IL223631A

Fused heterocyclic compounds as phosphodiesterases (pdes) inhibitors

Abstract

This record has no abstract on file.

Term

No projected expiry on record.

20 claims: 3 independent, 17 dependent

1
223631/3 Claims 1. A compound represented by the formula (I):wherein 5 ring A represents a 6-membered ring optionally substituted by substituent(s) selected from the group consisting of (1) a halogen atom, (2) cyano, (3) a C1-6 alkyl group optionally substituted by 1 to 3 10 substituents selected from the group consisting of (a) a halogen atom, (b) hydroxy and (c) a C1-6 alkyl-carbonyloxy group, and (4) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, 15 any one or two of from Z1 to Z4 represent -N=, and the others represent -CH=;the nitrogen atom of -N= for Z1 to Z4 may be oxidized;Y represents (1) an oxygen atom, 20 (2) a methylene group optionally substituted by 1 or 2 C1-6 alkyl group(s) (the two substituents for the methylene group optionally form, together with the adjacent carbon atom, a C3-6 cycloalkane), or (3) -NRc- wherein Rc is (i) a hydrogen atom, (ii) a C1-6 alkyl 25 group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, a C3-7 cycloalkyl group, a C1-6 alkoxy group, a trimethylsilyl- C1-6 alkoxy group and a C1-6 alkoxy-carbonyl group, or (iii) a 326 223631/3 C3-7 cycloalkyl group;and R represents a group represented by the formula: R1-L· wherein R1 represents a phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally substituted by substituent(s) selected from the group consisting of (a) a halogen atom, (b) a C1-6 alkoxy-carbonyl group, 10 (c) a C1-6 alkyl group optionally substituted by one or more substituents selected from the group consisting of i) a halogen atom, ii) a hydroxy group, and iii) a C1-6 alkoxy group optionally substituted by 15 trimethylsilyl, (d) a C6-14 aryl group, and (e) a C1-6 alkyl-carbonyl group;L represents a sulfur atom, an oxygen atom, a methylene group, -CO-, -NRa-, -CH2O-, -OCH2-, -NRaCOO-, -OCONRa-, -NRaCONRb-, - 20 NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONRa-, N- Ra and Rb are the same or different and each represents a hydrogen atom, or a C1-6 alkyl group, or L and R1 in combination optionally form a bi- or tri-cyclic 25 fused heterocyclic group optionally substituted by substituent(s) selected from the group consisting of (a) a halogen atom, (b) a C1-6 alkoxy-carbonyl group, (c) a C1-6 alkyl group optionally substituted by C6-14 aryl 30 group(s), and 327 223631/3 (d) an oxo group;and ring B1 represents a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted by substituent(s) selected 5 from the group consisting of (a) a halogen atom, and (b) a C1-6 alkyl group;provided that 3,3'-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-b]pyridin-10 2-one), 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, and 3,3'-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-c]pyridin- 2-one) 15 are excluded;or a salt thereof.
17
A medicament comprising the compound or salt according to 10 claim 1.
19
Use of a compound represented by the formula (I):20 wherein ring A represents a 6-membered ring optionally substituted by substituent(s) selected from the group consisting of (1) a halogen atom, (2) cyano, 25 (3) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) hydroxy and (c) a C1-6 alkyl-carbonyloxy group, and 334 223631/3 (4) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, any one or two of from Z1 to Z4 represent -N=, and the others represent -CH=;5 the nitrogen atom of -N= for Z1 to Z4 may be oxidized;Y represents (1) an oxygen atom, (2) a methylene group optionally substituted by 1 or 2 C1-6 alkyl group(s) (the two substituents for the methylene group 10 optionally form, together with the adjacent carbon atom, a C3-6 cycloalkane), or (3) -NRc- wherein Rc is (i) a hydrogen atom, (ii) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, 15 a C3-7 cycloalkyl group, a C1-6 alkoxy group, a trimethylsilyl-C1-6 alkoxy group and a C1-6 alkoxy-carbonyl group, or (iii) a C3-7 cycloalkyl group;and R represents a group represented by the formula: 20 wherein R1 represents a phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally substituted by substituent(s) selected from the group consisting of 25 (a) a halogen atom, (b) a C1-6 alkoxy-carbonyl group, (c) a C1-6 alkyl group optionally substituted by one or more substituents selected from the group consisting of (i) a halogen atom, 30 (ii) a hydroxy group, and (iii) a C1-6 alkoxy group optionally substituted by trimethylsilyl, 335 223631/3 (d) a C6-14 aryl group, and (e) a C1-6 alkyl-carbonyl group;L represents a sulfur atom, an oxygen atom, a methylene group, -CO-, -NRa-, -CH2O-, -OCH2-, -NRaCOO-, -OCONRa-, -NRaCONRb-, - 5 NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONRa-, Ra and Rb are the same or different and each represents a hydrogen atom, or a C1-6 alkyl group, or L and R1 in combination optionally form a bi- or tri-cyclic 10 fused heterocyclic group optionally substituted by substituent(s) selected from the group consisting of (a) a halogen atom, (b) a C1-6 alkoxy-carbonyl group, (c) a C1-6 alkyl group optionally substituted by C6-14 aryl 15 group(s), and (d) an oxo group;and ring B1 represents a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted by substituent(s) selected 20 from the group consisting of (a) a halogen atom, and (b) a C1-6 alkyl group;or a salt thereof for the production of an agent for preventing or treating schizophrenia, autism, Alzheimer's disease, bipolar disorders, Parkinson's disease, 25 Huntington's disease, obesity, drug addiction or attention deficit/hyperactivity disorder. 30 336 223631/3

Independent claims3

1,778 paragraphs in 22 sections, as filed

WO 2011/163355 PCT/US2011/041443

DESCRIPTION

Title of Invention

FUSED HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASES (PDES) INHIBITORS

Technical Field [0001]

The present invention relates to fused heterocyclic compounds.

Background of the Invention [0002]

Phosphodiesterases (PDEs) are a superfamily of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural'and functional'properties. These enzymes metabolically inactivate the ubiquitous intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); PDEs selectively catalyze the hydrolysis of the 3'-ester bond, forming the inactive 5'-monophosphate. On the basis of substrate specificity, the PDE families can be further classified into three groups: i) the cAMP-PDEs (PDE4, PDE7, PDE8), ii) the cGMP-PDEs (PDE5, PDE6 and PDE9), and iii) the dual-substrate PDEs (PDE1, PDE2, PDE3, PDE10 and PDE11).

The cAMP and cGMP are involved in the regulation of virtually every physiological process such as pro-inflammatory mediator production and action, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, lipogenesis, glycogenolysis and gluconeogenesis. Especially, in neurons, these second messengers have important role in the regulation of synaptic transmission as well as in neuronal differentiation and survival (Nat. Rev. Drug Discov. 2006, vol. 5: 660-670). Regulation of these processes by cAMP and cGMP are accompanied by activation of protein kinase A (ΡΚΆ) and protein kinase G (PKG), which in turn phosphorylate a variety of substrates, including transcription factors, ion channels and receptors that regulate a variety of

physiological processes. Intracellular cAMP and cGMP 1 WO 2011/163355 PCT/US2011/041443 concentrations seem to be temporally, spatially, and functionally compartmentalized by regulation of adenyl and guanyl cyclases in response to extracellular signaling and their degradation by PDEs (Circ. Res. 2007, vol. 100(7): 950-966) . PDEs provide the only means of degrading the cyclic nucleotides cAMP and cGMP in cells, thus PDEs play an essential role in cyclic nucleotide signaling. Thereby, PDEs could be promising targets for various therapeutic drugs.

Phosphodiesterase 10A (PDE10A) was discovered in 1999 by three independent groups (Proc. Natl. Acad. Sci. USA 1999, vol. 96: 8991-8996, J. Biol. Chem. 1999, vol. 274: 18438-18445,

Gene 1999, vol. 234: 109-117). Expression studies have .shown that PDE10A has the most restricted distribution within the all known PDE families; the PDE10A mRNA is highly expressed only in brain and testes (Eur. J. Biochem. 1999, vol. 266: 1118-1127, J. Biol. Chem. 1999, vol. 274: 18438-18445). In the brain, mRNA and protein of PDE10A are highly enriched in medium spiny neurons (MSNs) of the striatum (Eur. J. Biochem. 1999, vol. 266: 1118-1127, Brain Res. 2003, vol. 985: 113-126). MSNs are classified into two groups: the MSN that express Di dopamine receptors responsible for a direct (striatonigral) pathway and the MSN that express D2 dopamine receptors responsible for an indirect (striatopallidal) pathway. The function of direct pathway is to plan and execution, while indirect pathway is to act as a brake on behavioral activation. As PDE10A expresses in both MSNs, PDE10A inhibitors could activate both of these pathways. The antipsychotic efficacy of current medications, D2 or D2/5-HT2A antagonists, mainly derives from their activation of the indirect pathway in the striatum. As PDE10A inhibitors are able to activate this pathway, this suggests that PDE10A inhibitors are promising as antipsychotic drugs. The excessive D2 receptor antagonism in the brain by D2 antagonists causes problems of extrapyramidal side effects and hyperprolactinaemia. However the expression of PDE10A is limited to these striatal pathways in the brain, thus side 2 WO 2011/163355 PCT/US2011/041443 effects by PDE10A inhibitors were expected to be weaker compared with current D2 antagonists. Regarding hyperprolactinaemia, PDE10A inhibitors would produce no prolactin elevation due to lack of D2 receptor antagonism in 5 the pituitary. Moreover, the presence of PDE10A in a direct pathway makes it likely that PDE10A inhibition will have some advantage over current D2 antagonists; the direct pathway is thought to promote desired action, and activation of this pathway by PDE10A inhibitors may counteract extrapyramidal 10 symptoms induced by excessive D2 receptor antagonism. In addition, activation of this pathway could facilitate striatal-thalamic outflow, promoting the execution of procedural strategies. Furthermore, enhancement of second messenger levels without blockade of dopamine and/or other 15 neurotransmitter receptors may also provide therapeutic advantages with fewer adverse side-effects compared with current antipsychotics (e.g., hyperprolactinaemia and weight gain). This unique distribution and function in the brain indicates that PDE10A represents an important new target for 20 the treatment of neurological and psychiatric disorders, in particular psychotic disorders like schizophrenia.

As a phosphodiesterase (PDE) 10 inhibitor, compounds represented by the formulae:

3 PCT/US2011/041443 WO 2011/163355

were disclosed in W02008/004117 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, compounds represented by the formulae: 5 [0003]

were disclosed in W02010/0057121 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, io compounds represented by the formulae:

4 PCT/US2011/041443 WO 2011/163355

were also disclosed in W02010/57126 Pamphlet.

Further as a phosphodiesterase (PDE) 10 inhibitor, a compound represented by the formula:

. wherein Z is

was disclosed in W02006/072828 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, a compound represented by the general formula 5 WO 2011/163355 PCT/US2011/041443

was also disclosed in W02008/001182 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, a compound represented by the general formula

was also disclosed in W02010/090737 Pamphlet.

Summary of Invention

Technical Problem 10 [0004]

However, development of new phosphodiesterase (PDE) 10A inhibitors is further requested.

Solution to Problem [0005] is The present inventors discovered that a compound expressed by the formula (I) or a salt thereof (referred to as compound (I) in this specification) has a PDE 10A inhibitory action and after extensive investigation, completed the present invention. 6 WO 2011/163355 PCT/US2011/041443

In this specification, the compound (I) or a prodrug thereof is also referred to the compound of the present invention.

That is, the present invention provides the following. 5 [1] A compound represented by the formula (I):

wherein ring A represents an optionally substituted 6-membered ring, any one or two of Z1 to Z4 represent -N=, and the others io represent -CH=, Y represents an oxygen atom, a sulfur atom, an optionally substituted methylene group or -NRC- wherein Rc represents a hydrogen atom or a substituent, and R represents 15 (1) a group represented by the formula: wherein R1 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, 20 L is a sulfur atom, an oxygen atom, an optionally substituted methylene group, -CO-, -NRa-, -CH2O-, -OCH2-, -NRaCOO-, -OCONR3-, -NRaCONRb-, -NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONR3-,

25 wherein 7 WO 2011/163355 PCT/US2011/041443

Ra and Rb are the same or different and each is a hydrogen atom or an optionally substituted Ci_6 alkyl group, or L and R1 in combination optionally form an optionally 5 substituted bi- or tri-cyclic fused heterocyclic group, and ring B1 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, or (2) a group represented by the formula:

R2 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, ring B2 is a benzene ring, a pyridine ring, a pyrimidine 15 ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, and ring D is an optionally further substituted 5- or 6-.membered ring, provided that 20 3,3'-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2- one), 1- cyclohexyl-3-(4—{[4-(methylsulfonyl)piperazin-1- yl]methyl}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 3- (4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 25 3,3'-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-c]pyridin- 2- one), and 3- [8-(4-methylpiperazin-l-yl)naphthalen-2-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one are excluded, 30 or a salt thereof.

[1'] The compound of the aforementioned [1], wherein R is (1) a group represented by the formula: 8 WO 2011/163355 PCT/US2011/041443 R1-L-

wherein each symbol is as defined in the aforementioned [1], or (2) a group represented by the formula: R‘ wherein ring B2 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, and ring D is an optionally further substituted 5- or 6-membered ring, R2 is as defined in the aforementioned [1], provided that when ring B2 is a benzene ring, ring D is not a benzene ring, or a salt thereof.

[1" ] The compound of the aforementioned [1], wherein R is (1) a group represented by the formula: wherein R1 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, L is a sulfur atom, an oxygen atom, an optionally substituted methylene group, -CO-, -NRa~, -CH2O-, -OCH2-, -NRaCOO-, -OCONR3-, -NRaCONRb-, -NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONR3-,

wherein

Ra and Rb are as defined in the aforementioned [1], or L and R1 in combination optionally form an optionally 9 WO 2011/163355 PCT/US2011/041443 substituted bi- or tri-cyclic fused heterocyclic group, and ring B1 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, 5 provided that when L is an oxygen atom, R1 is not an optionally substituted phenyl, or (2} a group represented by the formula:

wherein each symbol is as defined in the aforementioned [1], io or a salt thereof.

[2] The compound of the aforementioned [1], wherein any one of Z1 to Z4 is -N=, and the others are -CH=, or a salt thereof.

[3] The compound of the aforementioned [1], wherein the is partial structure of the formula (I):

is a group represented by the formula:

wherein 20 Y1 is an optionally substituted methylene group or -NRC- wherein Rc is a hydrogen atom or a substituent, and 10 WO 2011/163355 PCT/US2011/041443 ring A1 is an optionally substituted pyridine ring, or a group represented by the formula:

wherein 5 Y2 is -NRd- wherein Rd is a substituent, and ring A2 is an optionally substituted pyridine ring, or a salt thereof.

[4] The compound of the aforementioned [1], wherein L is an oxygen atom, or -NRa- wherein Ra is a hydrogen atom or an io optionally substituted Ci_6 alkyl group, or L and R1 in combination optionally form an optionally substituted bi- or tri-cyclic fused heterocyclic group, or a salt thereof.

[5] The compound of the aforementioned [3], wherein the 25 partial structure of formula (I):

is a group represented by the formula:

wherein ring A1 and Y1 are as defined in the aforementioned [3], 20 or a salt thereof. 11 [6] The compound of the aforementioned [3], wherein the partial structure of formula of formula (I): WO 2011/163355 PCT/US2011/041443

is a.group represented by the formula:

wherein the R3''' represents a hydrogen atom, a halogen atom, an optionally substituted C1-4 alkyl group, or an optionally substituted C1-4 alkoxy group, and 10 Y1 is as defined in the aforementioned [3], or a salt thereof.

[7] The compound of the aforementioned [3], wherein the partial structure of formula (I):

15 is a group represented by the formula: 12 WO 2011/163355 PCT/US2011/041443

wherein R3a and R3b represent the same or different a hydrogen atom, a halogen atom, cyano, an optionally substituted Ci_4 alkyl group 5 or an optionally substituted Ci_4. alkoxy group, and R4 represents an optionally substituted Ci_4 alkyl group, provided that when one of R3a and R3b is a hydrogen atom, the other is not a hydrogen atom, or a salt thereof. 10 [8] The compound of the aforementioned [1], wherein ring B1 is an optionally substituted benzene ring, or a salt thereof.

[9] The compound of the aforementioned [1], wherein R1 is a 5-to 10-membered heterocyclic group which is optionally substituted, or a salt thereof. is [10] The compound of the aforementioned [9], wherein the 5- to 10-membered heterocyclic group which is optionally substituted is a group represented by the formula:

wherein Rx represents a hydrogen atom or an optionally 20 substituted Ci_6 alkyl group, or a salt thereof.

[11] l-Ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof. 25 [12] l-Ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5- 13 WO 2011/163355 PCT/US2011/041443 b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one, or a salt thereof.

[13] l-Ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5- 5 b]pyridin-2-one, or a salt thereof.

[14] 6-Methyl-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof.

[15] l-Ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5- 10 b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one, or a salt thereof.

[16] .1,7-Dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof. 25 [17] 1-Ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5 b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof.

[18] A medicament comprising the compound of the aforementioned [1], or a salt thereof. 20 [19] The medicament of the aforementioned [18], which is a phosphodiesterase 10A inhibitor.

[20] The medicament of the aforementioned [18], which is an agent for the prophylaxis or treatment of schizophrenia.

[21] A method for preventing or treating schizophrenia in a 25 mammal, which comprises administering an effective amount of compound represented by the formula (I) :

wherein 14 WO 2011/163355 PCT/US2011/041443 ring A represents an optionally substituted 6-membered ring, any one or two of Z1 to Z4 represent -N=, and the others represent -CH=, Y represents an oxygen atom, a sulfur atom, an optionally 5 substituted methylene group, or -NRC- wherein Rc represents a hydrogen atom or a substituent, and R represents (1) a group represented by the formula:

io wherein R1 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, L is a sulfur atom, an oxygen atom, an optionally substituted methylene group, -CO-, -NRa~, -CH2O-, -OCH2-, - 15 NRaCOO-, -OCONRa-, -NRaCONRb-, -NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONRa-,

wherein

Ra and Rb are the same or different and each is a 20 hydrogen atom or an optionally substituted Ci_6 alkyl group, or L and R1 in combination optionally form an optionally substituted bi- or tri-cyclic fused heterocyclic group, and ring B1 is a benzene ring, a pyridine ring, a pyrimidine 25 ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, or (2) a group represented by the formula:

15 WO 2011/163355 PCT/US2011/041443 wherein R2 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, ring B2 is a benzene ring, a pyridine ring, a pyrimidine 5 ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, and ring D is an optionally further substituted 5- or 6-membered ring, to the mammal. io [22] Use of a compound represented by the formula (I):

wherein each symbol is as defined above, or salt thereof for the production of an agent for the prophylaxis or treatment of schizophrenia. 15 [23] A compound represented by the formula (I):

wherein each symbol is as defined above, or salt thereof for use in the prophylaxis or treatment of schizophrenia. 20 [24] Use of a compound represented by the formula (I): 16 PCT/US2011/041443 WO 2011/163355

wherein each symbol is as defined above, or a salt thereof for use in the prophylaxis or treatment of schizophrenia. 5 [25] A compound represented by the formula (I'):

wherein

17 PCT/US2011/041443 WO 2011/163355 R1 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, 1/ is a sulfur atom, -CO-, -NRa-, .-CH2O-, -OCH2-, -NRaCOO-, -OCONRa-, -NRaCONRb-, -NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONRa-, o n^n k,N‘

wherein

Ra and Rb are the same or different and each is a hydrogen atom or an optionally substituted Ci_6 alkyl group, R1' is an optionally substituted 5- to 10-membered heterocyclic 10 group, or L and R1 in combination optionally form a bi- or tri-cyclic fused heterocyclic group which is optionally substituted by 1 to 3 substitutents selected from (a) a halogen atom, (b) an optionally esterified carboxy group, and 15 (c) an optionally substituted alkyl group, and ring B1 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, or 20

by the formula: R2 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, ring B2 is a benzene ring, a pyridine ring, a pyrimidine ring, 25 a pyrazine ring or a pyridazine ring, each of which is optionally substituted, and ring D' is optionally further substituted 5- or 6-membered heterocycle, 18 WO 2011/163355 PCT/US2011/041443 or a salt thereof.

Brief Description of the Drawings [0006] 5 Fig. 1 shows increase of cAMP (Fig. 1A) and cGMP (Fig. IB) contents in the mouse striatum by oral administration of compounds. Sixty min after oral administration of the compounds, striatum was isolated from mice and then cAMP and cGMP contents were measured using EIA kits. io Fig. 2 shows inhibition of MK-801-induced hyperlocomotion by compounds in mice. By orally administered 60 min before MK-801 (0.3 mg/kg, s.c.) treatment, compounds produced the inhibition of MK-801-induced hyperlocomotion. 15 Detailed Description of the Invention [0007]

In the present specification, unless otherwise specified, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. 20 In the present specification, unless otherwise specified, the term "optionally halogenated" or "halogeno" means the optionally presence of one or more (e.g., 1 to 3) halogen atoms as substituents.

[0008] 25 In the present specification, unless otherwise specified, examples of the "alkyl (group)" include a Ci_6 alkyl (group).

In the present specification, unless otherwise specified, examples of the "Ci_6 alkyl (group)" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 30 pentyl, isopentyl, neopentyl, hexyl and the like.

In the present specification, unless otherwise specified, the "optionally halogenated Ci_6 alkyl (group)" means a Ci_6 alkyl (group) optionally substituted by halogen atom(s), and examples thereof include trifluoromethyl and the like. 35 [0009] 19 WO 2011/163355 PCT/US2011/041443

In the present specification, unless otherwise specified, examples of the "alkenyl (group)" include a C2-6 alkenyl (group)

In the present specification, unless otherwise specified, examples of the "C2-6 alkenyl (group)" include vinyl, 1-propen- 1- yl, 2-propen-l-yl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5-hexen-l-yl and the like.

[0010]

In the present specification, unless otherwise specified, examples of the "alkynyl (group)" include a C2_6 alkynyl group. Examples of the "C2_6 alkynyl (group)" include ethynyl, 1-propyn-l-yl, 2-propyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl and the like.

In the present specification, unless otherwise specified, examples of the "C3-7 cycloalkyl-C2_6 alkynyl (group)" include cyclopropylethynyl and the like.

[0011]

In the present specification, unless otherwise specified, examples of the "C3-7 cycloalkyl (group)" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0012]

In the present specification, unless otherwise specified, examples of the "C6-i4 aryl (group)" include phenyl, 1-naphthyl, 2- naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like.

[0013]

In the present specification, unless otherwise specified, examples of the "C7-16 aralkyl (group)" include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like.

[0014]

In the present specification, unless otherwise specified, examples of the "C6-14 aryl-C2_6 alkenyl (group)" include styryl and the like. 20 WO 2011/163355 PCT/US2011/041443 [0015]

In the present specification, unless otherwise specified, examples of the "carbocycle having 5 or 6 carbon atoms" include a C5_6 cycloalkane (e.g., cyclopentane, cyclohexane), a C5_6 cycloalkene (e.g., cyclopentene, cyclohexene), a C5-6 cycloalkadiene (e.g., cyclopentadiene, cyclohexadiene) and a benzene ring.

In the present specification, unless otherwise specified, examples of the "C3-6 cycloalkane" include cyclopropane, cyclobutane, cyclohexane and cyclopentane.

[0016]

In the present specification, unless otherwise specified, examples of the "5- or 6-membered heterocycle" include a 5- or 6-membered heterocycle containing, besides carbon atoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples of the "5- or 6-membered heterocycle containing, besides carbon atoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom" include a pyrrolidine ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan ring, a 1,2,3-thiadiazole ring, a 1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a tetrazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring and the like.

In the present specification, unless otherwise specified, "heterocyclic group" (and the heterocyclic moiety of the substituent) is a non-aromatic heterocyclic group or a 21 WO 2011/163355 PCT/US2011/041443 heteroaryl group (i.e., an aromatic heterocyclic group), and examples thereof include a 3- to 14-membered heterocyclic group containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. The "heterocyclic 5 group" can be monocyclic, bicyclic or tricyclic.

In the present specification, unless otherwise specified, examples of the "3- to 14-membered heterocyclic group" include 3- to 14-membered aromatic heterocyclic groups containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom io and an oxygen atom, such as pyrrolyl (e.g., 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl., 3-thienyl) , pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4- 15 isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4- thiazolyl, 5-thiazolyl), triazolyl (e.g., 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 20 1,2,4-oxadiazol-5-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, isoindolyl (e.g., 1- 25 isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo[b]furanyl (e.g., 2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6- 30 benzo[b]furanyl, 7-benzo[b]furanyl), benzo[c]furanyl (e.g., 1-benzo[c]furanyl, 4-benzo[c]furanyl, 5-benzo[c]furanyl), benzo[b]thienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzo[c]thienyl (e.g., 1-benzo[c]thienyl, 4- 35 benzo[c]thienyl, 5-benzo[c]thienyl), indazolyl (e.g., 1- 22 WO 2011/163355 PCT/US2011/041443 indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6- indazolyl, 7-indazolyl), benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), 1,2-benzisoxazolyl (e.g., 1,2-benzisoxazol-3- 5 yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2- benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzoxazolyl (e.g., 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl 7- benzoxazolyl), 1,2-benzisothiazolyl (e.g., 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2- io benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,2- benzisothiazol-7-yl), benzothiazolyl (e.g., 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazol.yl, 7-benzothiazolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), quinolyl (e.g., 2- 15 quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6- 20 quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), pyrazolo[1,5-a]pyridyl (e.g., pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, 25 pyrazolo[1,5-a]pyridine-7-yl), imidazo[1,2-a]pyridyl (e.g., imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl) and the like; and 30 3- to 14-membered saturated or unsaturated non-aromatic heterocyclic groups containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as tetrahydrofuryl, oxazolidinyl, imidazolinyl (e.g., 1- imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl 35 (e.g., 1-aziridinyl, 2-aziridinyl), azetidinyl (e.g., 1- 23 WO 2011/163355 PCT/US2011/041443 azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl), azepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (e.g., 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl), azonanyl (e.g., 1-azonanyl, 2-azonanyl, 3-azonanyl, 4-azonanyl, 5-azonanyl), piperazinyl (e.g., 1,4-piperazin-l-yl, 1,4-piperazin-2-yl), diazepinyl (e.g., 1,4-diazepin-l-yl, 1,4-diazepin-2-yl, 1,.4-diazepin-5-yl, 1,4-diazepin-6-yl), diazocanyl (e.g., 1,4-diazocan-l-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl, 1,5-diazocan-l-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl (e.g., 4-morpholinyl), thiomorpholinyl (e.g., 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihydropyranyl, dihydroquinolyl, dihydroisoquinolyl (e.g., 3,4- dihydroisoquinolin-2-yl) and the like.

[0017]

In the present specification, unless otherwise specified, examples of the "aromatic heterocyclic group" (and the aromatic heterocyclic moiety of the substituent) include those similar to the "3- to 14-membered aromatic heterocyclic group containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom" exemplified above as the aforementioned "heterocyclic group".

[0018]

In the present specification, unless otherwise specified, examples of the "non-aromatic heterocyclic group" (and the non-aromatic heterocyclic moiety of the substituent) include those similar to the "3- to 14-membered saturated or unsaturated non-aromatic heterocyclic group containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom" exemplified above as the aforementioned "heterocyclic group".

[0019]

In the present specification, unless otherwise specified, 24 WO 2011/163355 PCT/US2011/041443 examples of the "saturated heterocyclic group" (and the saturated heterocyclic moiety of the substituent) include a saturated heterocyclic group, from among the aforementioned "non-aromatic heterocyclic groups", and specific examples thereof include tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidyl, pyrrolidinyl, piperazinyl and the like.

In the present specification, unless otherwise specified, examples of the "5- or 6-membered saturated heterocyclic group" (and the 5- or 6-membered saturated heterocyclic moiety of the substituent) include a 5- or 6-membered saturated heterocyclic group, from among the aforementioned "saturated heterocyclic groups".

[0020]'

In the present specification, unless otherwise specified, examples of the "alkoxy (group)" include a Ci_6 alkoxy (group).

In the present specification, unless otherwise specified, examples of the "Ci_6 alkoxy (group)" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

[0021]

In the present specification, unless otherwise specified, examples of the "C3_7 cycloalkyloxy (group)" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

[0022]

In the present specification, unless otherwise specified, examples of the "C6-14 aryloxy (group)" include phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like.

[0023]

In the present specification, unless otherwise specified, examples of the "C7.-16 aralkyloxy (group)" include benzyloxy, phenethyloxy and the like.

[0024]

In the present specification, unless otherwise specified, examples of the "alkyl-carbonyloxy (group)" include a Ci_6 25 WO 2011/163355 PCT/US2011/041443 alkyl-carbonyloxy (group).

In the present specification, unless otherwise specified, examples of the "Ci-g alkyl-carbonyloxy (group)" include acetoxy, propionyloxy and the like.

[0025]

In the present specification, unless otherwise specified, examples of the "alkoxy-carbonyloxy (group)" include a Ci-e alkoxy-carbonyloxy (group).

In the present specification, unless otherwise specified, examples of the "Ci_g alkoxy-carbonyloxy (group)" include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like.

[0026]

In the present specification, unless otherwise specified, examples of the "mono-alkyl-carbamoyloxy (group)" include a mono-Ci-6 alkyl-carbamoyloxy (group) .

In the present specification, unless otherwise specified, examples of the "mono-Ci_6 alkyl-carbamoyloxy (group)" include methylcarbamoyloxy, ethylcarbamoyloxy and the like.

[0027]

In the present specification, unless otherwise specified, examples of the "di-alkyl-carbamoyloxy (group)" include a di-Ci_6 alkyl-carbamoyloxy (group) .

In the present specification, unless otherwise specified, examples of the "di-Ci_6 alkyl-carbamoyloxy (group)" include dimethylcarbamoyloxy, diethylcarbamoyloxy and the like.

[0028]

In the present specification, unless otherwise specified, examples of the "C6-i4 aryl-carbonyloxy (group)" include benzoyloxy, naphthylcarbonyloxy and the like.

[0029]

In the present specification, unless otherwise specified, examples of the "mono- or di-C6-i4 aryl-carbamoyl (group)" include phenylcarbamoyl, naphthylcarbamoyl and the like.

[0030] 26 WO 2011/163355 PCT/US2011/041443

In the present specification, unless otherwise specified, examples of the "mono- or di-C6-i4 aryl-carbamoyloxy (group)" include phenylcarbamoyloxy, naphthylcarbamoyloxy and the like. [0031]

In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the "heterocyclyl-oxy (group)" include those similar to the aforementioned "heterocyclic group". Specific examples of the "heterocyclyl-oxy (group)" include a 5- to 14-membered heterocyclyl-oxy (group) containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0032] '

In the present specification, unless otherwise specified, examples of the aromatic heterocyclic moiety of the "aromatic heterocyclyl-oxy (group)" include those similar to the "aromatic heterocyclic group" exemplified as the aforementioned "heterocyclic group". Specific examples of the "aromatic heterocyclyl-oxy (group)" include a 3- to 14-membered aromatic heterocyclyl-oxy containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0033]

In the present specification, unless otherwise specified, examples of the "Ci_6 alkylsulfonyloxy group" include methylsulfonyloxy, ethylsulfonyloxy and the like.

[0034]

In the present specification, unless otherwise specified, examples of the "halogeno Ci_6 alkylsulfonyloxy group" include halogenomethylsulfonyloxy, halogenoethylsulfonyloxy and the like.

[0035]

In the present specification, unless otherwise specified, examples of the "alkylsulfanyl (group) " include a Ci-g alkylsulfanyl (group).

In the present specification, unless otherwise specified, 27 WO 2011/163355 PCT/US2011/041443 examples of the "Ci-6 alkylsulfanyl (group)" include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl and the like. 5 [0036]

In the present specification, unless otherwise specified, examples of the "C3-7 cycloalkylsulfanyl (group)" include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl and the like. io [0037]

In the present specification, unless otherwise specified, examples of the "C6-i4 arylsulfanyl (group)" include phenylsulfanyl, 1-naphthylsulfanyl, 2-naph’thylsulfanyl and the like. is [0038]

In the present specification, unless otherwise specified, examples of the "C7_i6 aralkylsulfanyl (group)" include benzylsulfanyl, phenethylsulfanyl and the like.

[0039] ___________________ 20 In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the "heterocyclyl-sulfanyl (group)" include those similar to the aforementioned "heterocyclic group". Specific examples of the "heterocyclyl-sulfanyl (group)" include a 3- to 14-membered heterocyclyl- 25 sulfanyl (group) containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0040]

In the present specification, unless otherwise specified, examples of the "alkyl-carbonyl (group)" include a Ci_6 alkyl- 30 carbonyl.

In the present specification, unless otherwise specified, examples of the "Ci_6 alkyl-carbonyl (group)" include acetyl, propionyl, pivaloyl and the like.

[0041] 35 In the present specification, unless otherwise specified, 28 WO 2011/163355 PCT/US2011/041443 examples of the "C3-7 cycloalkyl-carbonyl (group)" include cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.

[0042]

In the present specification, unless otherwise specified, examples of the "C6-14 aryl-carbonyl (group)" include benzoyl, 1- naphthoyl, 2-naphthoyl and the like.

[0043]

In the present specification, unless otherwise specified, examples of the "C7-16 aralkyl-carbonyl (group)" include phenylacetyl, 3-phenylpropionyl and the like.

[0044]

In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the "heterocyclyl-carbonyl (group)" include those similar to the above-mentioned "heterocyclic group". Specific examples thereof include a 3-to 14-membered heterocyclyl-carbonyl (group) containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. More specific examples thereof include picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2- furoyl, 3-furoyl, 4-morpholinylcarbonyl, 4- thiomorpholinylcarbonyl, aziridin-l-ylcarbonyl, aziridin-2-ylcarbonyl, azetidin-l-ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-l-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin- 3- ylcarbonyl, piperidin-l-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, azepan-l-ylcarbonyl, azepan-2-ylcarbonyl, azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl, azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-4-ylcarbonyl, 1,4-piperazin-l-ylcarbonyl, 1,.4-piperazin-2-ylcarbonyl, 1,4-diazepan-l-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl, 1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl, 1,4-diazocan-l-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl, 1,4-diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl, 1,5-diazocan-l-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl, 1,5-diazocan-3-ylcarbonyl and the like. 29 WO 2011/163355 PCT/US2011/041443 [0045]

In the present specification, unless otherwise specified, examples of the "optionally esterified carboxy (group)" include carboxy, optionally substituted alkoxy-carbonyl, optionally substituted C6-14 aryloxy-carbonyl, optionally substituted C7-i6 aralkyloxy-carbonyl, optionally substituted silyloxy-carbonyl (e.g., trimethylsilyloxycarbonyl (TMS-O-CO-), triethylsilyloxycarbonyl (TES-O-CO-, tert- butyldimethylsilyloxycarbonyl (TBS-O-CO-), triisopropylsilyloxycarbonyl (TIPS-O-CO-), tert- butyldiphenylsilyloxycarbonyl (TBDPS-O-CO-)) and the like.

[0046]

In the present specification, unless otherwise specified, examples of the "alkoxy-carbonyl (group)" include a Ci_6 alkoxycarbonyl (group).

In the present specification, unless otherwise specified, examples of the "Ci-6 alkoxy-carbonyl (group)" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertbutoxycarbonyl and the like.

[0047]

In the present specification, unless otherwise specified, examples of the "C6-i4 aryloxy-carbonyl (group)" include phenoxycarbonyl and the like.

In the present specification, unless otherwise specified, examples of the "C7-16 aralkyloxy-carbonyl (group)" include benzyloxycarbonyl, phenethyloxycarbonyl and the like.

[0048]

In the present specification, unless otherwise specified, examples of the "alkylsulfonyl (group)" include a Ci_6 alkylsulfonyl (group).

In the present specification, unless otherwise specified, examples of the "Ci_6 alkylsulfonyl (group)" include methylsulfonyl, ethylsulfonyl and the like.

[0049]

In the present specification, unless otherwise specified, 30 WO 2011/163355 PCT/US2011/041443 examples of the "C3-7 cycloalkylsulfonyl (group)" include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.

[0050] 5 In the present specification, unless otherwise specified, examples of the "C6-14 arylsulfonyl (group)" include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.

[0051] 10 In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the "heterocyclyl-sulfonyl (group)" include those similar to the aforementioned "heterocyclic group". Specific examples of the "heterocyclyl-sulfonyl (group)" include a 3- to 14-membered heterocyclyl- 15 sulfonyl (group) containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0052]

In the present specification, unless otherwise specified, examples of the "alkylsulfinyl (group)" include a Ci_6 20 alkylsulfinyl (group).

In the present specification, unless otherwise specified, examples of the "C1-6 alkylsulfinyl (group)" include methylsulfinyl, ethylsulfinyl and the like.

[0053] 25 In the present specification, unless otherwise specified, examples of the "C3-7 cycloalkylsulfinyl (group)" include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and the like.

[0054] 30 In the present specification, unless otherwise specified, examples of the "Cg-u arylsulfinyl (group)" include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.

[0055] 35 In the present specification, unless otherwise specified, 31 WO 2011/163355 PCT/US2011/041443 examples of the heterocyclic moiety of the "heterocyclyl-sulfinyl (group)" include those similar to the aforementioned "heterocyclic group". Specific examples of the "heterocyclyl-sulfinyl (group)" include a 3- to 14-membered heterocyclyl-sulfinyl (group) containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0056]

In the present specification, unless otherwise specified, examples of the "alkyl-carbamoyl (group)" include a mono- or di-Ci-6 alkyl-carbamoyl.

In the present specification, unless otherwise specified, examples of the "mono- or di-Ci-6 alkyl-carbamoyl (group)" include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like.

[0057]

In the present specification, unless otherwise specified, examples of the "mono- or di-alkylamino (group)" include a mono- or di-Ci-6 alkylamino (group) .

In the present specification, unless otherwise specified, examples of the "mono- or di-Ci_6 alkylamino (group)" include methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like.

[0058]

In the present specification, unless otherwise specified, examples of the "alkyl-carbonylamino (group)" include a mono-or di-Ci-6 alkyl-carbonylamino.

In the present specification, unless otherwise specified, examples of the "mono- or di-Ci-6 alkyl-carbonylamino (group)" include acetylamino, propionylamino, pivaloylamino and the like.

[0059]

In the present specification, unless otherwise specified, examples of the "heterocyclyl (group)" of the "heterocyclyl- amino (group)" include those similar to the above-mentioned "heterocyclic group". Examples of the "heterocyclyl-amino 32 WO 2011/163355 PCT/US2011/041443 (group)" include 2-pyridyl-amino and the like.

[0060]

In the present specification, unless otherwise specified, examples of the "heterocyclyl-carbonyl" of the "heterocyclyl- 5 carbonylamino (group)" include those similar to the above-mentioned "heterocyclyl-carbonyl". Examples of the "heterocyclyl-carbonylamino (group)" include pyridyl-carbonyl amino .

[0061] io In the present specification, unless otherwise specified, examples of the "heterocyclyl (group)" of the "heterocyclyl-oxycarbonylamino (group)" include those similar to the above-mentioned "heterocyclic group". Examples of the "heterocyclyl-oxycarbonylamino (group)" include 2-pyridyl-oxycarbonylamino. 15 [0062]

In the present specification, unless otherwise specified, examples of the "heterocyclyl (group)" of the "heterocyclyl-sulfonylamino (group)" include those similar to the above-mentioned "heterocyclic group". Examples of the "heterocyclyl- 20 sulfonylamino (group)" include 2-pyridyl-sulfonylamino and the like.

[0063]

In the present specification, unless otherwise specified, examples of the "alkoxy-carbonylamino (group)" include a Ci_6 25 alkoxy-carbonylamino (group).

In the present specification, unless otherwise specified, examples of the "Ci_6 alkoxy-carbonylamino (group)" include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like. 30 [0064]

In the present specification, unless otherwise specified, examples of the "alkylsulfonylamino (group)" include a Ci_6 alkylsulfonylamino (group).

In the present specification, unless otherwise specified, 35 examples of the "Ci_6 alkylsulfonylamino (group)" include 33 WO 2011/163355 PCT/US2011/041443 methylsulfonylamino, ethylsulfonylamino and the like.

[0065]

In the present specification, unless otherwise specified, examples of the "mono- or di-C3_7 cycloalkylamino (group)" 5 include cyclopropylamino, cyclopentylamino, cyclohexylamino and the like.

[0066]

In the present specification, unless otherwise specified, examples of the "C3_7 cycloalkyl-carbonylamino (group)" include io cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like.

[0067]

In the present specification, unless otherwise specified, examples of the "C3_8 cycloalkoxy-carbonylamino (group)" include 15 cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxycarbonylamino and the like.

[0068]

In the present specification, unless otherwise specified, examples of the "C3_8 cycloalkylsulfonylamino (group)" include 20 cyclopropylsulfonylamino, cyclopentylsulfonylamino, cyclohexylsulfonylamino and the like.

[0069]

In the present specification, unless otherwise specified, examples of the "mono- or di-C6-i4 arylamino (group) " include 25 phenylamino, diphenylamino and the like.

[0070]

In the present specification, unless otherwise specified, examples of the "mono- or di-C7_i6 aralkylamino (group)" include benzylamino and the like. so [0071]

In the present specification, unless otherwise specified, examples of the "Οε-κ aryl-carbonylamino (group)" include benzoylamino, naphthoylamino and the like.

[0072] 35 In the present specification, unless otherwise specified, 34 WO 2011/163355 PCT/US2011/041443 examples of the "C6-i4 arylsulfonylamino (group)" include phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like.

[0073] 5 [Substituent Group A] (1) a halogen atom; (2) nitro; (3) cyano; (4) an optionally esterified carboxy group; io (5) an optionally substituted alkyl group; (6) an optionally substituted alkenyl group; (7) an optionally substituted alkynyl group (e.g., an optionally substituted C3-7 cycloalkyl-C2-6 alkynyl group); (8) an optionally substituted C3-7 cycloalkyl group; 15 (9) an optionally substituted C6-14 aryl group; (10) an optionally substituted C7_i6 aralkyl group; (11) an optionally substituted C6-i4 aryl-C2-6 alkenyl group; (12) an optionally substituted heterocyclic group; (13) a hydroxy group; 20 (14) an optionally substituted alkoxy group; (15) an optionally substituted C3-7 cycloalkyloxy group; (16) an optionally substituted C6-i4 aryloxy group; (17) an optionally substituted C7_i6 aralkyloxy group; (18) an optionally substituted alkyl-carbonyloxy group; 25 (19) an optionally substituted alkoxy-carbonyloxy group; (20) an optionally substituted mono-alkyl-carbamoyloxy group; (21) an optionally substituted di-alkyl-carbamoyloxy group; (22) an optionally substituted C6-14 aryl-carbonyloxy group; (23) an optionally substituted mono- or di-C6-i4 aryl-30 carbamoyloxy group; (24) an optionally substituted heterocyclyl-oxy group (e.g., an optionally substituted aromatic heterocyclyl-oxy group); (25) an optionally substituted Ci_6 alkylsulfonyloxy group (e.g an optionally substituted halogeno Ci_6 alkylsulfonyloxy group) 35 (26) a mercapto group; 35 WO 2011/163355 PCT/US2011/041443 (27) an optionally substituted alkylsulfanyl group; (28) an optionally substituted C3_7 cycloalkylsulfanyl group; (29) an optionally substituted C6~i4 arylsulfanyl group; (30) an optionally, substituted C7_i6 aralkylsulfanyl group; (31) an optionally substituted heterocyclyl-sulfanyl group; (32) a formyl group; (33) an optionally substituted alkyl-carbonyl group; (34) an optionally substituted C3_7 cycloalkyl-carbonyl group; (35) an optionally substituted C6-i4 aryl-carbonyl group; (36) an optionally substituted C7_i6 aralkyl-carbonyl group; (37) an optionally substituted heterocyclyl-carbonyl group; (38) an optionally substituted alkylsulfonyl group; (39) an optionally substituted C3_7 cycloalkylsulfonyl group; (40) an optionally substituted C6-i4 arylsulfonyl group; (41) an optionally substituted heterocyclyl-sulfonyl group; (42) an optionally substituted alkylsulfinyl group; (43) an optionally substituted C3_7 cycloalkylsulfinyl group; (44) an optionally substituted C6-i4 arylsulfinyl group; (45) an optionally substituted heterocyclyl-sulfinyl group; (46) a sulfo group; (47) a sulfamoyl group; (48) a sulfinamoyl group; (49) a sulfenamoyl group; (50) a thiocarbamoyl group; (51) an optionally substituted carbamoyl group [e.g., an optionally substituted alkyl-carbamoyl and the like]; (52) an optionally substituted amino group [e-g., amino, an optionally substituted mono- or di-alkylamino group, an optionally substituted mono- or di-C3_7 cycloalkylamino group, an optionally substituted mono- or di-C6-i4 arylamino group, an optionally substituted mono- or di-C7_i6 aralkylamino group, an optionally substituted heterocyclyl-amino group, an optionally substituted C6-i4 aryl-carbonylamino group, 36 WO 2011/163355 PCT/US2011/041443 a formylamino group, an optionally substituted alkyl-carbonylamino group (e.g., a mono- (Ci_6 alkyl-carbonyl)-amino group), an optionally substituted C3_7 cycloalkyl-carbonylamino group, 5 an optionally substituted heterocyclyl-carbonylamino group, an optionally substituted alkoxy-carbonylamino group, an optionally substituted C3-8 cycloalkoxy-carbonylamino group, an optionally substituted heterocyclyl-oxycarbonylamino group, an optionally substituted carbamoylamino group, 10 an optionally substituted alkylsulfonylamino group, an optionally substituted C3_8 cycloalkylsulfonylamino group, an optionally substituted heterocyclyl-sulfonylamino group, an optionally substituted C6-i4 arylsulfonylamino group] ; (53) an optionally substituted alkoxy-carbonyl group; 15 (54) an optionally substituted C6-14 aryloxy-carbonyl group; (55) an optionally substituted C7-16 aralkyloxy-carbonyl group. [0074]

The number of the substituents is preferably 0 (i.e., unsubstituted), or 1 or 2. 20 The number of the substituents is more preferably 0 (i.e., unsubstituted).

[0075]

Among Substituent Group A, examples of the substituent of the "optionally substituted alkoxy-carbonyl group", 25 "optionally substituted alkyl group", "optionally substituted alkenyl group", "optionally substituted alkynyl group", "optionally substituted alkoxy group", "optionally substituted alkyl-carbonyloxy group", 30 "optionally substituted alkoxy-carbonyloxy group", "optionally substituted mono-alkyl-carbamoyloxy group", "optionally substituted di-alkyl-carbamoyloxy group", "optionally substituted C1-6 alkylsulfonyloxy group" "optionally substituted halogeno Ci_6 alkylsulfonyloxy group", 35 "optionally substituted alkylsulfanyl group", 37 WO 2011/163355 PCT/US2011/041443 "optionally substituted alkyl-carbonyl group", "optionally substituted alkylsulfonyl group", "optionally substituted alkylsulfinyl group", "optionally substituted alkyl-carbamoyl group", "optionally substituted mono- or di-alkylamino group", "optionally substituted alkyl-carbonylamino group", "optionally substituted mono-(Ci_6 alkyl-carbonyl)-amino group", "optionally substituted alkoxy-carbonylamino group" and "optionally substituted alkylsulfonylamino group" include substituents selected from the following Substituent Group B. The number of the substituents is 1 to the maximum substitutable number, more preferably 1 to 3.

[0076]

Among Substituent Group A, examples of the substituent of the "optionally substituted Ce-14 aryloxy-carbonyl group", "optionally substituted C7-16 aralkyloxy-carbonyl group", "optionally substituted C3-7 cycloalkyl-C2-6 alkynyl group", "optionally substituted C3-7 cycloalkyl group", "optionally substituted C6-14 aryl group", "optionally substituted C7-16 aralkyl group", "optionally substituted C6-i4 aryl-C2-6 alkenyl group", "optionally substituted heterocyclic group", "optionally substituted C3-7 cycloalkyloxy group", "optionally substituted C6-14 aryloxy group", "optionally substituted C7-i6 aralkyloxy group", "optionally substituted C6-i4 aryl-carbonyloxy group", "optionally substituted mono- or di-Cg-i4 aryl-carbamoyloxy group", "optionally substituted heterocyclyl-oxy group", "optionally substituted aromatic heterocyclyl-oxy group", "optionally substituted 03-7 cycloalkylsulfanyl group", "optionally substituted C6-14 arylsulfanyl group", "optionally substituted C7-16 aralkylsulfanyl group", "optionally substituted heterocyclyl-sulfanyl group", "optionally substituted ¢3-7 cycloalkyl-carbonyl group", 38 WO 2011/163355 PCT/US2011/041443 "optionally substituted C6-i4 aryl-carbonyl group", "optionally substituted C7_i6 aralkyl-carbonyl group", "optionally substituted heterocyclyl-carbonyl group", "optionally substituted C3_7 cycloalkylsulfonyl group", 5 "optionally substituted C6-i4 arylsulfonyl group", "optionally substituted heterocyclyl-sulfonyl group", "optionally substituted C3_7 cycloalkylsulfinyl group", "optionally substituted C6-14 arylsulfinyl group", "optionally substituted heterocyclyl-sulfinyl group", 10 "optionally substituted carbamoyl group", "optionally substituted amino group", "optionally substituted mono- or di-C3-7 cycloalkylamino group", "optionally substituted mono- or di-C6-i4 arylamino group", "optionally substituted mono- or di-C7_i6 aralkylamino group", 15 "optionally substituted heterocyclyl-amino group", "optionally substituted C6-i4 aryl-carbonylamino group", "optionally substituted C3_B cycloalkyl-carbonylamino group", "optionally substituted heterocyclyl-carbonylamino group", "optionally substituted C3_8 cycloalkoxy-carbonylamino group", 20 "optionally substituted heterocyclyl-oxycarbonylamino group", "optionally substituted carbamoylamino group", "optionally substituted C3_8 cycloalkylsulfonylamino group", "optionally substituted heterocyclyl-sulfonylamino group" and "optionally substituted C6-i4 arylsulfonylamino group" include 25 substituents selected from the following Substituent Group B and the following Substituent Group B'. The number of the substituents is 1 to the maximum substitutable number, more preferably 1 to 3, further more preferably 1.

[0077]

30 In the present specification, Substituent Group B consists of (a) a halogen atom; (b) a hydroxy group; (c) a nitro group; 35 (d) a cyano group; 39 WO 2011/163355 PCT/US2011/041443 (e) an optionally substituted C6-i4 aryl group (the C6-i4 aryl group is optionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, optionally halogenated Ci_6 alkyl by 1 to 5 3 halogen atoms, mono- or di-Ci-g alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_i6 aralkylamino, C3-7 cycloalkyl, Ci_6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3_7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, Ci_6 alkoxy-carbonyl, C6-14 aryloxy-carbonyl, C7_i6 aralkyloxy-carbonyl, Ci_6 io alkylsulfanyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-14 aryl-carbamoyl and the like); (f) an optionally substituted C6-i4 aryloxy group (the Ce-14 aryloxy group is optionally substituted by 1 to 5 (preferably 15 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, optionally halogenated Ci_6 alkyl by 1 to 3 halogen atoms, mono- or di-Ci_6 alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_i6 aralkylamino, C3_7 cycloalkyl, Ci-6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3_7 20 cycloalkyl-carbonyl, Ce-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, Ci_6 alkoxy-carbonyl, C6-14 aryloxy-carbonyl, C7_i6 aralkyloxy-carbonyl, Ci_6 alkylsulfanyl, Ci_6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-i4 aryl-carbamoyl and the like) ; 25 (g) an optionally substituted C7_i6 aralkyloxy group (the C7_i6 aralkyloxy group is optionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, optionally halogenated Ci_6 alkyl by 1 to 3 halogen atoms, mono- or di-Ci_6 30 alkylamino, mono- or di-C6_i4 arylamino, mono- or di-C7_i6 aralkylamino, C3_7 cycloalkyl, Ci_6 alkoxy, formyl, Ci_6 alkyl- carbonyl, C3~7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, Ci-e alkoxy-carbonyl, C6-i4 aryloxy-carbonyl, C7-i6 aralkyloxy-carbonyl, Ci-6 alkylsulfanyl, Ci_6 alkylsulfinyl, 35 C1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci-6 40 WO 2011/163355 PCT/US2011/041443 alkyl-carbamoyl, mono- or di-Cg-u aryl-carbamoyl and the like); (h) an optionally substituted 5- to 10-membered heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g., furyl, pyridyl, 5 thienyl, 1-pyrrolidinyl, 1-piperidyl, 4-piperidyl, piperazinyl 1-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, 1-azocanyl, 1-azonanyl, 3,4-dihydroisoquinolin-2-yl and the like) (the heterocyclic group is optionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected io from a halogen atom, hydroxy, cyano, amino, optionally halogenated Ci_6. alkyl by 1 to 3 halogen atoms, mono- or di-Ci_6 alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_i6 aralkylamino, C3_7 cycloalkyl, Ci_g alkoxy, formyl, Cx-6 alkyl-carbonyl, C3-7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 15 aralkyl-carbonyl, Ci_6 alkoxy-carbonyl, C6-i4 aryloxy-carbonyl, C7-i6 aralkyloxy-carbonyl, Ci_6 alkylsulfanyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-i4 aryl-carbamoyl and the like) ; (i) an optionally substituted amino group [e.g., an amino 20 group optionally substituted by 1 or 2 substituent (s) selected from the group consisting of Ci_6 alkyl, C2-6 alkenyl, C6-14 aryl, C7_i6 aralkyl, a heterocyclic group and heterocyclyl-alkyl (the Ci_6 alkyl, C2-6 alkenyl, Cg-i4 aryl, C7_i6 aralkyl, heterocyclic group and heterocyclyl-alkyl are each optionally substituted 25 by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, C1-6 alkyl optionally halogenated by 1 to 3 halogen atoms (which is not a substituent for alkyl and alkenyl), mono- or di-Ci_6 alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_i6 aralkylamino, C3-7 30 cycloalkyl, C1-6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3_7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, C1-6 alkoxy-carbonyl, C3_7 cycloalkyloxy-carbonyl, C6-i4 aryloxy- carbonyl, C7-i6 aralkyloxy-carbonyl, C1-6 alkylsulfanyl, C3_7 cycloalkylsulfanyl, Ci_e alkylsulfinyl, C3_7 cycloalkylsulfinyl, 35 C1-6 alkylsulfonyl, C3_7 cycloalkylsulfonyl, carbamoyl, 41 WO 2011/163355 PCT/US2011/041443 thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6_ 14 aryl-carbamoyl and the like). Examples of the "heterocyclic group" and the "heterocyclyl-" of the "heterocyclyl-alkyl" include those similar to the above-mentioned "heterocyclic group"]; (j) C3-7 cycloalkyl; (k) an optionally substituted Ci_6 alkoxy group (the Ci_6 alkoxy group is optionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, amino, mono- or di-Ci-6 alkylamino, mono- or di-C6-i4 arylamino, C3-7 cycloalkyl, Ci_6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3-7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, Ci-g alkoxy-carbonyl, C6_i4 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, Ci_6 alkylsulfanyl, Ci_6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-i4 aryl-carbamoyl, trimethylsilyl (TMS) and the like); (l) a formyl group; (m) a C1-6 alkyl-carbonyl group (e.g., acetyl); (n) a C3-7 cycloalkyl-carbonyl group; (0) a C6-14 aryl-carbonyl group; (p) a C7_i6 aralkyl-carbonyl group; (q) a C1-6 alkoxy-carbonyl group; (r) a C6-14 aryloxy-carbonyl group; (s) a C7-16 aralkyloxy-carbonyl group; (t) a C1-6 alkylsulfanyl group; (u) a C1-6 alkylsulfinyl group; (v) a C1-6 alkylsulfonyl group; (w) a carbamoyl group; (x) a thiocarbamoyl group; (y) a mono-Ci_6 alkyl-carbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl and the like); (z) a di-Ci_6 alkyl-carbamoyl group (e.g.,. dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like); (aa) a mono- or di-C6-i4 aryl-carbamoyl group (e.g., 42 WO 2011/163355 PCT/US2011/041443 phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like); (bb) a mono- or di-(5- to 7-membered heterocyclyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom 5 and an oxygen atom)-carbamoyl group (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like); and (cc) a Ci_6 alkyl-carbonyloxy group (e.g., acetoxy and the like).

[0078] io In the present specification, Substituent Group B' consists of (a) an optionally substituted Ci_6 alkyl group (the Ci_6 alkyl group is optionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1) substituents selected from a halogen atom, 15 hydroxy, cyano, amino, mono- or di-Ci_6 alkylamino, mono- or di- C6-14 arylamino, mono- or di-C7_i6 aralkylamino, C3_7 cycloalkyl, Ci-6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3_7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, Ci_6 alkoxy-carbonyl, Ce-14 aryloxy-carbonyl, C7_i6 aralkyloxy-carbonyl, Ci_6 20 alkylsulfanyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl,' carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-14 aryl-carbamoyl and the like); (b) an optionally substituted C2-6 alkenyl group (the C2-6 alkenyl group is optionally substituted by 1 to 5 (preferably 25 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, mono- or di-Ci_6 alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_i6 aralkylamino, C3_7 cycloalkyl, Ci_6 alkoxy, formyl, Ci_6 alkyl-carbonyl, C3_7 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7_i6 aralkyl-carbonyl, 30 C1-6 alkoxy-carbonyl, C6-14 aryloxy-carbonyl, C7_i6 aralkyloxy-carbonyl, C1-6 alkylsulfanyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl, carbamoyl, thiocarbamoyl·, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-C6-i4 aryl-carbamoyl and the like) ; and (c) an optionally substituted C2-e alkynyl group (the C2_6 35 alkynyl group is optionally substituted by 1 to 5 (preferably 43 WO 2011/163355 PCT/US2011/041443 1 to 3, more preferably 1) substituents selected from a halogen atom, hydroxy, cyano, amino, mono- or di-Ci_6 alkylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_is aralkylamino, C3_7 cycloalkyl, Ci_6 alkoxy, formyl, Ci-6 alkyl-carbonyl, C3_7 cycloalkyl-carbonyl, C6_i4 aryl-carbonyl, C7-ie aralkyl-carbonyl, Ci_6 alkoxy-carbonyl, C6-i4 aryloxy-carbonyl, C7_i6 aralkyloxy-carbonyl, Ci_6 alkylsulfanyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_6 alkyl-carbamoyl, mono- or di-Cg-i4 aryl-carbamoyl and the like) .

[0079]

Each symbol in formula (I) is explained in the following.

[0080]

Ring A is an optionally substituted 6-membered ring.

Any one or two of Z1 to Z4, which are ring A-constituting atoms, is(are) -N=, and the others are -CH=. That is, the "6-membered ring" of the "optionally substituted 6-membered ring" for ring A is a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring, preferably a pyridine ring or a pyrimidine ring.

Preferably, Z1 or Z2 is -N= and the others are -CH=; or Z1 and Z3 are -N= and the others are -CH=.

More preferably, Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; or Z1 and Z3 are -N= and the others (i.e., Z2 and Z4) are -CH=.

Particularly preferably, Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=.

[0081]

The nitrogen atom of -N= for Z1 to Z4 may be oxidized.

For example, when Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are each -CH=, a compound represented by the formula: 44 PCT/US2011/041443 WO 2011/163355

wherein each symbol is as defined above, is also encompassed in the compound represented by the formula (I). Particularly, when Z1 is -N=, the nitrogen atom of -N= for Z1 is preferably oxidized.

[0082]

Examples of the substituent of the "optionally substituted 6-membered ring" for ring A include substituents selected from the above-mentioned Substituent Group A.

Among them, a halogen atom, cyano, an optionally substituted alkyl group, an optionally substituted alkoxy group and the like are preferable, a halogen atom, cyano, an optionally substituted Ci_6 alkyl group and an optionally substituted Ci_6 alkoxy group are more preferable, a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, a Ci_6 alkyl group (preferably methyl) optionally substituted by 1 to 3 substituents selected from the group consisting of (1) a halogen atom (preferably a fluorine atom) , (2) hydroxy and (3) a Ci_6 alkyl-carbonyloxy group (preferably acetoxy), and a Ci_6 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) are further more preferable, and a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, methyl, hydroxymethyl, acetoxymethyl, trifluoromethyl, methoxy, difluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy are particularly preferable.

The number of the substituents of the "optionally 45 WO 2011/163355 PCT/US2011/041443 substituted 6-membered ring" for ring A is 0 (i.e., unsubstituted), or 1 to 3, preferably 0, or 1 to 2, more preferably 0 or 1. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

[0083]

Ring A is preferably a pyridine ring or a pyrimidine ring, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, cyano, an optionally substituted alkyl group and an optionally substituted alkoxy group [preferably a halogen atom, cyano, an optionally substituted Ci_6 alkyl group and an optionally substituted Ci_6 alkoxy group, more preferably a halogen atom (preferably a chlorine atom, a fluorine atom) , cyano, a Ci_6 alkyl group (preferably methyl) optionally substituted by 1 to 3 substituents selected from the group consisting of (1) a halogen atom (preferably a fluorine atom), (2) hydroxy, and (3) a Ci_6 alkyl-carbonyloxy group (preferably acetoxy), and a Ci_6 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom), further more preferably a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, methyl, trifluoromethyl, hydroxymethyl, acetoxymethyl, methoxy, difluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy, further more preferably a fluorine atom, methyl, hydroxymethyl and methoxy].

[0084]

In another embodiment, ring A is preferably (1) a pyridine ring which is optionally substituted by one substituent selected from (i) a Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy and a Ci_6 alkyl-carbonyloxy group (preferably methyl, trifluoromethyl, acetoxymethyl, hydoroxymethyl), (ii) a halogen atom (preferably chlorine, fluorine), (iii) cyano, and (iv) a Ci_4 alkoxy group optionally substituted by 1 to 3 halogen atoms (preferably methoxy, difluoromethoxy, 46 WO 2011/163355 PCT/US2011/041443 difluoroethoxy, trifluoroethoxy) [preferably a pyridine ring which is optionally substituted by (1) a pyridine ring which is optionally substituted by one substituent selected from (i) a Ci_6 alkyl group optionally 5 substituted by 1 to 3 substituents selected from a halogen atom and hydroxy (preferably methyl, trifluorometyl, hydroxymethyl), (ii) a halogen atom (preferably chlorine, fluorine) , (iii) cyano, and (iv) a C1-4 alkoxy optionally substituted by 1 to 3 halogen atoms (preferably methoxy, 10 difluoromethoxy, difluoroethoxy, trifluoroethoxy)], or (2) a pyrimidine ring.

[0085] Y is an oxygen atom, a sulfur atom, an optionally substituted methylene group or -NRC-. 15 [0086]

Examples of the substituent of the "optionally substituted methylene group" for Y include substituents selected from the above-mentioned Substituent Group A.

Among them, an optionally substituted alkyl group and the 20 like are preferable.

The number of the substituents of the "optionally substituted methylene group" for Y is 0 (i.e., unsubstituted), 1 or 2. When the number of the substituents is 2, the respective substituents may be the same or different. 25 The "alkyl group" of the "optionally substituted alkyl group" exemplified as the substituent of the "optionally substituted methylene group" for Y is preferably a Ci_6 alkyl group (preferably methyl) or the like.

As the substituent of the "optionally substituted alkyl 30 group" exemplified as the substituent of the "optionally substituted methylene group" for Y, a halogen atom, a hydroxy group, a C3-7 cycloalkyl group, an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci_6 alkoxy group), a Ci_6 alkoxy-carbonyl group and the like are preferable. 35 The number of the substituents of the "optionally 47 WO 2011/163355 PCT/US2011/041443 substituted alkyl group" exemplified as the substituent of the "optionally substituted methylene group" for Y is preferably 0 (i.e., unsubstituted), or 1 to 5, particularly preferably 0 (i.e., unsubstituted). When the number of the substituents is not less than 2, the respective substituents may be the same or different.

When the number of the substituents of the "optionally substituted methylene group" for Y is 2, these two substituents optionally form, together with the adjacent carbon atom, an optionally substituted C3-6 cycloalkane (preferably cyclobutane).

As the substituent of the "optionally substituted C3-6 cycloalkane", a halogen atom, a hydroxy group, a C3-7 cycloalkyl group, an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci-6 alkoxy group) , a Ci_6 alkoxy-carbonyl group and the like are preferable.

The number of the substituents of the "optionally substituted C3-6 cycloalkane" is preferably 0 (i.e., unsubstituted), or 1 to 5, particularly preferably 0 (i.e., unsubstituted). When the number of the substituents is not less than 2, the respective substituents may be the same or different.

[0087]

Rc is a hydrogen atom or a substituent.

[0088]

Examples of the substituent for Rc include substituents selected from the above-mentioned Substituent Group A.

Among them, an optionally substituted alkyl group, an optionally substituted C3-7 cycloalkyl group and the like are preferable.

The "alkyl group" of the "optionally substituted alkyl group" exemplified as the substituent for Rc is preferably a Ci_ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) or the like.

As the substituent of the "optionally substituted alkyl 48 WO 2011/163355 PCT/US2011/041443 group" exemplified as the substituent for Rc, a halogen atom (preferably a fluorine atom) , a hydroxy group, a C3-7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., methoxy, ethoxy, a trimethylsilyl-Ci_6 5 alkoxy group (preferably trimethylsilyl-ethoxy)) , a Ci_6 alkoxycarbonyl group (preferably ethoxycarbonyl) and the like are preferable.

The number of the substituents of the "optionally substituted alkyl group" exemplified as the substituent for Rc 10 is preferably 0 (i.e., unsubstituted), or 1 to 5, more preferably 0 (i.e., unsubstituted), or 1 to 3. When the number of the substituents is not less than 2, . the respective substituents may be the same or different.

The "optionally substituted C3-7 cycloalkyl group" 15 exemplified as the substituent for Rc is preferably cyclopropyl or the like.

As the substituent of the "optionally substituted C3-7 cycloalkyl group" exemplified as the substituent for Rc, a halogen atom, a hydroxy group, a C3_7 cycloalkyl group, an 20 optionally substituted Ci_6 alkoxy group (e.g., methoxy, ethoxy, a trimethylsilyl-Ci-6 alkoxy group), a C1-6 alkoxy-carbonyl group and the like are preferable.

The number of the substituents of the "optionally substituted C3-7 cycloalkyl group" is preferably 0 (i.e., 25 unsubstituted), or 1 to 5, particularly preferably 0 (i.e., unsubstituted). When the number of the substituents is not less than 2, the respective substituents may be the same or different.

[0089] 30 Y is preferably an oxygen atom, an optionally substituted methylene group, or -NRC- wherein Rc is preferably a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C3-7 cycloalkyl group, more preferably an oxygen atom, a methylene group optionally 35 substituted by 1 or 2 Ci_6 alkyl group (s) (preferably methyl) 49 WO 2011/163355 PCT/US2011/041443 (the two substituents for the methylene group optionally form, together with the adjacent carbon atom, a C3_6 cycloalkane (preferably cyclobutane)), or -NRC- wherein Rc is (i) a hydrogen atom, (ii) a Ci_6 alkyl group (preferably methyl, ethyl 5 propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 (preferably 1 or 2) substituents selected from the group consisting of a halogen atom (preferably a fluorine atom) , a hydroxy group, a C3_7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., methoxy, io ethoxy, a trimethylsilyl-Ci_6 alkoxy group (preferably trimethylsilyl-ethoxy)) and a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), or (iii) a C3_7 cycloalkyl group (preferably cyclopropyl), particularly preferably -NRC- wherein Rc is preferably a Ci_6 15 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl), a diCi_6 alkylmethylene group (preferably dimethylmethylene group) or the like, more preferably -NRC-wherein Rc is preferably a Ci_6 alkyl group (preferably methyl, ethyl, isopropyl). 20 In another embodiment, Y is preferably -NRC- wherein Rc is preferably an optionally substituted Ci_6 alkyl group, more preferably a Ci-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl), optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen 25 atom (preferably a fluorine atom) , a hydroxy group, a C3_7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci-6 alkoxy group (preferably trimethylsilyl-ethoxy)) and a Ci_6 alkoxycarbonyl group (preferably ethoxycarbonyl). 30 [0090]

In another embodiment, Y is preferably -NRC- wherein Rc is preferably an optionally substituted Ci_6 alkyl group, more preferably an optionally substituted Ci_4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl). 35 [0091] 50 WO 2011/163355 PCT/US2011/041443

In another embodiment, Y is preferably a methylene group which is optionally substituted by 1 to 2 Ci_6 alkyl group (s) (preferably methyl), or -NRC- wherein Rc is (1) a hydrogen atom, (2) a Ci_6 alkyl which is optionally substituted by 1 to 3 5 substituents selected from the group consisting of hydoxy and a halogen atom (preferably methyl, ethyl, propyl, isopropyl, hydroxymethyl, difluoromethyl), or (3) a C3-7 cycloalkyl (preferably cyclopropyl).

[0092] 10 The partial structure of the formula (I):

is preferably, for example, a group represented by the formula: is wherein Y1 is an optionally substituted methylene group, or -NRC-wherein Rc is a hydrogen atom or a substituent, and ring A1 is an optionally substituted pyridine ring, or a group represented by the formula: 0 20 51 WO 2011/163355 wherein PCT/US2011/041443 Y2 is -NRd- wherein Rd is a substituent, and ring A2 is an optionally substituted pyridine ring.

[0093]

Examples of the "optionally substituted methylene group" for Y1 include those similar to the "optionally substituted methylene group" for Y.

[0094]

Examples of the "substituent" of the "optionally substituted pyridine ring" for ring A1 include those similar to the "substituent" of the "optionally substituted 6-membered ring" for ring A.

[0095]

Examples of the "substituent" for Rd include those similar to the "substituent" for Rc.

Among them, an optionally substituted alkyl group and the like are preferably.

The "alkyl group" of the "optionally substituted alkyl group" exemplified as the substituent for Rd is preferably a Ci_ 6 alkyl group (preferably a Ci_4 alkyl group, more preferably methyl, ethyl, propyl, isopropyl, isobutyl) or the like.

As the substituent of the "optionally substituted alkyl group" exemplified as the substituent for Rd, a halogen atom (preferably a fluorine atom), a hydroxy group, a C3-7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci_6 alkoxy group (preferably trimethylsilyl-ethoxy)), a C1-6 alkoxy-carbonyl group (preferably ethoxycarbonyl) and the like are preferable, and a halogen atom (preferably a fluorine atom), a hydroxy group, an optionally substituted Ci_6 alkoxy group (e.g., methoxy, ethoxy, a trimethylsilyl-Ci-6 alkoxy group (preferably trimethylsilyl-ethoxy)), a C1-6 alkoxy-carbonyl group (preferably ethoxycarbonyl) and the like are more preferable.

The number of the substituents of the "optionally substituted alkyl group" exemplified as the substituent for Rd 52 WO 2011/163355 PCT/US2011/041443 is preferably 0 (i.e., unsubstituted), or 1 to 5, more preferably 0 (i.e., unsubstituted), or 1 to 3. When the number of the substituents is not less than 2, the respective substituents may be the same or different. 5 [0096]

Examples of the "substituent" of the "optionally substituted pyridine ring" for ring A2 include those similar to the "substituent" of the "optionally substituted 6-membered ring" for ring A. io [0097]

The partial structure of the formula (I):

is more preferably a group represented by the formula:

o 15 wherein each symbol is as defined above,further more preferably a group represented by the formula:

R3 is a hydrogen atom, a halogen atom, cyano, an optionally 20 substituted Ci-6 alkyl group or an optionally substituted Ci-6 alkoxy group, and Y1 is as defined above.

[0098] 53 WO 2011/163355 PCT/US2011/041443

The "optionally substituted Ci_6 alkyl group" for R3 is preferably an optionally substituted Ci-4 alkyl group, more preferably a Ci_4 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) .

The "optionally substituted Ci_6 alkoxy group" for R3 is preferably an optionally substituted C1-4 alkoxy group, more preferably a Ci_4 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) . R3 is preferably a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, Ci_6 alkyl (preferably Ci_4 alkyl, more preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) , or C1-6 alkoxy (preferably C]_4 alkoxy, more preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom), particularly preferably a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, trifluoromethyl, difluoromethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy.

In another embodiment, R3 is preferably a hydrogen atom, a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, an optionally substituted Ci_4 alkyl group or an optionally substituted Ci_4 alkoxy group, more preferably a hydrogen atom, a halogen atom (preferably a chlorine atom, a fluorine atom), an optionally substituted Ci-4 alkyl group or an optionally substituted Ci_4 alkoxy group.

[0099]

The partial structure of the formula (I):

O 54 WO 2011/163355 PCT/US2011/041443 is particularly preferably a group represented by the formula

wherein R3''' is a hydrogen atom, a halogen atom, an optionally 5 substituted Ci_6 alkyl group (preferably an optionally substituted C1--4 alkyl group) or an optionally substituted C1-6 alkoxy group (preferably an optionally substituted C1-4 alkoxy group), and Y1 is as defined above. 10 [0100]

In another embodiment, the group represented by the formula:

wherein R4' is an optionally substituted Ci_6 alkyl group, and R3 is as defined above. 55 WO 2011/163355 PCT/US2011/041443 [0101]

The "optionally substituted Ci_6 alkyl group" for R4' is preferably an optionally substituted Ci_4 alkyl group, more preferably a Ci_4 alkyl group (preferably methyl, ethyl, propyl, 5 isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom (preferably a fluorine atom) , a hydroxy group, a C3-7 cycloalkyl group (preferably cyclopropyl), an optionally substituted C1-6 alkoxy group (preferably Ci_4 alkoxy) (e.g., 10 methoxy, ethoxy, a trimethylsilyl-Ci_6 alkoxy group (preferably trimethylsilyl-ethoxy)), and a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl). R4' is preferably an optionally substituted C3.-6 alkyl group, more preferably an optionally substituted Ci_4 alkyl 15 group.

[0102]

In another embodiment, the partial structure of the formula (I):

20 is preferably a group represented by the formula:

R3'''' and R3f'' ' ’ represent the same or different a hydrogen atom, a halogen atom, cyano, an optionally 25 substituted C1-6 alkyl group or an optionally substituted C1-6 56 WO 2011/163355 PCT/US2011/041443 alkoxy group, and R4' is as defined above.

[0103]

The "optionally substituted Ci_6 alkyl group" for R3'''' or R3''' ’' is preferably an optionally substituted Ci_4 alkyl group, more preferably a Ci_4 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom).

The "optionally substituted Ci_6 alkoxy group" for R3'''' or R3''''' is preferably an optionally substituted Ci_4 alkoxy group, more preferably a Ci_4 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom). R3'' ’' is preferably a hydrogen atom, a halogen atom, an optionally substituted Ci_6 alkyl group or an optionally substituted Ci-6 alkoxy group, more preferably a hydrogen atom or an optionally substituted Ci_6 alkyl group, further more preferably a hydrogen atom or an optionally substituted Ci-4 alkyl group (preferably methyl, hydroxymethly). R3'''' ’ is preferably a hydrogen atom, a halogen atom, cyano, an optionally substituted Ci_6 alkyl group or an optionally substituted Ci_6 alkoxy group, more preferably a hydrogen atom, a halogen atom, cyano, an optionally substituted Ci_4 alkyl group or an optionally substituted Ci_4 alkoxy group.

[0104]

The group represented by the formula:

is preferably a group represented by the formula: 57 WO 2011/163355 PCT/US2011/041443

wherein R3a and R3b represent the same or different a hydrogen atom, a halogen atom, cyano, an optionally substituted Ci_4 alkyl 5 group or an optionally substituted Ci_4 alkoxy group, and R4 represents an optionally substituted Ci_4 alkyl group, provided that when one of R3a and R3b is a hydrogen atom, the other is not a hydrogen atom, and more preferably a group represented by the formula:

R3' represents a hydrogen atom, or an optionally substituted Ci_4 alkyl group (preferably, methyl, hydroxymethly), R3'’ represents a hydrogen atom, a halogen atom, cyano, an is optionally substituted Ci_4 alkyl group or an optionally substituted Ci_4 alkoxy group, and R4 represents an optionally substituted Ci_4 alkyl group, provided that when one of R3' and R3'' is a hydrogen atom, the other is not a hydrogen atom. 20 [0105] R3'' is preferably a hydrogen atom, a halogen atom, an optionally substituted Ci_4 alkyl group (preferably, methyl) or an optionally substituted Ci_4 alkoxy group (preferably, 58 WO 2011/163355 methoxy). PCT/US2011/041443 [0106] R is (1) a group represented by the formula:

(2) a group represented by the formula:

[0107]

That is, the compound represented by the formula (I) or a io salt thereof encompasses a compound represented by the formula

[0108]

Each symbol for R is explained in the following. is [0109]

R1 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, 20 L is a sulfur atom (-S-), an oxygen atom (-0-), ah optionally substituted methylene group, -CO-, -NRa~, -CH2O-, -OCH2-, -NRaCOO-, -OCONR3-, -NRaCONRb~, -NRaCOCH2-, -CH2CONRa-, 59 WO 2011/163355 PCT/US2011/041443 -NRaCO-, -CONRa~,

wherein

Ra and Rb are the same or different and each is a hydrogen atom or an optionally substituted Ci_6 alkyl group, or L and R1 in combination optionally form an optionally substituted bi- or tri-cyclic fused heterocyclic group, and ring B1 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or' a pyridazine ring, each of which is optionally substituted.

[0110]

Examples of the "5- to 10-membered heterocyclic group" of the "optionally substituted 5- to 10-membered heterocyclic group" for R1 include. a 5- to 10-membered heterocyclic group from among the "3- to 14-membered heterocyclic groups" exemplified above.

Among them, a 5- or 6-membered monocyclic heterocyclic group, a bicyclic fused heterocyclic group (preferably a 9- to 10-membered bicyclic fused heterocyclic group) and the like are preferable.

The nitrogen atom(s) contained in the "5- to 10-membered heterocyclic group" of the "optionally substituted 5- to 10-membered heterocyclic group" for R1 may be oxidized.

[0111]

The "5- or 6-membered monocyclic heterocyclic group" is preferably, for example, a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group such as imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiadiazolyl and the like. Among them, imidazolyl, pyridyl and thiadiazolyl are preferable, and the following groups: 60 PCT/US2011/041443 WO 2011/163355

and the like are more preferable, and the following groups:

5 are particularly preferable.

[0112]

Examples of the aforementioned "bicyclic fused heterocyclic group" include (1) a fused heterocyclic group formed by condensation of a phenyl group with a 5- or β ίο membered heterocycle, (2) a fused heterocyclic group formed by condensation of a 5- or 6-membered heterocyclic group with a carbocycle having 5 or 6 carbon atoms, and (3) a fused heterocyclic group formed by condensation of a 5- or 6-membered heterocyclic group with a 5- or 6-membered 15 heterocycle. Among them, the following groups:

61 PCT/US2011/041443 WO 2011/163355

wherein Rf is absent or a hydrogen atom (when Rf is absent, -N(Rf)~ is =N-; Rf is preferably absent), and the like are preferable, and the following groups:

and the like are more preferable.

[0113]

Examples of the substituent of the "phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally io substituted" for R1 include substituents selected from the above-mentioned Substituent Group A.

Among them, (a) a halogen atom, (b) an optionally esterified carboxy group, is (c) an optionally substituted alkyl group, 62 WO 2011/163355 PCT/US2011/041443 (d) an optionally substituted C6-i4 aryl group, (e) an optionally substituted alkyl-carbonyl group, and the like are preferable, (a) a halogen atom (preferably fluorine, bromine, chlorine), 5 (b) a Ci-6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (c) a Ci-6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a halogen atom (preferably a fluorine atom), io (ii) a hydroxy group, and (iii) an optionally substituted Ci_6 alkoxy group (e.g., a Ci_s alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl), (d) a C6-i4 aryl group (preferably phenyl) , 15 (e) a Ci-6 alkyl-carbonyl group (preferably acetyl) , and the like are more preferable.

The number of the substituents of the "phenyl group or 5 to 10-membered heterocyclic group, each of which is optionally substituted" for R1 is preferably 0 (i.e., unsubstituted), or : 20 to 3. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

[0114] R1 is preferably a phenyl group, imidazolyl, pyridyl, thiadiazolyl (preferably the following group:

63 PCT/US2011/041443 WO 2011/163355

10 15 20 or the like, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) an optionally esterified carboxy group, (c) an optionally substituted alkyl group, (d) an optionally substituted C6-14 aryl group, and (e) an optionally substituted alkyl-carbonyl group [preferably (a) a halogen atom (preferably fluorine, bromine, chlorine), (b) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (c) a C1-6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a halogen atom (preferably fluorine), (ii) a hydroxy group, and (iii) an optionally substituted Ci_6 alkoxy group (e.g., a C1-6 alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl) , (d) a C6-i4 aryl group (preferably phenyl) , and (e) a C1-6 alkyl-carbonyl group (preferably acetyl) ] .

[0115]

In another embodiment, R1 is preferably 64 PCT/US2011/041443 WO 2011/163355

wherein

Rx is a hydrogen atom or an optionally substituted Ci_6 alkyl group (preferably a Ci_6 alkyl group) , 5 or the like.

[0116]

Examples of the substituent of the "optionally substituted methylene group" for L include substituents selected from the above-mentioned Substituent Group A. io The "optionally substituted methylene group" for L is preferably (unsubstituted) methylene.

[0117]

Preferable examples of the substituent of the "optionally substituted Ci_6 alkyl group" for Ra include substituents 15 selected from the above-mentioned Substituent Group A.

Ra is preferably a hydrogen atom, a Ci_6 alkyl group or the like, more preferably a hydrogen atom, methyl or the like. [0118]

Preferable examples of the substituent of the "optionally 20 substituted Ci_6 alkyl group" for Rb include substituents selected from the above-mentioned Substituent Group A.

Rb is preferably a hydrogen atom, a Ci_6 alkyl group or the like, more preferably a hydrogen atom, methyl or the like. [0119] 25 L is preferably an oxygen atom (-0-), -CO-, -NRa-, -NRaCOO- wherein Ra is preferably a hydrogen atom or a Ci-6 alkyl group (preferably methyl), or o more preferably an oxygen atom or -NRa- wherein Ra is a hydrogen atom or a Ci_6 alkyl group (preferably methyl), or the

30 65 WO 2011/163355 PCT/US2011/041443 like, further more preferably an oxygen atom or the like.

[0120]

The "optionally substituted bi- or tri-cyclic fused 5 heterocyclic group formed by L and R1 in combination" means that the moiety represented by the formula:

is a moiety represented by the formula:

Ry is an optionally substituted bi- or tri-cyclic fused heterocyclic group, and B1 is as defined above.

That is, the substituent on the ring-constituting atom of 15 the "phenyl group" or the "5- to 10-membered heterocyclic group" for R1 and the substituent on the main chain-constituting atom of L form a ring together with the ring-constituting atom and the main chain-constituting atom. In the present specification, this structure is sometimes represented

[0121]

Examples of the "bi- or tri-cyclic fused heterocyclic group" of the "optionally substituted bi- or tri-cyclic fused 25 heterocyclic group" formed by L and R1 in combination include a bi- or tri-cyclic group, from among the aforementioned "3- to 14-membered heterocyclic groups containing 1 to 5 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen 66 WO 2011/163355 PCT/US2011/041443 atom".

The "bi- or tri-cyclic fused heterocyclic group" is preferably the following group:

wherein X is -CH2-, -NH-, an oxygen atom or a sulfur atom, X' is =CH- or =N-, and

Rf is absent or a hydrogen atom (when Rf is absent, -N(Rf)-10 is =N~; Rf is preferably absent) , or the like, more preferably the following group: 67 WO 2011/163355 PCT/US2011/041443

,Ν N.

IN

[0122]

Examples of the substituent of the "optionally substituted bi- or tri-cyclic fused heterocyclic group" 5 optionally formed by L and R1 in combination include substituents selected from the aforementioned Substituent Group A and an oxo group.

Among them, (a) a halogen atom, io (b) an optionally esterified carboxy group, (c) an optionally substituted alkyl group, (d) an oxo group and the like are preferable, and (a) a halogen atom, 15 (b) a Ci-6 alkoxy-carbonyl group (preferably ethoxycarbonyl) , (c) a Ci_6 alkyl group (preferably methyl) optionally substituted by C6-14 aryl group (s) (preferably phenyl), 68 WO 2011/163355 PCT/US2011/041443 (d) an oxo group and the like are more preferable, and (a) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (b) a Ci_6 alkyl group (preferably methyl) optionally substituted by C6-i4 aryl group (s) (preferably phenyl), and (c) an oxo group are further more preferable.

In another embodiment, as the substituents of the "optionally substituted bi- or tri-cyclic fused heterocyclic group" optionally formed by L and R1 in combination, (a) a halogen atom, (b) an. optionally esterified carboxy group, (c) an optionally substituted alkyl group, and the like are preferable, and (a) a halogen atom, (b) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (c) a Ci_6 alkyl group (preferably methyl) optionally substituted by C6-14 aryl group (s) (preferably phenyl), and the like are more preferable, and (a) a C1-6 alkoxy-carbonyl group (preferably ethoxycarbonyl), and (b) a C1-6 alkyl group (preferably methyl) optionally substituted by C6_i4 aryl group (s) (preferably phenyl) are further more preferable.

The number of the substituents of the "optionally substituted bi- or tri-cyclic fused heterocyclic group" optionally formed by L and R1 in combination is preferably 0 (i.e., unsubstituted), or 1 to 3. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

[0123]

The "optionally substituted bi- or tri-cyclic fused heterocyclic group" optionally formed by L and R1 in combination is preferably 69 WO 2011/163355 PCT/US2011/041443

each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl) 5 (b) Ci_6 alkyl group (preferably methyl) optionally substituted by C6-i4 aryl group (s) (preferably phenyl), and (c) an oxo group.

[0124]

The partial structure of the formula (1-1): is preferably a group represented by the following formula: 70 PCT/US2011/041443 WO 2011/163355

Rz wherein

Rf is absent or a hydrogen atom (when Rf is absent 71 WO 2011/163355 PCT/US2011/041443 N(Rf)- is =N-; Rf is preferably absent);

Rz is (i) a hydrogen atom, (ii) a Ci_4 alkyl group optionally substiuted by one substituent selected from (1) a hydroxy group (preferably, methyl, ethyl, hydroxyethyl, buthyl, hydroxy isobutyl) and (2) a Ci_4 alkoxy group optionally substituted by trimethylsilyl (preferably, trimethylsilylmethoxy) , or (iii) a Ci_6 alkyl-carbonyl group (preferably, acetyl);

Rwl is a halogen atom (preferably, fluorine); m is 0 to 2;

Rw2 is a hydrogen atom or a methyl group;

Rw3 is a hydrogen atom or a Ci_2 alkoxy-carbonyl group (preferably, ethoxycarbonyl);

Rw4 is a hydrogen atom or benzyl;

Rw5 is a hydrogen atom or methyl;

Rw6 is a hydrogen atom, a halogen atom (preferably, fluorine, chlorine), or a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms (preferably, trifluoromethyl);

Rw7 is a Ci_6 alkoxyl-carbonyl group (preferably, ethoxycarbonyl);

Rw8 is a halogen atom (preferably, chlorine, bromine), or a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms (preferably, trifluoromethyl); n is 0 to 2;

Rw9 is a hydrogen atom or a halogen atom (preferably, bromine); more preferably a group represented by the following formula: 72 PCT/US2011/041443 WO 2011/163355

wherein

Rwl is a halogen atom (preferably, fluorine); m is 0 to 1; 5 Rz is (i) a hydrogen atom, (ii) a Ci_4 alkyl group optionally substiuted by one hydroxy group (preferably methyl, hydroxyethyl, hydroxyisobutyl) and

Rw3 is a hydrogen atom or a C1-2 alkoxy-carbonyl group (preferably, ethoxycarbonyl). 10 [0125]

In another embodiment, the partial structure of the formula (I—1): R1—L- is preferably a group represented by the following formula:

wherein

Rx is an optionally substituted Ci_6 alkyl group, each of which is further optionally substituted.

The "optionally substituted Ci_6 alkyl group" for Rx is 73 WO 2011/163355 PCT/US2011/041443 preferably a Ci-6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a halogen atom (preferably a fluorine atom), (ii) a hydroxy group, and (iii) an optionally substituted Ci-6 alkoxy group (e.g., a

Ci_6 alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl), more preferably a Ci_6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a hydroxy group, and (ii) an optionally substituted Ci_6 alkoxy group (e.g., a Ci_6 alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl).

[0126]

As the substituent that the group represented by the formula:

wherein

Rx is an optionally substituted Ci-6 alkyl group, optionally further has, (a) a halogen atom, (b) an optionally esterified carboxy group, (c) an optionally substituted alkyl group, (d) an optionally substituted C6-i4 aryl group, (e) an optionally substituted alkyl-carbonyl group, and the like are preferable, and (a) a halogen atom (preferably fluorine), (b) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (c) a Ci_6 alkyl group (preferably methyl) 74 WO 2011/163355 PCT/US2011/041443 and the like are more preferable.

The number of the substituents is preferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0 (i.e., unsubstituted), or 1. When the number of the substituents is 5 not less than 2, the respective substituents may be the same or different.

[0127]

The cyclic moiety of the group represented by the formula:

or the like, more preferably 15 [0128]

Examples of the substituent of the "benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, each of which is optionally substituted" for ring B1 include substituents selected from the above-mentioned 20 Substituent Group A.

Among them, a halogen atom, an optionally substituted alkyl group and the like are preferable, a halogen atom, an optionally substituted Ci_6 alkyl group and the like are more preferably, and 25 a halogen atom (preferably a fluorine atom), a Ci_6 alkyl group (preferably methyl) and the like are further more preferable. 75 WO 2011/163355 PCT/US2011/041443 [0129]

The number of the substituents of the "benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, each of which is optionally substituted" for ring B1 is preferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0 or 1. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

Ring B1 is preferably an optionally substituted benzene ring, more preferably a benzene ring optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and an optionally substituted alkyl group [more preferably a halogen atom and an optionally substituted Ci-6 alkyl group, further more preferably a halogen atom (preferably a fluorine atom) and a Ci_6 alkyl group (preferably methyl), particularly preferably a halogen atom (preferably a fluorine atom)].

[0130]

The compound represented by the formula (1-1) or a salt thereof is preferably a compound wherein Z1 is -N= and the others (i.e., Z2, Z3, and Z4) are -CH=; or Z1 and Z3 are -N= and the others (i.e., Z2 and Z4) are -CH= [preferably Z1 is -N= and the others (i.e., Z2, Z3, and Z4) are -CH=]; ring A is a pyridine ring or a pyrimidine ring, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, cyano, an optionally substituted alkyl group and an optionally substituted alkoxy group [preferably a halogen atom, cyano, an optionally substituted Ci_6 alkyl group and an optionally substituted Ci_6 alkoxy group, further more preferably a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, a Ci_6 alkyl group (preferably methyl) optionally substituted by 1 to 3 substituents selected from the group consisting of (1) a halogen atom (preferably a fluorine atom), (2) hydroxyl, and (3) Ci_6 alkyl-carbonyl group (preferably acetoxy) , and a Ci_6 76 WO 2011/163355 PCT/US2011/041443 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom)]; Y is an oxygen atom, an optionally substituted methylene group, or -NRC- wherein Rc is preferably a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C3_7 cycloalkyl group {preferably an oxygen atom, a methylene group optionally substituted by 1 or 2 Ci-6 alkyl groups (preferably methyl) (the two substituents for the methylene group optionally form, together with the adjacent carbon atom, a C3_6 cycloalkane (preferably cyclobutane)), or -NRC- wherein Rc is preferably (i) a hydrogen atom, (ii) a Ci_6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom (preferably a fluorine atom) , a hydroxy group, a C3_7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., methoxy, ethoxy, a trimethylsilyl-Ci-6 alkoxy group (preferably trimethylsilyl-ethoxy)), and an Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), or (iii) a C3_7 cycloalkyl group (preferably cyclopropyl)}; R1 is a phenyl group or a 5- to 10-membered heterocyclic group [preferably imidazolyl, pyridyl, thiadiazolyl (preferably the following group:

77 10 15 PCT/US2011/041443 WO 2011/163355

], each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) an optionally esterified carboxy group, (c) an optionally substituted alkyl group, (d) an optionally substituted C6-14 aryl group, and (e) an optionally substituted alkyl-carbonyl group [preferably (a) a halogen atom (preferably fluorine, bromine, chlorine) (b) a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (c) a C1-6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a halogen atom (preferably fluorine), (ii) a hydroxy group, and (iii) an optionally substituted Ci_6 alkoxy group (e.g., a C1-6 alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl), (d) a C6_i4 aryl group (preferably phenyl), and (e) a C1-6 alkyl-carbonyl group (preferably acetyl) ] ; L is an oxygen atom (-0-) , -CO-, -NRa-, -NRaCOO- wherein Ra is preferably a hydrogen atom or a Ci_6 alkyl group (preferably methyl), or 20 78 WO 2011/163355 PCT/US2011/041443 [preferably an oxygen atom, or -NRa- wherein Ra is a hydrogen atom or a Ci_6 alkyl group (preferably methyl)]; or L and R1 in combination optionally form a bi- or tri-cyclic 5 fused heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkoxy-carbonyl group (preferably ethoxycarbonyl), (b) a Ci_6 alkyl group (preferably methyl) optionally substituted by Ce-14 aryl group (s) (preferably phenyl), and io (c) an oxo group (preferably

ring B1 is preferably an optionally substituted benzene ring, 15 more preferably a benzene ring optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen 79 WO 2011/163355 PCT/US2011/041443 atom and an optionally substituted alkyl group [preferably a halogen atom and an optionally substituted Ci-g alkyl group, more preferably a halogen atom (preferably a fluorine atom) and a Ci_6 alkyl group (preferably methyl)], 5 or a salt thereof.

[0131]

In another embodiment, the compound represented by the formula (1-1) or a salt thereof is preferably a compound wherein io Z1 is -N=, Z2, Z3 and Z4 are -CH=, Y is -NRC- or a di-Ci_6 alkylmethylene group,

Rc is a Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen 15 atom, a hydroxy group, a C3-7 cycloalkyl group, a trimethylsilyl-Ci-6 alkoxy group and a Ci_6 alkoxy-carbonyl group, R1 is a 5- to 10-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, 20 (b) a C1-6 alkoxy-carbonyl group, (c) a C1-6 alkyl group optionally substituted by one or more (preferably 1 to 3) substituents selected from the group consisting of (i) a hydroxy group, and 25 (ii) an optionally substituted Cx_6 alkoxy group (e.g., a

Ci_6 alkoxy group optionally substituted by trimethylsilyl), and (d) a C1-6 alkyl-carbonyl group; L is an oxygen atom, or -NRa- wherein Ra is a hydrogen atom or 30 a C1-6 alkyl group, or L and R1 in combination optionally form a bi- or tri-cyclic fused heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of (a) a halogen atom, 35 (b) a Ci_6 alkyl group optionally substituted by C6-i4 aryl 80 WO 2011/163355 PCT/US2011/041443 group(s), and (c) an oxo group, and ring B1 is a benzene ring, or a salt thereof.

[0132]

The compound represented by the formula (1-1) or a salt thereof is more preferably a compound wherein Z1 is -N=, Z2, Z3 and Z4 are -CH=, Y is -NRC- wherein Rc is a Ci_6 alkyl group, or a di-Ci-e alkylmethylene group, R1 is

wherein Rx is a hydrogen atom or a Ci_6 alkyl group, L is an oxygen atom, and ring B1 is a benzene ring, or a salt thereof.

[0133]

In the partial structure of the formula (1-2):

R2 is a phenyl group or a 5- to 10-membered heterocyclic group, each of which is optionally substituted, ring B2 is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, each of which is optionally substituted, and ring D is an optionally further substituted 5- or 6-membered ring.

[0134]

Examples of the "5- to 10-membered heterocyclic group" of 81 WO 2011/163355 PCT/US2011/041443 the "phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally substituted" for R2 include those similar to the "5- to 10-membered heterocyclic group" of the "optionally substituted 5- to 10-membered heterocyclic group" for R1.

Among them, a 5- or 6-membered monocyclic heterocyclic group, a bicyclic fused heterocyclic group (preferably a 9- or 10-membered bicyclic fused heterocyclic group) and the like are preferable.

[0135]

The "5- or 6-membered monocyclic heterocyclic group" is preferably, for example, a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group such as imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiazolyl and the like, (preferably pyridyl, pyrimidinyl,

and the like are preferable, and the following group: N=\ N=x N-

and are more preferable. [0136]

Examples of the aforementioned "bicyclic fused heterocyclic group" include (1) a fused heterocyclic group formed by condensation of a phenyl group with a 5- or 6-membered heterocycle, (2) a fused heterocyclic group formed by condensation of a 5- or 6-membered heterocyclic group with a benzene ring, and (3) a fused heterocyclic group formed by condensation of a 5- or 6-membered heterocyclic group with a 5- or 6-membered heterocycle. Among them, the following group 82 PCT/US2011/041443 WO 2011/163355

5 are more preferable.

[0137]

Examples of the substituent of the "phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally substituted" for R2 include substituents selected from the io above-mentioned Substituent Group A.

Among them, an optionally substituted alkyl group and the like are preferable, a Ci_g alkyl group and the like are more preferable, and methyl is further more preferable.

[0138] is The number of the substituents of the "phenyl group or 5- to 10-membered heterocyclic group, each of which is optionally substituted" for R2 is preferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0 or 1. When the number of the substituents is not less than 2, the respective substituents 20 may be the same or different.

[0139] R2 is preferably a 5- to 10-membered heterocyclic group (preferably the following group: 83 PCT/US2011/041443 WO 2011/163355

more preferably the following group:

further more preferably the following group:

5 ) , optionally substituted by 1 to 3 (preferably 1) substituents selected from an optionally substituted alkyl group (preferably a Ci_6 alkyl group, more preferably methyl).

[0140] io Examples of the substituent of the "benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, each of which is optionally substituted" for ring B2 include substituents selected from the above-mentioned Substituent Group A. is The number of the substituents is preferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

Ring B2 is preferably an optionally substituted benzene 20 ring, more preferably a benzene ring. 84 WO 2011/163355 PCT/US2011/041443 [0141]

The "5- or 6-membered ring" of the "optionally further substituted 5- or 6-membered ring" for ring D is a carbocycle having 5 or 6 carbon atoms (e.g., benzene) or a 5- or 6-membered heterocycle (e.g., pyrrolidine, dihydropyrrole, dihydropyrazole).

Among them, a pyrrolidine ring, a dihydropyrrole ring and a dihydropyrazole ring are preferable, and a pyrrolidine ring is more preferable.

[0142]

Examples of the substituent of the "optionally further substituted 5- or 6-membered ring" for ring D include substituents selected from the above-mentioned Substituent Group A.

Throng them, an optionally substituted alkyl group and the like are preferable, a Ci_6 alkyl group and the like are more preferable, and methyl is further more preferable.

The number of the substituents of the "optionally further substituted 5- or 6-membered ring" for ring D is preferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0 or 1, more preferably 0. When the number of the substituents is not less than 2, the respective substituents may be the same or different.

Ring D is preferably a pyrrolidine ring, a dihydropyrrole ring or a dihydropyrazole ring, each of which is optionally substituted, more preferably a pyrrolidine ring, a dihydropyrrole ring or a dihydropyrazole ring.

[0143]

The partial structure of the formula (1-2):

is preferably a structure represented by the formula: 85 PCT/US2011/041443 WO 2011/163355

wherein each symbol is as defined above.

[0144]

The partial structure of the formula (1-2):

wherein

Rxl and Rx2 are the same or different and each is a hydrogen atom or an optionally substituted Ci-6 alkyl group,

Rx3 - Rx5 are each a hydrogen atom or an optionally 15 substituted Ci_6 alkyl group, and the ring-constituting atom(s) optionally further have substituent (s), and the like, more preferably 86 WO 2011/163355 PCT/US2011/041443

particularly preferably

Examples of the "optionally substituted Ci_6 alkyl group" for Rxl or Rx2 include those similar to the "optionally 10 substituted Ci_6 alkyl group" exemplified as the substituent for ring D.

Examples of the "optionally substituted Ci_6 alkyl group" for Rx3 - Rx5 include those similar to the "optionally substituted Ci_6 alkyl group" exemplified as the substituent for is ring D.

Examples of the substituent that the aforementioned ring-constituting atom(s) optionally further have include those similar to exemplified as the substituent for ring B2 or ring D [0145] 20 The compound represented by the formula (1-2) or a salt thereof is preferably a compound wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; or Z1 and Z3 are -N= and the others (i.e., Z2 and Z4) are -CH= [preferably Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are - 25 CH=] ; ring A is a pyridine ring or a pyrimidine ring, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, cyano, an optionally substituted alkyl group and an optionally substituted alkoxy 87 WO 2011/163355 PCT/US2011/041443 . group [preferably a halogen atom, cyano, optionally substituted Ci_6 alkyl and optionally substituted Ci_6 alkoxy, more preferably a halogen atom (preferably a chlorine atom, a fluorine atom) , cyano, Ci_6 alkyl (preferably methyl) optionally 5 substituted by 1 to 3 halogen atoms (preferably a fluorine atom), and Ci_6 alkoxy (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) ] ; Y is an oxygen atom, an optionally substituted methylene group io or -NRC- wherein Rc is preferably a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C3-7 cycloalkyl group {preferably an oxygen atom, a methylene group optionally substituted by 1 or 2 Ci_6 alkyl group (s) (preferably methyl) 15 (the two substituents for the methylene group optionally form, together with the adjacent carbon atom, a C3_6 cycloalkane (preferably cyclobutane)), or -NRC- wherein Rc is preferably (i) a hydrogen atom, (ii) a Ci_6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 20 1 to 3 substituents. selected from the group consisting of a halogen atom (preferably a fluorine atom), a hydroxy group, a C3-7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci_6 alkoxy group (preferably trimethylsilyl-ethoxy) ) , and a Ci_6 alkoxy- 25 carbonyl group (preferably ethoxycarbonyl) , or (iii) a C3-7 cycloalkyl group (preferably cyclopropyl)}; R2 is a 5- to 10-membered heterocyclic group (preferably the following group: 30 optionally substituted by 1 to 3 (preferably 1) substituents selected from an optionally substituted alkyl group (preferably a C1-6 alkyl group, more preferably methyl); 88 WO 2011/163355 PCT/US2011/041443 ring B2 is an optionally substituted benzene ring (preferably a benzene ring); and ring D is a pyrrolidine ring, a dihydropyrrole ring or a dihydropyrazole ring, each of which is optionally substituted 5 (preferably a pyrrolidine ring, a dihydropyrrole ring or a dihydropyrazole ring), or a salt thereof.

[0146]

The compound represented by the formula (I) or a salt io thereof is preferably a compound (W-l) wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; or Z1 and Z3 are -N= and the other (i.e., Z2 and Z4) are -CH=; wherein the nitrogen atom of -N= for Z1 may be oxidized; ring A is 25 (1) a pyridine ring which is optionally substituted by one substituent selected from (i) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy and a Ci_6 alkyl-carbonyloxy (preferably methyl, trifluoromethyl, acetoxymethyl, hydoroxymethyl), (ii) a 20 halogen atom (preferably chlorine, fluorine) , (iii). cyano, and (iv) a Ci-4 alkoxy optionally substituted by 1 to 3 halogen atoms (preferably methoxy, difluoromethoxy, difluoroethoxy, trifluoroethoxy), or (2) a pyrimidine ring, 25 Y is a oxygen atom, a methylene group which is optionally substituted by 1 to 2 Ci-6 alkyl group (s) (preferably methyl)(the two substituents for the methylene group optionally form, together with the adjacent carbon atom, a C3_6 cycloalkane (preferably cyclobutane)), or -NRC- wherein Rc is 30 (1) a hydrogen atom, (2) a Ci_6 alkyl group which is optionally substituted by 1 to 3 (preferably 1 or 2) substituents selected from the group consisting of (i) a Ci_6 alkoxy group optionally substituted by trimethylsilyl, and (ii) a halogen atom (preferably methyl, ethyl, propyl, isopropyl, 35 trimethylsilyl-ethoxy-methyl, difluoromethyl), or (3) a C3-7 89 WO 2011/163355 PCT/US2011/041443 cycloalkyl (preferably cyclopropyl), R is (1) a group represented by the formula:

wherein the partial structure: R1—L- is a group represented by the following formula: 90 WO 2011/163355 PCT/US2011/041443

Rz wherein

Rf is absent or a hydrogen atom (when Rf is absent, -N(Rf) 91 WO 2011/163355 PCT/US2011/041443 is =N~; Rf is preferably absent);

Rz is (i) a hydrogen atom, (ii) a C1-4 alkyl group optionally substiuted by one substituent selected from (1) a hydroxy group (preferably methyl, ethyl, hydroxyethyl, buthyl, 5 hydroxyisobutyl) and (2) a Ci_4 alkoxy group optionally substituted by trimethylsilyl (preferably trimethylsilylmethoxy), or (iii) a Ci_6 alkyl-carbonyl group (preferably acetyl);

Rwl is a halogen atom (preferably fluorine); 10 m is 0 to 2;

Rw2 is a hydrogen atom or a methyl group;

Rw3 is a hydrogen atom or a Ci_2 alkoxy-carbonyl group (preferably ethoxycarbonyl);

Rw4 is a hydrogen atom or benzyl; 15 Rw5 is a hydrogen atom or methyl;

Rw6 is a hydrogen atom, a halogen atom (preferably fluorine, chlorine), or a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms (preferably trifluoromethyl);

Rw7 is a C1-6 alkoxyl-carbonyl group (preferably 20 ethoxycarbonyl);

Rw8 is a halogen atom (preferably chlorine, bromine), or a Ci_6 alkyl optionally substituted by 1 to 3 halogen atoms (preferably trifluoromethyl).; n is 0 to 2; and 25 RwS is a hydrogen atom or a halogen atom (preferably bromine); and ring B1 is a benzene ring optionally substituted by one halogen atom (preferably fluorine); or (2) a group represented by the formula:

wherein R2 is a 5- to 10-membered heterocyclic group (preferably the 92 WO 2011/163355 PCT/US2011/041443

optionally substituted by one Ci_6 alkyl group (preferably methyl); 5 ring B2 is a benzene ring; and ring D is a pyrrolidine ring, a dihydropyrrole ring, a dihydropirazole ring, (i.e., the partial structure of the formula:

or a salt thereof. [0147]

In another embodiment, the compound represented by the 15 formula (I) or a salt thereof is preferably a compound (W-2) wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; or Z1 and Z3 are -N= and the other (i.e., Z2 and Z4) are -CH=; ring A is 20 (1) a pyridine ring which is optionally substituted by one substituent selected from (i) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen 93 WO 2011/163355 PCT/US2011/041443 atom or hydroxy (preferably methyl, trifluorometyl, hydroxymethyl), (ii) a halogen atom (preferably chlorine, fluorine) , (iii) cyano, and (iv) a Ci_4 alkoxy optionally substituted by 1 to 3 halogen atoms (preferably methoxy, 5 difluoromethoxy, difluoroethoxy, trifluoroethoxy), or (2) a pyrimidine ring, Y is a methylene group which is optionally substituted by 1 to 2 Ci_6 alkyl group (s) (preferably methyl), or -NRC- wherein Rc is (1) a hydrogen atom, (2) a Ci_6 alkyl which is optionally io substituted by 1 to 3 substituents selected from the group consisting of hydoxy and a halogen atom (preferably methyl, ethyl, propyl, isopropyl, hydroxymethyl, difluoromethyl), or (3) a C3-7 cycloalkyl (preferably cyclopropyl), R is 15 (1) a group represented by the formula:

the partial structure: R1—L- 20 is a group represented by the following formula: 94 WO 2011/163355 PCT/US2011/041443

atom (preferably fluorine); m is 0 to 1; 5 Rz is (i) a hydrogen atom, (ii) a Ci_4 alkyl group optionally substiuted by one hydroxy (preferably methyl, hydroxyethyl, hydroxyisobutyl); and

Rw3 is a hydrogen atom or a C1-2 alkoxy-carbonyl group (preferably, ethoxycarbonyl), and 10 ring B1 is a benzene ring; or (2) a group represented by the formula:

wherein R2 is a 5- to 10-membered heterocyclic group (preferably the 15 following group: 95 optionally substituted by one Ci_6 alkyl group (preferably methyl); and the partial structure of the formula: WO 2011/163355 PCT/US2011/041443

or a salt thereof.

[0148] 10 In another embodiment, the compound represented by the formula (I) or a salt thereof is preferably a compound represented by the formula:

wherein is R3' is a hydrogen atom, or a Ci_6 alkyl which may optionally be substituted by one hydroxy (i.e., methyl, hydroxymethyl); R3'' is a hydrogen atom, a halogen atom (preferably fluorine) , a Ci_6 alkyl group (preferably methyl) or a Ci_6 20 alkoxy group (preferably methoxy); R4 is a Ci_6 alkyl group (preferably methyl, ethyl, isopropyl); 96 WO 2011/163355 PCT/US2011/041443 or a salt thereof.

[0149]

In another embodiment, the compound represented by the formula (I) or a salt thereof is preferably a compound wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; ring A is a pyridine ring optionally substituted by a halogen atom, cyano, an optionally substituted alkyl group or an optionally substituted alkoxy group [preferably a halogen atom, cyano, optionally substituted Ci_6 alkyl or optionally substituted Ci_6 alkoxy, more preferably a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, Ci_6 alkyl (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) , or Ci-6 alkoxy (preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom)]; Y is -NRC- wherein Rc is preferably an optionally substituted alkyl group, more preferably a Ci_6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom (preferably a fluorine atom), a hydroxy group, a C3_7 cycloalkyl group (preferably cyclopropyl), an optionally substituted Ci_6 alkoxy group (e.g., a trimethylsilyl-Ci_6 alkoxy group (preferably trimethylsilyl-ethoxy)) and a Ci_6 alkoxy-carbonyl group (preferably ethoxycarbonyl)]; and R is (1) a group represented by the formula:

the partial structure: R1—L- is a group represented by the following formula: 97 WO 2011/163355 PCT/US2011/041443

wherein

Rx is an optionally substituted Ci-6 alkyl group [preferably a Ci_6 alkyl group (preferably methyl, ethyl, 5 butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a hydroxy group and (ii) an optionally substituted Ci_6 alkoxy group (e.g., a Ci_6 alkoxy group (preferably ethoxy) optionally substituted by trimethylsilyl)]; and io ring B1 is an optionally substituted benzene ring [preferably a benzene ring optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and an optionally substituted alkyl group (preferably a halogen atom and an optionally substituted Ci_6 15 alkyl group, more preferably a halogen atom (preferably a fluorine atom) and a Ci_6 alkyl group (preferably methyl))], or (2) a group represented by the formula:

20 wherein, R2 is a 5- to 10-membered heterocyclic group (preferably the following group:

25 optionally substituted by 1 to 3 (preferably 1) substituents selected from an optionally substituted alkyl group (preferably a Ci_6 alkyl group, more preferably 98 WO 2011/163355 PCT/US2011/041443 methyl); ring B2 is an optionally substituted benzene ring (preferably a benzene ring); and ring D is a pyrrolidine ring, a pyrrole ring or a pyrazole ring, each of which is optionally substituted (preferably a pyrrolidine ring, a pyrrole ring or a pyrazole ring), or a salt thereof.

[0150]

In another embodiment, the compound represented by the formula (I) or a salt thereof is preferably a compound wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=; or Z1 and Z3 are -N= and the others (i.e., Z2 and Z4) are -CH=; or Z1 and Z4 are -N= and the others (i.e., Z2 and Z3) are -CH=; ring A is a pyridine ring, a pyrimidine ring or a pyrazine ring, each of which is optionally substituted by 1 or 2 (preferably 1) substituents selected from a halogen atom, an optionally substituted Ci_6 alkyl group (preferably a Ci_2 alkyl group such as methyl, ethyl and the like) and an optionally substituted Ci-6 alkoxy (e.g., methoxy) [preferably a halogen atom (preferably a fluorine atom) and a methyl group]; Y is -NRC- wherein Rc is preferably a Ci_3 alkyl group (e.g., methyl, ethyl, isopropyl), preferably -N(-CH2CH3)and R is a group represented by the formula:

the partial structure:

Ri—L- is a group represented by the following formula:

wherein 99 WO 2011/163355 PCT/US2011/041443

Rx is an optionally substituted Ci-g alkyl group [preferably a Ci_6 alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a 5 hydroxy group and (ii) an optionally substituted Ci_6 alkoxy group (e.g., methoxy)]; and ring B1 is an optionally substituted benzene ring [preferably a benzene ring optionally substituted by one substituent selected from the group consisting of a halogen io atom and an optionally substituted Ci-6 alkyl group, more preferably a halogen atom (preferably a fluorine atom) and a Ci_6 alkyl group (preferably methyl) ] or a pyridine ring [more preferably a benzene ring], or a salt thereof. 15 Among the embodiments of the above-mentioned formula (I), a compound wherein ring A is a pyridine ring wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=, and each of -CH= for Z3 and Z4 has one substituent instead of a hydrogen atom, or the one of -CH= for Z3 and Z4 has one substituent instead of 20 a hydrogen atom, is preferable, and a compound wherein ring A is a pyridine ring wherein Z1 is -N= and the others (i.e., Z2, Z3 and Z4) are -CH=, and -CH= for Z4 has one substituent instead of a hydrogen atom, is more preferable. Examples of the substituent include a halogen atom, an optionally substituted 25 Ci_6 alkyl group (preferably a Ci_2 alkyl group such as methyl, ethyl and the like) and an optionally substituted Ci_6 alkoxy (e.g., methoxy) [preferable examples thereof include a halogen atom (preferably a fluorine atom) and a methyl group].

[0151] 30 In another embodiment, the compound represented by the formula (I) or a salt thereof is preferably a compound represented by the formula (I') or a salt thereof.

[0152]

As the compound represented by the formula (I) or a salt 35 thereof, 100 WO 2011/163355 PCT/US2011/041443 l-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4, 5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof; l-ethyl-6-methoxy-3-{4- [ (3-methyl-3H-imidazo [4,5-b]pyridin-2- 5 yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof; l-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl) oxy] phenyl}-1,3-dihydro-2H-iinidazo [4,5-b]pyridin-2-one, or a salt thereof; io 6-methyl-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b] pyridin-2-yl) oxy] phenyl} -1,3-dihydro-2H-im.idazo [4,5-b]pyridin-2-one, or a salt thereof; l-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or 25 a salt thereof; 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof; and l-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5- 20 b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, or a salt thereof are preferable.

[0153]

When the compound (I) is a salt, for example, metal salts, 25 ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids can be included. Preferable examples of metal salts, for example, include alkali metal salts such as sodium salts, potassium salts and the like; alkali earth metal salts 30 such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and the like. Preferable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, 35 dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. 101 WO 2011/163355 PCT/US2011/041443

Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.

Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Among them, salts that are pharmacologically acceptable are preferable. For example, in the case when acidic functional group are present in the compound, for example, inorganic salts including alkali metal salts (e.g., sodium salts, potassium salts etc.), alkali earth metal salts (e.g., calcium salts, magnesium salts, barium salts etc.) and the like, ammonium salts and the like are preferable. In contrast, in the case when basic functional group are present in the compound, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid etc. or salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc. are preferable.

In the following, compound (I) and a salt thereof are generally also referred to as the compound of the present invention.

[0154]

The compound (I) can be obtained in the crystal form.

Either single crystalline form or crystalline mixture can be included in the compound (I).

The compound of the formula (I) can be a pharmaceutically 102 WO 2011/163355 PCT/US2011/041443 acceptable co-crystal or a co-crystal salt. The term "co-crystal" or "co-crystal salt" as used herein means a crystalline material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability. A cocrystal or a co-crystal salt can be obtained according to a per se known co-crystallization method.

The compound (I) can be provided as a solvate (e.g., hydrate) or as a non-solvate and both are included in the compound (I).

The compounds labeled with isotopes (e.g., 2H, 3H, 1:LC, 14C, 18F, 35S, 125I etc.) are also included in the compound (I).

Compound (I) labeled or substituted with an isotope can be utilized as, for example, a tracer (PET tracer) used for Positron Emission Tomography (PET) and is useful in the fields of medical diagnosis and the like.

[0155]

[Manufacturing method]

The methods for manufacturing compound (I), and compound (la), compound (la') and compound (lb) encompassed in compound (I) are 71··ζ2'Ζ3 R-/r r

I wherein L1 in compound (la) is a sulfur atom, an oxygen atom, an optionally substituted methylene group, -CO-, -NRa-, -CH2O-, -OCH2-, -NRaCOO-, -OCONR3-, -NRaCONRb-, -NRaCOCH2-, -CH2CONRa-, -NRaCO-, -CONR3-, 0 1^N- or the "optionally substituted methylene group" for L1 means the 103 WO 2011/163355 PCT/US2011/041443 same as the "optionally substituted methylene group" for L, L2 in compound (la') forms, together with R1, an optionally substituted bi- or tri-cyclic fused heterocyclic group, the "optionally substituted bi- or tri-cyclic fused heterocyclic group" formed by L2 and R1 in combination means the same as the "optionally substituted bi- or tri-cyclic fused heterocyclic group" optionally formed by L and R1, and other symbols are each as defined above.

Compound (I) comprises compounds (la), (la') and (lb).

[0156]

The compound of the present invention and starting compounds therefor can be produced by a means known per se, for example, according to the methods shown by the following schemes and the like. In the following, the "room temperature" generally means 0 - 30°C, and each symbol in the chemical structural formulas described in the schemes is, unless otherwise specified, as defined above. The compounds in the formulas also include the salts formed, and examples of such salts include those similar to the salts of compound (I) and the like. The compounds obtained in respective steps can be used for the next reaction in the form of a reaction mixture or as a crude product. They can also be isolated from a reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization, distillation, chromatography and the like. When the compounds in the formulas are commercially available, the commercially available products can be directly used. In addition, when each ring in the formula (I) has a substituent, the corresponding precursor has the same substituent.

[0157]

When the starting compound contains an amino group, a carboxy group, a hydroxy group or a heterocyclic group, these groups may be protected with a protective group generally used in the peptide chemistry and the like. In this case, after the reaction, the target compound can be obtained by removing the 104 WO 2011/163355 PCT/US2011/041443 protective group as necessary. The protective group can be introduced or removed by a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 3rd Ed." by Theodora W. Greene, Peter G. M. Wuts, 5 Wiley-Interscience Corporation (1999) and the like. In the formula, P1 - P3 are each a nitrogen-protective group of an amino group or an amide group, a hydroxy-protective group, a carboxy-protective group, or a hydrogen atom, and those known per se can be used. io Examples of the nitrogen-protective group of an amino group or an amide group include a formyl group, and a Ci_6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.), a phenylcarbonyl group, a Ci_6 alkyl-oxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl(Boc) 15 etc.), an allyloxycarbonyl(Alloc) group, a phenyloxycarbonyl group, a fluorenylmethoxycarbonyl(Fmoc) group, a C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a C7-10 aralkyl-oxycarbonyl group (e.g., benzyloxycarbonyl (Z) etc.), a C7-10 aralkyl group (e.g., benzyl etc.), a 2- 20 (trimethylsilyl)ethoxymethyl(SEM) group, a trityl group, a phthaloyl group, an Ν,Ν-dimethylaminomethylene group, a tertbutyl carbamate group, a benzylcarbamate group and the like, each of which may have substituent(s). Examples of the substituent these may have include a phenyl group, a halogen 25 atom (e.g., fluorine, chlorine, bromine, iodine etc.), a Ci_6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl etc.), a nitro group and the like. The number of the substituents is about 1 to 3.

[0158] 30 Examples of the carboxy-protective group include a Ci_6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc.), an allyl group, a benzyl group, a phenyl group, a trityl group, a tri C1-6 alkylsilyl group and the like, each of which may have substituent(s). Examples of the 35 substituents these may have include a halogen atom (e.g., 105 WO 2011/163355 PCT/US2011/041443 fluorine, chlorine, bromine, iodine etc.), a formyl group, a Ci_6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, butylcarbonyl etc.), a nitro group and the like. The number of the substituents is about 1 to 3.

[0159]

Examples of the hydroxy-protective group include a Ci_6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc.), a C7_io aralkyl group (e.g., benzyl etc.), a formyl group, a Ci_6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.) , a benzoyl group, a C7_i0 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a tetrahydropyranyl group, a furyl group, a silyl group and the like, each of which may have substituent (s). Examples of the substituent these may have include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a Ci_6 alkyl group (e.g., methyl, ethyl, n-propyl etc.), a phenyl group, a C7_i0 aralkyl group (e.g., benzyl etc.), a Ci-6 alkoxy group (e.g., methoxy, ethoxy, n-propoxy etc.), a nitro group and the like. The number of the substituents is about 1 to 4.

Preferable examples of P1 - P3 include a tert-butylcarbamate group, a benzylcarbamate group, a benzyl group, a Ci-6 alkyl group (e.g., a methyl group, an ethyl group) and the like. In addition, P1 - P3 themselves can sometimes be the substituent of the compound of the present invention and, for example, a tert-butylcarbamate group, a benzylcarbamate group, a benzyl group, a Ci_6 alkyl group (e.g., a methyl group, an ethyl group) and the like can be mentioned.

As the "leaving group" for X1 - X12, a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom etc.), optionally halogenated Ci_6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, trifluoroethanesulfonyloxy etc.), C6-io arylsulfonyloxy optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy etc.), optionally halogenated Ci_6 alkylsulfonyl (e.g., methanesulfonyl, 106 WO 2011/163355 PCT/US2011/041443 ethanesulfonyl, trifluoroethanesulfonyl etc.) and the like are used. In addition, X1 - X12 also include a substituent convertible to a leaving group, and the substituent can be converted to a leaving group by a reaction known per se in a desired step. For example, X1 - X12 may be a methylthio group convertible to a methanesulfonyl group by an oxidation reaction.

[0160]

When compound (I) contains optical isomer, stereoisomer, regioisomer, rotamer or tautomer, they are also encompassed in compound (I), and each can be obtained as a single isomer by a synthetic method and separation method known per se. For example, when compound (I) is an optically active form, the racemate can be separated into (+) form and (-) form by a conventional optical resolution method.

The method of optical resolution may be a method known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method etc. described in detail below. 1) Fractional recrystallization method A method wherein a salt of a racemate with an optically active compound (e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.) is formed, which is separated by a fractional recrystallization method, and if desired, a neutralization step to give a free optical isomer. 2) Chiral column method A method wherein a racemate or a salt thereof is applied to a column for separation of an optical isomer (a chiral column) to allow separation. In the case of a liquid chromatography, for example, a mixture of the optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.) and the 107 PCT/US2011/041443 WO 2011/163355

like, and developed with water, various buffers (e.g., phosphate buffer, etc.) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine etc.) solely or in admixture to separate the optical isomer. In the case of a gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like is used to allow separation. 3) Diastereomer method A method wherein a racemate is prepared into a diastereomeric mixture by chemical reaction with an optically active reagent, which is made into a single substance by a typical separation means (e.g., a fractional recrystallization method, a chromatography method etc.) and the like, and is subjected to a chemical treatment such as hydrolysis and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained. For example, when compound (I) contains hydroxy, or primary or secondary amino group within a molecule, the compound and an optically active organic acid (e.g., MTPA [ot-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-menthoxyacetic acid etc.) and the like are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively. When compound (I) has a carboxy group, this compound and an optically active amine or an optically active alcohol reagent are subjected to condensation reaction to give diastereomers of the amide compound or the ester compound, respectively. The separated diastereomer is converted to an optical isomer of the original compound by acid hydrolysis or base hydrolysis.

[0161]

Each step described below can be performed without solvent, or by dissolving or suspending in an appropriate solvent, where two or more kinds of solvents may be used by mixing them at an appropriate ratio. Of those recited as examples of the solvent to be used in the manufacturing method 108 WO 2011/163355 PCT/US2011/041443 of the compound of the present invention, the following solvents are specifically used. alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, 1-pentanol, etc. ethers: diethyl ether, diisopropyl ether, diphenylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc. aromatic hydrocarbons : benzene, chlorobenzene, toluene, xylene, etc. saturated hydrocarbons: cyclohexane, hexane, etc. amides : Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone, etc. halogenated hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, etc. nitriles: acetonitrile, propionitrile, etc. sulfoxides: dimethylsulfoxide, etc. aromatic organic bases: pyridine, lutidine, etc. esters: methyl acetate, ethyl acetate, butyl acetate, etc.

[0162]

Of those recited as examples of the base or deoxidizer to be used in the manufacturing method of the compound of the present invention, the following bases and deoxidizers are specifically used. inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc. basic salts: 109 WO 2011/163355 PCT/US2011/041443 sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, etc. organic bases: triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, N1,N2-dimethylethane-l,2-diamine, pyridine, lutidine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, etc. metal alkoxides: sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. alkali metal hydrides: sodium hydride, potassium hydride, etc. metal amides: sodium amide, lithiumdiisopropylamide, lithiumhexamethyl disilazide, etc.

[0163]

Compound (la) can be produced by scheme 1. In addition, of compounds (la), the following compound (Ia-I) and compound (Ia-II) can also be produced by scheme 2.

Compound (la') can be produced by scheme 3. In addition, of compounds (la'), the following compound (Ia'-I) and compound (la'-II) can also be produced by scheme 4, and the following compound (la'-III) can also be produced by scheme 5.

Compound (lb) can be produced by scheme 6. In addition, of compounds (lb), the following compound (Ib-I) can also be produced by scheme 7.

Compound (Ia-III) can be produced by scheme 8.

In the formulas shown in these schemes 1-8, when the starting compound in each reaction has a hydroxy group, an amino group and the like, these groups may be appropriately subjected to a general protection and deprotection reactions (e.g., the reaction described in step 2). The protective 110 WO 2011/163355 PCT/US2011/041443 groups may be selected, introduced or removed according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 3rd Ed." by Theodora W Greene, Peter G. M. Wuts, Wiley-Interscience Corporation (1999), or a method analogous thereto and the like. In addition, when the starting compound in each reaction has an amino group, a compound introduced with a nitro group instead of an amino group may be used as a starting compound, and after the reaction, the nitro group may be reduced to give a desired amino group (e.g., the reaction described in step 7).

In addition, compound (I) can also be produced by an appropriate combination of the reaction of each step shown by these schemes 1-8.

[0164]

Scheme 1 A.‘Z< ρΐ_Ι_ι_# giv Λ NH J.

=/ <,«Y lie

Step 2

IH I

NH lid

iia

StepS

Z^'C

HV or I» wherein X1 - X3 are each a leaving group, and the other symbols are as defined above.

The compound of the present invention can be produced by subjecting compound (Ila) to a series of reaction steps of Steps 1, 2, 3, 2' and 6.

In addition, the compound can also be produced by subjecting compound (Ila) to a series of reaction steps in Steps 4, 2' and 6.

Furthermore, the compound can also be produced by 111 WO 2011/163355 PCT/US2011/041443 subjecting compound (Ilf) to a series of reaction steps in

Steps 5, 2' and 6.

[0165] (Step 1)

Compound (lie) can be produced by subjecting compound (Ila) and compound (lib) to a substitution reaction. Compound (Ila) is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (lib). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. In addition, when an acidic substance is released by the reaction, the reaction can be performed in the presence of a deoxidizer to remove the acidic substance from the reaction system. As such deoxidizer, for example, inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like are used. The deoxidizer is generally used in about 0.05 - 20 mol, preferably about 1-10 mol, per 1 mol of compound (lib).

While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 -200°C, preferably 50 - 150°C. In addition, microwave irradiation may be performed to promote the reaction.

[0166] (Step 2)

Compound (lid) can be produced by removing the protective group (P2) of compound (lie) . When P2 is a hydrogen atom, this step can be omitted. The protective group can be removed according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 3rd Ed." by Theodora W. Greene, Peter G. M. Wuts, Wiley-Interscience 112 WO 2011/163355 PCT/US2011/041443

Corporation (1999), and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, 5 ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min io .- 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 0 - 50°C. In addition, microwave irradiation may be performed to promote the reaction [0167] (Step 3) is Compound (He) can be produced by subjecting compound (lid) to a cyclization reaction. The reaction can be performed according to a manufacturing method known per se or a method analogous thereto and, for example, a method using a carbonating agent can be mentioned. Examples of the 20 carbonating agent include 1,1'-carbonylbis(ΙΗ-imidazole), phosgene, triphosgene, diethyl carbonate, dimethyl carbonate, di-tert-butyl dicarbonate and the like. When these carbonating agents are used, the reaction is considered to proceed via a reactive derivative of amine. The synthesis from compound 25 (lid) to compound (lie) sometimes proceeds via compound (He) . The carbonating agent is generally used in about 0.2 - 5.0 mol preferably about 0.5 - 2.0 mol, per 1 mol of compound (lid).

In addition, a base can be used to promote the reaction. Examples of the base include inorganic bases, organic bases, 30 metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (lid) . This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the 35 reaction proceeds and, for example, solvents such as ethers, 113 WO 2011/163355 PCT/US2011/041443 aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending 5 on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 0 - 100°C. In addition, microwave irradiation may be performed to promote the reaction [0168] io (Step 4)

Compound (lie) can also be produced by subjecting compound (Ila) and compound (lib) to a condensation reaction. This reaction can also be performed according to a manufacturing method known per se, for example, the method 15 described in Synlett, vol. 13, page 2083 (2006) and the like, or a method analogous thereto. Compound (Ila) is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (lib). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is 20 not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are 25 preferable. In addition, when an acidic substance is released from the reaction, the reaction can be performed in the presence of a deoxidizer to remove the substance from the reaction system. As such deoxidizer, inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, 30 metal amides and the like are used. The deoxidizer is generally used in about 0.05 - 20 mol, preferably about 1-10 mol, per 1 mol of compound (lib) . In addition, for example, basic salts, organic bases and the like can also be used to promote the reaction. Such basic salts, organic bases and the 35 like are generally used in about 0.05 - 20 mol, preferably 114 WO 2011/163355 PCT/US2011/041443 about 1-10 mol, per 1 mol of compound (lib). While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 200 hr, preferably 30 min -48 hr. The reaction temperature is generally 0 - 200°C, preferably 50 - 150°C. In addition, microwave irradiation may be performed to promote the reaction.

[0169] (Step 5)

Compound (lie) can be produced by subjecting compound (Ilf) and compound (Ilg) to a substitution reaction, or a coupling reaction in the presence of a metal catalyst.

Compound (Ilg) is used in about 0.5 - 20 mol, preferably about 0.8 - 10 mol, per 1 mol of compound (Ilf). As the metal catalyst, a metal complex having a variety of ligands is used and, for example, palladium compounds [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, dichlorobis(triethylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, complex of [I,!'' — bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and 2- dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl(DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl(Xphos), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane)(Xantphos), or dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane (SPhos), etc.], nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (0), bis(triethylphosphine)nickel (II) chloride, bis(triphenylphosphine)nickel (II) chloride, etc.], copper compounds [e.g., copper oxide, copper(I) iodide, copper sulfate, copper(II) chloride, etc.] and the like can be mentioned. The metal catalyst is used in about 0.0001 - 5 mol, 115 WO 2011/163355 PCT/US2011/041443 preferably about 0.001 - 1 mol, per 1 mol of compound (Ilf).

This reaction is preferably performed in the presence of a base. Examples of the base include inorganic bases,· organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Ilf).

To promote the reaction, for example, sodium iodide, potassium iodide and the like may be added. Such sodium iodide, potassium iodide and the like are used in about 0.05 - 100 mol, preferably about 0.1 - 50 mol, per 1 mol of compound (Ilf). In addition, when a metal catalyst unstable to oxygen is used in this reaction, for example, the reaction is preferably performed in an inert gas stream such as argon gas, nitrogen gas and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides, esters, water and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min - 50 hr. The reaction temperature is -10 to 250°C, preferably 50 to 150°C.

In addition, microwave irradiation may be performed to promote the reaction.

[0170] (Step 2')

Compound (Ilh) can be produced by removing the protective group (P1) of compound (lie) . When P1 is a hydrogen atom, this step can be omitted. This reaction may be performed according to a method similar to that of the above-mentioned (Step 2). [0171] (Step 6)

Compound (la), which is the compound of the present invention, can be produced by subjecting compound (Ilh) and R1- 116 WO 2011/163355 PCT/US2011/041443 X3 to a substitution reaction in the presence of a base. iV'-X3 is used in about 0.05 - 100 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Ilh) . Examples of the base include inorganic bases, basic salts, organic bases, metal amides, alkali metal hydrides and the like. The base is used in about 0.5 - 10.0 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Ilh). To promote the reaction, for example, sodium iodide, potassium iodide and the like may be added. Such sodium iodide, potassium iodide and the like are used in about 0.05 - 100 mol, preferably about 0.1 - 50 mol, per 1 mol of compound (Ilh). This reaction is advantageously performed in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min - 24 hr. The reaction temperature is generally -20 - 250°C, preferably 0 - 230°C. In addition, microwave irradiation may be performed to promote the reaction. [0172]

Compounds (Ila), (lib) , (lie), (lid) , (He), (Ilf), (Ilg) and (Ilh) and R^-X3 may be commercially available products, or can be produced according to a method known per se or a method analogous thereto. In addition, compound (Ila) can be produced according to the method described in Synlett, vol. 13, page 2083 (2006) and the like, or a method analogous thereto.

Compound (Ilf) can also be produced according to the method described in Tetrahedron Letters, vol. 47, page 7567 (1993), Journal of Medicinal Chemistry, vol. 10, page 2697 (1990) and the like, or a method analogous thereto. Compound (Ilh) and R1-X3 can also be produced by a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction and the like, which may be used alone or in a 117 WO 2011/163355 PCT/US2011/041443

combination of two or more thereof. These reactions may be performed, for example, according to the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC 5 FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like.

[0173]

Scheme 2 ,z2-z3 Z1 A "Z4

r1-l1-/b^>—n'h nh2 lllc ,z2-z3 Z1 A "z4 >=< 10 wherein X4 is a leaving group, and other symbols are as defined above.

Compound (Ia-I) and compound (Ia-II), which are the compounds of the present invention, can be produced by 15 subjecting compound (Ilia) to a series of reaction steps in Steps 1', 7 and 3', and Steps 1', 7, 3' and 8, respectively. [0174] (Step 1')

Compound (Illb) can be produced by reacting compound 20 (Ilia) with compound (Ila'). Compound (Ilia) is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (Ila' ). This reaction is advantageously performed in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds and, 25 for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. In addition, when an acidic substance is released by the reaction, the 30 reaction can be performed in the presence of a deoxidizer to 118 WO 2011/163355 PCT/US2011/041443 remove the substance from the reaction system. As the deoxidizer, for example, inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like are used. The deoxidizer is generally used in about 0.05 - 20 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Ila'). In addition, for example, basic salts, organic bases and the like can also be used to promote the reaction. Such basic salts, organic bases and the like are generally used in about 0.05 - 20 mol, preferably about 0.1 -10 mol, per 1 mol of compound (Ila' ) . While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 50 -150°C. In addition, microwave irradiation may be performed to promote the reaction.

[0175] (Step 7)

Compound (IIIc) can be produced by subjecting compound (Illb) to a reduction reaction. This reaction can be performed according to a method known per se such as the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like, or a method analogous thereto. For example, a method using a reducing agent can be mentioned. Examples of the reducing agent include zinc, tin chloride, and complexes of hydrogen and, for example, palladium-carbon, palladium hydroxide-carbon, rhodium-carbon, platinum-carbon, Raney-nickel or the like. The reducing agent is generally used in about 0.0001 - 100 mol, preferably about 0.01 - 10 mol, per 1 mol of compound (Illb). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such 119 WO 2011/163355 PCT/US2011/041443 as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. 5 [0176] (Step 3')

Compound (Ia-I), which is the compound of the present invention, can be produced by subjecting compound (IIIc) to a cyclization reaction. This reaction can be performed according io to a manufacturing method known per se, for example, the method described in Australian Journal of Chemistry, vol. 4, page 775 (1982), Shinjikken Kagaku Koza (Courses in

Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd 15 edition, ACADEMIC PRESS, INC. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like, or a method analogous thereto. For example, a method using a carbonating agent can be mentioned. Examples of the carbonating agent include 1,1'-carbonylbis(1H-imidazole), 20 phosgene, triphosgene, diethyl carbonate, dimethyl carbonate, di-tert-butyl dicarbonate, bis(2,5-dioxopyrrolidin-l-yl)carbonate and the like. The carbonating agent is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (IIIc). In addition, a base can be used 25 to promote the reaction. Examples of the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (IIIc). This reaction is advantageously performed in 30 a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases, 35 water and the like or a mixed solvent thereof and the like are 120 WO 2011/163355 PCT/US2011/041443 preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 0 - 100°C. In addition, 5 microwave irradiation may be performed to promote the reaction [0177] (Step 8)

Compound (Ia-II), which is the compound of the present invention, can be produced by reacting compound (Ia-I) with Rd- 10 X4 in the presence of a base. The Rd-X4 is used in about 0.05 -100 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Ia-I). Examples of the base include inorganic bases, basic salts, organic bases, metal amides and the like. The base is used in about 0.5 - 10.0 mol, preferably about 1.0 - 5.0 mol, 15 per 1 mol of compound (Ia-I) . To promote the reaction, for example, sodium iodide, potassium iodide and the like may be added. Such sodium iodide, potassium iodide and the like are used in about 0.05 - 100 mol, preferably about 0.1 - 50 mol, per 1 mol of compound (Ia-I). This reaction is advantageously 20 performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides and the like or a mixed solvent thereof 25 and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min - 24 hr. The reaction temperature is generally -20 to 250°C, preferably 0 to 230°C. In addition, microwave irradiation may be performed to 30 promote the reaction.

[0178]

Compounds (Ilia), (Ila'), (Illb) and (IIIc) maybe commercially available products, or can be produced according to a method known per se or a method analogous thereto. In 35 addition, Rd-X4 may be a commercially available product, or can 121 WO 2011/163355 PCT/US2011/041443 also be produced by a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction and the like, which may be used alone or in a combination of two or more thereof. These reactions may be performed 5 according to, for example, the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. io (1989) and the like.

[0179]

Scheme 3

'/r r1-l2-vb

15 iVa wherein X5 above. is a leaving group, and other symbols are as defined

Compound (la'), which is the compound of the present invention, can be produced by subjecting compound (IVa) to the reaction step of Step 5'.

[0180] 20 (Step 5')

Compound (la'), which is the compound of the present invention, can be produced by subjecting compound (Ilf) and compound (IVa) to a substitution reaction in the presence of a metal catalyst as necessary. Compound (Ilf) is used in about 25 0.5-20 mol, preferably about 0.8 - 10 mol, per 1 mol of compound (IVa). As the metal catalyst, a metal complex having a variety of ligands is used and, for example, palladium compounds [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), 30 bis(triphenylphosphine)palladium(II) chloride, dichlorobis(triethylphosphine)palladium(0), 122 WO 2011/163355 PCT/US2011/041443 tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, complex of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 5 dichloromethane, complex of tris (dibenzylideneacetone) dipalladium(0) and 2-dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl(DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl(Xphos), (9,9-dimethyl-9H-xanthene-4,5- lo diyl)bis(diphenylphosphane)(xantphos), or dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.], nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (0), bis (triethylphosphine)nickel (II) chloride, bis(triphenylphosphine)nickel (II) chloride, etc.], rhodium is compounds [e.g., tris(triphenylphosphine)rhodium (III) chloride, etc.], cobalt compound, copper compounds [e.g., copper oxide, copper(I) iodide, copper sulfate, copper(II) chloride, etc.], platinum compound and the like can be mentioned. Of these, a palladium compound and a copper 20 compound are preferable. The metal catalyst is used in about 0.0001 - 5 mol, preferably about 0.001 - 1 mol, per 1 mol of compound (Ilf). This reaction is preferably performed in the presence of a base. Examples of the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, 25 metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Ilf). In addition, when a metal catalyst unstable to oxygen is used in this reaction, for example, the reaction is preferably performed in an inert gas stream such as argon gas, 30 nitrogen gas and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, 35 sulfoxides, esters, water and the like or a mixed solvent 123 WO 2011/163355 PCT/US2011/041443 thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min - 50 hr. The reaction temperature is -10 to 250°C, preferably 50 to 150°C.

In addition, microwave irradiation may be performed to promote the reaction.

[0181]

Compound (Ilf) and compound (IVa) may be commercially available products, or can also be produced according to the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989), Heterocycles, vol. 4, page 799 (1985) and the like, or a method analogous thereto. [0182]

Scheme 4

hM /=\ Z2-Z3 Z1' A "Z4 )==<

Cl na'N°3 χ·"ν>χ' VC n

Step 9

Rd-Xs

Step 8'

Step 1"

la’-H n

wherein W is an optionally substituted methylene group or a carbonyl group, X6 - X8 are each a leaving group, n is an integer of 1 to 5, and other symbols are as defined above. Examples of the substituent that the "methylene group" of the "optionally substituted methylene group" for W may have include 1 or 2 substituent selected from substituent group A.

Compound (Ia'-I) and compound (Ia'-II), which are the 124 WO 2011/163355 PCT/US2011/041443 compounds of the present invention, can be produced by- subjecting compound (Va) to a series of reaction steps in Steps 6', 9, Ί', 1", 7" and 3", and Steps 6', 9, 7', 1", Τ', 3" and 8', respectively.

[0183] (Step 6')

Compound (Vb) can be produced by subjecting compound (Va) and compound (Vh) to a substitution reaction. This reaction may be performed according to a method similar to that in (Step 6) above.

[0184] (Step 9)

Compound (Vd) can be produced by subjecting compound (Vb) and compound (Vc) to a substitution reaction. Compound (Vc) is used in about 0.5 - 10.0 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Vb). This reaction can be performed in the presence of a base to promote the reaction. Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 0.5 - 10.0 mol, preferably 0.8 -5.0 mol, per 1 mol of compound (Vb). In addition, to promote the reaction, for example, sodium iodide, potassium iodide and the like may be added. Such sodium iodide, potassium iodide and the like are used in about 0.05 - 100 mol, preferably about 0.1 - 50 mol, per 1 mol of compound (Vc). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min -24 hr. The reaction temperature is generally -20 to 250°C, preferably 0 to 230°C. In addition, microwave irradiation may 125 WO 2011/163355 PCT/US2011/041443 be performed to promote the reaction.

[0185] (Step 7')

Compound (Ve) can be produced by subjecting compound (Vd) 5 to a reduction reaction. This reaction may be performed according to a method similar to that in the above-mentioned (Step 7) .

[0186] (Step 1") io Compound (Vf) can be produced by reacting compound (Ve) with compound (Ila'). This reaction may be performed according to a method similar to that in the above-mentioned (Step 1'). [0187] (Step 7") 75 Compound (Vg) can be produced by subjecting compound (Vf) to a reduction reaction. This reaction may be performed according to a method similar to that in the above-mentioned (Step 7) .

[0188] 20 (Step 3")

Compound (la'-I), which is the compound of the present invention, can be produced by subjecting compound (Vg) to a cyclization reaction. This reaction can be performed according to a manufacturing method known per se, for example, the 25 method described in Bioorganic and Medicinal Chemistry Letters, vol. 6, page 1702 (2009); Journal of Medicinal Chemistry, vol. 13, page 3881 (2009); ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the 30 like, or a method analogous thereto and, for example, a method using a carbonating agent can be mentioned. Examples of the carbonating agent include 1,1'-carbonylbis(ΙΗ-imidazole), phosgene, triphosgene, diethyl carbonate, dimethyl carbonate, di-tert-butyl dicarbonate and the like. The carbonating agent 35 is generally used in about 0.2 - 5.0 mol, preferably about 0.5 126 WO 2011/163355 PCT/US2011/041443 - 2.0 mol, per 1 mol of compound (Vg) . When an acidic substance is released by the reaction, the reaction can be performed in the presence of a deoxidizer to remove the substance from the reaction system. As such deoxidizer, 5 inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like are used. The deoxidizer is generally used in about 0.2 - 10 mol, preferably about 0.5 - 6.0 mol, per 1 mol of compound (Vg). This reaction is advantageously performed in a solvent inert to the reaction io Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the 15 like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 0 - 100°C. In addition, microwave irradiation may be performed to promote the reaction 20 [0189] (Step 8')

Compound (Ia'-II), which is the compound of the present invention, can be produced by reacting compound (la'-I) with Rd-X8 in the presence of a base. This reaction may be 25 performed according to a method similar to that in the above-mentioned (Step 8).

[0190]

Compounds (Va), (Vb), (Vc), (Vd), (Ve), (Vf) and (Vg) and Rd-X8 may be commercially available products, or they can be 30 produced according to a method known per se or a method analogous thereto. In addition, compound (Vc) can also be produced according to a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction and the like, which may be used alone or in a combination of 35 two or more thereof. These reactions can also be performed 127 WO 2011/163355 PCT/US2011/041443 according to, for example, the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989); 5 Comprehensive Organic Transformations, VCH Publishers Inc. (1989), Synthesis, vol. 7, page 577 (1982), Journal of Organic

Chemistry, vol. 1, page 284 (2007), Russian Journal of General

Chemistry, vol. 9, page 1457 (2003) and the like. Compound (Vb) can also be produced according to the method described in io Tetrahedron Letters, vol. 22, page 3747 (2006) and the like, or a method analogous thereto.

[0191]

15 wherein X9 is a leaving group, and other symbols are as defined above.

Compound .(Ia'-III), which is the compound of the present invention, can be produced by subjecting compound (Ilh') to a series of reaction steps in Steps 10 and 11. 20 Compound (la'-III) can also be produced by subjecting compound (Ilh') to a series of reaction steps in Steps 10, 5" and 11'.

[0192] (Step 10) 25 Compound (Via) can be produced by reacting compound (Ilh') with a trifluoromethanesulfonylating agent. Examples of the trifluoromethanesulfonylating agent include trifluoromethanesulfonylchloride, trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide), N-(5- 128 WO 2011/163355 PCT/US2011/041443 chloropyridin-2-yl)-1,1,1-trifluoro-N- [(trifluoromethyl)sulfonyl]methanesulfonamide and the like.

The trifluoromethanesulfonylating agent is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (Ilh'). In addition, bases such as basic salts, organic bases and the like can be used to promote the reaction. The base is generally used in about 0.2 - 20.0 mol, preferably about 0.5 - 10.0 mol, per 1 mol of compound (Ilh'). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 100°C, preferably 0 - 70°C.

[0193] (Step 5")

Compound (Vic) can be produced by condensing compound (Via) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane. The condensation reaction is performed by reacting compound (Via) with 4,4,5,5-tetramethyl-l,3,2-dioxaborolane in the presence of a metal catalyst. The 4,4,5,5-tetramethyl-l,3,2-dioxaborolane is used in about 0.1 - 10 mol, preferably about 0.8 - 2.0 mol, per 1 mol of compound (Via). As the metal catalyst, palladium compound [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, dichlorobis(triethylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, complex of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 129 WO 2011/163355 PCT/US2011/041443 dichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and 2- dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl(DavePhos), 2-dicyclohexylphosphino-2', 4' , 6'-triisopropylbiphenyl(Xphos), 5 (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane)(xantphos) or dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane (SPhos) etc.] are preferable. . The metal catalyst is used in about 0.000001 - 5.0 mol, preferably about 0.0001 - 1.0 mol, per 1 mol of compound (Via) io This reaction is generally performed in the presence of a base Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Via). 15 When a metal catalyst unstable to oxygen is used in these reactions, the reaction is preferably performed, for example, in an inert gas stream such as argon gas, nitrogen gas and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly 20 limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending 25 on the reagent and solvent to be used, it is generally 1 min -200 hr, preferably 5 min - 100 hr. The reaction temperature is -10 to 250°C, preferably 0 to 150°C. In addition, microwave irradiation may be performed to promote the reaction.

[0194] 30 (Step 11)

Compound (Ia'-III), which is the compound of the present invention, can be produced by condensing compound (Via) and compound (VIb). The condensation reaction is performed by reacting compound (Via) with compound (VIb) in the presence of 35 a metal catalyst. Compound (VIb) is used in about 0.1 - 10 mol 130 WO 2011/163355 PCT/US2011/041443 preferably about 0.8 - 2.0 mol, per 1 mol of compound (Via).

As the metal catalyst, palladium compound [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, dichlorobis(triethylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, complex of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and 2- dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl(DavePhos), 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl(Xphos), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane)(xantphos) or dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.] is preferable.

The metal catalyst is used in about 0.000001 - 5.0 mol, preferably about 0.0001 - 1.0 mol, per 1 mol of compound (Via). This reaction is generally performed in the presence of a base. Examples of the base include inorganic bases, basic salts and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Via). When a metal catalyst unstable to oxygen is used in these reactions, the reaction is preferably performed, for example, in inert gas stream such as argon gas, nitrogen gas and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min -200 hr, preferably 5 min - 100 hr. The reaction temperature is -10 to 250°C, preferably 0 to 150°C. In addition, microwave 131 WO 2011/163355 PCT/US2011/041443 irradiation may be performed to promote the reaction.

[0195] (Step 11')

Compound (la'-III), which is the compound of the present invention, can be produced by reacting compound (Vic) with Ar-X9 in the presence of a base and a metal catalyst. This reaction may be performed according to a method similar to that in the above-mentioned (Step 11).

[0196]

Compounds (Ilh'), (Via), (VIb) and (Vic) and Ar-X9 may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

[0197]

Scheme 6

Ilf wherein X10 is a leaving group, and other symbols are as defined above.

Compound (lb), which is the compound of the present invention, can be produced by subjecting compound (Vila) to the reaction step of Step5"'.

[0198] (Step 5'")

Compound (lb), which is the compound of the present invention, can be produced by reacting compound (Vila) with compound (Ilf) in the presence of a base and a metal catalyst. This reaction may be performed according to a method similar to that in the above-mentioned (Step 5).

[0199]

Compound (Vila) and compound (Ilf) may be commercially 132 WO 2011/163355 PCT/US2011/041443 available products, or method known per se or can also be produced according to a method analogous thereto.

[0200]

Scheme 7

Step 8"

Rd-X11

wherein X11 and X12 are each a leaving group, and other symbols are as defined above.

Compound (Ib-I), which is the compound of the present invention, can be produced by subjecting compound (Villa) to io the reaction steps in Steps 4', 8", 2" and 6"'.

[0201] (Step 4')

Compound (VUIb) can be produced by subjecting compound (Villa) and compound (Ila") to a condensation reaction, or to 15 a coupling reaction in the presence of a metal catalyst. This reaction can also be performed according to a manufacturing method known per se, the method described in Synlett, vol. 13, page 2083 (2006) and the like, or a method analogous thereto. Compound (Ila") is generally used in about 0.2 - 5.0 mol, 20 preferably about 0.5 - 2.0 mol, per 1 mol of compound (Villa). As the metal catalyst, a metal complex having a variety of ligands is used and, for example, palladium compounds [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), 25 bis(triphenylphosphine)palladium(II) chloride, dichlorobis(triethylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), complex of 133 WO 2011/163355 PCT/US2011/041443 palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, complex of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane, complex of 5 tris(dibenzylideneacetone)dipalladium(0) and 2- dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl(DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl(Xphos), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane)(Xantphos) or dicyclohexyl (2',6'-io dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.], nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (0), bis(triethylphosphine)nickel (II) chloride, bis(triphenylphosphine)nickel (II) chloride, etc.], copper compounds [e.g., copper oxide, copper(I) iodide, copper 15 sulfate, copper(II) chloride, etc.] and the like can be mentioned. The metal catalyst is used in about 0.0001 - 5 mol, preferably about 0.001 - 1 mol, per 1 mol of compound (Ilf).

This reaction is preferably performed in the presence of a base. Examples of the base include inorganic bases,- organic 20 bases, metal alkoxides, alkali metal hydrides, metal amides and the like. This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic 25 hydrocarbons, saturated hydrocarbons, amides, ha.logenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. In addition, when an acidic substance is released by the reaction, the reaction can be performed in the presence 30 of a deoxidizer to remove the substance from the reaction system. As such deoxidizer, for example, inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like are used. The deoxidizer is generally used in about 0.05 - 20 mol, preferably about 1 - 35 10 mol, per 1 mol of compound (Villa) . In addition, for 134 WO 2011/163355 PCT/US2011/041443 example, basic salts, organic bases and the like can be used to promote the reaction. Such basic salts, organic bases and the like are generally used in about 0.05 - 20 mol, preferably about 1-10 mol, per 1 mol of compound (Villa). While the 5 reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 200 hr, preferably 30 min -48 hr. The reaction temperature is generally 0 - 200°C, preferably 50 - 150°C. In addition, microwave irradiation may be performed to promote the reaction. io [0202] (Step 8")

Compound (VIIIc) can be produced by reacting compound (VUIb) with Rd-Xu in the presence of a base. This reaction can be performed according to a method similar to that in the 15 above-mentioned (Step 8).

[0203] (Step 2")

Compound (VUId) can be produced by removing the protective group (P3) of compound (VIIIc). When P3 is a 20 hydrogen atom, this step can be omitted. This reaction can be performed according to a method similar to that in the above-mentioned (Step 2).

[0204] (Step 6") 25 Compound (Ib-I), which is the compound of the present invention, can be produced by reacting compound (VUId) with R2-X12 in the presence of a base. This reaction may be performed according to a method similar to that in the above-mentioned (Step 6). so [0205]

Compounds (Villa) , (Ila") , (VUIb) , (VIIIc) and (VUId) , and Rd-Xn and R2-X12 may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto. 135 WO 2011/163355 PCT/US2011/041443 [0206] Scheme £

Ilia' z2-z3 z1 a"z4

1 Z' W -L1-^ B1'/-NH NO2

Step 2“ O -L1—

Z,Z'Z3 z A

Ia-III ,14 Z2Z3 Z1 A "z4 >=< B1 y—NH NH2

Me' rN'R<

O X13 and X1* are each a leaving group, and the other are as defined above.

Step 3" R1-X14 Step 6" wherein symbols

Compound (Ia-III), which is the compounds of the present invention, can be produced by subjecting compound (Ilia') to a series of reaction steps in Steps 1'" , Ί’", 3''', 8''', 2''', and 6''' .

[0207] (Step 1" ')

Compound (Illb') can be produced by reacting compound (Ilia') with compound (Ila'). Compound (Ilia') is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 2.0 mol, per 1 mol of compound (Ila'). This reaction is advantageously performed in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof and the like are preferable. In addition, when an acidic substance is released by the reaction, the reaction can be performed in the presence of a deoxidizer to remove the substance from the reaction system. As the deoxidizer, for example, inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides 136 WO 2011/163355 PCT/US2011/041443 and the like are used. The deoxidizer is generally used in about 0.05 - 20 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Ila'). In addition, for example, basic salts, organic bases and the like can also be used to promote the reaction. Such basic salts, organic bases and the like are generally used in about 0.05 - 20 mol, preferably about 0.1 -10 mol, per 1 mol of compound (Ila'). While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is generally 0 - 200°C, preferably 50 -150°C. In addition, microwave irradiation may be performed to promote the reaction.

[0208] (Step 7" ')

Compound (IIIc') can be produced by subjecting compound (Illb') to a reduction reaction. This reaction can be performed according to a method known per se such as the method described in Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like, or a method analogous thereto. For example, a method using a reducing agent can be mentioned. Examples of the reducing agent include zinc, tin chloride, and complexes of hydrogen and, for example, palladium-carbon, palladium hydroxide-carbon, rhodium-carbon, platinum-carbon, Raney-nickel or the like. The reducing agent is generally used in about 0.0001 - 100 mol, preferably about 0.01 - 10 mol, per 1 mol of compound (Illb'). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases and the like or a mixed solvent thereof 137 WO 2011/163355 PCT/US2011/041443 and the like are preferable.

[0209] (Step 3" ' )

Compound (Ille) can be produced by subjecting compound 5 (IIIc') to a cyclization reaction. This reaction can be produced according to a manufacturing method known per se, for example, the method described in Australian Journal of Chemistry, vol. 4, page 775 (1982), Shinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (The io Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989);’ Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like, or a method analogous thereto. For example, a method using a carbonating agent can be mentioned. is Examples of the carbonating agent include 1,1'-carbonylbis(1H-imidazole), phosgene, triphosgene, diethyl carbonate, dimethyl carbonate, di-tert-butyl dicarbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate and the like. The carbonating agent is generally used in about 0.2 - 5.0 mol, preferably about 0.5 - 20 2.0 mol, per 1 mol of compound (IIIc'’). In addition, a base can be used to promote the reaction. Examples of the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in about 1.0 - 20 mol, preferably about 1.0 - 5.0 mol, 25 per 1 mol of compound (IIIc'). This reaction is advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated 30 hydrocarbons, nitriles, sulfoxides, aromatic organic bases, water and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 72 hr, preferably 30 min - 24 hr. The reaction temperature is 35 generally 0 - 200°C, preferably 0 - 100°C. In addition, 138 WO 2011/163355 PCT/US2011/041443 microwave irradiation may be performed to promote the reaction [0210] (Step 8" ' )

Compound (Illf) can be produced by reacting compound 5 (Ille) with Rd-X13 in the presence of a base. Rd-X13 is used in about 0.05 - 100 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Ille). Examples of the base include inorganic bases, basic salts, organic bases, metal amides and the like. The base is used in about 0.5 - 10.0 mol, preferably about 1.0 io - 5.0 mol, per 1 mol of compound (Ille). To promote the reaction, for example, sodium iodide, potassium iodide and the like may be added. Such sodium iodide, potassium iodide and the like are used in about 0.05 - 100 mol, preferably about 0.1 - 50 mol, per 1 mol of compound (Ille). This reaction is 15 advantageously performed in a solvent inert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides and the like or 20 a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min -24 hr. The reaction temperature is generally -20 to 250°C, preferably 0 to 230°C. In addition, microwave irradiation may 25 be performed to promote the reaction.

[0211] (Step 2" ')

Compound (Illg) can be produced by removing the protective group (P1) of compound (Illf). When P1 is a 30 hydrogen atom, this step can be omitted. This reaction may be performed according to a method similar to that of the above-mentioned (Step 2).

[0212] (Step 6' " ) 35 Compound (Ia-III), which is the compound of the present 139 WO 2011/163355 PCT/US2011/041443 invention, can be produced by subjecting compound (Illg) and

Rx-X14 to a substitution reaction in the presence of a base. R1-X14 is used in about 0.05 - 100 mol, preferably about 0.1 - 10 mol, per 1 mol of compound (Illg). Examples of the base 5 include inorganic bases, basic salts, organic bases, metal amides, alkali metal hydrides and the like. The base is used in about 0.5 - 10.0 mol, preferably about 1.0 - 5.0 mol, per 1 mol of compound (Illg). This reaction is advantageously performed in a solvent inert to the reaction. The solvent is io not particularly limited as long as the reaction proceeds and, for example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides and the like or a mixed solvent thereof and the like are preferable. While the reaction time varies 15 depending on the reagent and solvent to be used, it is generally 10 min - 100 hr, preferably 30 min - 24 hr. The reaction temperature is generally -20 - 250°C, preferably 0 -230°C. In addition, microwave irradiation may be performed to promote the reaction. 20 [0213]

Compounds (Ilia'), (Ila'), (Illb') , (IIIc') , (Hie) , (Illf) and (Illg) may be commercially available products, or can be produced according to a method known per se or a method analogous -thereto. In addition, Rd-X13 and F^-X14 may be 25 commercially available products, or can also be produced by a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction and the like, which may be used alone or in a combination of two or more thereof.

These reactions may be performed according to, for example, 30 the method described in Shinjikken Kagaku Koza (Courses in

Experimental Chemistry), vols. 14 and 15 (The Chemical Society of Japan ed. ) , ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989) and the like.. 140 WO 2011/163355 PCT/US2011/041443 [0214]

Compound (I) obtained by the above-mentioned methods can be isolated and purified by, for example, general separation means such as recrystallization, distillation, chromatography and the like. When the thus-obtained compound (I) of the present invention is in a free form, it can be converted to a salt thereof by a known method or a comparable method (e.g., neutralization etc.). Alternatively, when it is obtained as a salt, it can be converted to a free form or other salt by a known method or a comparable method.

In any of the above-mentioned manufacturing methods and steps, compound (I) can be synthesized by known protection and deprotection reactions, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, substituent exchanging reactions and the like, which may be used alone or in a combination of two or more thereof.

[0215]

Compound (I) may be used as a prodrug. A prodrug of compound (I) means a compound converted to compound (I) by a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in the living body, that is, a compound converted to compound (I) by oxidation, reduction, hydrolysis, etc. due to an enzyme, a compound converted to compound (I) by hydrolysis etc. due to gastric acid, and the like. A prodrug of compound (I) may be a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound (I) to eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in compound (I) to acylation, alkylation, phosphorylation 141 WO 2011/163355 PCT/US2011/041443 or boration (e.g., a compound obtained by subjecting a hydroxy group in the compound (I) to acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxy group in compound (I) to esterification or amidation (e.g., a compound obtained by subjecting a carboxy group in compound (I) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation, etc.) and the like. Any one of these compounds can be produced from compound (I) by a method known per se. In addition, a prodrug of compound (I) may also be a compound converted into compound (I) under physiological conditions, such as those described in IYAKUHIN no KAIHATSU (Development of

Pharmaceuticals), Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

[0216]

The compound of the present invention has an excellent PDE10A inhibitory activity and is useful for the following diseases and symptoms in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats, etc. particularly in humans): psychotic disorder (e.g., brief psychotic disorder, shared psychotic disorder); psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; delusional disorder; anxiety disorder; movement disorder; mood disorder; major depressive disorder; 142 WO 2011/163355 PCT/US2011/041443 a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; major depressive episode of the mild, moderate or severe type; manic or mixed mood episode; hypomanic mood episode; depressive episode with atypical features; depressive episode with melancholic features; depressive episode with catatonic features; mood episode with postpartum onset; post-stroke depression; dysthymic disorder; minor depressive disorder; autism; drug addiction; neurodegenerative disorder; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with- cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy;

Alzheimer's disease; dementia; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS-related dementia; frontotemporal dementia; delirium; amnestic disorder; 143 WO 2011/163355 PCT/US2011/041443 post-traumatic stress disorder; mental retardation; learning disorder (e.g., reading disorder, mathematics disorder, or a disorder of written expression); attention-deficit/hyperactivity disorder; age-related cognitive decline; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; bipolar disorders comprising bipolar I disorder, and bipolar II disorder; cyclothymic disorder;

Parkinson's disease;

Huntington's disease; paranoid; schizophrenia (e.g., paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia); schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; personality disorder of the paranoid type; personality disorder of the schizoid type; obesity; metabolic syndrome; non-insulin dependent diabetes mellitus (NIDDM); glucose intolerance; [0217]

In particular, the compound of the present invention is useful for preventing or treating schizophrenia.

[0218]

Since the compound of the present invention demonstrates excellent metabolic stability, superior therapeutic effects on the aforementioned diseases are expected even at a low dosage.

The compound of the present invention shows low toxicity and can be administered safely, as it is, or in a dosage form 144 WO 2011/163355 PCT/US2011/041443 which is manufactured according to a per se known method for manufacturing pharmaceutical formulations (e.g., methods described in Japanese Pharmacopoeia) such as tablets (inclusive of sugar coated tablet, film coated tablet, sublingual tablet, orally disintegrable tablet, and buccal), pills, powders, granules, capsules (inclusive of soft capsule, and microcapsule), troches, syrups, liquid dosage forms, emulsions, controlled-release preparations (e.g., quick-release preparation, sustained-release preparation, sustained-release microcapsule), aerosols, films (e.g., orally disintegrable film, adhesive film for application to oral-cavity mucosa), injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, percutaneous absorbent, ointment, lotion, patch, suppositories (e.g., rectal suppository, vaginal suppository), pellets, transnasal preparations, pulmonary preparations (inhalant), eye drops and the like, in an oral or parenteral route (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic instillation, intracerebral, intrarectal, intravaginal , intraperitoneal, directly to lesion).

The compound of the present invention can be administered orally or non-orally (e.g., including local, rectal and venous routes).

[0219]

Here, as a pharmaceutical acceptable carrier, common organic or inorganic carrier substances are used as formulation raw materials. Carriers are added as vehicles, lubricants, binders and disintegrants in the solid formulations; and as solvents, solubilizing agents, suspending agents, isotonization agents, buffers and soothing agents in the liquid formulations. If desired, formulation additives such as antiseptics, antioxidants, colorants, sweeteners, etc. can be used. 145 WO 2011/163355 PCT/US2011/041443 [0220]

Favorable examples of the vehicles are as follows: lactose, sucrose, D-mannitol, D-sorbitol, starch, a-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum Arabic, pullulan, light silicic anhydride, synthetic aluminum silicate and magnesium metasilicic aluminate.

Favorable examples of the lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.

[0221]

Favorable examples of the binders are as follows: a-starch, sucrose, gelatin, gum Arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

[0222]

Favorable examples of the disintegrants are as follows: lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride and low-substituted hydroxypropylcellulose.

[0223]

Favorable examples of the solvents are as follows: water for injection, physiological saline, Linger solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

[0224]

Favorable examples of the solubilizing agents are as follows: polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzylbenzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

[0225]

Favorable examples of the suspending agents are as 146 WO 2011/163355 PCT/US2011/041443 follows: surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylamino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose; polysorbates, and polyoxyethylene-hardened castor oil.

[0226]

Favorable examples of the isotonization agents include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

Favorable examples of the buffers include buffer solutions of phosphates, acetates, carbonates and citrates.

Favorable examples of the soothing agents include benzyl alcohol.

Favorable examples of the antiseptics include para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Favorable examples of the antioxidants include sulfites and ascorbates.

[0227]

Favorable examples of the colorants include water soluble edible tar dyes (e.g., edible dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and 2); water insoluble lake dyes (e.g., aluminum salts of the aforementioned water soluble edible tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide).

Favorable examples of the sweeteners include sodium saccharin, dipotassium glycyrrhizate, aspartame and stevia. [0228]

The medical compositions of the present invention can be manufactured by the common methods in the field of formulation technology, for example, methods listed in the Japanese pharmacopoeia. Specific manufacturing methods for formulations are described in detail below. 147 WO 2011/163355 PCT/US2011/041443

The content of the compound of the present invention in the medical compositions of the present invention varies based on the dosage forms, dosages of the compound of the present invention, etc. For example, the content approximately ranges from 0.01 to 100 wt% and preferably from 0.1 to 95 wt% relative to the entire amount of the composition.

[0229]

The dosage of the compound of the present invention depends upon injection targets, administration routes, target diseases, symptoms, etc. For example, in the case of oral administration in patients with schizophrenia (adults, bodyweight of approximately 60 kg), generally a single dose ranges from approximately 0.1 to 20 mg/kg bodyweight, preferably from approximately 0.2 to 10 mg/kg bodyweight, further preferably from approximately 0.5 to 10 mg/kg bodyweight, and this dosage is preferably administered once daily or several times daily (e.g., 3 times).

[0230]

The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of psychosis, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, major depression, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss, e.g., nicotinic «7 agonists, nicotinic a 7 partial agonists, nicotinic a7 positive allosteric modulators, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, Glycine transporter 1 inhibitors, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, triple reuptake inhibitors, cannabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and 148 WO 2011/163355 PCT/US2011/041443 galantamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range, and can be administered either simultaneously or sequentially.

Drugs suitable in combination with the compounds of the present invention include, but are not limited to, other suitable schizophrenia drugs such as Haloperidol, Clozapine, Olanzapine, Risperidone, Aripiprazole, Ziprasidone,

Paliperidone, and Quetiapine fumarate; bipolar disorder drugs, including, but not limited to, Lithium, Olanzapine,

Aripiprazole, and Valproic acid; Parkinson's disease drugs, including, but not limited to, Levodopa, Bromocriptine, Pergolide, Pramipexole, Tolcapone, Procyclidine,

Trihexyphenidyl, and Benztropine; agents used in the treatment of major depression, including, but not limited to, Amitriptyline, Protriptyline, Desipramine, Nortriptyline, Paroxetine, Fluoxetine, Sertraline, Bupropion, Escitalopram, Mirtazapine, Venlafaxine, Duloxetine; agents used in the treatment of Alzheimer's disease, including, but not limited to, Galantamine, Tacrine, Donepezil, Rivastigmine, Memantine, Neotropin, Selegiline, Estrogen and Iodoquinol; agents used in the treatment of dementia, including, but not limited to, Thioridazine, Haloperidol, Risperidone, Tacrine, Donepezil, and Rivastigmine; agents used in the treatment of epilepsy, including, but not limited to, Phenytoin, Phenobarbital, Carbamazepine, Valproic acid, Ethosuximide, Gabapentin, Phenobarbital, Solfeton and Felbatol; agents used in the treatment of multiple sclerosis, including, but not limited to, Tolterodine, Oxybutynin, Oxycodone, Interferon beta-lb, Interferon beta-la, Azathioprine, Methotrexate and Glatiramer; agents used in the treatment of Huntington's disease, including, but not limited to, Amitriptyline, Protripthline, Desipramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Tetrabenazine, Haloperidol, Chlorpromazine, Thioridazine, Sulpiride, Quetiapine, Clozapine, and Risperidone; agents 149 WO 2011/163355 PCT/US2011/041443 useful in the treatment of diabetes, including, but not limited to, PPAR ligands (e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues (e.g., sulfonylurea drugs, such as Glyburide, Glimepiride, Chlopropamide, Tolbutamide, and Glipizide, and non-sulfonyl secretagogues), α-glucosidase inhibitors (such as Acarbose, Miglitol, and Voglibose), insulin sensitizers (such as the PPAR-γ agonists, e.g., the glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and llbeta-HSD inhibitors), hepatic glucose output lowering compounds (such as glucagon antagonists and metformin, e.g., Glucophage and Glucophage XR), insulin and insulin derivatives (both long and short acting forms and formulations of insulin); and antiobesity drugs, including, but not limited to, β-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors, Ciliary Neurotrophic Factor and derivatives (e.g., Axokine), appetite suppressants (e.g., Sibutramine), and lipase inhibitors (e.g., Orlistat).

[0231]

The form of administration of concomitant drugs with the compound of the present invention is not particularly limited and is acceptable as long as the compound of the present invention is combined with concomitant drugs at the time of administration. Examples of such forms of administration are as follows: (1) administration of a single formula obtained by simultaneous formulation of the compound of the present invention with a concomitant drug, (2) simultaneous administration via the same administration route for two kinds of formulas obtained by independent formulations of the compound of the present invention and a concomitant drug, (3) administrations at different times via the same administration route for two kings of formulas obtained by independent formulations of the compound of the present invention and a concomitant drug, 150 WO 2011/163355 PCT/US2011/041443 (4) simultaneous administration via different administration routes for two kinds of formulas obtained by independent formulations of the compound of the present invention and a concomitant drug, 5 (5) administrations at different times via different administration routes for two kinds of formulas obtained by independent formulations of the compound of the present invention and a concomitant drug (For example, administration in the order of the composition of the present invention and io then a concomitant drug, or administration in the reversed order). These forms of administration are summarized below and abbreviated as a concomitant agent of the present invention. [0232]

When administering the concomitant agent of the present 15 invention, a concomitant drug and the compound of the present invention can be administered at the same time, but the compound of the present invention can be administered after a concomitant drug is administered or after the compound of the present invention is administered, a concomitant drug can be 20 administered. When administering at different times, the time difference depends upon the active ingredients to be administered, drug forms and methods of administration. For example, when a concomitant drug is administered first, the compound of the present invention can be administered within 1 25 min to 3 days, preferably within 10 min to 1 day and more preferably within 15 min to 1 hour after the concomitant drug is administered. However, if the compound of the present invention is administered first, a concomitant drug can be administered within 1 min to 1 day, preferably within 10 min. 30 to 6 hours and more preferably within 15 min to 1 hour after the compound of the present invention is administered.

[0233]

If there are no problems with side effects of the concomitant drugs, any dosages can be set. A daily dosage as a 35 concomitant drug depends upon dosages, administration subjects, 151 WO 2011/163355 PCT/US2011/041443 administration routes, target diseases, symptoms, etc. For example, in the case of oral administration in patients with schizophrenia (adults, bodyweight of approximately 60 kg), a normal daily dosage ranges from about 0.1 to 20 mg/kg 5 bodyweight, preferably from about 0.2 to 10 mg/kg bodyweight and more preferably from about 0.5 to 10 mg/kg bodyweight. It is preferable that this dosage is administered once daily to several times daily (e.g., 3 times).

If the compound of the present invention is used in io combination with a concomitant drug, the respective dosages can be reduced within a safe range with consideration of the opposite effects of the respective drugs.

[0234]

The concomitant agent of the present invention exhibits 15 low toxicity. For example, the compound of the present invention or(and) the aforementioned concomitant drug can be combined with a pharmaceutically acceptable carrier according to the known method to prepare a medical composition such as tablets (including sugar-coated tablets and film-coated 20 tablets), powder agents, granular agents, capsules (including soft capsules), liquids, injection solutions, suppositories, sustained-release agents, etc. These compositions can be administered safely orally or non-orally (e.g., including local, rectal and venous routes). 25 [0235]

The pharmaceutically acceptable carriers that can be used for manufacturing the concomitant agent of the present invention can be the same as those used in the medical composition of the present invention as mentioned above. 30 [0236] A mixing ratio between the compound of the present invention and a concomitant drug in the concomitant agent of the present invention can be selected appropriately based on the administration subjects, administration routes and 35 diseases. 152 WO 2011/163355 PCT/US2011/041443

The aforementioned concomitant drugs can be combined at an appropriate proportion if two or more drugs are combined. A dosage of the concomitant drug can be selected appropriately based on the dosages used clinically. In addition, a mixing ratio between the compound of the present invention and a concomitant drug can be selected appropriately based on the administration subjects, administration routes, target diseases, symptoms, combinations, etc. For example, if the administration subject is humans, a concomitant drug can be used in an amount ranging from 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.

[0237]

For example, the content of the compound of the present invention in the concomitant agent of the present invention varies with the drug form of formulations. Generally, it is present in a range from about 0.01 to 99.9 wt%, preferably from about 0.1 to 50 wt% and more preferably from about 0.5 to 20 wt% relative to the entire formula.

[0238]

The content of a concomitant drug in the concomitant agent of the present invention varies with the drug form of formulations. Generally it is present in a range from about 0.01 to 99.9 wt%, preferably from about 0.1 to 50 wt% and more preferably from about 0.5 to 20 wt% relative to the entire formula.

[0239]

The content of an additive such as carriers in the concomitant agent of the present invention varies with the drug form of formulations. Generally it is present in a range from about 1 to 99.99 wt% and preferably from about 10 to 90 wt% relative to the entire formula.

[0240]

When the compound of the present invention and a concomitant drug are formulated independently, the same 153 WO 2011/163355 PCT/US2011/041443 contents can be applied.

[0241]

Since the dosages may fluctuate under various conditions as mentioned above, a dosage less than the aforementioned dosages may be sufficient or it may be necessary to administer at a dosage exceeding the range.

[0242]

Examples

The present invention is explained in detail by referring to the following Reference Examples, Examples, Formulation Examples, and Experimental Examples. These examples are mere embodiments, which do not limit the present invention, and can be modified within the range not deviating from the scope of the present invention.

The "room temperature" in the following Reference Examples and Examples is generally about 10°C to about 35°C. % in the yield means mol/mol%, % of solvent used for chromatography means % by volume, and % used for others means wt%. In proton NMR spectrum, OH and NH protons and the like that cannot be identified since they are broad bands are not recorded in the data. In silica gel chromatography, Kiesselgel 60 manufactured by Merck &amp; Co., Inc. was used, and Chromatorex NH manufactured by Fuji Silysia Chemical Ltd. was used in basic silica gel chromatography.

Other abbreviations used in the text mean the following. s: singlet d: doublet dd: doublet of doublets dt: doublet of triplets t: triplet tt: triplet of triplets td: triplet of doublets q: quartet septet: septet m: multiplet 154 WO 2011/163355 PCT/US2011/041443 br: broad J: coupling constant Hz: Hertz CDC13: deuterated chloroform 5 DMSO-d6: deuterated dimethyl sulfoxide XH NMR: proton nuclear magnetic resonance HPLC: high performance liquid chromatography THF: tetrahydrofuran DMF: Ν,Ν-dimethylformamide 10 DMSO: dimethyl sulfoxide DMA: N,N-dimethylacetamide DIEA: diisopropylethylamine NMP: N-methylpyrrolidone Boc20: di-tert-butyl dicarbonate 15 DMAP: 4-dimethylaminopyridine TEA: triethylamine

NaHMDS: sodiumbis(trimethylsilyl) amide mCPBA: meta-chloroperbenzoic acid DMTMM: 4-(4,6-dimethoxy-l,3, 5-triazin-2-yl)-4- 20 methylmorpholinium chloride n-hydrate CDI: 1,1'-carbonylbis(lH-imidazole) DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

Pd(Ph3P) 4: tetrakis(triphenylphosphine)palladium(0)

Pd2 (dba)3: tris(dibenzylideneacetone)dipalladium(0) 25 TBAF: tetra-n-butylammonium fluoride TMEDA: tetramethylethylenediamine IPE: diisopropyl ether DME: 1,2-dimethoxyethane DIPEA: N,N-diisopropylethylamine 30 LC-MS: liquid chromatography-mass spectrometry spectrum ESI: electrospray-ionization method aq.: aqueous solution sat.: saturated rt: room temperature 35 [0243] 155 WO 2011/163355 PCT/US2011/041443

All reagents and solvents were of commercial quality and used without further purification. Column chromatography was performed using Merck silica gel 60 (230-400 mesh). The compounds and/or intermediates were purified by preparative 5 high performance liquid chromatography (prep. HPLC) using a Gilson High through Put purification system.

The columns were reversed phase YMC CombiPrep Pro C18, S 5 pm, 19 x 50 mm. A gradient elution was used (flow rate 20 mL/min), typically starting with 5% acetonitrile/95% water and io progressing to 100% acetonitrile over a Period of 7 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA).

Mass spectrometric analysis was performed according to liquid chromatography/mass spectroscopy (LCMS) methods. The method employed a Waters LC-MS System (Agilent HP1100 HPLC and 15 a Micromass ZMD mass spectrometer for the LCMS instrument, a CAPCELL PAK C18, UG120, S-3 pm, 1.5 x 35 mm for the chromatography column), and a solvent system that was a 5-95% gradient of acetonitrile in water with 0.04% TFA over a 3.60 min period (flow rate 0.5 mL/min molecular weight range 200- 20 800; cone Voltage 20 V; column temperature 40°C) . All masses were reported as those of the protonated parent ions.

Example [0244] 25 Example 1 3-(4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

la) N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine 156 PCT/US2011/041443 WO 2011/163355

To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 mL) was added dropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) in NMP (50 mL). After the 5 addition was complete, the mixture was stirred at ambient temperature for 1 h. After this time, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4) and filtered. The filtrate was io concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-white solid. MS (ESI+): [M+H]+ 226. 15 [0245] lb) N-(1,3-benzoxazol-2-yl)-Ν' -(3-nitropyridin-2-yl)benzene-1, 4-diamine

A mixture of N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine 20 (0.50 g) and 2-chloro-3-nitropyridine (0.352 g) in NMP (3.0 mL) was stirred at 140°C for 1.5 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 χ 100 mL). The combined organic extracts were washed with brine (100 25 mL), dried (Na2SO4) , filtered and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)-N'-(3- nitropyridin-2-yl)benzene-1,4-diamine (0.335 g) as a red solid 157 WO 2011/163355 PCT/US2011/041443 MS (ESI+): [M+H]+ 348.

[0246] lc) N2-[4- (1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine

5 A solution of N-(1,3-benzoxazol-2-yl)-N'-(3-nitropyridin- 2-yl)benzene-1,4-diamine (0.330 g) in methanol (20 mL) was treated with palladium on carbon (0.060 g, 10% wt on activated carbon) and the mixture was hydrogenated (1 atm H2) for 1 h. After this time, the reaction mixture was filtered through io diatomaceous earth. The filtrate was concentrated under reduced pressure to afford N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.294 g) as a yellow solid. MS (ESI+): [M+H]+ 318. is [0247]

Id) 3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of N2-[4-(1,3-benzoxazol-2- 20 ylamino)phenyl]pyridine-2,3-diamine (0.080 g) and triethylamine (0.0638 g) in THF (1.5 mL) at 0°C, was added dropwise a solution of triphosgene (0.030 g) in THF (0.6 mL). The reaction mixture was stirred at 0°C for 0.5 h. The cold bath was removed and the stirring continued at ambient 25 temperature for another 0.5 h. After this time, a saturated aqueous solution of sodium bicarbonate was added. The organic layer was extracted with ethyl acetate (3 χ 100 mL). The combined organic extracts were washed with brine (50 mL), 158 WO 2011/163355 PCT/US2011/041443 dried (Na2SO4) , filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylene chloride) to afford 3-[4-(1,3-5 benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (0.038 g) as a white solid. MS (ESI+) : [M+H]+ 344. XH NM [R (50 0 MHz, DMSO-dg) δ 7.08 (1H, dd, J = 8 .0, 5.5 Hz) r 7.15 (1H, dt, J = 7.5, 1.0 Hz) , 7.24 (1H, dt, J = 7.5, 1 .0 Hz), 7.39 (1H, dd, J = 7.5, 1.5 Hz) , 7.48 (1H, d, J = 7.5 Hz), 7.52 (1H, d, J = 8 .0 Hz), 7.60-1 '.63 (2H, m), 7.88-7. .91 (2H, m) r 7.93 (1H, dd, J = 5.0, 1.5 Hz) , 10.79 (1H, s), 11.34 (1H, s) .

[0248]

Example 2 15 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2a) N- (4-nitrophenyl)-lH-benzimidazol-2-amine

20 nitroaniline (9.05 g) in NMP (130 mL) was stirred at 120°C for 3 days. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (750 mL) and washed with water (750 mL). The aqueous layer was extracted 25 with ethyl acetate (750 mL) and the combined organic extracts were washed with water (3 χ 750 mL) then brine (750 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was triturated with 1:1 ethyl acetate/heptane (200 mL) and the 159 WO 2011/163355 PCT/US2011/041443 solid that formed was collected by filtration to afford N-(4-nitrophenyl)-lH-benzimidazol-2-amine (4.00 g) as an orange solid. 1H NMR (500 MHz, DMSO-cfe) δ 7.06-7.08 (2H, m) , 7.36-7.37 (1H, 5 m), 7.45-7.46 (1H, m), 8.00 (1H, d, J = 9.0 Hz), 8.23-8.25 (2H, m), 10.43 (1H, brs), 11.31 (1H, brs).

[0249] 2b) 1-(4-nitrophenyl)-2,3-dihydro-lH-imidazo[1,2-a]benzimidazole

A mixture of N-(4-nitrophenyl)-lH-benzimidazol-2-amine (1.00 g) in DMF (20 mL) at ambient temperature was treated with a 60% dispersion of sodium hydride in mineral oil (393 mg) then stirred for 5 min. The mixture was treated with a 15 solution of 1,2-dibromoethane (738 mg) in DMF (1 mL) then stirred at ambient temperature for 1 h. After this time, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (80 mL) and extracted with ethyl acetate (2 χ 100 mL). The combined organic layers 20 were washed with 5% aqueous lithium chloride (2 χ 50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-2,3- 25 dihydro-lH-imidazo[1,2-a]benzimidazole (63 mg) as a yellow solid. MS (ESI+): [M+H]+ 281.

[0250] 2c) 4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)aniline

160 WO 2011/163355 PCT/US2011/041443

Same procedure of example 1c) with 1-(4-nitrophenyl)-2,3 dihydro-lH-imidazo[1,2-a]benzimidazole (61 mg) gave'4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)aniline (55 mg) as an off-white solid. 5 MS (ESI+): [M+H]+ 251.

[0251] 2d) N-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl) phenyl] -3-nitropyridin-2-amine

io A mixture of 4-(2,3-dihydro-lH-imidazo[1,2- a]benzimidazol-l-yl)aniline (55 mg) and 2-chloro-3-nitropyridine (35 mg) in NMP (3 mL) was stirred at 140°C overnight. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted 15 with ethyl acetate (2 χ 75 mL). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl 20 acetate/methylene chloride) to afford N-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]-3-nitropyridin-2-amine (34 mg) as a dark brown solid. MS (ESI+): [M+H]+ 373.

[0252] 25 2e) N2-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]pyridine-2,3-diamine

Same procedure of example lc) with N-[4-(2,3-dihydro-lH- imidazo[1,2-a]benzimidazol-l-yl)phenyl]-3-nitropyridin-2-amine 30 (34 mg) gave N2-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol- l-yl) phenyl]pyridine-2,3-diamine (20 mg) as a yellow solid. 161 WO 2011/163355 PCT/US2011/041443 MS (ESI+): [M+H] + 343.

[0253] 2f) 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of N2-[4-(2,3-dihydro-lH-imidazo[l,2-a]benzimidazol-l-yl)phenyl]pyridine-2,3-diamine (20 mg) and l,lz -carbonyldiimidazole (19 mg) in ,THF (5 mL) was stirred at ambient temperature overnight. After this time, the solids io that formed were collected by filtration to afford 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg) as off-white crystals. MS (ESI+): [M+H]+ 369. is NMR (500 MHz, DMSO-dg) δ 4.38-4.41 (2H, m) , 4.59-4.63 (2H, m) , 7.06-7.10 (3H, m) , 7.29-7.31 (1H, m), 7.39 (1H, dd, J = 7.5, 1.0 Hz), 7.43-7.45 (1H, m), 7.65 (2H, d, J = 9.0 Hz), 7.93-7.95 (3H, m), 11.34 (1H, brs).

[0254] 20 Example 3 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]- 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-[4-(2,3-dihydro-lH-imidazo[1,2-25 a]benzimidazol-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5—

b]pyridin-2-one (57 mg) and methyl iodide (0.012 mL) in DMF (2.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0°C. The mixture was stirred at 0°C for 1 h, and then added H2O. The precipitate was collected and washed with MeOH to give 30 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]- 162 WO 2011/163355 PCT/US2011/041443 1-methyl-1, 3-dihydro-2H-imidazo [4,5-b] pyridin-2-one (43 mg) as white powder. MS (ESI+): [M+H]+ 383.0. ΧΗ NMR (300 MHz, DMSO-d6) δ 3.44 (3H, s) , 4.33-4.46 (2H, m) , 5 4.53-4.71 (2H, m), 7.01-7.12 (2H, m), 7.13-7.22 (1H, m), 7.24- 7.35 (1H, m), 7.39-7.50 (1H, m), 7.55-7.74 (3H, m), 7.82-8.15 (3H, m) .

[0255]

Example 4 io 1-[4-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]- 1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

o 4a) 1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one 15 A mixture of N-(4-nitrophenyl)-lH-benzimidazol-2-amine (947 mg) and N,W-diisopropylethylamine (1.45 g) in THF (10 mL) at -78°C was treated dropwise with.a solution of bromoacetyl bromide (826 mg) in THF (2.0 mL) then the resulting mixture 20 was allowed to warm to ambient temperature overnight. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 χ 100 mL). The organic layers were washed with brine (50 mL), dried over sodium sulfate,.and filtered and the filtrate was concentrated under 25 reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92 mg) as a yellow solid. XH NMR (300 MHz, CDC13) δ 4.84 (2H, s) , 7.31 (1H, d, J = 7.8 30 Hz), 7.40 (1H, td, J = 7.8, 1.2 Hz), 7.63 (1H, d, J = 9.6 Hz),

7.81 (1H, d, J = 7.5 Hz), 7.91 (2H, d, J = 9.3 Hz), 8.36 (2H 163 WO 2011/163355 PCT/US2011/041443 d, J= 9.0 Hz).

[0256] 4b) 1-(4-aminophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one nA /a

Same procedure of example 1c) with 1-(4-nitrophenyl)-1,2 dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92 mg) gave 1-(4-aminophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (82 mg) as a yellow solid. 10 MS (ESI+) : [M+H]+ 265.

[0257] 4c) 1—{4—[(3-nitropyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

NH NO2 15 Same procedure of example 2d) with 1-(4-aminophenyl)-1,2 dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (82 mg) gave 1—{4— [(3-nitropyridin-2-yl)amino]phenyl}-!,2-dihydro-3H- imidazo[1,2-a]benzimidazol-3-one (7 mg) as a yellow solid. MS (ESI+): [M+H]+ 387. 20 [0258] 4d) 1—{4—[(3-aminopyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one Ολ nA, //

•NH NH2

Same procedure of example lc) with l-{4-[(3-nitropyridin 25 2-yl)amino]phenyl]-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol- 3-one (7 mg) gave 1-{4-[(3-aminopyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (7 mg) as a yellow solid. MS (ESI+): [M+H]+ 357. 164 WO 2011/163355 PCT/US2011/041443 [0259] 4e) 1-[4-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

\—_/~N nA /=

NH 10 15

Same procedure of example 2f) with l-{4-[(3-aminopyridin- 2- yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol- 3- one (7 mg) gave 1-[4-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,2-dihydro-3H-imidazo[1,2- a]benzimidazol-3-one (4 mg) as yellow crystals. MS ,(ESI+) : [M+H]+ 383. A NMR (500 MHz, CDC13) δ 4.80 (2H, s) , 7.08 (1H, dd, J= 8.0, 5.5 Hz), 7.33-7.36 (3H, m), 7.59 (1H, d, J = 8.0 Hz), 7.78 (1H d, J = 8.0 Hz), 7.81-7.83 (3H, m), 7.92 (2H, d, J = 9.5 Hz), 8.09 (1H, dd, J= 5.0, 1.0 Hz).

[0260]

Example 5 1-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

20 5a) 1-(4-nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-

A mixture of ΙΗ-pyrrolo[2,3-b]pyridin-2(3H)-one (431 mg), l-bromo-4-nitrobenzene (778 mg), copper(I) iodide (122 mg), 25 W1, T^-dimethylethane-l,2-diamine (113 mg) and potassium iodide (1.36 g) in 1,4-dioxane (10 ml) was sparged with argon for 5 min then heated overnight at 95°C. After this time, the reaction mixture was cooled to ambient temperature, diluted 165 WO 2011/163355 PCT/US2011/041443 with ethyl acetate (100 mL), filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 1-(4- 5 nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (207 mg) as a white solid. MS (ESI+): [M+H]+ 256.

[0261] 5b) 1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2- 10 one

Same procedure of example lc) with l-(4-nitrophenyl)-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (145 mg) gave 1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 15 mg) as a yellow solid. MS (ESI+): [M+H]+ 226.

[0262] 5c) 1-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Same procedure of example la) with 1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg) and 2-chlorobenzo[d]oxazole (98 mg) gave 1-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 25 (126 mg) as yellow crystals. MS (ESI+): [M+H]+ 343. NMR (500 MHz, DMSO-dg) δ 3.80 (2H, s) , 7.08 (1H, dd, J= 7.5 5.5 Hz), 7.15 (1H, td, J= 8.0, 1.5 Hz), 7.24 (1H, td, J= 7.5

1.0 Hz), 7.45-7.49 (3H, m), 7.52 (1H, d, J = 8.0 Hz), 7.70 (1H 30 dd, J = Ί.0, 1.0 Hz), 7.87 (2H, d, J = 9.0 Hz), 8.08-8.09 (1H, 166 WO 2011/163355 m), 10.79 (1H, brs). PCT/US2011/041443 [0263]

Example 6 3-[4-(1,3-benzoxazol-2-ylamino)phenyl][1,3]oxazolo[4,5-5 b]pyridin-2(3H)-one

o 6a) 3-(4-nitrophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one

A solution of oxazolo[4,5-b]pyridin-2(3H)-one (200 mg) in io DMF (3.5 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (62 mg) and the resulting mixture stirred at ambient temperature for 5 min. The mixture was treated with l-fluoro-4-nitrobenzene (248 mg) then stirred at 100°C for 17 h. After this time, the reaction mixture was 15 cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with water (2 χ 50 mL), 5% aqueous lithium chloride (50 mL) then brine (50 mL) , dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography 20 (silica, heptane to 1:1 ethyl acetate/heptane) to afford 3-(4-nitrophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (73 mg) as a yellow solid. MS (ESI+): [M+H]+ 258.

[0264] 25 6b) 3-(4-aminophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one

Same procedure of example lc) with 3-(4- nitrophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (70 mg) gave 3-(4-aminophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (55 mg) 167 WO 2011/163355 PCT/US2011/041443 as an off-white solid. MS (ESI+): [M+H]+ 228.

[0265] 6c) 3-[4-(1,3-benzoxazol-2-ylamino)phenyl][1,3]oxazolo[4,5-5 b]pyridin-2(3H)-one

Same procedure of example la) with 3-(4-aminophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (50 mg) and 2- chlorobenzo[d]oxazole (40 mg) gave 3-[4-(1,3-benzoxazol-2-io ylamino)phenyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one (58 mg) as brown crystals. MS (ESI+): [M+H]+ 345. NMR (500 MHz, DMSO-de) δ 7.15-7.18 (1H, m) , 7.23-7.27 (2H, m) , 7.49 (1H, dd, J= 7.5, 0.5 Hz), 7.52 (1H, d, J = 8.0 Hz), 15 7.68-7.71 (2H, m), 7.81 (1H, dd, J= 8.0, 1.5 Hz), 7.92-7.95 (2H, m), 8.11 (1H, dd, J = 5.5, 1.5 Hz), 10.88 (1H, s).

[0266]

Example 7 3- [4-(lH-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H- 20 imidazo[4,5-b]pyridin-2-one

o 7a) N- [4-(benzyloxy)phenyl]-3-nitropyridin-2-amine

A mixture of 2-chloro-3-nitropyridine (2.0 g), 4-25 (benzyloxy)aniline hydrochloride (3.6 g), and cesium carbonate (12.3 g) in NMP (50 ml) was heated at 100°C for 5 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column 30 chromatography (SiO2, hexane/AcOEt=l/l) to give N-[4- 168 WO 2011/163355 PCT/US2011/041443 (benzyloxy)phenyl]-3-nitropyridin-2-amine (3.04 g) as a brown solid. MS (ESI+): [M+H]+ 322.0.

[0267] 5 7b) N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine

A mixture of N- [4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (1.5 g), Fe (2.6 g), and CaCl2 (260 mg) in EtOH (30 mL) and H2O (6.0 mL) was heated at 100°C for 6 h. After cooling to 20 rt, the precipitate was removed by Celite, and the filtrate was concentrated. The residue was partitioned between AcOEt and sat.NaHCO3aq. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=3/2 to 1/1). The 25 obtained solid was rinsed with 2Pr20-hexane to give N2-[4- (benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g) as a pale pink solid. MS (ESI+): [M+H]+ 292.1.

[0268] 20 7c) 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI (668 mg), and DBU (1.2 mL) in THF (25 mL) was 25 heated at 60°C overnight. After cooling to rt, the mixture was partitioned between AcOEt and H20. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=97/3 to 9/1) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H- 30 imidazo[4,5-b]pyridin-2-one (993 mg) as a pale brown solid. MS (ESI+): [M+H]+ 318.0.

[0269] 169 7d) 3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one WO 2011/163355 PCT/US2011/041443

A mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-5 imidazo[4,5-b]pyridin-2-one (500 mg) and Pd-C (100 mg) in MeOH (30 mL) was stirred at room temperature for 5.5 h. The mixture was filtered by Celite, and the filtrate was concentrated. The resulting solid was rinsed with ΛΡη2Ο to give 3-(4- hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 io mg) as a pale brown solid.

[0270] 7e) 3—{4— [ (1—{ [2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-(4-hydroxyphenyl)-1, 3-dihydro-2H-imidazo[4,5-b]pyridin 2-one (370 mg), 2-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-IH-benzimidazole (507 mg) and cesium carbonate (1.17 g) in DMF (10 mL) was heated at 100°C for 4 h. After cooling to rt, the 20 mixture was partitioned between AcOEt and H20. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=l/l to 0/1) to give 3-{4-[ (1—{ [2- (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- 25 yl)oxy]phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as white crystals. MS (ESI+): [M+H]+ 474.0.

[0271] 7f) 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H- 30 imidazo[4,5-b]pyridin-2-one 170 PCT/US2011/041443 WO 2011/163355

A mixture of 3—{4—[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), 1 M TBAF in THF (6.3 mL) , and TMEDA 5 in THF (20 mL) was heated at 50°C for 24 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=l/3 then AcOEt/MeOH=95/5). The obtained product 10 was recrystallized from MeOH-iPr2O to give 3-[4-(lH- benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) as white crystals. MS (ESI+): [M+H]+ 343.9. NMR (300 MHz, DMSO-d6) δ 7.11 (3 H, dd, J = 5.7, 3.8 Hz), 15 7.32 - 7.47 (3 H, m), 7.54 (2 H, d, J = 8.0 Hz), 7.74 (2 H, d, J = 8.3 Hz), 7.95 (1 H, d, J = 4.9 Hz), 12.04 (2 H, brs).

[0272]

Example 8 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-1-ethyl-l,3-dihydro-2H- 20 imidazo[4,5-b]pyridin-2-one hydrochloride

2-Chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazole (1.861 g) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 25 (1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at room temperature. The mixture was heated at 200 °C for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5% - 50% 30 EtOAc in hexane) to give l-ethyl-3-{4-[(1—{[2-(trimethylsilyl) ethoxy]methyl}-lH-benzimidazol-2- 171 WO 2011/163355 PCT/US2011/041443 yl)oxy]phenyl} -1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of l-ethyl-3-{4-[(1- {[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 5 mg) and 2 M HC1 in EtOH (6.0 mL) was stirred at 70°C for 4 h.

After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3- [4-(lH-benzimidazol-2-yloxy)phenyl]-1-ethyl-l, 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg). 10 MS (ESI+): [M+H]+ 372.1. τΗ NMR (300 MHz, DMSO-d6) δ 1.17-1.43 (3H, m) , 3.78-4.15 (2H, m), 7.12-8.06 (10H, m), 8.62 (2H, brs).

[0273]

Example 9 15 1-[4-(lH-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one dihydrochloride

9a) 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g), 4-methylbenzenesulfonic acid hydrate (0.178 g), and (2-chloropyridin-3-yl)acetic acid (Journal of Medicinal Chemistry, 1990, 33, 2697 - 2706.) (1.61 g) in 1-pentanol (15 mL) was 25 stirred at 140°C for 24 h. After cooling to room temperature, the mixture was added to SiC>2, and the mixture was concentrated and purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39 g) as a pale 30 yellow solid. MS (ESI+): [M+H]+ 317.0. 172 WO 2011/163355 PCT/US2011/041443 [0274] 9b) 1-[4-(benzyloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2, 3-b]pyridin-2-one

o A mixture of 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (350 mg), iodomethane (0.145 mL), and sodium hydride (49 mg) (60% in mineral oil) in DMF (5 mL) was stirred at 0°C to room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (198 mg) as an orange solid. MS (ESI+): [M+H]+ 345.4.

[0275] 9c) 1-(4-hydroxyphenyl)-3,3-dimethyl-l,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one

Same procedure of example lc) with l-[4-(benzyloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (198 mg) gave 1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (139 mg) as a white solid. MS (ESI+): [M+H]+ 255.4.

[0276] 9d) 3,3-dimethyl-l-{4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}- lH-benzimidazol-2-yl)oxy]phenyl}-l,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one 173 PCT/US2011/041443 WO 2011/163355

Same procedure of example 7e) with 1-(4-hydroxyphenyl)-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (139 mg) and 2-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH- 5 benzimidazole (155 mg) gave 3,3-dimethyl-l-{4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (258 mg) as white crystals. MS (ESI+): [M+H]+ 501.1. io [0277] 9e) 1-[4-(lH-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one dihydrochloride A mixture of 3,3-dimethyl-l-{4-[(1—{[2- 15 (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (258 mg) and 2N HC1 in EtOH (5 mL) in EtOH (5 mL) was stirred at 60°C for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to 20 give 1-[4-(lH-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one dihydrochloride (152 mg) . MS (ESI+): [M+H]+ 371.0. XH NMR (300 MHz, DMSO-d6) δ 1.45 (6H, s) , 7.12-7.23 (3H, m) , 25 7.38-7.48 (2H, m) , 7.49-7.72 (4H, m), 7.87 (1H, dd, J =7.4, 1.7 Hz), 8.13 (1H, dd, J = 5.3, 1.9 Hz), 8.67 (3H, brs).

[0278]

Example 10 3-[4-(l-benzyl-2-methyl-lH-benzimidazol-4-yl)phenyl]-l-{[2- 30 (trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 174 PCT/US2011/041443 WO 2011/163355 Λ,

'a; 10a) 3-[4-(benzyloxy)phenyl]-l-{[2- (trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[2-(Chloromethoxy)ethyl](trimethyl)silane (1.673 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and sodium hydride (0.504 g) (60% in mineral oil) in DMF (5.0 mL) at 0°C. The mixture was io stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. After the reaction, the reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-{[2- 15 (trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.75 g) as a white solid. MS (ESI+): [M+H]+ 448.1 [0279] 10b) 3-(4-hydroxyphenyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}- 20 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one ho·

Same procedure of example 7d) with 3—[4— (benzyloxy)phenyl]-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.82 g) gave 3-(4- 25 hydroxyphenyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.23 g) as a white solid. MS (ESI+): [M+H]+ 358.4. 175 WO 2011/163355 PCT/US2011/041443 [0280] 10c) 4-(2-oxo-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,2-dihydro-3H-imidazo[4, 5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate

N-Phenylbis(trifluoromethanesulfonimide) (4.46 g) was added to a solution of 3-(4-hydroxyphenyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.23g) and triethylamine (8.69 mL) in THF (20 mL) at room temperature. The mixture was stirred at 70°C under a dry atmosphere (CaCl2 tube) for 3h. The mixture was neutralized with sat.NaHCO3aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in hexane) to give 4-(2-oxo-l-{ [2-(trimethylsilyl)ethoxy]methyl}-!,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (2.90 g) as tan oil. MS (ESI+): [M+H]+ 490.3.

[0281] lOd) 3-[4-(4,4,5,5-tetramethyl·-1,3,2-dioxaborolan-2- yl)phenyl]-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of 4-(2-oxo-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (2.6 g), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.77 mL), triethylamine (2.23 mL), [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) 176 WO 2011/163355 PCT/US2011/041443 dichloromethane adduct (0.218 g) and THF (21.2 mL) was heated at 100°C for 3h under microwave irradiation. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in 5 hexane) to give 3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil. MS (ESI+): [M+H]+ 468.2.

[0282] io lOe) 3-[4-(l-benzyl-2-methyl-lH-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Benzyl chloride (1.527 mL) was added to a solution of 4- 15 bromo-2-methyl-lH-benzimidazole (1.40g) and sodium hydride (0.531 g) in DMF (10 mL) at 0°C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, 20 eluted with 5% - 50% EtOAc in hexane) to give l-benzyl-4-bromo-2-methyl-lH-benzo[d]imidazole (1.88 g) as tan oil. The mixture of l-benzyl-4-bromo-2-methyl-lH-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l-{[2-(trimethylsilyl)ethoxy]methyl}-!,3-dihydro- 25 2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100°C for lh under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, 30 dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give 3-[4-(l-benzyl-2-methyl-lH- 177 WO 2011/163355 PCT/US2011/041443 benzimidazol-4-yl)phenyl]-l-{[2- (trimethylsilyl)ethoxy]methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals. MS (ESI+): [M+H]+ 562.4. 5 [0283]

Example 11 3-(4-quinolin-8-ylphenyl)-l-{[2- (trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of 4-(2-oxo-l-{[2-(trimethylsilyl)ethoxy]methyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (500 mg), 8-quinolineboronic acid (265 mg), Pd(Ph3P)4 (35.4 mg), 2 M Na2CO3 25 (1.02 mL) and CH3CN (10 mL) was heated at 150°C for 20 min under microwave irradiation. The mixture was diluted with sat .NaHCO3aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by 20 column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-(4-quinolin-8-ylphenyl)-l-{[2-(trimethylsilyl)ethoxy]methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (410 mg) as white crystals. MS (ESI+): [M+H]+ 469.1. 25 [0284]

Example 12 l-Ethyl-3-[4-(ΙΗ-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

30 12a) 1-(4-nitrophenyl)-ΙΗ-pyrazolo[3,4-b]pyridine 178 PCT/US2011/041443 WO 2011/163355

N

To a stirred solution of lH-pyrazolo[3,4-b]pyridine (300 mg) in DMF (3.0 mL) was added sodium hydride (101 mg) (60% in mineral oil) with ice-cooling. The mixture was stirred at room 5 temperature for 30 min, and then l-fluoro-4-nitrobenzene (355 mg) was added. After stirring at room temperature for 2h, the mixture was warmed up to 50°C. The mixture was stirred at 50°C for 12 h. Cesium carbonate (821 mg) was added and the mixture was stirred at 100°C for 12h, and treated with water and AcOEt. io The insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was used for the next reaction. 15 [0285] 12b) 4-(lH-pyrazolo[3,4-b]pyridin-l-yl)aniline

nh2

Same procedure of example lc) with 1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine obtained from example 12a) gave 4-(lH-pyrazolo[3,4-b]pyridin-l-yl)aniline (50 mg). 20 MS (ESI+): [M+H]+ 211.1.

[0286] 12c) 3-[4-(lH-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

25 o A mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (120 mg), Pd2(dba)3 (21.8 mg), Xantphos (27.5 mg), and sodium tert-butoxide (34.3 mg) in 2-propanol (8.0 mL) and toluene (2.0 mL) was stirred at 90°C for 16h, treated with water and extracted with EtOAc. The organic layer was separated, dried 30 over MgSO4 and concentrated in vacuo. The residue was suspended 179 WO 2011/163355 PCT/US2011/041443 in DMSO/ CH3CN and the insoluble material was collected by filtration to give 3-[4-(lH-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg). The filtrate was concentrated and chromatographed on silica 5 gel eluting with AcOEt/Hexane=2/l. Removal of solvent gave second crop (10 mg). MS (ESI+): [M+H]+ 329.0.

[0287] 12d) l-Ethyl-3-[4-(iH-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-1,3- 10 dihydro-2H-imidazo[4, 5-b]pyridin-2-one

o A mixture of 3-[4-(lH-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) and iodoethane (10.5 μΐ) was stirred at 50°C for 30 min, 15 treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with Hexane/AcOEt=2/1 -1/2. The product was crystallized from AcOEt/hexane to give 1-ethyl-3-[4-(IH-pyrazolo[3,4-b]pyridin-l-yl)phenyl]-1,3- 20 dihydro-2H-imidazo[4,5-b]pyridin-2-one (13 mg). MS (ESI+): [M+H]+ 357.4. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 7.20 (1H, dd, J = 7.7, 5.1 Hz), 7.35-7.48 (1H, m), 7.64-7.77 (1H, m) , 7.83-7.97 (2H, m) , 7.97-8.07 (1H, m) , 25 8.39-8.50 (3H, m), 8.53 (1H, s), 8.73 (1H, dd, J= 4.5, 1.5 Hz) .

[0288]

Example 13 3-[1-(lH-benzimidazol-2-yl)-2,3-dihydro-lH-indol-5-yl]-1- 30 ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 180 WO 2011/163355 PCT/US2011/041443 13a) tert-butyl 5-nitro-2,3-dihydro-lH-indole-l-carboxylate

Boc

To a stirred mixture of 5-nitroindoline (5.0 g) and Boc20 (7.07 mL) in THF (100mL) was added DMAP (0.5 g) at room 5 temperature. The mixture was stirred at 60°C for 3h. The mixture was quenched with water, treated with sat. NaHCO3aq. and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was used for the next reaction without further purification. io [0289] 13b) tert-butyl 5-amino-2,3-dihydro-lH-indole-l-carboxylate

Boc 1

Under H2 atmosphere, a mixture of tert-butyl 5-nitro-2,3-dihydro-lH-indole-l-carboxylate, obtained from example 13a), 15 and 10% Pd-C (5 g) in EtOH (100 mL) was stirred at room temperature for 12h, filtered and concentrated in vacuo to give tert-butyl 5-amino-2,3-dihydro-lH-indole-l-carboxylate (6.80 g). XH NMR (300 MHz, DMSO-d6) δ 1.47 (9H, s) , 2.91 (2H, t, J = 8.5 20 Hz), 3.79 (2H, t, J = 8.5 Hz), 4.73 (2H, brs), 6.33 (1H, dd, J = 8.7, 2.3 Hz), 6.43 (1H, s), 6.95-7.53 (1H, m).

[0290] 13c) tert-butyl 5-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole-l-carboxylate

A mixture of tert-butyl 5-amino-2,3-dihydro-lH-indole-l- carboxylate (4.10 g), tert-butyl 2-chloropyridin-3-ylcarbamate (4.20 g) , Pd2(dba)3 (0.48 g) , Xantphos (0.608 g), sodium tert- butoxide (2.52 g) in 2-propanol (64 mL) and toluene (12 mL) 181 WO 2011/163355 PCT/US2011/041443 was stirred at 90°C for 40 h, and treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN and the precipitate was collected by filtration to give tert- 5 butyl 5- (2-oxo-l,2-dihydro-3H-imidazo[4,5-b] pyridin-3-yl) -2,3-dihydro-lH-indole-l-carboxylate (1.64 g). The filtrate was evaporated and then the residue was chromatographed on silica gel eluting with AcOEt/ Hexane = 2/1 to afford second crop (1.4 g). io MS (ESI+): [M+H]+ 353.3.

[0291] 13d) tert-butyl 5-(l-ethyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole-l-carboxylate

is A mixture of tert-butyl 5-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole-l-carboxylate (900 mg), ethyl iodide (418 mg) and cesium carbonate (1.25 g) in DMF (10 mL) was stirred at 50°C for 12 h, treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 20 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/ Hexane to give tert-butyl 5-(1-ethyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole-l-carboxylate (830 mg) as an amorphous solid MS (ESI+): [M+H]+ 381.2. 25 [0292] 13e) 3-(2,3-dihydro-lH-indol-5-yl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred solution of tert-butyl 5-(l-ethyl-2-oxo-l,2- 30 dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole- 1-carboxylate (100 mg) in EtOAc (2 mL) was added 4N HC1 in 182 WO 2011/163355 PCT/US2011/041443

AcOEt solution (2.0 mL) . The mixture was stirred at 50°C for 2h and evaporated. The residue was treated with sat.NaHCChaq. and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3-(2,3-dihydro-lH-indol-5- 5 yl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. This residue was used for the next reaction. MS (ESI+): [M+H]+ 281.2.

[0293] 13f) 3- [1- (lH-benzimidazol-2-yl) -7., 3-dihydro-lH-indol-5-yl] -1-io ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-(2,3-dihydro-lH-indol-5-yl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one obtained from example 13e) and 2-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH- 15 benzimidazole (108 mg) in NMP (2.0 mL) was stirred at 120°C for 12 h, treated with sat.NaHCOsaq. and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC and crystallized from AcOEt/ Hexane to give 3-[1-(lH-benzimidazol-2-yl)-2,3- 20 dihydro-lH-indol-5-yl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg). MS (ESI+): [M+H]+ 397.4. NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.2 Hz), 3.33-3.39 (2H, m) , 3.92-4.03 (2H, m), 4.24 (2H, t, J = 8.7 Hz), 6.96- 25 7.20 ( 3H, m), 7.30-7.36 (1H, m) , 7.38-7.48 (3H, m) , 7.56-7.70 (1H, m) , 7.91-8.03 (1H, m), 8.36 (1H, d, J = 8.7 Hz), 11.72 (1H, s) .

[0294]

Example 14 30 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8- one 183 PCT/US2011/041443 WO 2011/163355

14a) 4-chloro-5-nitropyrimidine

The mixture of 5-nitropyrimidin-4-ol (1.04 g) and 5 phosphorus oxychloride (5.66 g) in acetonitrile (10 mL) was stirred at reflux for 2 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was io diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (50 mL) then brine (50 mL), and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:3 ethyl acetate/heptane) to afford 4- 15 chloro-5-nitropyrimidine (383 mg, 33%) as a colorless oil. ΧΗ NMR (300 MHz, CDC13) δ 9.19 (s, 1H), 9.25 (s, 1H).

[0295] 14b) N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine

20 A mixture of 4-chloro-5-nitropyrimidine (380 mg) and benzene-1,4-diamine (257 mg) in N-methylpyrrolidone (5 mL) was stirred overnight at ambient temperature. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 χ 50 mL). The combined organic layers 25 were washed with saturated sodium bicarbonate (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the 184 WO 2011/163355 PCT/US2011/041443 filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 3:97 methanol/methylene chloride) to afford N-(5- nitropyrimidin-4-yl)benzene-1,4-diamine (260 mg) as a brown 5 oil. MS (ESI+): [M+H]+ 232. ΤΗ NMR (300 MHz, CDC13) δ 3.79 (br s, 2H) , 6.74 (d, J = 8.7 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 8.74 (s, 1H), 9.28 (s, 1H), 9.92 (br s, 1H). io [0296] 14c) N-l,3-benzoxazol-2-yl-N'-(5-nitropyrimidin-4-yl)benzene-1, 4-diamine

A mixture of N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine 15 (256 mg), 2-chloro-l,3-benzoxazole (110 mg) in N- methylpyrrolidone (3 mL) was stirred at 120°C for 45 min.

After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 20 water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:3 ethyl acetate/methylene chloride) to afford N-l,3-benzoxazol-2-yl-N'-(5- 25 nitropyrimidin-4-yl)benzene-1,4-diamine (107 mg) as a red solid. MS (ESI+): [M+H]+ 349.

[0297] 14d) N4-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5- 30 diamine 185 PCT/US2011/041443 WO 2011/163355

A mixture of N-l,3-benzoxazol-2-yl-N'-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (54 mg) and 5% palladium on carbon (22 mg, 50% water by weight) in methanol (5 mL) was stirred 5 under an atmosphere of hydrogen (balloon) for 1 h. After this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford N4-[4-(1, 3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (49 mg) as a brown solid. io MS (ESI+) : [M+H]+ 319. TH NMR (300 MHz, DMSO-cfe) δ 5.14 (br s, 2H), 7.11 (td, J= 7.5, 1.2 Hz, 1H), 7.21 (td, J = 7.5, 0.9 Hz, 1H), 7.43 (dd, J = 8.4, 0.6 Hz, 1H), 7.48 (d, J= 7.5 Hz, 1H), 7.70 (s, 4H), 7.76 (s, 1H), 8.02 (s, 1H), 8.28 (br s, 1H), 10.52 (br s, 1H). 15 [0298] 14e) 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one

A mixture of N4-[4-(1,3-benzoxazol-2- 20 ylamino)phenyl]pyrimidine-4,5-diamine (55 mg) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (53 mg) in DMF (5 mL) was stirred overnight at 80°C then at 95°C for 3 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate 25 (100 mL) . The organic layer was washed with water (50 mL), 5% aqueous lithium chloride (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 186 WO 2011/163355 PCT/US2011/041443 methanol/methylene chloride), solvent exchanged with acetonitrile and freeze dried from acetonitrile/water to afford 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one (19 mg) as off-white crystals. 5 MS (ESI+): [M+H] + 345. ΧΗ NMR (500 MHz, DMSO-cfe) δ 7.16 (td, J= 7.5, 1.0 Hz, 1H), 7.25 (td, J= 7.5, 1.0 Hz, 1H), 7.48 (d, J= 7.0 Hz, 1H), 7.52 (d, J= 7.5 Hz, 1H) , 7.62 (d, J= 9.0 Hz, 2H) , 7.91 (d, J = 9.0 Hz, 2H), 8.33 (s, 1H), 8.56 (s, 1H), 10.84 (br s, 1H), io 11.62 (br s, 1H) .

[0299]

Example 19 l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-l-methyl-lH-benzimidazole (500 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (789 mg) and NaH (132 mg) in DMF (10 mL) at room temperature. The mixture was heated at 150°C 20 for lh under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give l-ethyl'-3-{4- [ (1-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5— 25 b]pyridin-2-one (950 mg) as white crystals. MS (API+): [M+H]+ 386.2. XH NMR (300 MHz, DMSO-d6) δ 1.17-1.45 (3H, m), 3.76 (3H, s), 3.92-4.06 (2H, m), 7.08-7.27 (3H, m), 7.39-7.53 (2H, m), 7.56-7.64 (2H, m), 7.65-7.73 (1H, m) , 7.73-7.84 (2H, m) , 7.96-8.08 30 (1H, m) .

Anal. Calcd for C22H19N5O2: C, 68.56; H, 4.97 ;N, 18.17 . Found: C, 68.40; H, 5.00; N, 17.94 .

Mp: 184-186°C 187 WO 2011/163355 PCT/US2011/041443 [0300]

Example 24 3-[4-(2, 3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]- 1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-[4-(2,3-dihydro-lH-imidazo[1,2- a] benzimidazol-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5- b] pyridin-2-one (150 mg) and ethyl iodide (0.1 mL) in DMF (4.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at io 0°C. The mixture was stirred at 0°C for 1 h, and then H2O was added. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-lH-imidazo[1,2-a]benzimidazol-l-yl) phenyl] -1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23 mg) as white powder. 15 MS (ΆΡΙ+): [M+H]+ 397.1. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.30 (3H, t, J=7.2Hz), 3.98 (2H, q, J=7.2Hz), 4.34-4.46 (2H, m), 4.55-4.67 (2H, m), 7.03-7.11 (2H, m), 7.13-7.21 (1H, m), 7.27-7.35 (1H, m), 7.40-7.49 (1H, m) , 7.62-7.71 (3H, m), 7.90-8.01 (3H, m) . 20 [0301]

Example 31 l-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

25 31a) 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (12.5 g), 4-benzyloxyaniline hydrochloride (19.3 g), 9,9- 188 WO 2011/163355 PCT/US2011/041443 dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2.0 g) and sodium tert-butoxide (12.6 g) in toluene (160 mL) - 2-propanol (40.0 mL) was stirred at 100°C under Ar overnight. The reaction mixture was concentrated in vacuo. The residue 5 was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 g) as a light brown solid. MS (API+): [M+H]+ 318.1. 10 1H NMR (300 MHz, DMSO-d6) δ 5.18 (2H, s) , 7.02-7.22 (3H, m) , 7.29-7.59 (8H, m) , 7.86-7.94 (1H, m), 11.11-11.64 (1H, m) . [0302] 31b) 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 15

The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.50 g), sodium hydride (380 mg) and iodoethane (1.60 mL) in DMF (40 mL) was stirred at 20°C under a dry atmosphere (CaCl2 tube) for lh. The mixture was 20 concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a colorless solid. 25 MS (API+): [M+H]+ 346.4. XH NMR (300 MHz, CDC13) δ 1.40 (3H, t, J = 7.2 Hz), 4.02 (2H, q, J = 7.2 Hz), 5.11 (2H, s), 7.01-7.17 (3H, m) , 7.22-7.29 (1H, m) , 7.29-7.49 (5H, m) , 7.53-7.61 (2H, m), 8.00-8.09 (1H, m) . [0303] 30 31c) l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 189 PCT/US2011/041443 WO 2011/163355

A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro 2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.83 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.42 g) as a white solid. MS (API+): [M+H]+ 256.1. XH NMR (300 MHz, DMSO-d6) δ 1.27 (3H, t, J = 7.2 Hz), 3.95 (2H, q, J = 7.2 Hz), 6.84-6.95 (2H, m), 7.08-7.18 (1H, m), 7.32-7.40 (2H, m), 7.57-7.67 (1H, m), 7.89-7.99 (1H, m), 9.67-9.79 (1H, m). (0304] 31d) ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate

ci n-Butyllithium (1.6M in hexane, 45.1 mL) was added to a solution of 2-chloroimidazo[1,2-a]pyridine (10 g) in THF (120 mL) at -78°C. After stirring for 30 min, ethyl chlorocarbonate (7.82 g) in THF (10 mL) was added to the mixture at the same temperature and stirred for 1 h and then 10 h at room temperature. The mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (13.20 g) as an off-white solid. MS (API+): [M+H]+ 225.0. NMR (300 MHz, DMSO-d6) δ 1.37 (3 H, m) , 4.40 (2 H, m) , 7.31 (1 H, s), 7.66 (1 H, s), 7.72 - 7.86 (1 H, m), 9.17 - 9.32 (1 190 WO 2011/163355 PCT/US2011/041443 H, m) .

[0305] 31e) l-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4, 5-b]pyridin-2-one

The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (220 mg), NaH (70 mg) and l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (255 mg) in DMF (2 mL) was stirred at 100°C under a dry atmosphere io (CaCl2 tube) for Ih. The mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give l-ethyl-3-[4-(imidazo[1,2-a]pyridin- 2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 is mg) as white crystals. MS (API+): [M+H]+ 372.4. XH NMR (300 MHz, DMSO-d6) δ 1.23-1.36 (3H, m), 3.92-4.06 (2H, m), 6.90-7.00 (1H, m), 7.11-7.23 (1H, m) , 7.23-7.41 (3H, m) , 7.44-7.54 (1H, m), 7.60-7.75 (4H, m) , 7.94-8.10 (1H, m), 8.47- 20 8.60 (1H, m) .

[0306]

Example 39 l-ethyl-3-(4—{[1-(2-hydroxyethyl)-lH-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 25 39a) ethyl {2-[4-(l-ethyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-lH-benzimidazol-l-yl[acetate

Ethyl bromoacetate (0.240 mL) was added to a solution of 191 WO 2011/163355 PCT/US2011/041443 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and sodium hydride (86 mg) in DMF (2 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 2h. 5 The reaction mixture was diluted with MeOH (5 ml), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give ethyl {2-[4-(l-ethyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H- 10 benzimidazol-l-yl]acetate (480 mg) as off-white crystals. MS (API+): [M+H]+ 458.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.24 (3H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.2 Hz), 3.99 (2H, q, J = 7.2 Hz), 4.22 (2H, q, J = 7.0 Hz), 5.18-5.28 (2H, m), 7.11-7.25 (3H, m), 7.42-7.60 (4H, m), 15 7.65-7.72 (1H, m), 7.74-7.83 (2H, m), 7.96-8.05 (1H, m) .

[0307] 39b) l-ethyl-3-(4—{[1-(2-hydroxyethyl)-lH-benzimidazol-2-yl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 Lithium aluminum hydride (33.2 mg) was added to a solution of ethyl {2-[4-(l-ethyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-lH-benzimidazol-1-yl]acetate (200 mg) in THF (4 mL) at 0°C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) 25 for 30 min. The mixture was quenched with EtOAc and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give l-ethyl-3-(4—{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]oxyJphenyl)-1,3-dihydro-2H-imidazo[4,5— 30 b]pyridin-2-one (100 mg) as colorless crystals. MS (API+): [M+H]+ 416.5. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.0 Hz), 3.75-3.88 (2H, m), 3.99 (2H, q, J = 7.0 Hz), 4.23-4.37 (2H, m), 4.98- 192 WO 2011/163355 PCT/US2011/041443 5.07 (1H, m), 7.09-7.28 (3H, m) , 7.39-7.65 (4H, m) , 7.65-7.87 (3H, m), 7.95-8.08 (1H, m).

[0308]

Example 40 5 l-ethyl-3-(4—{[1-(2-hydroxy-2-methylpropyl)-lH-benzimidazol-2-yl]oxy]phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Bromomethylmagnesium (3M in ether, 1.924 mL) was added to a solution of ethyl {2-[4-(l-ethyl-2-oxo-l,2-dihydro-3H- 10 imidazo[4,5-b]pyridin-3-yl)phenoxy]-lH-benzimidazol-1- yljacetate (220 mg) in THF (40 mL) at 0°C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 3h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography 15 (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-ethyl-3-(4-{[1-(2-hydroxy-2-methylpropyl)-lH-benzimidazol-2-yl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (130 mg) as white crystals. MS (API+): [M+H]+ 444.4. 20 XH NMR (300 MHz, DMSO-d6) δ 1.24 (6H, s), 1.31 (3H, t, J = 7.2 Hz), 3.99 (2H, q, J = 7.2 Hz), 4.11 (2H, s), 4.79 (1H, s), 7.07-7.26 (3H, m), 7.37-7.46 (1H, m), 7.50-7.64 (3H, m), 7.65-7.81 (3H, m), 7.96-8.05 (1H, m) .

[0309] 25 Example 48 l-ethyl-3-[1-(l-methyl-lH-benzimidazol-2-yl)-2,3-dihydro-lH-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-(2,3-dihydro-lH-indol-5-yl)-1-ethyl-l,3-30 dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro- 193 WO 2011/163355 PCT/US2011/041443 1—{[2-(trimethylsilyl)ethoxy]methyl]-lH-benzimidazole (101 mg) in NMP (2 mL) was stirred at 120°C for lOh, treated with saturated NaHCO3 solution and extracted with AcOEt. The organic layer was dried over MgSC>4 and concentrated in vacuo. The

5 residue was dissolved in DMF (2 mL), and then iodomethane (0.022 mL) and CS2CO3 (0.176 g) were added. The mixture was stirred at room temperature for 3h, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN 10 and the precipitate was filtered off. The residue was purified by prep. HPLC, and then chromatographed on silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/ Hexane gave the title compound (12 mg). MS (API+): [M+H] + 411.4. 15 XH NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.0 Hz), 3.26 (2H, t, J = 8.1 Hz), 3.77 (3H, s), 3.96 (2H, q, J = 6.8 Hz), 4.20 (2H, t, J = 8.5 Hz), 7.06-7.25 (4H, m) , 7.27-7.36 (1H, m), 7.43-7.54 (3H, m) , 7.59-7.71 (1H, m), 7.87-8.05 (1H, m).

[0310] 20 Example 62 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride

62a) tert-butyl {4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-25 benzimidazol-2-yl)oxy]phenyl]carbamate

A mixture of 2-chloro-l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-benzimidazole (8.7 g), tertbutyl 4-hydroxyphenylcarbamate (6.4 g) and cesium carbonate 30 (20 g) in DMF (60 mL) was stirred at 60°C for 24 h. After 194 WO 2011/163355 PCT/US2011/041443 cooling to room temperature, to the mixture was added SiO2, the mixture was evaporated, and then the residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give tert-butyl {4—[(l—{[2— (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}carbamate (14 g) as brown oil. MS (API+) : [M+H]+ 456.2.

[0311] 62b) 4—[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]aniline

A mixture of tert-butyl {4—[(l—{[2— (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl[carbamate (14 g) and 4N HCl/AcOEt (30 ml) in EtOAc (30 mL) was stirred at room temperature overnight. The mixture was neutralized with IN NaOHaq., and extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give 4-[(1-([2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]aniline (5.4 g) as an orange solid. MS (API+): [M+H]+ 356.2.

[0312] 62c) 2-chloro-4-methylpyridin-3-amine Q-

Cl nh2 A mixture of 4-methylpyridin-3-amine (0.62 g), 12N hydrogen chloride (3.8 mL) and 30% hydrogen peroxide (0.75 mL) was stirred at 0°C to room temperature for 1 h. The mixture was neutralized with K2CO3, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2-chloro-4-methylpyridin-3-amine (0.75 g) as an orange solid. 195 MS (API+): [M+H] + 143.1.

[0313] 62d) tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate WO 2011/163355 PCT/US2011/041443

Cl HN—

O

To a mixture of 2-chloro-4-methylpyridin-3-amine (0.75 g) and di-tert-butyl dicarbonate (1.3 mL) in THF (10 mL) was added dropwise hexamethyldisilazane sodium salt (2M in THF,

6.1 mL) at 0°C. The mixture was stirred at 0°C to room temperature overnight. The mixture was neutralized with IN 10 HClaq., and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo to give tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (1.2 g) as an orange solid. XH NMR (300 MHz, DMSO-d6) δ 1.34 (9H, brs), 2.15 (3H, s), 7.23 15 (1H, d, J = 4.9 Hz), 8.05 (1H, d, J = 4.9 Hz), 8.79 (1H, brs).

[0314] 62e) 7-methyl-3-{4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of sodium 2-methylpropan-2-olate (0.16 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.054 g), tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (0.28 g), 4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH- 25 benzimidazol-2-yl)oxy]aniline (0.41 g) and Pd2(dba)3 (0.043 g) in toluene (40 mL) and 2-propanol (10 mL) was stirred at 100°C under N2 overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% 30 - 100% EtOAc in hexane) to give 7-methyl-3-{4-[(1—{[2- 196 (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.21 g) as white crystals. MS (API+): [M+H]+ 488.3. 5 [0315] 62f) 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride WO 2011/163355 PCT/US2011/041443

o A mixture of 7-meth-yl-3-{4-[ (l-{ [2- io (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.053 g) and 2N HC1 in EtOH (5.0 mL) was stirred at 60°C for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to 15 give 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-7-methyl-l,3- dihydro-2H-imidazo [4,5-^-b] pyridin-2-one dihydrochloride (0.030 9) · MS (API+): [M+H]+ 358.1. XH NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s) , 4.57 (3H, brs), 6.97 20 (1H, d, J = 5.3 Hz), 7.15 (2H, dd, J = 6.1, 3.4 Hz), 7.40 (2H, dd, J= 5.9, 3.2 Hz), 7.52-7.62 (2H, m), 7.71-7.80 (2H, m) , 7.85 (1H, d, J = 5.3 Hz), 11.54 (1H, s).

[0316]

Example 64 25 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-l-ethyl-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride

64a) l-ethyl-7-methyl-3-{4-[(l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- 197 WO 2011/163355 PCT/US2011/041443 yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 7-methyl-3-{4-[(1—{[2-(trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- 5 yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.15 g) , iodoethane (0.027 mL) and sodium hydride (0.015 g) (60% in oil) in DMF (4.0 mL) was stirred at room temperature for 4 h. To. the mixture was added H2O, and the mixture was extracted with AcOEt. -The organic layer was dried (MgSO4) and io concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give l-ethyl-7-methyl-3-{4-[(l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4, 5-b]pyridin-2-one (90 15 mg) as pale yellow crystals. MS (API+): [M+H]+ 516.3.

[0317] 64b) 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-l-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride

A mixture of l-ethyl-7-methyl-3-{4-[(l-{[2-(trimethylsilyl) ethoxy]methyl}-lH-benzimidazol-2-yl)oxy]phenyl} -1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.090 g) and 2N HC1 in EtOH (5.0 mL) was stirred at 60°C for 25 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to give 3-[4-(lH-benzimidazol-2-yloxy)phenyl]-l-ethyl-7-methyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.040 g). 198 WO 2011/163355 PCT/US2011/041443 MS (API+): [M+H]+ 386.2. XH NMR (300 MHz, DMSO-de) δ 1.32 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 7.01 (1H, d, J =5.3 Hz), 7.20 (2H, dd, J = 5.9, 3.2 Hz), 7.40-7.49 (2H, m), 7.58-7.66 (2H, 5 m) , 7.72-7.81 (2H, m), 7.87 (1H, d, J = 4.9 Hz), 8.12 (3H, brs) .

[0318]

Example 65 l-Ethyl-3-[4-(lH-imidazo[1,2-a]benzimidazol-l-yl)phenyl]-1,3-io dihydro-2H-imidazo[4,5-b]pyridin-2-one

65a) 3-(4-aminophenyl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

15 The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (10.0 g), 4-nitroaniline (8.0 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2 g) and sodium tert-butoxide (12.5 g) in toluene (160 mL) - 2-propanol (40.0 mL) was stirred at 100°C under Ar overnight. The reaction 20 mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give 3-(4-nitrophenyl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (4.0 g) as a light brown solid. A mixture of 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5- 25 b]pyridin-2-one (3.50 g), sodium hydride (0.400 g) and iodoethane (2.0 mL) in DMF (40 mL) was stirred at 20°C under a dry atmosphere (CaCl2 tube) for lh. The mixture was concentrated under reduced pressure. The residue was purified 'by column chromatography (NH silica gel, eluted with 0% - 30% 30 EtOAc in hexane) to give l-ethyl-3-(4-nitrophenyl)-1,3- 199 WO 2011/163355 PCT/US2011/041443 dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a brown solid. A mixture of l-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under balloon 5 pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-aminophenyl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.00 g) as a brown solid. MS (API+): [M+H]+ 255.1. io [0319] 65b) 2-chloro-l-(2,2-diethoxyethyl)-lH-benzimidazole

A mixture of 2-chloro-lH-benzimidazole (6.10 g), bromoacetaldehyde diethyl acetal (7.22 mL), EtOH (70 mL), and 15 8 M NaOH aqueous solution (10 mL) was refluxed for 3 d. The reaction mixture was poured into water and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography 20 eluting with hexane/AcOEt (10/1) to give 2-chloro-l-(2,2-diethoxyethyl)-IH-benzimidazole (5.50 g). MS (API+): [M+H]+ 269.1. NMR (300 MHz, CDC13) δ 1.10 (6H, t, J = 7.2 Hz), 3.39 (2H, dq, J = 9.1, 7.2 Hz), 3.72 (2H, dq, J = 9.1, 7.2 Hz), 4.29 (2H, 25 d, J = 5.7 Hz), 4.72 (1H, t, J = 5.7 Hz), 7.23-7.32 (2H, m), 7.39-7.47 (1H, m) , 7.64-7.72 (1H, m) . mp 29-31°C.

Anal. Calcd for C13H17CIN2O2: C, 58.10; H, 6.38; N, 10.42. Found: C, 57.80; H, 6.31; N, 10.47. 30 [0320] 65c) l-ethyl-3-[4-(ΙΗ-imidazo[1,2-a]benzimidazol-l-yl)phenyl]- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 200 PCT/US2011/041443 WO 2011/163355

A mixture of 2-chloro-l-(2,2-diethoxyethyl)-1H-benzimidazole (860 mg) and 3-(4-aminophenyl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (636 mg) was heated at 5 150°C for 50 min. The reaction mixture was partitioned between AcOEt/THF (1/1) and 1 M NaOH aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure.· The residue-was purified by basic silica gel column chromatography eluting with THF and io recrystallized from THF to give l-ethyl-3-[4-(IH-imidazo[1,2- a] benzimidazol-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5- b] pyridin-2-one (311 mg). MS (API+): [M+H] + 395.3. XH NMR (300 MHz, CDC13) δ 1.43 (3H, t, J = 7.2 Hz), 4.05 (2H, q, 15 J = 7.2 Hz), 7.10 (1H, dd, J = 7.9, 5.3 Hz), 7.17-7.22 (1H, m) , 7.29 (1H, dd, J= 7.9, 1.5 Hz), 7.32-7.37 (2H, m), 7.44 (1H, d, J = 2.6 Hz), 7.62 (1H, d, J = 7.6 Hz), 7.80 (1H, d, J = 8.3 Hz), 7.91-7.96 (2H, m), 8.08 (1H, dd, J = 5.3, 1.5 Hz), 8.15-8.20 (2H, m). 20 mp 220-221°C.

Anal. Calcd for C23Hi8N6O: C, 70.04; H, 4.60; N, 21.31. Found: C, 70.12; H, 4.63; N, 21.39.

[0321]

Example 66 25 l-ethyl-3-[1-(1,3-thiazol-2-yl)-lH-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one A mixture of 3-(2,3-dihydro-lH-indol-5-yl)-1-ethyl-l,3-

201 WO 2011/163355 PCT/US2011/041443 dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg), 2-chlorothiazole (48.0 mg) and Cs2CO3 (174 mg) in DMF. (3 mL) was stirred at 100°C for 3 days, treated with saturated NaHCO3 solution, and extracted with AcOEt. The organic layer was 5 separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC and crystallized from AcOEt/Hexane to give the title compound as white crystals (27.0 mg). MS (API+): [M+H]+ 362.0. ίο TH NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 6.93 (1H, d, J = 3.4 Hz), 7.08-7.22 (1H, m) , 7.54-7.64 (2H, m) , 7.65-7.78 (2H, m), 7.88-8.08 (3H, m), 8.41-8.52 (1H, m).

[0322] 15 Example 69 3-[1-(lH-benzimidazol-2-yl)-lH-indol-5-yl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[1-(lH-benzimidazol-2-yl)-2,3-dihydro-lH- 20 indol-5-yl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and manganese dioxide (439 mg) in toluene (8 mL) was stirred at 100°C for 5h, filtered, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on 25 silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/ Hexane gave the title compound (28.0 mg). MS (API+): [M+H]+ 395.2.

[0323]

Example 70 30 l-ethyl-3-[1-(5-methylpyridin-2-yl)-lH-indazol-5-yl]-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one 202 70a) 1-(5-methylpyridin-2-yl)-lH-indazol-5-amine PCT/US2011/041443 WO 2011/163355

To a stirred solution of 5-nitro-lH-indazole (500 mg) in 5 DMF (10 mL) was added 60% sodium hydride (129 mg) at room temperature. The mixture was stirred for 30min, and 5-bromo-2-chloropyridine (649 mg) was added. The mixture was exposed to microwave irradiation at 230°C for lh, treated with sat. ammonium chloride solution, and extracted with AcOEt. The io organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give a mixture of 1-(5-bromopyridin-2-yl)-5-nitro-lH-indazole and 2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole. is To the mixture of 1-(5-bromopyridin-2-yl)-5-nitro-lH- indazole and 2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole were added methylboronic acid (141 mg), Pd(Ph3P)4 (91 mg), DME (3 mL) and a solution of CS2CO3 (766 mg) in H2O (1 mL) , successively. The mixture was exposed to microwave irradiation 20 at 140°C for lh, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo to give a mixture of 1-(5-methylpyridin-2-yl)-5-nitro-ΙΗ-indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole.

The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-lH- 25 indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20 mL), and 10% Pd/C (250 mg) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 12h, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 30 AcOEt/Hexane to give the title compound as white crystals (76 203 WO 2011/163355 PCT/US2011/041443 mg) . NMR (300 MHz, DMSO-d6) δ 2.33 (3H, s), 5.06 (2H, s), 6.84 (1H, d, J = 1.5 Hz), 6.91 (1H, dd, J = 8.9, 2.1 Hz), 7.71-7.87 (2H, m) , 8.09 (1H, s) , 8.33 (1H, d, J = 2.3 Hz), 8.38-8.46 (1H, m) .

[0324] 70b) 3-[1-(5-methylpyridin-2-yl)-lH-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Under argon atmosphere, a mixture of 1-(5-methylpyridin- 2- yl)-lH-indazol-5-amine (71 mg), tert-butyl 2-chloropyridin- 3- ylcarbamate (80 mg), Pd2(dba)3 (29.0 mg), Xantphos (36.6 mg) and sodium tert-butoxide (33.5 mg) in 2-propanol (2 mL) and toluene (0.5 mL) was stirred at 90°C for 24h, treated with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/ Hexane to give the title compound as white crystals (70.0 mg). MS (API+): [M+H]+ 343.3.

[0325] 70c) l-ethyl-3-[1-(5-methylpyridin-2-yl)-lH-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[1-(5-methylpyridin-2-yl)-lH-indazol-5-yl]-1, 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) and iodoethane (35.1 mg) in DMF (2 mL) was stirred at 50°C for 3h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/ Hexane 204 WO 2011/163355 PCT/US2011/041443 to give the title compound as white crystals (25.0 mg). MS (API+): [M+H]+ 371.0.

[0326]

Example 71 5 l-ethyl-3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-lH-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

71a) 2-Chloro-3H-imidazo[4,5-b]pyridine

io 2-(Methylthio)-3H-imidazo[4,5-b]pyridine (3.5 g) was dissolved in cone. HC1 (10 mL), and then the mixture was cooled to 0°C. Chlorine gas was bubbled through the mixture for 2h in iced bath. The mixture was poured onto ice, and neutralized to pH 7 with aqueous ammonium solution. The is precipitate was collected by filtration to give the title compound as white crystals (1.0 g). MS (API+): [M+H]+ 154.0.

[0327] 71b) l-ethyl-3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro- 20 lH-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Under nitrogen atmosphere, a mixture of 3-(2,3-dihydro-lH-indol-5-yl)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (60.3 mg) 25 in NMP (4 mL) was stirred at 150°C for 2h, treated with water, and extracted with AcOEt. The organic layer was dried over

MgSO4 and concentrated in vacuo. The residue was purified by 205 WO 2011/163355 PCT/US2011/041443 prep. HPLC. Crystallization from EtOH/ H2O to give the title compound (18.0 mg). MS (API+): [M+H]+ 398.2. TH NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.0 Hz), 3.36-3.41 5 (2H, m), 3.97 (2H, q, J = 7.1 Hz), 4.19-4.34 (2H, m) , 6.98- 7.10 (1H, m), 7.12-7.20 (1H, m), 7.39-7.49 (2H, m) , 7.62-7.72 (2H, m), 7.93-8.01 (1H, m) , 8.02-8.17 (1H, m), 8.41 (1H, d, J = 9.1 Hz).

[0328] io Example 72 3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-lH-indol-5-yl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

15 72a) tert-Butyl 5-[1-(1-methylethyl)-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-lH-indole-l-carboxylate

A mixture of tert-butyl 5-(2-oxo-l,2-dihydro-3H-20 imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-indole-l- carboxylate (1480 mg) and 2-iodopropane (714 mg) in DMF (5 mL) was stirred at 60°C for 4h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on 25 silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (570 mg).

τΗ NMR (300 MHz, DMSO-d6) δ 1.44-1.60 (15H, m), 3.12 (2H, t, J = 8.7 Hz), 3.92-4.01 (2H, m) , 4.65-4.74 (1H, m) , 7.07-7.15 (1H, m), 7.31-7.45 (2H, m), 7.72-7.79 (2H, m), 7.90-7.99 (1H, m). 206 WO 2011/163355 PCT/US2011/041443 [0329] 72b) 3-(2,3-dihydro-lH-indol-5-yl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

5 To a stirred mixture of tert-butyl 5-[1-(1-methylethyl)- 2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-lH-indole-l-carboxylate in AcOEt/ EtOH (1/1, 10 mL) was added 4N HC1 in AcOEt (4 mL). The mixture was stirred at 80°C for 2h, evaporated, treated with saturated NaHCO3, and extracted with io AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and the suspension was collected by filtration to give the title compound as white crystals (313 mg). MS (API+): [M+H]+ 295.1. is [0330] 72c) 3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-lH-indol-5-yl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 A mixture of 3-(2,3-dihydro-lH-indol-5-yl)-1-(1- methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (115 mg) in NMP (4 mL) was stirred at 140°C for 1.5h, treated with saturated NaHCO3, and extracted with AcOEt. The organic layer was dried 25 over MgSO4, passed through celite pad covered with activated carbon and concentrated in vacuo. The residue was purified by prep. HPLC. The product was crystallized from EtOH/ hexane to give the title compound (15.0 mg). MS (API+): [M+H]+ 412.4. 207 WO 2011/163355 PCT/US2011/041443 XH NMR (300 MHz, DMSO-ds) δ 1.51 (6H, d, J = 7.2 Hz), 3.38-3.45 (2H, m), 4.20-4.35 (2H, m) , 4.72 (1H, sep, J= 7.2 Hz), 6.97-7.17 (2H, m) , 7.36-7.50 (2H, m) , 7.60-7.81 (2H, m) , 7.96 (1H, d, J = 5.3 Hz), 8.01-8.18 (1H, m) , 8.34-8.47 (1H, m) , 12.20 5 (1H, brs).

[0331]

Example 75 l-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

75a) 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H- 15 imidazo[4,5-b]pyridin-2-one (2.50 g), sodium hydride (0.378 g) and iodoethane (1.60 mL) in DMF (25 mL) was stirred at 20°C under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by column 20 chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70g) as a colorless solid. MS (API+): [M+H]+ 346.4. ςΗ NMR (300 MHz, CDC13) δ 1.40 (3H, t, J = 7.2 Hz), 4.02 (2H, q, 25 J = 7.2 Hz), 5.11 (2H, s) , 7.01-7.17 (3H, m) , 7.22-7.29 (1H, m) , 7.29-7.49 (5H, m) , 7.53-7.61 (2H, m) , 8.00-8.09 (1H, m) . [0332] 75b) l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 208 PCT/US2011/041443 WO 2011/163355

o I A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under 5 balloon pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.42 g) as a white solid. MS (API+): [M+H]+ 256.1. 10 ΧΗ NMR (300 MHz, DMSO-d6) δ 1.27 (3H, t, J = 7.2 Hz), 3.95 (2H, q, J = 7.2 Hz), 6.84-6.95 (2H, m) , 7.08-7.18 (1H, m), 7.32-7.40 (2H, m), 7.57-7.67 (1H, m) , 7.89-7.99 (1H, m), 9.67-9.79 (1H, m) .

[0333] 15 75c) ΙΗ-imidazo[4,5-b]pyridine-2-thiol

To a solution of pyridine-2,3-diamine (5 g) in EtOH (150 mL) was added carbon disulfide (23 mL) at room temperature.

The mixture was stirred at 40°C under Ar for 10 h. The mixture 20 was cooled to room temperature. The resulting white solid was filtered and washed with ether to give ΙΗ-imidazo[4,5-b]pyridine-2-thiol (5.61 g). MS (API+): [M+H]+ 152.2. 1H NMR (300 MHz, DMSO-d6) δ 7.13 (1 H, m) , 7.47 (1 H, d, J=6.8 25 Hz), 7.97 - 8.36 (1 H, m), 12.72 (1 H, br. s.), 13.13 (1 H, br s.) .

[0334] 75d) 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine 30

To a solution of ΙΗ-imidazo[4,5-b]pyridine-2-thiol (2 g) 209 WO 2011/163355 PCT/US2011/041443 in acetone (30 mL) were added Mel (0.910 mL) and K2CO3 (5.48 g) at room temperature. After stirring for 10 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, eluted with 10% -100% EtOAc in hexane) to give 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (1.0 g) as a white solid. MS (API+): [M+H]+ 166.3. XH NMR (300 MHz, DMSO-d6) δ ppm 2.71 (3 H, s) , 6.83 - 7.34 (1 H, m), 7.68 - 8.02 (1 H, m), 8.02 - 8.32 (1 H, m), 12.68 - 13.33 (1 H, m) .

[0335] 75e) 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine

To a solution of 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (500 mg) in EtOAc (10 mL) was added mCPBA (1393 mg) at 0°C. After stirring for 10 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The crude material was recrystallized from ethyl acetate to give 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (593 mg). MS (API+): [M+H]+ 198.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 3.52 (3H, s), 7.32-7.41 (1 H, m) , 7.50 - 7.61 (1 H, m), 7.67 - 7.76 (1 H, m), 8.53 - 8.63 (1 H , m) .

[0336] 75f) 2-(methylsulfonyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-ΙΗ-imidazo[4,5-b]pyridine

Sodium hydride (146 mg) was added to a solution of 2- (methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) and [2- (chloromethoxy)ethyl]trimethylsilane (609 mg) in DMF (3 mL) at 210 WO 2011/163355 PCT/US2011/041443 room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH (2 mL) , and concentrated in vacuo. The residue was purified by column chromatography 5 (silica gel, eluted with 0% - 30% EtOAc in hexane) to give 2-(methylsulfonyl)-1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-imidazo[4,5-b]pyridine (250 mg) as light brown oil. MS (API+): [M+H]+ 328.3.

[0337] io 75g) l-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1- 15 {[2-(trimethylsilyl)ethoxy]methyl}-lH-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF(dry) (3 mL) was heated at 200°C for 3h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HC1. The mixture was neutralized with aq. 20 NaHCO3 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give l-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2- 25 yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals. MS (API+): [M+H]+ 373.1. XH NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.1 Hz), 3.99 (2H, q, J = 7.1 Hz), 7.10-7.26 (2H, m), 7.55-7.64 (2H, m) , 7.66- 30 7.72 (1H, m), 7.73-7.84 (3H, m) , 7.97-8.06 (1H, m), 8.11-8.23 (1H, m) .

[0338]

Example 85 211 WO 2011/163355 PCT/US2011/041443 l-ethyl-3-{4-[(1-methyl-lH-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

85a) N-benzyl-N-methyl-2-nitropyridin-3-amine

The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 mL) and 3-chloro-2-nitropyridine (5 g) was stirred at 60°C under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography io (silica gel, eluted with 0% - 30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil. MS (API+): [M+H]+ 244.1. 3H NMR (300 MHz, DMSO-d6) δ 2.75 (3H, s) , 4.44 (2H, s), 7.16- 15 7.47 (5H, m), 7.51-7.62 (1H, m) , 7.72-7.82 (1H, m) , 7.92-8.02 .(1H, m) .

[0339] 85b) N3-methylpyridine-2,3-diamine

ccN N NH2 20 A mixture of N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) and 10% Pd-C (0.569 g) in EtOH (50 mL) was hydrogenated under balloon pressure at room temperature over weekend. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give N3-methylpyridine- 25 2,3-diamine (1.14 g) as pale yellow oil. MS (API+) : [M+H]+ not detected. ΤΗ NMR (300 MHz, DMSO-d6) δ 2.68 (3H, d, J = 4.9 Hz), 4.85 (1H, q, J = 4.9 Hz), 5.35 (2H, s), 6.41-6.58 (2H, m), 7.21-7.32 (1H, m) . 212 WO 2011/163355 PCT/US2011/041443 [0340] 85c) 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

CDI (2.251 g) was added to a solution of N3- 5 methylpyridine-2,3-diamine (1.14 g) in THF(dry) (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) over weekend. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc io in hexane) to give 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1 g) as a white solid. MS (API+) : [M+H]+ not detected. XH NMR (300 MHz, DMSO-d6) δ 3.29 (3H, s) , 7.02 (1H, dd, J = 7.9 5.3 Hz), 7.40 (1H, dd, J = 7.9, 1.5 Hz), 7.90 (1H, dd, J = 5.3 15 1.5 Hz), 11.51 (1H, brs).

[0341] 85d) 2-chloro-l-methyl-lH-imidazo[4,5-b]pyridine

The mixture of 1-methyl-1,3-dihydro-2H-imidazo[4,5- 20 b]pyridin-2-one (1.1 g) and phosphorus oxychloride (6.87 mL) was stirred at 100°C under a dry atmosphere (CaCl2 tube) for 5h The mixture was neutralized with sat.NaHCCb at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in 25 vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 2-chloro-l-methyl-lH-imidazo[4,5-b]pyridine (600 mg) as a white solid. MS (API+): [M+H]+ 168.0. 30 ΤΗ NMR (300 MHz, DMSO-d6) δ 3.83 (3H, s) , 7.34 (1H, dd, J = 8.1 4.9 Hz), 8.06 (1H, dd, J = 8.1, 1.7Hz), 8.42 (1H, dd, J = 4.9, 1.7 Hz). 213 WO 2011/163355 PCT/US2011/041443 [0342] 85e) l-ethyl-3-{4-[(1-methyl-lH-imidazo[4,5-b]pyridin-2-yl) oxy]phenyl}-!, 3-dihydro-2H-imidazo [4,5-b]pyridin-2-one

5 The mixture of sodium hydride (14.32 mg), 2-chloro-l-

methyl-lH-imidazo[4,5-b]pyridine (100 mg) and l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (152 mg) in DMF (3 mL) was stirred at 180°C under a dry atmosphere (CaCl2 tube) for 20 min. The mixture was neutralized with IN io HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give l-ethyl-3-{4-[ (1-methyl-lH-imidaz'o [4,5- 15 b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as white crystals. MS (API+): [M+H]+ 387.2. 1H NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.2 Hz), 3.80 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 7.14-7.28 (2H, m), 7.60-7.68 (2H, 20 m) , 7.66-7.74 (1H, m), 7.78-7.86 (2H, m), 7.87-7.95 (1H, m), 7.96-8.06 (1H, m), 8.21-8.35 (1H, m).

[0343]

Example 86 l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- 25 yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

86a) N-benzyl-N-methyl-3-nitropyridin-2-amine

The mixture of 2-chloro-3-nitropyridine (15 g), Na2CO3 30 (10.03 g) and N-methylbenzylamine (24.42 mL) in THF (150 mL) 214 WO 2011/163355 PCT/US2011/041443 was stirred at 80°C under a dry atmosphere (CaCl2 tube) overnight. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in 5 vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in hexane) to give N-benzyl-N-methyl-3-nitropyridin-2-amine (19 g) as yellow oil. MS (API+): [M+H]+ not detected. τΗ NMR (300 MHz, CDC13) δ 2.81 (3H, s) , 4.94 (2H, s), 6.59-6.82 ίο (1H, m), 7.21-7.44 (5H, m) , 8.09-8.18 (1H, m) , 8.27-8.43 (1H, m) .

[0344] 86b) N2-methylpyridine-2,3-diamine

15 A mixture of N-benzyl-N-methyl-3-nitropyridin-2-amine (15 g) and 10% Pd-C (6.56 g) in EtOH (300 mL) was hydrogenated under balloon pressure at room temperature over weekend. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give N2-methylpyridine-2,3-diamine 20 (7.00 g) as a tan solid. MS (API+): [M+H] + not detected. XH NMR (300 MHz, DMSO-d6) δ 2.81 (3H, d, J = 4.9 Hz), 4.60 (2H, s), 5.56 (1H, q, J = 4.9 Hz), 6.32 (1H, dd, J = 7.2, 4.9 Hz), 6.64 (1H, dd, J = 7.2, 1.7 Hz), 7.37 (1H, dd, J = 4.9, 1.7 Hz) 25 [0345] 86c) 3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of N2-methylpyridine-2,3-diamine (7 g) and CDI (13.82 g) in THF (100 mL) was refluxed for 5h. The reaction 30 mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 100% 215 WO 2011/163355 PCT/US2011/041443

EtOAc in hexane) to give 3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7 g) as a light brown solid. MS (API+): [M+H]+ not detected. . ΤΗ NMR (300 MHz, DMSO-d6) δ 3.30 (3H, s), 6.96-7.01 (1H, m), 5 7.24-7.34 (1H, m) , 7.90-7.98 (1H, m) .

[0346] 86d) 2-chloro-3-methyl-3H-imidazo[4,5-b]pyridine

The mixture of 3-methyl-l,3-dihydro-2H-imidazo[4,5- 10 b]pyridin-2-one (1.0 g) in phosphorus oxychloride (10 g) was stirred at 100°C under a dry atmosphere (CaCl2 tube) for 5h.

The mixture was neutralized with sat.NaHCC>3 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in is vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 2-chloro-3-methyl-3H-imidazo[4,5-b]pyridine (230 mg) as a white solid. MS (API+): [M+H]+ 168.0. 20 ΧΗ NMR (300 MHz, DMSO-d6) δ 3.80 (3H, s) , 7.33 (1H, dd, J = 8.0, 4.9 Hz), 8.04 (1H, dd, J = 8.0, 1.5 Hz), 8.39 (1H, dd, J = 4-.9, 1.5 Hz).

[0347] 86e) l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- 25 yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-3-methyl-3H-imidazo[4,5-b]pyridine (150 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (228 mg) and NaH (39.4

30 mg) in DMF (2 mL) at 100°C. The mixture was stirred at 180°C under a dry atmosphere (CaCl2 tube) for lh. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The 216 WO 2011/163355 PCT/US2011/041443 organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 100% EtOAc in hexane) to give l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) as white crystals. MS (API+): [M+H]+ 387.2. XH NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.2 Hz), 3.78 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 7.14-7.27 (2H, m), 7.58-7.67 (2H, m), 7.67-7.74 (1H, m), 7.76-7.86 (3H, m), 7.97-8.06 (1H, m), 8.16-8.28 (1H, m).

[0348]

Example 96 3,3-dimethyl-l-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

o 96a) 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine

Mel (44.7 mL) was added to a mixture of K2CO3 (148 g) and ΙΗ-imidazo[4,5-b]pyridine-2-thiol (54 g) in DMF (500 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) overnight. The mixture was poured into water at room temperature and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give 3-methyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine as a crude product (12 g).

The mixture of 3-methyl-2-(methylsulfanyl)-3H- imidazo[4,5-b]pyridine (12 g) and mCPBA (33.0 g) in EtOAc (200 mL) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 3 h. The mixture was neutralized with sat.NaHCO3 at 0°C and extracted with EtOAc. The organic layer 217 WO 2011/163355 PCT/US2011/041443 was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5- 5 b]pyridine (lOg) as white crystals. MS (API+): [M+H]+ 212.1. XH NMR (300 MHz, DMSO-d6) δ 3.66 (3H, s), 4.12 (3H, s), 7.43-7.56 (1H, m), 8.25-8.38 (1H, m) , 8.56-8.67 (1H, m) .

[0349] 10 96b) 3,3-dimethyl-l-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(4-hydroxyphenyl)-3,3- 15 dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (119 mg) and NaH (20.45 mg) in DMF (2 mL) at 100°C. The mixture was heated at 180°C for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column 20 chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3,3-dimethyl-l-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg) as white crystals. MS (API+): [M+H]+ 386.2. 25 τΗ NMR (300 MHz, DMSO-d6) δ 1.46 (6H, s) , 3.77 (3H, s), 7.09-7.28 (2H, m), 7.55-7.69 (4H, m), 7.75-7.92 (2H, m), 8.13 (1H, m) , 8.17-8.28 (1H, m) .

[0350]

Example 97 30 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1- propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 218 97a) 3-[4-(benzyloxy)phenyl]-1-propyl-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one PCT/US2011/041443 WO 2011/163355

5 NaH (1.260 g) was added to a solution of 3—[4— (benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and 1-iodopropane (3.07 mL) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was io diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-l-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil. 15 MS (API+) : [M+H] + 360.4. XH NMR (300 MHz, DMSO-d6) δ 0.71-1.12 (3H, m) , 1.60-1.88 (2H, m) , 3.76-4.02 (2H, m), 5.19 (2H, s), 7.08-7.23 (3H, m), 7.28-7.58 (7H, m), 7.59-7.69 (1H, m), 7.89-8.00 (1H, m).

[0351] 20 97b) 3-(4-hydroxyphenyl)-1-propyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-1-propyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) and 10% Pd-C 25 (0.444 g) in EtOH (40 mL) was hydrogenated under balloon pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-1-propyl-l,3-dihydro-2H-imidazo[4,5- 219 WO 2011/163355 PCT/US2011/041443 b]pyridin-2-one (1.05 g) as a light brown solid. MS (API+): [M+H]+ 270.1. XH NMR (300 MHz, DMSO-d6) δ 0.83-0.98 (3H, m) , 1.63-1.82 (2H, m), 3.77-3.95 (2H, m) , 6.82-6.97 (2H, m) , 7.07-7.20 (1H, m) , 5 7.29-7.44 (2H, m) , 7.57-7.69 (1H, m), 7.87-8.00 (1H, m), 9.21-10.52 (1H, m).

[0352] 97c) 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-1-propyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin- 10 2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and 15 NaH (65.3 mg) in DMF (5 mL) at 100°C. The mixture was heated at 180°C for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-{4-[(3-methyl- 20 3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as white crystals. MS (API+): [M+H]+ 401.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 0.88-1.00 (3H, m) , 1.68-1.86 (2H, 25 m), 3.78 (3H, s), 3.86-3.97 (2H, m), 7.13-7.29 (2H, m), 7.59-7.66 (2H, m), 7.67-7.73 (1H, m), 7.74-7.86 (3H, m), 7.95-8.06 (1H, m), 8.14-8.29 (1H, m).

[0353]

Example 98 30 1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 220 PCT/US2011/041443 WO 2011/163355

98a) 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

5 NaH (1.260 g) was added to a solution of 3—[4— (benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and 2-iodopropane (3.15 mL) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was io diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil. 15 MS (API+) : [M+H]+ 360.4. ςΗ NMR (300 MHz, DMSO-d6) δ 1.50 (6H, d, J = 7.2 Hz), 4.64-4.80 (1H, m), 5.19 (2H, s), 7.05-7.24 (3H, m) , 7.28-7.59 (7H, m) , 7.70-7.79 (1H, m), 7.87-8.00 (1H, m).

[0354] 20 98b) 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-

1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5g) and 10% Pd-C 25 (0.444 g) in EtOH (40 mL) was hydrogenated under balloon pressure at room temperature for 5 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (670 mg) as a light brown solid. 221 WO 2011/163355 PCT/US2011/041443 MS (API+): [M+H] + 270.1. ΤΗ NMR (300 MHz, DMSO-dg) δ 1.40-1.59 (6H, m) , 4.62-4.80 (1H, m), 6.81-6.94 (2H, m) , 7.04-7.19 (1H, m) , 7.29-7.42 (2H, m) , 7.63-7.81 (1H, nt) , 7.87-8.02 (1H, m), 9.52-9.91 (1H, m) . 5 [0355] 98c) 1-(1-methylethyl) —3—{4—[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

io 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (270 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (330 mg) and NaH (53.9 mg) in DMF (5 mL) at 100°C. The mixture was heated at 180°C for 30 min under microwave irradiation. The 15 reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}—1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 20 mg) as white crystals. MS (API+) : [M+H] + 401.2. NMR (300 MHz, DMSO-d6) δ 1.43-1.67 (6H, m), 3.81 (3H, s), 4.64-4.91 (1H, m), 7.08-7.31 (2H, m), 7.54-7.70 (2H, m), 7.70-7.89 (4H, m), 7.93-8.07 (1H, m) , 8.18-8.28 (1H, m) . 25 [0356]

Example 99 l-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

30 99a) 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 222 PCT/US2011/041443 WO 2011/163355

The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), cyclopropylboronic acid (731 mg), TEA (1976 μΐ), pyridine (1835 μΐ), copper(II) 5 acetate (1030 mg) and THF (4727 μΐ) was heated at 140°C for 30 min under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give 3-[4- 10 (benzyloxy)phenyl]-1-cyclopropyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals. MS (API+): [M+H]+ 358.1. ΧΗ NMR (300 MHz, DMSO-d6) δ 0.91-1.01 (2H, m) , 1.01-1.11 (2H, m) , 2.92-3.07 (1H, m), 5.18 (2H, s), 7.08-7.21 (3H, m), Ί.3Q- 15 Ί.46 (3H, m), 7.45-7.53 (4H, m), 7.53-7.62 (1H, m) , 7.89-8.00 (1H, m) .

[0357] 99b) l-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 20 HO· A mixture of 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) and 10% Pd-C (17.87 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature for 2h. The catalyst was removed 25 by filtration and the filtrate was concentrated in vacuo to give l-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (89 mg) as a white solid. MS (API+): [M+H]+ 268.1. ΧΗ NMR (300 MHz, DMSO-d6) δ 0.89-1.00 (2H, m) , 1.01-1.11 (2H, 30 m) , 2.92-3.07 (1H, m) , 6.83-6.95 (2H, m), 7.07-7.20 (1H, m) , 7.28-7.40 (2H, m), 7.50-7.62 (1H, m), 7.87-8.00 (1H, m), 9.76 223 WO 2011/163355 PCT/US2011/041443 (1H, brs).

[0358] 99c) l-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was added to a solution of l-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (17.96 mg) in DMF (2 mL) at 100°C. The mixture was io heated at 180°C for lh under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- 15 yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals. MS (API+): [M+H]+ 399.2. XH NMR (300 MHz, DMSO-d6) . δ 0.94-1.03 (2H, m) , 1.03-1.13 (2H, m), 2.93-3.10 (1H, m), 3.78 (3H, s), 7.16-7.27 (2H, m), 7.58- 20 7.67 (3H, m), 7.70-7.87 (3H, m), 7.94-8.06 (1H, m), 8.15-8.27 (1H, m) .

[0359]

Example 100 1-(difluoromethyl)-3-[4-[(l-methyl-lH-benzimidazol-2- 25 yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

100a) 3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

224 WO 2011/163355 PCT/US2011/041443

Difluorochloroacetic acid sodium salt (1.922 g) was added to a solution of 3-[4-(benzyloxy)phenyl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 g), lithium bromide (1.095 g) and NaH (0.290 g) in DMF(20 ml) at 0°C. The mixture was stirred at 140°C under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (420 mg) as a white solid. MS (API+): [M+H]+ 368.1. ΧΗ NMR (300 MHz, DMSO-d6) δ 5.20 (2H, s) , 6.99-8.28 (13H, m) . [0360] 100b) 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one HO- A mixture of 3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (420 mg) and 10% Pd-C (60.8 mg) in EtOH (50 mL) was hydrogenated under balloon pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as a white solid. MS (API+) : [M+H]+ 278.1. XH NMR (300 MHz, DMSO-d6) δ 6.85-6.98 (2H, m) , 7.16-7.29 (1H, m), 7.32-7.45 (2H, m), 7.60-8.04 (2H, m) , 8.05-8.16 (1H, m) , 9.82 (1H, s).

[0361] 100c) 1-(difluoromethyl)-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}—1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

225 WO 2011/163355 PCT/US2011/041443 2-Chloro-l-methyl-lH-benzimidazole (70 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100°C. The mixture was heated at 180°C for 5 lh under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-(difluoromethyl)—3—{4—[(1-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H- io imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals. MS (API+): [M+H]+ 408.1. TH NMR (300 MHz, DMSO-d6) δ 3.77 (3H, s) , 7.08-7.34 (3H, m) , 7.37-7.54 (2H, m), 7.57-7.67 (2H, m), 7.66-8.09 (4H, m), 8.12-8.19 (1H, m). 15 [0362]

Example 101 1-(difluoromethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (124 mg) and NaH (25.6 mg) in DMF (3 mL) at 100°C. The mixture was heated at 180°C for lh under microwave irradiation. The 25 reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(3-methyl-3H-imidazo[4, 5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 30 mg) as white crystals. MS (API+): [M+H]+ 409.1. XH NMR (300 MHz, DMSO-d6) δ 3.78 (3H, s) , 7.07-7.37 (2H, m) , 226 WO 2011/163355 PCT/US2011/041443 7.54-8.37 (9H, m).

[0363]

Example 102 3,3-dimethyl-l-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-5 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

NaH (17.28 mg) was added to a solution of l-[4-(lH-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (40 mg) and Mel (10.13 μΐ) in io DMF(1 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3,3- 15 dimethyl-1-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (35 mg) as white crystals. MS (API+): [M+H]+ 385.2. NMR (300 MHz, DMSO-dg) δ 1.45 (6H, s) , 3.76 (3H, s), 7.09- 20 7.25 (3H, m), 7.37-7.52 (2H, m), 7.53-7.66 (4H, m) , 7.80-7.93 (1H, m), 8.06-8.20 (1H, m).

[0364]

Example 103 l-cyclopropyl-3-{4-[(l-methyl-lH-benzimidazol-2- 25 yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-l-methyl-lH-benzimidazole (15 mg) was added to a solution of l-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (24.06 mg) and NaH (5.40 mg) in 30 DMF (1 mL) at 100°C. The mixture was heated at 180°C for 1 h under microwave irradiation. The reaction mixture was diluted 227 WO 2011/163355 PCT/US2011/041443 with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give l-cyclopropyl-3-{4-[(1-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- 5 b]pyridin-2-one (5.0 mg) as white crystals. MS (API+): [M+H]+ 398.2. XH NMR (300 MHz, DMSO-d6) δ 0.94-1.04 (2H, m), 1.04-1.13 (2H, m), 2.96-3.08 (1H, m), 3.77 (3H, s), 7.10-7.29 (3H, m), 7.38-7.51 (2H, m), 7.54-7.67 (3H, m), 7.67-7.79 (2H, m) , 7.95-8.06 ίο (1H, m) .

[0365]

Example 106 6-chloro-l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

106a) tert-butyl (2,5-dichloropyridin-3-yl)carbamate B0C2O (17.05 mL) was added to a solution of 2,5-dichloropyridin-3-amine (11.4 g) and NaHMDS (1.9M, 81'mL) in 20 THF (200 mL) at 0°C. The mixture was stirred at 0°C under a dry atmosphere (CaCl2 tube) for lh. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column 25 chromatography (NH silica gel, eluted with 0% - 20% EtOAc in hexane) to give tert-butyl (2,5-dichloropyridin-3-yl)carbamate (15.6 g) as colorless oil. MS (API+): [M+H]+ not detected. τΗ NMR (300 MHz, DMSO-d6) δ 1.48 (9H, s), 8.20-8.23 (1H, m), 30 8.23-8.26 (1H, m) , 9.07-9.11 (1H, m) .

[0366] 228 106b) 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one WO 2011/163355 PCT/US2011/041443

The mixture of tert-butyl (2,5-dichloropyridin-3- 5 yl)carbamate (7.0 g), 4-(benzyloxy)aniline (7.95 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.231 g),

Pd2(dba)3 (0.974 g) and sodium tert-butoxide (3.58 g) in toluene (160 mL) - 2-propanol (40.0 mL) was stirred at 100°C under Ar overnight. The reaction mixture was concentrated in io vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give intermediate. To the intermediate in DMF (100 mL) were added NaH (3.19 g) and ethyl iodide (20.75 g). The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) 15 for lh. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 g) as a colorless 20 solid. MS (API+) : [M+H] + 380.2. XH NMR (300 MHz, DMSO-d6) δ 1.21-1.36 (3H, m) , 3.88-4.02 (2H, m) , 5.18 (2H, s), 7.10-7.21 (2H, m) , 7.29-7.56 (7H, m), 7.85-7.93 (1H, m), 7.94-8.00 (1H, m) . 25 [0367] 106c) 6-chloro-l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl-30 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500 mg) and 10% 229 WO 2011/163355 PCT/US2011/041443

Pd-C (140 mg) in EtOAc (10 mL) was hydrogenated under balloon pressure at room temperature for 3h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5 eluted with 0% - 50% EtOAc in hexane) to give 6-chloro-l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) as a white solid. MS (API+): [M+H]+ 290.1. XH NMR (300 MHz, DMSO-d6) δ 1.22-1.32 (3H, m) , 3.86-4.01 (2H, io m), 6.83-6.96 (2H, m), 7.26-7.46 (2H, m), 7.84-7.94 (1H, m) , 7.92-8.04 (1H, m), 9.74 (1H, s).

[0368] 106d) 6-chloro-l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-!,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-l-methyl-lH-benzimidazole (50 mg) was added to a solution of 6-chloro-l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) and NaH (13.2 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180°C 20 for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 6-chloro-l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-l,3-dihydro-2H- 25 imidazo[4,5-b]pyridin-2-one (100 mg) as colorless crystals. MS (API+): [M+H]+ 420.1. ςΗ NMR (300 MHz, DMSO-d6) δ 1.25-1.34 (3H, m), 3.76 (3H, s), 3.92-4.04 (2H, m), 7.09-7.29 (2H, m), 7.37-7.52 (2H, m), 7.54-7.65 (2H, m), 7.69-7.81 (2H, m), 7.93-7.99 (1H, m) , 7.99-8.07 30 (1H, m) .

Anal. Calcd for C22H18N5O2CI: C, 62.93; H, 4.32 ;N, 16.68; Cl, 8.44 . Found: C, 62.74; H, 4.38; 230 WO 2011/163355 PCT/US2011/041443 N,16.4O;C1,.

Mp: 208-210°C [0369]

Example 107 5 6-chloro-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 6-chloro-l-ethyl-3-(4- 10 hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127 mg) and NaH (18.74 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180°C for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column 15 chromatography (NH silica gel, eluted with 0% - 50% EtOAc in hexane) to give 6-chloro-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as colorless crystals. MS (API+): [M+H]+ 421.1. 20 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.41 (3H, m) , 3.77 (3H, s) , 3.93-4.03 (2H, m), 7.15-7.28 (1H, m), 7.60-7.68 (2H, m), 7.72-7.86 (3H, m), 7.94-7.99 (1H, m), 7.99-8.08 (1H, m), 8.18-8.27 (1H, m) .

[0370] 25 Example 108 l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-ecarbonitrile

231 108a) 3-[4-(benzyloxy)phenyl]-l-ethyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridine-6-carbonitrile WO 2011/163355 PCT/US2011/041443

The mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl- 5 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1 g), zinc cyanide (2.474 g), 2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1’-biphenyl (0.216 g), Pd2(dba)3 (0.241 g) and DMF (20 mL) was heated at 150°C for lh under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated io in vacuo. The residue was purified, by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-l-ethyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridine-6-carbonitrile (710 mg) as colorless oil. 15 MS (API+): [M+H]+ 371.2,. XH NMR (300 MHz, DMSO-d6) δ 1.25-1.35 (3H, m) , 3.85-4.09 (2H, m), 5.19 (2H, s), 7.08-7.24 (2H, m), 7.28-7.57 (7H, m), 8.11-8.22 (1H, m), 8.38-8.50 (1H, m) .

[0371] 20 108b) l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile

A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-2-oxo-2, 3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile (500 mg) and 25 10% Pd-C (71.8 mg) in EtOAc (50 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1- 232 WO 2011/163355 PCT/US2011/041443 ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile (90 mg) as a white solid. MS (API+): [M+H] + 281.2. 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.34 (3H, m) , 3.90-4.01 (2H, 5 m) , 6.81-6.99 (2H, m) , 7.29-7.39 (2H, m) , 8.12-8.19 (1H, m) , 8.38-8.48 (1H, m) , 9.71-9.84 (1H, m) .

[0372] 108c) l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6- 10 carbonitrile

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (45 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile (61.5 15 mg) and NaH (9.0 mg) in DMF (1 mL) at room temperature. The mixture was heated at 180°C for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 50% 20 EtOAc in hexane) to give l-ethyl-3-{4-[(3-methyl-3H- imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile (11 mg) as white crystals. MS (API+): [M+H]+ 412.2. 25 ΧΗ NMR (300 MHz, DMSO-d6) δ 1.27-1.40 (3H, m) , 3.78 (3H, s), 3.94-4.08 (2H, m), 7.14-7.26 (1H, m), 7.60-7.71 (2H, m), 7.71-7.88 (3H, m), 8.18-8.30 (2H, m) , 8.44-8.54 (1H, m).

[0373]

Example 109 30 l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-2- oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile 233 PCT/US2011/041443 WO 2011/163355

2-Chloro-l-methyl-lH-benzimidazole (15 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine-6-carbonitrile (25.5 mg) and sodium 5 hydride (4.0 mg) in DMF (1.0 mL) at room temperature. The mixture was heated at 180°C for 30min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in io hexane) to give l-ethyl-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-2-OXO-2,3-dihydro-lH-imidazo[4, 5-b]pyridine-6-carbonitrile (5 mg) as white crystals. MS (API+): [M+H]+ 411.2. XH NMR (300 MHz, DMSO-d6) δ 1.27-1.36 (3H, m), 3.77 (3H, s), 15 3.92-4.09 (2H, m), 7.08-7.33 (2H, m), 7.38-7.53 (2H, m), 7.55-7.67 (2H, m), 7.68-7.82 (2H, m) , 8.12-8.31 (1H, m) , 8.41-8.59 (1H, m) .

[0374]

Example 112 20 l-ethyl-3-{4-[(l-methyl-4,5,6,7-tetrahydro-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

112a) 2-(methylsulfanyl)-4,5,6,7-tetrahydro-lH-benzimidazole

25 To a solution of 4,5,6,7-tetrahydro-lH-benzimidazole-2- thiol (500 mg) in acetone (5 mL) were added K2CO3 (1344 mg) and 234 WO 2011/163355 PCT/US2011/041443

Mel (0.223 mL) at room temperature. After stirring for 1 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. The residue was purified by column 5 chromatography (silica gel, eluted with 40% - 90% EtOAc in hexane) to give 2-(methylsulfanyl)-4,5, 6,7-tetrahydro-lH-benzimidazole (545 mg) as a white solid. MS (API+): [M+H]+ 169.0. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.69 (4 H, br. s.), 2.47 - 2.65 (4 io H, m) , 3.33 (3 H, s), 11.43 - 11.98 (1 H, m) .

[0375] 112b) 2-(methylsulfonyl)-4,5,6,7-tetrahydro-lH-benzimidazole

To a solution of 2-(methylsulfanyl)-4,5,6,7-tetrahydro- 15 lH-benzimidazole (280 ijig) in EtOAc (5 mL) was added mCPBA (766 mg) at 0°C. After stirring for 10 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, 20 eluted with 20% - 80% EtOAc in hexane) to give 2- (methylsulfonyl)-4,5,6,7-tetrahydro-lH-benzimidazole (200 mg) as white crystals. MS (API+): [M+H]+ 201.0. ΤΗ NMR (300 MHz, DMSO-d6) δ 1.67 - 1.88 (4 H, m), 2.51 - 2.65 25 (4 H, m), 3.23 (3 H, s), 13.17 (1 H, none) [0376] 112c) 1-methyl-2-(methylsulfonyl)-4,5, 6,7-tetrahydro-lH-benzimidazole

30 Sodium hydride (55.8 mg) (60% in mineral oil) was added to a solution of 2-(methylsulfonyl)-4,5,6,7-tetrahydro-lH- 235 WO 2011/163355 PCT/US2011/041443 benzimidazole (233 mg) and Mel (0.080 mL) in DMF(dry) (10 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH (2 mL), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in hexane) to give 1-methyl-2-(methylsulfonyl)-4,5,6, 7-tetrahydro-lH-benzimidazole (200 mg) as a white solid. MS (API+): [M+H]+ 215.0. NMR (300 MHz, DMSO-dg) δ 1.59 - 1.93 (3 H, m), 2.50 (5 H, br s.), 3.18 - 3.43 (6 H, m) [0377] 112d) l-ethyl-3-{4-[(l-methyl-4,5,6,7-tetrahydro-lH- benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

1-Methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-lH-benzimidazole (84 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (18.8 mg) (60% in mineral oil) in DMA (3 mL) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 120°C set by IR sensor, fixed hold time : on, Absorption level : High) for 1 h in a Biotage Initiator 60EXP. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20% - 100%

EtOAc in hexane) to give l-ethyl-3-{4-[(l-methyl-4,5,6,7- tetrahydro-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (8.90 mg) as white crystals. 236 WO 2011/163355 PCT/US2011/041443 MS (API+): [M+H]+ 390.1. 2Η NMR (300 MHz, DMSO-dg) δ 1.29 (4 H, s) , 1.64 - 1.83 (5 H, m) 2.31 - 2.40 (3 H, m), 2.42 - 2.47 (2 H, m) , 3.35 - 3.40 (1 H, m), 3.90 - 4.03 (2 H, m), 7.11 - 7.22 (1 H, m) , 7.28 - 7.39 (1 5 H, m), 7.59 - 7.72 (3 H, m), 7.93 - 8.02 (1 H, m).

[0378]

Example 115 l-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

115a) IH-imidazo[4,5-c]pyridine-2-thiol

To a solution of pyridine-3,4-diamine (5 g) in EtOH (80 mL) was added carbon disulfide (10 mL) at room temperature. 15 The mixture was stirred at 4 0°C under a dry atmosphere (CaCl2 tube) for 10 h. The mixture was cooled to room temperature.

The resulting white solid was collected by filtration and washed with ether to give IH-imidazo[4,5-c]pyridine-2-thiol (6.1 g) as a white solid. 20 MS (API+): [M+H]+ 152.0 XH NMR (300 MHz, DMSO-d6) δ 7.17 (1 H, d, J=5.29 Hz), 8.25 (1 H d, <J=5.67 Hz), 8.38 (1 H, s), 12.87 (2 H, br. s.).

[0379] 115b) 2-(methylsulfanyl)-IH-imidazo[4,5-c]pyridine

To a solution of IH-imidazo[4,5-c]pyridine-2-thiol (4g) in acetone (50 mL) were added potassium carbonate (11 g) and

Mel (1.8 mL). After stirring for 3 h, the mixture was filtered

The filtrate was concentrated under reduced pressure. The 237 WO 2011/163355 PCT/US2011/041443 residue was purified by column chromatography (silica gel, eluted with 10% - 70% EtOAc in hexane) to give 2-(methylsulfanyl)-lH-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid. MS (API+): [M+H]+ 166.0. XH NMR (300 MHz, DMSO-d6) δ 2.72 (3 H, s) , 7.42 - 7.52 (1 H, m) , 8.09 - 8.27 (1 H, m), 8.77 (1 H, s) [0380] 115c) 2-(methylsulfonyl)-IH-imidazo[4,5-c]pyridine

To a solution of 2-(methylsulfanyl)-lH-imidazo[4,5-c]pyridine (4 g) in EtOAc (50 mL) was added mCPBA (11.14 g) at 0°C. After stirring for 10 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The crude material was recrystallized from ethyl acetate to give 2-(methylsulfonyl)-lH-imidazo[4,5-c]pyridine (1.100 g) as a white solid. MS (API+): [M+H]+ 198.1. 1H NMR (300 MHz, DMSO-d6) δ 3.39 (3 H, s), 7.76-8.03 (1 H, m), 8.21 - 8.31 (1 H, m), 9.23 (1 H, s), 13.93 - 14.52 (1 H, m). [0381] . 115d) 2-(methylsulfonyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-IH-imidazo[4,5-c]pyridine

NaH (122 mg) (60% in mineral oil) was added to a solution of 2-(methylsulfonyl)-lH-imidazo[4,5-c]pyridine (500 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.538 mL) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH (2 mL), and 238 WO 2011/163355 PCT/US2011/041443 concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in hexane) to give 2-(methylsulfonyl)-l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-imidazo[4,5-c]pyridine (330 5 mg) as a light brown solid. MS (API+): [M+H]+ 328.1.

[0382] 115e) l-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-(Methylsulfonyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-ΙΗ-imidazo[4,5-c]pyridine (350 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (220 mg) and NaH (41.4 mg) (60% in mineral is oil) in THF (1 mL) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 120°C set by IR sensor, fixed hold time : on, Absorption level : High) for 30 min in a Biotage Initiator 60EXP. The mixture was poured into water, and extracted with ethyl acetate, and the extract 20 was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0% - 20%

MeOH in EtOAc) to give intermediate (230 mg) as a white solid. To a solution of the intermediate (120 mg) in THF (2 mL) was 25 added TBAF (0.955 mL) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 100°C set by IR sensor, fixed hold time : on, Absorption level : Normal) for 1 h in a Biotage Initiator 60EXP. The mixture was poured into water, the mixture was extracted with ethyl acetate, and 30 the extract was washed with brine (20 mL x 2), dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by column chromatography (NH-silica 239 WO 2011/163355 PCT/US2011/041443 gel, eluted with 0% - 5% Methanol in EtOAc; and then, silica gel, eluted with 0% - 5% Methanol in EtOAc) to give l-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32.8 mg) as white crystals. 5 MS (API+): [M+H]+ 373.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.32 (3 H, none), 3.91 - 4.10 (2 H, m), 7.13 - 7.26 (1 H, m), 7.43 - 7.56 (3 H, m) , 7.62 - 7.77 (3 H, m), 7.95 - 8.03 (1 H, m) , 8.03 - 8.14 (1 H, m) , 8.54 - 8.67 (1 H, m) . io [0383]

Example 118 l-ethyl-6-methyl-3-{4-[(3-methyl-3ff-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl]-1,3-dihydro-2tf-imidazo[4,5-b]pyridin-2-one

15 118a) N- [4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine

To a mixture of 4-(benzyloxy)aniline hydrochloride (4.10 g) and 2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA (7.27 mL) at room temperature, and the 20 mixture was stirred at room temperature for 2 h. The mixture was heated to 60°C. After stirring at 60°C overnight, K2CO3 (4.81 g) was added to the mixture. The mixture was heated to 100°C and stirred at 100°C overnight. The mixture was poured into water and the mixture was extracted with AcOEt. The 25 combined organic layer was washed with brine, dried over Na2SO filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5% - 30% AcOEt in hexane) to give N- [4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as a red solid. 30 :H NMR (300 MHz, DMSO-d6) δ 2.26 (3H, s) , 5.11 (2H, s) , 6.96- 240 7.05 (2H, m) , 7.29-7.54 (7H, m) , 8.32-8.38 (2H, m), 9.78 (1H, s) .

[0384] 118b) N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine WO 2011/163355 PCT/US2011/041443

To a solution of N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) in acetic acid (10 mL) and THF (10 mL) was added zinc (2.59 g) at 0°C, and the mixture was stirred at 0°C for 2 h. After stirring at room temperature io overnight, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with AcOEt, washed with sat. NaHCCh, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5% - 50% AcOEt in 15 hexane) to give N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) as a blue solid. MS (API+): [M+H]+ 306.4. XH NMR (300 MHz, DMSO-d6) δ 2.08 (3H, s), 4.93 (2H, s), 5.04 (2H, s), 6.70 (1H, d, J = 1.9 Hz), 6.89 (2H, d, J = 9.1 Hz), 20 7.23-7.54 (9H, m).

[0385] 118c) 3-[4-(benzyloxy)phenyl]-6-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

25 A solution of N2-[4-(benzyloxy)phenyl]-5-methylpyridine- 2,3-diamine (0.63 g) and CDI (0.67 g) in THF (20 mL) was refluxed overnight. The mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 3-[4-(benzyloxy)phenyl]-6-methyl-l,3-dihydro-2H-imidazo[4,5— 30 b]pyridin-2-one (0.64 g) as an off-white solid. MS (API+): [M+H]+ 332.2. 241 WO 2011/163355 PCT/US2011/041443 2Η NMR (300 MHz, DMSO-de) δ 2.30(3H, s) , 5.18(2H, s) , 7.09-7.78(11H, m) , 11.23(1H, brs).

[0386] 118d) 3- [4- (benzyloxy) phenyl] -1-ethyl-6-methyl-l, 3-dihydro-2.fi-5 imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-l,3-dihydro-2.fi-imidazo [4,5-b]pyridin-2-one (0.64 g) , iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5 mL) was io stirred at 50°C for 4 h. After .-stirring at room temperature over weekend, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed, with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-l,3- .15 dihydro-2H-imidazo [4,5-b]pyridin-2-one (0.68 g) as a brown oil MS (API+): [M+H]+ 360.2.

[0387] 118e) l-ethyl-3- (4-hydroxyphenyl) -6-methyl-l, 3-dihydro-2.fi-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-6-methyl- 1,3-dihydro-2.fi-imidazo [4,5-b] pyridin-2-one (0.68 g) and 10% palladium on carbon (0.30 g) in MeOH (15 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The 25 catalyst was removed by filtration and the filtrate was concentrated in vacuo to give l-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.50 g) as a pale yellow solid. MS (API+) : [M+H]+ 270.2. 30 NMR (300 MHz, DMSO-dg) δ 1.27 (3H, t, J = 7.2 Hz), 2.33 (3H,

s), 3.92 (2H, q, J = 7.2 Hz), 6.83-6.91 (2H, m), 7.31-7.39 (2H 242 WO 2011/163355 PCT/US2011/041443 m) , 7.48 (1H, d, J = 1.5 Hz), 7.74-7.81 (1H, m) .

[0388] 118f) l-ethyl-6-methyl-3-{4-[ (3-methyl-3ii-imidazo [4,5-b]pyridin-2-yl) oxy] phenyl}-1, 3-dihydro-2iZ-imidazo [4,5- 5 b] pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo [4,5—Jb]pyridine (156 mg) and l-ethyl-3- (4-hydroxyphenyl) -6-methyl-l, 3-dihydro-2if-imidazo [4,5-b] pyridin- 10 2-one (166 mg) in DMF (3 mL) was added NaH (30 mg) at room temperature, and the mixture was stirred at 150°C under microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. is The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50% - 100% AcOEt in hexane) and column chromatography (dry charge, silica gel, eluted with 50% - 100% AcOEt in hexane), and recrystallized from MeOH to give l-ethyl-6-methyl-3-{4-[(3-methyl-3ff-imidazo[4,5-b]pyridin-2- 20 yl) oxy]phenyl}-l, 3-dihydro-2J?-imidazo [4,5-b]pyridin-2-one (43 mg) as white crystals. MS (API+): [M+H]+ 401.3. TH NMR (300 MHz, DMSO-d6) δ 1.30 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 3.77 (3H, s), 3.96 (2H, q, J = 7.2 Hz), 7.20 (1H, dd, J =

25 7.7, 5.1 Hz), 7.54-7.66 (3H, m), 7.75-7.87 (4H, m), 8.21 (1H, dd, J = 4.9, 1.5 Hz). mp 217-219°C

Anal. Calcd for C22H20N6O2: C, 65.99; H, 5.03; N, 20.99. Found: C 65.93; H, 5.16; N, 20.89. 30 [0389]

Example 119 l-ethyl-6-methoxy-3- { 4- [ (3-methyl-3ii-imidazo [4., 5-b] pyridin-2- 243 WO 2011/163355 PCT/US2011/041443 yl) oxy] phenyl} -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one

119a) 3- [4- (benzyloxy) phenyl] -l-ethyl-6-methoxy-l, 3-dihydro-2H-imidazo [4,5—Jb] pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (190 mg), Pd2dba3 (23 mg), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (48 mg) and KOH (145 mg) in dioxane (3 mL) and water (3 mL) was stirred at 100°C under Ar atmosphere for 6 h. The mixture was cooled to room temperature, and cetyltrimethylammonium bromide (50 mg) and iodomethane (0.034 mL) were added. After stirring at 100°C for 2 h, the mixture was cooled to room temperature. Iodomethane (0.034 mL) was added to the mixture. After stirring at room temperature, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methoxy-l,3-dihydro-2ff-imidazo[4,5-b]pyridin-2-one (125 mg) as a dark yellow oil. MS (API+): [M+H]+ 376.3. XH NMR (300 MHz, CDC13) δ 1.39 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 3.98 (2H, q, J = 7.4 Hz), 5.11 (2H, s), 6.90 (1H, d, J = 2.3 Hz), 7.06-7.15 (2H, m) , 7.29-7.49 (5H, m), 7.53-7.62 (2H, m) , 7.73 (1H, d, J = 2.6 Hz).

[0390] 119b) l-ethyl-3- (4-hydroxyphenyl) -6-methoxy-l, 3-dihydro-2ii-imidazo[4,5-b]pyridin-2-one 244 PCT/US2011/041443 WO 2011/163355

A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-6-methoxy- 1,3-dihydro-2#-imidazo[4,5-b]pyridin-2-one (120 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) was hydrogenated 5 under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give l-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2fl-imidazo[4,5-b]pyridin-2-one (75 mg) as white crystals. io MS (API+): [M+H]+ 286.1. XH NMR (300 MHz, CDC13) δ 1.41 (3H, t, J = 7.2 Hz), 3.89 (3H, s), 4.00 (2H, q, J = 7.2 Hz), 6.76 (2H, d, J = 8.7 Hz), 6.94 (1H, d, J = 2.3 Hz), 7.16 (1H, brs), 7.29 (2H, d, J = 8.7 Hz) 7.73 (1H, d, J = 2.3 Hz). is [0391] 119c) l-ethyl-6-methoxy-3-{ 4- [ (3-methyl-3ii-imidazo [4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 To a solution of 3-methyl-2-(methylsulfonyl)-3ff- imidazo[4,5-b]pyridine (67 mg) and l-ethyl-3-(4-hydroxyphenyl)-6-methoxy-l,3-dihydro-2 ff-imidazo[4,5-b]pyridin 2-one (75 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and the mixture was stirred at 150°C under 25 microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by column chromatography (dry charge NH silica gel, eluted with 50% - 100% AcOEt in hexane) and 245 223631/2 column chromatography (dry charge, silica gel, eluted with 50% - 100% AcOEt in hexane), and recrystallized from MeOH to give 1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17 5 mg) as white crystals. MS (API+): [M+H]+ 417.4. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (3H, t, J = 7.2 Hz), 3.77 (3H, s), 3.86 (3H, s), 3.98 (2H, q, J = 7.2 Hz), 7.20 (1H, dd, J = 7.9, 4.9 Hz), 7.50 (1H, d, J = 2.3 Hz), 7.58-7.65 (2H, m), 10 7.73 (1H, d, J = 2.3 Hz), 7.76-7.84 (3H, m), 8.21 (1H, dd, J = 4.9, 1.3 Hz). Anal. Calcd for C22H20N6O3: C, 63.45; H, 4.84; N, 20 .18. Found: C, 63.52; H, 4.86; N, 20.12.

Mp: 197-198°C 15 [0392]

Example 120 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 [0393]

Method A 120a) 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 246 223631/2

10 15 20

A mixture of tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (2.00 g), 4-(benzyloxy)aniline hydrochloride (2.91 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (381 mg), sodium t-butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2-propanol (6 mL) and toluene (24 mL) was stirred at 100°C under N2 atmosphere for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH, and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (NH silica gel, eluted with 15% - 50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (988 mg) as a colorless solid. MS (API+): [M+H]+ 332.3. 1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 5.12 (2H, s), 6.87 (1H, d, J = 5.3 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.28-7.50 (5H, m), 7.57 (2H, d, J = 8.7 Hz), 7.96 (1H, d, J = 5.3 Hz), 9.93 (1H, brs).

[0394] 120b) 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 247 223631/2 10 15 20

Iodoethane (0.289 mL) was added to a mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at room temperature. The mixture was stirred at 50°C for 4 h. The mixture was diluted with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 30% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (801 mg) as an off- white solid. MS (API+): [M+H]+ 360.4 1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 4.19 (2H, q, J = 7.2 Hz), 5.11 (2H, s), 6.81 (1H, d, J = 5.3 Hz), 7.10 (2H, d, J = 8.7 Hz), 7.30-7.47 (5H, m), 7.53 (2H, d, J = 9.1 Hz), 7.91 (1H, d, J = 5.3 Hz).

[0395] 120c) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 248 223631/2 10 15 20

A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (800 mg) and 10% Pd-C (118 mg) in EtOH (20 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid.

To a mixture of this solid and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (480 mg) in DMF (10 mL) was added 60% sodium hydride (58.9 mg) at 100°C. The mixture was heated at 180°C for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 30% - 50% AcOEt in hexane and silica gel, eluted with 15% - 30% AcOEt in hexane). The crude

materials were purified by HPLC (C18, eluted with H2O/MeCN containing 0.1% trifluoroacetic acid). To this obtained solution was added sat. NaHCO3 aq, the mixture was extracted with AcOEt, and the extract was dried over MgSO4 and concentrated in vacuo to give 1-ethyl-7-methyl-3-{4-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (119 mg) as colorless crystals 249 223631/2 (Form A). MS (API+): [M+H]+ 401.3 [0396]

Alternative methods for 1-ethyl-7-methyl-3-{4-[(3-methyl-5 3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (method B-F) are described below. [0397]

Method B 120d) 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-10 imidazo[4,5-b]pyridin-2-one

HO

A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (21.4 g) and 10% Pd-C (3.17 g) in EtOH (400 mL) was hydrogenated under balloon 15 pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The solid was washed with THF-hexane to give 1-ethyl-3-(4- hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10.90 g) as a solid. 20 MS (API+): [M+H]+ 270.4

1H NMR (300 MHz, CDCl3) δ 1.44 (3H, d, J = 6.9 Hz), 2.65 (3H, s), 4.21 (2H, q, J = 6.9 Hz), 6.74 (2H, d, J = 8.7 Hz), 6.90 (1H, d, J = 5.3 Hz), 7.22 (2H, d, J = 8.7 Hz), 7.94 (1H, d, J 250 223631/2 = 5.3 Hz).

[0398] 120e) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- 5 b]pyridin-2-one

\\ /"N

K JN

ο I

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (1.0 g) and 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin- 10 2-one (1.3 g) in DMF (10 mL) was added 60% NaH (0.23 g) at room temperature, and the mixture was stirred at 180°C under microwave irradiation for 30 min. To the mixture was added

EtOH (10 mL). The formed crystals were collected by filtration and washed with EtOH. This microwave reaction was repeated two 15 additional times with the same amount of starting material.

The combined crystals were recrystallized from EtOH containing 5% distilled water (270 mL) and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- 20 b]pyridin-2-one (3.3 g) as white crystals (Form A). MS (API+): [M+H]+ 401.3 1H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 3.77 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 7.00 (1H, d, J = 251 223631/2 5.7 Hz), 7.20 (1H, dd, J = 7.9, 4.9 Hz), 7.58-7.66 (2H, m), 7.71-7.78 (2H, m), 7.80 (1H, dd, J = 7.9, 1.1 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.22 (1H, dd, J = 4.9, 1.5 Hz).

Anal. Calcd for C22H20N6O2: C, 65.99; H, 5.03; N, 20.99. Found: C, 65.76; H, 5.07; N, 20.85.

[0405]

Powder X-ray Diffraction (PXRD) Analysis:

Form A is characterized by PXRD Pattern using CuKa X-ray radiation, having peaks selected from a list consisting of: 9.302 angstrom ; middle 8.1102 angstrom ; middle 5.6255 angstrom ; high 5.487 angstrom ; middle 4.8439 angstrom ; high 4.371 angstrom ; high 3.7479 angstrom ; low 3.6043 angstrom ; high 3.5092 angstrom ; middle 3.2178 angstrom ; high 10 15 d-value.

[0406]

Method D 120l) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (crystals of Form G) 252 223631/2 10 15 20 25

Crystals of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg, Form A) was dissolved in EtOH (20 mL) at 80°C and the solution was allowed to cool to room temperature. The mixture was stirred at room temperature for 350 h. The solid was collected by filtration to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) as crystals (Form G).

Crystals of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40.0 g, Form A) was dissolved in DMSO (400 mL) at 95oC and the solution was allowed to cool to 85oC. To the solution was slowly added EtOH (400 mL) at 85oC, and then the mixture was allowed to cool to 80oC. To the solution was added seed crystals (Form G: 50 mg) at 80oC. The mixture was stirred and maintained at 73oC for 20 h. The solid was collected by filtration and washed with EtOH (500 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (19.5 g) as white crystals (Form G).

Method E 120m) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- 253 223631/2 10 15 20 25 b]pyridin-2-one (crystals of Form G)

Crystals of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H- imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (600 mg, Form A) was stirred in

EtOH (60 mL) at room temperature for 168 h. The solid was collected by filtration to give 1-ethyl-7-methyl-3-{4-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (350 mg) as crystals (Form G). MS (API+): [M+H]+ 401.1. 1H NMR (400 MHz, DMSO-d6) δ1.25-1.38 (3H, m), 2.61 (3H, s), 3.78 (3H, s), 4.04-4.18 (2H, m), 6.96-7.04 (1H, m), 7.17-7.25 (1H, m), 7.59-7.66 (2H, m), 7.71-7.77 (2H, m), 7.78-7.83 (1H, m), 7.85-7.91 (1H, m), 8.16-8.28 (1H, m).

Anal. Calcd for C22H20N6O2: C, 65.99; H, 5.03; N, 20.99. Found: C, 65.73; H, 5.12; N, 20.85.

Method F 120n) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (crystals of Form G)

Crystals of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H- imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (3.0 g) obtained in 120s') was dissolved in DMSO (33 mL) at 90oC. To the solution was slowly added EtOH (30 mL) at 80-90oC. To the solution was added 254 223631/2 crystals (Form G) obtained in 120m) as seed crystals at 80-90oC.

The mixture was stirred at 60-65oC for 6 h and at room temperature for 18 h. The solid was collected by filtration and washed with EtOH (15 mL) to give 1-ethyl-7-methyl-3-{4- 5 [(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.3 g) as white crystals (Form G).

Method G 10 120p) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (crystals of Form G)

Crystals of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- 15 imidazo[4,5-b]pyridin-2-one (3.0 g) obtained by 120s') was dissolved in DMSO (33 mL) at 90-95oC. To the solution was slowly added AcOEt (30 mL) at 70-90oC. To the solution was added crystals (Form G) obtained in 120n) as seed crystals at 80-90oC. The mixture was stirred at 45-50oC for 25 min and at 20 70-75oC for 3 h. The mixture was gradually cooled to 0-5oC and stirred for 1 h. The solid was collected by filtration and washed with AcOEt (15 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.6 g) as white crystals (Form 25 G). 255 223631/2

Method H 120q) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- 5 b]pyridin-2-one (crystals of Form G) A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5- b]pyridine (20.4 g, 96.55 mmol) in DMA (117 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (26.0 g, 96.55 mmol) and 10 potassium tert-butoxide (11.4 g) in DMA (96 mL) at room temperature. The mixture was stirred at 95-100oC for 1.5 h. Water (221 mL) was added at 80-100oC. The precipitate was collected at room temperature and dried over under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H- 15 imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35.8 g) as crude product. The obtained crude 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-

imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10.0 g) was dissolved in DMSO 20 (150 mL) at 90-100oC. The solution was filtered through filter paper and washed with DMSO (10 mL). The combined filtrate was slowly added to a mixture of crystals (Form G: 100 mg) obtained in 120p) (as seed crystals) in AcOEt (100 mL) at 5-30oC. After stirring at room temperature for 17 h, the mixture 25 was stirred at 70oC for 1 h. The mixture was gradually cooled 256 223631/2 to 25oC and stirred for 2 h. The mixture was stirred at 0-10oC for 1 h and at room temperature for 1 h. The solids were collected by filtration and dried at 50oC under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-5 imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (8.0 g) as white crystals (Form G).

[0407]

Method I 10 120r) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (crystals of Form G) A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (40.8 g, 193.09 mmol) in DMA (234 mL) was added to 15 a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (52.0 g, 193.09 mmol) and potassium tert-butoxide (22.8 g) in DMA (192 mL) at room temperature. The mixture was stirred at 90-100oC for 1 h. Water (442 mL) was added at 80-100oC. The precipitate was collected 20 at room temperature and dried over under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (72.4 g) as crude product. The crude 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- 25 yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 257 10 15 20 25 223631/2 (60.0 g) was dissolved in DMSO (900 mL) at 90-100oC. The solution was filtered through filter paper and washed with DMSO (60 mL). The combined filtrate was slowly added to a mixture of crystals (Form G: 600 mg) obtained in 120q) (as seed crystals) in AcOEt (600 mL) at 0-30oC. The mixture was stirred at 70oC for 0.5 h and cooled to room temperature. After stirring at room temperature for 1 h, the mixture was stirred at 0-10oC for 1 h and at room temperature for 1 h. The solids were collected by filtration and dried at 50oC under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H- imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (47.9 g) as white crystals (Form G). MS (ESI+): [M+H]+ 401.2 1H NMR (500 MHz, CDCl3) δ 1.42 (3H, t), 2.62 (3H, s), 3.84 (3H, s), 4.15-4.27 (2H, m), 6.81-6.92 (1H, m), 7.10-7.18 (1H, m), 7.52-7.61 (2H, m), 7.73-7.80 (1H, m), 7.82-7.87 (2H, m), 7.917.95 (1H, m), 8.20-8.29 (1H, m).

[0408]

Method J 120s) 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (crystals of Form G) 120s')A solution of 3-methyl-2-(methylsulfonyl)-3H- imidazo[4,5-b]pyridine (78.4 g, 371.33 mmol) in DMA (420 mL) 258 223631/2 was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7- methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100.0 g, 371.33 mmol) and potassium tert-butoxide (51.5 g) in DMA (370

mL) at room temperature. The mixture was stirred at 90-100oC 5 for 1 h. Water (780 mL) was added at 90-100oC. The precipitate was collected at room temperature and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H- imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127.7 g) as crystals. The 10 obtained crystals (125.0 g) were dissolved in DMSO (1375 mL) at 90-95oC. To the solution was slowly added EtOH (1250 mL) at 80-95oC, and then the mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with EtOH (625 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl- 15 3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103.9 g) as crystals. 120s'') The mixture of the obtained crystals (55.0 g) in a solution of DMSO (275 mL) and EtOH (275 mL) was stirred at 70 20 75oC for 0.5 h and then the mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with EtOH (165 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (52.2 g) as crystals (Form A). The 25 obtained crystals (5.0 g) were dissolved in DMSO (50 mL) at 259 10 15 223631/2 95oC. The solution was filtered through filter paper and washed with DMSO (5 mL). To the combined filtrate was added EtOH (50 mL) slowly at 73-95oC. To the solution was added crystals (Form G: 5 mg) obtained in 120p) (as seed crystals) at 73oC. The mixture was allowed to cool to room temperature. After stirring at 70-75oC for 7 h, the mixture was cooled to room temperature. After stirring at 70-75oC for 8 h, the mixture was cooled to room temperature. After stirring at 70-75oC for 2 h, the mixture was stirred at room temperature for 1 h, and at 0-10oC for 1 h. The solids were collected by filtration and dried at 50oC under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.5 g) as white crystals (Form G).

[0409]

Powder X-ray Diffraction (PXRD) Analysis:

Form G is characterized by PXRD Pattern using CuKa X-ray radiation, having peaks selected from a list consisting of: 9.2245 angstrom ; middle 7.8796 angstrom ; high 6.763 angstrom ; middle 6.2059 angstrom ; middle 6.1289 angstrom ; middle 5.7268 angstrom ; high 260 223631/2 5.1275 angstrom ; middle 4.638 angstrom ; middle 4.267 angstrom ; middle 3.9939 angstrom ; middle 3.9345 angstrom ; middle 3.7921 angstrom ; high 3.7479 angstrom ; high 3.0579 angstrom ; middle d-value.

[0410]

Example 121 5 7-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one \\

N—\ A

O I 121a) 3-[4-(benzyloxy)phenyl]-7-methyl-1-(1-methylethyl)-1,3-10 dihydro-2H-imidazo[4,5-b]pyridin-2-one

261 WO 2011/163355 PCT/US2011/041443 A suspension of 3-[4-(benzyloxy)phenyl]-7-methyl-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture 5 was poured into water, and the mixture was extracted with

AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15% - 20% AcOEt in hexane) to give the title compound (218 mg) as io colorless oil. MS (API+): [M+H]+ 374.3 XH NMR (300 MHz, CDC13) δ 1.68 (6H, d, J = 6.8 Hz), 2.60 (3H, s), 4.72-4.88 (1H, m), 5.11 (2H, s), 6.78 (1H, d, J = 5.3 Hz), 7.06-7.13 (2H, m), 7.28-7.47 (5H, m) , 7.47-7.55 (2H, m), 7.88 15 (1H, d, J = 5.3 Hz).

[0411] 121b) 7-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-l-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (215 mg) and 10% Pd-C (30.6 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The 25 catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-7-methy1-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a solution of this solid in DMF (10 ml) were added sodium hydride (27.8 mg) and 3-methyl-2- 30 (methylsulfonyl)-3H-imidazo[4,5-b]pyridine (164 mg) at 100°C.

The mixture was heated at 180°C for 30 min under microwave irradiation. The precipitate was collected by filtration and washed with AcOEt and MeOH to give the title compound (175 mg) 262 WO 2011/163355 PCT/US2011/041443 as colorless crystals. MS (API+): [M+H]4" 415.4

NMR (300 MHz, DMSO-d6) δ 1.60 (6H, d, J = 6.8 Hz), 2.62 (3H, s), 3.78 (3H, s), 4.83 (1H, quin, J = 6.8 Hz), 6.98 (1H, d, J 5 = 5.3 Hz), 7.20 (1H, dd, J = 7.9, 4.9 Hz), 7.57-7.64 (2H, m), 7.68-7.75 (2H, m), 7.80 (1H, dd, J= 7.9, 1.5 Hz), 7.84 (1H, d, J = 5.3 Hz), 8.22 (1H, dd, J = 4.9, 1.5 Hz). mp 270 - 271°C.

[0412] io Example 122 6-methyl-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b] pyri'dih-2-yl) oxy]phenyl}-1,3-dihydro-2H-imidazo [4,5-b]pyridin-2-one

15 122a) 3-[4-(benzyloxy)phenyl]-6-methyl-l-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaH (84 mg) was added to a solution of 3—[4— (benzyloxy)phenyl]-6-methyl-l,3-dihydro-2H-imidazo[4,5- 20 b]pyridin-2-one (346 mg) and 2-iodopropane (0.208 mL) in DMF(dry) (4 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The mixture was poured into water, and the mixture was extracted' with EtOAc. The organic layer was separated, washed 25 with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel,

EtOAc/hexane) to give the title compound (283 mg) as a yellow oil. MS (API+): [M+H]+ 374.2. 263 WO 2011/163355 PCT/US2011/041443 [0413] 122b) 3- (4-hydroxyphenyl)-6-methyl-l-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

5 A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-l-(1- methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (283 mg) and 10% palladium on carbon (50% wet) (87 mg) in MeOH (4.2 mL) and EtOAc (4.2 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and io washed with MeOH (10 mL) to remove the catalyst. The filtrate was concentrated in vacuo to give the title, compound (210 mg) as a gray solid. NMR (300 MHz, CDC13) δ 1.59 (5H, d, J = 7.2 Hz), 2.40 (3H, s), 4.82 (1H, t, J = 7.0 Hz), 6.60-6.90 (2H, m), 7.25 (2H, s), 15 7.27-7.32 (2H, m), 7.87 (1H, s).

[0414] 122c) 6-methyl-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (198 mg) and 3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (177 mg) in DMF (1.5 mL) was added NaH (40.0 mg), and 25 the mixture was stirred at 100°C for 1 h. The mixture was heated at 180°C for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was 264 WO 2011/163355 PCT/US2011/041443 purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (125 mg) as white crystals. MS (API+): [M+H]+ 415.1. τΗ NMR (300 MHz, DMSO-d6) δ 1.52 (6H, d, J = 7.2 Hz), 2.36 (3H,

5 s), 3.77 (3H, s), 4.71 (1H, quin, J = 6.9 Hz), 7.20 (1H, dd, J = 7.9, 4.9 Hz), 7.53-7.71 (3H, m) , 7.71-7.86 (4H, m), 8.22 (1H, dd, J =4.9, 1.5 Hz).

Anal. Calcd for C23H22N6O2: C, 66.65; H, 5.35; N, 20.28. Found: C, 66.55; H, 5.44; N, 20.23. 10 mp 252 °C [0415]

Example 123 1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-3,3-dimethyl-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

123a) 1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 20 g) was-added to a solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF(dry) (10 mL) at 100°C. The mixture was stirred at 100°C under a dry atmosphere overnight. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 25 0% - 30% EtOAc in hexane) to give ethyl 2-(4- bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as a colorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) as a colorless solid. The mixture of 2-(4- bromophenoxy)imidazo[1,2-a]pyridine (410 mg), 1,3-dihydro-2H- 265 WO 2011/163355 PCT/US2011/041443 pyrrolo[2.3-b]pyridine-2-one (164 mg), trans-N,N'~ dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide (116 mg), K2CO3 (338 mg) and THF(dry) (5 mL) was heated at 180°C for 3 h under microwave irradiation. The solid was removed by 5 filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (72 mg) as an orange solid (mixture with 1,3-dihydro-2H-pyrrolo[2.3-b]pyridine-2-one, ca. 20% purity). 10 This product was subjected to the next reaction without further purification. MS (API+)·: [M+H]+ 343.1.

[0416] 123b) 1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-3,3- 25 dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of 1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (72 mg, mixture with 1,3-dihydro-2H-pyrrolo[2.3-b]pyridine-2-one, ca. 20% 20 purity), iodomethane (0.110 mL), and sodium hydride (70.8 mg) in DMF (1 mL) was stirred at 0°C to room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The 25 residue was purified by column chromatography (silica gel, EtOAc/hexane) and column chromatography (NH silica gel, EtOAc/hexane) to give the title compound (7.40 mg) as a colorless oil. MS (API+): [M+H]+ 371.3. 30 TH NMR (300 MHz, CDCI3) δ 1.46-1.55 (6H, m) , 6.81 (1H, t, J = 6.2 Hz), 7.02 (1H, dd, J = 7.6, 5.3 Hz), 7.12 (1H, s), 7.14- 7.22 (1H, m), 7.29-7.41 (2H, m) , 7.48-7.59 (4H, m), 8.03 (1H, 266 WO 2011/163355 PCT/US2011/041443 d, J = 6.8 Hz), 8.17 (1H, dd, J = 5.3, 1.5 Hz). •[0417]

Example 124 l-ethyl-3- [4- (imidazo [1,2-a]pyridin-2-yloxy) phenyl] -6-methyl-5 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 124a) ethyl 2-[4-(l-ethyl-6-methyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]imidazo[1,2-a]pyridine-3-carboxylate

The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (504 mg), l-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (302 mg) and NaH (67.3 mg) in DME (4 mL) was heated at 50°C for 1 h. The mixture is was heated at 200°C for 3 h under microwave irradiation. The mixture was poured into sat. NaHCO3, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 EtOAc/hexane) to give the title compound (62.0 mg) as a white solid. MS (API+): [M+H]+ 458.2.

[0418] 124b) l-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-6- 25 methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

267 WO 2011/163355 PCT/US2011/041443

To a solution of ethyl 2-[4-(l-ethyl-6-methyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]imidazo[1,2-a]pyridine-3-carboxylate (62 mg) in EtOH (4 mL) was added sodium hydroxide (1.084 mL). The mixture was stirred at 50°C 5 for 2 h. Hydrochloric acid (2.168 mL) was added to the mixture, and the mixture was stirred at 60°C for 10 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (42.0 mg) as a colorless oil. 10 MS (API+): [M+H]+ 386.2. ΤΗ NMR (300 MHz, CDC13) δ 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 4.00 (2H, q,. J = 7.2 Hz), 6.76-6.86 (1H, m) , 7.10 (2H, s) , 7.13-7.22 (1H, m), 7.30-7.40 (2H, m) , 7.51 (1H, d, J = 9.1 Hz), 7.68-7.75 (2H, m), 7.88 (1H, s), 8.02 (1H, d, J = 6.4 Hz). 15 Anal. Calcd for C22H19N5O2-0.5 H20: C, 67.06; H, 5.11; N, 17.77. Found: C, 67.25; H, 5.16; N, 17.71.

[0419]

Example 125 7-ethyl-9-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-7,9- 20 dihydro-8H-purin-8-one

125a) 2-(4-bromophenoxy)-l-methyl-lH-benzimidazole

Triethylamine (18 mL) was added to a mixture of 2-chloro-25 1-methyl-lH-benzimidazole (7.2 g) and p-bromophenol (22.5 g) at room temperature. The mixture was stirred at 120°C for 6 h.

The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with 1 N NaOH aq. and brine, dried over MgSCL and concentrated 268 WO 2011/163355 PCT/US2011/041443 in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 15% EtOAc in hexane) to give 2-(4-bromophenoxy)-l-methyl-lff-benzimidazole (3.2 g) as colorless crystals. 5 MS (API+) : [M+H]+ 304.92. ΤΗ NMR (300 MHz, CDC13) δ 3.73 (3H, s), 7.13-7.35 (5H, m) , 7.50-7.61 (3H, m).

[0420] 125b) N- (diphenylmethylidene)-4-[(l-methyl-lH-benzimidazol-2-

To a suspension of 2-(4-bromophenoxy)-1-methyl-lif-benzimidazole (1.0 g) , Pd2(dba)3 (0.076 g) , sodium tert-butoxide (0.48 g) and xantphos (0.19 g) in dioxane (10 mL) was 15 added benzophenone imine (0.83 .mL) , and the mixture was stirred at 100°C under Ar atmosphere for 6 h. After stirring at room temperature overnight, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The 20 residual crystals were washed with AcOEt to obtain N-(diphenylmethylidene) -4- [ (l-methyl-l.H-benzimidazol-2-yl)oxy]aniline (0.81 g) as pale yellow crystals. MS (API+): [M+H]+ 404.2. NMR (300 MHz, DMSO-d6) δ 3.67 (3H, s) , 6.74-6.82 (2H, m) , 25 7.07-7.26 (6H, m) , 7.33-7.59 (8H, m) , 7.64-7.71 (2H, m) .

[0421] 125c) 4- [ (l-methyl-lif-benzimidazol-2-yl) oxy] aniline

To a suspension of N- (diphenylmethylidene)-4-[(1-methyl- 30 lff-benzimidazol-2-yl)oxy]aniline (810 mg) in THF (10 mL) was added 1 N HC1 aq (10 mL) at room temperature, and the mixture 269 WO 2011/163355 PCT/US2011/041443 was stirred at room temperature for 1 h. The mixture was neutralized with sat. NaHCO3 aq. and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography 5 (silica gel, eluted with 5% - 100% AcOEt in hexane) to give 4-[(l-methyl-lH-benzimidazol-2-yl)oxy]aniline (440 mg) as colorless crystals. MS (API+) : [M+H]+ 240.2. XH NMR (300 MHz, DMSO-d6) δ 3.68 (3H, s) , 5.06 (2H, s), 6.55-io 6.64 (2H, m), 6.99-7.18 (4H, m) , 7.30-7.43 (2H, m) . (0422] 125d) 6-chloro-N-{4-((l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine

15 To a solution of 4-( (l-methyl-lH-benzimidazol-2- yl)oxy]aniline (0.30 g) and TEA (0.26 mL) in THF (15 mL) was added 4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the mixture 20 was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5% - 50% AcOEt in hexane) to give 6-chloro-N-{ 4- ( (l-methyl-lii-benzimidazol-2-yl) oxy] phenyl}-5- 25 nitropyrimidin-4-amine (0.24 g) as a yellow solid. MS (API+): [M+H]+ 397.3. NMR (300 MHz, CDC13) δ 3.75 (3H, s) , 7.17-7.26 (3H, m) , 7.43-7.51 (2H, m) , 7.54-7.65 (3H, m), 8.48 (1H, s), 9.22 (1H, s) . 30 (0423] 125e) AT4— {4 — [ (l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine 270 PCT/US2011/041443 WO 2011/163355

A mixture of 6-chloro-2\7'-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (240 mg) and 10% palladium on carbon (160 mg) in MeOH (10 mL) and THF (10 mL) 5 was hydrogenated under balloon pressure at room temperature overnight. To the mixture was added TEA (0.50 mL) . The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 5% MeOH in AcOEt) io to give ?/-{4-[ (l-methyl-lH-benzimidazol-2- yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) as a colorless solid. MS (API+): [M+H]+ 333.4.

[0424] is 125f) 9—{4— [ (l-methyl-lfr-benzimidazol-2-yl) oxy]phenyl}-7,9-dihydro-8 H-purin-8-one

A solution of 7\74-{4-[(l-methyl-lii-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) and CDI (39 mg) 20 in THF (20 mL) was refluxed for 3 h. CDI (39 mg) was added to the mixture. After refluxing overnight, the mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 9-{ 4-[ (l-methyl-lif-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8ff-purin-8-one (56 mg) as white 25 crystals. MS (API+): [M+H]+ 359.3.

[0425] 125g) 7-ethyl-9-{4-[(l-methyl-lff-benzimidazol-2-yl) oxy] phenyl} -7,9-dihydro-87i-purin-8-one 271 PCT/US2011/041443 WO 2011/163355

A mixture of 9-{4-[ (l-methyl-lH-benzimidazol-2-yl) oxy]phenyl}-7, 9-dihydro-8iZ-purin-8-one (56 mg), iodoethane (20 pL) and cesium carbonate (120 mg) in DMF (3 mL) was 5 stirred at 50°C for 4 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual crystals were recrystallized from AcOEt to give 7-ethyl-9-{4-[ (l-methyl-lH-benzimidazol-2- 10 yl) oxy]phenyl}-7,9-dihydro-8Ji-purin-8-one (40 mg) as white crystals. MS (API+): [M+H]+ 387.4. NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 3.77 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 7.11-7.24 (2H, m), 7.40-7.51 (2H,

15 m) , 7.58-7.66 (2H, m), 7.72-7.79 (2H, m), 8.64 (1H, s) , 8.65 (1H, s) . mp 242-243°C

Anal. Calcd for C2iH18N6O2: C, 65.27; H, 4.70; N, 21.75. Found: C, 64.99; H, 4.77; N, 21.70. 20 [0426]

Example 126 6-chloro-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}—1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

126a) 3-[4-(benzyloxy)phenyl]-6-chloro-l-(1-methylethyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one 272 PCT/US2011/041443 WO 2011/163355

Di-tert-butyl dicarbonate (17.05 mL) was added to a solution of 2,5-dichloropyridin-3-amine (11.4 g) and NaHMDS (81 mL) in THF(dry) (200 mL) at 0°C. The mixture was stirred at 5 0°C under a dry atmosphere for 1 h. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 20% EtOAc in io hexane) to give tert-butyl 2,5-dichloropyridin-3-ylcarbamate (15.6 g) as colorless oil. The mixture of tert-butyl 2,5-dichloropyridin-3-ylcarbamate (7.5 g), 4-benzyloxyaniline hydrochloride (10.08 g), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (1.319 g), Pd2(dba)3 (1.044 g) is and sodium tert-butoxide (6.57 g) in toluene (160 mL) - 2- propanol (40.0 mL) was stirred at 100°C under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give intermediate. To the

20 intermediate in DMF (100 mL) were added 2-iodopropane (5.69 mL) and NaH (2.280 g), and the mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for lh. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH 25 silica gel, eluted with 0% - 50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-6-chloro-l-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as a colorless solid. MS (API+): [M+H]+ 394.2. TH NMR (300 MHz, DMSO-d6) δ 1.41-1.57 (6H, m) , 4.57-4.78 (1H, 30 m) , 5.18 (2H, s), 7.09-7.21 (2H, m) , 7.26-7.60 (7H, m) , 7.81- 8.08 (2H, m).

[0427] 273 WO 2011/163355 PCT/US2011/041443 126b) 6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-l-(1- 5 methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (600 mg) and 10% Pd-C (162 mg) in EtOAc (50 mL) was hydrogenated under balloon pressure at room temperature for lh. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column io chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) as a white solid. MS (API+): [M+H] + 304.1. 15 ςΗ NMR (300 MHz, DMSO-dg) δ 1.38-1.65 (6H, m) , 4.54-4.82 (1H, m), 6.84-6.96 (2H, m), 7.30-7.41 (2H, m), 7.89-7.94 (1H, m), 7.93-7.98 (1H, m), 9.74 (1H, s).

[0428] 126c) 6-chloro-l-(1-methylethyl)-3-{4-[(3-methyl-3H- 20 imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (100 mg) was added to a solution of 6-chloro-3-(4- 25 hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5— b]pyridin-2-one (148 mg) and NaH (20.83 mg) in DMF (3 mL) at room temperature. The mixture was heated at 180°C for 30min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified 274 WO 2011/163355 PCT/US2011/041443 by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give 6-chloro-l-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals. 5 MS (API+): [M+H]+ 435.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.38-1.64 (6H, m) , 3.77 (3H, s), 4.71 (1H, s), 7.15-7.28 (1H, m), 7.57-7.67 (2H, m), 7.69-7.86 (3H, m), 7.90-8.10 (2H, m), 8.16-8.27 (1H, m).

[0429] io Example 127 6-(difluoromethoxy)-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

O 15 127a.} 3-[4-(benzyloxy)phenyl]-l-ethyl-6-hydroxy-l,3-dihydro-2ff-imidazo[4,5-b]pyridin-2-one

,OH

O A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-l-ethyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.72 g), Pd2dba3 20 (0.21 g), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-1,1'-biphenyl (0.44 g) and KOH (1.10 g) in dioxane (15 mL) and water (15 mL) was stirred at 100°C under Ar atmosphere for 3 h. After stirring at room temperature overnight, the mixture was acidified with 1 N HC1 aq (11 mL) 25 and diluted with water. The mixture was extracted with AcOEt.

The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 70% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-l-ethyl-6-hydroxy-l,3- 275 WO 2011/163355 PCT/US2011/041443 dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.31 g) as a pale yellow solid. MS (API+): [M+H]+ 362.3. ΤΗ NMR (300 MHz, DMSO-d6) δ 1.25 (3H, t, J = 7.2 Hz), 3.90 (2H, 5 q, J = 7.2 Hz), 5.17 (2H, s), 7.08-7.17 (3H, m), 7.30-7.56 (8H, m) , 9.58 (1H, brs).

[0430] 127b) 3- [4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-6-hydroxy- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), sodium chlorodifluoroacetate (253 mg), K2CO3 (172 mg), DMF (3 mL), and water (0.60 mL) was refluxed overnight. The reaction mixture is was poured into water, and the mixture was extracted with

AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10% - 40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6- 20 (difluoromethoxy)-1-ethyl-l, 3-dihydro-2#-imidazo[4,5-b]pyridin-2-one (110 mg) as a pale yellow oil. MS (API+) : [M+H]+412.1. ΧΗ NMR (300 MHz, CDC13) δ 1.39 (3H, t, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 5.10 (2H, s), 6.50 (1H, t, J = 73.3 Hz), 7.04- 25 7.17 (3H, m), 7.27-7.49 (5H, m) , 7.50-7.61 (2H, m), 7.92 (1H, d, J = 2.3 Hz).

[0431] 127c) 6-(difluoromethoxy)-l-ethyl-3-(4-hydroxyphenyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one 276 PCT/US2011/041443 WO 2011/163355

HO

F

O °Ύ A mixture of 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-l, 3-dihydro-2if-imidazo[4,5-b]pyridin-2-one (110 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) was 5 hydrogenated under balloon pressure at room temperature for 2h The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 6-(difluoromethoxy)-l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2ff-imidazo[4,5-b]pyridin-2-one (86 mg) as a pale yellow oil. 70 MS (API+) : [M+H]+ 322.3.

[0432] 127d) 6-(difluoromethoxy)-l-ethyl-3-{4-[ (3-methyl-37i-imidazo [4,5-b]pyridin-2-yl) oxy] phenyl}-1,3-dihydro-2ii-imidazo[4,5-b]pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3ίΖ-imidazo[4,5-b]pyridine (62 mg) and 6-(difluoromethoxy)-1-ethyl-3- (4-hydroxyphenyl) -1,3-dihydro-2if-imidazo [4,5-b]pyridin-2-one (86 mg) in DMF (3 mL) was added NaH (13 mg) at 20 room temperature, and the mixture was stirred at 180°C under microwave irradiation for 30 min. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, 25 NH silica gel, eluted with 50% - 100% AcOEt in hexane) and recrystallized from AcOEt/hexane to give 6-(difluoromethoxy)- l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl) oxy]phenyl}-1,3-dihydro-2£f-imidazo [4,5-b] pyridin-2-one (56 mg) as white crystals. 277 WO 2011/163355 PCT/US2011/041443 . MS (API+) : [M+H]+ 453.4. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.30 (3H, t, J = 7.2 Hz), 3.77 (3H, s), 4.00 (2H, q, J = 7.2 Hz), 7.21 (1H, dd, J = 7.9, 4.9 Hz), 7.24 (1H, t, J = 74.0 Hz), 7.59-7.67 (2H, m), 7.73-7.84 (4H, 5 m) , 7.92 (1H, d, J = 2.3 Hz), 8.22 (1H, dd, J = 4.9, 1.5.Hz). Anal, Calcd for C22Hi8N6O3F2: C, 58.41; H, 4.01; N, 18.58. Found C, 58.30; H, 4.15; N, 18.43.

Mp: 195-197°C [0433] io Example 128 6-(2,2-difluoroethoxy)-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

15 128a) 3- [4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2,2-Difluoroethyl trifluoromethanesulfonate (213 mg) was added to a solution of 3-[4-(benzyloxy)phenyl]-l-ethyl-6- 20 hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and potassium carbonate (229 mg) in DMF (5 mL) at room temperature. The mixture was stirred at ambient temperature under a dry atmosphere (CaCl2 tube) for 3 h. The mixture was quenched with water at room temperature and extracted with 25 AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 278 WO 2011/163355 PCT/US2011/041443 15% - 50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (301 mg) as colorless oil. MS (API+): [M+H]+426.4 5 ΧΗ NMR (300 MHz, CDC13) δ 1.39 (3H, d, J = 7.3 Hz), 3.98 (2H, q, J = 7.3 Hz), 4.24 (2H, td, J = 13.0, 4.0 Hz), 5.11 (2H, s) , 6.10 (1H, tt, J = 55.0, 4.0 Hz), 6.96 (1H, d, J = 2.6 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.28-7.48 (5H, m), 7.56 (2H, d, J = 8.7 Hz), 7.73 (1H, d, J = 2.6 Hz). io [0434] 128b) 6-(2,2-difluoroethoxy)-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

15 A mixture of 3-[4-(benzyloxy)phenyl]-6-(2,2- difluoroethoxy)-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and 10% Pd-C (37.5 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the 20 filtrate was concentrated in vacuo to give 6-(2,2- difluoroethoxy)-l-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To.a solution of this product and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (153 mg) in DMF (5 mL) was added sodium 25 hydride (34.1 mg) at 100°C, and the mixture was heated at 180°C for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with sat. NaHCO3 aq. and brine, dried over MgSO4 and concentrated in vacuo. The 30 residue was purified by column chromatography (NH silica gel, eluted with 15% - 50% AcOEt in hexane) to give 6-(2,2- 279 WO 2011/163355 PCT/US2011/041443 difluoroethoxy)-l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (264 mg) as a colorless solid. The solid was crystallized from AcOEt-hexane. 5 MS (API+): [M+H]+467.3 NMR (300 MHz, CDC13) δ 1.42 (3h, t, J = 7.2 Hz), 3.84 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 4.26 (2H, td, J = 13.0, 4.1 Hz), 6.12 (1H, tt, J = 55.0, 4.0 Hz), 6.98 (1H, d, J = 2.6 Hz), 7.15 (1H, dd, J = 7.9, 4.9 Hz), 7.56 (2H, d, J = 8.7 Hz), io 7.72-7.82 (2H, m), 7.88 (2H, d, J = 9.0 Hz), 8.25 (1H, dd, J = 4.9, 1.5 Hz).

Anal. Calcd for C23H20N6O3F2 - 0.5H2O: C, 58.10; H, 4.45;

N,17.68; F, 8.15. Found: C, 58.20; H, 4.39; N, 17.65. mp 171 - 172°C is [0435]

Example 129 1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

129a) 3-[4-(benzyloxy)phenyl]-l-ethyl-6- (2,2,2- trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.144 mL) 25 was added to a solution of 3-[4-(benzyloxy)phenyl]-l-ethyl-6- hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and potassium carbonate (229 mg) in DMF (5 mL) at room 280 WO 2011/163355 PCT/US2011/041443 temperature. The mixture was stirred at ambient temperature under a dry atmosphere (CaCl2 tube) for 3 h. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and 5 brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (308 mg) as colorless oil. io MS (API+): [M+H] +444.4 ΧΗ NMR (300 MHz, CDC13) δ 1.40 (3H, d, J = 7.2 Hz), 3.99 (2H, q, J = 7.2 Hz), 4.40 (2H, q, J = 7.9 Hz), 5.11 (2H, s), 6.99 (1H, d, J = 2.3 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.28-7.49 (5H, m) , 7.55 (2H, d, J = 9.1 Hz), 7.74 (1H, d, J = 2.6 Hz). 15 [0436] 129b) l-Ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl]-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

20 A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-6-(2,2,2- trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (305 mg) and 10% Pd-C (36.6 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the 25 filtrate was concentrated in vacuo to give l-ethyl-3-(4-hydroxyphenyl)-6-(2,2,2-trifluoroethoxy)-ΙΗ-imidazo[4,5-b]pyridin-2(3H)-one as colorless solid. To a solution of this product and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (149 mg) in DMF (5 mL), sodium hydride (33.1 mg) 30 was added at 100°C and the mixture was heated at 180°C for 30 min under microwave irradiation. The mixture was quenched with 281 WO 2011/163355 PCT/US2011/041443 water at room temperature and extracted with AcOEt. The organic layer was separated, washed with sat. NaHCO3 aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 15% - 50% AcOEt in hexane) to give l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (262 mg) as colorless solid. The solid was crystallized from AcOEt-hexane. MS (API+) : [M+H]+ 485.3 ΧΗ NMR (300 MHz, CDC13) δ 1.42 (3H, t, J = 7.3 Hz), 3.85 (3H, s), 4. 01 (2H, q, J = 7.3 Hz), 4.43 (2H, q, J = 8.0 Hz), 7.02 (1H, d ., J = 2.3 Hz) , 7.15 (1H, dd, J = 7.9, 4.9 Hz) , 7.56 (2H, d, J = 9.0 Hz), 7.75-7.82 (2H, m) , 7.87 (2H, d, J = = 9.4 Hz), 8.25 ( 1H, dd, J = 4.9, 1.5 Hz)

Anal. Calcd for C23H19N6O3F3 - 0.5H2O: C, 55.98; H, 4.09; N, 17.03. Found: C, 55.88; H, 4.19; N, 16.94. mp 178 - 179°C

[0437]

Example 130 l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy)phenyl}-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

130a) methyl 2-fluoro-4-(trifluoromethyl)pyridine-3-

To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3- carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF(dry) (10 mL) was added Mel (0.317 mL). The mixture was stirred at room 282 WO 2011/163355 PCT/US2011/041443 temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity). 5 MS (API+): [M+H]+ 224.0 [0438] 130b) methyl 2-{ [4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylate

\ io A mixture of 4-(benzyloxy)aniline (1010 mg), DIEA (1.771 mL) and methyl 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylate (1130 mg) in NMP (10 mL) was stirred at 150°C for 2 h and at 200°C for 1 h under microwave irradiation. The mixture was poured into water, and the mixture was extracted with 15 EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel,

EtOAc/hexane) to give the title compound (225 mg). MS (API+) : [M+H]+ 403.3 20 [0439] 130c) 2-{[4-(benzyloxy)phenyl]amino]-4-(trifluoromethyl)pyridine-3-carboxylic acid

To a mixture of methyl 2-{[4-(benzyloxy)phenyl]amino]-4-25 (trifluoromethyl)pyridine-3-carboxylate (255 mg) in MeOH (5 mL) was added IN NaOH (2.54 mL), and the mixture was stirred at 60°C for 3 h. After MeOH was evaporated, to the water phase was added IN HC1 (pH = ca. 2). The precipitate was collected by filtration to give the title compound (221 mg). 30 MS (API+) : [M+H]+ 389.3 [0440] 283 130d) 3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one WO 2011/163355 PCT/US2011/041443

To a solution of 2-{[4-(benzyloxy)phenyl]amino}-4- 5 (trifluoromethyl)pyridine-3-carboxylic acid (221 mg) and Et3N (0.238 mL) in toluene (15 mL) was added diphenylphosphoryl azide (0.245 mL) at room temperature. The mixture was stirred at 110°C for 4 h. After cooling, the solvent was evaporated, and the precipitate was collected by filtration to give the io title compound (197 mg) . MS (API+): [M+H]+ 386.2 [0441] 130e) 3-[4-(benzyloxy)phenyl]-l-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of NaH (40.9 mg), 3-[4-(benzyloxy) phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) in DMF(dry) (3 mL) was added iodoethane (0.082 mL), and the mixture was stirred at room temperature for 3 h. To 20 the mixture was added sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg). MS (API+): [M+H]+ 414.1 25 [0442] 130f) l-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(benzyloxy)phenyl]-l-ethyl-7- 284 WO 2011/163355 PCT/US2011/041443 (trifluoromethyl) -1, 3-dihydro-2H-imidazo [4,5-b]pyridin-2-one (197 mg) and 10% palladium on carbon (50% wet, 68 mg) in MeOH (6.5 mL) and EtOAc (6.5 mL) was hydrogenated under balloon pressure at room temperature for 4 h. The solid was filtrated and washed with MeOH (10 mL) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (103 mg). MS (API+): [M+H]+ 324.2 [0443] 130g) l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and l-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5 b]pyridin-2-one (103 mg) in DMF(dry) (1.5 mL) was added NaH (19.12 mg), and the mixture was stirred at 100°C for lh. The mixture was heated at 180°C for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg). MS (API+): [M+H]+ 455.3. XH NMR (300 MHz, DMSO-dg) δ 1.30 (3H, t, J = 7.0 Hz), 3.78 (3H, s), 4.00-4.10 (2H, m), 7.21 (1H, dd, J = 7.7, 5.1 Hz), 7.48 (1H, d, J = 5.3 Hz), 7.60-7.69 (2H, m), 7.72-7.78 (2H, m) , 7.81 (1H, dd, J = 7.9, 1.5 Hz), 8.17 (1H, d, J = 5.7 Hz), 8.22 (1H, dd, J = 4.9, 1.5 Hz).

Anal. Calcd for C22H17N6O2F3: C, 58.15; H, 3.77; N, 18.49. Found 285 WO 2011/163355 PCT/US2011/041443 C, 58.05; H, 3.84; N, 18.33. m.p. 244-246°C [0444]

Example 132 5 l-ethyl-6-fluoro-3-{4-[(l-methyl-lH-benzimidazol-2- yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

132a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine

io A mixture of 4-(benzyloxy)aniline (2.26 g) , 2-chloro-5- fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120°C for 5h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and 15 collected by filtration. The solid obtained above was dissolved in EtOH (20 mL), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for lh, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g). 20 TH NMR (300 MHz, DMSO-dg) δ 5.04 (2H, s) , 5.39 (2H, s) , 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s) .

[0445] 132b) l-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H- 25 imidazo[4,5-b]pyridin-2-one

286 WO 2011/163355 PCT/US2011/041443 A mixture of N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine (0.85 g) and 1,1'-carbonylbis(lH-imidazole) (0.45 g) in DME (10 mL) was stirred at 100°C for 4h, and then Cs2CO3 (0.90 g) and 1,I'-carbonylbis(1H-imidazole) (0.892 g) were added successively. The mixture was stirred at 100°C for lOmin, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (10 mL), and then Cs2CO3 (3.58 g) and iodoethane (1.29 g) were added successively. The mixture was stirred at 100°C for 2h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (30 mL) , and Pd/C (1.5 g) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 30 min, filtered and evaporated. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (0.52 g). MS (API+): [M+H]+ 274.3.

[0446] 132c) l-ethyl-6-fluoro-3-{4-[(l-methyl-lH-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred solution of l-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30min, and then 2-chloro-l-methyl-lH-benzimidazole (67.1 mg) was added. The mixture was exposed to microwave irradiation at 180°C for 30min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from

AcOEt/Hexane gave the title compound (104 mg). 287 WO 2011/163355 PCT/US2011/041443 MS (API+): [M+H]+ 404.2. λΗ NMR (300 MHz, DMSO-dg) δ 1.30 (3H, t, J = 7.2 Hz), 3.76 (3H, s), 3.98 (2H, q, J = 7.2 Hz), 7.09-7.25 (2H, m), 7.39-7.52 (2H, m) , 7.56-7.64 (2H, m) , 7.73-7.79 (2H, m), 7.83-7.91 (1H, m) , 5 7.96-8.01 (1H, m).

[0447]

Example 133 1-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

133a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine

A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 mL) 15 was stirred at 120°C for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 mL) , and Pt/C (2 g) was added. Under H2 atmosphere, 20 the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g). ΧΗ NMR (300 MHz, DMSO-d6) δ 5.04 (2H, s) , 5.39 (2H, s), 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, 25 S) .

[0448] 133b) l-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 288 PCT/US2011/041443 WO 2011/163355

A mixture of N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine (0.85 g) and 1,1'-carbonylbis(ΙΗ-imidazole) (0.45 g) in DME (10 mL) was stirred at 100°C for 4 h, and then Cs2CO3 (0.90 g) and 1,1'-carbonylbis(1H-imidazole) (0.892 g) were added successively. The mixture was stirred at 100°C for 10 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (10 mL) , and then Cs2CC>3 (3.58 g) and iodoethane (1.29 g) were added successively. The mixture was stirred at 100°C for 2 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (30 mL) , and Pd/C (1.5 g) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 30 min, filtered and evaporated. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (0.52 g). MS (API+): [M+H]+ 274.3.

[0449] 133c) l-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

To a stirred solution of l-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30min, and then 3-methyl-2-(methylsulfonyl)-3H- imidazo[4,5-b]pyridine (85 mg) was added. The mixture was exposed to microwave irradiation at 180°C for 30min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. 289 WO 2011/163355 PCT/US2011/041443

Crystallization from AcOEt/Hexane gave the title compound (96 mg) . MS (API+): [M+H] + 405.2. XH NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.2 Hz), 3.77 (3H, 5 s), 3.98 (2H, q, J = 7.2 Hz), 7.21 (1H, dd, J = 7.9, 4.9 Hz), 7.57-7.66 (2H, m), 7.72-7.91 (4H, m) , 7.95-8.05 (1H, m), 8.18-8.24 (1H, m) .

[0450]

Example 134 io 3-[4-(2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

15 134a) ethyl N-(3-nitropyridin-2-yl)glycinate

To a solution of 2-chloro-3-nitropyridine (25.3 g) in EtOH (300 mL) were added ethyl 2-aminoacetate hydrochloride (28.7 g) and triethylamine (28.9 mL) at room temperature, and 20 the mixture was refluxed for 1 day. The mixture was concentrated under reduced pressure. The residual crystals were removed by filtration and washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20% 25 - 70% AcOEt in hexane). The residual crystals were removed by filtration and washed with IPE. The filtrate was concentrated under reduced pressure to give the title compound (26.9 g). ΧΗ NMR (300 MHz, CDC13) δ 1.30 (3H, t, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz), 4.38 (2H, d, J = 5.3 Hz), 6.72 (1H, dd, J = 8.3, 290 WO 2011/163355 PCT/US2011/041443 4.5 Hz), 8.40 (1H, dd, J = 4.5, 1.9 Hz), 8.44 (1H, dd, J = 8.3 1.9 Hz), 8.50 (1H, brs) .

[0451] 134b) ethyl N-(3-aminopyridin-2-yl)glycinate

A mixture of ethyl N-(3-nitropyridin-2-yl)glycinate (26 g) and 10% palladium on carbon (50% wet, 7.3 g) in AcOEt (250 mL) was hydrogenated under balloon pressure at room temperature for 8 h. The catalyst was removed by filtration. io To the filtrate were added triethylamine (5.0 mL) and 10% palladium on carbon (50% wet, 7.3 g). The mixture was hydrogenated under balloon pressure at room temperature overnight. The mixture was concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 15 eluted with 10% - 50% AcOEt in hexane) to give the title compound (18 g). XH NMR (300 MHz, DMSO-d6) δ 1.17 (3H, t, J = 7.2 Hz), 3.98-4.13 (4H, m) , 4.72 (2H, s), 6.07 (1H, t, J = 6.0.Hz), 6.38 (1H, dd, J = 7.3, 5.1 Hz), 6.70 (1H, dd, J = 7.5, 1.5 Hz), 7.31 (1H, dd 20 J = 4.9, 1.5 Hz) .

[0452] 134c) ethyl (2-oxo-l, 2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate

OEt 25 To a solution of ethyl N-(3-aminopyridin-2-yl)glycinate (18 g) in THF (200 mL) was added CDI (15 g) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure

The residual crystals were washed with AcOEt to give the title 291 WO 2011/163355 PCT/US2011/041443 compound (5.5 g). XH NMR (300 MHz, CDC13) δ 1.30 (3H, t, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz), 4.77 (2H, s), 7.02 (1H, dd, J = 7.6, 5.3 Hz), 7.31 (1H, dd, J = 7.6, 1.1 Hz), 8.05 (1H, dd, J = 5.3, 1.1 Hz), 5 9.70 (1H, brs) .

[0453] 134d) ethyl (2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)acetate

OEt A mixture of ethyl (2-oxo-l,2-dihydro-3H-imidazo[4,5-io b]pyridin-3-yl)acetate (14.5 g) and phosphoryl chloride (100 mL) was stirred at 100°C overnight. The mixture was poured into ice, neutrallized with saturated sodium bicarbonate solution and extracted with AcOEt. The organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The 15 residue was diluted with AcOEt and insoluble crystals were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10% - 40% AcOEt in hexane) to give the title compound (5.46 g). 20 XH NMR (300 MHz, CDC13) δ 1.29 (3H, t, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz), 5.07 (2H, s), 7.23-7.32 (1H, m), 7.99 (1H, dd, J = 8.1, 1.5 Hz), 8.36 (1H, dd, J = 4.9, 1.5 Hz).

[0454] 134e) ethyl {2-[(4-nitrophenyl)amino]-3H-imidazo[4,5- 25 b]pyridin-3-yl[acetate

EtO

A mixture of ethyl (2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (2.8 g) and 4-nitroaniline (1.6 g) was stirred at 292 WO 2011/163355 PCT/US2011/041443 150°C for 1 h to give the title compound (4.0 g) . XH NMR (300 MHz, DMSO-d6) δ 1.22 (3H, t, J = 7.2 Hz), 4.18 (2H, q, J = 7.2 Hz),' 5.21 (2H, s), 7.20 (1H, dd, J = 7.6, 4.9 Hz), 7.85 (1H, d, J = 7.6 Hz), 8.06-8.20 (3H, m) , 8.23-8.34 (2H, m) 5 9.98 (1H, brs).

[0455] 134f) 2—{2—[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl]ethanol

io imidazo[4,5-b]pyridin-3-yl}acetate (3.6 g) in THF (120 mL) was added lithium borohydride (0.77 g) at room temperature, and the mixture was refluxed for 2 h. The mixture was cooled to room temperature, quenched with water and extracted with AcOEt 15 The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% AcOEt in hexane) to give the title compound (2.2 g). TH NMR (300 MHz, DMSO-d6) δ 3.80 (2H, t, J = 5.5 Hz), 4.45 (2H, 20 t, J = 5.5 Hz), 7.17 (1H, dd, J = 7.6, 4.9 Hz), 7.82 (1H, dd, J = 7.6, 1.1 Hz), 8.06-8.19 (3H, m), 8.23-8.33 (2H, m) .

[0456] 134g) 1-(4-nitrophenyl)-2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

To a solution of 2-{2-[(4-nitrophenyl)amino]-3H- imidazo[4,5-b]pyridin-3-yl]ethanol (2.2 g) and triethylamine (10 mL) in THF (100 mL) was added methanesulfonyl chlorode 293 WO 2011/163355 PCT/US2011/041443 (1.1 mL) at 0°C, and the mixture was stirred at 0°C for 2 h.

The mixture was poured into water and extracted with AcOEt.

The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of 5 the residue and potassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water. The formed crystals were collected by filtration to give the title compound (1.7 g). XH NMR (300 MHz, DMSO-d6) δ 4.40-4.51 (2H, m) , 4.64-4.75 (2H, io m), 7.16 (1H, dd, J = 8.0, 4.9 Hz), 7.83 (1H, d, J = 8.0 Hz), 8.03 (2H, d, J = 9.1 Hz), 8.09 (1H, d, J = 4.9 Hz), 8.35 (2H, d, J = 9.1 Hz).

[0457] 134h) 4- (2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5— 15 b]pyridin-l-yl)aniline

A mixture of 1-(4-nitrophenyl)-2,3-dihydro-lH-imidazo[2r ,1':2,3]imidazo[4,5-b]pyridine (1.7 g) and 10% palladium on carbon (50% wet, 1.0 g) in MeOH (150 mL) was 20 hydrogenated under balloon pressure at room temperature for 1 day. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g). MS (API+): [M+H]+ 252.4. 25 [0458] 134i) 3-[4-(2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-

294 WO 2011/163355 PCT/US2011/041443

The mixture of 2-chloro-3-nitropyridine (189 mg), 4-(2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)aniline (300 mg) and DIPEA (1.0 mL) in DMSO (5 mL) was stirred at 120°C for 4h. The mixture was diluted with AcOEt and 5 THF, and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of the residue and 10% palladium on carbon (50% wet, 0.20 g) in MeOH (30 mL) was hydrogenated under balloon pressure at room temperature for 1 day. The catalyst was io removed by filtration and the filtrate was concentrated under reduced pressure. A solution of the residue and CDI (193 mg) in THF (15 mL) was refluxed for overnight. To the mixture was added CDI (193 mg), and the mixture was refluxed for 5 h. After cooling to is room temperature, the formed precipitate was collected by filtration to give the title compound (165 mg). TH NMR (300 MHz, DMSO-d6) δ 4.38-4.49 (2H, m) , 4.58-4.70 (2H, m), 7.05-7.14 (2H, m), 7.40 (1H, dd, J = 7.9, 1.5 Hz), 7.67 (2H, d, J = 9.1 Hz), 7.74 (1H, dd, J = 7.7, 1.3 Hz), 7.91-7.99 20 (3H, m), 8.02 (1H, dd, J = 4.9, 1.5 Hz), 11.36 (1H, s).

[0459] 134j) 3-[4-(2,3-dihydro-lH-imidazo[2',1':2,3]imidazo [4,5-b]pyridin-l-yl)phenyl]-1-ethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 3-[4-(2,3-dihydro-lH-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-l-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (165 mg), iodoethane (0.054 mL) and cesium carbonate (291 mg) in DMF (3 mL) was 30 stirred at 50°C for 6 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced 295 WO 2011/163355 PCT/US2011/041443 pressure. The residual crystals were dissolved in THF, and the solution was filtered through NH-silica gel. The filtrate was concentrated under reduced pressure. The residual crystals were recrystallized from EtOH to give the title compound (94 5 mg) . TH NMR (300 MHz, DMSO-d6) δ 1.30 (3H, t, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.37-4.49 (2H, m) , 4.57-4.71 (2H, m), 7.10 (1H, dd, J = 7.9, 4.9 Hz), 7.17 (1H, dd, J = 7.7, 5.1 Hz), 7.62-7.71 (3H, m), 7.74 (1H, dd, J = 7.7, 1.3 Hz), 7.91-8.06 (4H, io m) . MS (ESI+): [M+H]+ 398.1.

mp 255-256°C

Srnial. Calcd for C22H19N7O: C, 66.49; H, 4.82; N, 24.67. Found: C, 66.24; H, 4.85; N, 24.41. 15 [0460]

Example 135 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 0 20 135a) 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Mel (0.377 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-7-methyl-l,3-dihydro-2H-imidazo[4,5- 25 b]pyridin-2-one (2.0 g) and NaH (0.362 g) in DMF (20 mL) at 20°C. The mixture was stirred at 20°C under a dry atmosphere for lh. The mixture was diluted with sat. NaHCCh at 20°C and extracted with EtOAc. The organic layer was separated, washed 296 WO 2011/163355 PCT/US2011/041443 with water and brine, dried over MgSO4 and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) . This product was subjected to the next reaction without further 5 purification.

[0461] 135b) 3-(4-hydroxyphenyl)-1,7-dimethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

0 10 A mixture of 3-[4-(benzyloxy)phenyl]-l,7-dimethyl-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and 10% Pd-C (0.308 g) in DMF (10 mL) - EtOAc (100 mL) was hydrogenated under balloon pressure at 20°C for lh. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The is residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give 3-(4-hydroxyphenyl)-1,7-dimethyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.30 g) as a light brown solid. This product was subjected to the next reaction without further 20 purification.

[0462] 135c) 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

o 25 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) was added to a solution of 3-(4-hydroxyphenyl)-1,7- dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (725 mg) 297 WO 2011/163355 PCT/US2011/041443

and potassium tert-butoxide (351 mg) in DMA (4ml) at 20°C. The mixture was stirred at 150°C under a dry atmosphere for 30 min The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH 5 silica gel, eluted with 0% - 50% EtOAc in hexane) to give 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as colorless crystals. MS (API+): [M+H]+ 387.1. 10 ΧΗ NMR (300 MHz, DMSO-d6) δ 2.59-2.69 (3H, s) , 3.66 (3H, s) , 3.78 (3H, s), 6.91-7.06 (1H, m) , 7.13-7.28 (1H, m), 7.56-7.66 (2H, m) , 7.70-7.76 (2H, m) , 7.77-7.83 (1H, m), 7.83-7.89 (1H, m) , 8.15-8.28 (1H, m) .

[0463] 15 Example 136 l-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide

20 Triisopropylsilyl chloride (2.384 mL) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 g) and NaH (0.594 g) in DMF (20mL) at 20°C. The mixture was stirred at 20°C under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was poured into 25 sat. NaHCO3 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 25% EtOAc in hexane) to give l-ethyl-7-methyl-3-(4-{[tris(1- 30 methylethyl)silyl]oxy[phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) as light brown crystals. 298 WO 2011/163355 PCT/US2011/041443

Trifluoroacetic anhydride (3.92 mL) was added to a suspenstion of l-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4 g) and urea hydrogen peroxide (2.74 g) in EtOAc (20 mL) at 0°C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) overnight. The mixture was neutralized with sat. NaHCO3 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 100% EtOAc in hexane) to give l-ethyl-7-methyl-3-(4—{[tris (1-methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (250 mg) as colorless crystals.

Tetrabutylammonium fluoride (0.566 mL) was added to a solution of l-ethyl-7-methyl-3-(4—{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (250 mg) in THF (5 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% EtOAc in hexane) to give l-ethyl-3-(4-hydroxyphenyl)-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (170 mg) as a colorless solid. 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (126 mg) was added to a solution of l-ethyl-3-(4-hydroxyphenyl)-7-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one 4-oxide (170 mg) and NaH (23.83 mg) in DMA (1 mL) at room temperature. The mixture was stirred at 150°C under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give l-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide as colorless crystals. 299 WO 2011/163355 MS (API+): [M+H]+ 417.2. ΧΗ NMR (300 MHz, DMSO-d6) δ 1.23-1.40 (3H, m) , 2.58 (3H, s) , 3.77 (3H, s), 4.01-4.19 (2H, m), 6.96-7.05 (1H, m), 7.15-7.29 (1H, m), 7.40-7.57 (4H, m) , 7.75-7.90 (2H, m) , 8.15-8.29 (1H, 5 m).

[0464]

Example 137 (l-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2- yl)oxy]phenyl}-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7- io yl)methyl acetate PCT/US2011/041443

The mixture of l-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (500 mg) in acetic anhydride (10 mL) is was stirred at 80°C under a dry atmosphere (CaCl2 tube) for 2 h The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% EtOAc in hexane) to give [l-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxyjphenyl)-2,3-dihydro-lH- 20 imidazo[4,5-b]pyridin-7-yl]methyl acetate (300 mg) as colorless oil.

Tetrabutylammonium fluoride (1.241 mL) was added to a solution of [l-ethyl-2-oxo-3-(4—{[tris(1-methylethyl)silyl]oxyjphenyl)-2,3-dihydro-lH-imidazo[4, 5- 25 b]pyridin-7-yl]methyl acetate (300 mg) in THF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% 30 EtOAc in hexane) to give [l-ethyl-3-(4-hydroxyphenyl)-2-oxo- 2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl]methyl acetate (170 mg) as a white solid. 300 WO 2011/163355 PCT/US2011/041443 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (110 mg) was added to a solution of [l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl]methyl acetate (170 mg) and potassium tert-butoxide (69.9 mg) in DMA (1 mL) at 5 room temperature. The mixture was stirred at 100°C under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 100% EtOAc in hexane) to give (l-ethyl-3-{4-[(3-methyl-3H-imidazo[4, δ ιό b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl)methyl acetate (10 mg) as colorless crystals. MS (API+): [M+H]+ 459.2. 1H NMR (300MHz, DMSO-d6) 51.28-1.41 (3H, m), 2.14 (3H, s), 3.78 (3H, s), 4.00-4.18 (2H, m), 5.40 (2H, s), 7.15-7.26 (2H, 15 m), 7.56-7.87 (5H, m) , 7.95-8.04 (1H, m) , 8.12-8.28 (1H, m) . [0465]

Example 138 l-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5— b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-

To a stirred mixture of [l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl]methyl acetate (150 mg) and EtOH (3 mL) was added 1 N NaOH (2 mL) at 0°C. The 25 mixture was stirred at 0°C for 30 min, treated with saturated NH4CI solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMA (4 mL) and KOtBu (52 mg) was added at room temperature. The mixture was stirred for 2 min, and then 3- 30 methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added. The mixture was stirred at 150°C for 30 min, treated 301 WO 2011/163355 PCT/US2011/041443 with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/MeOH = 20/1. The product was crystallized from AcOEt/Hexane to give 5 l-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (46 mg). MS (API+): [M+H]+ 417.2. NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J = 7.2 Hz), 3.78 (3H, io s), 4.13 (2H, q, J = 7.2 Hz), 4.80 (2H, d, J = 5.5 Hz), 5.67 (1H, t, J = 5.5 Hz), 7.14-7.26 (2H, m) , 7.59-7.68 (2H, m) , 7.71-7.87 (3H, m), 7.97 (1H, d, J = 5.3 Hz), 8.17-8.28 (1H, m) [0466]

Alternative route for l-ethyl-7-(hydroxymethyl)-3-{4-[(3- 15 methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one is described below. ' [0467] 138a) l-ethyl-7-methyl-3-(4—{[tris(1- methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5- 20 b]pyridin-2-one

To a stirred mixture of l-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10 g) and ΙΗ-imidazole (3.79 g) in DMF (100 mL) was added 25 triisopropylsilyl chloride (9.54 mL) at 0°C. The mixture was stirred at room temperature for 3 days, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/Hexane = 1/10) to give 30 the title compound (11.5 g) . MS (API+) : [M+H]+ 426.2. NMR (300 MHz, DMSO-d6) 51.05-1.19 (18H, m) , 1.23-1.37 (6H, 302 WO 2011/163355 PCT/US2011/041443 m) , 2.59 (3H, s), 4.08 (2H, d, J = 7.2 Hz), 6.89-7.05 (3H, m) , 7.46 (2H, d, J = 8.7 Hz), 7.80-7.86 (1H, m) .

[0468] 138b) l-ethyl-7-methyl-3-(4—{[tris(l-5 methylethyl)silyl]oxy]phenyl)-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 4-oxide

To a stirred mixture of l-ethyl-7-methyl-3-(4-{[tris (1-methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5- 10 b]pyridin-2-one (5 g) and urea hydrogen peroxide (2.32 g) in CH2C12 (50 mL) was added trifluoroacetic anhydride (3.32 mL) at 0°C. The mixture was stirred at room temperature for 12 h, and treated with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with AcOEt. The is organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, AcOEt) to give the title compound (1.0 g). MS (API+): [M+H]+ 442.3. :H NMR (300MHz, DMSO-d6) 50.99-1.17 (18H, m), 1.22-1.36 (6H, 20 m), 2.56 (3H, s), 4.06 (2H, q, J = 7.2 Hz), 6.82-6.91 (2H, m), 6.92-7.00 (1H, m), 7.14-7.24 (2H, m), 7.73 (1H, d, J = 6.8 Hz) [0469] 138c) [l-ethyl-2-oxo-3-(4-{[tris(l- methylethyl)silyl]oxyjphenyl)-2,3-dihydro-lH-imidazo[4,5— 25 b]pyridin-7-yl]methyl acetate

A mixture of l-ethyl-7-methyl-3-(4-{[tris(1- methylethyl)silyl]oxyjphenyl)-1,3-dihydro-2H-imidazo[4,5- b] pyridin-2-one 4-oxide (1 g) and Ac20 (20 mL) was stirred at 303 WO 2011/163355 PCT/US2011/041443 80°C for 2 h, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.49 g). MS (API+): [M+H]+ 484.3. 5 τΗ NMR (300 MHz, DMSO-d6) 51.03-1.15 (18H, m) , 1.24-1.39 (6H, m) , 2.13 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 5.37 (2H, s), 6.91-7.09 (2H, m), 7.07-7.29 (1H, m), 7.45-7.50 (2H, m), 7.95 (1H, d, J = 5.3 Hz).

[0470] io 138d) [l-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl]methyl acetate

To a stirred solution of [l-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxyjphenyl)-2,3-dihydro-lH-imidazo[4,5- 15 b]pyridin-7-yl]methyl acetate (480 mg) in THF (5 mL) was added . a solution of tetrabutylammonium fluoride (778 mg) in THF (2 mL) at 0°C. The mixture was stirred at 0°C for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was 20 purified by silica gel column chromatography (AcOEt/Hexane = 1/1) to give the title compound (276 mg). MS (API+): [M+H]+ 328.1. XH NMR (300 MHz, DMSO-d6) 51.30 (3H, t, J = 7.2 Hz), 2.12 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 5.36 (2H, s), 6.80-6.95 (2H, m) , 25 7.12 (1H, d, J = 5.3 Hz), 7.28-7.41 (2H, m), 7.93 (1H, d, J = 5.3 Hz), 9.71 (1H, s).

[0471] 138e) l-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H- 30 imidazo[4,5-b]pyridin-2-one 304 PCT/US2011/041443 WO 2011/163355

,ΟΗ

To a stirred mixture of [l-ethyl-3- (4-hydroxyphenyl) -2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-7-yl]methyl acetate (150 mg) and EtOH (3 mL) was added IN NaOH (2 mL) at 0°C. The 5 mixture was stirred at 0°C for 30 min, treated with saturated NH4C1 solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMA (4 mL) and KOtBu (52 mg) was added at room temperature. The mixture was stirred for 2 min, and then 3- 10 methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added. The mixture was stirred at 150°C for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, AcOEt/MeOH = 15 20/1) and crystallized from AcOEt/hexane to give the title compound (46 mg). MS (API+): [M+H] + 417.2. \H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J = 7.2 Hz), 3.78 (3H, s), 4.13 (2H, q, J = 7.2 Hz), 4.80 (2H, d, J = 5.5 Hz), 5.67 20 (1H, t, J = 5.5 Hz), 7.14-7.26 (2H, m), 7.59-7.68 (2H, m), 7.71-7.87 (3H, m), 7.97 (1H, d, J = 5.3 Hz), 8.17-8.28 (1H, m) [0472]

Example 139 l-ethyl-3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1, 3- 25 dihydro-2H-imidazo[4,5-b]pyridin-2-one 139a) 1-(5-methylpyridin-2-yl)-2H-indazol-5-amine 305 WO 2011/163355 PCT/US2011/041443

To a stirred solution of 5-nitro-lH-indazole (500 mg) in DMF (10 mL) was added 60% sodium hydride (129 mg) at room temperature. The mixture was stirred for 30 min, and 5-bromo- 2-chloropyridine (649 mg) was added. The mixture was exposed 5 to microwave irradiation at 230°C for 1 h, treated with sat. ammonium chloride solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo.

The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give a mixture of 1-(5-bromopyridin-2-yl)-5- 10 nitro-lH-indazole and 2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole.

To the mixture of 1-(5-bromopyridin-2-yl)-5-nitro-lH-indazole and 2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole were added methylboronic acid (141 mg), Pd(Ph3P)4 (91 mg), DME (3 15 mL) and a solution of Cs2CO3 (766 mg) in H2O (1 mL) , successively. The mixture was exposed to microwave irradiation 140°C for 1 h, treated with water, and extracted with AcOEt.

The organic layer was dried over MgSO4 and concentrated in vacuo to give a mixture of 1-(5-methylpyridin-2-yl)-5-nitro- 20 ΙΗ-indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole.

The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-lH- indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20 mL), and 10% Pd/C (250 mg) was added.

Under H2 atmosphere, the mixture was stirred at room 25 temperature for 12 h, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (61 mg). XH NMR (300 MHz, DMSO-d6) δ 2.36 (3H, s), 5.04 (2H, s), 6.58 (1H, d, J = 1.9 Hz), 6.86 (1H, dd, J = 9.1, 1.9 Hz), 7.44 (1H, 30 d, J = 9.1 Hz), 7.75-7.90 (1H, m) , 7.95-8.06 (1H, m), 8.35 (1H, d, J = 2.3 Hz), 8.72 (1H, d, J = 0.8 Hz).

[0473] 139b) 3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 306 PCT/US2011/041443 WO 2011/163355

Under argon atmosphere, a mixture of 1-(5-methylpyridin- 2- yl)-2H-indazol-5-amine (60 mg), tert-butyl 2-chloropyridin- 3- ylcarbamate (67.3 mg), Pd2(dba)3 (24.5 mg), Xantphos (31.0 mg) and sodium tert-butoxide (28.3 mg) in 2-propanol (2 mL) and toluene (0.5 mL) was stirred at 90°C for 24 h, treated with water and extracted with EtOAc. The organic layer was separated, dried over MgSC>4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/ Hexane to give the title compound as white crystals (31 mg). MS (API+): [M+H]+ 343.3.

[0474] 139c) l-ethyl-3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-

A mixture of 3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31 mg) and iodoethane (15.5 mg) in DMF (2 mL) was stirred at 50°C for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (5.4 mg). MS (API+): [M+H]+ 371.0.

[0475]

Example compounds shown in the following Tables 1-12 (including compounds shown in the above-mentioned Examples) were obtained by a method known per se, or a method similar to those in the above-mentioned Examples, or a method analogous thereto.

Particularly, the Example compounds described in the 307 WO 2011/163355 PCT/US2011/041443 column under "Referred Example No." in Tables 1-12 were produced according to the synthetic method described in the Referred Example.

In addition, the compound of each Example in Tables 1 -5 12 was synthesized using the compound described in the column under "Raw material".

[0476] [Table 1] 308 309

Example No. MS STRUCTURE SALT Name Reffered Example No. Raw Material, Conditions 14 345 ,,Ο 9-(4-( 1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one 1 4-chloro-5-nitropyrimidine 15 363 cqj3 3-(4-(3,4-dihydropyrimido[1,2-a]benzimidazol-1 (2H)-yl)phenyl]-1,3-dihydro-2H-imidazo(4,5-b]pyridin-2-one 2 1,3-dibromopropane 16 397 σΟ 3-(4-(2,3,4,5-tetrahydro-1 H-[1,3]diazepino[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 2 1,4-diiodobutane 17 358 &amp; 3-(4-(1,3-benzoxazol-2-ylamino)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 12c, 3, 1c, 1a 12c) tert-butyl 2-chloropyridin-3-ylcarbamate, 4-nitroaniline 16 502.1 .¾ ,-ό 5< 'OyC- 1-ethyI-3-{4-[(1-{[2- (trimethylsilyl)ethoxy]methyl)-1H- benzimidazol-2-yl)oxy]phenyl)-1,3-dihydro- 2K-imidazo[4,5-b]pyridin-2-one 12d 3-{4-[(1-([2-(trimethylsilyl)ethoxy]methyl}-1H- benzimidazol-2-yl)oxy]phenyl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 19 386.2 1-ethyl-3-{4-((1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-im idazo[4,5-b]pyridin-2-one 3 3-(4-(1 H-benzimidazoi-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride 20 371.3 D 3-[4-(1H-benzimidazol-2-ylamino)phenyl]-1- ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2- one - 3-(4-aminophenyl)-1 -ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, phenylenediamine, 1,1 '-thiocarbonyldiimidazole, N.N'-dioyolohexylcarbodiimide WO 2011/163355 PCT/US2011/041443 WO 2011/163355 PCT/US2011/041443 [0477] [Table 2]

310 WO 2011/163355 PCT/US2011/041443 [0478] [Table 3]

311 WO 2011/163355 PCT/US2011/041443 [0479] [Table 4]

312 WO 2011/163355 PCT/US2011/041443 [0480] [Table 5]

313 WO 2011/163355 PCT/US2011/041443 [0481] [Table 6]

314 WO 2011/163355 PCT/US2011/041443 [0482] [Table 7]

315 WO 2011/163355 PCT/US2011/041443 [0483] [Table 8]

316 WO 2011/163355 PCT/US2011/041443 [0484] [Table 9]

317 WO 2011/163355 PCT/US2011/041443 [0485] [Table 10]

318 WO 2011/163355 PCT/US2011/041443 [0486] [Table 11]

Raw Material 2-bromo-1 -methyl-1 H-imidazole 4-bromophenol 4-bromophenol 4-bromophenol 4-(benzyloxy)laniline © _c c co I a· c Φ S- 4 © C c co ? o a· c © Λ 4 o Q. (= CM CM CM Exar 0. IO id r- id b- ID b- o’ b- o’ b- o’ b- O Z © b- id’ ID ID’ xf b- s b- S b- © co’ co’ co' o: CM •E c C>1 ·>· ID a> φ £ c O- o c 1 T3 n CD CM £± £= © •9 S’ s.| -S fc. 5 CL ώ a. a, 8 85 Ζΰ | φ V 2-yl)oxy yridin-2· >.co Ό e ££ Q. Q-S ?o » ή SLoi §3 -benzim :o[4,5-b] H-imida >-2H-imi sz c Q.·© O s? .<1 «V c 21 ώ 9 Π -r- rsi Z to V Ό co c i'Ss ID *9. NAME -methyl-1 H-imida o-2H-imidazo[4,5· ethyl-3H-imidazo| 1,3-dihydro-2H-py one iethyl-3H-imidazoi l}spiro[cydobutan b]pyridln]-2’(TH) ή S CO CM φ 5, S O f E € CO, CO iZu yl-3-{4-[(1 -methyl-,3-dihydro-2H-imi one £ £ § eSt CO T- ~ £=2^S S-I-g: 9 5 S’ 5.S -1? it g s re £ ·— 4 i Zr w " έ A B. S2 T3 *T^ >> S,£ X v m «λ i CO >* τ-“ £ Φ t X co "5. it 144-[(3-m yl)oxy]pheny § M CO i -ethyl-5-meth |oxy]phenyl}-1 II si H Q. 3-{4-[(3-bromi ethyl-1,3-dih) ?» m N JO b to STRUCTURE /-5" ό Q>o Φ o Φ 0 if Φ Φ Φ o?r Φ -1 O 5 ΰζ H 7-o U " (¼ dn o z^'m Z' CO 5 cd co CM cd CM cd CO ό co O CM m co co co •M· ? Example No. n o> M" 05 ID 05 co 05 ’ί ο ID O O 319 WO 2011/163355 PCT/US2011/041443 [0487] [Table 12]

320 223631/2 5 [0516]

Test Example 1 PDE Enzyme Inhibition

Human PDE10A enzyme was generated from Sf9 or COS-7 cells transfected with the full-length gene. Cloned enzyme was io extracted from homogenized cell pellets. The extracted enzyme from sf9 cells was partially purified using His-tag affinity column. The enzyme was stored at -70°C until use. PDE activity was measured using a SPA (Scintillation Proximity Assay) (GE Healthcare). To evaluate the inhibitory activity, 10 pL of

15 serial diluted compounds were incubated with 20 pL of PDE

enzyme in assay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl2, 1.7 mM EGTA, 0.1% BSA (pH 7.4)) for 30 min. at room temperature.

Final concentration of DMSO in the assay was 1 percent as 321 223631/2 compounds were tested in duplicate in 96-well half-area plates (Corning). To start the reaction, 10 pL of substrate [3H] cGMP (25 or 50 nM; enclosed in SPA kits from GE Healthcare or purchased from PerkinElmer, respectively) was added for a 5 final assay volume of 40 pL. After 60 min incubation at room temperature, yttrium SPA beads containing Zinc sulphate were added (20 pL at 6 mg/mL) to terminate the PDE reaction. After being settled for 60 min, assay plates were counted in a scintillation counter (PerkinElmer) to allow calculation of io inhibition rate. Inhibition rate was calculated on the basis of 0% control wells with DMSO and 100% control wells without enzyme. The results are shown in Table 40.

[Table 40]

Ex. No. Percent inhibition (10 pM) Percent inhibition (1 pM) Percent inhibition (0.1 pM) 1 100 98 2 103 104 3 99 8 98 9 99 99 12 99 93 13 101 100 24 98 27 102 31 98 99 39 101 100 40 101 99 48 100 96 64 101 100 65 101 100 71 97 99 72 110 104 75 101 98 85 99 95 86 98 97 97 98 97 98 101 99 99 105 100 100 100 99 101 99 101 102 106 99 103 103 101 322 223631/2 106 102 103 107 102 103 108 102 100 109 102 99 112 98 99 115 97 100 118 104 102 119 103 99 120 106 109 121 99 103 122 107 109 123 101 96 124 99 99 125 101 99 126 100 98 127 . 101 101 128 91 94 . 129 96 89 130 98 95 132 107 104 133 101 104 134 104 101 135 99 94 136 98 81 137 98 88 138 105 93

Test Example 2 (1) Animals

Male ICR mice were supplied by CLEA Japan, Inc (Japan). 5 After arrival to the vivarium, animals were allowed more than 1 week for acclimation. They were housed under a 12 h-12 h light/dark cycle in a temperature- and humidity-controlled laboratory and allowed food and water ad libitum. The care and use of the animals and the experimental protocols used in this io research were approved by the Experimental Animal Care and Use Committee of Takeda Pharmaceutical Company, Ltd (Osaka, Japan) (2) Drug administration

The compounds were suspended in 0.5% (w/v) methylcellulose in distilled water, and the suspension was 15 administered by orally. MK-801 hydrogen maleate ((5R,10S)- ( + )- 5-Methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine 323 223631/2 maleate, Sigma-Aldrich, St Louis, MO) was dissolved in saline, and administered subcutaneously (s.c.). All drugs were dosed in a volume of 20 mL/kg body weight for mice. (3) Measurement of Striatal Tissue Cyclic Nucleotides

Male ICR mice (28-42 g) were sacrificed by focused microwave irradiation of the brain at 60 min after administration of the compounds. Striatum were isolated and homogenized in 0.5 N HC1 followed by centrifugation.

Supernatant concentrations of cyclic nucleotides were measured using enzyme immunoassay kits (Cayman Chemical, Ann Arbor, MI)-. Values were expressed as the percentage of the average of the vehicle-treated samples. All data were represented as means plus the standard errors of the means (n = 8). The variance of data was judged by Bartlett's test. The statistical significance was determined by the Dunnett's t-test (for homogenous data) or the Steel's test (for non-homogenous data) with significance set at #P < 0.05. (4) Inhibition of MK-801-induced hyperlocomotion

The widely used animal models of psychosis have been the measurement of the extent of hyperlocomotion induced by psychostimulants (e.g., amphetamine, cocaine, methamphetamine, MK-801 and phencyclidine) in rodents (Schizophrenia Bulletin 2010, vol. 36: 1066-1072; Psychopharmacology 1999, vol. 145: 237-250). The compounds were tested for its ability to antagonize MK-801-induced hyperlocomotion in mice. Male ICR mice (28-42 g) were habituated to the locomotor chambers with infrared sensors (Brain Science Idea Co., Ltd. Japan) for more than 60 min. Animals were removed from each chamber and treated with either vehicle or test compounds (p.o.) and immediately returned to the chamber. After 60 min, animals were again removed from the chambers and treated with either saline or MK-801 (0.3 mg/kg, s.c.), and then immediately returned to the test chamber. Activity count was recorded every 1 min bins. Total amounts of activity were measured during 120 min after MK-801 treatment. Data were represented 324 223631/2 as means plus the standard errors of the means (n = 8-9). Statistical analysis was performed with the Welch'' s t-test for comparison between control group and MK-801 + vehicle treated group with significance set at ***p < 0.001 and the Dunnett's test for comparisons with vehicle-treated group with significance set at #P < 0.05.

[0517]

Compounds in Figures (Fig.l and Fig.2) correspond to the compounds of the following Examples.

Compound A: Example 118 Compound B: Example 119 Compound C: Example 120 Compound D: Example 122 Compound E: Example 133 Compound F: Example 135 Compound G: Example 138 [0518]

Formulation Example 1 (1) Compound of Example 1 (2) Lactose (3) Cornstarch (4) Soluble starch (5) Magnesium stearate 10.0 g 70.0 g 50.0 g 7.0 g 3.0 g

After 10.0 g of the compound of Example 1 and 3.0 g of magnesium stearate are granulated in 70 mL aqueous solution of soluble starch (7.0 g as soluble starch) and then dried, the resulting mixture is mixed with 70.0 g of lactose and 50.0 g of cornstarch (lactose, cornstarch, soluble starch and magnesium stearate are all products in compliance with Japanese Pharmacopoeia 14th Edition). The mixture is compressed to obtain a tablet. 325

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CA2803156A1	Canada	A1	2011-12-29
US2011319394A1	United States of America	A1	2011-12-29
WO2011163355A1	World Intellectual Property Organization (WIPO)	A1	2011-12-29
UY33463A	Uruguay	A	2012-01-31
TW201213324A	Taiwan Province of China	A	2012-04-01
AR081976A1	Argentina	A1	2012-10-31
SG186341A1	Singapore	A1	2013-01-30
AU2011270994A1	Australia	A1	2013-02-07
DOP2012000318A	Dominican Republic	A	2013-02-15
AU2011270994A2	Australia	A2	2013-03-14
ECSP13012405A	Ecuador	A	2013-03-28
PE20130346A1	Peru	A1	2013-03-30
CL2012003602A1	Chile	A1	2013-04-05
EP2585462A1	European Patent Office (EPO)	A1	2013-05-01
CO6670576A2	Colombia	A2	2013-05-15
CR20130024A	Costa Rica	A	2013-05-15
MX2012015098A	Mexico	A	2013-05-28
EA201390022A1	Eurasian Patent Organization (EAPO)	A1	2013-05-30
CN103153995A	China	A	2013-06-12
MA34385B1	Morocco	B1	2013-07-03
US2013172328A1	United States of America	A1	2013-07-04
JP2013533242A	Japan	A	2013-08-22
EA201390022A8	Eurasian Patent Organization (EAPO)	A8	2013-08-30
KR20130098286A	Republic of Korea	A	2013-09-04
US8563575B2	United States of America	B2	2013-10-22
US2013303553A1	United States of America	A1	2013-11-14
TN2012000614A1	Tunisia	A1	2014-04-01
US2014228320A1	United States of America	A1	2014-08-14
US8846713B2	United States of America	B2	2014-09-30
NZ605889A	New Zealand	A	2014-10-31
US8940758B2	United States of America	B2	2015-01-27
JP5739526B2	Japan	B2	2015-06-24
AU2011270994B2	Australia	B2	2015-12-10
US9226921B2	United States of America	B2	2016-01-05
EA022705B1	Eurasian Patent Organization (EAPO)	B1	2016-02-29
GEP201606507B	Georgia	B	2016-07-11
CN103153995B	China	B	2016-08-10
MX341446B	Mexico	B	2016-08-19
TWI546302B	Taiwan Province of China	B	2016-08-21
BR112012032087A2	Brazil	A2	2016-11-16
IL223631AThis record	Israel	A	2016-11-30
MY165585A	Malaysia	A	2018-04-05
KR101875238B1	Republic of Korea	B1	2018-07-05
CA2803156C	Canada	C	2019-01-08
EP2585462B1	European Patent Office (EPO)	B1	2020-02-26

2 legal events, as the office reported them to INPADOC

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Point at a mark for the event

Events

Legal events, newest first
	Event	Code
2017-05-29	Patent renewedKB	KB
2017-03-30	Patent grantedGrantedFF	FF

Fused heterocyclic compounds as phosphodiesterases (pdes) inhibitors

Abstract

Term

WO 2011/163355 PCT/US2011/041443

DESCRIPTION

FUSED HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASES (PDES) INHIBITORS

3 PCT/US2011/041443 WO 2011/163355

4 PCT/US2011/041443 WO 2011/163355

61 PCT/US2011/041443 WO 2011/163355

63 PCT/US2011/041443 WO 2011/163355

IN

77 10 15 PCT/US2011/041443 WO 2011/163355

IH I

160 WO 2011/163355 PCT/US2011/041443

NH 10 15

N

O

224 WO 2011/163355 PCT/US2011/041443

HO

K JN

267 WO 2011/163355 PCT/US2011/041443

,OH

HO

F

294 WO 2011/163355 PCT/US2011/041443

Priority claims9

Members45

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Events

Numbers

Titles2

Classification