyridin-2-yl)-lH-pyrrolo[2,3 -c]pyridine (25-3).

To a solution of 5-bromo-2-chloro-4-(l,3-dioxolan-2-yl)pyridine (16 g, 54.4 mmol) in N,N-dimethylformamide (300 mL) were added lH-pyrrolo[2,3-c]pyridine (6.43 g, 54.4 mmol) and cesium carbonate (53.2 g, 163 mmol). The resulting mixture was stirred for 16 hours at 80 °C. After cooling down to ambient temperature, the resulting mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 1 - (5-bromo-4-(l,3-dioxolan-2-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c ]pyridine as a light yellow solid: MS (ESI, m/z): 346.2, 348.2 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.61 (s, 1H), 8.79 (s, 1H), 8.39 (d, J= 3.6 Hz, 1H), 8.30 (d, J= 5.4 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J= 5.1 Hz, 1H), 6.87 d, J= 3.3 Hz, 1H), 6.04 (s, 1H), 4.21-4.00 (m, 4H).

25-3 25-4

Synthesis of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinaldehyde (25-4). To a suspension of l-(5-bromo-4-(l,3-dioxolan-2-yl)pyridin-2-yl)-lH-pyrrolo[2,3 -c]pyridine (5 g, 13.72 mmol) in water (200 mL) was added hydrochloric acid (20 mL, 37% w/w). The resulting solution was stirred for 16 hours at 40 °C. After cooling down to ambient temperature, the resulting solution was neutralized by the addition of potassium carbonate (14 g, 101 mmol).

Solid was collected by filtration and washed with water (3 x 50 mL), dried in a vacuum oven to afford 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinaldehyde as a light yellow solid: MS (ESI, /// r): 302.1, 304.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 10.27 (s, 1H), 9.75 (s, 1H),

8.98 (s, 1H), 8.45 (d, J= 3.6 Hz, 1H), 8.38 (d, J= 3.3 Hz, 1H), 8.17 (s, 1H), 7.68 (d, J= 4.5 Hz,

1H), 6.90 (d, J= 3.6 Hz, 1H).

Step 5

Synthesis of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)-5-((trimethylsilyl)ethynyl )isonicotinaldehyde (25-5). To a stirred solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l- yl)isonicotinaldehyde (4 g, 11.92 mmol) and triethylamine (2.41 g, 23.83 mmol) in tetrahydrofuran (120 mL) were added copper (I) iodide (0.23 g, 1.19 mmol),

ethynyltrimethylsilane (1.76 g, 17.87 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.84 g, 1.19 mmol) at ambient temperature under nitrogen atmosphere. After additional 1 hour, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2- (lH-pyrrolo[2,3-c]pyridin-l-yl)-5-((trimethylsilyl)ethynyl)i sonicotinaldehyde as a light yellow solid: MS (ESI, m/z): 320.1 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 10.55 (s, 1H), 8.85 (s, 1H), 7.93 (d, J= 3.6 Hz, 1H), 7.83 (d, J= 3.3 Hz, 1H), 7.68-7.64 (m, 1H), 7.55-7.45 (m, 2H), 6.77 (d, J= 3.0 Hz, 1H), 0.32 (s, 9H).

Step 6

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine 2-oxide (25-6). To a stirred solution of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)-5-

((trimethylsilyl)ethynyl)isonicotinaldehyde (3 g, 7.98 mmol) in ethanol (120 mL) were added sodium acetate (1.31 g, 15.97 mmol) and hydroxylamine hydrochloride (0.83 g, 11.97 mmol) at ambient temperature. After additional 2 hours, to the resulting solution was added potassium carbonate (2.64 g, 19.16 mmol) and the resulting mixture was stirred for 16 hours at 80 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was taken up into dichloromethane (100 mL), washed with water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 7-(lH-pyrrolo[2,3- c]pyridin-l-yl)-2,6-naphthyridine 2-oxide as a light yellow solid: MS (ESI, m/z): 263.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.67 (s, 1H), 9.38 (s, 1H), 8.97 (s, 1H), 8.32-8.30 (m, 2H), 8.24 (t, J= 7.2 Hz, 1H), 8.19-8.18 (m, 2H), 7.69 (d, J= 5.4 Hz, 1H), 6.91 (d, J= 3.3 Hz, 1H). Step 7

25-6 25-7

Synthesis of l-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (25-7). A solution of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine 2-oxide (0.85 g, 3.21 mmol) in phosphorus oxy chloride (30 mL) was refluxed for 3 hours. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was dissolved into dichloromethane (50 mL), washed with saturated aqueous solution of sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-chloro-7- (lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine as a light yellow solid: MS (ESI, m/z): 281.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.79 (s, 1H), 9.65 (s, 1H), 8.54 (d, J= 3.3 Hz, 1H), 8.49 (d, J= 2.7 Hz, 1H), 8.34-8.31 (m, 2H), 8.18 (d, J= 5.4 Hz, 1H), 7.70 (d, J= 5.1 Hz, 1H), 6.93 (d, J= 3.3 Hz, 1H).

Step 8

81 %

25-7 25

Synthesis of l-fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (25). A mixture of l-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (30 mg, 0.11 mmol) and potassium fluoride (60.8 mg, 1.05 mmol) in dimethyl sulfoxide (5 mL) was irradiated for 30 min at 120 °C by a microwave (100 W). After cooling down to ambient temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers was washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine as a colorless solid: MS (ESI, m/z): 265.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.81 (s, 1H), 9.65 (s, 1H), 8.55 J= 3.3 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J= 5.4 Hz, 1H), 8.25 (d, J= 5.1 Hz, 1H), 8.08 (d, J= 5 Hz, 1H), 7.69 (d, J= 5.7 Hz, 1H), 6.93 (d, J= 3.3 Hz, 1H).

Example 26

Synthesis of 3- lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (26):

25-6 26

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (26). A solution of 7-(lH- pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine-2-oxide (100 mg, 0.38 mmol, 25-6) in N,N- dimethylformamide (10 mL) was treated with trichlorophosphine (157 mg, 1.14 mmol) at 0 °C for 30 min. The reaction was quenched with saturated aqueous solution of sodium bicarbonate (2 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3- c]pyridin-l-yl)-2,6-naphthyridine as a light yellow solid: MS (ESI, m/z): 247.2 [M + 1] ⁺ ; 1H

MR (400 MHz, DMSO- ₆ ) δ 9.73 (s, 1H), 9.57 (s, 1H), 9.54 (s, 1H), 8.70 (d, J= 5.6 Hz, 1H), 8.49 (s, 1H), 8.40 (d, J= 3.2 Hz, 1H), 8.32 (d, J= 5.2 Hz, 1H), 8.11 (d, J= 5.6 Hz, 1H), 7.70 (d, J= 1.2 Hz, 1H), 6.92 (d, J= 3.2 Hz, 1H).

Examples 27 & 28

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridin-l-amine (27) & 1-methoxy- 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (28):

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridin-l-amine (27) & 1-methoxy- 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (28). Ammonia gas was bubbled into a solution of l-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine (20 mg, 0.07 mmol, 25-7) in methanol (5 mL) for 1 h at ambient temperature. The resulting solution was kept for 16 hours at 80 °C in a sealed tube. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichlorom ethane to afford l-methoxy-7- (lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridine as a light yellow solid: MS (ESI, m/z): 277.2 [M + 1] ⁺ ; 1H NMR (300 MHz, CD ₃ OD) δ 9.65 (s, 1H), 9.28 (s, 1H), 8.25-8.20 (m, 3H), 8.09 (d, J = 6.9 Hz, 1H), 7.67 (d, J= 4.8 Hz, 1H), 7.50 (d, J= 5.7 Hz, 1H), 6.85 (d, J= 3.3 Hz, 1H), 4.16 (s, 3H); and 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-2,6-naphthyridin-l-amine as a light yellow solid (6 mg, 32%): MS (ESI, m/z): 262.2 [M + 1] ⁺ ; 1H NMR (300 MHz, OMSO-d ₆ ) δ 9.69 (s, 1H), 9.22 (s, 1H), 8.44 (s, 1H), 8.30-8.27 (m, 2H), 7.95 (d, J= 5.7 Hz, 1H), 7.68 (d, J= 5.1 Hz, 1H), 7.24 (br s, 2H), 7.13 (d, J= 6.0 Hz, 1H), 6.90 (d, J= 3.3 Hz, 1H).

Example 29 Synthesis of l-(5-(l-(2-fluoroethyl)-lH-pyrazol-3-yl)pyrimidin-2-yl)-lH-p yrrolo[2,3- c] pyridine (29):

29

Scheme 28

Step 1

29-1

76%

Synthesis of l-(5-bromopyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyridine (29-1). To a stirred solution of lH-pyrrolo[2,3-c]pyridine (0.73 g, 6.22 mmol) and 5-bromo-2-fluoropyrimidine (1 g, 5.65 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.56 g, 11.30 mmol). The resulting mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (4 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5- bromopyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 275.1, 277.1 [M + 1] ⁺ ; 1H NMR (400 MHz, CDC1 ₃ ) δ 9.91 (s, 1H), 8.42 (d, J= 4.8 Hz, 1H), 8.28 (d, J= 5.2 Hz, 1H), 8.01 (s, 2H), 7.52 (t, J= 4.4 Hz, 1H), 6.69 (d, J= 4.8 Hz, 1H).

Step 2

87% Synthesis of l-(5-(lH-pyrazol-3-yl)pyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyrid ine (29-2). A mixture of l-(5-bromopyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyridine (300 mg, 1.09 mmol), potassium carbonate (301 mg, 2.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.11 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was heated to 80 °C under nitrogen atmosphere, followed by the addition of (lH-pyrazol-3-yl)boronic acid (244 mg, 2.18 mmol) in several portions. After additional 16 hours, the resulting mixture was cooled down to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 1-(5-(1Η- pyrazol-3-yl)pyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 263.2 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 10.08 (s, 1H), 9.40 (s, 2H), 9.08 (s, 1H), 8.59 (d, J= 6.3 Hz, 1H), 8.33 (d, J= 6.3 Hz, 1H), 7.94 (d, J= 1.8 Hz, 1H), 7.29 (d, J= 3.3 Hz, 1H), 7.03 (d, J= 2.4 Hz, 1H).

Synthesis of l-(5-(l-(2-fluoroethyl)-lH-pyrazol-3-yl)pyrimidin-2-yl)-lH-p yrrolo[2,3- c]pyridine (29). A solution of l-(5-(lH-pyrazol-3-yl)pyrimidin-2-yl)-lH-pyrrolo[2,3- c]pyridine (100 mg, 0.38 mmol) in N,N-dimethylformamide (10 mL) was treated with sodium hydride (76 mg, 1.91 mmol, 60% w/w dispersed into mineral oil) for 10 min at 0 °C followed by the addition of l-bromo-2-fluoroethane (242 mg, 1.91 mmol). After stirring for 16 hours at ambient temperature, the reaction was quenched by water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(l-(2-fluoroethyl)-lH-pyrazol-3-yl)pyrimidin-2-yl)- lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 308.9 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.97 (s, 1H), 9.29 (s, 2H), 8.48 (d, J= 3.6 Hz, 1H), 8.35 (d, J= 5.1 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J= 5.1 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J= 3.0 Hz, 1H), 4.92 (t, J= 4.2 Hz, 1H), 4.75 (t, J= 4.2 Hz, 1H), 4.59 (t, J= 4.2 Hz, 1H), 4.48 (t, J= 4.2 Hz, 1H).

Example 30

Synthesis of l-(5-(3-fluoroprop-l-ynyl)-4-vinylpyridin-2-yl)-lH-pyrrolo[2 ,3-c]pyridine (30):

30

Step 1

Synthesis of 5-(3-hydroxyprop-l-ynyl)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)is onicotinaldehyde (30-1). To a stirred solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l- yl)isonicotinaldehyde (3 g, 9.43 mmol, 25-4) in tetrahydrofuran (100 mL) were added

trimethyl(prop-2-yn-l-yloxy)silane (1.45 g, 11.32 mmol), copper(I) iodide (0.18 g, 0.94 mmol), N-ethyl-N-isopropylpropan-2-amine (24.3 g, 189 mmol) and bis(triphenylphosphine)

palladium(II) dichloride (0.33 g, 0.47 mmol). The resulting mixture was stirred for 2 hours at ambient temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 5-(3-hydroxyprop-l-yn-l-yl)-2-(lH-pyrrolo[2,3- c]pyridin-l-yl)isonicotinaldehyde as a yellow solid: MS (ESI, m/z): 278.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 9.72 (s, 1H), 8.64 (s, 1H), 8.31-8.30 (m, 2H), 7.88 (s, 1H), 7.86-7.65 (m, 1H), 7.14 (d, J= 7.5 Hz, 1H), 6.87 (d, J= 3.3 Hz, 1H), 5.45 (t, J= 6.0 Hz, 1H), 4.38 (d, J= 6.0 Hz, 2H).

Synthesis of 5-(3-(tert-butyldimethylsilyloxy)prop-l-ynyl)-2-(lH-pyrrolo[ 2,3-c]pyridin-l- yl)isonicotinaldehyde (30-2). To a stirred solution of 5-(3-hydroxyprop-l-yn-l-yl)-2- (lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinaldehyde (1.8 g, 6.17 mmol) in N,N- dimethylformamide (50 mL) were added triethylamine (1.25 g, 12.33 mmol) and tert- butylchlorodimethylsilane (1.39 g, 9.25 mmol). The resulting solution was stirred for 2 hours at ambient temperature and quenched with water (150 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 5-(3-(tert-butyldimethylsilyloxy)prop-l- ynyl)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinaldehyde as a light yellow solid: MS (ESI, m/z): 392.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 10.37 (s, 1H), 9.82 (s, 1H), 8.90 (s, 1H), 8.52 (d, J= 3.6 Hz, 1H), 8.33 (d, J= 5.4 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J= 5.4 Hz, 1H), 6.92 (d, J = 3.3 Hz, 1H), 4.69 (s, 2H), 0.92 (s, 9H), 0.17 (s, 6H).

Synthesis of l-(5-(3-(tert-butyldimethylsilyloxy)prop-l-ynyl)-4-vinylpyri din-2-yl)-lH- pyrrolo[2,3-c]pyridine (30-3). To a mixture of 5-(3-(tert-butyldimethylsilyloxy)prop-l- ynyl)-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)isonicotinaldehyde (0.4 g, 0.92 mmol) and

methyltriphenylphosphonium bromide (0.49 g, 1.38 mmol) in tetrahydrofuran (20 mL) was added 1 M solution of lithium hexamethyldisilazide (1 mL, 1 mmol) in tetrahydrofuran at -20 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at ambient temperature and quenched by saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(3-(tert- butyldimethylsilyloxy)prop-l-ynyl)-4-vinylpyridin-2-yl)-lH-p yrrolo[2,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 390.2 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.79 (s, 1H), 8.67 (s, 1H), 8.50 (d, J= 3.6 Hz, 1H), 8.29 (d, J= 5.4 Hz, 1H), 8.11 (s, 1H), 7.66 (d, J= 5.1 Hz, 1H), 7.17-7.07 (m, 1H), 6.88 (d, J= 3.6 Hz, 1H), 6.53 (d, J= 8.7 Hz, 1H), 5.79 (d, J= 11.1 Hz, 1H), 4.43 (s, 2H), 0.92 (s, 9H), 0.17 (s, 6H).

Step 4

Synthesis of 3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-4-vinylpyridin-3-yl)pro p-2-yn-l-ol (30-4).

A solution of l-(5-(3-(tert-butyldimethylsilyloxy)prop-l-ynyl)-4-vinylpyri din-2-yl)-lH- pyrrolo[2,3-c]pyridine (0.2 g, 0.51 mmol) in dichloromethane (20 mL) was treated with triethylamine trihydrofluoride (66 mg, 0.41 mmol) for 2 hours at ambient temperature. The reaction was quenched with saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 3-(6-(lH-pyrrolo[2,3- c]pyridin-l-yl)-4-vinylpyridin-3-yl)prop-2-yn-l-ol as a light yellow solid: MS (ESI, m/z): 276.2 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.78 (s, 1H), 8.65 (s, 1H), 8.48 (d, J= 3.6 Hz, 1H), 8.29 (d, J= 5.4 Hz, 1H), 8.10 (s, 1H), 7.66 (d, J= 5.1 Hz, 1H), 7.17-7.07 (m, 1H), 6.88 (d, J = 3.6 Hz, 1H), 6.53 (d, J= 8.7 Hz, 1H), 5.79 (d, J= l l . l Hz, 1H), 5.46 (t, J= 6.0 Hz, 1H), 4.41 (d, J= 6.0 Hz, 2H). Step 5

Synthesis of l-(5-(3-fluoroprop-l-ynyl)-4-vinylpyridin-2-yl)-lH-pyrrolo[2 ,3-c]pyridine (30).

To a stirred solution of 3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-4-vinylpyridin-3- yl)prop-2-yn-l-ol (140 mg, 0.31 mmol) in dichloromethane (20 mL) was added

diethylaminosulfurtrifluoride (492 mg, 3.05 mmol) at -78 °C. The resulting mixture was stirred for 2 hours at ambient temperature and quenched with saturated aqueous solution of sodium bicarbonate (50 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(3-fluoroprop-l-ynyl)-4-vinylpyridin-2-yl)-lH-pyrrolo[2 ,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 278.1 [M + 1] ⁺ ; 1H MR (300 MHz, CD ₃ OD) δ 9.74 (s, 1H), 8.65 (s, 1H), 8.27 (d, J= 3.6 Hz, 1H), 8.21 (d, J= 5.4 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J= 6.3 Hz, 1H), 7.20-7.11 (m, 1H), 6.84 (d, J= 3.9 Hz, 1H), 6.36 (d, J= 17.7 Hz, 1H), 5.73 (d, J= 11.1 Hz, 1H), 5.39 (s, 1H), 5.36 (s, 1H).

Example 31

Synthesis of l-(5-(4-(2-chloroethyl)piperidin-l-yl)pyridin-2-yl)-lH-pyrro lo[2,3-c]pyridine (31):

31 Scheme 30

1 -1 31 -1 Synthesis of 2-(l-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidi n-4-yl)ethanol (31-

1). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (0.8 g, 2.49 mmol, 1-1) in dimethyl sulfoxide (30 mL) were added 2-(piperidin-4-yl)ethanol (0.64 g, 4.98 mmol), copper(I) iodide (0.28 g, 1.49 mmol), cesium carbonate (3.24 g, 9.97 mmol) and 2-(dimethylamino)acetic acid (0.1 g, 0.99 mmol). The resulting mixture was stirred for 16 hours at 130 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with 1-2% methanol in dichloromethane to afford 2-(l-(6-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidin-4-yl)ethan ol as a colorless solid: MS (ESI, m/z): 323.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 8.90 (s, 1H), 8.30-8.27 (m, 2H), 8.06 (d, J = 6.0 Hz, 1H), 7.99 (d, J= 3.6 Hz, 1H), 7.78 (s, 2H), 6.84 (d, J= 3.6 Hz, 1H), 4.35 (t, J= 5.7 Hz, 1H), 3.84-3.78 (m, 2H), 3.48-3.43 (m, 2H), 2.78-2.71 (m, 2H), 1.79-1.73 (m, 2H), 1.68-1.54 (m, 1H), 1.42-1.37 (m, 2H), 1.29-1.21 (m, 2H). Step 2

Synthesis of l-(5-(4-(2-chloroethyl)piperidin-l-yl)pyridin-2-yl)-lH-pyrro lo[2,3-c]pyridine (31). To a solution of 2-(l-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidi n-4- yl)ethanol (100 mg, 0.31 mmol) in dichloromethane (10 mL) was added

diethylaminosulfurtrifluoride (DAST, 548 mg, 3.40 mmol) at -78 °C. The resulting solution was stirred for 10 hours at ambient temperature and quenched with brine (30 mL), extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(4-(2-chloroethyl)piperidin-l-yl)pyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 341.1 [M + 1] ⁺ ; 1H MR (400 MHz, CDCI ₃ ) δ 9.53 (s, 1H), 8.34-8.31 (m, 1H), 8.27 (d, J= 2.4 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.66 (t, J= 4.8 Hz, 1H), 7.45-7.43 (m, 2H), 6.76 (d, J= 7.2 Hz, 1H), 3.79-3.76 (m, 2H), 3.65 (t, J = 7.6 Hz, 2H), 2.89-2.83 (m, 2H), 1.91-1.89 (m, 2H), 1.81-1.77 (m, 3H), 1.49-1.41 (m, 2H).

Example 32

Synthesis of l-(5-(2-fluoroethoxy)-4-methylpyridin-2-yl)-lH-pyrrolo[2,3-c ]pyridine (32): Scheme 31

Synthesis of 6-bromo-4-methylpyridin-3-ol (32-1). To a stirred solution of 6-bromo-4- methylpyridin-3 -amine (2.0 g, 10.7 mmol) in aqueous 40% sulfuric acid (20 mL) was added sodium nitrite (1.1 g, 16.1 mmol) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C and 24 hours at ambient temperature. The resulting mixture was diluted with water (200 mL) and neutralized by potassium carbonate. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1.5% methanol in dichloromethane to afford 6-bromo-4-methylpyridin-3-ol as a light yellow solid: MS (ESI, m/z): 188.0, 190.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 7.89 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 2.13 (s, 3H).

Synthesis of 2-bromo-5-(2-fluoroethoxy)-4-methylpyridine (32-2). To a stirred solution of 6-bromo-4-methylpyridin-3-ol (0.50 g, 1.31 mmol) in N,N-dimethylformamide (20 mL) were added potassium carbonate (0.55 g, 3.95 mmol) and l-bromo-2-fluoroethane (0.25 mg, 1.99 mmol). The resulting mixture was stirred for 16 hours at 30 °C and quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1% methanol in dichloromethane to afford 2- bromo-5-(2-fluoroethoxy)-4-methylpyridine as a light yellow solid: MS (ESI, m/z): 234.1, 236.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 8.07 (s, 1H), 7.48 (s, 1H), 4.85-4.82 (m, 1H), 4.69- 4.66 (m, 1H), 4.41-4.38 (m, 1H), 4.31-4.27 (m, 1H), 2.18 (s, 3H).

Ste 3

Synthesis of l-(5-(2-fluoroethoxy)-4-methylpyridin-2-yl)-lH-pyrrolo[2,3-c ]pyridine (32).

To a stirred mixture of lH-pyrrolo[2,3-c]pyridine (70 mg, 0.59 mmol) and cesium carbonate (770 mg, 2.37 mmol) in dimethyl sulfoxide (20 ml) were added 2-bromo-5-(2- fluoroethoxy)-4-methylpyridine (173 mg, 0.59 mmol), dimethylglycine (36.7 mg, 0.36 mmol) and copper (I) iodide (67.7 mg, 0.36 mmol). The resulting mixture was stirred for 2 hours at 130 °C under a nitrogen atmosphere. After cooling down to ambient temperature, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1% methanol in dichloromethane to afford l-(5-(2-fluoroethoxy)-4-methylpyridin-2-yl)-lH-pyrrolo[2,3-c ]pyridine as a light yellow solid: MS (ESI, m/z): 272.2 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.61 (s, 1H), 8.28 (s, 1H), 8.24 (d, J= 5.1 Hz, 1H), 8.19 (d, J= 3.3 Hz, 1H), 7.75 (s, 1H), 7.64-7.62 (m, 1H), 6.78 (d, J= 3.0 Hz, 1H), 4.89 (t, J= 3.6 Hz, 1H), 4.73 (t, J= 3.6 Hz, 1H), 4.49 (t, J= 3.6 Hz, 1H), 4.39 (t, J= 3.6 Hz, 1H), 2.33 (s, 3H).

Example 33

S nthesis of l-(4-methoxy-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]p yridine (33):

Synthesis of l-(5-bromo-4-methoxypyridin-2-yl)-lH-pyrrolo[2,3-c] pyridine (33-1). A solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-ol (100 mg, 0.35 mmol, 23-1) N,N-dimethylformamide (10 mL) was treated with sodium hydride (15 mg, 0.38 mmol, 60% w/w dispersed by mineral oil) for 10 min at 0 °C followed by the addition of iodomethane (54 mg, 0.38 mmol). The resulting solution was stirred for 2 hours at ambient temperature, then quenched with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers was washed with brine (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichlorom ethane to afford l-(5-bromo-4-methoxypyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 304.1, 306.1 [M + l] ⁺ ; 1H MR (300 MHz, CD ₃ OD) δ 9.72 (s, 1H), 8.54 (s, 1H), 8.28-8.23 (m, 2H), 7.72 (d, J= 5.4 Hz, 1H), 7.37 (s, 1H), 6.87 (d, J= 3.3 Hz, 1H), 4.11 (s, 3H).

Step 2

33-1 71 % 33 Synthesis of l-(4-methoxy-5-(prop-l-ynyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]p yridine (33).

To a stirred solution of l-(5-bromo-4-methoxypyridin-2-yl)-lH-pyrrolo[2,3- c]pyridine (60 mg, 0.18 mmol) in 1,4-dioxane (20 mL) were added dibutyl(prop-l-yn-l- yl)(propyl)stannane (84 mg, 0.27 mmol) and bis(triphenylphosphine)palladium(II) chloride (6 mg, 0.09 mmol). The resulting mixture was stirred at 80 °C for 4 hours under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(4-methoxy-5-(prop-l-ynyl)pyridin-2-yl)- lH-pyrrolo[2,3-c]pyridine as a light yellow solid: MS (ESI, m/z): 264.1 [M + 1] ⁺ ; 1H NMR (300 MHz, CD ₃ OD) δ 9.70 (s, 1H), 8.38 (s, 1H), 8.23-8.21 (m, 2H), 7.68 (d, J= 8.1 Hz, 1H), 7.27 (s, 1H), 6.84 (d, J= 3.3 Hz, 1H), 4.06 (s, 3H), 2.11 (s, 3H).

Example 34

Synthesis of N-(4-methoxyphenyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotin amide (34):

34

Step 1

34-1

Synthesis of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinic acid (34-1). To a solution of 1H- pyrrolo[2,3-c]pyridine (1.0 g, 8.5 mmol) in N,N-dimethylformamide (30 mL) were added methyl 6-chloronicotinate (1.7 g, 10.2 mmol) and cesium carbonate (8.3 g, 25.4 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 100 °C. After cooling down to ambient temperature, the resulting mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with 1-3% methanol (1% acetic acid, v/v) in dichloromethane to afford 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinic acid as a colorless solid: MS (ESI, m/z): 240.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 13.80 (br s, 1H), 10.08 (s, 1H), 9.18 (s, 1H), 9.00 (d, J = 3.3 Hz, 1H), 8.55-8.51 (m, 2H), 8.24 (d, J= 6.0 Hz, 1H), 8.16 (d, J= 8.7 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H).

Synthesis of N-(4-methoxyphenyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotin amide (34).

To a solution of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinic acid (239 mg, 1 mmol) in N,N-dimethylformamide (30 mL) were added 4-methoxybenzenamine (246 mg, 2 mmol), triethylamine (202 mg, 2 mmol) and O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 760 mg, 2 mmol). The resulting solution was stirred for 16 hours at ambient temperature, then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-2% methanol in dichloromethane to afford N-(4-methoxyphenyl)-6-(lH-pyrrolo[2,3-c]pyridin-l- yl)nicotinamide as a light yellow solid: MS (ESI, m/z): 345.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO-i ) δ 10.34 (s, 1H), 9.88 (s, 1H), 9.15 (s, 1H), 8.61-8.52 (m, 1H), 8.43 (d, J= 3.3 Hz, 1H), 8.33 (d, J= 5.1 Hz, 1H), 8.05 (d, J= 8.7 Hz, 1H), 7.72-7.68 (m, 3H), 6.98-6.92 (m, 3H), 3.76 (s, 3H).

Example 35

Synthesis of N-(3-fluoropropyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-amine (35):

Step 1

(91%)

35-1

Synthesis of tert-butyl 6-bromopyridin-3-ylcarbamate (35-1). To a solution of 6- bromopyridin-3 -amine (5.4 g, 28.9 mmol) in dichloromethane (200 mL) were added

triethylamine (4.4 g, 43.3 mmol) and di-tert-butyl dicarbonate (7.6 g, 34.7 mmol). The resulting solution was stirred for 4 hours at ambient temperature and quenched with water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to afford tert-butyl (6- bromopyridin-3-yl)carbamate as a colorless solid: MS (ESI, m/z): 273.1, 275.1 [M + 1] ⁺ ; 1H

MR (300 MHz, OMSO-d ₆ ) δ 9.72 (s, 1H), 8.45 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 5.4 Hz, 1H), 7.53 (d, J= 5.7 Hz, 1H), 1.48 (s, 9H).

Synthesis of tert-butyl 6-bromopyridin-3-yl(3-fluoropropyl)carbamate (35-2). To a solution of tert-butyl (6-bromopyridin-3-yl)carbamate (2.0 g, 7.3 mmol) in dimethylformamide (50 mL) was added sodium hydride (0.6 g, 14.7 mmol, 60% dispersed into mineral oil) at 0 °C. After stirring for 10 min, l-fluoro-3-iodopropane (2.7 g, 14.7 mmol) was added to the resulting solution. The resulting solution was stirred for 2 hours at ambient temperature, then quenched with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 5—10% ethyl acetate in petroleum ether to afford tert-butyl 6-bromopyridin-3-yl(3-fluoropropyl)carbamate as a light yellow solid: MS (ESI, m/z): 333.2, 335.2 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 8.28 (s, 1H), 7.49-7.47 (m, 2H), 4.57 (t, J = 5.6 Hz, 1H), 4.45 (t, J= 5.6 Hz, 1H), 3.81 (t, J= 7.2 Hz, 2H), 2.05-2.00 (m, 1H), 1.99-1.92 (m, 1H), 1.49 (s, 9H).

Synthesis of tert-butyl 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl(3- fluoropropyl)carbamate (35-3). To a solution of lH-pyrrolo[2,3-c]pyridine(125 mg, 1.1 mmol) in dimethyl sulfoxide (15 mL) were added cesium carbonate (919 mg, 2.8 mmol), tert- butyl (6-bromopyridin-3-yl)(3-fluoropropyl)carbamate (235 mg, 0.7 mmol), dimethylglycine (29.1 mg, 0.3 mmol) and copper(I) iodide (81 mg, 0.4 mmol) at ambient temperature under nitrogen atmosphere. After stirring for 16 hours at 130 °C, the resulting mixture was cooled down to ambient temperature and diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1.5% methanol in dichloromethane to afford tert-butyl 6-(lH-pyrrolo[2,3-c]pyridin-l- yl)pyridin-3-yl(3-fluoropropyl)carbamate as a light yellow solid: MS (ESI, m/z): 371.1 [M + 1] ⁺ ; 1H NMR (400 MHz, CDC1 ₃ ) δ 9.67 (br s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 8.40 (br s, 1H), 7.88 (d,

J= 3.2 Hz, 1H), 7.82 (d, J= 7.2 Hz, 1H), 7.61 (d, J= 4.4 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 6.76 (d, J= 3.2 Hz, 1H), 4.75 (t, J= 4.8 Hz, 1H), 4.64 (t, J= 4.8 Hz, 1H), 4.01 (t, J= 4.8 Hz, 1H), 3.95 (t, J= 4.8 Hz, 1H), 1.49 (s, 9H), 1.33-1.24 (m, 2H).

Step 4

35-3 35 Synthesis of N-(3-fluoropropyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-amine (35).

A solution of tert-butyl (6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)(3- fluoropropyl)carbamate (150 mg, 0.4 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (3 mL) for 2 hours at ambient temperature. The reaction was diluted with water (30 mL) and neutralized with potassium carbonate. The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column, eluted with 0.5-1.5% methanol in dichloromethane to afford N-(3-fluoropropyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-amine as an off white solid: MS (ESI, m/z): 271.1 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 9.38 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.60 (d, J= 4.4 Hz, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.17- 7.11 (m, 1H), 6.71 (d, J= 3.2 Hz, 1H), 4.75 (t, J= 4.8 Hz, 1H), 4.64 (t, J= 4.8 Hz, 1H), 4.05 (br s, 1H), 3.45 (t, J= 4.8 Hz, 2H), 2.16-2.12 (m, 1H), 2.10-2.03 (m, 1H).

Example 36

Synthesis of N-(2-fluoroethyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3 -amine (36):

36

Scheme 35

36 Step 1

Synthesis of tert-butyl 6-bromopyridin-3-yl(2-fluoroethyl)carbamate (36-1). A solution of tert-butyl (6-bromopyridin-3-yl)carbamate (200 mg, 0.73 mmol, 35-1) in N,N- dimethylformamide (20 mL) was treated with sodium hydride (117 mg, 2.93 mmol, 60% w/w dispersed by mineral oil ) at 0 °C for 40 min, followed by the addition of l-bromo-2- fluoroethane (186 mg, 1.46 mmol). After additional 2 hours at ambient temperature, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 6- bromopyridin-3-yl(2-fluoroethyl)carbamate as a light yellow solid: MS (ESI, m/z): 319.0, 321.0 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 8.32 (s, 1H), 7.51-7.45 (m, 2H), 4.70 (t, J= 4.8 Hz, 1H), 4.58 (t, J= 4.8 Hz, 1H), 3.92 (t, J= 4.8 Hz, 1H), 3.86 (t, J= 4.8 Hz, 1H), 1.46 (s, 9H).

L

Synthesis of tert-butyl 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl(2- fluoroethyl)carbamate (36-2). To a solution of lH-pyrrolo[2,3-c]pyridine (129 mg, 1.09 mmol) in dimethyl sulfoxide (15 mL) were added cesium carbonate (951 mg, 2.92 mmol), tert- butyl (6-bromopyridin-3-yl)(2-fluoroethyl)carbamate (233 mg, 0.73 mmol), 2- (dimethylamino)acetic acid (30 mg, 0.29 mmol) and copper(I) iodide (83 mg, 0.44 mmol) at ambient temperature under an atmosphere of nitrogen. After stirring for 16 hour at 120 °C, the reaction was cooled down to ambient temperature and diluted with water (80 mL). The resulting mixture was extracted with ethyl acetate (2 x 60 mL) and the combined organic layers was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to give tert-butyl 6-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl(2-fluoroethyl)carbam ate as a colorless solid: MS (ESI, m/z): 357.2 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 9.67 (br s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 8.40 (br s, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.82 (d, J= 7.8 Hz, 1H), 7.62 (d, J= 4.4 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 6.76 (d, J= 3.2 Hz, 1H), 4.76 (t, J= 4.8 Hz, 1H), 4.64 (t, J= 4.8 Hz, 1H), 4.01 (t, J= 4.8 Hz, 1H), 3.94 (t, J= 4.8 Hz, 1H), 1.49 (s, 9H).

Step 3

36-2 ³⁶ Synthesis of N-(2-fluoroethyl)-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3 -amine (36).

A solution of tert-butyl (6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)(2- fluoroethyl)carbamate (150 mg, 0.41 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (3 mL) for 2 hours at ambient temperature. The resulting solution was concentrated under reduced pressure and the residue was dissolved into dichloromethane again (50 mL). The resulting solution was washed with saturated aqueous solution of sodium bicarbonate (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to give N-(2-fluoroethyl)-6- (lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine as a colorless solid: MS (ESI, m/z): 257.2 [M + 1] ⁺ ; 1H NMR (400 MHz, CDC1 ₃ ) δ 9.40 (s, 1H), 8.34 (d, J= 5.2 Hz, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.77 (d, J= 3.2 Hz, 1H), 7.59 (d, J= 5.2 Hz, 1H), 7.39 (t, J= 9.6 Hz, 1H), 7.18-7.15 (m, 1H), 6.70 (d, J= 3.2 Hz, 1H), 4.77 (t, J= 4.8 Hz, 1H), 4.66 (t, J= 4.8 Hz, 1H), 4.21 (br s, 1H), 3.56 (t, J= 4.8 Hz, 1H), 3.53 (t, J= 4.8 Hz, 1H).

Example 37

Synthesis of l-(2-fluoro-3,3'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (37):

Synthesis of 6-chloro-3,3'-bipyridin-2-amine (37-1). To a solution of 3-bromo-6- chloropyridin-2-amine (1 g, 4.82 mmol) in 1,4-dioxane (40 mL) and water (4 mL) were added pyridin-3-ylboronic acid (0.65 g, 5.30 mmol), potassium carbonate (1.33 g, 9.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.48 mmol). The resulting solution was stirred for 16 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 6-chloro-3,3'-bipyridin-2-amine as a light yellow solid: MS (ESI, m/z): 206.1 [M + 1] ⁺ ; 1H NMR (400 MHz, OMSO-d ₆ ) δ 8.66 (s, 1H), 8.57 (dd, J= 2.0 Hz, 4.4 Hz, 1H), 7.84-7.82 (m, 1H), 7.48-7.45 (m, 1H), 7.38 (d, J= 7.6 Hz, 1H), 6.69 (d, J= 11.6 Hz, 1H), 6.28 (br s, 2H).

Step 2

37-1 37-2

Synthesis of N,N-di-Boc protected 6-chloro-3,3'-bipyridin-2-amine (37-2). To a solution of 6-chloro-3,3'-bipyridin-2-amine (0.68 g, 3.31 mmol) in dichloromethane (30 mL) were added di-tert-butyl dicarbonate (1.51 g, 6.95 mmol), triethylamine (0.67 g, 6.61 mmol) and N,N- dimethylpyridin-4-amine (40 mg, 0.33 mmol). The resulting solution was stirred for 4 hours at ambient temperature then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0.5-1% methanol in dichloromethane to afford N,N-di-Boc protected 6-chloro-3,3'-bipyridin-2-amine as a light yellow solid: MS (ESI, m/z): 406.1 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO-^) δ 8.64 (dd, J= 1.2 Hz, 4.8 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.10 (d, 7= 8.1 Hz, 1H), 7.81-7.75 (m, 2H), 7.58-7.54 (m, 1H), 1.23 (s, 9 H), 1.20 (s, 9H).

Step 3

Synthesis of tert-butyl 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-ylcarbama te (3).

To a solution of tert-butyl N-tert-butyloxycarbonyl-6-chloro-3,3'-bipyridin-2- ylcarbamate (0.9 g, 2.22 mmol) in tetrahydrofuran (40 mL) were added lH-pyrrolo[2,3- c]pyridine (0.39 g, 3.33 mmol), sodium 2-methylpropan-2-olate (0.43 g, 4.43 mmol) and 2-di- tert-butylphosphino-2 ' ,4 ' , 6 ' -tri-i so-propyl- 1 , 1 ' -bipheny 1)(2 " ' -amino- 1 " , 1 " ' -biphenyl-2 ' ' - yl)palladium(II) mesylate (0.18 g, 0.22 mmol) under nitrogen atmosphere. The resulting solution was stirred for 16 hours at 50 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford tert-butyl 6- (lH-pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-ylcarbamate as a light yellow solid: MS (ESI, m/z): 388.2 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 10.06 (s, 1H), 9.75 (s, 1H), 8.70 (s, 1H), 8.55 (d, J= 4.0 Hz, 1H), 8.40 (d, J= 3.2 Hz, 1H), 8.30 (d, J= 5.2 Hz, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.92 (d, J= 4.4 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.65 (d, J= 5.2 Hz, 1H), 7.48 (dd, J= 4.8 Hz, 11.6 Hz, 1H), 6.87 (d, J = 3.2 Hz, 1H), 1.24 (s, 9H).

Synthesis of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-amine (37-4). A solution of tert-butyl 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-ylcarbama te (0.5 g, 1.29 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL) for 2 hours at ambient temperature. The resulting solution was concentrated under reduced pressure and the residue was dissolved into dichloromethane (100 mL), washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtration was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 6-(lH- pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-amine as a light yellow solid: MS (ESI, m/z): 288.2 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 10.00 (s, 1H), 8.68 (d, J= 5.6 Hz, 1H), 8.58 (t, J = 3.6 Hz, 1H), 8.27-8.26 (m, 2H), 7.92 (d, J= 8.0 Hz, 1H), 7.62 (d, J= 5.2 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.78 (d, J = 3.2 Hz, 1H), 6.33 (br s, 2H). Step 5

37-4 37

Synthesis of l-(2-fluoro-3,3'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (37). To a solution of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,3'-bipyridin-2-amine (100 mg, 0.35 mmol) in

hydrogenfluoride-pyridine (3 mL, 64-70% w/w) was added sodium nitrite (144 mg, 2.09 mmol) at -20 °C. The resulting solution was stirred for 2 hours at ambient temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers was washed with brine (3 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(2-fluoro-3,3'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine as an off-white solid: MS (ESI, m/z): 291.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 9.80 (s, 1H), 8.91 (s, 1H), 8.66 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.48-8.43 (m, 2H), 8.34 (d, J= 5.2 Hz, 1H), 8.13 (dd, J= 1.2 Hz, 8.0 Hz, 1H), 8.02 (dd, J= 1.2 Hz, 8.4 Hz, 1H), 7.70 (d, J= 0.8 Hz, 1H), 7.58 (dd, J= 4.8 Hz, 8.0 Hz, 1H), 6.93 (d, J= 3.2 Hz, 1H).

Example 38

Synthesis of 3-(5-fluoro-lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (38):

38 Scheme 37

38-1

Synthesis of tert-butyl 6-fluoro-4-methylpyridin-3-ylcarbamate (38-l).To a solution of 6- fluoro-4-methylpyridin-3 -amine (5.0 g, 39.6 mmol) in dichloromethane (100 mL) were added triethylamine (6.1 g, 59.5 mmol) and di-tert-butyl dicarbonate (10.4 g, 47.6 mmol). The resulting mixture was stirred for 4 hours at ambient temperature then concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 5-10% ethyl acetate in petroleum ether to afford tert-butyl 6-fluoro-4-methylpyridin-3-ylcarbamate as a colorless solid: MS (ESI, m/z): 227 ^' .1 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 8.38 (s, 1H), 6.76 (s, 1H), 6.16 (br s, 1H), 2.30 (s, 3H), 1.51 (s, 9H). Ste 2

Synthesis of tert-butyl 5-fluoro-lH-pyrrolo[2,3-c]pyridine-l-carboxylate (38-3). A solution of tert-butyl (6-fluoro-4-methylpyridin-3-yl)carbamate (3.7 g, 16.3 mmol) in dry tetrahydrofuran (50 mL) was treated with 2.5 M solution of n-butyllithium (16.3 mL, 40.9 mmol) in hexane at -78 °C for 30 min, followed by the addition of N,N-dimethylformamide

(1.4 g, 19.6 mmol). After additional 3 hours at ambient temperature, the reaction was quenched by saturated aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was dissolved into dichloromethane (25 mL) followed by the addition of triethylamine (1.6 g, 16.3 mmol) and methanesulfonyl chloride (1.8 g, 16.3 mmol). The resulting mixture was stirred for 2 hours at ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10-20% ethyl acetate in petroleum ether to afford tert-butyl 5-fluoro-lH-pyrrolo[2,3- c]pyridine-l-carboxylate as a light yellow solid: MS (ESI, m/z): 237.1 [M + 1] ⁺ ; 1H MR (300 MHz, CDC1 ₃ ) δ 9.01 (s, 1H), 7.87 (d, J= 3.3 Hz, 1H), 7.14 (s, 1H), 6.64 (d, J= 3.6 Hz, 1H), 1.69 (s, 9H).

Step 3

38-3 38-4

Synthesis of 5-fluoro-lH-pyrrolo[2,3-c] pyridine (38-4). A solution of tert-butyl 5-fluoro-lH- pyrrolo[2,3-c]pyridine-l-carboxylate (1.3 g, 5.5 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (2 mL) for 2 hours at ambient temperature. The resulting solution was concentrated under reduced pressure and the residue was dissolved into dichloromethane (50 mL), washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtration was concentrated under reduced pressure to afford 5-fluoro-lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m 137.1 [M + l] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 1 1.66 (br s, 1H), 8.34 (s, 1H), 7.71 (t, J= 2. Hz, 1H), 7.17 (s, 1H), 6.51 (t, J = 2.1 Hz, 1H).

Step 4

Synthesis of 3-(5-fluoro-lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinoline (38). To a solution of 5- fluoro-lH-pyrrolo[2,3-c]pyridine (50 mg, 0.37 mmol) in tetrahydrofuran (10 mL) were added 3- bromoisoquinoline (115 mg, 0.55 mmol), sodium 2-methylpropan-2-olate (70.6 mg, 0.74 mmol) and 2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl- 1 , 1 '-biphenyl)(2' ' ' -amino- 1 " , 1 " ' -biphenyl- 2"-yl)palladium(II) mesylate (29.2 mg, 0.037 mmol) under nitrogen atmosphere. The resulting mixture was kept for 4 hours at 50 °C. After cooling down to ambient temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 3-(5-fluoro-lH- pyrrolo[2,3-c]pyridin-l-yl)isoquinoline as a colorless solid: MS (ESI, m/z): 264.1 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO- ₆ ) δ 9.42 (s, 1H), 9.33 (s, 1H), 8.49 (d, J= 3.3 Hz, 1H), 8.29 (s, 1H), 8.21 (d, J= 8.1 Hz, 1H), 8.06 (d, J= 8.4 Hz, 1H), 7.85 (t, J= 8.1 Hz, 1H), 7.68 (t, J= 7.8 Hz, 1H), 7.37 (d, J= 1.2 Hz, 1H), 6.90 (d, J= 3.3 Hz, 1H). Example 39

Synthesis of 7-(lH-pyrrolo[2,3-c]py trahydro-l,6-naphthyridine (39):

39

Synthesis of (E)-ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)acr ylate (39-1). To a solution of 5-bromo-2-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-4-amine (1 g, 3.46 mmol, 22-2) in N,N-dimethylformamide (50 mL) were added ethyl acrylate (1.38 g, 13.83 mmol), triethylamine (1.40 g, 13.83 mmol), palladium(II) acetate (0.078 g, 0.35 mmol) and tri-o- tolylphosphine (0.21 g, 0.69 mmol) at ambient temperature under nitrogen atmosphere. The resulting solution was stirred for 16 hours at 120 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford (E)- ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)acr ylate as a light yellow solid: MS (ESI, m/z): 309.2 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.65 (s, 1H), 8.56 (s, 1H), 8.36-8.32 (m, 2H), 7.94-7.83 (m, 2H), 6.97 (t, J= 4.2 Hz, 2H), 6.90 (br s, 2H), 6.60 (d, J= 15.9 Hz, 1H), 4.21 (q, J= 7.8 Hz, 2H), 1.21 (t, J = 7.8 Hz, 3H).

Synthesis of ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)pro panoate (39-2). To a stirred solution of (E)-ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-yl)acrylate (0.5 g, 1.62 mmol) in methanol (120 mL) was added palladium on charcoal (50 mg, 10% w/w). The resulting mixture was kept under a hydrogen atmosphere (1 atm.) for 2 hours at ambient temperature. Then, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness to afford ethyl 3-(4-amino-6-(lH-pyrrolo[2,3- c]pyridin-l-yl)pyridin-3-yl)propanoate as a light yellow solid: MS (ESI, m/z): 311.1 [M + 1] ⁺ ; 'H NMR (300 MHz, DMSO- ₆ ) δ 9.34 (s, 1H), 8.22 (d, J= 5.4 Hz, 1H), 8.02 (d, J= 3.3 Hz, 1H), 7.97 (s, 1H), 7.62 (d, J= 4.5 Hz, 1H), 6.87 (s, 1H), 6.74 (d, J= 7.2 Hz, 1H), 6.26 (br s, 2H), 4.08 (q, J= 7.8 Hz, 2H), 2.75-2.71 (m, 2H), 2.54-2.51 (m, 2H), 1.15 (t, J= 7.8 Hz, 3H).

Step 3

39-2 39-3

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4-dihydro-l,6-naphthyrid in-2(lH)-one (39- 3). A solution of ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)pro panoate (50 mg, 0.16 mmol) and sodium ethanolate (54.8 mg, 0.81 mmol) in ethanol (5 mL) was refluxed for 2 hours. After cooling down to ambient temperature, the resulting mixture was neutralized by the addition of acetic acid (0.2 mL) and concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4-dihydro-l,6-naphthyrid in-2(lH)-one as a colorless solid: MS (ESI, m/z): 265.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 10.56 (br s, 1H), 9.49 (s, 1H), 8.32 (s, 1H), 8.26 (d, J= 5.4 Hz, 1H), 8.07 (d, J= 3.3 Hz, 1H), 7.66 (d, J= 5.4 Hz, 1H), 7.16 (s, 1H), 6.82 (d, J= 2.7 Hz, 1H), 2.96 (t, J= 4.8 Hz, 2H), 2.57 (t, J= 4.8 Hz, 2H).

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,2,3,4-tetrahydro-l,6-nap hthyridine (39).

A solution of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4-dihydro-l,6-naphthyrid in- 2(lH)-one (28 mg, 0.11 mmol) in tetrahydrofuran (10 mL) was treated with lithium aluminum hydride (6 mg, 0.16 mmol) at ambient temperature for 2 hours. The reaction was quenched by the addition of sodium sulfate decahydrate (322 mg, 0.1 mmol) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford 7-(lH-pyrrolo[2,3- c]pyridin-l-yl)-l,2,3,4-tetrahydro-l,6-naphthyridine as a colorless solid: MS (ESI, m/z): 251.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.43 (s, 1H), 8.21 (d, J= 5.4 Hz, 1H), 8.00 (d, J = 3.3 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J= 5.4 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J= 6.3 Hz, 1H), 6.68 (s, 1H), 3.27 (t, J= 4.8 Hz, 2H), 2.68 (t, J= 6.0 Hz, 2H), 1.83-1.79 (m, 2H). Example 40

Synthesis of 2-fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (40):

40 Scheme 39

40

Step 1

39-1 40-1

Synthesis of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridin-2(lH)-one (40-1). A solution of (E)-ethyl 3-(4-amino-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)acr ylate (150 mg, 0.49 mmol, 39-1) in ethanol (5 mL) was treated with sodium ethanolate (166 mg, 2.43 mmol) for 1 hour at 78 °C. After cooling down to ambient temperature, the reaction was quenched by water (2 mL) and neutralized with acetic acid (0.2 mL). The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichloromethane to afford 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6- naphthyridin-2(lH)-one as an off white solid: MS (ESI, m/z): 263.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) 5 12.11 (br s, 1H), 9.59 (s, 1H), 8.89 (s, 1H), 8.31 (d, J= 5.4 Hz, 1H), 8.18 (d, J= 3.6 Hz, 1H), 8.05 (d, J= 3.6 Hz, 1H), 7.66-7.64 (m, 1H), 7.49 (s, 1H), 6.88 (d, J= 3.3 Hz, 1H), 6.55 (d, J= 9.0 Hz, 1H).

Synthesis of 2-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (40-2). A solution of 7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridin-2(lH)-one (100 mg, 0.38 mmol) in trichloro phosphorous oxide (5 mL) was stirred for 1 hour at 80 °C. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was taken up by dichloromethane (50 mL) and washed with saturated aqueous solution of sodium bicarbonate (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine as an off white solid: MS (ESI, m/z): 381.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.85 (s, 1H), 9.55 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.50 (d, J= 3.3 Hz, 1H), 8.32-8.28 (m, 2H), 7.72-7.61 (m, 2H), 6.93 (d, J= 3.3 Hz, 1H).

Step 3

Synthesis of 2-fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (40). A mixture of 2-chloro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (100 mg, 0.37 mmol) and potassium fluoride (62 mg, 1.07 mmol) in dimethylsulfoxide (3 mL) was irradiated with microwave (100 W) for 1 hour at 120 °C. After cooling down to ambient temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2- fluoro-7-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine as an off white solid: MS (ESI, m/z): 265.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 10.08 (s, 1H), 9.59 (s, 1H), 9.16 (d, J= 3.3 Hz, 1H), 8.96 (t, J= 8.7 Hz, 1H), 8.56-8.51 (m, 2H), 8.13 (t, J= 9.0 Hz, 1H), 7.61-7.58 (m, 1H), 7.35-7.58 (d, J= 6.6 Hz, 1H).

Example 41

Synthesis of l-(5-(lH-l,2,4-triazol-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]p yridine (41):

41

Scheme 40

1-1 87% 41 -1 Synthesis of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinonitrile (41-1). To a solution of l-(5- iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (1 g, 3.11 mmol, 1-1) in N,N-dimethylformamide (50 mL) were added dicyanozinc (0.73 g, 6.23 mmol), tetrakis(triphenylphosphine)palladium(0) (0.36 g, 0.31 mmol) and potassium iodide (0.052 g, 0.311 mmol). The resulting mixture was stirred for 16 hours at 100 °C under nitrogen atmosphere. After cooling down to ambient temperature, the reaction was diluted with water (150 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers was washed with brine (5 x 80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography, eluted with 20-30% ethyl acetate in petroleum ether to afford 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinonitrile as an off white solid: MS (ESI, m/z): 221.0 [M + 1] ⁺ ; 1H MR (400 MHz, OMSO-d ₆ ) δ 9.85 (s, 1H), 9.07 (d, J= 1.2 Hz, 1H), 8.50 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 3.6 Hz, 1H), 8.34 (d, J= 5.2 Hz, 1H), 8.08 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 5.2 Hz, 1H), 6.94 (d, J= 3.2 Hz, 1H).

Step 2

Synthesis of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinimidohydrazide (41-2). A solution of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)nicotinonitrile (600 mg, 2.72 mmol) in methanol (20 mL) was treated with sodium methanolate (736 mg, 13.63 mmol) for 4 hours at ambient temperature, followed by the addition of

hydrazine (190, 5.95 mmol). After additional 4 hours at ambient temperature, the mixture was concentrated under reduced pressure and the residue was used in the next step without further purification: (ESI, m/z): 253.2 [M + 1] ⁺ . Step 3

Synthesis of l-(5-(lH-l,2,4-triazol-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]p yridine (41).

A solution of the above crude 6-(lH-pyrrolo[2,3-c]pyridin-l- yl)nicotinimidohydrazide in formic acid (15 mL) was refluxed for 16 hours. After cooling down to ambient temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(lH-l,2,4-triazol-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]p yridine as a colorless solid: MS (ESI, m/z): 263.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 10.08 (s, 1H), 9.26 (d, J= 2.0 Hz, 1H), 9.04 (d, J= 3.6 Hz, 1H), 8.68 (br s, 1H), 8.65-8.62 (m, 1H), 8.54 (d, J = 6.4 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 8.8 Hz, 1H), 7.31 (t, J = 3.2 Hz, 1H).

Examples 42 & 43

Synthesis of l-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidin-4 -ol (42) and l-(5- (4-fluoropiperidin-l-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyrid ine (43):

1-1 39% 42 41 % 43 Step 1

1-1 39% 42

Synthesis of l-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidin-4 -ol (42). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (0.5 g, 1.56 mmol, 1-1) in dimethyl sulfoxide (20 mL) were added piperidin-4-ol (0.3 g, 3.11 mmol), cesium carbonate (2.1 g, 6.23 mmol), copper(I) iodide (0.18 g, 0.93 mmol) and 2-(dimethylamino)acetic acid (64.2 mg, 0.62 mmol). The resulting mixture was stirred for 16 hours at 130 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 60 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(6-(lH-pyrrolo[2,3- c]pyridin-l-yl)pyridin-3-yl)piperidin-4-ol as a light yellow solid: MS (ESI, m/z): 295.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- e) 6 8.91 (s, 1H), 8.30-8.21 (m, 2H), 8.06 (d, J= 5.7 Hz, 1H), 8.00 (d, J= 3.3 Hz, 1H), 7.62 (s, 2H), 6.84 (d, J= 3.3 Hz, 1H), 4.74 (d, J= 5.2 Hz, 1H), 3.71-3.57 (m, 3H), 2.98-2.91 (m, 2H), 1.89-1.81 (m, 2H), 1.53-1.42 (m, 2H).

Step 2

Synthesis of l-(5-(4-fluoropiperidin-l-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c] pyridine (43).

To a solution of l-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)piperidin-4 -ol (100 mg, 0.34 mmol) in dichloromethane (10 mL) was added diethylaminosulfurtrifluoride ( DAST, 548 mg, 3.40 mmol) at -78 °C. The resulting solution was stirred for 4 hours at ambient temperature and quenched with water (30 mL), extracted with dichloromethane (3 x 50 mL). The combined organic layers was washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(4-fluoropiperidin-l-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c] pyridine as a colorless solid: MS (ESI, m/z): 297.1 [M + 1] ⁺ ; 1H MR (400 MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.3 l(d, J= 3.2 Hz, 1H), 8.27 (d, J= 6.0 Hz, 1H), 8.06 (d, J= 6.0 Hz, 1H), 7.86 (d, J= 3.6 Hz, 1H), 6.67 (dd, J= 3.2 Hz, 8.8 Hz, 1H), 7.55 (d, J= 8.8 Hz, 1H), 6.89 (d, J= 3.6 Hz, 1H), 4.93-4.91 (m, 0.5H), 4.84- 4.79 (m, 0.5H), 3.53-3.47 (m, 2H), 3.35-3.31 (m, 2H), 2.17-1.94 (m, 4H).

Examples 44 & 45

Synthesis of l-(6'-fluoro-3,4'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (44) & Synthesis of N,N-dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4'-bipyridi n-2 ^, -amine (45) :

44 45

Scheme 42

Synthesis of l-(6'-fluoro-3,4'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (44). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.31 mmol, 1-1) in 1,4-dioxane (20 mL) and water (5 mL) was added 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (105 mg, 0.47 mmol), potassium carbonate (129 mg, 0.93 mmol) and

tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The resulting mixture was stirred for 3 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichloromethane to afford l-(5-(pyridin- 3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a colorless solid: MS (ESI, m/z): 291.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.87 (s, 1H), 9.16 (d, J= 2.1 Hz, 1H), 8.54 (dd, J= 2.4 Hz, 8.7 Hz, 1H), 8.43 (d, J= 3.3 Hz, 1H), 8.38 (d, J= 5.1 Hz, 1H), 8.32 (d, J= 5.1 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.90 (dd, J = 1.8 Hz, 3.6 Hz, 1H), 7.76 (s, 1H), 7.69 (dd, J = 0.9 Hz, 5.4 Hz, 1H), 6.90 (d, J= 3.3 Hz, 1H).

Step 2

Synthesis of N,N-dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4'-bipyridi n-2 ^, -amine (45).

To a solution of dimethylamine in methanol (5 mL, 33% w/w ) was added l-(6'- fluoro-3,4'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (50 mg, 0.17 mmol). The resulting solution was kept for 16 hours at 100 °C in a sealed tube. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford N,N- dimethyl-6-(lH-pyrrolo[2,3-c]pyridin-l-yl)-3,4'-bipyridin-2' -amine as a colorless solid: MS (ESI, m/z): 316.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.84 (s, 1H), 9.04 (d, J= 2.1 Hz, 1H), 8.43-8.39 (m, 2H), 8.30 (d, J= 5.4 Hz, 1H), 8.20 (d, J= 6.0 Hz, 1H), 8.00 (d, J= 8.7 Hz, 1H), 7.67 (dd, J= 0.6 Hz, 5.1 Hz, 1H), 7.03-6.89 (m, 2H), 6.89 (d, J= 3.3 Hz, 1H).

Example 46 Synthesis of l-(5-(pyrimidin-4-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (46):

1-1 80% ⁴⁶ " ¹

Synthesis of l-(5-(tributylstannyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridin e (46-1). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (1.51 g, 4.67 mmol, 1-1) in acetonitrile (50 mL) were added 1, 1,1,2,2,2-hexabutyldistannane (8.13 g, 14.01 mmol), triphenylphosphine (0.37 g, 1.40 mmol), triethylamine (4.73 g, 46.71 mmol) and palladium(II) acetate (0.11 g, 0.47 mmol). The resulting solution was refluxed for 16 hours under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5- (tributylstannyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 486.0 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 9.66 (s, 1H), 9.60 (s, 1H), 8.38 (d, J= 5.6 Hz, 1H), 7.95 (d, J= 1.6 Hz, 1H), 7.73 (d, J= 4.8 Hz, 1H), 7.62 (d, J= 6.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 6.74 (d, J= 2.8 Hz, 1H), 1.65-1.61 (m, 6H), 1.42-1.35 (m, 6H), 1.15-1.13 (m, 6H), 0.95-0.91 (m, 9H).

Synthesis of l-(5-(pyrimidin-4-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (46). To a solution of l-(5-(tributylstannyl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridin e (120 mg, 0.25 mmol) in N,N-dimethylformamide (20 mL) were added 4-bromopyrimidine (59 mg, 0.37 mmol), copper(I) iodide (5 mg, 0.026 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The resulting mixture was stirred for 4 hours at 40 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers was washed with brine (3 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5-(pyrimidin-4-yl)pyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 274.0 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO-i ) δ 9.89 (s, 1H), 9.44 (d, J= 2.0 Hz, 1H), 9.32 (d, J= 1.2 Hz, 1H), 8.95 (d, J= 5.6 Hz, 1H), 8.78 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 8.45 (d, J= 3.6 Hz, 1H), 8.33 (d, J= 5.2 Hz, 1H), 8.28 (dd, J= 1.2 Hz, 5.2 Hz, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.68 (d, J= 5.2 Hz, 1H), 6.92 (d, J= 3.6 Hz, 1H). Example 47

Synthesis of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (47):

47-1

Synthesis of (E)-ethyl 3-(4-aminopyridin-3-yl)acrylate (47-1). To a solution of 3- bromopyridin-4-amine (5 g, 28.9 mmol) in N,N-dimethylformamide (50 mL) were added ethyl acrylate (4.4 g, 43.3 mmol), triphenylphosphine (1.7 g, 6.4 mmol), palladium(II) acetate (0.65 g, 2.9 mmol) and triethylamine (2.9 g, 28.9 mmol). The resulting mixture was stirred for 4 hours at 100 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford (E)-ethyl 3-(4-aminopyridin-3-yl)acrylate as a yellow solid: MS (ESI, m/z): 193.0 [M + 1] ⁺ ; 1H MR (400 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 16.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 16.4 Hz, 1H), 5.10 (br s, 2H), 4.25 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H).

Step 2

Synthesis of l,6-naphthyridin-2(lH)-one (47-2). Sodium (0.96 g, 41.6 mmol) was dissolved into anhydrous ethanol (60 mL) at 0 °C followed by the addition of (E)-ethyl 3-(4-aminopyridin- 3-yl)acrylate (2.1 g, 10.4 mmol). The resulting solution was refluxed for 2 hours, then cooled down to ambient temperature and neutralized with acetic acid (2.5 g, 41.6 mmol). The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 1,6- naphthyridin-2(lH)-one as a yellow solid: MS (ESI, m/z): 147.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 12.18 (br s, 1H), 8.83 (s, 1H), 8.46 (d, J= 5.7 Hz, 1H), 8.00 (d, J= 9.3 Hz, 1H), 7.20 (d, J= 5.7 Hz, 1H), 6.57 (d, J= 9.6 Hz, 1H).

Step 3

47-2 47-3

Synthesis of 2-chloro-l,6-naphthyridine (47-3). A solution of l,6-naphthyridin-2(lH)-one (2 g, 13.68 mmol) in phosphoryl trichloride (20 mL) was refluxed for 16 hours. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was taken up by dichlorom ethane (100 mL) and washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichlorom ethane to afford 2-chloro-l,6-naphthyridine as a yellow solid: MS (ESI, m/z): 165.0 [M + 1] ⁺ ; 1H NMR (300 MHz, DMSO-i ) δ 9.43 (s, 1H), 8.83 (d, J= 6.0 Hz, 1H), 8.69 (d, J= 11.7 Hz, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.86 (d, J= 9.6 Hz, 1H).

Synthesis of 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6-naphthyridine (47). To a solution of 1H- pyrrolo[2,3-c]pyridine (48 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) were added 2- chloro-l,6-naphthyridine (60 mg, 0.37 mmol) and cesium carbonate (119 mg, 0.37 mmol). The resulting mixture was stirred for 12 hours at 120 °C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-(lH-pyrrolo[2,3-c]pyridin-l-yl)-l,6- naphthyridine as a yellow solid: MS (ESI, m/z): 247.0 [M + 1] ⁺ ; 1H NMR (300 MHz, OMSO-d ₆ ) δ 10.24 (br s, 1H), 9.37 (s, 1H), 8.78-8.74 (m, 2H), 8.58 (d, J= 3.6 Hz, 1H), 8.38 (d, J= 4.8 Hz, 1H), 8.27 (d, J= 9.0 Hz, 1H), 8.02 (d, J= 6.0 Hz, 1H), 7.71 (d, J= 5.1 Hz, 1H), 6.96 (d, J= 3.6 Hz, 1H).

Example 48

Synthesis of N-(6-(lH-pyrrolo [2,3-c] pyridin-l-yl)pyridin-3-yl)-3-(2- fluoroethoxy)benzamide (48):

4-2 48-1 48

Step 1 Synthesis of N-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-3-hydroxyb enzamide (48-1).

To a solution of 6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-amine (100 mg, 0.48 mmol) in N,N-dimethylformamide (15 mL) was added 4-methoxybenzoic acid (98 mg, 0.71 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (271 mg, 0.71 mmol) and triethylamine (144 mg, 1.43 mmol). The resulting solution was stirred for 16 hours at ambient temperature under nitrogen atmosphere. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-2% methanol in dichloromethane to afford N-(6-(lH- pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-3-hydroxybenzamide as a light yellow solid: MS (ESI, m/z): 331.0 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 10.58 (s, 1H), 9.83 (br s, 1H), 9.67 (s, 1H), 8.97 (d, J= 2.4 Hz, 1H), 8.40 (dd, J= 2.7 Hz, 9.0 Hz, 1H), 8.28-8.25 (m, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.65 (d, J= 5.4 Hz, 1H), 7.45-7.33 (m, 3H), 7.03 (dd, J= 2.7 Hz, 9.0 Hz, 1H), 6.83 (d, J= 3.3 Hz, 1H).

Step 2

48-1 48

Synthesis of N-(6-(lH-pyrrolo [2,3-c] pyridin-l-yl)pyridin-3-yl)-3-(2- fluoroethoxy)benzamide (48). To a solution of N-(6-(lH-pyrrolo[2,3-c]pyridin-l- yl)pyridin-3-yl)-3-hydroxybenzamide (40 mg, 0.12 mmol) in N,N-dimethylformamide (10 mL) were added l-bromo-2-fluoroethane (23 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) at ambient temperature. The resulting mixture was stirred for 16 hours at 80 °C. After cooling down to ambient temperature, the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford N-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-yl)-3-(2-fluoroethoxy)benzamide as a colorless solid: MS (ESI, m/z): 377.0 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO-i ) δ 10.58 (s, 1H), 9.68 (br s, 1H), 8.98 (d, J= 2.4 Hz, 1H), 8.41 (dd, J= 2.7 Hz, 8.7 Hz, 1H), 8.28-8.25 (m, 2H), 7.92 (d, J= 8.7 Hz, 1H), 7.72-7.48 (m, 4H), 7.24 (dd, J = 2.4 Hz, 7.5 Hz, 1H), 6.84 (d, J= 3.6 Hz, 1H), 4.88 (d, J= 3.9 Hz, 1H), 4.72 (d, J= 3.9 Hz, 1H), 4.41 (d, J= 3.9 Hz, 1H), 4.30 (d, J= 3.9 Hz, 1H).

Example 49

Radiochemical Synthesis of [ ³ H]-6

Scheme 46

6 [ ³ H]-6 Radiochemical Synthesis of [ ³ H]-6: To a tritiation vessel were added 3-(lH-pyrrolo[2,3- c]pyridin-l-yl)isoquinoline (2.8 mg, 11.4 μηιοΐ) and Rhodium black (2.4 mg, 23.3 μιηοΐ), followed by THF (0.3 mL). The vessel was hooked up to the tritiation manifold and put through two freeze-thaw cycles (liquid nitrogen). While the reaction was frozen, tritium gas (1.02 Ci) was added. The black suspension was warmed to RT and stirred for 16 h. The reaction was frozen with liquid nitrogen and excess tritium gas was removed, then the vessel was removed from the reaction port. When the suspension had warmed to RT, it was filtered through a small plug of celite using EtOH. The filtrate was concentrated to give a thin film that was taken up in EtOH, concentrated, taken up in 10 mL EtOH and counted resulting in a total of 494.7 mCi. Analysis by RP-HPLC (Gemini C18, 4.6 x 150 mm, 254 nm, (55:45) 0.05M pH 9.5 TEAA:CH3CN, 1 mL/min). A portion of the batch was purified by reverse phase HPLC (Gemini C18, 10x250mm, 254 nm, (60:40) 0.05M pH 9.5 TEAA:CH ₃ CN, 5 mL/min, to give a batch of 135.18 mCi of [ ³ H]-6 in 99.4 mL EtOH. The specific activity was determined to be 37.8 Ci/mmol.

Radiochemical Synthesis of [ ¹⁸ F]-Ligands

General Methods

[ ¹⁸ F]Fluoride was transported to the radiochemistry lab on an anion exchange resin and eluted prior to use. Unless specifically stated, the [ ¹⁸ F]fluoride containing anion exchange resin was eluted with Kryptofix222 (7 mg, 19 μπιοΐ) and K ₂ C0 ₃ (2.1 mg, 15 μπιοΐ) in acetonitrile/water (80/20, 0.7 ml) and transferred to a vented 1-ml V-shaped vial in a microwave cavity. The fluoride was dried under argon flow and microwave heating (35 W/90 °C). Additional aliquots of acetonitrile (3 x 0.5 ml) were added for azeotropic drying at 35 W/90 °C. Example 50

Synthesis of [ ¹⁸ F] l-(5-(l-(2-fluoroethyl)-lH-pyrazol-3-yl)pyridin-2-yl)-lH-pyr rolo[2,3- c]pyridine ([ ¹⁸ F]-104):

[ ¹⁸ F]-104 Scheme 47

Step 1

Synthesis of l-(5-(lH-pyrazol-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridin e (50-1). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.31 mmol, 1-1) in 1,4- dioxane (20 mL) and water (5 mL) were added lH-pyrazol-3-ylboronic acid (53 mg, 0.47 mmol), potassium carbonate (129 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The resulting mixture was stirred for 3 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-5% methanol in dichloromethane to afford l-(5-(lH-pyrazol-3-yl)pyridin-2-yl)-lH-pyrrolo[2,3-c]pyridin e as a colorless solid: MS (ESI, m/z): 262.1 [M + 1] ⁺ ; 1H MR (400 MHz, δ 13.09 (s, 1H), 9.78 (s, 1H), 9.06 (s, 1H), 8.40 (dd, J= 1.6 Hz, 6.8 Hz, 1H), 8.30 (s, 1H), 8.28 (d, J= 5.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.67 (d, J= 5.6 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J = 3.2 Hz, 1H).

Synthesis of 2-(3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin-3-yl)-lH-pyra zol-l-yl)ethyl 4- methylbenzenesulfonate (50-2). To a solution of l-(5-(lH-pyrazol-3-yl)pyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine (0.20 g, 0.77 mmol) in acetonitrile (20 mL) were added cesium carbonate (0.50 g, 1.53 mmol) and ethane- 1,2-diyl bis(4-methylbenzenesulfonate) (0.42 g, 1.15 mmol) at ambient temperature. After stirring for 2 hours at 60 °C, the reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.5-1.5% methanol in dichloromethane to afford 2-(3-(6-(lH-pyrrolo[2,3-c]pyridin-l-yl)pyridin- 3-yl)-lH-pyrazol-l-yl)ethyl 4-methylbenzenesulfonate as an off white solid: MS (ESI, m/z): 460.2 [M + 1] ⁺ ; 1H MR (300 MHz, δ 10.03 (s, 1H), 9.02 (d, J= 3.3 Hz, 1H), 8.98 (d, J= 2.1 Hz, 1H), 8.52 (d, J= 5.7 Hz, 1H), 8.37 (dd, J= 2.4 Hz, 6.3 Hz, 1H), 8.30 (d, J= 6.3 Hz, 1H), 8.09 (d, J= 9.3 Hz, 1H), 7.83 (d, J= 2.4 Hz, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.88 (d, J= 1.5 Hz, 1H), 4.45 (br s, 4H), 2.23 (s, 3H).

Step 3 Radiochemical synthesis of [ F] l-(5-(l-(2-fluoroethyl)-lH-pyrazol-3-yl)pyridin-2-yl)-lH- pyrrolo[2,3-c]pyridine ([ ¹⁸ F]-104): A solution of 2-(3-(6-(lH-pyrrolo[2,3-c]pyridin-l- yl)pyridin-3-yl)-lH-pyrazol-l-yl)ethyl 4-methylbenzenesulfonate (1 mg) in DMSO or DMF (0.25 ml) was added to the microwave vial containing the dry [ ¹⁸ F]fluoride, the vent line was removed, and the reaction mixture was heated at 110 °C (75 W) for 10 min. After cooling to < 50 °C, the reaction was diluted with H ₂ 0 (0.6 ml), mixed and injected into the semi-preparative HPLC column. The product was purified using Zorbax Eclipse XDB-C-18, 5 μπι, 9.4 x 250 mm (Agilent), at a flow rate of 5 mL/min. The mobile phase was acetonitrile / aq. NaH ₂ P0 ₄ (10 mM) from 30 to 70% in 15 min. The radioactive fraction of interest was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 mL) and transferred into a sterile container. The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a Gemini, 5 μπι, 4.6 x 150 mm column (Phenomenex) at a flow rate of 1 mL/min. The mobile phase was a mixture consisting of 50% of acetonitrile and 50% of 0.1 % trifluoroacetic acid in water. Concentration of [ ¹⁸ F]-104 was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of compound 104, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [ ¹⁸ F]-104 was 4.2 min, the chemical and radiochemical purities were 100%.

Example 51

Radiochemcial synthesis of [ ¹⁸ F] 7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline ([ ¹⁸ F]-17):

[ ¹⁸ F]-17

Synthesis of 7-(methylthiomethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoqu inoline (51-1).

A solution of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinolin-7-ol (0.4 g, 1.53 mmol, 15) in N,N-dimethylformamide (6 mL) was treated with sodium hydride (80 mg, 2 mmol, 60% w/w dispersed into mineral oil) at 0 °C for 10 min, followed by the addition of

(chloromethyl)(methyl)sulfane (289 mg, 3 mmol). The resulting mixture was stirred for 2 hours at ambient temperature and quenched with saturated aqueous solution of ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers was washed with brine (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 7- (methylthiomethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquin oline as a light yellow solid: MS (ESI, m/z): 322.1 [M + 1] ⁺ ; 1H MR (300 MHz, DMSO- ₆ ) δ 9.64 (s, 1H), 9.30 (s, 1H), 8.32 (d, J= 3.3 Hz, 1H), 8.28 (d, J= 5.4 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J= 9.0 Hz, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.68 (dd, J= 0.9 Hz, 5.1 Hz, 1H), 7.57 (dd, J= 2.4 Hz, 9.0 Hz, 1H), 6.86 (d, J= 3.3 Hz, 1H), 5.47 (s, 2H), 2.25 (d, J= 4.5 Hz, 3H).

Synthesis of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)-7-((6-(trifluoromethyl)-lH - benzo[d] [l,2,3]triazol-l-yloxy)methoxy)isoquinoline (51-3). To a solution of 7- (methylthiomethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquin oline (0.15 g, 0.46 mmol) in dichloromethane (10 mL) was added sulfuryl dichloride (0.18 g, 1.31 mmol) at 0 °C. The resulting solution was stirred for 1 hour at ambient temperature and concentrated under reduced pressure to afford crude 7-(chloromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinol ine. A solution of the above crude 7-(chloromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l-yl)isoquinol ine in dichloromethane (10 mL) was added to a solution of 6-(trifluorom ethyl)- 1H- benzo[d][l,2,3]triazol-l-ol (0.3 g, 1.48 mmol) and sodium hydride (59 mg, 1.48 mmol) in N,N- dimethylformamide (20 mL) at 0 °C. After additional 3 hours at ambient temperature, the reaction was quenched by the addition of saturated aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers was washed with brine (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-3% methanol in dichloromethane to afford 3-(lH-pyrrolo[2,3- c]pyridin-l-yl)-7-((6-(trifluoromethyl)-lH-benzo[d][l,2,3]tr iazol-l-yloxy)methoxy)isoquinoline as a colorless solid: MS (ESI, m/z): Ml.1 [M + 1] ⁺ ; 1H MR (400 MHz, DMSO- ₆ ) δ 9.68 (s, 1H), 9.42 (s, 1H), 8.36-8.33 (m, 3H), 8.30 (d, J= 5.6 Hz, 1H), 8.15 (s, 1H), 8.13-8.11 (m, 1H), 7.91 (s, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.68 (dd, J= 0.4 Hz, 5.2 Hz, 1H), 7.64 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 6.88 (d, J= 3.2 Hz, 1H), 6.48 (s, 2H). Step 3

51-3 [ ¹⁸ F]-17

Radiochemical synthesis [ F] 7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline ([ ¹⁸ F]-17). A solution of 3-(lH-pyrrolo[2,3-c]pyridin-l-yl)-7-((6- (trifluoromethyl)-lH-benzo[d][l,2,3]triazol-l-yloxy)methoxy) isoquinoline (0.6 mg , 51-3) in DMSO (0.25 mL) and acetonitrile (0.15 mL) was added to the microwave vial containing the dry [ ¹⁸ F] fluoride, the vent line was removed, and the reaction mixture was heated at 90 °C for 5 min, then at 110 °C for 5 min and 120 °C for 5 min (50 W). After cooling down to < 50 °C, the reaction was diluted with H ₂ 0 (0.6 mL), mixed and injected into the semi-preparative HPLC column. The product was purified using Zorbax Eclipse XDB-C-18, 5 μπι, 9.4 x 250 mm

(Agilent), at a flow rate of 5 mL/min. The mobile phase was acetonitrile / aq. NaH ₂ P0 ₄ (10 mM) from 30 to 70% in 15 min. The radioactive fraction of interest was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 mL) and transferred into a sterile container. The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a Xbridge Phenyl, 3.5 μπι, 4.6 x 150 mm column (Waters) at a flow rate of 2 mL/min. The mobile phase was a mixture consisting of 50% of acetonitrile and 50%) of 0.1%) trifluoroacetic acid in water. Concentration of [ ¹⁸ F]-17 was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of compound 17, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [ ¹⁸ F]-17 was 5.3 min.

Example 52

Radiochemcial synthesis of [ ¹⁸ F] l-(2'-fluoro-[3,4'-bipyridin]-6-yl)-lH-pyrrolo[2,3- c]pyridine ([ ¹⁸ F]-44):

Synthesis of l-(6'-nitro-3,4'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine (52-1). To a solution of l-(5-iodopyridin-2-yl)-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.31 mmol) in 1,4-dioxane (30 mL) were added bis(pinacolato)diboron (158 mg, 0.62 mmol), potassium acetate (60 mg, 0.62 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.031 mmol) at ambient temperature. The resulting mixture was stirred for 3 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, 4-bromo-2-nitropyridine (125 mg, 0.62 mmol) was added to the mixture followed by the addition of potassium carbonate (85 mg, 0.62 mmol), water (3 mL) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.031 mmol). The resulting mixture was stirred for 4 hours at 80 °C under nitrogen atmosphere. After cooling down to ambient temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0.3-3% methanol in dichloromethane to afford l-(6'-nitro-3,4'-bipyridin-6-yl)-lH-pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 318.1 [M + 1] ⁺ ; 1H MR (300 MHz, OMSO-d ₆ ) δ 9.93 (s, 1H), 9.24 (d, J= 2.1 Hz, 1H), 8.81-7.92 (m, 2H), 8.65 (dd, J= 2.4 Hz, 8.7 Hz, 1H), 8.47 (d, J= 3.3 Hz, 1H), 8.41 (dd, J= 1.5 Hz, 5.1 Hz, 1H), 8.33 (d, J= 5.1 Hz, 1H), 8.10 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 5.7 Hz, 1H), 6.93 (d, J= 3.6 Hz, 1H). Step 2

52-1 [ ¹⁸ F]-44

Step 2. Radiochemical synthesis [ F] l-(2'-fluoro-[3,4'-bipyridin]-6-yl)-lH-pyrrolo[2,3- c]pyridine ([ ¹⁸ F]-44). A solution of l-(2'-nitro-[3,4'-bipyridin]-6-yl)-lH-pyrrolo[2,3-c]pyridine (0.4 mg, 52-1) in DMSO (0.25 mL) was added to the microwave vial containing the dry

[ ¹⁸ F] fluoride, the vent line was removed, and the reaction mixture was heated at 140 °C (75 W) for 3 min. After cooling down to < 50 °C, the reaction was diluted with H ₂ 0 (0.6 mL), mixed and injected into the semi-preparative HPLC column. The product was purified using Zorbax Eclipse XDB-C-18, 5 μπι, 9.4 x 250 mm (Agilent), at a flow rate of 5 mL/min. The mobile phase was acetonitrile / aq. NaH ₂ P0 ₄ (10 mM) 45 / 55. The radioactive fraction of interest was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 mL) and transferred into a sterile container. The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a Gemini, 5 μπι, 4.6 x 150 mm column (Phenomenex) at a flow rate of 1 mL/min. The mobile phase was acetonitrile / 0.1% trifluoroacetic acid in water (10 mM) from 50 to 85% in 10 min. Concentration of [ ¹⁸ F]-52 was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of compound 52, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound

[ ¹⁸ F]-52 was 6.6 min.

Example 53

Radiochemcial synthesis of [ ¹⁸ F] </2-7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin-l- yl)isoquinoline (d ₂ , [ ¹⁸ F]-17):

Scheme 50

15

d ₂ [ ¹⁸ F]-17 Step 1 Radiochemcial synthesis of [d ₂ , F] -7-(fluoromethoxy)-3-(lH-pyrrolo[2,3-c]pyridin- l-yl)isoquinoline [d ₂ , ¹⁸ F] -17): The [ ¹⁸ F]fluoride containing anion exchange resin was eluted with Kryptofix222 (7 mg, 19 μιηοΐ) and K ₂ C0 ₃ (2.1 mg, 15 μιηοΐ) in acetonitrile/water (80/20, 0.7 mL) and transferred to a vented 5-ml V-shaped. The [ ¹⁸ F]fluoride was dried under argon flow heating (95 °C). Additional aliquots of acetonitrile (3 x 0.5 mL) were added for azeotropic drying at 90 °C. Dibromomethane-i¾ (50 μί) in dry acetonitrile was added to the dry

[ ¹⁸ F]fluoride and the reaction vessel sealed. The mixture was heated at 95 °C for 5 minutes. After cooling, the reaction vessel was opened and the [i¾ _; ¹⁸ F]bromofluoromethane was transfer true teflon tubing to a 0.9 mL vial containing 15 (0.36mg, 1.38 μιηοΐ) and cesium carbonate (4 mg, 120 μπιοΐ) in dimethylformamide (300 μΐ at rt. The resulting reaction mixture was heated for 15 Dminutes at 70 °C. The solution was transferred in a 0.9 mL vial containing water (700 μΐ at rt, mixed and injected into the semi-preparative FIPLC column. The product was purified using Zorbax Eclipse XDB-C-18, 5 μπι, 9.4 x 250 mm (Agilent), at a flow rate of 5 mL/min. The mobile phase was acetonitrile / aq. NaH ₂ P0 ₄ (10 mM) from 30 to 70% in 15 min. The radioactive fraction of interest was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 mL) and transferred into a sterile container. The final product was tested for chemical and radiochemical purity by means of an analytical FIPLC system (Waters) using a Xbridge Phenyl, 3.5 μπι, 4.6 x 150 mm column (Waters) at a flow rate of 2 mL/min. The mobile phase was a mixture consisting of 50% of acetonitrile and 50% of 0.1 % trifluoroacetic acid in water. [d ₂ , ¹⁸ F]-17 concentration was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of 17, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for [<¾, ¹⁸ F]-17 was 5.3 min. Procedures for tissue homogenate binding assays

The frozen human brain samples of Alzheimer's disease (AD) were purchased from Analytic Biological Services Inc. They were postmortem tissue from donors with clinical diagnosis of AD. As much of the white matter was dissected out of the frontal cortex in order to enrich the tissue preparations for gray matter. Brain homogenates of gray matter enriched frontal cortex were prepared by homogenizing the tissue in ice cold Phosphate Buffered Saline (PBS), pH 7.4 at 80 mg wet weight tissue per 1 mL for 45 seconds at 4 °C on setting 16 of Polytron. The homogenate was further diluted with ice cold PBS to 30 mg wet weight tissue per 1 mL and homogenized for an additional minute as described above. Homogenates were aliquotted in 5 ml/tube and store at -70 °C until use. For hot saturation binding assay, various concentrations of radioligand were prepared in Assay Buffer (PBS plus 0.1% BSA) plus 20% DMSO ranging from 0.02 to 57 nM for [ ³ H]compound of Example 49. 25 μΐ of radioligand was added to 225 μΐ of membranes diluted to 0.5 mg/ml in Assay Buffer) for final cone of radioligand ranging from 0.002 to 5.7 nM and final membrane of 100 μg wet weight/assay tube (incubation, filtration, and determination of amount of radioligand used in assay are described below). Self-block with unlabeled compound was used to determine non-specific binding. Saturation data was analyzed using

Graphpad/Prism software. Figure 1 shows an example of hot saturation binding of [ ³ H]-6. The radioligand shows high affinity for tau in AD brain homogenates with measured dissociation constant of 0.2 nM.

For displacement tau binding assay, unlabeled test compounds were dissolved in DMSO at 1 mM. Dilutions of tests compounds to various concentrations were made in 100% DMSO at lOOOx final assay concentration and 0.225 μΐ aliquots were dispensed into assay plates. Brain homogenates were diluted to 0.5 mg/mL from original 30 mg/mL volume in Assay Buffer, and 200 μΐ were added to the assay plate for a final concentration of 100 μg wet weight/assay tube. [ ³ H]-6 was prepared at lOx final concentration in Assay Buffer plus 20% DMSO and 25 μΐ was added to the assay plate for final assay concentration of 0.25 nM. The assay plate was incubated at room temperature (25 °C) for 90 minutes. Unbound and bound ligand were separated by filtration of bound onto GF/C filter plates (pre-treated for 30 min with 0.2% polyethyleninamine) using a Packard UniFilter Harvester and washing away unbound with 2.5 ml per well ice cold 5 mM Tris at pH 7.4. Filter plates were dried for 1 hour in a vacuum oven and 50 μΐ/well MicroScint-20 were added. Plates were counted 1 min per well by Packard Topcount. Total amount of radioligand used in the assay was determined by counting 25 μΐ of lOx ligand stock. Data was analyzed using Activity Base software to generate 4p fit of dose responses; and, Ki values were calculated. Tau Ki data for representative compounds of the invention are found in Table l .As shown in Figure 2, compound 6 (unlabeled) self-displaced [ ³ H]-6 with Ki value of 0.43 nM

Homogenates from AD and non-AD human brain samples were assessed for their immunoreactivity to anti-Αβ antibody 6E10 and an anti-phospho-tau antibody PHF6 or AT8. The brain sections with the highest levels of PHF6 or AT8 immunoreactivity were chosen for the displacement tau binding assay and the brain sections with the highest levels of 6E10 combined with low levels of PHF6 or AT8 immunoreactivity were chosen for the amyloid tissue

homogenate binding assay. Procedure for the amyliod binding assay (counterscreen) was identical to the Tau binding assay using [3HJ-105

[ ³ H]-105

as the reference radioligand.

Tau Ki and/or Amyloid Ki data for representative compounds of the instant invention are found in Table 1.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.