WO2017038909A1

WO2017038909A1 - Heterocyclic compounds

Info

Publication number: WO2017038909A1
Application number: PCT/JP2016/075585
Authority: WO
Inventors: Summon Koul; Suresh KURHADE; Keshav Naik; Videsh Salunkhe; Rakesh Kulkarni; Vishwajeet PARDESHI; Debnath Bhuniya; Bheemashankar Kulkarni; Kasim Abbaas MOOKHTIAR
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2015-08-28
Filing date: 2016-08-25
Publication date: 2017-03-09

Abstract

The present invention provides a heterocyclic compound a TLR7 and/or TLR9 and/or TLR-7/8/9 and/or TLR-7/8 and/or TLR-7/9 inhibitory action, which is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases and the like, in particular, acute decompensated heart failure, non-alcoholic steatohepatitis (NASH), IgA nephropathy, Duchenne muscular dystrophy (DMD), systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, transplant rejection and graft-versus-host disease, hepatocellular carcinoma (HCC) and the like. The present invention is a compound represented by the formula (1) : wherein each symbol is as described in the specification, or a salt thereof.

Description

DESCRIPTION

HETEROCYCLIC COMPOUNDS

Technical Field

[0001]

The present invention relates to a heterocyclic compound having a Toll-like receptors (TLR) 7 and/or TLR9 and/or TL.R- 7/8/9 and/or TLR-7/8 and/or TLR-7/9 inhibitory action, which may be useful as an agent for the prophylaxis or treatment of ^· TLR7 and/or TLR9 and/or TLR-7/8/9 and/or TLR-7/8 related diseases such as autoimmune diseases, inflammatory diseases and the like, in particular, acute heart failure, nonalcoholic steatohepatitis (NASH) , IgA nephropathy, Duchenne muscular dystrophy (DMD) , cell proliferation, rheumatoid arthritis, systemic lupus erythematosus (SLE) , psoriasis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, allergic diseases, infectious diseases affecting immune system, asthma, type 1 diabetes or other disorders, hepatocellular carcinoma (HCC) , B-Cell Lymphoma and the like. Background of the Invention

[0002]

Toll-Like Receptors (TLRs) are conserved membrane pattern recognition receptors (PRRs) of innate immunity responsible for clearing microbial pathogens. TLRs are expressed in many immune and non-immune cells and contain pattern recognition motifs that recognize microbial products, namely, the pathogen associated molecular patterns (PA Ps, ex: nucleic acids, lipoprotein and polysaccharides) (Kawai et . al . , 2011,

Immunity, 27; 34 (5) : 637-50) . In addition to PAMPs, several TLRs also recognize endogenous ligands resulting from cellular insult due to inflammatory response and cell-death, called damage associated molecular patterns (DAMPs) (Abdelsadik et . al, 2011, Human Immunology, 72, 1188-1193). Till date, ten functional TLRs (TLRl-10) have been identified in human, of which TLR1, TLR2, TLR4, TLR5 and TLR6, that recognize lipoproteins and lipopolysaccharides are expressed oh the plasma membrane and TLR3, TLR7, TLR8 and TLR9 that recognize nucleic acids are expressed in endosomal compartments. While

TLR7 and TLR8 both recognize ssRNA, TLR9 recognizes CpG-rich hypomethylated DNA (Table 1) .

Table 1: Summary of Function and Expression of TLR7 and 9

[0003]

Engagement^' of a cognate ligand to TLRs induces

conformational changes allowing formation of homo- or

heteromeric interactions within TLRs and recruitment of adaptor proteins such as MyD88, TIRAP, TRIF, and^■ TRAM. TLR7 and TLR9 are localized mainly to ER in the steady state but traffic to the endo/lysosomal compartment with the help of UNC93bl during activation (Kawai T and Akira S, 2007, Sem Immunol, 19, 24). TLR7 and TLR9 activate NF-κΒ and -IRF7 via MyD88 to induce pro-inflammatory cytokines (TNFa, IL-Ιβ, IL-6) and type I interferons (IFNcr and IFN ) respectively.- The activation of NF-κΒ during TLR7 and TLR9 signaling is

initiated from the endosomes whereas IRF7 activation is initiated from the .lysosome-related organelle (LRO) after TLR7 and TLR9 are transported from the endosome to this vesicle. MyD88-dependent IRF7 activation in pDCs. is mediated by

activation of IRAKI, TRAF6, TRAF3 and ,ΙΚΚα. In conventional DCs and macrophages, TLR7 and TLR9 induce inflammatory responses by. activating NF-κΒ via MyD88 but fail to activate IRF7 [Kawai et . al . , 2011, Immunity, 27, 34 (5) : 637-50] .

TLR-7/9 activation plays a -major role in the inter-phase of innate and adaptive immunity. They not only activate

inflammatory cytokines, up-regulate MHC molecules and co- stimulatory signals in antigen-presentation (innate immune response) but also prime and amplify T-, and B-cell effectors function (adaptive immune response) [Hannessy et . al . , 2010, Nat Rev Drug Discov. , 9 ( 4 ) : 293-307 ; Koegh et . al . , 2011,

Trends Pharmacol Sci, 32 (7) : 435-42] .

[0004]

It has been demonstrated that mitochondrial DNA that escapes from autophagy cell autonomously leads to TLR9

mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. It has been shown that TLR9 signalling pathway is involved in inflammatory responses in failing hearts in response to pressure overload and plays an important role in the

pathogenesis^' of heart failure [Nature, 2012, Vol 485, 251] . This indicates that TLR9 antagonists may have potential in the treatment of acute heart failure.

[0005]

There is genetic proof of concept to show that T.LR9 antagonists may have potential for the treatment of non- alcoholic steatohepatitis [NASH] . It has been demonstrated that hepatic macrophages, which are key cells inducing liver inflammation, were decreased in TLR9 KO mice on. a Choline deficient amino acid defined (CDAA) diet. In these mice, IL-Ιβ production in Kupffer cells was suppressed and steatohepatitis and liver fibrosis was reduced [Gastroenterology, 2010 Jul; 139 (1) :323-34] .

[0006]

There is increasing evidence of role of TLR-7 and 9 in the pathogenesis of various autoimmune diseases including rheumatoid arthritis (RA) . Human synovial tissue from RA patients showed the expression of TLR7 and 9 (along with TLR- 2/3/4).,. The expression of TLR7 was significantly up-regulated in RA synovial fibroblasts (RASFs) compared with healthy

controls or patients with non-inflammatory arthritis.

Stimulation of cultured RASFs with TLR7 ligands resulted in significant up-regulation of chemokines, cytokines,

metalloproteinases and type I IFNs [Roelofs et . al . , 2005, Arthritis Rheum. 52 ( 8 ): 2313-22 ] .

[0007]

Recent studies have shown that the development and

progression of Systemic Lupus Erythematosus (SLE) are driven by the over-expression of TLR-7, 8 and 9 within B-cells and pDCs [Komatsuda et . al., 2008, Clin Exp Immunol . ; 152 (3):482- 7; Migita et . al . , 2007, J Rheumatol., 34 (3): 493-500]. A knockout of TLR7 in a spontaneous murine model of SLE (MRL- /Mplpr/lpr) , showed decreased anti-RNA antibodies, diminished spelinic immune activation and suppressed the development of nephritis [Nickerson et . al . , 2010, J Immunol., 15, 184

(4): 1840-8; Christensen et . al., 2006, Immunity, 25 (3): 417- 28], validating the target in the pathogenesis of this disease.

[0008]

Antagonists of these nucleic acid-recognizing TLRs have primarily been oligonucleotide-based molecules. IMO-3100, an oligonucleotide based antagonist of TLR7 and TLR9 has

demonstrated clinical activity in psoriasis^" patients . This antagonist has also shown encouraging results in mouse models of lupus, collagen induced arthritis and psoriasis. IMO-8400, a TLR-7/8/9 antagonist has been shown to suppress the

production of autoimmune antibodies, improve kidney

histopathology and decrease blood urea nitrogen and

proteinuria in lupus prone mice.

[0009]

The small molecule anti-malarial drugs like chloroquine, hydroxychloroquine and quinacrine, that are also known to show TLR-7/8/9 antagonism, have been used since the 1950s to treat immune-mediated inflammatory disorders (IMID) such as

rheumatoid arthritis (RA) and systemic lupus erythematosus

(SLE) . However, side effects associated with these drugs and also the suboptimal efficacy has limited the use of these anti-malarials in IMID.

[0010]

IMO-8400, lead TLR-7/9 antagonist (oligonucleotide) from Idera Pharma, has been shown to inhibit TLR-mediated signaling and tumor cell survival in B-cell lymphoma models. Phase I/II dose escalation trials are on going in patients with relapsed or refractory Waldenstrom's Macroglobulinemia over 24 weeks. Patient screening in a Phase 1/2 trial of IMO-8400 in patients with diffuse large B-cell lymphoma (DLBCL) harboring the Myd88 L265P oncogenic mutation is also in progress. Recently FDA has granted Orphan Drug Designation for IMO-8400 for the treatment of Waldenstrom's macroglobulinemia [Press Release from Idera Pharma, December 2014] .

[0011]

Proliferation of human hepatocellular carcinoma (HCC) cell lines has been studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG-ODN respectively) and inhibition with a specific antagonist (IRS-954) or chloroquine. The effect of these interventions has been confirmed in a xenograft model and diethylnitrosamine (DEN) /nitrosomorpholine (NMOR) -induced model of HCC. . It has been demonstrated that.

TLR7and TLR9 expression was up-regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS-954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumor growth in the mouse xenograft model [Liver International (2014), Liver

International ISSN 1478-3223] . This indicates that TLR-7/9 antagonists may have a potential therapeutic application for the treatment of HCC.

[0012] There is literature prior art disclosing small molecule. TLR-7/8/9, TLR-7/9 and TLR9 antagonists. Coley Pharmaceuticals has disclosed series of 4-aminoquinoline derivatives as

inhibitors of immune stimulation involving at least one of

TLR9, TLR8, TLR7 and TLR3 (US 7410975). Eisai R & D has

disclosed benzoxazole compounds as antimalarials, claiming the compounds being antagonists of TLR9 (WO 2010/036908) . In a patent application (WO 2011/115183)^', Dainippon Pharma has disclosed monocyclic pyrimidine derivatives that are effective in the prophylaxis and/or treatment of disorders associated with signal transmission mediated by Toll-like receptors (TLR) . The biological data disclosed in the application substantiate the claimed compounds as TLR9 antagonists. In a very recent patent application by Janus Biotherapeutics (WO 2013/052550), imidazoloquinoline-based compounds have been described as immune system modulators. Two more patent applications from Janus Biotherapeutics (WO 2012/167046 and WO 2012/167053) have described pyrazinopyrimidines and imidazolopyrimidines as immune system modulators. In all the three patent applications, biological data reveal that the claimed compounds demonstrate TLR9 antagonism. Four patent applications from Kowa Company Ltd (WO 2013/108837, WO 2013/180066, WO 2013/161871 and WO

2014/034719) have described pyrazole, pyridine, thiophene and quinoline derivatives as TLR-3/7/9 inhibitors. In all the four patent applications, biological data demonstrates that the compounds are potent TLR-7 and. -9 antagonists.- In patent applications WO 2013/108837, WO 2013/161871 and WO 2014/034719, selected compounds have been shown to be efficacious in CIA mouse models of rheumatoid arthritis. In patent application WO2013181579, Eisai R & D has disclosed

tetrahydropyrazolopyrimidine compounds as TLR-7 and/or 8

antagonists or inhibitors effective for the treatment of

systemic lupus erythematosus and lupus nephritis.

[0013]

Despite several discoveries in this area, there are no safe and efficacious, orally administered small molecule TLR- 7/8/9 antagonists available in the market. CPG-52364 from Coley Pharma and Pfizer has been discontinued from clinical trials in 2008 for unknown reason. Therefore, there is a strong need for a novel small molecule TLR-7/8/9 antagonist that will be orally available and will have potential clinical utility. These compounds will have medical application in the disease area of inflammation and/or autoimmune disorders like acute decompensated heart failure, non-alcoholic

steatohepatitis (NASH) , IgA nephropathy, Duchenne muscular dystrophy (DMD) and cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, Sjogren's Syndrome, multiple sclerosis, inflammatory bowel disease, allergic diseases, infectious diseases affecting immune system, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, transplant rejection and graft-versus-host disease, hepatocellular

carcinoma (HCC) , etc.

[0014]

Patent 1 discloses a compound represented by the formula:

[0015]

[0016]

wherein each symbol is as defined in the specification, .

as a TLR9 inhibitor.

[0017]

Patent 2 discloses a compound represented by the formula:

[0018]

[0019]

wherein each symbol is as defined in the specification, as a TLR-7/9 inhibitor.

Document List:

Patent Document

[0020]

Patent Document 1: WO 2011/115183

Patent Document 2: WO 2015/088045

Summary of the Invention

Problems to be Solved by the Invention

[0021]

The present invention aims to provide a compound having a TLR7 and/or TLR9 and/or TLR-7/8/9 and/or TLR-7/8 and/or TLR- 7/9 inhibitory action, which may be useful as an agent for the' prophylaxis or treatment of autoimmune diseases and/or

inflammatory diseases and the like, in particular, acute decompensated heart failure, non-alcoholic steatohepatitis (NASH) , IgA nephropathy, Duchenne muscular dystrophy (DMD) , systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, ^' type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B- cell malignancies, transplant rejection and graft-versus-host disease, hepatocellular carcinoma (HCC) and the like.

Means of Solving the Problems

[0022]

The present inventors have conducted intensive studies, and have found that a compound represented by the formula (I) shown below unexpectedly has a TLR7 and/or TLR9 and/or TLR- 7/8/9 and/or TLR-7/8 and/or TLR-7/9 inhibitory action, and therefore, may be useful as an agent for the prophylaxis or treatment of autoimmune diseases, inflammatory diseases and the like, in particular, acute decompensated heart failure, non-alcoholic steatohepatitis (NASH) , IgA nephropathy,

Duchenne muscular dystrophy (DMD), systemic lupus

erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, type ί diabetes, myasthenia gravis, hematopoetic disfunction, B-cell

malignancies, transplant rejection and graft-versus-host

disease, hepatocellular carcinoma (HCC) and the like, and completed the present invention based on these findings.

[0023]

Accordingly, the present invention provides the

following:

[1] A compound represented by the formula (I):

[0024]

[0025]

wherein

Ring A is an optionally further substituted 5-membered

nitrogen-containing aromatic heterocycle,

X¹ and X² are independently a carbon atom or a nitrogen atom, R¹ and R² are independently a hydrogen atom or a substituent, Ring B is an optionally further substituted 6-membered

aromatic ring,

Z¹, Z² and Z³ are independently a carbon atom or a nitrogen atom, W¹ is an optionally substituted C1-3 alkylene,

Ring C is an optionally substituted heterocycle,

Ring D is an optionally further substituted aromatic ring, W² is a bond or a linker, and

Ring E is an optionally substituted heterocycle,

or a salt thereof (hereinafter to be referred as compound (I [0026]

[2] The compound or salt of the above-mentioned [1], wherein Ring A is

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom) , or

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) R¹ and R² are both hydrogen atoms;

Ring B is

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom, and

(b) a Ci-6 alkyl group, or

(2) pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z is a carbon atom) ;

W¹ is -CH2-, -(CH₂)₂- or -(CH₂)₃-;

Ring C is

(1) morpholine optionally substituted by 1 to 3 Ci_6 alkyl groups,

(2) piperazine optionally substituted by 1 to 3 CI-Q alkyl groups, or

(3) piperidine;

Ring Ό is

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom,

(b) an optionally halogenated Ci-₆ alkyl group,

(c) a Ci-6 alkoxy group, and

(d) a carbamoyl group,

(2) pyridine, or ,

(3) pyrazole;

2 is a bond, -CH₂-, -C^'(=0) - or -0-; and

Ring E is

(1) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a Ci-6 alkyl group optionally substituted by 1 ^' to 3 substituerits selected from

(i) a hydroxy group, and

(ii) a Ci-6 alkoxy group, and

(c) a Ci-6 alkoxy-carbonyl group,

(2) piperazine optionally substituted by 1 to 3 substituents selected from

(a) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom,

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group, and

(iv) a 5- to 14-membered aromatic heterocyclic group, (b) a C3-10 cycloalkyl group,

(c) a Ci-6 alkoxy-carbonyl group, and

(d) a 3- to 14-membered non-aromatic heterocyclic group, or

(3) tetrahydropyridine optionally substituted by 1 to 3 substituents selected from

(a) a Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and

(b) a Cx-6 alkoxy-carbonyl group.

[0027]

[3] 7- [4- (4-Isopropylpiperazin-l-yl) phenyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, ] benzoxazine or a salt thereof.

[4] 7- [4- [ (4-Isopropylpiperazin-l-yl)methyl]phenyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine or a salt thereof .

[0028] [5] A medicament comprising the compound or salt of the above- mentioned [1] .

[6] The medicament of the above-mentioned [5], which is a TLR7, TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9 inhibitor.

[7] The medicament of the above-mentioned [5], which is an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.

[8] The medicament of the above-mentioned [7], wherein the autoimmune diseases and/or inflammatory diseases is selected from systemic lupus erythematosus, Sjogren's syndrome,

rheumatoid arthritis, psoriasis and inflammatory bowel disease.

[0029]

[9] The compound or salt of the above-mentioned [1] for use in the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.

[10] The compound or salt of the above-mentioned [9], wherein - the autoimmune diseases and/or inflammatory diseases is

selected from systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis and inflammatory bowel disease.

[0030]

[11] A method of inhibiting TLR7 , TLR9 , TLR-7/8, TLR-7/9 or TLR-7/8/9 in a mammal, which comprises administering an

effective amount of the compound ^' or salt of the above- mentioned [1] to the mammal.

[12] A method for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases in a mammal, which

comprises administering an effective amount of the compound or salt of the above-mentioned [1] to the mammal.

[13] The method of the above-mentioned [12] , wherein the autoimmune diseases and/or inflammatory diseases is selected from systemic lupus erythematosus, Sjogren's syndrome,

rheumatoid arthritis, psoriasis and inflammatory bowel disease.

[0031]_,

[14] Use of the compound or salt of the above-mentioned [1] for the production of an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.

[15] Use of the above-mentioned [14], wherein the autoimmune diseases and/or inflammatory diseases is selected from

systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis and inflammatory bowel - disease .

Effect of the Invention

[0032]

According to the present invention, a compound having a TLR7 and/or TLR9 and/or TLR-7/8/9 and/or TLR-7/8 and/or^'TLR- 7/9 inhibitory action, which may be useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or

inflammatory diseases and the like, in particular, acute decompensated heart failure, non-alcoholic steatohepatitis (NASH) , IgA nephropathy, Duchenne muscular dystrophy (DMD) , systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B- cell malignancies, transplant rejection and graft-versus-host disease, hepatocellular carcinoma (HCC) and the like, can be provided.

Brief Description of the Drawings

[0033]

Figure 1 shows reduction in arthritic score with Example Al after 11 days of treatment in CAIA mice model.

[0034]

[Detailed Description of the Invention]

The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.

In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

In the' present specification, examples of the "Ci-₆ alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3 , 3-dimethylbutyl and 2-ethylbutyl.

In the present specification, examples of the "optionally halogenated Ci-6 alkyl group" include a Ci-₆ alkyl group

optionally having 1 to 7, preferably 1 to 5, halogen atoms.

Specific examples thereof include methyl, chloromethyl,

difluoromethyl, trichloromethyl , trifluoromethyl , ethyl, 2- bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl,

pentafluoroethyl , propyl, 2, 2-difluoropropyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , 4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl .

In the present specification, examples of the "C₂-₆ alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-

2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4- methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

In the present specification, examples of the "C₂-e alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, ^"3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl .

In the present specification, examples of the "C3-10

cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1 ] heptyl , bicyclo [2.2.2] octyl, bicyclo [ 3.2.1 ] octyl and adamantyl.

In the present specification, examples of the "optionally halogenated C3-10 cycloalkyl group" include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2 , 3-difluorocyclopropyl , cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the "C3-10

cycloalkenyl group" include cyclopropenyl, cyclobutenyl , cyclopentenyl, cyclohexenyl , cycloheptenyl and cyclooctenyl.

In the present specification, examples of the "Ce_i4 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.

In the present specification,, examples of the "C7-16

aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .

[0035]

In the present specification, examples of the "Ci_₆ alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the "optionally halogenated Ci-6 alkoxy group" include a C - alkoxy group

optionally having 1 to 7, preferably 1 to 5, halogen atoms.

Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 , 2 , 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4 , 4 , 4-trifluorobutoxy, isobutoxy, sec- butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the "C3-10

cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and

cyclooctyloxy .

In the present specification, examples of the "Ci_₆ alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

. In the present specification, examples of the "optionally halogenated Ci-6 alkylthio group" include a Ci-₆ alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms.

Specific examples thereof include methylthio,

difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.

In the present specification, examples of the "Ci_₆ alkyl- carbonyl group" include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyl , hexanoyl and heptanoyl .

In the present specification, examples of the "optionally halogenated Ci-₆ alkyl-carbonyl group" include a Ci-e alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl , trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the "Ci-₆ alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl ,

isobutoxycarbonyl, sec-butoxycarbonyl , tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl .

In the present specification, examples of the "Cs-i aryl- carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the "C₇_i6 aralkyl-carbonyl group" include phenylacetyl and

phenylpropionyl .

In the present, specification, examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group" include

nicotinoyl, isonicotinoyl , thenoyl and furoyl.

In the present specification, examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and

pyrrolidinylcarbonyl .

In the present specification, examples of the "mono- or di-Ci-6 alkyl-carbamoyl group" include methylcarbamoyl ,

ethylcarbamoyl, dimethylcarbamoyl , diethylcarbamoyl and N- ethyl-N-methylcarbamoyl .

In the present specification, examples of the "mono- or di-C₇-i6 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .

In the present specification, examples of the "Ci_₆ alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl , sec- butylsulfonyl and tert-butylsulfonyl

In the present specification, examples of the "optionally halogenated Ci-₆ alkylsulfonyl group" include a Ci_₆

alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include

methylsulfonyl , difluoromethylsulfonyl ,

trifluoromethylsulfonyl, ethylsulfonyl , propylsulfonyl ,

isopropylsulfonyl, butylsulfonyl, 4 , 4 , -trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .

In the present specification, examples of the "C₆-i4

arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .

[0036]

In the present specification, examples of the

"substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an

optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally

substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.

In the present specification, examples of the

"hydrocarbon group" (including "hydrocarbon group" of

"optionally substituted hydrocarbon group") include a Ci_₆ alkyl group, a C₂-6 alkenyl group, a C₂-6 alkynyl group, a C3-10.

cycloalkyl group, a C3-10 cycloalkenyl group, a C₆-i4 aryl group and a C7-16 aralkyl group.

[0037]

In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent ( s ) selected from the following substituent group A.

[substituent group A]

(1) a halogen atom, (2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated Ci-6 alkoxy group,

(7) a C₆-i4 aryloxy group (e.g., phenoxy, naphthoxy) ,

(8) a C7-16 aralkyloxy group (e.g., benzyloxy) ,

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy)

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy) ,

(11) a Ci-6 alkyl-carbonyloxy group (e.g., acetoxy,

propanoyloxy) ,

(12) a Ce-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,

(13) a Ci-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,

(14) a mono- or di-Ci-₆ alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,

(15) a C6_i4 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) ,

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) ,^'

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) ,

(18) an optionally halogenated Ci-s alkylsulfonyloxy group (e. ^■ methylsulfonyloxy, trifluoromethylsulfonyloxy) ,

(19) a Ce-1 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy)

(20) an optionally halogenated Ci-6 alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group, .(25) an optionally halogenated Ci_₆ alkyl-carbonyl group,

(26) a C₆-i4 aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a Ci-6 alkoxy-carbonyl group,

(30) a C₆-i4 aryloxy-carbonyl group (e . g. , phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,

(31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl , phenethyloxycarbonyl) ,

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-Ci_₆ alkyl-carbamoyl group,

(35) a Ce-14 aryl-carbamoyl group (e.g., phenylcarbamoyl ) ,

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl) ,

(38) an optionally halogenated Ci_₆ alkylsulfonyl group,

(39) a Cs-14 arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl) ,

(41) an optionally halogenated Ci-₆ alkylsulfinyl group,

(42) a C₆-i4 arylsulfinyl group (e.g., phenylsulfinyl , 1- naphthylsulfinyl, 2-naphthylsulfinyl ) ,

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl) ,

(44) an amino group,

(45) a mono- or di-Ci_₆ alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,

dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,

(46) a mono- or di-C_S-i4 arylamino group (e.g., phenylamino) ,

(47) a 5- to 14-membered aromatic heteropyclylamino group (e.g., pyridylamino) , (48), a C7-16 aralkylamino group (e.g., benzylamino) , (49) a formylamino group,

(50) a Ci-6 alkyl-carbonylamlno group, (e.g., acetylamino, propanoylainino, butanoylamino) ,

(51) a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl ) amino group (e.g., N- acetyl-N-methylamino) ,

(52) a C6-1 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,

(53) a Ci-6 alkoxy-carbonylamino group (e.g.,

methoxycarbonylamino, ethoxycarbonylamino,

propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino) ,

(54) a C7-16 aralkyloxy-carbonylamino group (e.g.,

benzyloxycarbonylamino) ,

(55) a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,

(56) a C6-14 arylsulfonylamino group optionally substituted by a Ci_6 alkyl group (e.g., phenylsulfonylamino,

toluenesulfonylamino) ,

(57) an optionally halogenated Ci-₆ alkyl group,

(58) a C₂-6 alkenyl group,

(59) a C₂-6 alkynyl group,

(60) a C3-10 cycloalkyl group,

(61) a C3-10 cycloalkenyl group and

(62.) a C6-14 aryl group.

[0038]

The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

In the present specification, examples of the

"heterocyclic group" (including "heterocyclic group" of

"optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom_..

[0039]

In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

Preferable, examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl , oxazolyl, isoxazolyl, pyridyl,

pyrazinyl, pyrimidinyl, pyridazinyl, 1 , 2 , 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2 , 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

8- to 14-membered fused polycyclic (preferably bi or

tricyclic) aromatic heterocyclic groups such as

benzothiophenyl , benzofuranyl , benzimidazolyl, benzoxazolyl , benzisoxazolyl, benzothiazolyl, benzisothiazolyl,

benzotriazolyl , imidazopyridinyl , thienopyridinyl ,

furopyridinyl, pyrrolopyridinyl , pyrazolopyridinyl ,

oxazolopyridinyl , thiazolopyridinyl , imidazopyrazinyl ,

imidazopyrimidinyl, thienopyrimidinyl , furopyrimidinyl,

pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl , thiazolopyrimidinyl, pyrazolotriazinyl , naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl,

quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β- carbolinyl, phenanthridinyl, acridinyl, phenazinyl,

■ phenothiazinyl, phenoxazinyl and the like.

[0040] In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include a 3- to 1.4 -membered - (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl ,

tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl , imidazolidinyl, oxazolinyl, oxazolidinyl , pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl ,

tetrahydroisothiazolyl, tetrahydrooxazolyl ,

tetrahydroisooxazolyl , piperidinyl, piperazinyl,

tetrahydropyridinyl , dihydropyridinyl, dihydrothiopyranyl , tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl , tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl , azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and

9- to 14-membered fused polycyclic (preferably bi or

tricyclic) non-aromatic heterocyclic groups such as

dihydrobenzofuranyl , dihydrobenzimidazolyl ,

dihydrobenzoxazolyl, dihydrobenzothiazolyl ,

dihydrobenzisothiazolyl , dihydronaphtho [ 2 , 3-b] thienyl ,

tetrahydroisoquinolyl, tetrahydroquinolyl , 4H-quinolizinyl, indolinyl, isoindolinyl , tetrahydrothieno [2, 3-c] pyridinyl, tetrahydrobenzazepinyl , tetrahydroquinoxalinyl ,

tetrahydrophenanthridinyl, hexahydrophenothiazinyl ,

hexahydrophenoxazinyl, tetrahydrophthalazinyl,

tetrahydronaphthyridinyl, tetrahydroquinazolinyl ,

tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β- carbolinyl, tetrahydroacrydinyl , tetrahydrophenazinyl ,

tetrahydrothioxanthenyl, octahydroisoquinolyl and the like. [0041]

In the present specification, preferable examples of the "7- to 10-membered bridged heterocyclic group" include

quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl .

In the present specification, examples of the "nitrogen- containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.

In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent ( s ) selected from the above- mentioned substituent group A.

The number of the substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0042]

In the present specification, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a

sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a Ci-₆ alkyl group, a C₂-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C₇_i6 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected^' from a halogen atom, an

optionally halogenated Ci_₆ alkoxy group, a hydroxy group,^■ a nitro group, a cyano group, an amino group and a carbamoyl group".

Examples of the "acyl group" also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the

hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.

. Preferable examples of the "acyl group" include a formyl group, a carboxy group, a Ci-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C3-10 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,

cyclopentanecarbonyl, cyclohexanecarbonyl,

cycloheptanecarbonyl) , a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl) , a C₆-i4 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic

heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a Ce-i4 aryloxy-carbonyl group (e.g., phenyloxycarbonyl ,

naphthyloxycarbonyl) , a C₇-i₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl , phenethyloxycarbonyl ) , a carbamoyl group, a mono- or di-Ci-₆ alkyl-carbamoyl group, a mono- or di-C₂-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C₃_io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-C6-i₄ aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C₇-is aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a thiocarbamoyl group, a mono- or di-Ci-₆ alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C₂-6 alkenyl-thiocarbamoyl group (e..g., diallylthiocarbamoyl) , a mono- or di-C₃-i₀

cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C₆-i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C₇-i₆ aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,

phenethylthiocarbamoyl) , a 5- to l4-membered aromatic

heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl ) , a sulfino group, a Ci_₆ alkylsulfinyl group (e.g.,

methylsulfinyl, ethylsulfinyl ) , a sulfo group, a Ci_₆ alkylsulfonyl group, a Ce-i4 arylsulfonyl group, a phosphono group and a mono- or di-Ci-6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .

[0043]

In. the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a Ci-₆ alkyl group, a C₂-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-i4 aryl group, a C7-16 aralkyl group, a Ci-₆ alkyl-carbonyl group, a C₆-₁₄ aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-e alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C₇_i6 aralkyl-carbamoyl group, a Ci-₆ alkylsulfonyl group and a C₆-i₄ arylsulfonyl ^' group, each of which optionally has 1 to 3 substituents selected from

substituent group A".

' Preferable examples of the optionally substituted amino group. include an amino group, a mono- or di- (optionally

halogenated Ci-e alkyl) amino group (e.g., methylamino,

trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C₂-6 alkenylamino group (e.g., diallylamino) , a mono- or di-C₃_io cycloalkylamino group (e.g., cyclopropylamino , cyclohexylamino) , a mono- or di-C6-i4 arylamino group (e.g., phenylamino) , a mono- or di-C₇-i6 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated Ci-6 alkyl ) -carbonylamino group (e.g., acetylamino, propionylamino) , a mono- or di-C₆-i4 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C₇-i6 aralkyl-carbonylamino group (e.g., benzylcarbonylamino), , a mono- or di-5- to 14-membered aromatic

heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino) , a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,

piperidinylcarbonylamino) , a mono- or di-Ci-6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to 14-membered aromatic heterocyclylamino group (e.g.,

pyridylamino) , a carbamoylamino group, a (mono- or di-Ci__s alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a

(mono- or di-C₇-i6 aralkyl-carbamoyl ) amino group (e.g.,

benzylcarbamoylamino) , a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C₆-i4

arylsulfonylamino group (e.g., phenylsulfonylamino) , a (Ci_₆ alkyl) (Ci-₆ alkyl-carbonyl ) amino group (e.g., N-acetyl-N- methylamino) and a (Ci_₆ alkyl) (C₆-i4 aryl-carbonyl) amino group

(e.g., N-benzoyl-N-methylamino) .

[0044]

In the present specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group

optionally having "1 or 2 substituents selected from a CH

alkyl group, a C₂-e alkenyl group, a C3-10 cycloalkyl group, a Ce- 14 aryl group, a C₇_i₆ aralkyl group, a Ci-_S alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C₇_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic

heterocyclic group, a carbamoyl group, a mono- or di-Ci-₆ alkyl- carbamoyl group and a mono- or di-C₇_i₆ aralkyl-carbamoyl. group, each of which optionally has 1 to 3 substituents selected from substituent group A" .

Preferable examples of the optionally substituted

carbamoyl group include a carbamoyl group, a mono- or di-Ci-₆ alkyl-carbamoyl group, a mono- or di-C₂-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C₃-io cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl ,

cyclohexylcarbamoyl) , ^'a mono- or di-C₆-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C₇-i6 aralkyl-carbamoyl group, a mono- or di-Ci-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C₆-i4 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl ) and- a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl ) .

[0045]

In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Ci-₆ alkyl group, a C₂-6 alkenyl group, a C3-10 cycloalkyl group, a C₆- 14 aryl group, a C₇-i₆ aralkyl group, a Ci-_S alkyl-carbonyl group, a C₆-i4 aryl-carbonyl group, a C₇_i₆ aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic

heterocyclic group, a carbamoyl group, a mono- or di-Ci_₆ alkyl- carbamoyl group and a mono- or di-C₇_i₆ aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".

Preferable examples of the optionally substituted

thiocarbamoyl group include a thiocarbamoyl group, .a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl, dimethylthiocarbamoyl ,

diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C₂-6 alkenyl-thiocarbamoyl group (e.g.,

diallylthiocarbamoyl) , a mono- or di-C₃-io cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl ,

cyclohexylthiocarbamoyl ) , a mono- or di-C6-i aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C_i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,

phenethylthiocarbamoyl) , a mono- or di-Ci-6 alkyl-carbonyl- thiocarbamoyl group (e.g., acetylthiocarbamoyl,

propionylthiocarbamoyl ) , a mono- or di-C₆-i₄ aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl ) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,. pyridylthiocarbamoyl ) . [0046]

In the present specification, examples of the "optionally substituted sulfamoyl group" include a sulfamoyl group

optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C₂-6 alkenyl group, a C3-10 cycloalkyl group, a C₆- 14 aryl group, a C₇_i6 aralkyl group, a Ci-g alkyl-carbonyl group, a C₆-i4 aryl-carbonyl group, a C₇-i₆ aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic

Preferable examples of the optionally substituted

sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl , ethylsulfamoyl , dimethylsulfamoyl, diethylsulfamoyl , N-ethyl-N- methylsulfamoyl ) , a mono- or di-C₂-6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl ) , a mono- or di-C3-io cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,

cyclohexylsulfamoyl ) , a mono- or di-C₆-i4 aryl-sulfamoyl group (e.g., phenylsulfamoyl ) , a mono- or di-C₇-i6 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl , phenethylsulfamoyl ) , a mono- or di-Ci-6 alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl , ^'propionylsulfamoyl ) , a mono- or di-C6-i aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered

aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl ) .

[0047]

In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a Ci_₆ alkyl group, a C₂-₆ alkenyl group, a C3-10 cycloalkyl group, a C₆-i4 aryl group, a C₇- 16 aralkyl group, a Ci_₆ alkyl-carbonyl group, a C₆-i4 aryl- carbonyl group, a C₇-i_e aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-₆ alkyl-carbamoyl group, a mono- or di-C₇_i6 aralkyl-carbamoyl group, a Ci_₆

alkylsulfonyl group and a C₆-i4 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from

substituent group A".

Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci-₆ alkoxy group, a C₂-e

alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C₃_io cycloalkyloxy group (e.g., cyclohexyloxy) , a C₆-i4 aryloxy group (e.g., phenoxy, naphthyloxy) , a C₇_i₆ aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a Ci-₆ alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a Ce- aryl-carbonyloxy group

(e.g., benzoyloxy) , a C₇_i6 aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy) , a 5- to 14-membered aromatic

heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) , a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy) , a Ci-s alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyridyloxy) , a .carbamoyloxy group, a Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a

C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a Ci-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,

ethylsulfonyloxy) and a C₆-i4 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .

[0048]

In the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group

optionally having "a substituent selected from a Ci-₆ alkyl group, a C₂-6 alkenyl group, a C3-10_. cycloalkyl group, a C6-1 aryl group, a 0_Ί-ι₅ aralkyl group, a Ci-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3

substituents selected from- substituent group A" and a

halogenated sulfanyl group.

Preferable examples of the optionally substituted

sulfanyl group include a sulfanyl (-SH) group, a Ci-6 alkylthio group, a C₂-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C₃_i₀ cycloalkylthio group (e.g., cyclohexylthio) , a Ce-1 arylthio. group (e.g., phenylthio, naphthylthio) , a C₇-i6 aralkylthio group (e.g., benzylthio, phenethylthio) , a Ci-₆ alkyl-carbonylthio group (e.g. ,

acetylthio, propionylthio, butyrylthio, isobutyrylthio,

pivaloylthio) , a C₆-i4 aryl-carbonylthio group (e.g.,

benzoylthio) , a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .

[0049]

In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally

"having "1 to 3 substituents selected from a Ci-6 alkyl group, a C₂-6 alkenyl group, a C3-10 cycloalkyl group, a C₆-i4 aryl group and a C₇-i6 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".

Preferable examples of the optionally substituted silyl group include, a tri-Ci-₆ alkylsilyl group (e.g., trimethylsilyl , tert-butyl (dimethyl) silyl) .

[0050]

In the present specification, examples of the

"hydrocarbon ring" include a C₆-i4 aromatic hydrocarbon ring, C₃- 10 cycloalkane and C3-10 cycloalkene.

In the present specification, examples of the "C₆-i4 aromatic hydrocarbon ring" include benzene and naphthalene.

In the present specification, examples of the "C3-10 ^' cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

In the present specification, examples of the "C3-10 cycloalkene" include cyc.lopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and^' cyclooctene .

In the present specification, examples of the

"heterocycle" include an aromatic heterocycle and a non- 5 aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0051]

In the present specification, examples, of- the "aromatic 10 heterocycle" include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocycle"

15 include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine,

pyrimidine, pyridazine, 1 , 2 , 4-oxadiazole, 1 , 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole, triazole, tetrazole, 20 triazine and the like; and

_^,- 8- to 14-membered fused polycyclic (preferably bi or

tricyclic) aromatic heterocycles such as benzothiophene , benzofuran, benzimidazole, benzoxazole, benzisoxazole ,

benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,

25 thienopyridine, furopyridine, pyrrolopyridine,

pyrazolopyridine , oxazolopyridine , thiazolopyridine,

imidazopyrazine, imidazopyrimidine, thienopyrimidine ,

furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine ,

oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,

30 pyrazolotriazine, naphtho [2 , 3-b] thiophene, phenoxathiin,

indole, isoindole, lH-indazole, purine, isoquinoline,

quinoline, phthalazine, naphthyridine, quinoxaline,

quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like.

35 [0052] In the. present specification, examples of the "non- aromatic heterocycle" include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic

heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,

thiazolidine, tetrahydroisothiazole, tetrahydrooxazole,

tetrahydroisoxazole, piperidine, piperazine,

tetrahydropyridine , dihydropyridine, dihydrothiopyran,

tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine,

thiomorpholine , azepanine, diazepane, azepine, azocane,

diazocane, oxepane and the like;, and

9- to 14-membered fused polycyclic (preferably bi or

tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2 , 3-b] thiophene,

tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine , indoline, isoindoline, tetrahydrothieno [2, 3-c] pyridine,

tetrahydrobenzazepine, tetrahydroquinoxaline,

tetrahydrophenanthridine, hexahydrophenothiazine ,

hexahydrophenoxazine, tetrahydrophthalazine,

tetrahydronaphthyridine, tetrahydroquinazoline,

tetrahydrocinnoline, tetrahydrocarbazole , tetrahydro-β - carboline, tetrahydroacridine, tetrahydrophenazine,

tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the "nitrogen- containing heterocycle" include a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.

In the present specification, the "non-aromatic heterocycle" encompasses a spiroheterocycle and a bicycloheterocycle .

In. the present specification, examples of the

"spiroheterocycle" include 6-azaspiro [3.3] heptane, 7- azaspiro [3.5] nonane, 2-oxa-7-azaspiro [ 3.5] nonane, 3,9- diazaspiro [ 5.5 ] undecane and the like.

In the present specification, examples of the

"bicycloheterocycle" include 6-oxa-3-azabicyclo [3.1.1] heptane, 3, 6-diazabicyclo [3.1.1] heptane and the like.

[0053]

In the present specification, examples of the "Ci-₆

alkylene group" include -CH₂-, -(CH₂)₂-, -(CH₂)3-_/ -(CH₂)₄-, - (CH₂)₅- -(CH₂)₆-, -CH(CH₃)-, -C(CH₃)₂-, -CH(C₂H₅)-, -CH(C₃H₇)-, - CH (CH (CH₃) ₂) -, - (CH (CH₃) ) ₂-, -CH₂-CH (CH₃) -, -CH (CH₃) -CH₂-, -CH₂- CH₂-C (CH₃) 2-, -C (CH₃) ₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-C (CH₃) ₂- and - C (CH₃) ₂-CH₂-CH₂-CH₂- .

In the present specification, examples of the "C₂_₆ alkenylene group" include -CH=CH-, -CH₂-CH=CH-, -CH=CH-CH₂-, - C (CH₃) ₂-CH=CH-, -CH=CH-C (CH₃) 2-, -CH₂-CH=CH-CH₂-, -CH₂-CH₂-CH=CH-, -CH=CH-CH₂-CH₂-, -CH=CH-CH=CH-, -CH=CH-CH₂-CH₂-CH₂- and -CH₂-CH₂- CH₂-CH=CH-.

In the present specification, examples^' of the "C₂-6 alkynylene group" include -C≡C-, -CH₂-C≡C-, -C≡C-CH₂-, -C(CH₃)₂- C≡C-, -CsC-C (CH₃) 2-, -CH₂-C≡C-CH₂-, -CH₂-CH₂-C≡C-, -C≡C-CH₂-CH₂- , -C≡C-C≡C-, -C≡C-CH₂-CH₂-CH₂- and -CH₂-CH₂-CH₂-C≡C- .

[0054]

The definition of each symbol in the formula (I) is explained in detail in the following.

[0055]

Ring A is an optionally further substituted 5-membered nitrogen-containing aromatic heterocycle.

X¹ and X² are independently a carbon atom or a nitrogen atom.

[0056]

Examples of the "5-membered nitrogen-containing aromatic heterocycle" of the "optionally further substituted 5-membered nitrogen-containing aromatic heterocycle" for Ring A include 5-membered aromatic heterocycles containing at least one nitrogen atom, from among the above-mentioned aromatic .

heterocycle, specifically, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1 , 2 , 4-thiadiazole , 1, 3, 4-thiadiazole, triazole, tetrazole and the like.

[0057]

The "5-membered nitrogen-containing aromatic heterocycle" of the "optionally further substituted 5-membered nitrogen- containing aromatic heterocycle" for Ring A is preferably imidazole (X¹ is a carbon atom and X² is a nitrogen atom) , triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) or pyrazole (X¹ is a nitrogen atom and X² is a carbon atom), more preferably imidazole (X¹ is a carbon atom and X² is a nitrogen atom) or triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) .

[0058] - The "5-membered nitrogen-containing aromatic heterocycle" of the "optionally further substituted 5-membered nitrogen- containing aromatic heterocycle" for Ring A optionally- has 1 or 2 substltuents at substitutable position(s), in addition to -W¹-Ring C. Examples of the substituent include substituents selected from the above-mentioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.

[0059]

Ring A is preferably imidazole (X¹ is a carbon atom and X² is a nitrogen atom) , triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) or pyrazole (X is a nitrogen atom and X is a carbon atom) , each optionally further substituted.

[0060]

Ring A is more preferably imidazole (X¹ is a carbon atom and X² is a nitrogen atom), triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) or pyrazole (X¹ is a nitrogen atom and X² is a carbon atom) , each optionally further substituted by one Ci-6 alkyl group (e.g. methyl) .

[0061]

Ring A is further more preferably

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom) optionally further substituted by one Ci_₆ alkyl group (e.g.

methyl) ,

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom), or

(3) pyrazole (X¹ is a nitrogen atom and X² is a carbon atom) .

[0062]

Ring A is still more preferably

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom), or

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) .

[0063]

R¹ and R² are independently a hydrogen atom or a

substituent.

R¹ and R² are preferably independently a hydrogen atom or an optionally substituted Ci-io alkyl group (preferably an optionally substituted Ci-6 alkyl group (e.g. methyl)).

R¹ and R² are more preferably independently a hydrogen atom or a Ci-io alkyl group (preferably a Ci-₆ alkyl group (e.g. methyl) ) .

R¹ and R² are further more preferably independently a hydrogen atom or a Ci-₆ alkyl group (e.g. methyl) .^'

R¹ and R² are still more preferably both hydrogen atoms.

[0064]

Ring B is an optionally further substituted 6-membered aromatic ring.

Z¹, Z² and Z³ are independently a carbon atom or a

nitrogen atom.

[0065]

Examples of the "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for Ring B include benzene and 6-membered aromatic heterocycles.

Examples of the 6-membered aromatic heterocycle include 6-membered aromatic heterocycles, from among the above- mentioned aromatic heterocycle, specifically, pyridine, pyrazine, pyrimidine, pyridazine and triazine.

[0066],

The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for Ring B is preferably benzene or a 6-membered nitrogen-containing aromatic

heterocycle- (preferably pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom) , ^' pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is a carbon atom), pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ) .

[0067]

The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for Ring B optionally has 1 to 3 substituents at substitutable position(s), in addition to -Ring D- ²-Ring E. Examples of the substituent include substituents selected from the above-mentioned

substituent group A. When the number of the substituents is plural, the respective substituents may be the same or

different.

[0068]

Ring B is preferably benzene or a 6-membered nitrogen- containing aromatic heterocycle (preferably pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is . a carbon atom),

pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ) , each optionally further substituted.

[0069]

Ring B is more preferably benzene or a 6-membered

nitrogen-containing aromatic heterocycle (preferably pyridine (Z¹ is a nitrogen atom,■ Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom), pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is a carbon atom) , pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ) , each optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl).

[0070]

Ring B is further more preferably

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl),

(2) pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) ,

(3) pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom) ,

A) pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is a carbon atom) ,

(5) pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and

Z³ is a nitrogen atom) .

[0071]

Ring B is still more preferably (1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl) , or

(2) pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom) .

[0072]

W¹ is an optionally substituted C1-3 alkylene.

Examples of the "C1-3 alkylene" of the "optionally substituted C1-3 alkylene" for W¹ include -CH₂-, -(CH₂)₂-, - (CH₂)₃-, -CH(CH₃)-, -C(CH₃)₂-, -CH(C₂H₅)-, -CH₂-CH (CH₃) - and - CH (CH₃) -CH2-.

The "Ci-3 alkylene" of the "optionally substituted Ci_₃ alkylene" for W¹ is preferably -CH₂-, -(CH₂)₂-, -(CH₂)₃-, - CH(CH₃)- or -C(CH₃)₂-.

[0073]

The "Ci-3 alkylene" of the "optionally substituted C1-3 alkylene" for W¹ optionally has 1 to 3 substituents at

substitutable position (s). Examples of the substituent include substituents selected from the above-mentioned substituent group A. When the number of the substituents - is plural, the respective substituents may be the same or different.

[0074]

W¹ is preferably a C1-3 alkylene (e.g., -CH₂-, -(CH₂)₂-, - (CH₂)₃-, -CH(CH₃)-, -C(CH₃)₂-) optionally substituted by oxo group ( s ) .

W¹ is more preferably -CH₂-, -(CH₂)₂-, -(CH₂)₃-, -CH(CH₃)-, -C(CH₃)₂-, -C(=0)- or -CH₂-C(=0)- (wherein the left bond is bonded to Ring C, and the right bond is bonded to Ring A) .

W¹ is further more preferably -CH₂-, -(CH₂)₂- or -(CH₂)3~.

[0075]

Ring C is an optionally substituted heterocycle.

The "heterocycle" of the "optionally substituted

heterocycle" for Ring C is preferably a 4- to 10-membered nitrogen-containing non-aromatic heterocycle (preferably morpholine, piperazine, piperidine, pyrrolidine, 1,1-,

dioxidothiomorpholine, 6-oxa-3-azabicyclo [3.1.1] heptane, 6- azaspiro [3.3] heptane, 7-azaspiro [ 3.5 ] nonane, 2-oxa-7- azaspiro [3.5] nonane, more preferably morpholine, piperazine, piperidine) .

[0076]

The "heterocycle" of the "optionally substituted

heterocycle" for Ring C optionally has 1 to 3 substituents at substitutable position(s). Examples of the substituent include substituents selected from the above-mentioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.

[0077]

Ring C is preferably an optionally substituted 4- to 10- membered nitrogen-containing non-aromatic heterocycle

(preferably morpholine, piperazine, piperidine, pyrrolidine, 1, 1-dioxidothiomorpholine, 6-oxa-3-azabicyclo [3.1.1] heptane, 6-azaspiro [3.3] heptane, 7-azaspiro [3.5] nonane, 2-oxa-7- azaspiro [3.5] nonane, more preferably morpholine, piperazine, piperidine) .

[0078] ·

Ring C is more preferably a 4- to 10-membered nitrogen- containing non-aromatic heterocycle (preferably morpholine, piperazine, piperidine, pyrrolidine, 1 , 1-dioxidothiomorpholine, 6-oxa-3-azabicyclo [3.1.1] heptane, 6-azaspiro [3.3 ] heptane, 7- azaspiro [3.5] nonane, 2-oxa-7-azaspiro [3.5] nonane, more

preferably morpholine, piperazine, piperidine) optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a hydroxy group,

(c) a carboxy group,

^■(d) a Ci-6 alkyl group (e.g. methyl), and

(e) a Ci-6 alkoxy-carbonyl group (e.g. methoxycarbonyl) .

[0079]

Ring C is further more preferably (1) morpholine optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a Ci-6 alkyl group (e.g. methyl) ,

(2) piperazine optionally substituted by 1 to 3 Ci_₆ alkyl groups (e.g. methyl),

(3) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a hydroxy group,

(4) pyrrolidine substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a carboxy group, and

(c) a Ci-6 alkoxy-carbonyl group (e.g. methoxycarbonyl) ,

(5) 1, 1-dioxidothiomorpholine,

(6) 6-oxa-3-azabicyclo [3.1.1] heptane,

(7) 6-azaspiro [3.3] heptane optionally substituted by 1 to 3 substituents selected from,.'

(a) a hydroxy group, and

^■(b) a Ci-6 alkyl group (e.g. methyl),

(8) 7-azaspiro [3.5] nonane ^' optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a Ci-6 alkyl group (e.g. methyl), or

(9) 2-oxa-7-azaspiro [ 3.5 ] nonane .■

[008Ό]

Ring C is still more preferably

(1) morpholine optionally substituted by 1 to 3 Ci__s alkylgroups (e.g. methyl),

(2) piperazine optionally substituted by 1 to 3 Ci_₆ alkyl groups (e.g. methyl), or

(3) piperidine.

[0081]

Ring D is an optionally further substituted aromatic ring. Examples of the "aromatic ring" of the "optionally further substituted aromatic ring" for Ring D include a C₆-i4 aromatic hydrocarbon ring and an aromatic heterocycle.

[0082]

The "aromatic ring" of the "optionally further

substituted aromatic ring" for Ring D is preferably benzene or a 5- to 10-membered nitrogen-containing aromatic heterocycle (preferably pyridine, pyrazole, indole, more preferably

pyridine, pyrazole) .

[0083]

The "aromatic ring" of the "optionally further

substituted aromatic ring" for Ring D optionally has 1 to 3 substituents at substitutable _. position ( s ) , in addition to -W²- Ring E and -Ring B. Examples of the substituent include

substituents selected from the above-mentioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.

[0084]

Ring D is preferably benzene or a 5- to 10-membered nitrogen-containing aromatic heterocycle (preferably pyridine, pyrazole, indole, more preferably pyridine, pyrazole) , each optionally further substituted.

[0085]

Ring D is more preferably benzene or a 5- to 10-membered nitrogen-containing aromatic heterocycle . (preferably pyridine, pyrazole, indole, more preferably pyridine, pyrazole) , each optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a^' chlorine atom), (b) an optionally halogenated Ci_₆ alkyl group (e.g. methyl, trifluoromethyl) ,

(c) a Ci-6 alkoxy group (e.g. methoxy) , and

(d) a carbamoyl group.

[0086]

Ring D is further more preferably (1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(b) an optionally halogenated Ci_6 alkyl group (e.g. methyl, trifluoromethyl). ,

(c) a Ci-6 alkoxy group (e.g. methoxy) , and

(d) a carbamoyl group,

(2) pyridine optionally further substituted by 1 to 3

substituents selected from

(b) a Ci-6 alkyl group (e.g. methyl), and

(c) a Ci-6 alkoxy group (e.g. methoxy),

(3) pyrazole, or

(4) indole.

[0087]

Ring D is still more preferably

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(b) an optionally halogenated Ci-₆ alkyl group (e.g. methyl, trifluoromethyl) ,

(c) a Ci-6 alkoxy group (e.g. methoxy), and

(d) a carbamoyl group,

(2) pyridine, or

(3) pyrazole.

[0088]

W² is a bond or a linker.

Examples of the linker for W² include a linker in which the number of atoms in the main chain is 1 to 4 (preferably 1 or 2) .

Examples of the linker in which the number of atoms in the main chain is 1 to 4 include linkers wherein the main chain consists of 1 to 4 atoms selected from a carbon atom, a nitrogen atom, a sulfur atom (optionally oxidized) and an oxygen atom, each of which optionally has substituent ( s )

selected from the above-mentioned substituent group A at substitutable ^'position ( s ) , and specific examples thereof include

(1) a Ci-4 alkylene group (e.g., -CH₂-, -(CH₂)₂-, -CH₂-CH (CH₃) -, -CH (CH₃) -CH₂-, -(CH₂)₃-, -(CH₂)₄- etc.) optionally substituted by the above-mentioned substituent group A (preferably a halogen atom (e.g., a fluorine atom, a chlorine atom), an oxo group and a hydroxy group) ;

(2) a C₂-4 alkenylene group (e.g., -CH=CH-, -CH=CH-CH₂-, -CH₂- CH=CH- etc.) optionally substituted by the above-mentioned substituent group A;

(3) -Z- wherein Z is 0, NR⁶ (R⁶ is a hydrogen atom or a

substituent), S, S (0) , or S(0)₂;

(4) - (CH₂) mi-Z- (CH₂) m2~ wherein Z is as defined above, ml and m2 are each independently an integer of 0 to 3, and ml+m2 is an integer of 1 to 3;

(5) -Z^a- (CH₂) _m-Z^b- wherein Z^a and Z^b are each independently 0, C(0), NR⁶ (R⁶ is a hydrogen atom or a substituent), S, S (0) or S(0)₂, and m is an integer of 1 to 2 ;

(6) -CO-NR⁶- or -NR⁶-C0- wherein R⁶ is as defined above;

(7) -S(0)₂-NR⁶- or -NR⁶-S(0)₂- wherein R⁶ is as defined above;

(8) a C₃_6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene etc.);

(9) a divalent non-aromatic heterocyclic group (e.g., 1,2- aziridinediyl, 1 , 3-azetidinediyl , 1 , 3-pyrrolidinediyl , 1,3- piperidinediyl , 1 , 4-piperidinediyl, 1 , 4-morpholinediyl etc.);

(10) -Z^a-Y-Z^b- wherein Z^a and. Z^b are as defined above, and Y is a divalent non-aromatic heterocyclic group (e.g., 1,2- aziridinediyl, 1, 3-azetidinediyl, 1 , 3-pyrrolidinediyl , 1,3- piperidinediyl etc.);

and- the like.

W² is preferably a bond or a linker in which the number of atoms in the main chain is 1 or 2.

W² is more preferably

(1) a bond,

(2) a i-2 alkylene group (e.g., -CH₂-, -(CH₂)₂-) optionally substituted by an oxo group; or

(3) -Z- wherein Z is 0 or S(0)₂.

W² is further more preferably a bond, -CH₂^, -C(=0)-, - C(=0)-CH₂- (wherein the left bond is bonded to Ring D, and the right bond is bonded to Ring E) , -0- or -S(0)₂-.

W² is still more preferably a bond, -CH₂-, -C(=0)- or -0- .

[0089]

Ring E is an optionally substituted heterocycle.

Examples of the "heterocycle" of the "optionally

substituted heterocycle" for Ring E include an aromatic

heterocycle and a non-aromatic heterocycle.

[0090]

The "heterocycle" of the "optionally substituted

heterocycle" for Ring E is preferably a 3- to 14-membered nitrogen-containing non-aromatic heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine,

tetrahydropyridine, 7-azaspiro [3.5] nonane, 3,9- diazaspiro [5.5] undecane, 2-oxa-7-azaspiro [3.5] nonane, 3,6- diazabicyclo [3.1.1 ] heptane, more preferably piperidine,

piperazine, tetrahydropyridine) .

[0091]

The "heterocycle" of the "optionally substituted

heterocycle" for Ring E optionally has 1 to 3 substituents at substitutable position (s). Examples of the substituent include substituents selected from the above-mentioned^■ substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.

[0092]

Ring E is preferably an optionally substituted^■ 3- to 14- membered nitrogen-containing non-aromatic heterocycle

(preferably azetidine, pyrrolidine, piperidine, piperazine, tetrahydropyridine, 7-azaspiro [3.5] nonane, 3,9- diazaspiro [5.5] undecane, 2-oxa-7-azaspiro [3.5] nonane, 3,6- diazabicyclo [3.1.1] heptane, more preferably piperidine,

piperazine, tetrahydropyridine) . [0093]

Ring E is more preferably a 3- to 14-membered nitrogen- containing non-aromatic heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine, tetrahydropyridine , 7- azaspiro [3.5] nonane, 3, 9-diazaspiro [5.5] undecane, 2-oxa-7- azaspiro [3.5] nonane, 3, 6-diazabicyclo [3.1.1] heptane, more preferably piperidine, piperazine, tetrahydropyridine) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom),

(b) a hydroxy group,

(c) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group (e.g. methoxy) , and

(iv) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g. oxazolyl) ) ,

(d) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(e) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) , and

(f) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g. oxetanyl) ) .

[0094]

Ring E is further more preferably

(1) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a Ci-6 alkyl group (e.g. methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a Ci-6 alkoxy group (e.g. methoxy), and

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl), (2) piperazine optionally substituted by 1 to 3 substituents selected from

(a) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group (e.g. methoxy) , and

(b) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl), and

(d) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g. oxetanyl) ) ,

(a) a Ci-6 alkyl group (e.g. methyl, ethyl-, propyl,

isopropyl) optionally substituted by 1 to 3 hydroxy groups, and

(b) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl),

(4) azetidine optionally substituted by 1 to 3 Ci-6 alkyl groups (e.g. methyl, isopropyl),

(5) pyrrolidine optionally substituted by 1 to 3 Cis alkyl groups (e.g. methyl),

(6) 7-azaspiro [ 3.5 ] nonane optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a^'Ci-6 alkyl group (e.g. methyl),

(7) 3, 9-diazaspiro [5.5] undecane optionally substituted by 1 to 3 Ci-6 alkyl groups (e.g. methyl, isopropyl),

(8) 2-oxa-7-azaspiro [3.5] nonane, or

(9) 3, 6-diazabicyclo [3.1.1] heptane optionally substituted by 1 to 3 Ci-6 alkyl groups (e.g. methyl).

[0095]

Ring E is still more preferably

(1). piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b)^' a Ci- 6 alkyl group (e.g. methyl, ethyl, isopropyl) optionally substituted by 1 to^' 3 substituents selected from

(i) a hydroxy group, and

(ii) a Ci- 6 alkoxy group (e.g. methoxy) , and

(c) a Ci- 6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) ,

(2) piperazine optionally substituted by- 1 to 3 ^"substituents selected from

(a) a Ci- 6 alkyl group (e.g. methyl, ethyl, propyl, .

isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group (e.g. methoxy), and

(iv) a 5- to 14-membered aromatic heterocyclic group

(preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g. oxazolyl)),

(b) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl), and

(d) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g. oxetanyl)), or

(a) a Ci- 6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 hydroxy groups, and

(b) a Ci- 6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl).

[0096] Preferable examples of compound (I) include the following compounds .

[0097]

[Compound A]

Compound (I.) wherein

Ring A is imidazole (X¹ is a carbon atom- and X² is a nitrogen atom), triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) or pyrazole (X¹ is a nitrogen atom and X² is a carbon atom) , each optionally further substituted;

R¹ and R² are independently a hydrogen atom or an optionally substituted Ci-io alkyl group (preferably an optionally

substituted Ci_₆ alkyl group (e.g. methyl));

Ring B is benzene or a 6-membered nitrogen-containing aromatic heterocycle (preferably pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrazine (Z¹ is a nitrogen atom, Z² is a carbon, atom and Z³ is a nitrogen atom), pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is a carbon atom) , pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ) , each optionally further substituted;

W¹ is an optionally substituted Ci-₃ alkylene;

Ring C is an optionally substituted 4- to 10-membered

nitrogen-containing non-aromatic heterocycle (preferably morpholine, piperazine, piperidine, pyrrolidine, 1,1- dioxidothiomorpholine, 6-oxa-3-azabicyclo [3.1.1] heptane, 6- azaspiro [3.3] heptane, 7-azaspiro [3.5] nonane, 2-oxa-7- azaspiro [3.5] nonane, more preferably morpholine, piperazine, piperidine) ;

Ring D is benzene or a 5- to 10-membered nitrogen-containing aromatic heterocycle (preferably pyridine, pyrazole, indole, more preferably pyridine, pyrazole) , each optionally further substituted;

W² is a bond or a linker in which the number of atoms in the main chain is 1 or 2; and

Ring E is an optionally substituted 3- to 14-membered

nitrogen-containing non-aromatic heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine,

tetrahydropyridine, 7-azaspiro [3.5] nonane, 3,9- diazaspiro [5.5] undecane, 2-oxa-7-azaspiro [3.5] nonane, 3,6- diazabicyclo [3.1.1] heptane, more preferably piperidine, piperazine, tetrahydropyridine) .

[0098]

[Compound B]

Compound (I) wherein

Ring A is imidazole (X¹ is a carbon atom and X² is a nitrogen atom) , triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) or pyrazole (X¹ is a nitrogen atom and X² is a carbon atom) , each optionally further substituted by one Ci_₆ alkyl group (e.g. methyl);

R¹ and R² are independently a hydrogen atom or a Ci_io alkyl group (preferably a C_H alkyl group (e.g. methyl));

Ring B is benzene or a 6-membered nitrogen-containing aromatic heterocycle (preferably pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom; Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a carbon atom; or Z¹ is a carbon atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom) , pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z³ is a carbon atom), pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ) , each optionally further substituted by l^'to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl);

W¹ is a Ci-3 alkylene (e.g., -CH₂-, -(CH₂)₂-, "(CH₂)₃-, -CH(CH₃)-, -C(CH₃)₂-) optionally substituted by oxo group (s);

Ring C is a 4- to 10-membered nitrogen-containing non-aromatic heterocycle (preferably morpholine, piperazine, piperidine, pyrrolidine, 1 , 1-dioxidothiomorpholine , 6-oxa-3- azabicyclo [3.1.1] heptane, 6-azaspiro [3.3] heptane, 7- azaspiro [3.5] nonane, 2-oxa-7-azaspiro [3.5] nonane, more

(a) a halogen atom (e.g., a fluorine atom),

(b) a hydroxy group,

(c) a carboxy group,

(d) a Ci-6 alkyl group (e.g. methyl), and

(e) a Ci-6 alkoxy-carbonyl group (e.g. methoxycarbonyl) ;

Ring D is benzene or a 5- to 10-membered nitrogen-containing aromatic heterocycle (preferably pyridine, pyrazole, indole, more preferably pyridine, pyrazole) , each optionally further substituted by 1 to. 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a chlorine atom), (b) an optionally halogenated Ci-₆ alkyl group (e.g. methyl, trifluoromethyl) ,

(c) a Ci-6 alkoxy group (e.g. methoxy) , and

(d) a carbamoyl group;

W² is

(1) a bond,

(2) a Ci-2 alkylene group (e.g., -CH₂-, -(CH₂) 2^_) optionally substituted by an oxo group; or

(3) -Z- wherein Z is 0 or S(0)₂; and

Ring E is a 3- to 14-membered nitrogen-containing non-aromatic heterocycle (preferably azetidihe, pyrrolidine, piperidine, piperazine, tetrahydropyridine, 7-azaspiro [3.5] nonane, 3,9- diazaspiro [5.5] undecane, 2-oxa-7-azaspiro [3.5] nonane, 3,6- diazabicyclo [3.1.1] heptane, more preferably piperidine,

piperazine, tetrahydropyridine) optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a hydroxy group,

(c) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group (e.g. methoxy) , and

(iv) a 5- to 14-membered aromatic heterocyclic group (preferably a 5^ or 6-membered monocyclic aromatic heterocyclic group (e.g. oxazolyl) ) ,

(d) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(e) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl ) , and

(f) a 3- to 14-membered non-aromatic heterocyclic group

(preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g. oxetanyl) ) .

[0099]

[Compound C]

Compound (I) wherein

Ring A is

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom) optionally further substituted by one Ci-₆ alkyl group (e.g. methyl) ,

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom), or

(3) pyrazole (X¹ is a nitrogen atom and X² is a carbon atom) ; R¹ and R² are independently a hydrogen atom or a Ci_₆ alkyl group (e.g. methyl);

Ring B is

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl),

(3) pyrazine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a nitrogen atom) , (4) pyrimidine (Z¹ is a nitrogen atom, Z² is a nitrogen atom and Z'³ is a carbon atom) , or

(5) pyridazine (Z¹ is a carbon atom, Z² is a nitrogen atom and Z³ is a nitrogen atom) ;

W¹ is -CH₂-, -(CH₂)₂-, -(CH₂)₃-, -CH(CH₃)-, -C(CH₃)₂-, -C(=0)- or -CH₂-C(=0)- (wherein the left bond is bonded to Ring C, and the right bond is bonded to Ring A) ;

Ring C is

(1) morpholine optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a Ci-6 alkyl group (e.g. methyl),

(3) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a hydroxy group,

(4) pyrrolidine substituted by 1 to 3 substituents selected from

(a) a hydroxy group-,

(b) a carboxy group, and

. (c) a Ci_6 alkoxy-carbonyl group (e.g. methoxycarbonyl ) ,

(5) 1, 1-dioxidothiomorpholine ,

(6) 6-oxa-3-azabicyclo [3.1.1] heptane,

(7) 6-azaspiro [ 3.3 ] heptane optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a Ci-6 alkyl group (e.g. methyl),

(8) 7-azaspiro [3.5 ] nonane optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a Ci-6 alkyl group (e.g. methyl), or

( 9) 2-oxa-7-azaspiro [3.5] nonane;

Ring D is (1) b¾nzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(b) an optionally halogenated Ci_₆ alkyl group (e.g. methyl, trifluoromethyl) ,

.(c) a Ci-6 alkoxy group (e.g. methoxy) , and

(d) a carbamoyl group,

(2) pyridine optionally further substituted by 1 to 3

substituents selected from

(b) a Ci-6 alkyl group (e.g. methyl), and

(c) a Ci-6 alkoxy group (e.g. methoxy),

(3) pyrazole, or

(4) indole;

2 is a bond, -CH₂-, -C(=0)-, -C(=0)-CH₂- (wherein the left bond is bonded to Ring D, and the right bond is bonded to Ring E) , -0- or -S(0)₂-; and

Ring E is

(1) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a Ci-6 alkyl group (e.g. methyl, ethyl, isopropyl)

optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a Ci-6 alkoxy group (e.g. methoxy), and

(c) a Ci- 6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) ,

(2) piperazine ^' optionally substituted by 1 to -3 substituents selected from

(a) a Ci- 6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci- 6 alkoxy group (e.g. methoxy), and

(iv) a 5- to 14-membered aromatic heterocyclic group

(preferably a 5- or β-membered monocyclic aromatic heterocyclic group (e.g. oxazolyl) ) ,

(b) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) , and

(d) a 3- to 14-membered non-aromatic heterocyclic group

(preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g. oxetanyl) ) ,

-(a) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 hydroxy groups, and

(b) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl),

(4) azetidine optionally substituted by 1 to 3 Ci-₆ alkyl groups (e.g. methyl, isopropyl),

(5) pyrrolidine optionally substituted by 1 to 3 Ci-6 alkyl groups (e.g. methyl),

(a) a hydroxy group,

(b) a Ci-6 alkyl group (e.g. methyl),

(8) 2-oxa-7-azaspiro [3.5] nonane, or

[0100]

[Compound D],

Compound (I) wherein

Ring A is

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom) , or

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom); R¹ and R² are both hydrogen atoms;

Ring B is (1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a Ci-6 alkyl group (e.g. methyl), or

(2) pyridine (Z¹ is a nitrogen atom, Z² is ^'a carbon atom and Z³ is a carbon atom) ;

W¹ is -CH₂-, -(CH₂)₂- or -(CH₂)₃-;

Ring C is

(1) morpholine optionally substituted by 1 to 3 Ci-6 alkyl groups (e.g. methyl),

(2) piperazine optionally substituted by 1 to 3 Ci-₆ alkyl groups (e.g. methyl), or

(3) piperidine;

Ring D is

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(b) an optionally halogenated Ci-₆ alkyl group (e.g. methyl, trifluoromethyl) , .^.. ^. (c) a Ci-6 alkoxy group (e.g. methoxy).,,. and

(d) a carbamoyl group,

(2) pyridine, or

(3) pyrazole;

2 is a bond, -CH₂-, -C(=0)- or -0-; and

Ring E is

(1) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a Ci-6 alkyl group (e.g. methyl, ethyl, isopropyl)

optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a Ci-6 alkoxy group (e.g. methoxy) , and

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) ,

(2) piperazine optionally substituted by 1 to 3 substituents selected from (a) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

. isopropyl) optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a hydroxy group,

(iii) a Ci-6 alkoxy group (e.g. methoxy) , and

(b) a C3-10 cycloalkyl group (e.g. cyclopropyl) ,

(c) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl) , and

(3) tetrahydropyridine optionally substituted ^'by 1 to 3 substituents selected from

(a) a Ci-6 alkyl group (e.g. methyl, ethyl, propyl,

isopropyl) optionally substituted by 1 to 3 hydroxy groups, and

(b) a Ci-6 alkoxy-carbonyl group (e.g. tert-butoxycarbonyl).

[0101]

Examples of the salt of the compound represented by the formula (I) include metal salts, ammonium salts, salts with an organic base, salts with an inorganic acid, salts, with an organic acid, salts with a basic or acidic amino acid, and the like.

[0102]

Preferable examples of the metal salt include alkaline metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt, and the like.

[0103]

Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine,

triethanolamine, cyclohexylamine, dicyclohexylamine, Ν,Ν'- dibenzylethylenediamine or the like.

[0104]

Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like.

[0105]

Preferable examples of the salt with an organic acid 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 or the like.

[0106]

Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine or the like. Preferable examples of the salt with an acidic amino acid include- salt with aspartic acid, glutamic acid or the like.

[0107]

Among the above-mentioned salts, pharmaceutically acceptable salts are preferable.

[0108]

Compound (I) may be in the form of a prodrug. The prodrug of compound (I) means a compound which is converted to compound (I) with a reaction due to an enzyme, gastric acid and the like under the physiological condition in the living body, that is, a compound which is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis and the like; a compound which is converted, to compound (I) by hydrolysis and the like due to gastric acid, and the like.

[0109]

Examples of the prodrug of compound (I) include 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 an eicosanoylation, alanylation, pentylamin^'ocarbonylation, (5-methyl-2-oxo-l, 3-dioxolen-4-yl ) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,

pivaloyloxymethylation or tert-butylation) ; a compound

obtained by subjecting a hydroxy group in compound (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting a hydroxy group in compound (I) to an acetylation, palmitoylation, propanoylation,

pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation) ;^' a compound obtained by subjecting a carboxyl group in compound (I) to an

esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (I) to a Ci-e alkyl 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) and the like. Among them, a compound esterified by Ci_₆ alkyl (e.g., methyl, ethyl, tert-butyl and the like) are preferably used. These compounds can be produced from compound (I) according to a method known per se.

[0110]

The prodrug of compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, 1990, Published by HIROKAWA SHOTEN.

[0111]

Each symbol of the compound in the following Schemes is as defined above, unless otherwise specified. Each compound described in the following Schemes may be in the form of a salt as long as it does not inhibit the reaction. Examples of the salt include those similar to ^'the salt of compound (I).

[0112]

The compound obtained in each step can be used directly for the next reaction as the reaction mixture or as a crude product, or can also be isolated according to a conventional method from the reaction mixture, and can also be easily purified according to a separation means (e.g.,

recrystallization, distillation, chromatography etc.).

[0113]

The production methods of the compound of the present invention are described in the following.

Compound (I) can be produced according to a method known per se, for example, the production method shown in Scheme 1,

11, 14, 16 or 18, or a method analogous thereto.

In each of the following production methods, each starting compound used for the production of compound (I) may be in the form of a salt. Examples of the salt include those similar to the salt of compound (I) .

[0114]

Each starting compound to be used for the production of compound (I) can be used directly for the next reaction as the reaction mixture or as a crude product, or can also be

isolated according to a conventional method from the reaction mixture, and can also be purified according to a separation means (e.g., extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography etc.). Examples of the solvent used for the above-mentioned recrystallization include water, alcohols, ethers,

hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, esters, sulfoxides, organic acids and the like. These solvents may be used alone, or two or more kinds of solvents may be mixed at a suitable ratio, for example, 1:1 - 1:10. In addition, the compounds in the Schemes may be commercially available, or can be produced according to a method known per se or a method analogous thereto. [0115]

When compound (I) and intermediate for the production of compound (I) have a convertible functional group (e.g., a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a sulfanyl group, a Ci_₆ alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group, a C₇-i₆ aralkyloxy-carbonyl group, a sulfo group, a halogen atom, an optionally halogenated Ci-6 alkylsulfonyloxy group, a cyano group, an aminocarbonyl group, a boryl group etc.), various compounds can be produced by converting such functional group according to a method known per se or a method analogous thereto.

Carboxyl group can be converted, for example, by

reactions such as esterification, reduction, amidation, conversion reaction to optionally protected amino group and the like.

Amino group can be converted, for example, by reactions such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.

Hydroxy group can be converted, for example, by reactions such as esterification, carbamoylation, sulfonylation,

alkylation, fluorination, arylation, oxidation, halogenation and the like.

Carbonyl group can be converted, for example, by

reactions such as reduction, oxidation,' fluorination,

imination (including oximation, hydrazonation) ,

(thio) ketalization, alkylidenation, thiocarbonylation and the like.

Sulfanyl group can be converted, for example, by

reactions such as alkylation, oxidation and the like.

Ci-6 alkoxy-carbonyl group, C₆-i₄ aryloxy-carbonyl group and C7-16 aralkyloxy-carbonyl group can be converted, for example, by reactions such as reduction, hydrolysis and the like.

Sulfo group can be converted, for example, by reactions such as sulfonamidation, reduction and the like. Halogen atom can be converted, for example, by various nucleophilic substitution reactions, various coupling

reactions and the like.

Optionally halogenated Ci-e alkylsulfonyloxy group can be converted, for example, by various nucleophilic substitution reactions, various coupling reactions and the like.

Cyano group can be converted, for example, by reactions such as reduction, hydrolysis and the like.

Aminocarbonyl group can be converted, for example, by reactions such as dehydration, reduction and the like.

Boryl group can be converted, for example, by oxidation, various coupling reactions and the like.

In each of the above-mentioned reactions, when the compound is obtained in a free form, it may be converted to a salt according to a conventional method. When it is obtained as a salt, it may be converted to a free form or other salt according to a conventional method.

The conversion of these functional group can be carried out according to a method known per se, for example, the method described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock, or the like.

[0116]

In. each reaction in the production method of compound (I) and each reaction of the synthesis of the starting materials, when the starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a sulfanyl group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these

substituents . By removing the protecting group as necessary after the reaction, the object compound can be obtained.

Examples of the amino-protecting group include a formyl group; and a Ci-₆ alkyl-carbonyl group (e.g., acetyl,

ethylcarbonyl etc.), a phenylcarbonyl group, a Ci-e alkyl- oxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc) etc.), an allyloxycarbonyl (Alloc) group, a phenyloxycarbonyl group, a fluorenylmethoxycarbonyl (Fmoc) group, a C7-10 aralkyl-carbonyl group (e.g.,

benzylcarbonyl etc.), a C₇_io aralkyl-oxycarbonyl group (e.g., benzyloxycarbonyl (Z) etc.), a C₇_io aralkyl group (e.g., benzyl etc.), a 2- (trimethylsilyl) ethoxymethyl (SE ) group, a trityl group, a phthaloyl group, an N, N-dimethylaminomethylene group, an allyl group and the like, each of which optionally has substituent (s) , and the like. As these substituents , a phenyl group, a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc.), a Ci-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl , butylcarbonyl etc.), a nitro group and the like are used, and the number of the substituents is about 1 to 3.

Examples of the carboxyl-protecting 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 trialkylsilyl group and the like, each of which optionally has substituent ( s ) . As these

substituents, a halogen atom (e.g., a fluorine atom, a

chlorine atom, a bromine atom, an iodine, atom etc.), a formyl group, a Ci-.₆ alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, butylcarbonyl etc. ) , a nitro group and the like are used, and the number of the substituents is about 1 to 3.

Examples of the hydroxyl-protecting group include a Ci_₆ alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc.), a C7-10 aralkyl group (e.g., benzyl etc.), a formyl group, a Ci-6 alkyl-carbonyl group (e.g., acetyl,

ethylcarbonyl . etc : ) , a benzoyl group, a C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a tetrahydropyranyl group, a furanyl group, a silyl group and the like, each of which optionally has substituent ( s ) . As these substituents, a

halogen atom (e.g., a fluorine atom, a chlorine atom, a

bromine atom, an iodine atom etc.), a Ci-6 alkyl group (e.g., methyl, ethyl, n-propyl etc.), a phenyl group, a C₇_io aralkyl group (e.g., benzyl etc.), a Ci-₆ alkoxy group (e.g., methoxy, ethoxy, n-propoxy etc.), a nitro group and the like are used, and the number of the substituents is about 1 to 4.

Examples of the protected carbonyl group include cyclic acetal (e.g., 1 , 3-dioxane ) , noncyclic acetal (e.g., di-Ci-6 alkylacetal) and the like.

Examples of the sulfanyl-protecting group include a Ci_6 alkyl group, a phenyl group, a trityl group, a C₇_io aralkyl group (e.g., benzyl), a Ci_₆ alkyl-carbonyl group, a benzoyl group, a C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl) , a Ci-6 alkoxy-carbonyl group, a C₆-i₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl) , a C₇_i₄ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , a 2- tetrahydropyranyl group, a Ci-₆ alkylamino-carbonyl group (e.g., methylaminocarbonyl , ethylaminocarbonyl ) and the like. These protecting groups are optionally substituted by 1 to 3

substituents selected from a halogen atom, a is alkyl group, a Ci-6 alkoxy group and a nitro group.

These protecting groups can be introduced and removed by a method known per se, for example, the method described in Greene's Protective Groups in Organic Synthesis, 4^th Edition, Wiley-Interscience, Theodora W. Greene, Peter G. M. Wuts or the like. Specifically, a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N- methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method/ and the like can be employed.

[0117]

The solvent, acid and base recited in the production methods of the compound of the present invention are explained in the following.

Examples of the "solvent" include "alcohols", "ethers", "hydrocarbons", "amides", "halogenated hydrocarbons",

"nitriles", "ketones", "esters", "sulfoxides", "water" and the like. Examples of the "alcohols" include methanol, ethanol, 1- propanol, 2-propanol, tert-butyl alcohol and the like.

Examples of the "ethers" include diethyl ether,

diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4- dioxane, 1, 2-dimethoxyethane, tert-butyl methyl ether and the like.

Examples of the "hydrocarbons" include benzene, toluene, cyclohexane, hexane, petroleum ether and the like.

Examples of the "amides" include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone,

hexamethylphosphoric triamide and the like.

Examples of the "halogenated hydrocarbons" include

dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, chlorobenzene, benzotrifluoride and the like.

Examples of the "nitriles" include acetonitrile,

propionitrile and the like.

Examples of the "ketones" include acetone, ethyl methyl ketone and the like.

Examples of the "esters" include ethyl acetate, tert- butyl acetate and the like.

Examples of the "sulfoxides" include dimethyl sulfoxide arid the like.

Examples of the "acid" include "organic acids", "mineral acids", "Lewis acids" and the like.

Examples of the "organic acids" include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

Examples of the "mineral acids" include hydrochloric acid, sulfuric acid and the like.

Examples of the "Lewis acids" include boron trichloride, boron tribromide and the like.

Examples of the "base" include "inorganic bases", "basic salts", "aromatic amines", "tertiary amines", "alkali metal hydrides", "alkali metals", "metal amides", "alkyl metals", "aryl metals", "metal alkoxides" and the like. Examples of the "inorganic bases" include sodium , hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like.

Examples of the "basic salts" include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen

carbonate, sodium acetate, ammonium acetate and the like.

Examples of the "aromatic amines" include pyridine, 2,6- lutidine and the like.

Examples of the "tertiary amines" include triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, cyclohexyldimethylamine , 4-dimethylaminopyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine , 1 , 8-diazabicyclo [ 5 , , 0 ] undec-7-ene and the like.

Examples of the "alkali metal hydrides" include sodium hydride, potassium hydride and the like.

Examples of the "alkali metals" include sodium, lithium, potassium and the like.

Examples of the "metal amides" include sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.

Examples of the "alkyl metals" include butyllithium, sec- butyllithium, tert-butyllithium and the like.

Examples of the "aryl metals" include phenyllithium and the like.

Examples of the "metal alkoxides" include sodium

methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like.

[0118]

Compound (I) can be produced, for example, according to the method shown in the following Scheme 1 or a method

analogous thereto.

[0119]

Compound (I) can be prepared by subjecting Intermediates (II) and (III) to Suzuki coupling as shown in Scheme 1. [0120]

Scheme 1: Preparation of Compound (I)

[0122] ^■

wherein LG¹ is a leaving group selected from a halogen atom, trifluoromethanesulfonyloxy and _. the like, and the other ^■ symbols are as defined above.

[0123]

The Suzuki coupling can be carried out according to the method described in Chemical Reviews 95 (7): 2457-2483, for example, by reacting Intermediate (II) with Intermediate (III) in the presence of a catalysis and a base, in a solvent.

Examples of the catalyst include palladium(O) complexes such as tetrakis (triphenylphosphine) palladium, 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex and the like.

Intermediate (III) may be commercially available, or can also be produced according to a method known per se or a method analogous thereto.

[0124] Intermediate (II) can be prepared by subjecting

Intermediate (IV) to substitution reaction as shown in Scheme 2.

[0125]

Scheme 2: Preparation of Intermediate (II)

[0126]

LG

(ID

[0127]

wherein LG² is a leaving group selected from a chlorine atom, a bromine atom-, methanesulfonyloxy, trifluoromethanesulfonyloxy and the like, and the other symbols are as defined above.

[0128]

The substitution reaction can be carried out according to the method described in J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992, for example, by reacting

Intermediate (IV) with Intermediate (V) in the presence of a base, in a solvent.

Intermediate (V) may be commercially available, or can also be produced according to a method known per se or a method analogous thereto. [0129]

Intermediate (IV) wherein -W¹- is -CH₂- can be prepared by subjecting Intermediate (VI) to reduction, and then

subjecting the resulting Intermediate (VII) to substitution reaction, as shown in Scheme 3.

[0130]

Scheme 3: Preparation of Intermediate (IV) wherein - ¹- is -

CH₂-

[0131]

[0132]

wherein R³ is methyl, ethyl or the like, and the other symbols are as defined above.

[0133]

The reduction is a nucleophilic acyl substitution reaction followed by nucleophilic addition. The reaction requires addition of 2 equivalent of hydrides (H^~) to the carbonyl group of Intermediate (VI) . The reaction proceeds via the formation of aldehyde intermediate which then reacts with 2 equivalent of hydride reagent to form Intermediate (VII) [W. Reusch., "Carboxyl Derivative Reactivity", Virtual Textbook of Organic Chemistry] . The reduction can be carried out in

presence of a reagent such as LiALH₄ and the like and a Lewis acid such as AICI₃ and the like. The reaction may be carried out in solvent such as THF and the like in an inert atmosphere. The reaction temperature may be changed from -55°C to 0°C and finally to 70°C.

The substitution reaction can be carried out as described above .

[0134]

Intermediate (VI) wherein X¹ is a carbon atom and X² is a nitrogen atom can be prepared as shown in Scheme 4.

[0135]

Scheme 4 : Preparation of Intermediate (VI) wherein X¹ is a carbon atom and X² is a nitrogen atom

[0136]

[0137]

wherein LG³ is a leaving group selected from a halogen atom such as chlorine, bromine and the like, and the other symbols are as defined above.

[0138]

Intermediate (VIII) may be commercially available, or can also be produced according to a method known per se or a method analogous thereto.

Intermediate (VIII) can be condensed with dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate or the like in a solvent such as ethanol to give Intermediate (IX) . The reaction temperature may be room temperature. Intermediate (IX) can be subjected to the oxime formation to give Intermediate (X) . The reaction may be carried out in a solvent such as glacial acetic acid. Isoamyl nitrite may be added for oxime formation.

Hydrogenation of Intermediate (X) can convert oxime to amine to give Intermediate (XI) . The reaction may be carried out in a solvent such as THF under hydrogen atmosphere.

Platinum oxide and the like may be used as catalyst for the reaction .

Acylation of Intermediate (XI) can give Intermediate

(XII) . The acylation may be carried out with a suitable acid chloride in an anhydrous solvent such as dimethylformamide under inert atmosphere.

Intermediate (XII) can be subjected to base catalyzed rearrangement to give Intermediate (XIII). The base used for the rearrangement can be sodium carbonate or the like. The reaction may be carried out in a polar solvent such as acetone water or a mixture of acetone and water.

Decarboxylation of Intermediate (XIII) can give

Intermediate (VI) . The decarboxylation can be carried out by heating Intermediate (XIII) at higher temperature, for example

180-190°C [J. Chem.Soc, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 4, 1049-1058; 1982].

[0139]

Intermediate (VI) wherein X¹ and X² are nitrogen atoms can be prepared as shown in Scheme 5:

[0140]

Scheme 5: Preparation of Intermediate (VI) wherein X¹ and X² are nitrogen atoms

[0141]

[0142]

wherein each symbol is as defined above.

[0143]

Intermediate (XIV) may be commercially available, or can also be produced according to a method known per se or a method analogous thereto.

Intermediate (XIV) can be subjected to O-alkylation in presence of a base such as K2CO3 to give Intermediate (XV) . The reaction can be carried out in a polar solvent such as acetone under heating conditions.

Diazotization of Intermediate (XV) can give Intermediate (XVI) . The diazotization can be carried out in a conventional way using HCl and NaN0₂ in water under continuous cooling, ^"followed by using a suitable acetate (e.g., 2- chloroacetoacetate) .

Cyclization of Intermediate (XVI) in presence of a base such as triethylamine can give Intermediate (VI) . The reaction may be carried out in an inert solvent such as toluene under heating conditions [J. Heterocyclic Chem. , 13, 1339 (1976)].

[0144]

Intermediate (IV) wherein W¹ is -CH₂-CH₂- or -(CH₂)₃- can be prepared by subjecting Intermediate (XVII) to homologation, and then subjecting the resulting Intermediate (XVIII) to reduction, and then subjecting the resulting Intermediate (XIX) to substitution reaction, as shown in Scheme 6.

[0145]

Scheme 6: Preparation of Intermediate (IV) wherein W¹ is -CH₂ CH₂- or -(CH₂)₃- [0146

(XVII) (XVIII)

W¹ is -(CH₂)2- or -(CH₂)₃- (XIX) (IV)

[0147]

wherein ^1' is -CH₂- or -CH₂-CH₂-, R⁴ is -CHO or -COOEt, and the other symbols are as defined above.

[0148]

Homologation can be carried out by reaction Intermediate (XVII) with a suitable triphenyl phosphonium ylide to give the next homologue in the series [Baxter, A. et al . , PCT Int.

Appl., 2001058890, 2001]. For example, the reaction of

Intermediate (XVII) with methoxymethyl triphenyl phosphonium ylide or ethoxycarbonylmethyl triphenylphosphonium ylide followed by hydrolysis or reduction can give Intermediate (XIX) .

The substitution reaction can be carried out as described above.

[0149]

Intermediate (XVII) can be prepared by subjecting

Intermediate (VII) wherein -W¹- is -CH₂- to oxidation using suitable oxidizing agents, e.g., Dess-Martin periodinane and the like as shown in Scheme 7.

[0150]

Scheme 7: Preparation of Intermediate (XVII)

[0151]

[0152]

wherein each symbol is as defined above.

[0153]

Intermediate (XVII) wherein X¹ is a carbon atom and X² is a nitrogen atom can alternatively be prepared as shown in Scheme 8.

[0154]

Scheme 8: Preparation of Intermediate (XVII) wherein X¹ is a carbon atom and X² is a nitrogen atom

[015-5]

[0156]

wherein each symbol is as defined above.

[0157]

Intermediate (XX) can be subjected to acylation in

presence of a base such as CS2CO3 and the like to give

Intermediate (XXI) . The reaction may be carried out in a polar solvent such as dimethylformamide . The reaction temperature may range from room temperature to 60°C.

Intermediate (XX) can be commercially available or can be prepared according to methods well known in literature or analogous thereto [Tetrahedron, 58, 8145-8152, (2002)].

Intermediate (XXI) can be subjected to cyclization to give Intermediate (XXII). The cyclization reaction can be carried out by reacting Intermediate (XXI) with ammonium

acetate in an acidic solvent such as glacial acetic acid in sealed containers [J. Med. Che . , 53, 5827-5843 (2010)].

Oxidation of Intermediate (XXII) can give Intermediate (XVII) . The reaction can be carried out in a solvent such as dioxane under heating conditions. Se0₂ and the like can be used for the oxidation reaction [Acta Chemica Scandinavica, 20, 2649-2657 (1966)].

[0158]

Intermediate (II) wherein ¹ is -CH₂- can alternatively be prepared by subjecting Intermediate (XVII) to reductive amination as shown in Scheme 9.

[0159]

Scheme 9: Preparation of Intermediate (II) wherein W¹ is -CH₂- [0160]

[0161]

wherein each symbol is as defined above.

[0162]

^■ The reductive amination can be carried out according to the method described in Organic Reactions, 1, 59, 2002, for example, by reacting Intermediate (XVII) with Intermediate (V) in the presence of a reducing agent, in a solvent.

Examples of the reducing agent include sodium

cyanoborohydride (NaBH₃CN) , sodium triacetoxyborohydride [NaBH (OCOCH₃)₃] and the like. Intermediate (XVII) can be prepared according to the method described in Scheme 7 or Scheme 8 or method analogous thereto .

[0163]

Intermediate (II) wherein W¹ is -CH₂-CH₂- or -(CH₂)₃- can be prepared by subjecting Intermediate (XVIII) to reductive amination as shown in Scheme 10.

[0164]

Scheme 10: Preparation of Intermediate (II) wherein W¹ is -CH₂- CH₂- or -(CH₂)₃- [0165]

(II)

[0166]

wherein each symbol is as defined above.

[0167]

The reductive amination can be carried out as described above.

[0168]

Compound (I) can alternatively be prepared by subjecting Intermediate (XXIII) to substitution reaction as shown in Scheme 11. [0169]

Scheme 11: Preparation of Compound (I)

[0170]

[0171]

wherein each symbol is as defined above.

[0172]

The substitution reaction can be carried out as described above .

[0173]

Intermediate (XXIII) wherein W¹ is -CH₂- can be prepared by subjecting Intermediate (VII) and Intermediate (III) to Suzuki coupling, and then subjecting the resulting

Intermediate (XXIV) to substitution reaction, as shown in

Scheme 12.

[0174]

Scheme 12: Preparation of Intermediate (XXIII) wherein W¹ is -

CH₂-

[0175]

[0176]

wherein each symbol is as defined above.

[0177]^'

The Suzuki coupling and substitution reactions can be carried out as described above.

[0178]

Intermediate (XXIII) wherein W¹ is -CH₂-CH₂- or -(CH₂)₃- can be prepared by subjecting Intermediate (XIX_.) to Suzuki- coupling, and then subjecting the resulting Intermediate (XXV) to substitution reaction, as shown in Scheme 13.

.[0179]

Scheme 13: Preparation of Intermediate (XXIII) wherein W¹ is - CH₂-CH₂- or -(CH₂)₃-

[0181]

wherein each' symbol is as defined above.

[0182]

The Suzuki coupling and substitution reaction can be carried out as described above.

[0183]

Compound (I) can alternatively be prepared by subjecting Intermediate (XXVI) to Suzuki coupling as shown in Scheme 14.

[0184]

Scheme 14: Preparation of Compound (I)

[0185]

[0186]

LG⁴ is a leaving group selected from a halogen atom, trifluoromethanesulfonyloxy and the like, and the other

symbols are as defined above.

[0187]

The Suzuki coupling can be carried out as described above. Intermediate (XXVII) may be commercially available or may be prepared by methods known^" in literature or methods

analogous thereto.

[0188]

Intermediate (XXVI) can be prepared by subjecting

Intermediate (II) to borylation reaction as shown in Scheme 15.

[0189]

Scheme 15: Preparation of Intermediate (XXVI)

[0190]

[0191]

wherein each symbol is as defined above.

[0192]

The borylation reaction is the synthesis of boronates by cross coupling of bis (pinacolato) diboron with aryl halides and vinyl halides [J. Org. Chem. , 1995, 60, 7508-7510], for example, by reacting Intermediate (II) with

bis (pinacolato) diboron in the presence of a catalyst.

Examples of the catalyst include palladium (0) complexes such as tetrakis (triphenylphosphine ) palladium, 1,1- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane complex and the like.

[0193]

Compound (I) wherein -W²- is -CO- can be prepared by subjecting Intermediate (XXVIII) to amide coupling with

Intermediate (XXIX) as shown in Scheme 16.

[0194]

Scheme 16: Preparation of Compound (I) wherein - ²- is -CO- [0195]

[0196]

wherein each symbol is as defined above.

[0197]

The amide coupling may be carried out using any suitableamide coupling regent such as oxalyl chloride, thionyl

chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, alkyl

chloroformate and the like in the presence of an organic non- nucleophillic base such as triethylamine, di- isopropylethylamine, pyridine, N-methyl pyrrolidine, N,N- dimethylaminopyridine, DBU, DABCO, other hindered amines and pyridines. The amide coupling reaction may be carried out in a solvent such as dichloromethane , dichloroethane, DMF,

dimethylacetamide, THF, acetonitrile or mixture thereof at a temperature ranging from -5 to 150°C. The reaction may be carried out optionally in presence of catalytic amount of DMF. The amide coupling may also be carried out by heating the corresponding ester and amine either in the absence of a solvent or in presence of a high boiling solvent such as toluene, xylene, DMSO. The amide coupling may be carried out in presence of a trialkyl aluminium (Chem. Commun. 2008, 1100- 1102) .

Intermediate (XXIX) may be commercially available or prepared according to method known in literature.

[0198]

Intermediate (XXVIII) can be prepared by subjecting Intermediate (II) to Suzuki coupling with Intermediate (XXX) as shown in Scheme 17.

[0199]

Scheme 17 : Preparation of Intermediate (XXVIII)

[0200]

(XXVIII)

[0201]

wherein each symbol is as defined above.

[0202]

The Suzuki coupling can be carried out as described above Intermediate (XXX) may be commercially available or prepared according to method known in literature. '[0203]

Compound (I) wherein -W²- is -CH₂- can be prepared by subjecting Intermediate (XXXI) to reductive amination with Intermediate (XXIX) as shown in Scheme 18.

[0204]

Scheme 18: Preparation of Compound (I) wherein- -W²- is -C¾- [0205]

[0206]

wherein each symbol is as defined above.

[0207]

The reductive amination can be carried out as described above .

[0208]

Intermediate (XXXI) can be prepared by subjecting

Intermediate (II) to Suzuki coupling with intermediate (XXXII) as shown in Scheme 19.

[0209] Scheme 19: Preparation of Intermediate (XXXI)

[0210]

[0211J

wherein each symbol is as defined above.

[0212]

The Suzuki coupling can be carried out as described above. Intermediate (XXXII) may be commercially available or prepared according to method known in literature.

[0213]

Compound (I) obtained in each scheme can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, each material

compound used in each scheme can be isolated and purified by those similar to the above-mentioned known separation and purification means. The material compound may be used directly in the next step as the reaction mixture without isolation.

[0214]

When compound (I) has isomers such as an optical isomer, a stereoisomer, a regioisomer and a rotamer and the like, such isomers and a mixture thereof are also encompassed in compound (I) . For example, when compound (I)^' has an optical isomer, the optical isomer resolved from racemate is also encompassed in compound (I) . These isomers can be obtained as single products according to synthetic methods known per se, separation

methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), optical

resolutions (e.g., fractional recrystallization method, chiral column method, diastereomer method and the like) .

[0215]

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.

[0216]

2) Chiral column method

A method wherein a racemate or a salt thereof is applied to a column (a chiral column) for separation of an optical isomer 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-OV (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.) and the 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.) as an eluent, 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.

[0217]

3) Diastereomer method A method wherein a racemic mixture 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 group, or primary or secondary amino group within a molecule, the compound and an optically active organic acid (e.g., MTPA [cc-methoxy-a- (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 ca boxyl group, the 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.

[0218]

Compound (I) may be a crystal, and the crystal form may be single or a mixture of crystal forms, both of which are encompassed in compound (I) . The crystal can be produced according to a crystallization method known per se.

The compound (I) may be a solvate (e.g., hydrate) or a non-solvate (e.g., non-hydrate etc.) and both are encompassed in compound ( I ) .

The compounds labeled with isotopes (e.g., ³H, ¹⁴C, ³⁵S,

¹²⁵I etc.) and the like are also encompassed in compound (I).

A deuterium conversion form wherein ¹H is converted to ²H(D) is also encompassed in compound (I).

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

[0219]

Since the compound of the present invention has a superior TLR7, TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9 inhibitory action, may show low toxicity (e.g., phototoxicity, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interactions, carcinogenicity and the like, particularly phototoxicity) , and may be superior in stability (particularly metabolic stability) ,

pharmacokinetics (absorption,- distribution, metabolism, excretion etc.) and high solubility, it may be useful as a medicament. The compound of the present invention has a TLR7 , TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9 inhibitory action to mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, human etc.), and may be used for the prophylaxis or treatment of the following diseases and

symptoms in the mammals:

(1) inflammatory disease (e.g., acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary diseases (COPD) , inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic

inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, stomach mucosa injury,

meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, lung infarction, silicosis, pulmonary sarcoidosis, etc.),

(2) autoimmune disease (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylopoietic

spondylarthritis, polymyositis, dermatomyositis (DM) ,

polyarteritis nodosa (PN) , mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, Type Γ· and Type II diabetes, autoimmune hemolytic anemia, autoimmune neutrophenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis,

dermatitis, radiodermatitis , etc. ) ,

(3) osteoarticular degenerative disease (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis, etc.),

(4) neoplastic disease (e.g., malignant tumor, neovascular glaucoma, infantile hemangioma, multiple myeloma, acute

myeloblastic leukemia, chronic sarcoma, multiple myeloma, chronic myeloid leukemia, metastasis melanoma, Kaposi's

sarcoma, vascular proliferation, cachexia, metastasis of

breast cancer and the like, cancer (e.g., colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma,

pancreatic cancer (e.g., pancreatic ductal carcinoma, etc.), stomach cancer (e.g., papillary adenocarcinoma, mucinous

adenocarcinoma, adenosquamous carcinoma, etc.), breast cancer (e.g., infiltrating ductal carcinoma, noninfiltrating ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor, etc.), prostate cancer (e.g., hormone-dependent prostate

cancer, hormone-independent prostate cancer, etc.), liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (e.g., medullary thyroid

carcinoma, etc.), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of renal pelvis and urinary duct, etc.) uterine cancer, brain tumor (e.g.., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic

astrocytoma, etc.), melanoma, sarcoma, urinary bladder cancer, hematologic cancer including multiple myeloma and the like, pituitary adenoma, glioma, acoustic schwannoma, retina sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colon cancer, rectal

cancer, hepatoma, pancreatic endocrine tumor,

cholangiocarcinoma, gallbladder cancer, penile cancer,

ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, cancer of uterine body, uterus sarcoma, trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin' s disease, myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, chronic myeloproliferative disorder, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,

unknown primary cancer) ) .

The medicament of the present invention may be used as an agent for the prophylaxis or treatment of, preferably,

autoimmune disease, inflammatory disease, osteoarticular

degenerative disease or neoplastic disease, particularly

preferably, psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus.

As. used herein, the "prophylaxis" of the above-mentioned diseases means, for example, administration of a medicament containing the compound of the present invention to patients before onset of a disease but having a high _.risk of the onset due to some factor associated with the disease or patients who developed the disease but without subjective symptoms, or administration of a medicament containing the compound of the present invention to patients having a risk of recurrence of disease after treatment of the disease.

[0220]

In particular, the compound of the present invention may be useful for the prophylaxis or treatment of TLR7, TLR9, TLR- 7/8, TLR-7/9 or TLR-7/8/9-related diseases such as autoimmune diseases, inflammatory diseases and the like, in particular, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease and the like.

[0221]

Since the compound of the present invention may be superior in metabolic stability, it may be expected to have an excellent therapeutic effect on the above-mentioned diseases even in a low dose.

Since the compound of the present invention may have low toxicity, a pharmaceutical composition containing the compound of the present invention (hereinafter to be referred to as the "medicament of the present invention") is obtained as, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet and the like) , pill, powder, granule, capsule (including soft capsule, microcapsule) , troche, syrup, liquid, emulsion, suspension, controlled-release preparation (e.g., immediate-release preparation, sustained-release preparation, sustained-release microcapsule), aerosol, films (e.g., orally disintegrable films, oral cavity mucosa patch film), injection (e.g., subcutaneous injection, intravenous injection,

intramuscular injection, intraperitoneal injection), drip infusion, transdermal absorption type preparation, ointment, lotion, adhesive preparation, suppository (e.g., rectal suppository, vaginal suppository) , pellet, nasal preparations, pulmonary preparation (inhalant), eye drop and the like by using the compound of the present invention alone or along with a pharmacologically acceptable carrier according to a method known per se as a production method of pharmaceutical preparations (e.g., the method described in the Japanese

Pharmacopoeia etc.). It may be safely administered orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation,

intracerebral, rectal, vaginal, intraperitoneal, intratumor, tumor proximal administration, administration to a lesion and the like) .

[0222]

Examples of the pharmacologically acceptable carrier include various organic or inorganic carrier substances

conventionally used as preparation materials, which are added as excipient, lubricant, binder or disintegrant for solid preparations; as solvent, solubilizing agent, suspending agent, isotonicity agent, buffer or soothing agent for liquid

preparation, and the like. Where necessary, preparation

additives such as preservative, antioxidant, colorant,

sweetener, absorbent, humectant and the like can also be

appropriately used in suitable amounts.

[0223]

Examples of the excipient include lactose, sucrose, D- mannitol, D-sorbitol, starch, pregelatinized starch,

cornstarch, dextrin, microcrystalline cellulose, low- substituted hydroxypropyl cellulose, sodium

carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

[0224]

Examples of the binder include pregelatinized starch, microcrystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose,

hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and the like.

[0225]

Examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and the like.

[0226]

Examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

[0227]

Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl

benzoate, ethano.l, tris (hydroxymethyl) aminomethane,

cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

[0228]

Examples of the suspending agent include surfactants such as stearyltriethanolamine , sodium lauryl sulfate,

laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; and hydrophilic polymers such as polyvinyl alcohol,

polyvinylpyrrolidone, sodium carboxymethylcellulose,

methylcellulose, hydroxymethyl cellulose, hydroxyethyl

cellulose, hydroxypropyl cellulose, polysorbate,

polyoxyethylene hydrogenated castor oil and the like.

[0229]

Examples of the isotonicity agent include glucose, D- sorbitol, sodium chloride, glycerol, D-mannitol and the like.

Examples of the buffer include buffers such as phosphates, acetates, carbonates, citrates and the like, and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol,

dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include sulfites, ascorbic acid, -tocopherols and the like.

[0230] Examples of the colorant include water-soluble edible tar pigments (e.g., Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2), water insoluble lake pigments (e.g., aluminum salts of the above-mentioned water-soluble edible tar pigment), natural pigments (e.g., beta-carotene, chlorophyll, red iron oxide) and the like.

Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate , aspartame, stevia and the like.

[0231]

While the content of the compound of the present

invention in the medicament of the present invention varies depending on the dosage form, dose of the compound of the present invention, and the like, it is, for example, about 0.1 to 100 wt%, preferably about 0.1 to 95 wt%.

[0232]

While the dose of the compound of the present invention varies depending on the subject of administration,

administration route, target disease, symptom and the like, for example, for oral administration to a systemic lupus erythematosus patient (adult, about 60 kg weight) , it is generally about 0.1 - about 20 mg/kg body weight, preferably about 0.2 - about 10 mg/kg body weight, more preferably about 0.5 - about 10 mg/kg body weight, which is desirably

administered once to several times (e.g., once to 3 times) a day depending on the symptom.

[0233]

The compound of the present invention may be administered as a single active substance, or may be administered in

combination with other medicaments such as other drugs used in the treatment of TLR7, TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9- related diseases such as autoimmune diseases, inflammatory diseases and the like, in particular, systemic lupus

erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease and the like

(hereinafter to be abbreviated as concomitant drug) . Examples of the concomitant drug include

(1) non-steroidal antiinflammatory drugs (NSAIDs)

(1) Classical NSAIDs

alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ^' ethenzamide, sulpyrine, antipyrine, migrenin, aspirin,

mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,

allopurinol, sodium aurothiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like.

(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX- 2 selective inhibitor and the like)

salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and the like.

(iii) nitric oxide-releasing NSAIDs

(2) disease-modifying anti-rheumatic drugs (DMARDs)

(i) Gold preparation

auranofin and the like.

(ii) penicillamine

D-penicillamine and the like.

(iii) aminosalicylic acid preparation

sulfasalazine, mesalazine, olsalazine, balsalazide and the like.

(iv) antimalarial drug

chloroquine and the like.

(v) pyrimidine synthesis inhibitor

leflunomide and the like. (vi) prograf

(3) anti-cytokine drug

(I) protein drug

(i) TNF inhibitor

etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-a, soluble TNF-a receptor, TNF-a binding protein, anti-TNF-a antibody and the^' like.

(ii) interleukin-1 inhibitor

anakinra (interleukin-1 receptor antagonist) , soluble interleukin-1 receptor and the like.

(iii) interleukin-6 inhibitor

tocilizumab (anti-interleukin-6 receptor antibody) , anti- interleukin-6 antibody and the like.

(iv) interleukin-10 drug

interleukin-10 and the like.

(v) interleukin-12/23 inhibitor

ustekinumab, briakinumab (anti-interleukin-12/23

antibody) and the like.

(vi) B cell activation inhibitor

rituxan, benlysta and the like.

(vii) co-stimulatory molecules-related protein preparation

abatacept and the like.

(II) non-protein drug

(i) MAPK inhibitor

BMS-582949 and the like.

(ii) gene modulator

inhibitor of molecule involved in signal transduction, such as NF-K, NF-κΒ, IKK-1, IKK-2, AP-1 and the like, and the like.

(iii) cytokine production inhibitor

iguratimod, tetomilast and the like.

(iv) TNF-a converting enzyme inhibitor

(v) interleukin-ΐβ converting enzyme inhibitor

VX-765 and the like.

(vi) interleukin-6 antagonist HMPL-004 and the like,

(vii) interleukin-8 inhibitor

IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.

(viii) chemokine antagonist

CCR9 antagonist (CCX-282, CCX-025), MCP-1 antagonist and the like.

(ix) interleukin-2 receptor antagonist

denileukin, diftitox and the like.

(x) therapeutic vaccines

TNF-cc vaccine and the like.

(xi) gene therapy drug

gene therapy drugs aiming at promoting the expression of gene having an anti-inflammatory action such as interleukin- , interleukin-10, soluble interleukin-1 receptor, soluble TNF-a receptor and the like.

(xii) antisense compound

ISIS-104838 and the like.

(4) integrin inhibitor

natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.

(5) immunomodulator (immunosuppressant)

methotrexate, cyclophosphamide, MX- 68, atiprimod

dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor,' interleukin, interferon,

intravenous immunoglobulin, anti-thymocyte globulin, RSLV-132 and the like.

(6) proteasome inhibitor

bortezomib, MLN9708 (ixazomib citrate), MLN2238

(ixazomib) , delanzomib and the like.

(7) steroid

. dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone,

beclomethasone dipropionate, estriol and the like.

(8) angiotensin converting enzyme inhibitor

enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.

(9) angiotensin II receptor antagonist

candesartan, candesartan cilexetil, azilsartan,

azilsartan medoxomil, valsartan, irbesartan, olmesartan, eprosartan and the like.

(10) diuretic drug

hydrochlorothiazide, spironolactone, furosemide,

indapamide, bendrofluazide, cyclopenthiazide and the like.

(11) cardiotonic drug

digoxin, dobutamine and the like.

(12) β receptor antagonist

carvedilol, metoprolol, atenolol and the like.

(13) Ca sensitizer

MCC-135 and the like.

(14) Ca channel antagonist

nifedipine, diltiazem, verapamil and the like.

(15) anti-platelet drug, anticoagulator

heparin, aspirin, warfarin and the like.

(16) HMG-CoA reductase inhibitor

atorvastatin, simvastatin and the like.

(17) contraceptive

(i) sex hormone . or derivatives thereof

gestagen or a derivative thereof (e.g., progesterone, 17cc-hydroxy progesterone, medroxyprogesterone,

medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethynodrel, levonorgestrel , norgestrel, ethynodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel , drospirenone, dienogest, trimegestone, nestorone, chlormadinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EM - 310525) or a combination agent of a gestagen or a derivative thereof and an estrogen or a derivative thereof (estradiol, estradiol benzoate, estradiol cypionate, estradiol

dipropionate, estradiol enanthate, estradiol hexahydrobenzoate estradiol phenylpropionate, estradiol undecanoate, estradiol , valerate, estrone, ethinylestradiol, mestranol) and the like.

(ii) antiestrogen

ormeloxifene, mifepristone, Org-33628 and the like.

(iii) spermatocide

ucarcide and the like.

(18) others

(i) T cell inhibitors

(ii) inosine monophosphate dehydrogenase (I PDH) inhibitor

mycophenolate mofetil and the like.

(iii) adhesion molecule inhibitor

ISIS-2302, selectin inhibitor, ELAM-l, VCAM-1, ICAM-1 and the like.

(iv) thalidomide

(v) cathepsin inhibitor

(vi) matrix metalloprotease (MMPs) inhibitor

V-85546 and the^' like.

(vii) glucose-6-phosphate dehydrogenase inhibitor

(viii) dihydroorotate dehydrogenase (DHODH) inhibitor

(ix) phosphodiesterase IV (PDE IV) inhibitor

roflumilast, CG-1088 and the like.

(x) phospholipase A₂ inhibitor

(xi) iNOS inhibitor

VAS-203 and the like.

(xii) microtubule stimulating drug

paclitaxel and the like.

(xiii) microtubule inhibitor

reumacon and the like.

(xiv) MHC class II antagonist

(xv) prostacyclin agonist

iloprost. and the like. (xvi) CD4 antagonist

zanolimumab and the like.

(xvii) CD23 antagonist

(xviii) LTB4 receptor antagonist

DW-1305 and the like.

(xix) 5-lipoxygenase inhibitor

zileuton and the like.

(xx) cholinesterase inhibitor

galanthamine and the like.

(xxi) tyrosine kinase inhibitor

Tyk2 inhibitor (the compounds described in WO

2010/142752) and the like.

(xxii) cathepsin B inhibitor

(xxiii) adenosine deaminase inhibitor

pentostatin and the like.

(xxiv) osteogenesis stimulator

(xxv) dipeptidylpeptidase inhibitor

(xxvi) collagen agonist

(xxvii) capsaicin cream

(xxviii) hyaluronic acid derivative

synvisc (hylan G-F 20), orthovisc and the like.

(xxix) glucosamine sulfate

(xxx) amiprilose

(xxxi) CD-20 inhibitor

rituximab, ibritumomab, tositumomab, ofatumumab and the like.

(xxxii) BAFF inhibitor

belimumab, tabalumab, atacicept, A-623 and the like.

(xxxiii) CD52 inhibitor

alemtuzumab and the like.

(xxxiv) IL-17 inhibitor

secukinumab (AIN-457), LY-2439821, A G827 and the like. Other concomitant drugs besides the above-mentioned include, for example, antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic, antitussive and expectorant drug, sedative, anesthetic, antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug, anticoagulant, tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, muscle relaxant, anticonvulsant, antidepressant, antiallergic drug, cardiac stimulants, therapeutic drug for arrhythmia,

vasodilator, vasoconstrictor, hypotensive diuretic,

therapeutic drug for diabetes, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for

pollakisuria/anischuria, antipruritic agent, therapeutic agent for atopic dermatitis, therapeutic agent for allergic rhinitis, hypertensor, endotoxin-antagonist or -antibody, signal

transduction inhibitor, inhibitor of inflammatory mediator activity, antibody to inhibit inflammatory mediator activity, inhibitor of anti-inflammatory mediator activity, antibody to inhibit anti-inflammatory mediator activity and the like.

Specific examples thereof include the following.

(1) Antibacterial agent

(i) sulfa drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.

(ii) quinolone antibacterial agent

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

(iii) antiphthisic

isoniazid, ethambutol (ethambutol hydrochloride) , p- aminosalicylic acid (calcium p-aminosalicylate ) , pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.

(iv) antiacidfast bacterium drug

diaphenylsulfone, rifampicin and the like.

(v) antiviral drug

idoxuridine, acyclovir, vidarabine, gancyclovir and the like.

(νί^') anti-HIV agent

zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.

(vii) antispirochetele

(viii) antibiotic

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline,

oxytetracycline, rolitetracycline , doxycycline, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, cephalexin, ■ ^" cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt thereof, griseofulvin,

lankacidin-group [Journal of Antibiotics (J. Antibiotics), 38, 877-885(1985)], azole compounds [2- [ (1R, 2R) -2- (2, 4- difluorophenyl) -2-hydroxy-l-methyl-3- (lH-1, 2, 4-triazol-l- yl) propyl] -4-[4-(2,2,3, 3-tetrafluoropropoxy)^■phenyl] -3 (2H, 4H) - 1, 2, 4-triazolone, fluconazole, itraconazole and the like] and the like.

(2) antifungal agent

(i) polyethylene antibiotic (e.g., amphotericin B, nystatin, trichomycin, etc.)

(ii) griseofulvin, pyrrolnitrin and the like.

(iii) cytosine metabolism antagonist (e.g., flucytosine)

(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole and croconazole)

(v) triazole derivative (e.g. fluconazole and itraconazole)

(vi) thiocarbamic acid derivative (e.g. trinaphthol) , and the like. (3) antiprotozoal agent

metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.

(4) antitussive and expectorant drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol

hydrochloride, methylephedrine hydrochloride, alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol , morphine hydrochloride, dextromethorfan hydrobromide, oxycodone

hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine and the like.

(5) sedative

chlorpromazine hydrochloride, atropine sulfate,

phenobarbital, barbital, amobarbital, pentobarbital,

thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam,

bromovalerylurea , chloral hydrate, triclofos sodium and the like.

(6) anesthetic

(6-1) local anesthetic

cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine

hydrochloride, ethyl aminobenzoate, oxethazaine and the like. (6-2) general anesthetic

(i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide, isoflurane, enflurane, etc.)

(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital, etc.) and the like.

(7) antiulcer drug histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.

(8) antiarrhythmic agent

(i) Na channel blocker (e.g., quinidine, procainamide,, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin)

(ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride) . (iii) K channel blocker (e.g., amiodarone)

(iv) Ca channel blocker (e.g., verapamil, diltiazem) and the like.

(9) hypotensive diuretic drug

hexamethonium bromide, clonidine hydrochloride,

hydrochlorothiazide, trichlormethiazide, furosemide,

ethacrynic acid, bumetanide, mefruside, azosemide,

spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminophylline and the like.

(10) anticoagulant

heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase and the like.

(11) tranquilizer

diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.

(12) antipsychotic

chlorpromazine hydrochloride, prochlorperazine,

trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine · maleate, levomepromazine maleate, promethazine hydrochloride,

haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) antitumor drug

6-0- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin., adriamycin, neocarzinostatin, cytosine arabinoside,

fluorouracil , tetrahydrofuryl-5-fluorouracil , picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride,

bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,

testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like.

(14) antihypolipidemic drug

clofibrate, ethyl 2-chloro-3- [ 4- ( 2-methyl-2- phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull, 38, 2792- 2796 ^' (1990) ] , pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.

(15) muscle relaxant

pridinol, tubocurarine, pancuronium, tolperisone

hydrochloride, chlorphenesin carbamate, baclofen,

chlormezanone, mephenesin, chlorzoxazone, eperisone,

tizanidine and the like.

(16) anticonvulsant

phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam and the like. (17) antidepressant

imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like.

(18) antiallergic drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate, tranilast, repirinast, amlexanox,

ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.

(19) cardiac

trans— π-oxocamphor , terephyllol, aminophylline,

etilefrine, dopamine, dobutamine, denopamine, bencirin, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(20) vasodilator

oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.

(21) vasoconstrictor

dopamine, dobutamine denopamine and the like.

(22) hypotensive diuretic

Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.

(23) antidiabetic drug

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone , glucagon, glymidine, glipizide, phenformin, buformin, metformin and the like.

(24) antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(25) liposoluble vitamins (i) vitamin A: vitamin Ai, vitamin A₂ and retinol palmitate

(ii) vitamin D: vitamin Di, D₂, D_3/ D₄ and D₅

(iii) vitamin E: a-tocopherol , β-tocopherol , γ-tocopherol , δ- tocopherol, dl- -tocopherol nicotinate

(iv) vitamin K: vitamin Κχ, K₂, K₃ and K₄

(v) folic acid (vitamin M) and the like.

(26) vitamin derivative

various derivatives of vitamins, for example, vitamin D₃ derivatives such^' as 5 , 6-trans-cholecalciferol, 2,5- hydroxycholecalciferol, 1-a-hydroxycholecalciferol. and the like, vitamin D₂ derivatives such as 5 , 6-trans-ergocalciferol and the like, and the like.

(27) antiasthmatic

isoprenaline hydrochloride, salbutamol sulfate,

procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate , tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate and the- like.

(28) therapeutic agent for pollakisuria/anischuria

flavoxate hydrochloride and the like.

(29) therapeutic agent for atopic dermatitis

sodium cromoglicate and the like.

[0234]

(30) therapeutic agent for allergic rhinitis

sodium cromoglicate-, chlorpheniramine maleate,

alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine and the like.

(31) hypertensive drug^'

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(32) Others

hydroxycam, ^'"diacerein, megestrol acetate, nicergoline, prostaglandins and the like.

[0235]

The dosage form of concomitant drugs 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 dosage forms are as follows :

(1) Administration of a single formula obtained 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 kinds of formulas obtained by independent formulations of .the compound of the present invention and a concomitant drug,

(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) 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 (e.g., administration in the order of the compound of the present invention and then a concomitant drug,- or administration in the reversed order).

These forms of administration are summarized below and abbreviated as a combination drug of the present invention.

[0236]

When administering the combination drug of the present invention, the concomitant drug and the compound of the

present invention can be administered simultaneously.

Alternatively, the compound of the present invention can be administered after a concomitant drug is administered, or a concomitant drug can be administered after the compound of the present invention is 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 the concomitant drug or a

pharmaceutical composition thereof is administered first, the compound of the present invention or a pharmaceutical

composition thereof can be administered within 1 min to 3 days, preferably within 10 min to 1 day and more preferably within 15 min to 1 hour after the concomitant drug or a

pharmaceutical composition thereof is administered. When the compound of the present invention or a pharmaceutical

composition thereof is administered first, the concomitant drug or a pharmaceutical composition thereof can be

administered within 1 min to 1 day, preferably within 10 min to 6 hours and more preferably within 15 min to 1 hour after the compound of the present invention or a pharmaceutical composition thereof is administered.

[0237]

If there are no problems with side effects of the

concomitant drugs, any dosages can be set. A dosage as a concomitant drug varies depending on dosages, administration subjects, administration routes, target diseases, symptoms, etc. For example, in the case of oral administration in

patients with systemic lupus erythematosus (adults, body

weight of approximately 60 kg) , a dosage range is generally about 0.1 to 20 mg/kg body weight, preferably from about 0.2 to 10 mg/kg body weight and more preferably from about 0.5 to 10 mg/kg body weight. It is preferable that this dosage is administered once daily to several times daily (e.g., once to 3 times) .

If the compound of the present invention is used in 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.

[0238]

The combination drug of the present invention exhibits low toxicity. For example, the compound of the present

invention or (and) the concomitant drug can be combined with a pharmaceutically acceptable carrier according to the known method to prepare a pharmaceutical composition such as tablets (including sugar-coated tablets and film-coated 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, venous routes etc.).

[0239]

The pharmaceutically acceptable carriers that can be used for manufacturing the combination drug of the present

invention can be the same as those used in the medicament of the present invention as mentioned above.

[0240]

A mixing ratio between the compound of the present invention and the concomitant drug in the combination drug of the present invention can be^' selected appropriately based on. the administration subjects, administration routes, diseases and the like.

The concomitant drug in the combination drug of the present invention 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 the 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 may be used in an amount ranging from about 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.

[0241]

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

[0242] . .

The content of the concomitant drug in the combination drug of the present invention varies with the form of

formulations. Generally it is present in a range from about 0.01 to 99.9 wt%, preferably from about 0.1 to about 50 wt% and more preferably from about 0.5 to about 20 wt% relative to the entire formula.

[0243]

The content of an additive such as carriers in the

combination drug of the present invention varies with the form of formulations. Generally it is present in a range from about 1 to 99.99 wt% and preferably from about 10 to about 90 wt% relative to the entire formula.

[024.4]

When the compound of the present invention and a

concomitant drug are formulated independently, the same

contents can be applied.

[0245]

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

[0246]

The present invention is explained in detail in the following by referring to Examples, Formulation Examples and Experimental Examples and which are merely exemplified and not to be construed as limitative, and the invention may be changed within the scope of the present invention. In the following Examples, the "room temperature" generally means about 10°C to about 35°C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise

specified. % means wt%, unless otherwise specified.

In silica gel column chromatography, NH means use of aminopropylsilane-bonded silica gel. In HPLC (high performance liquid chromatography) , C18 means use of octadecyl-bound silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified.

¹HNMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR. Peaks with very mild protons such as a hydroxyl group, an amino group and the like are not described.

In the following Reference Examples ( Synthesis of

Intermediates) and Examples, mass spectrum (MS), nuclear magnetic resonance spectrum (NMR) and melting point were measured by the following apparatus.

MS (mass spectrum) was measured by LC/MS (liquid

chromatograph mass spectrometer) . As the ionization method, API (Atmospheric Pressure Ionization, atmospheric pressure chemical ionization) method or ESI (Electron Spray Ionization) method was used. The data indicate measured value (found) found. Generally, a molecular ion peak is observed. In the case of a compound having an amino group (-NH₂) , a peak after elimination of NH₃ may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.

[0247] Synthesis of Intermediates:

Intermediate l-I: l-methyl-4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) phenyl] piperazine

[0248]

Intermediate 1-1

[0249]

Intermediate l-I was prepared from 1, 4-dibromobenzene in two steps according to the procedures described in WO

2008/088881.

[0250]

Intermediates l-II to 1-V as shown in Table 2 were prepared according to similar sequence of procedures as used for the preparation of Intermediate l-I.

[0251]

Table 2 :

[0252]

Intermediate 1-VI: tert-butyl 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) phenyl] -3, 6-dihydro-2H-pyridine-l- carboxylate

[0253]

[0254]

Step I: tert-butyl 4- (4-bromophenyl) -3, 6-dihydro-2H-pyridine- 1-carboxylate (1-2)

A mixture of l-bromo-4-iodobenzene 1-1 (6 g, 212 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl ) - 3, 6-dihydro-2H-pyridine-l-carboxylate (4.62 g, 149.4 mmol) and K₂C0₃ (8.76 g, 635.4 mmol) in a 4:1 mixture of dioxane/water (40 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane complex (0.345 g, 0.42 mmol), and the reaction mixture was again degassed for additional 15 minutes. After stirring at 100°C for 24 hours, the volatiles were removed by evaporation, and the obtained crude reaction mixture was diluted with water (100 mL) , followed by extraction with ethyl acetate (75 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂S0₄, and

concentrated under reduced pressure, followed by purification on silica gel column chromatography (100-200 mesh) using 10% EtOAc in hexanes to give the desired product 1-2 as a yellow syrup (3.8 g, 53%); LCMS : m/z 284.0 [M⁺-^tBu+2].

l-Bromo-4-iodobenzene 1-1 may be commercially available, or can also be produced according to a method known per se or a method analogous thereto.

[0255]

Step II: tert-butyl 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) phenyl] -3, 6-dihydro-2H-pyridine-l- carboxylate (Intermediate 1-VI)

A mixture of 1-2 (3.8 g, 112 mmol),

bis (pinacolato) diboron (3.41 g, 134 mmol) and KOAc (3.30 g, 336 mmol) in DMSO (50 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.182 g, 0.22 mmol), and the reaction mixture was again degassed for additional 15 minutes. After stirring at 100°C for 24 hours, the volatiles were removed by evaporation, and the obtained crude reaction mixture was diluted with water (50 mL) , followed by extraction with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na2S04, and concentrated under reduced pressure, followed by purification on silica gel column chromatography (100-200 mesh) using 10% EtOAc in hexanes to give the desired product Intermediate 1-VI as a yellow solid (3.5 g, 81%); LCMS : m/z 330.1 [M⁺^Bu+l] .

[0256]

Intermediate 1-VII : 2- [ 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl ) phenyl] -1-piperidyl] ethanol

[0257]

1 -4 Intermediate 1 -VII

[0258]

Step I: tert-butyl 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl ) phenyl] piperidine-l-carboxylate (1-3)

To a stirred solution of Intermediate 1-VI (1.4 g, 3.63 mmol) in anhydrous ethyl acetate (60 mL) was added 10% Pd/C (0.140 g, 10% W/W) and the reaction mixture was stirred under hydrogen atmosphere for 12 hours at room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the desired product 1-3 as colorless thick oil (1.32 g, 95%); LCMS: 332.0 [M⁺-^tBu+l] .

1HNMR (400 MHz, CDC1₃) : δ 1.33 (s, 12H) , 1.48 (s, 9H) , 1.61- 1.65 (m, 2H) , 1.68-1.82 (m, 2H) , 2.62-2.68 (m,- 1H) , 2.76-2.82 (m, 2H) , 4.23 (br.s, 2H) , 7.21 (d, j = 7.6 Hz, 2H) , 7.76 (d, J = 7.6 Hz, 2H)

[0259]

Step II: 4- [ 4- ( , 4 , 5, 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl) phenyl] piperidine hydrochloride salt (1-4 )

To a stirred solution of 1-3 (1.3 g, 3.35 mmol) in ethyl acetate (30 mL) was added 5N HC1 (10 mL) at room temperature and stirring was continued for .16 hours till white precipitate was obtained. The white precipitate . was collected by

filtration, washed with dry ethyl acetate and dried under vacuum to give the desired product 1-4 as a white solid [1.05 g, 97%]; LC S : 288.2 [M⁺+l] .

[0260]

Step III: 2- [ 4- [ 4- ( 4 , 4 , 5, 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl) phenyl] -1-piperidyl] ethanol (Intermediate 1-VII)

To a stirred suspension of 1-4 (0.75 g, 2.33 mmol) and potassium carbonate (0.80 g, 5.82 mmol) in anhydrous

acetonitrile (18 mL) was added 2-bromoethanol (0.43 mL, 5.823 mmol) at room temperature. The resulting reaction mixture was then heated at 60°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL) and water (20 mL) . The ethyl acetate layer was separated and washed with brine (20 mL) and dried over anhydrous Na₂S0₄. The solvent was

evaporated under reduced pressure and the crude product so obtained was purified by silica gel column chromatography (60- 120 mesh) using 5% MeOH in dichloromethane as eluent to give the desired product Intermediate 1-VII as an off-white solid (0.64 g, 83%); LCMS: 332.0 [M⁺+l] .

¹HNMR (400 MHz, CDC1₃) : δ 1.33 (s, 12H) , 1.95 (d, J = 13.2 Hz, 2H) , 2.15-2.20 (m, 2H) , 2.52-2.58 (m, 2H) , 2.88 (t, J = 5.2 Hz, 2H) , 3.40 (d, J = 11.4 Hz, 2H) , 3.62-3.64 (m, 1H) , 3.76-3.79 (m, 1H) , 3.85 (t, J = 5.2 Hz, 2H) , 7.25 (d, J = 7.2 Hz, 2H) , 7.77 (d, J = 7.6 Hz, 2H)

[0261]

Intermediate 1-VIII:. 2- [ 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl ) phenyl] piperazin-l-yl] ethanol

[0262]

Intermediate 1 -VIII

[0263]

Step I: 1- [4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) phenyl] piperazine hydrochloride salt (1-5)

To a stirred solution of Intermediate l-III (0.8 g, 2.07 mmol) in ethyl acetate (25 mL) was added 5N HC1 (8 mL) at room temperature. The reaction mixture so obtained was stirred for 16 hours. The solid separated during the reaction was

collected by filtration, washed with ethyl acetate and dried under vacuum to give the desired product 1-5 as a white solid (0.58 g, 86%) .

[0264]

Step^■ II : 2- [4- [4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl) phenyl] piperazin-l-yl] ethanol (Intermediate 1-VIII)

To a stirred suspension of 1-5- (0.55 g, 1.70 mmol) and potassium carbonate (0.587g, 4.25 mmol) in anhydrous

acetonitrile (20 mL) was added 2-bromoethanol (0.31 mL, 4.25 mmol) at room temperature, and the mixture was heated at 60°C for 16 hours. The reaction mixture was cooled to room

temperature and diluted with ethyl acetate (25 mL) and water (20 mL) . The layers were separated, and the organic layer was washed with brine (20 mL) and dried over anhydrous Na₂S0_^4. The solvent was evaporated under reduced pressure to give the desired crude product Intermediate 1-VIII as a brown solid that was used in the next step without further purification (0.40 g, 72% crude); LCMS : 333.0 [M⁺+l] .

¹HNMR (400 MHz, CDCI₃) : δ 1.32 (s, 12H) , 3.17 (t, J = 4.8 Hz, 2H), 3.21 (t, J = 5.2 Hz, 4H) , 3.28 (t, J = 4.8 Hz, 2H) , 3.66 (t, J = 5.2 Hz, 4H) , 6.93 (d, J = 8.8 Hz, 2H) , 7.70 (d, J = 7.6 Hz, 2H)

[0265]

Intermediate 1-IX: 2- [ 4- [ 3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) phenyl] piperazin-l-yl] ethanol

[0266]

Intermediate 1 -V 1 -6 Intermediate 1 -IX

[0267]

Step I: tert-butyl 4- [3- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) phenyl] piperazine-l-carboxylate (1-6)

1-6 was prepared from Intermediate 1-V according to similar procedure as used for the preparation of 1-5 from

Intermediate l-III; LCMS : m/z 289.2 [M⁺+l].

[0268]

Step II: 2- [ 4- [3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3, 2-dioxaborolan-2- yl) phenyl] piperazin-l-yl] ethanol (Intermediate 1-IX)

Intermediate 1-IX was prepared from 1-6 according to similar procedure as used for the preparation of Intermediate 1-VIII from 1-5; LCMS: m/z 333.3 [M⁺+l] .

[0269]

Intermediate 1-X: 2- [4- [3- (4, 4 , 5, 5-tetramethyl-l , 3 2- dioxaborolan-2-yl) phenyl] -3, 6-dihydro-2H-pyridin-l-yl ] ethanol [0270]

¾>' ^stel>¾

1--7C^N-^B∞ Intermediate 1-X

[0271]

Step I: tert-butyl 4- ( 3-bromophenyl ) -3 , 6-dihydro-2H-pyridine- 1-carboxylate (1-7)

A mixture of l-bromo-3-iodobenzene (5 g, 17.7 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl ) -

3, 6-dihydro-2H-pyridine-l-carboxylate (5.4 g, 17.7 mmol) and K₂C0₃ (5.1 g, 37.17 mmol) in a mixture of dioxane/water (4:1,

45 mL) was degassed in a stream of argon for 15 minutes. To the mixture, was added 1,1- ^'

bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (1.02 g, 0.888 mmol), and the reaction mixture was again degassed for additional 15 minutes. After stirring at 80°C for 3 hours, the crude reaction mixture was diluted with ethyl acetate (30 mL) and filtered through celite pad. The filtrate was concentrated under reduced pressure and the crude product so obtained was purified by silica gel column chromatography (60-120 mesh) using 2% EtOAc in hexanes as eluent to give the desired product 1-7 as a yellow syrup (2.0 g, 39%); LCMS : m/z 339.1 [M⁺+l] .

[0272]

Step II: 2- [ 4- [ 3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl) phenyl] -3, 6-dihydro-2H-pyridin-l-yl] ethanol (Intermediate 1-X)

A mixture of 1-7 (2.0 g, 5.917 mmol),

bis (pinacolato) diboron (1.9 g., 7.67 mmol) and KOAc (0.9 g, 8.8 mmol) in dioxane (20 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.48 g, 0.59 mmol), and the reaction mixture was again degassed for additional 15 minutes. After stirring at 80°C for 14 hours, the volatiles were removed by evaporation, and the obtained crude reaction mixture was diluted with water (20 mL) , and extracted with ethyl acetate (15 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography (60-120 mesh) using 5% EtOAc in hexanes as eluent to give the desired product Intermediate 1-X as a yellow solid (2.3 g, 95%); LCMS : m/z 330.2 [M-^Bu+l] .

[0273]

Intermediate 1-XI: 2- [ 4- [ 3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) phenyl] -3, 6-dihydro-2H-pyridin-l-yl ] ethanol [0274]

Intermediate 1 -X 1-8 Intermediate 1 -XI

[0275]

Step I: 4- [ 3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl ) phenyl J-1,2, 3, 6-tetrahydropyridine (1-8 )

To a solution of Intermediate 1-X (.0.5 g, 1.30 mmol) in dioxane (4 mL) was added 4.0M dioxane in HC1 (1.5 mL) at 0°C.

After stirring for 10 hours at room temperature, the volatiles were removed under reduced pressure and the desired crude product 1-8 obtained as a pale yellow solid was used in next step as such without any further purification (0.450 g, 85%);

LCMS: m/z 286.2 [M⁺+l] .

[0276]

Step II: 2- [ 4- [ 3- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2-dioxaborolan-2- _. yl) phenyl] -3, 6-dihydro-2H-pyridin-l-yl ] ethanol (Intermediate 1-XI)

To a solution_. of 1-8 (0.4 g, 1.24 mmol) in dioxane (8 mL) were added K2CO3 (0.5 g, 3.72 mmol) and 2-bromoethanol (2.5 mL, 3.11 mmol) at 60°C. The reaction mixture was heated for 6 hours and then the volatiles were removed under reduced

pressure. The obtained crude reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by s gel column chromatography (60-120 mesh) using 2% methanol dichloromethane to give the desired product Intermedia-be 1 as a white solid (0.4 g, 74%); LC S : m/z 330.3 [M⁺+l].

[0277]

Intermediate 1-XII : tert-butyl 4- [2-methyl-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl ) phenyl] piperazine-1- carboxylate

[0278

1-9 1 -10 1 -11

, Intermediate 1 -XII 1'^1Z

[0279]

Step I: tert-butyl 4- (2-methyl-4-nitrophenyl ) piperazine-1- carboxylate (1-10)

1-10 was prepared from 1-9 according to the procedure described in WO 2001/068643.

[0280]

Step II: tert-butyl 4- ( 4-amino-2-methylphenyl ) piperazine-1- carboxylate (1-11)

1-11 was prepared from 1-10 according to the procedure described in WO 2001/068643.

[0281]

Step III: tert-butyl 4- ( 4-bromo-2-methylphenyl ) piperazine-1- carboxylate (1-12)

A solution of 1-11 (4.6 g, 15.80 mmol) in acetonitrile (80 mL) was treated with copper (II) bromide (1.76 g, 7.90 mmol) and heated at 60°C. To this reaction mixture was added dropwise isopentylnitrite (3.10 mL, 23.70 mmol), and the mixture was stirred for another 2 hours. The volatiles were removed by evaporation, and the obtained residue was diluted with water (50 mL) , followed by extraction with ethyl acetate (25 mL x 2) . The combined organic layers were washed with brine (25 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The obtained residue was purified by silica gel (60-120 mesh) column chromatography using 4% EtOAc in hexanes as eluent to give the desired product 1-12 (3.02 g, 54%) as a brown solid.

¹HNMR (400 MHz, CDC1₃) : δ 1.48 (s, 9H) , 2.27 ( s , 3H) , 2.80 (t, J = 4.8 Hz, 4H) , 3.55 (t, J = 4.8 Hz, 4H) , 6.84 ( d , J = 8.8 Hz, 1H) , 7.25 (dd, J = 8.4 Hz,. 2.8 Hz, 1H) , 7.30 (d, J = 2 Hz, 1H)

[0282]

Step IV: tert-butyl 4- [2-methyl-4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3, 2- dioxaborolan-2-yl) phenyl] piperazine-l-carboxylate

(Intermediate 1-XII)

A mixture of 1-12 (3.0 g, 8.47 mmol) ,

bis (pinacolato) diboron (2.58 g, 10.16 mmol) and KOAc (2.49 g, 25.41 mmol) in 1,4-dioxane (25 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium(II) dichloride

dichlor methane complex (0.345 g, 0.420 mmol), and the

reaction mixture was again degassed for additional 15 minutes. After stirring at 80°C for 16 hours, the reaction mixture was filtered through a celite pad and washed with EtOAc (50 mL) , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel (60-120 mesh) column chromatography. using 4% EtOAc in hexanes as eluent to give the desired product Intermediate 1-XII (3.10. g, 91%) as an off-white solid; LCMS : m/z 403 [M⁺+l].

^XHNMR (400 MHz , CDCI3) : δ 1.34- (s, 12H) , 1.50 (s, 9H) , 2.30 (s, 3H), 2.87 (t, J = 4.8 Hz, 4H) , 3.56 (t,- J = 4.8 Hz, 4H) , 6.96 (d, J = 8 Hz, 1H), 7.61 (s, 1H) , 7.64 (d, J = 3.6 Hz, 1H)

[0283]

Intermediates 1-XIII to 1-XVI as shown in Table 3 were prepared according to similar procedure as used for the

preparation of Intermediate 1-XII. [0284] Table 3:

methoxy-4- (4,4,5,5- Hz, 4H) , 3.57 (t, J = tetramethyl-1, 3, 2- 10.0 Hz 4H) , 3.82 (s, dioxaborolan-2- 3H), 6.37-6.40 (m, IH) , yl) phenyl] piperazine- 6.46 (dd, J = 2.0 Hz, J

1-carboxylate = 8.0 Hz, IH) , 7.60 (d,

J= 8 Hz, IH)

[0285]

Intermediate 1-XVII: tert-butyl 4- [ 3-fluoro-4- ( 4 , 4 , 5 , 5

tetramethyl-1, 3, 2-dioxaborolan-2-yl ) phenyl] piperazine- carboxylate

[0286]

Intermediate 1 -XVII

[0287]

Step I: tert-butyl 4- (4-bromo-3-fluorophenyl) piperazine-1- carboxylate (1-14)

A mixture of 1-13 (5.0 g, 16.6 mmol), 1-Boc-piperizine (1.2 g, 6.66 mmol), BINAP (0.610 g, 0.99 mmol) and Cs₂C0₃ (8.0 g, 24.9 mmol) in toluene (50 mL) was degassed in a stream of argon for 30 minutes. To the mixture was added tris

(dibenzylideneacetone) dipalladium ( 0 ) (0.30 g, 0.33 mmol), and the reaction mixture was again degassed for additional 15

: minutes. After stirring at 90°C for 18 hours, the volatiles were removed by evaporation, and the obtained residue was diluted with water (50 mL) , followed by extraction with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (150 mL) , dried over anhydrous Na₂S0₄ and

concentrated under reduced pressure. The . obtained residue was purified by silica gel column chromatography (60-120 mesh) using 10% EtOAc in hexanes to give the desired product 1-14 (1.5 g, 30%) as a yellow solid; LCMS : m/z 303 [M⁺-^tBu+l] , 305.0 [M⁺-^tBu+2]. [0288]

Step II: tert-butyl 4- [ 3-fluoro-4- ( , 4 , 5 , 5-tetramethyl-l , 3, 2- dioxaborolan-2-yl) phenyl] piperazine-l-carboxylate

(Intermediate 1-XVII)

A mixture of 1-14 (0.8 g, 2.21 mmol) ,

bis (pinacolato) diboron (0.723 g, 2.91 mmol) and KOAc (0.650 g, 6.62 mmol) in 1,4-dioxane (10 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride

dichloromethane complex (0.1 g, 0.013 mmol), and the reaction mixture was again degassed for additional 15 minutes. After, stirring at 90°C for 16 hours, the reaction mixture was

filtered through a celite pad and washed with EtOAc (50 mL) , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by Combiflash using 15% EtOAc in hexanes to give the desired product Intermediate 1-XVII (0.25 g, 26%) as an off-white solid; LCMS : m/z 407 [M⁺+l] .

1HNMR (400 MHz, CDC1₃) : δ 1.27 (s, 12H) , 1.41 (s, 9H) , 3.23 (t, J = 10.0 Hz, 4H) , 3.56 (t, J = 10.0 Hz , 4H) , 6.49 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H) , 6.62 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H) , 7.61 (t, J = 15.2 Hz, 1H)

[0289]

Intermediate 1-XVIII: tert-butyl 4- [ 2-carbamoyl-4- ( 4 , 4 , 5 , 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl ) phenyl] piperazine-l- carboxylate

[0290}

[0291] ■ ^■

Step I: tert-butyl 4- (4-bromo-2-cyanophenyl) piperazi_.ne-1- carboxylate (1-16)

A mixture of 1-15 (3.0 g, 14.99 mmol) , 1-Boc-piperizine (3.33 g, 17.99 mmol) and Cs₂C0₃ (9.68 g, 29.98 mmol) in DMSO (60 mL) was stirred at 120°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 mL x 3) . The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give the desired product 1-16 (2.5 g, 44%) as yellow solid which was used in the next step without purification; LCMS : m/z 312 [M⁺- ^fcBu+l].

[0292]

Step II: tert-butyl 4- (4-bromo-2-carbamoylphenyl) piperazine-1- carboxylate (1-17)

To a solution of 1-16 (2.5 g, 6.83 mmol) in DMSO (6 mL) were added aqueous 30% H₂0₂ (0.15 mL, 8.88 mmol) and K₂C0₃ at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into ice cold water (100 mL) and extracted with diethyl ether (100 mL x 3) . The organic layer was dried over anhydrous a₂S0 and concentrated under reduced pressure. The crude product so obtained was purified by silica gel

column chromatography (60-120 mesh) using 30% EtOAc in hexanes as eluent to give the desired product 1-17 (1.3 g, 50%) as a white solid; LCMS: m/z 384.0 [M⁺+l] .

[0293]

Step III: tert-butyl 4- [2-carbamoyl-4- ( 4 , 4 , 5 , 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl ) phenyl] piperazine-l-carboxylate

(Intermediate 1-XVIIl)

A mixture of 1-17 (1.3 g, 3.33 mmol),

bis (pinacolato) diboron (1.03 g, 4.01 mmol) and KOAc (0.99 g, 10.05 mmol) in 1,4-dioxane (20 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.138 g, 0.016 mmol) , and the reaction mixture was again degassed for additional 15 minutes After stirring at 90°C for 16 hours, the reaction mixture was filtered through a celite pad and washed with EtOAc (150 mL) . The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column

chromatography (60-120 mesh) using 20% EtOAc in hexanes as eluent to give the desired product Intermediate 1-XVIII (1.0 71%) as an off-white solid; LCMS : m/z 432.2 [M⁺+l] .

1HNMR (400 MHz , CDC1₃) : δ 1.27 (s, 12H) , 1.32 (s, 9H) , 3.00 (t J = 10_. Hz, 4H) , 3.61 (t, J = 10 Hz , 4H) , 5.73 (br.s, 1H) , 7.10 (d, J = 8.4 Hz, 1H) , 7.85 (dd, J = 10 Hz, J = 2 Hz, 1H) , 8.52 (d, J = 1.6 Ηζ,^'ΙΗ), 8.73 (br.s, 1H)

[0294]

Intermediate 1-XIX: tert-butyl 4- [ 3-chloro-4- ( 4 , 4 , 5 , 5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl ) phenyl] piperazine-1- carboxylate

0295]

[0296]

Step I: tert-butyl 4- ( 3-amino-4 -nitrophenyl ) piperazine-1- carboxylate (1-19)

A mixture of 1-18 (5.0 g, 32.02 mmol), 1-Boc-piperizine (8.93 g, 48.04 mmol) and Et₃N (14.4 mL, 102.49 mmol) in N- methylpyrrolidinone (NMP) (20 mL) was heated at 120°C for 12 hours. Another batch of 1-Boc-piperizine (8.93 g, 48.04 mmol) and Et₃N (14.4 ml, 102.49 mmol) was added thereto and heating was continued at 120°C for another 36 hours. The reaction mixture was poured into ice cold water, and the solid so obtained was collected by filtration and washed with water and dried under vacuum to give the desired product 1-19 (8.0 g,

77%) as a yellow solid.

[0297]

Step II: tert-butyl 4- (3-chloro-4-nitrophenyl) piperazine-1- carboxylate (1-20)

A solution of 1-19 (3.0 g, 9.31 mmol) in acetonitrile (60 mL) was treated with copper (II) chloride (0.624 g, 4.65 mmol) and heated at 60°C. To this reaction mixture was added

dropwise isopentylnitrite (1.90 mL, 13.97 mmol), and the mixture was stirred for another 2 hours. The volatiles were removed by evaporation, and the obtained residue was diluted with water (50 mL) , followed by extraction with ethyl acetate (25 mL x 2) . The combined organic layers were washed with brine (25 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The obtained residue was purified by combiflash using EtOAc in hexanes as eluent to give the

desired product 1-20 (1.36 g, 42%) as a yellow solid.

[0298]

Step III: tert-butyl 4- ( 4-amino-3-chlorophenyl ) piperazine-1- carboxylate (1-21)

To a solution of 1-20 (2.7 g, 7.91 mmol) in a mixture of ethanol/THF (1:1, 40 mL) were added Fe powder (2.21 g, 39.58 mmol), NH₄C1 (4.23 g, 79.17 mmol) and water (5 mL) . The resulting reaction mixture .was heated to reflux for 6 hours. The reaction mixture was cooled and filtered through a celite pad and washed with ethanol . The solvent was evaporated under reduced pressure and the crude product so obtained was

purified by Combiflash using EtOAc in hexanes as eluent to give the desired product 1-21 (1.8 g, 72%) as a brown solid; LCMS: m/z 312.1 [M⁺+l] .

[0299]

Step IV: tert-butyl 4- (4-bromo-3-chlorophenyl) piperazine-1- carboxylate (1-22)

A solution of 1-21 (1.8 g, 5.78 mmol) in acetonitrile (60 mL) was treated with copper (II) bromide (0.645 g, 2.89 mmol) and heated at 60°C. At this temperature, isopentylnitrite

(1.18 mL, 8.68 mmol) was added dropwise thereto and stirring was continued for another 2 hours. The volatiles were removed by evaporation, and the residue so obtained was diluted with water (50 mL) , followed by extraction with ethyl acetate (25 mL x 2) . The combined organic layers were washed with brine (25 mL) , dried over anhydrous Na₂S04, and concentrated under reduced pressure. The obtained residue was purified by

combiflash using EtOAc in hexanes as eluent to give the

' desired product 1-22 (1.022 g, 47%) as a brown solid.

[0300]

Step V: tert-butyl 4- [ 3-chloro-4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) phenyl] piperazine-l-carboxylate

(Intermediate 1-XIX)

A mixture of 1-22 (0.8 g, 2.13 mmol),

bis (pinacolato) diboron (0.593 g, 2.34 mmol) and KOAc (0.628 g, 6.39 mmol) in 1,4-dioxane (10 mL) was degassed in a stream of argon for 15 minutes. To this mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride

dichloromethane complex (0.104 g, 0.012 mmol), and again

degassed for additional ^' E5 minutes. After stirring at 90°C for 16 hours, the reaction mixture was filtered through a celite pad and washed with EtOAc (50 mL) . The filtrate was

concentrated under reduced pressure and the obtained residue was purified by Combiflash using EtOAc in hexanes as eluent to give the desired product Intermediate 1-XIX (0.28 g, 31%) as an off-white solid; LCMS : m/z 423.1 [M⁺+l] .

¹HNMR (400 MHz, CDC1₃) : δ 1.34 (s, 12H) , 1.47 (s, 9H) , 3.20 (t, J = 4.8 Hz 4H) , 3.55 (t, J = 5.6 Hz 4H) , 6.73 (dd, J = 8.4 Hz, 2.4 Hz, 1H) , 6.84 (d, J= 2.8 Hz, 1H) , 7.61 (d, J= 8.8 Hz, 1H)

[0301]

Intermediate 1-XX: tert-butyl 4- [ [4- (4 , 4, 5, 5-tetramethyl-

1,3, 2-dioxaborolan-2-yl) phenyl] methyl] piperazine-l-carboxylate

[0302]

1-24 Intermediate 1-XX

[0303]

Intermediate 1-XX was prepared from 1-23 according to the similar sequence of procedures described in WO 2013/157022.

[0304]

Intermediate 1-XXI: tert-butyl 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl ) phenoxy] piperidine-l-carboxylate

[

Intermediate 1-XXI

[0306]

Step I: tert-butyl 4- ( 4-bromophenoxy) piperidine-l-carboxylate (1-26)

To a stirred suspension of sodium hydride (5.96 g, 149.04 mmol) in 30 mL DMF was added tert-butyl 4-hydroxypiperidine-l- carboxylate (15 g, 74.52 mmol) and the mixture was stirred at 80°C for 2.5 hours. l-Bromo-4-fluorobenzene (1-25) was added to the reaction mixture and the mixture was again- stirred at 120°C for 12 hours. The reaction mixture was cooled to 0°C and then poured into ice (200 g) . The mixture was extracted with ethyl acetate (200 mL x 3) . The organic layer was washed with brine (200 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography (100-200 mesh) using 5% EtOAc in hexanes as eluent to give the desired

product 1-26 (17.02 g, 64%); LCMS : m/z 301.9 [M⁺-^tBu+2].

[0307] Step II: tert-butyl 4- [ 4- ( 4 , 4 , 5, 5-tetramethyl-l , 3, 2- dioxaborolan-2-yl) phenoxy] piperidine-l-carboxylate

(Intermediate 1-XXI)

A mixture of 1-26 (5.0 g, 14.08 mmol),

bis (pinacolato) diboron (5.36 g, 21.12 mmol) and potassium acetate (2.76 g, 28.92 mmol) in dioxane (70 mL) was degassed in a stream of argon for 30 minutes. To this reaction mixture was added dppf . PdCl₂ : CH₂C1₂ complex (1.15 g, 1.41 mmol) and the reaction mixture was again degassed for additional 15 minutes. The reaction mixture was stirred at 90°C for 18 hours. After completion of the reaction, the reaction mixture was cooled to

25°C, and filtered over a celite pad and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified by silica gel (100-20.0 mesh size) column chromatography using 5% ethyl acetate in hexanes as eluent to give the desired product Intermediate 1-XXI (4.09 g, 72%) as a white solid; LCMS : m/z 348.1 [M⁺-^fcBu+l] .

[0308]

Intermediate 1-XXII: tert-butyl 4- [ 5- ( 4 , , 5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl) -2-pyridyl] piperazine-l-carboxylate [0309]

1-27 1-28 Intermediate 1 -XXII

[0310]

Step I: tert-butyl 4- ( 5-bromo-2-pyridyl ) piperazine-1- carboxylate (1-28)

1-28 was prepared from 1-27 according to the procedure described in WO 2008/146914.

[0311]

Step II: tert-butyl 4- [ 5- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl) -2-pyridyl] piperazine-l-carboxylate

(Intermediate 1-XXII)

A mixture of 1-28 (4.30 g, 12.57 mmol), bis (pinacolato) diboron (3.82 g, 15.07 mmol) and KOAc (2.94 g, 37.69 mmol) in 1,4-dioxane (30 mL) was degassed in a stream of argon for 15 minutes. To the mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.307 g, 0.376 mmol), and the

reaction mixture was again degassed for additional 15 minutes. After stirring at 100°C for 20 hours, the volatiles were removed by evaporation, and the obtained residue, was diluted with water (50 mL) , followed by extraction with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (100-200 mesh) using 50% EtOAc in hexanes to give the desired product Intermediate 1- XXII as a mixture of minor boronate ester together with major boronic acid (4.8 g, crude yield 98%) as a yellow solid; LCMS (for boronate ester): m/z 390.2 [M⁺+l] ; LCMS (for boronic acid) : m/z 308.1 [M⁺+l] .

[0312]

Intermediate 1-XXIII: tert-butyl 4- [ - ( 4 , 4 , 5 , 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl ) pyrazol-l-yl] piperidine-l-carboxylate [0313]

1_29 1-30 1-31 Intermediate 1 -XXIII

[0314]

Step I: tert-butyl 4-hydroxypiperidine-l-carboxylate (1-30) 1-30 was prepared from 1-29 according to the procedure described in WO 2013/160810.

[0315]

Step II: tert-butyl 4-methylsulfonyloxypiperidine-1- carboxylate (1-31) 1-31 was prepared from 1-30 according to the procedur described in WO 2012/167733.

[0316]

Step III: tert-butyl 4- [ 4- ( 4 , 4 , 5 , 5-tetramethyl-l , 3 , 2- dioxaborolan-2-yl ) pyrazol-l-yl] piperidine-l-carboxylate

(Intermediate 1-XXIII)

Intermediate 1-XXIII was prepared from 1-31 according the procedure described in WO 2012/167733; LCMS : m/z 378.1

[M⁺+l] .

[0317]

Intermediate 1-XXIV: tert-butyl 4- [ [ 4- ( 4 , 4 , 5 , 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl ) pyrazol-l-yl ] methyl ] piperidine-l- carboxylate

[0318]

1 -32 Intermediate 1-XXIV

[0319]

To a solution of 1-32 (1.2 gm, 6.18 mmol) in anhydrous DMF (10 mL) was added NaH (0.366 gm, 9.27 mmol, 60% suspension in oil) portion wise at 0°C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was^' again cooled to 0°C and to this

mixture was added a solution of tert-butyl 4- ( (methylsulfonyloxy) methyl) piperidine-l-carboxylate (2.2 gm, 7.42 mmol) [prepared from tert-butyl 4- (hydroxymethyl ) piperidine-l-carboxylate according to the

procedure described in J. Med. Chem. , 55(5), 2416-2426, 2012] in DMF (2 mL) .^■ The resulting reaction mixture was warmed to room temperature and stirred for 18 hours. After completion of the reaction, the reaction mixture was quenched with saturated NHC1 solution (10 mL) and concentrated to dryness. The crude reaction mixture so obtained was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3) . The combined organic layers were washed with brine (25 mL X 2 ) and dried over anhydrous a₂S04. The crude product obtained after evaporation of solvent was purified by silica gel column chromatography (60-120 mesh) using 10% EtOAc in hexanes as eluent to give the desired product Intermediate 1-XXIV (1 gm, 43%) as a colorless syrup; LCMS : m/z 392.3 [ ⁺+l] .

' [0320]

Intermediate 2-1: tert-butyl 4- ( 6-chloro-3-pyridyl ) piperazine- 1-carboxylate

[0321]

2-1

[0322]

Intermediate 2-1 was prepared from 5-bromo-2-chloro- pyridine according. to the procedure described in WO

2009/126584.

[0323]

Intermediate 3-1: 7-bromo-2- (morpholinomethyl ) -4H-imidazo [2 , 1- c] [1, 4 ] benzoxazine

[0324]

Intermediate 3-1

[0325]

Step I: methyl ( 2Z ) -2- ( 7-bromo-2-oxo-4H-l , 4-benzoxazin-3- ylidene) acetate (3-2)

To a suspension of 5-bromo-2-aminophenol (3-1) (purchased form Labex) (150 g, 802 mmol) in EtOH (1500 mL) was added dimethyl acetylene dicarboxylate (118.2 mL, 962 mmol) at room temperature over a period of 30 minutes. The reaction mixture was left overnight for complete precipitation. The yellow precipitate so obtained was collected by filtration and dried under vacuum to give the desired product 3-2. The filtrate was allowed to stand for 24 hours and the precipitate was again filtered and dried under vacuum to give the desired product 3- 2 (combined yield 211 g, 89%) .

1HNMR (400 MHz , DMSO-d₆) : δ 3.71 (s, 3H) , 5.63 (s, 1H) , 7.31- 7.46 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H) , 7.47 (d, J = 2.4 Hz, 1H) , 7.52 (d, J = 8.4 Hz, 1H) , 10.70 (br.s, 1H)

[0326]

Step II: methyl (2E) -2- (7-bromo-2-oxo-4H-l, 4-benzoxazin-3-yl) - 2-hydroxyimino-acetate (3-3)

To a suspension of 3-2 (210 g, 706 mmol) and

trichloroacetic acid (28.8 g, 176 mmol) in glacial acetic acid (1500 mL) was added isoamylnitrite (115.2 mL, 845 mmol, 1.2. eq.) dropwise at room temperature. After addition was complete the reaction mixture was stirred for another 4 hours (color changes from yellow to white) . After completion of the

reaction, the solid product obtained was collected by

filtration and washed with diethyl ether to remove excess acetic acid. The product was further dried under vacuum to give the desired product .3-3 as a white solid (183 g, 80%) . ¹HNMR (400 MHz, DMSO-d₆) : δ 3.83 (s, 3H) , 7.58-7.60 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H) , 7.67 (d, J = 2.4 Hz, 1H) , 7.77 (d, J = 8.4 Hz, 1H) , 13.20 (br.s, 1H)

[0327]

Step III: methyl (2Z) -2-amino-2- (7-bromo-2-oxo-4H-l, 4- benzoxazin-3-ylidene) acetate (3-4)

3-3 (20 g, 61 mmol) was suspended in anhydrous THF (100 mL) and platinum oxide (Pt0₂) was added thereto. The reaction mixture was hydrogenated using parr apparatus at 50 psi. After 1.5 hour (~3 times hydrogen filling was required during this time), no uptake of hydrogen was observed. The reaction was monitored by TLC and after completion of the reaction, the dark red solution was obtained that was filtered through celite pad and washed with THF multiple times (1500 mL, the product has low solubility in other solvents) . The filtrate was concentrated to dryness .to give the desired crude product

3-4, which was triturated with cold EtOH and filtered and dried under vacuum to give the desired product 3-4 as a deep red colored solid (14.3 g, 74%); LCMS : m/z 312.7 [M⁺+l].

XHNMR (400 MHz, DMSO-d₆) : δ 3.85 (s, 3H) , 6.14 (br.s, 2H) , 6.96 (d, J = 8.4 Hz, 1H) , 7.08-7.10 (dd, J = 2 Hz, J = 8 Hz, 1H) , 7.15 (d, J = 2 Hz, 1H) , 8.98 (br.s, 1H)

[0328]

Step IV: methyl 2- ( 7-bromo-2-oxo-4H-l , 4-benzoxazin-3-yl ) -2- [ (2-chl^'o.roacetyl ) amino] acetate (3-5)_,

To a solution of 3-4 (97 g, 311.8 mmol) in anhydrous DMF (500 mL) was added dropwise chloroacetyl chloride (37.2 mL, 467^'.8. mmol) at room temperature and the resulting reaction mixture was stirred for another 2.5 hours. The reaction

mixture was poured into ice-water, and the solid was collected by filtration and dried under vacuum to give the desired

product 3-5 as a yellow solid [121. g, 99% (considering

quantitative . yield as the product contains moisture)]. 3-5 was used as such in the next step without further drying.

[03291

Step V: 7-bromo-2-methoxycarbonyl-4H-imidazo [2 , 1- c] [ 1 , 4 ] benzoxazine-l-carboxylic acid (3-6)

To a suspension of 3-5 (98 g, 252.2 mmol) in a mixture of acetone/water (1:3, 800 mL) was added Na₂C0₃ (53.5 g, 505.2 mmol) at room temperature. The resulting reaction mixture was heated at 60°C for 4 hours till the reaction mixture became clear. The excess solvent was removed under reduced pressure and the resulting reaction mixture was washed with EtOAc (500 mL x 2 ) . The organic layer was separated and the aqueous layer was acidified using concentrated HCl till the pH was adjusted to ~2. The solid so obtained was collected by filtration and washed with water and dried under vacuum to give the desired product 3-6 as a white solid (61 g, 69%); LCMS : m/z 352.7

[M⁺+l] , 354.8 [M⁺+2] .

¹HNMR (400 MHz, DMS.O-d₆) : δ 3.80 (s, 3H) , 5.34 (s, 2H) , 7.38 (d, J = 8.8 Hz, 1H), 7.40-7.45 (dd, J = 8.8 Hz, J = 2.2 Hz, 1H) , 7.54 (d, J = 1.6 Hz, 1H) , 14.50 (br.s, 1H)

[0330]

Step VI: methyl 7-bromo-4H-imidazo [2 , 1-c] [ 1, 4 ] benzoxazine-2- carboxylate (3-7)

3-6 (75 g, 213.6 mmol) was placed in a flask and heated at 180-190°C (external temperature of oil bath) under stirring till the solid turned dark and became thick oil. After 1.5 hours, the reaction was cooled to room temperature. The thick oily product 3-7 was again solidified to give the desired product 3-7 as a dark grey solid (64 g, 95%); LCMS : m/z 308.7 [M⁺+l] , 310.8 [M⁺+2] .

¹HNMR (400 MHz , DMSO-d₆) : δ 3.80 (s, 3H) , 5.36 (s, 2H) , 7.35- 7.37 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H) , 7.43 (d, J = 2 Hz, 1H) , 7.84 (d, J = 8.8 Hz, 1H) , 8.75 (s, 1H) ^'

[0331]

Step VII: ( 7-bromo-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2- yl) methanol (3-8)

To a suspension of LiAlH₄ (7.3 g, 191.2 mmol) in

anhydrous THF (650 mL) at 0°C was added A1C1₃ (30 g, 225 mmol) in small portions over a period of 45 minutes. After addition was complete, the resulting reaction mixture was heated to 70°C (external temperature) for 1 hour. The reaction mixture was cooled to -55°C using dry ice-acetonitrile bath and 3-7 was added. thereto in portions. After complete addition, the reaction mixture was slowly allowed to warm to 0°C over a period of 1 hour and stirred at 0°C for another 1 hour, followed by stirring for 1 hour or more at room temperature. The reaction mixture was again cooled to 0°C and diluted with EtOAc (500 mL) . ^'The excess reagent was decomposed by addition of 10% aqueous NaOH (200 mL) and saturated aqueous NH₄C1 (200 mL) . The inorganic material was removed by filtration through celite pad and washed with 10% MeOH in EtOAc (~2 L) . The aqueous layer from the combined filtrate was separated and the organic layer was dried over anhydrous Na₂S0₄ followed by evaporation under reduced pressure to give the desired crude product 3-8. The crude product was taken in 80% EtOH in hexanes, and the resulting suspension was heated on water bath at 70°C for 15 minutes and then cooled to room temperature. The solid so obtained was collected by filtration to give the desired product 3-8. The mother liquor was concentrated to dryness and passed through silica gel column (60-120 mesh, eluent 5-10% MeOH in dichloromethane) to recover the remaining amount of the desired product 3-8 as a pale brown solid (combined yield 26.5 g, 84%); LCMS : m/z 280.8 [M⁺+l] , 282.8

[M⁺+2] .

¹HNMR (400 MHz, DMSO-d₆) : δ 4.40 (s, 2H) , 5.31 (s, 2H) , 7.30- 7.32 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H) , 7.38 (d, J = 2 Hz, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.78 (s, 1H)

[0332]

Step VIII: 7-bromo-2- (chloromethyl) -4H-imidazo [2 , 1- c] [1, 4 ] benzoxazine (3-9)

Thionyl chloride (0.1 mL, 1.42 mmol) was added to a solution of 3-8 (0.200 g, 0.71 mmol) and Et₃N (0.25 mL, 1.77 mmol) in dichloromethane (10 mL) at 0°C. The resulting

reaction mixture was allowed to warm to room temperature and stirred for another 2 hours.. After completion of the reaction, the reaction mixture was diluted with dichloromethane (25 mL) and water (25 mL) . The organic layer was separated and washed with brine (25 mL) . The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated to dryness to give the desired crude product 3-9 (0.21 g, 99% crude) as a brown sticky solid which was used further in the next step without further purification; LCMS: m/z 299.0 [M⁺+l] .

[0333]

Step IX: 7-bromo-2- (morpholinomethyl ) -4H-imidazo [2 , 1- c] [1, 4] benzoxazine (Intermediate 3-1)

To a solution of .3-9 (0.200 g, 0.68 mmol) in DMF (3 mL) were added DIPEA (0.3 mL, 1.70 mmol) and morpholine (0.1 mL, 1.02 mmol) dropwise at room temperature. The resulting

reaction mixture was heated to 60°C for 18 hours. After completion of the reaction, the reaction mixture was

concentrated to dryness and diluted with water (25 mL) and ' EtOAc (25 mL) . The organic layer was separated and the aqueous layer was back extracted with EtOAc (25 mL X 2) . The combined organic layers were washed with saturated brine solution (25 mL) and dried over anhydrous Na₂S0₄. The solvent was

evaporated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (60- 120 mesh) and eluted with 4% MeOH in dichloromethane as eluent to give the desired product Intermediate 3-1 (0.160 g, 67%) as a brown solid; LCMS : m/z 349.7 [M⁺+l], 351.7 [M⁺+2].

^NMR (400 MHz, DMSO-d₆) : δ 2.42-4.43 (t, J = 4.4 Hz, 4H) , 3.40 (s, 2H) , 3.56 (t, J = 4.4 Hz, 4H) , 5.29 (s, 2H) , 7.29 (dd, J = 2 Hz, J = 8.4 Hz, IH) , 7.37 (d, 'J = 2 Hz, IH) , 7.63 (d, J = 8 Hz, IH) , 7.79 (s, IH)

[0334]

Intermediates 3-II to 3-V as shown in Table 4 were prepared from their corresponding starting materials according to similar sequence of procedures as used for the synthesis of Intermediate 3-1.

[0335]

Table 4:

[0336]

Alternatively, Intermediate 3-1 was prepared by the synthetic route described below.

[0337]

3.8 3-10 Intermediate 3-I

[0338]

Step I: 7—bromo-4H-imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine-2- carbaldehyde (3-10)

A suspension of 3-8 (40 g, 142.3 mmol) in dichloromethane (1 L) was treated with Dess Martin periodinate (121 g, 284.6 mmol) in portions at 0°C. The reaction mixture was allowed to attain room temperature and stirred for 3 hours. After

completion of the reaction, the reaction mixture was cooled to 0°C and the Dess Martin periodinate was decomposed with

saturated aqueous sodium thiosulfate solution (100 mL)

followed by saturated aqueous NaHC0₃ solution (100 mL) . The solid material obtained was removed by filtration through celite pad and washed with 5% MeOH in dichloromethane (600 mL) . The aqueous layer of the filtrate was separated and the

organic layer was concentrated to dryness. The solid product so obtained was suspended in saturated aqueous NaHC0₃ solution (500 mL), and the suspension was stirred for 1 hour and

filtered. The desired crude product 3-10 so obtained was dried under vacuum and purified by silica gel column chromatography (60-120 mesh) using 0.5-2% MeOH in dichloromethane as e_.luent to give the desired pure product 3-10 as an off-white solid (30.5 g, 77%); LCMS : m/z 278.8 [M⁺+l], 280.8 [M⁺+2].

1HNMR (400 MHz, DMSO-d₆) : δ 5.37 (s, 2H) , 7.23-7.27 (m, 1H) , 7.29 (d, J = 1.6 Hz, 1H) , 7.33 (d, J = 1.6 Hz, 1H) , 8.02 (s, 1H) , 9.93 (s, 1H)

[0339]

Step II: 7-bromo-2- (morpholinomethyl ) -4H-imidazo [2 , 1- c] [1, 4] benzoxazine (Intermediate 3-1)

To a solution of 3-10 (30 g, 107.5 mmol) in a mixture of MeOH-DCM (1:1,_. 300 mL) were added morpholine (14 mL, 161.2 mmol), AcOH (6.2 mL, 107.5 mmol) and 4A activated powdered molecular sieves (30 g) successively at room temperature and the resulting reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to 0°C and treated with NaBH₃CN (16.9 g, 268.7 mmol) in portions. After addition was complete, the reaction was continued for another 5 hours and diluted with dichloromethane (250 mL) , saturated aqueous NaHC0₃ (150 mL) solution and water (100 mL) . The layers were separated and the aqueous layer was back

extracted with dichloromethane (100 mL x 2) . The combined organic layers were washed with brine, dried over anhydrous Na₂SC>4 and concentrated to dryness. The crude product so

obtained was purified by silica gel column chromatography (100-200 mesh) using 0.5 -5% MeOH in dichloromethane as eluent to give the desired product Intermediate 3-1 as an off-white solid (24.9 g, 66%); LCMS : m/z 349.7 [M⁺+l] , 351.7 [M⁺+2].

1HNMR (400 MHz, DMSO-d₆) : δ 2.42-4.43 (t, J =^'4.4 Hz, 4H) , 3.40 (s, 2H) , 3.56 (t, J = 4.4 Hz, 4H) . 5.29 (s, 2H) , 7.29 (dd, J = 2 Hz, J = 8.4 Hz, 1H) , 7.37 (d, J = 2 Hz, 1H) , 7.63 (d, J = 8 Hz, 1H) , 7.79 (s, 1H)

[0340]

Intermediate 3-VI: ( 7 -bromo-8-methyl-4H-imidazo [2, 1- c] [1, 4]benzoxazin-2-yl)methanol

0341]

Intermediate 3-VI

[0342]

Step I: 4-bromo-2-methoxy-5-methyl-aniline (3-12)

3-12 was prepared from 3-11 according to the procedure described in WO 2014/037750.

[0343]

Step II: 2-amino-5-bromo-4-methyl-phenol (3-13)

3-13 was prepared from 3-12 according to the procedure described in WO 2011/0263612.

[0344] 'Step III: methyl (2Z) -2- ( 7-bromo-6-methyl-2-oxo-4H-l , 4- benzoxazin-3-ylidene) acetate (3-14)

3-14 was prepared from 3-13 according to similar

procedure as used for the synthesis of 3-2 from 3-1; LCMS: m/z 312.0 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 2.21 (s, 3H) , 3.71 (s, 3H) , 5.63 ( 1H) , 7.47 (s, 1H) , 7.54 (s, 1H) , 10.65 (br.s, 1H)

[0345]

Step IV: methyl (2E) -2- (7-bromo-6-methyl-2-oxo-4H-l, 4- benzoxazin-3-yl) -2-hydroxyimino-acetate (3-15)

3-15 was prepared from 3-14 according to similar

procedure as used for the synthesis of 3-3 from 3-2; LCMS: m/z 341.0 [M⁺+l] .

^XHNMR (400 MHz, DMSO-d₆) : δ 2.41 (s, 3H) , 3.83 (s, 3H) , 7.75(s, 1H) , 7.77 (s, 1H) , 13.16 (br.s, 1H)

[0346]

Step V: methyl (2Z ) -2-amino-2- ( 7-bromo-6-methyl-2-oxo-4H-l, 4- benzoxazin-3-ylidene) acetate (3-16)

3-16 was prepared from 3-15 according to similar

procedure as used for the synthesis of 3-4 from 3-3; LCMS: m/z 327.0 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 2.19 (s, 3H) , 3.85 (s, 3H) , 6.12 (br.s, 2H) , 6.99 (s, 1H) , 7.15 (s, 1H) , 8.94 (br.s, 1H)

[0347]

Step VI: methyl 2- (7-bromo-6-methyl-2-oxo-4H-l, 4-benzoxazin-3- yl) -2- [ ( 2-chloroacetyl ) amino] acetate (3-17)

3-17 was prepared from 3-16 according to similar

procedure as used for the synthesis of 3-5 from 3-4.

[0348]

Step VII: 7-bromo-2-methoxycarbonyl-8-methyl-4H-imidazo [2 , 1- c] [1, 4 ] benzoxazine-l-carboxylic acid (3-18)

3-18 was prepared from 3-17 according to similar

procedure as used for the synthesis of 3-6 from 3-5; LCMS: m/z 367.0 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 2.32 (s, 3H) , 3.80 (s, 3H) , 5.29 ( 2 H) , 7.40 (s, 1H) , 7.55 (s, 1H)

[0349]

Step VIII: methyl 7-bromo-8-methyl-4H-imidazo [2, 1- c] [1, 4 ] benzoxazine-2-carboxylate (3-19)

3-19 was prepared from 3-18 according to similar

procedure as used for the synthesis of 3-7 from 3-6.

1HNMR (400 MHz, DMSO-d₆) : δ 2.32 (s, 3H) , 3.80 (s, 3H) , 5.32 (s, 2 H) , 7.42 (s, 1H) , 7.94 (s, 1H) , 8.68 (s, 1H)

[0350]

Step IX: (7-bromo-8-methyl-4H-imidazo [2, 1-c] [1, 4 ] benzoxazin-2- yl) methanol (Intermediate 3-VI)

Intermediate 3-VI was prepared from 3-19 according to similar procedure as used for the synthesis of 3-8 from 3-7;

LCMS: m/z 295.0 [M⁺+l] .

1HNMR (400 MHz, DMSO-d₆) : δ 2.32 (s, 3H) , 4.40 (d, J = 5.2 Hz,

2H), 5.07 (t, J = 5.2 Hz, 1H), 5.25 (s, 2H), 7.36 (s, 1H) ,

7.71 (s, 1H) , 7.72 (s, 1H)

[0351]

Intermediate 3-VII : 7-chloro-2- (morpholin-4-yl ) methyl-4H-5- oxa-3, 6, 9b-triaza-cyclopenta [a] naphthalene

[0352]

3-25 3_26 Intermediate 3-VII

[0353]

Step I: methyl 2- [( 6-chloro-3-nitro-2-pyridyl ) oxy] acetate (3- 21)

To a stirred solution of NaH (0.81 g, 60 % dispersion in mineral oil, 33.8 mmol) in anhydrous dioxane was added methyl glyco_.late (2.69 g, 29.9 mmol) at 0°C and the reaction mixture was stirred for 15 minutes. To the mixture was added portion wise 2 , 6-dichloro-3-nitro-pyridine 3-20 (5.0 g, 26.0 mmol) and the reaction mixture was stirred for 12 hours. The mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine, dried over- anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain crude solid, which was purified by silica gel column chromatography using

2-5% ethyl acetate in hexanes as eluent to give the desired product 3-21 as an off-white solid (3.81 g, 59 %); LCMS : m/z 247.0 [M⁺+l] .

[0354]

Step II: methyl 2- [( 3-amino-6-chloro-2-pyridyl ) oxy] acetate (3- 22)

To a stirred solution of 3-21 (7.5 g, 30.8 mmol) in a mixture of THF and methanol (1:1, 100 mL) was added Fe powder (8.51 g, 152.4 mmol) at room temperature. To the mixture were added ammonium chloride (16.3 g, 304.8 mmol) and water (10 mL) . The reaction mixture was heated to reflux for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and filtered through celite pad that was washed with 10%

methanol in dlchloromethane . The filtrate was concentrated, diluted with dichloromethane and washed with water. The

organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography using 25-35% ethyl acetate in hexanes as eluent to give the desired product

3-22 (6.5 g, 98%) as a dark brown oil; LC S: m/z 217.1 [M⁺+l] .

[0355]

Step III: 6-chloro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazin-2-one (3-23)

To a stirred solution of 3-22 (7.5 g, 34.7 mmol) in ethanol (100 mL) was added glacial acetic acid (10 mL) at room temperature. The reaction mixture was heated to reflux for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous sodium bicarbonate, solution (100 mL) . The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography using 35-50% ethyl acetate in hexanes as eluent to give the desired product 3-23 (4.5 gm, 70%) as an off-white solid; LCMS: m/z 185.3 [M⁺+l] .

^XHNMR (400 MHz, CDC1₃) : δ 4.82 (s, 2H) , 7.10 (d, J = 8.0 Hz,

1H) , 7.25 (d, J = 8.0 Hz, 1H) , 10.96 (s, 1H, -NH)

[0356]

Step IV: l-acetonyl-6-chloro-pyrido [2 , 3-b] [ 1 , 4 ] oxazin-2-one . (3-24)

To a stirred solution of 3-23 (3 g, 16.25 mmol) in DMF (15 mL) were added Cs₂C0₃ (7.94 g, 24.37 mmol) and 1- chloropropan-2-one (1.95 g, 21.12 mmol) at room temperature and the resulting suspension was heated at 60°C for 3 hours. The reaction mixture was cooled to room temperature and

diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with water (25 mL x 2 ) and brine (25 mL) , dried over anhydrous

Na₂S0₄ and concentrated under reduced pressure to give the desired product 3-24 (3 g, 83%) as a yellow solid.

[0357]

Step V: 7-chloro-2-methyl-4H-5-oxa-3 , 6, 9b-triaza- cyclopenta [a] naphthalene (3-25)

A mixture of 3-24 (3 g, 13.27 mmol) and ammonium acetate

(20.4 g, 26.54 mmol) in glacial acetic acid (15 mL) was heated at 110°C in sealed vessel for 18 hours. The reaction mixture was cooled to room temperature and poured into ice-water, and the pH was adjusted to ~9 using aqueous NH₃ followed by

extraction with ethyl acetate (50 mL x 3) . The combined organic layers were washed with water (50 mL) , brine (50 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (eluent 80% EtOAc in hexanes) to give the desired product 3-25 (2.5 g, 85%) as a yellow solid; LCMS : m/z 222.1 [M⁺+l] .

[0358]

Step VI: 7-chloro-4H-5-oxa-3 , 6, 9b-triaza- cyclopenta [a] naphthalene-2-carbaldehyde (3-26)

To a solution of 3-25 (2.5 g, 11.27 mmol) in dioxane (12 mL) was added Se0₂ (2.5 g, 22.55 mmol), and the mixture was heated at 100°C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite that was washed with EtOAc (30 mL) . The filtrate was washed with water (25 mL) , brine (25 mL) and dried over anhydrous Na₂S0₄. The organic layer was evaporated under reduced pressure and the crude product so obtained was purified by silica gel column chromatography using 70% EtOAc in hexanes as eluent to give the desired product 3-26 (0.3 g, 11%) as a yellow solid; LCMS:. m/z 236.1 [M⁺+l] .

[0359]

Step VII: 7-chloro-2- (morpholin-4-yl) methyl-4H-5-oxa-3 , 6, 9b- triaza-cyclopenta [ajnaphthalene (Intermediate 3-VII)

To a solution of 3-26 (0.3 g, 1.27 mmol) in a mixture of MeOH-DCE ^' (1:1, 15 mL) were added morpholine (0.22 g, 2.54 mmol), powdered 4 A molecular sieves (0.3 g) and 2 drops ofglacial acetic acid. The resulting reaction mixture was stirred for 2 hours. NaBH₃CN (0.24 g, 3.82 mmol) was added thereto and stirring was continued for another 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL) , and filtered over a pad of celite and the filtrate was washed with saturated aqueous solution of sodium bicarbonate (10 mL) followed by water (10 mL) and brine (10 mL) . The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 5% MeOH in dichloromethane as eluent to give the desired product Intermediate 3-VII (0.18 g, 46%) as a yellow solid; LCMS: m/z 307.1 [M⁺+l] .

1HNMR (400 MHz, CDCI3) : δ 2.51-2.59 (m, 4H) , 3.53 (s, 2H), .3.74

(t, J = 3.6 Hz, 4H) , 5.49 (s, 2H) , 7.09 (d, J = 8.4 Hz, 1H) , 7.24 (s, 1H) , 7.50 (d, J = 7.6 Hz, 1H)

[0360]

Intermediate 3-VIII: 7-bromo-2- (morpholinomethyl ) -4H- [ 1 , 2 , 4 ] triazolo [ 5, 1-c] [ 1 , 4 ] benzoxazine

[0361]

3-31 Intermediate 3-VIII

[0362]

Step I: 2- (2-amino-5-bromo-phenoxy) acetonitrile (3-27)

To a solution of 2-amino-5-bromo-phenol (5 g, 26.59 mmol) in acetone (15 mL) were added K₂C0₃ (5.5 g, 39.89 mmol) and 2- chloroacetonitrile (2.4 g, 31.9 mmol) at room temperature and the reaction mixture was then heated at 60°C for 4 hours. The reaction mixture was cooled to room temperature, the inorganic material was removed by filtration and the filtrate was

concentrated under reduced pressure. The crude product so obtained was taken into water and . the mixture was extracted with ethyl acetate (10 mL x 3) . The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give the desired product 3-27 (5 g, 83%) as a brown solid; LCMS : m/z 227.0 [M⁺+l] , 229.0 [M⁺+2].

[0363]

Step II: ethyl 2- [ (E) - [4-bromo-2- (cyanomethoxy) phenyl] azo] -2- chloroacetate (3-28)

To a solution of 3-27 (6 g, 26.43 mmol) in aqueous 0.5N HC1;(150 mL) was added dropwise a solution of NaN0₂ (1.82 g, 26.43 mmol) in water (15 mL) with vigorous stirring and ice cooling. The pH of the solution was adjusted to ~4 using NaOAc. Subsequently ethyl 2-chloroacetoacetate (4.35 g, 26.43 mmol) in MeOH (15 mL) was added to the reaction mixture at 0°C over a period of 10 minutes. The resulting reaction mixture was allowed to stir for 30 minutes and then diethyl ether was added thereto. The mixture was extracted with diethyl ether (50 mL x 3) . The combined organic layers were dried over anhydrous Na₂SC>4 and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography (60-120 mesh) using 50% EtOAc in hexanes as eluent to give the desired product 3-28 (7 g, 74%) as a brown solid.

[0364]

Step III: ethyl 7-bromo-4H- [1, 2 , 4 ] triazolo [5, 1- c] [1, 4] benzoxazine-2-carboxylate (3-29)

To a solution of 3-28 (7 g, 19.4 mmol) in toluene (70 mL) , was added triethylamine (7.8 g, 77.77 mmol) and the reaction mixture was heated at 100°^'C for 5 hours. The volatiles were removed by evaporation. The solid obtained was triturated with a mixture of hexane and ether (3:2, 100 mL) and collected by filtration to give the desired product 3-29 (5.2 g, 82 %) as a brown solid; LCMS: m/z 325.9 [M⁺+l] , 327.9 [M⁺+2].

[0365]

Step IV: (7-bromo-4H- [1, 2, 4] triazolo [5, 1-c] [1, 4] benzoxazin-2- yl)methanol (3-30)

3-30 was prepared from 3-29 according to the similar procedure described in WO 2013/0059833; LCMS : m/z 282.0 [M⁺+l] , 284.0 [M⁺+2] .

f

5 [0366]

Step V: 7-bromo-2- (chloromethyl) -4H- [1, 2, 4] triazolo [5, 1- c] [1, 4 ] benzoxazine (3-31)

To a solution of 3-30 (1 g, 3.54 mmol) and

diisopropylethylamine (0.68, 5.3 mmol) in dichloromethane (10

^■■io mL) was added thionyl chloride (0.54 g, 4.60 mmol) at 0°C and the reaction mixture was stirred for 1 hour at room

temperature. The resulting brown solution was concentrated under reduced pressure to give the desired product 3-31 (0.9 g, 85%) as brown oil; LCMS: m/z 300.0 [M⁺+l] , 302.0 [M⁺+2].

15 [0367]

Step VI: 7 -bromo-2- (morpholinomethyl) -4H- [1, 2, 4] triazolo [5, 1- c] [1, 4] benzoxazine (Intermediate 3-VIII)

A mixture of 3-31 (0.9 g, 3.0 mmol), morpholine (0.33 g, 3.9 mmol) and diisopropylethylamine (0.58 g, 4.5 mmol) in DMF

20 (10 mL) was heated at 60°C for 4 hours. The volatiles were

removed under reduced pressure, the reaction mixture was diluted with water and extracted with dichloromethane (25 mL x 3). The combined organic layers were dried over anhydrous

Na₂S0 and concentrated under reduced pressure to obtain crude

25 product, which was purified by combiflash using 3% MeOH in

dichloromethane as eluent to give the desired product

Intermediate 3-VIII (0.5 g, 74%) as a brown solid; LCMS: m/z

351.0 [M⁺+l] , 353.0 [M⁺+2] .

¹HNMR (400 MHz, DMSO-d₆) : δ 2.45-2.55 (m, 4H, merged in

30 residual solvent peak), 3.56 (t, J = 4.4 Hz, 4H) , 3.61 (s, 2H) , 5.59 (s, 2H) , 7.34 (dd, J = 8 Hz, J = 1.6 Hz, 1H) , 7.44 (d, J = 1.6 Hz, 1H) , 7.59 (d, J = 8.8 Hz, 1H)

[0368]

Intermediate 4-1: 2- (morpholinomethyl ) -7- ( 4 , 4 , 5, 5-tetramethyl- 35 1 , 3 , 2-dioxaborolan-2-yl ) -4H-imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine [0369]

[0370]

A mixture of Intermediate 3-1 (0.15 g, 0.427 mmol) , bis (pinacolato) diboron (0.129 g, 0.51 mmol) and KOAc (0.125 g, 1.26 mmol) in 1,4-dioxane (5 mL) was degassed with a stream of argon for 15 minutes. To this mixture was added 1,1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.02 g, 0.025 mmol) and the mixture was degassed for additional 15 minutes. After stirring at 90°C for 16 hours, the reaction mixture was filtered through a celite pad and washed with EtOAc (50 mL) . The ethyl acetate layer was washed with water (2.5 mL) followed by brine (25 mL) and concentrated under reduced pressure. The obtained residue, was purified by preparative TLC using 6% methanol in

dichloromethane as solvent system to give the desired product Intermediate 4-1 (0.055 g, 32%) as a brownish solid; LCMS : m/z 398.3 [M⁺+l] .

¹HNMR (400 MHz, CDC1₃) : δ 1.24 (s, 12H-) , 2.53-2.57 (m, 4H) , 3.53 (s, 2H) , 3.75 (t, J = 6.8 Hz, 4H) , 5.22 (s, 2H) , 7.23- 7.24 (m, 1H) , 7.29 (br.s, 1H) , 7.49-7.51 (m, 2H)

[0371] -

Intermediate 5-1: 7-bromo-2- ( 2-morpholinoethyl ) -4H- imidazo [2, 1-c] [ 1 , 4 ] benzoxazine

[0372]

Intermediate 5-1

[0373]

Step I: 7-bromo-2- [ (E, Z ) -2-methoxyvinyl ] -4H-imidazo [2,1- c] [ 1 , 4 ] benzoxazine (5-1)

To a suspension of methoxymethyl triphenylphosphonium chloride (7.98 g, 21.29 mmol) in anhydrous THF (200 mL) at 0°C was added t-BuOK (2.38 g, 21.29 mmol) followed by t-BuOH (1.01. mL, 16.30 mmol). The resulting brown reaction mixture was allowed to stir for 1.5 hour. The reaction mixture was then cooled to -78°C and a solution of 3-10 (1.98 g, 7.91 mmol) in THF was added thereto and the mixture was stirred at -78°C for additional 1 hour. The reaction mixture was gradually allowed to attain room temperature and stirred for 16 hours. The reaction mixture was diluted with saturated NH₄C1 solution (25 mL) and ethyl acetate (50 mL) . The layers were separated, the aqueous layer was back extracted with ethyl acetate (30 mL x 2), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂S0₄. The solvent was

evaporated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography using 60% EtOAc in hexanes as eluent to give the desired product 5-1 (2 g, 83%) as an off-white solid; LCMS : m/z 307.0 [M⁺+l] , 309.0 [M⁺+2] .

¹HNMR (400 MHz, CDC1₃) : δ 3.84 (s, 3H) , 5.24 (s, 2H) , 5.43 (d, J = 6.4 Hz, 1H), 6.19 (d, J = 6.4 Hz, 1H) , 7.16-7.20 (m, 2H) , 7.22-7.24 (m, 1H) , 7.57 (s, 1H)

[0374]

Step II: 2- ( 7-bromo-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2- yl) acetaldehyde (5-2)

To a solution of 5-1 (2.0 g, 6.51 mmol) in THF (25 mL) was added 6N aqueous HC1 (10 mL) at room temperature and stirred for 1.5 hour. The reaction mixture was taken in ethyl acetate (50 mL) and washed with saturated aqueous NaHC0₃ solution (25 mL x 2) .. The organic layer was separated and washed with brine (30 mL). , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The desired crude product 5-2 (1.75 g) so obtained was used in the next step without purification; LCMS : m/z 146.1 [M⁺/2+l] .

[0375]

Step III: 2- ( 7-bromo-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2- yl)ethanol (5-3)

To a solution of 5-2 (1.75 g, 6.01 mmol) in a mixture of THF/H₂0/MeOH (4:2:1, 20 mL) was added NaBH₄ (0.342 g, 9.02 mmol) in portions at 0°C over a period of 1 hour. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with saturated aqueous NH₄C1 solution (15 mL) and extracted with ethyl acetate (50 mL x 3) . The organic layer was washed with brine (50 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by silica gel column chromatography using 4% MeOH in dichloromethane as eluent to give the desired product 5-3 (0.51 g, 31% over tw,o steps) as pale brown syrup; LCMS: m/z 295.0 [M⁺+l].

¹HNMR .(400 MHz, DMSO-d₆) : δ 2.66 (t, J = 7 Hz, 2H) , 3.64 (q, J = 7.6 Hz, 2H) , 4.61 (t, J = 5.4, 1H) , 5.28 (s, 2H) , 7.29 (dd, J = 2 Hz, 8.4 Hz, 1H) , 7.35 (d, J = 2 Hz, 1H) , 7.57 (d, J = 8.8 Hz, 1H) , 7.65 (s, 1H)

[0376]

Step IV: (2- ( 7-bromo-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2- yl) ethyl methanesulfonate (5-4)

To a stirred solution of 5-3 (0.51 g, 1.73 mmol) and ■ triethylamine (0.36 mL, 2.60 mmol) in dichloromethane (5 mL) at 0°C was added methanesulfonyl chloride (0.168 mL, 2.07 mmol) and allowed to stir for 2 hours. The reaction mixture was diluted with water (15 mL) and CH₂C1₂ (25 mL) . The layers were separated and the organic layer was washed with brine (15 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the desired crude product 5-4

(0.650 g) so obtained was used for next step without any purification .

[0377]

Step V: 7-bromo-2- (2-morpholinoethyl) -4H-imidazo [2, 1- c] [1, 4] benzoxazine (Intermediate 5-1)

To a solution of 5-4 (0.65 g, 1.74 mmol) in anhydrous DMF

(2 mL) were added morpholine (0.45 mL, 5.22 mmol) and N,N- diisopropylethylamine (0.6 mL, 3.48 mmol) at room temperature. After stirring at 60°C under argon atmosphere for 16 hours, the excess solvent was removed under reduced pressure and the residue was diluted with ice cold water followed by extraction with ethyl acetate (25 mL x 3) . The combined organic layers were washed with brine (25 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure. The crude product so obtained was purified by combiflash using 3% MeOH in dichloromethane as an eluent to give the desired product

Intermediate 5-1 (0.35 g, 55%) as an off-white solid; LCMS : m/z 364.1 [M⁺+l] .

^XHNMR (400 MHz, DMSO) : δ 2.38-2.46 (m, 4H) , 2.54-2.64 (m, 2H) , 2.65-2.69 (m, 2H) , 3.57 (t, J = 4.6, 4H) , 5.27 (s, 2H) , 7.29 (dd, J = 2 Hz, 6.4 Hz, 1H) , 7.35 (d, J = 1.6 Hz, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.65 (s, 1H)

[0378]

Intermediate 6-1: 7-bromo-2- ( 3-morpholinopropyl ) -4H- imidazo [2, 1-c] [1,4] benzoxazine

[0379]

~ _Λ Intermediate 6-1

6-3 6-4

[0380]

Step I: ethyl (E, Z) -3- ( 7-bromo-4H-imidazo [2, 1- c] [1, 4 ] benzoxazin-2-yl) prop-2-enoate (6-1)

A mixture of 3-10 (0.8 g, 2.84 mmol) and

(carbethoxymethylene) triphenylphosphorane (2.97 g, 8.54 mmol) in toluene (25 mL) was refluxed. for 18 hours. The excess of solvent was removed by evaporation under reduced pressure and the obtained residue was purified by silica gel column

chromatography (100-200 mesh) using 60% EtOAc in hexanes as eluent to give the. desired product 6-1 (0.6 g, 60%) as a brown solid; LCMS: m/z 349.1 [M⁺+l] , 351.1 [M⁺+2].

¹HNMR (400 MHz, CDCI₃) : δ 1.32 (t, J = 7 Hz, 3H) , 4.25 (q, J = 7.6 Hz, 2H) , 5.28 (s, 2H) , 6.60 (d, J = 15.6 Hz, 1H) , 7.16 (d, J = 8.8 Hz,^' 1H) , 7.22 (d, J = 2 Hz, 1H) , 7.28 (d, J = 1.6 Hz, 1H) , 7.48 (s, 1H) 7.58 (d, J = 15.6 Hz, 1H)

[0381]

Step II: ethyl 3- ( 7-bromo-4H-imidazo [2 , 1-c] [ 1, 4 ] benzoxazin-2- yl) propanoate (6-2)

To a solution of 6-1 (0.55 g, 1.57 mmol) in a mixture of

EtOAc-MeOH (4:1, 15 mL) was added Pt0₂ (0.1 g) in one portion. The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere using balloon for 18 hours. The reaction mixture was filtered through a celite pad and washed with EtOAc (25 mL) . The filtrate was concentrated under reduced pressure and the crude product so obtained was

purified by silica gel column chromatography (60-120 mesh) using.25% EtOAc in hexanes as eluent to give the desired product 6-2 (0.18 g, 33%) as a pink solid; LCMS: m/z 351.0

[M⁺+l] , 353.0 [M⁺+2] .

^""^"HNMR (400 MHz, CDC1₃) : δ 1.23-1.27 (m, 3H) , 2.70 (t, J = 7.4 Hz, 2H) , 2.94 (t, J = 7.2 Hz, 2H),.4.14 (q, J = 7.4 Hz, 2H) , 5.23 (s, 2H) , 7.07-7.09 (m, 2H) , 7.17-7.19 (m, 1H) , 7.24 (d, J = 1.6 Hz, 1H)

[0382]

Step III: 3- (7-bromo-4H-imidazo [2 , 1-c] [1, 4 ] benzoxazin-2- yl) propan-l-ol (6-3)

To a solution of 6-2 (0.16 g, 0.45 mmol) in a mixture of THF/MeOH/H₂0 (3:2:1, 10 mL) was added NaBH₄ (0.026 g, 0.68 mmol) portion wise at room temperature. The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous NH₄C1 solution (5 mL) and concentrated to dryness. The crude residue obtained was diluted with EtOAc (25 mL) and water (20 mL) . The organic layer was separated, washed with brine (20 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (60-120 mesh) using 4% MeOH in dichloromethane as eluent to give the desired product 6-3 as a pale yellow solid (0.05 g, 36%); LCMS: m/z 309.0 [M⁺+l], 311.0 [M⁺+2] .

[0383]

Step IV: 3- ( 7-bromo-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2- yl) propyl methanesulfonate (6-4)

To a solution of 6-3 (0.06 g, 0.16 mmol) and Et₃N (0.045 mL, 0.32 mmol) in dichloromethane (3 mL) was added

methanesulfonyl chloride (0.015 mL, 0.19 mmol) at 0°C. After stirring for 1 hour, the reaction mixture was diluted with water (5 mL) and CH₂CI₂ (10 mL) . The layers were separated, and the organic layer was washed with brine (10 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure to give the desired crude product 6-4 (0.065 g) as a ^'■ yellow solid that was used for next step as such without any purification and characterization.

[0384]

Step V: 7-bromo-2- ( 3-morpholinopropyl ) -4H-imidazo [2, 1- c] [1, 4 ] benzoxazine (Intermediate 6-1)

To a solution of 6-4 (0.06 g, 0.15 mmol) in anhydrous DMF (2 mL) were added morpholine (0.02 mL, 0.23 mmol) and N,N- diisopropylethylamine (0.07 mL, 0.38 mmol) at room temperature. The reaction mixture was stirred at 60°C for 16 hours under argon atmosphere. The excess solvent was removed in vacuo and the residue was diluted with ice cold water followed by

extraction with ethyl acetate (10 mL x 2) . The combined

organic layers were washed with brine (15 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by silica gel column chromatography (60-120 mesh) using 4% MeOH in dichloromethane as eluent to give the desired product

Intermediate 6-1 (0.03 g, 49% over two steps from mesylate intermediate) as a brown solid; LCMS : m/z 190.6 [M⁺/2+l] .

[0385]

Example Al : 7- [4- ( 4-isopropylpiperazin-l-yl) phenyl] -2- (morpholinomethyl) -4H-imidazo [2 , 1-c] [1, 4 ] benzoxazine

[0386]

Intermediate 3-1

[0387]

A mixture of Intermediate 3-1 (0.16 g, 0.45 mmol) ,

Intermediate l-II (0.18 g, 0.54 mmol) and K₂C0₃ (0.189 g, 1.36 mmol) in a mixture of dioxane-water (4:1, 8 mL) was degassed for 30 minutes with argon. PdCl₂dppf . DCM (0.019 g, 0.02 mmol) was added thereto and the reaction mixture was heated at 90°C for 18 hours. After completion of the reaction (monitored by TLC) , the reaction mixture was taken into water (25 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with water (25 mL) and brine (25 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude■ product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example Al . The product was dissolved in 4M HC1 in dioxane (2.5 mL) and the solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give dihydrochloride salt of Example Al

(0.055 g, 30%) as an off-white solid; HPLC-MS : m/z 474.2 [M⁺+l] 1HNMR (400 MHz, DMSO-d₆) : δ 1.32 (d, J = 7.2 Hz, 6H) , 3.12-3.18 (m, 4H), 3.28-3.40 (m, 4H) , 3.48-3.50 (m, 3H) , 3.79-3.80 (m, 2H) , 3.92-3.97 (m, 4H) , 4.31 (s, 2H) , 5.37 (s, 2H) 7.10 (d, J = 9.2 Hz, 2H) , 7.44 (s, 1H) , 7.46 (d, J = 2 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 2H) , 7.73 (d, J = 8.4 Hz, 1H) , 8.19 (s, 1H) , 11.20 (br.s, 1H) , 11.30 (br.s, 1H)

The compounds of Examples A2 to A6 as shown in Table 5 were prepared according to similar procedure as used for the synthesis of Example Al .

[0388]

Table 5:

[0389]

Example A7: tert-butyl 4- [4- [2- (1-piperidylmethyl) -4H- imidazo [2,1-c] [1,4] benzoxazin-7-yl] phenyl] piperazine-1- carboxylate

[0390]

Intermediate 3-111 Example A7 [0391]

A mixture of Intermediate 3-III (0.50 g, 1.437 mmoL) ,

Intermediate l-III (0.723 g, 1.867 mmol) and K₂C0₃ (0.595 g, 4.31 mmol) in a mixture of dioxane-water (4:1, 15 mL) was degassed for 30 minutes with argon. PdCl₂dppf . DCM (0.060 g, 0.071 mmol) was added and the reaction mixture was heated at 90°C for 18 hours. After completion of the reaction (monitored by TLC) , the reaction mixture was taken into water (25 mL) and ethyl acetate (50 mL) . The organic layer was separated and washed with water (25 mL) and brine (25 mL) , dried over

anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography using 5 to 10% MeOH in dichloromethane as eluent to give the desired product Example A7 (0.5 g, 66%) as a dark brown solid; LCMS: m/z 530.3 [M⁺+l] .

¹HNMR (400 MHz, CDC1₃) : δ 1.25-1.28 (m, 6H) , 1.49 (s, 9H) ,

2...65-2.85 (m, 4H) , 3.20 (t, J = 5 Hz, 4H) , 3.49 (s,. 2H) , 3.60 (t, J = 5.2 Hz, 4H) , 5.26 (s, 2H) , 6.98 (d, J = 8.4 Hz, 2H) , 7.24-7.28 (m, 2H) , 7.32-7.34 (m, 1H) , 7.50 (d, J = 9.2 Hz, 2H) , 7.58-7.64 (m, 1H)

[0392]

The compounds of Examples A8 to A18 as described in Table 6 were prepared according to similar procedure as used for the synthesis of Example A7.

[0393]

Table 6

(morpholinomethyl ) - 4H-imidazo [2,1- c] [1, 4 ] benzoxazin- 7- yl] phenyl] piperazin

-l-carboxylate

tert-butyl 4- [5- [2-

3-1 and 1-

A9 (morpholinomethyl ) - LCMS: m/z 533.4 [M⁺+l]

XXII

4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazin- 7-yl]-2- pyridyl] piperazine- 1-carboxylate

tert-butyl 4- [3- [2- LCMS: m/z 432.3 [M⁺-BOC

A10 (morpholinomethyl) - 3-1 and 1-V + 1]

4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazin- 7- yl] phenyl] piperazin

e-l-carboxylate

3-1 and 1-

All LCMS: m/z 600.3[M⁺+1]

XIII

tert-butyl 4-[4-[2- (morpholinomethyl) - 4H-imidazo [2, 1-

merged in CDC1₃, 2H)

[0394]

Example A19: 7- [4- (4-ethylpiperazin-l-yl) phenyl] -2- (morpholinomethyl) -4H-imidazo [2 , 1-c] [1,4] benzoxazine [0395]

Intermediate 3-1 Example A19

[0396]

A mixture of Intermediate 3-1 (0.15 g, 4.27 mmol) ,

Intermediate 1-IV (0.16 g, 5.55 mmol) and K₂C0₃ (0.176 g, 12.80 mmol) in a mixture of dioxane-water (4:1, 5 mL) was degassed for 30 minutes with argon. Pd (PPh₃)₄ (0.059 g, 0.42 mmol) was added, thereto and the reaction mixture was stirred at 90°C for 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was taken into water (25 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with water (25 mL) and brine (25 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane to give the desired product Example A19. The product was dissolved in 4M HC1 in dioxane (3.0 mL) and the solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give dihydrochloride salt of Example A19; HPLC-MS : m/z 460.3 [M⁺+l]. ^""^"HNMR (400 MHz , DMSO-d₆) : δ 1.29 (t, J = 7.6 Hz, 3H) , 2.99-3.19 (m, 8 H) , 3.36-3.40 (m, 2H) , 3.54-3.56 (m, 2H) , 3.72-3.76 (m, 2H) , 3.89-3.98 (m, 4H) , 4.31 (s, 2H) , 5.36 (s, 2H) , 7.99 (d, J = 8.4 Hz, 2H) , 7.43 (s, 1H) , 7.44 (d, J = 2 Hz, 1H) , 6.64 (d, J = 9.2 Hz, 2H) , 7.72 (d, J = 8 Hz, 1H) , 8.14 (s, 1H) , 10.85 (br.s, lH) , 10^90 (br.s, 1H)

The compounds of Examples A20 to A27 as shown in Table 7 were prepared according to similar procedure as used for the synthesis of Example A19.

[0397]

Table 7:

2H) , 7.30 (d, J = 8.8

Hz, 1H) , 7.50 ( d , J = 7.2 Hz, 2H) , 7.85 (d, J = 11.2 Hz, 1H) , 8.13 (s, 1H) , 10.61 (br.s, 1H) , 10.70 (br.s, 1H)

HPLC-MS: m/z 464.3 [M⁺+l]

¹HNMR (400 MHz, DMSO-

2HCI

d₆) :

8-fluoro-7- [4- (4- δ 2.82 (d, J = 4.4 Hz methylpiperazin-1- 3H) , 3.14-3.19 (m, yl) phenyl] -2- 6H) , 3.39 (d, J = (morpholinomethyl ) 12.0 Hz, 2H) , 3.46- -4H-imidazo [2, 1- 3.50 (m, 2H) , 3.66- c] [ 1 , 4 ] benzoxazine 3.71 (m, 2H) , 3.75

A22 3-II and 1-1

(d, J = 11.2 Hz, 2H) , 3.91-3.98 (m, 2H) , 4.31 (s, 2H) , 5.35 (s, 2H) , 7.10 (d, J = 8.8 Hz, 2H) , 7.30 (d, J = 7.2 Hz, 1H) , 7.49 (d, J = 7.6 Hz, 2H) , 7.85 ( d , J = 10.8 Hz, 1H) , 8.14 (s, 1H), 10.82 (br.s, 2H)

/—\ HPLC-MS: m/z 475.1

[M⁺+l]

2HCI ^ R (400 MHz, DMSO-

3-VII and 1- d₆) :

A23

7-[4-(4- II δ 1.33 (d, J = 6.4 isopropylpiperazin Hz, 6H) , 3.10-3.21 -1-yl) phenyl] -2- (m, 5H) , 3.26 (t, J = (morpholin-4- 12.8 Hz, 2H) , 3.32-

HPLC-MS: m/z Alb.2

[M⁺+l]

^N R (400 MHz, DMSO- d₆) :

7- [4- (4- δ 1.33 (d, J = 6.4 isopropylpiperazin Hz, 6H), 3.12-3.16 -1-yl) phenyl] -2- (m, 2H^:) , 3.27-3.33 (morpholinomethyl ) (m, 4H) , 3.40-3.55 -4H- 3-VIII and 1- (m,. 4H) , 3.70-3.96

A27

[1,2,4] triazolo[5, II (m, 7H), 4.58 (s, 1- 2H) , 5.64 (s, 2H) , c] [ 1 , 4 ] benzoxazine 7.10 (d, J = 8 Hz,

2H), 7.46-7.52 (m, 2H) , 7.65 (d, J = 8. Hz, 2H) , 7.71 (d, J = 8.8 Hz, 1H) , 11.20 (br.s, 1H) , 11.50 (br.s, 1H)

[0398]

Example A28: tert-butyl 4- [4- [2- (morpholinomethyl) -4H- imidazo [2,1-c] [1,4] benzoxazin-7-yl] phenyl] piperazine-1- carboxylate

[0399]

Intermediate 3- Example A28

[0400]

A mixture of Intermediate 3-1 (0.10 g, 0.284 mmol) ,

Intermediate l-III (0.132 g, 0.341 mmol) and K₂C0₃ (0.117 0.854 mmol) in a mixture of dioxane-water (4:1, 5 mL) was degassed for 30 minutes with argon. Pd (PPh₃)₄ (0.032 g,

0.0284 mmol) was added and the reaction mixture was stirred at 90°C for 18 hours. After completion of the reaction (monitored by TLC) , the reaction mixture was taken into water (25 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with water (25 mL) and brine (25 mL) , dried over anhydrous a₂S0 and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography using 5% MeOH in dichloromethane to give the desired product Example A28 (0.080 g, 52%) as a creamy solid; LCMS: m/z 532.8 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 1.42 (s, 9H) , 2.40-2.48 (m, 4H) , 3.16 (t, J = 5 Hz, 4H) , 3.42 (s, 2H) , 3.47 (t, J = 5 Hz, 4H) , 3.57 (t, J = 4.5 Hz, 4H) , 5.28 (s, 2H) , 7.02 (d, J = 9.2 Hz, 2H) , 7.35 (s, 1H), 7.37 (s, 1Η),·7.58 (d, J = 8.8 Hz, 2H) , 7.67 (d, J = 8^'.8 Hz, 1H) , 7.80 (s, 1H)

[0401]

The compounds of Examples A29 to A35 as shown in Table 8 were prepared according to similar procedure as used for the synthesis of Example A28.

[0402]

Table 8:

yl] phenyl] piperazin

e-l-carboxylate

tert-butyl 4- [4- [2- (morpholinomethyl) - LC S: jn/z 529.3

A30 3-1 and 1-VI

4H-imidazo [2, 1- [M⁺+l] c] [1, 4 ] benzoxazin- 7-yl] phenyl] -3, 6- dihydro-2H- pyridine-1- carboxylate

0

tert-butyl 4- [4- [2- (morpholinomethyl ) - LCMS: m/z 547.4

A31 3-1 and 1-XXI

4H-imidazo [2, 1- [Μ⁺+1Γ c] [1, 4 ] benzoxazin- 7- yl] phenoxy] piperidi

ne-l-carboxylate

tert-butyl 4- [2- 3-1 and 1- LCMS: m/z 575.3

A32

carbamoyl-4- [2- XVIII [M⁺+l] (morpholinomethyl) - 4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazin- 7-

2H) , 7.38-7.42 (s,

2H) , 7.42-7.48 (m,

IH) , 7.55-7.58 (m,

IH)

/—\

tert-butyl 4- [3- [2-

(morpholinomethyl) -

LCMS: m/z 529.3

A35 4H-imidazo [2, 1- 3-1 and 1-X

[M⁺+l] c] [1, 4 ] benzoxazin- 7-yl] phenyl] -3,6- dihydro-2H- pyridine-1- carboxylate

[0403]

Example A36: tert-butyl 4- [4- [2- (morpholinomethyl) -4H- imidazo [2,1-c] [1,4] benzoxazin-7-yl ] phenyl] piperidine-1- carboxylate

[0404]

[0405]

A mixture of Example A30 (0.60 g, 1.136 mmol) and 10% Pd/C (0.120 g) in MeOH-EtOAc (1:1, 24 mL) was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 12 hours. The catalyst was removed by filtration through celite pad and washed with MeOH (20 mL) . The filtrate was concentrated under reduced pressure to give crude product that was purified by preparative TLC using 15% MeOH in dichloromethane as solvent system to give the desired product Example A36 as a white solid (0.50 g, 85%); LCMS : m/z 431.2 [M⁺-BOC+l] .

[0406]

Example A37 : 2- [ 4- [ 3- [2- (morpholinomethyl ) -4H-imidazo [2 , 1- c] [1,4] benzoxazin-7-yl] phenyl] -1-piperidyl ] ethanol

[0407]

Example A34 Example A37

[0408]

To a solution of Example A34 (0.06 g, 0.127 mmol) in ethyl acetate (5 mL) was added 10% Pd/C (0.012 g) and the mixture was stirred under hydrogen atmosphere (balloon

pressure) for 18 hours. The reaction was diluted with ethyl acetate (20 mL) . The catalyst was removed by filtration over a pad of celite and the filtrate was concentrated under reduced pressure to give crude product, which was purified by

preparative HPLC to give the desired product Example A37 as an off-white solid. The product so obtained was dissolved in 3M HC1 (2..5 mL) in MeOH and the solution was stirred for 3 hours at room temperature. The volatiles were removed under reduced pressure to obtain 2HC1 salt of Example A37 (0.02 g, 29%) as an off-white solid; HPLC-MS: m/z Alb.2 [M⁺+l].

XHNMR (400 MHz, DMSO-d₆) : δ 2.01-2.16 (m, 2H) , 2.87-2.91 (m, 1H) , 3.05-3.21 (m, 4H) , 3.27-3.41 (m, 4H) , 3.60-3.83 (m, 5H) , 3.95-4.06 (m, 2H) , 4.10-4.29 (m, 4H) , 4.31 (s, 2H) , 5.40 (s, 2H) , 7.26 (d, J = 7.2 Hz, 1H) , 7.42-7.59 (m, 4H) , 7.66 (br.s, 1H) , 7.79 (app t, J = 8.4 Hz, 1H) , 8.16 (d, J = 4.8 Hz, 1H) , 10.04 (br.s, 1H) , 10.90 (br.s, 1H)

[0409] Example A38 : 2- (morpholinomethyl) -7- (4-piperazin-l-ylphenyl) - 4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

[0410]

[0411]

4M HC1 in dioxane (1.5 mL) was added dropwise to a solution of Example A28 (0.08 g, 0.15 mmol) in dioxane (1 mL) at 0°C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was concentrated to dryness to give 3HC1 salt of the desired product Example A38 (0.037 g, 69%) as an off-white solid; 3HC1 salt formation is supported by ^""-HNMR analysis; HPLC-MS: m/z 432.2 [M⁺+l] .

¹HN R_.(400 MHz, DMSO-d₆) : δ 3.16-3.22 (m, 6H) , 3.37-3.49 (m, 8H) , 3.70-3.78 (m, 2H) , 3.95 (s, 2H) , 5.63 2H) 7.7 (d, J=

8.8 Hz, 2H) , 7.44 (d, J = 8.8 Hz, 2H) , 7.63 (d, J = 8.8 Hz 7.73 (d, J = 8 Hz, 1H),^'8.14 (s, 1H) , 9.28 (br.s, 2H) , 10.0 (br.s, 1H) , 11.0 (br.s, 1H)

[0412]

The compound of Example A39 as shown in Table 9 was prepared according to similar procedure as used for the synthesis of Example A38.

[0413]

Table 9:

[0414]

Example A40: 7- (2-fluoro-4- (piperazin-l-yl) phenyl) -2- (morpholinomethyl) -4H-imidazo [2,1-c] [1,4] benzoxazine

0415]

[0416]·

4M HC1 in methanol (6.3 mL) was added to a solution of Example A15 (0.350 g, 0.63 mmol) in MeOH at 0°C. After stirring for 2 hours at room temperature, the reaction mixture was concentrated to dryness and the obtained residue was neutralized using saturated aqueous NaHC0₃ solution (~10 mL) till the pH was adjusted to ~8. The volatiles were evaporated and the reaction mixture was diluted with 10% MeOH in

dichloromethane (25 mL) . The inorganic material was removed by filtration and the filtrate was concentrated under reduced pressure to give the desired product Example A40 as a brown solid (0.261 g, 91%); LCMS : m/z 225.7 [M⁺/2+l] .

1HNMR (400 MHz, CDC1₃) : δ 2.57 (br.s, 4H)^', 3.06 (t, J = 4.8 Hz, 4H) , 3.23 (t, J = 5.2 Hz, 4H) , 3.55-(s, 2H) , 3.76 (t, J = 4.8 Hz, 4H) , 5.27 (s, 2H) , 6.66 (dd, J = 14.4 Hz, J = 2.8 Hz, 1H) , 6.75 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H) , 7.22-7.24 (m, 2H) , 7.28-7.34 (m, 3H)

[0417]

The compounds of Examples A41 to A56 as shown in Table 10 were prepared according to similar procedure as used for the synthesis of Example A40.

[0418]

Table 10:

azol-4-yl] -4H- imidazo [2,1- c [1, ] benzoxazine

7- (2-methoxy-4-

A55 A29

(piperaz'in-1- yl) phenyl) -2- (morpholinomethyl) - 4H-imidazo [2, 1- c] [ 1 , ] benzoxazine

2-

LC S: m/z 215.3

A56 (morpholinomethyl) - A35

[M⁺/2 + 1]

7-[3-(l,2,3,6- tetrahydropyridin-

4-yl) phenyl] -4H- imidazo [2,1- c] [ 1 , 4 ] benzoxazine

[0419]

Example A57 : 7- [3-methyl-4- (4-methylpiperazin-l-yl) phenyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0420]

[0421]

To a solution of Example A47 (0.2 g, 0.44 mmol) in a mixture of DCE-MeOH (1:1, 3 mL) were added 37% aqueous HCHO (0.2 mL, 4.48 mmol), ~2 drops of AcOH and powdered molecular sieves (0.1 g, 4A) . The resulting reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (0.139 g, 2.24 mmol) was added thereto and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by TLG) , the solid was filtered, and the filtrate was taken into water (15 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with saturated aqueous NaHC0₃ solution (25 mL) , brine (25 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example A57. The product was dissolved in 4M HC1 in dioxane (2.5 mL) and the solution was stirred for 4 hours at room temperature. The solvent was evaporated under reduced pressure to give 2HC1 salt of the desired product

Example A57 (0.075 g, 36%) as an off-white solid; HPLC-MS : m/z 460.5 [M⁺+l] .

^XHNMR (400 MHz, DMSO-d₆) : δ 2.31 (s, 3H) , 2.81 (d, J = 4 Hz, 3H) , 3.09-3.23 (m, 8H) , 3.35-3.38 (m, 2H) , 3.44-3.46 (m, 2H) , 3.67-3.71 (m,. 2H) , 3.92-3.95 (m, 2H) , 4.28 (s, 2H) , 5.35 (s, 2H) , 7.10 (d, J = 8.4 Hz, 1H) , 7.41 (s, 1H) , 7.43 (d, J = 2 Hz, 1H) , 7.51 (d, J = 8.8, 1H) , 7.54 (d, J = 2 Hz, 1H) , 7.73 (d, J = 8 Hz, 1H) , 8.14 (s, 1H) , 11.02 (br.s, 2H)

[0422]

The compounds of Examples A58 to A70 as shown in Table 11 were prepared according to similar procedure as used for the synthesis of Example A57. Hydrochloride salts, wherever

applicable, were prepared according to similar procedure as used for the preparation of the 2HC1 salt of Example A57.

[0423]

Table 11 :

[0424]

Example A71: 7- [3- (l-methyl-3, 6-dihydro-2H-pyridin-4- yl)phenyl] -2- (morpholinomethyl ) -4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazine

[0425]

Example A56 Example A71

[0426] To a solution of ^"Example A56 (0.1 g, 0.223 mmol) in a mixture of DCE-MeOH (1:1, 6 mL) were added 37% aqueous HCHO (0.2 mL, 2.33 mmol), ~2 drops of AcOH and powdered molecular sieves (0.25 g, 4A) . The resulting reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (0.069 g, 1.11 mmol) was added thereto and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by TLC) , the solid was filtered, and the filtrate was taken into water (15 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with saturated aqueous NaHC0₃ solution (25 mL) , brine (25 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by preparative TLC using 15% MeOH in dichloromethane as solvent system to give the desired product Example A71 (0.080 g, 77%) as brown oil; LCMS : m/z 443.2 [M⁺+l],

[0427]

Example A72 : 7- [4- (4-isopropylpiperazin-l-yl) -3-methylphenyl] - 2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0428]

[0429]

To a solution of Example A47 (0.2 g, 0.44 mmol) in a mixture of DCE-MeOH (1:1, 4 mL) were added acetone (0.34 mL, 4.48 mmol), ~2 drops of AcOH and powdered molecular sieves (0.2 g, 4A) . The resulting reaction mixture was stirred for 1 hour, sodium cyanoborohydride (0.139 g, 2.24 mmol) was added thereto and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered,^' and the filtrate was taken into water (15 mL) and ethyl acetate (25 mL) . The organic layer was .separated and washed with saturated NaHC0₃ solution (25 mL) , brine (25 mL) and dried over anhydrous a₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example A72. The product was dissolved in 4M HC1 in dioxane (3, mL) and the solution was stirred for 4 hours at room temperature. The solvent was evaporated under reduced pressure to give 2HC1 salt of the desired product Example A72 (0.098 g, 39%) as an off-white solid; HPLC-MS: m/z 488.31

[M⁺+l]

^XHNMR (400 MHz , DMSO-d₆) : δ 1.34 (d, J = 6.4 Hz, 6H) , 2.34 (s, 3H) , 3.16-3.27 (m, 9H) , 3.38-3.72 (m, merged in DMSO water signal, 6H) , 3.95-3.98 (m, 2H) , 4.32 (s, 2H) , 5.37 (s, 2H) , 7-.12 (d, J = 8 Hz, 1H) , 7.43 (s, 1H) , 7.45 (d, J = 2 Hz, 1H) , 7.54 (d, J = 8 Hz, 1H) , 7.57 (d, J = 2 Hz, 1H)^', 7.77 (d, J = 8 Hz, 1H) , 8.1_.3 (s, 1H) , 10.20 (br.s, 1H) , 10.45 (br.s, 1H)

[0430]

The compounds of Examples A73 to A87 as shown in Table 12 were prepared according to similar sequence of procedures as used for the synthesis of Example A72.

[0431]

Table 12:

3.94-3.97 (m, 2H) ,

4.04 (d, J = 8.4 Hz, 2H) , 4.29 (s, 2H), 5.34 (s, 2H) , 7.37 (d, J = 2 Hz, IH) , 7.40 (app. t, J = 1.6 Hz, IH) , 7.68 (d, J = 8.4 Hz , IH) , 7.99 (s, IH) , 8.12 (s, IH) , 8.29 (s, IH) , 10.11 (br.s, IH), 10.99 (br.s, IH)

[0432]

Example A88: 7- [3- (l-isopropyl-3, 6-dihydro-2H-pyridin-4- yl) phenyl] -2- (morpholinomethyl ) -4H-imidazo [2, 1- c] [1, 4] benzoxazine

[0433]

Example A56 Example A88

[0434]

To a solution of Example A56 (0.1 g, 0.233 mmol) in a mixture of DCE-MeOH (1:1, 6 mL) were added acetone (0.10 mL, 1.39 mmol), ~2 drops of AcOH and powdered molecular sieves (0.25 g, 4A) . The resulting reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (0.072 g, 1.165 mmol) was added thereto and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by TLC) , the solid was filtered, and the filtrate was taken into water (15 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with saturated NaHC0₃ solution (25 mL) , brine (25 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude . product so obtained was purified by preparative TLC using 10% . eOH in dichloromethane as solvent system to give the desired product Example A88 (0.075 g, 65%) as a brown solid.

[0435]

Example A89: 7- [6- (4-ethylpiperazin-l-yl) -3-pyridyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0436]

[0437]

To a solution of Example A41 (0.07 g, 0.16 mmol) in a mixture of DCE-MeOH (1:1, 4 mL.) were added acetaldehyde (0.037 g, 0.83 mmol), AcOH (~ 2 drops) and activated powdered

molecular sieves (0.1 g, 4A) . The resulting reaction mixture was stirred for 1 hour, sodium cyanoborohydride (0.105 g, 1.67 mmol) was added thereto and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by^' TLC) , the solid was filtered, and the filtrate was taken into water (10 mL) and ethyl acetate (15 mL) . The organic layer was separated and washed with saturated NaHC0₃ solution (15 mL) , brine (15 mL) and dried over anhydrous Na₂S0₄. The ,crude product obtained after evaporation of solvent was purified by preparative TLC using 10% MeOH in dichloromethane as eluent to give the desired product Example A89. The product was dissolved in 4M HC1 in dioxane (2.5 mL) and the solution was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure and dried under vacuum to give 2HC1 salt of the desired compound Example A89 (0.021 g, 22%) as an off-white solid; HPLC-MS: m/z 461.2

[M⁺+l].

¹HN R (400 MHz, DMSO-d₆) : δ 1.28 (t, J = 7.6 Hz, 3H) , 2.99 - 3.28 (m, 4H) , 3.31-3.46 (m, 4H) , 3.47-3.50 (m, 2H) , 3.56 (d, J = 11.6 Hz, 2H) , 3.65-3.94 (merged in DMSO water signal, 4H) , 4.31 (s, 2H) , 4.47 (d, J = 14.4 Hz, 2H) , 5.37 (s, 2H) , 7.09 (d, J = 9.2 Hz, IH) , 7.47 (d, J = 1.6 Hz, IH) , 7.50 (s, IH) , 7.76 (d, J = 8.4 Hz, IH) , 8.04 (d, J = 9.2 Hz, IH) , 8.15 (s, IH) , 8.55 (d, J = 2.0 Hz, IH) , 10.85 (br.s, 2H)

[0438]

The compounds of Examples A90 to A92 as shown in Table 13 were prepared according to similar procedure as used for the synthesis of Example A89.

[0439]

Table 13:

Hz, 1H) , 7.18-7.20 (m,

3H) , 7.33 (d, J = 8.8 Hz, 1H) , 7.76 (d, J = 8.8 Hz, 1H) , 8.14 (s, 1H) , 10.82 (br.s, 2H)

[0440]

Example A93 : 7- [3- ( l-isopropyl-4-piperidyl ) henyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0441]

Example A93

[0442]

A mixture of Example A88 (0.075 g, 0.15 mmol) and 10% Pd/C (0.015 g) in MeOH (3 mL) was stirred under ' hydrogen

atmosphere (balloon pressure) at room temperature for 16 hours. The catalyst was removed by filtration through celite pad and washed with MeOH (20 mL) . The filtrate was concentrated under reduced pressure to give crude product that was purified by preparative HPLC to give the desired product Example A93. The product was dissolved in 6N aqueous HC1 (8 mL) and the

solution was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give 2HC1 salt of Example A93 as a yellow solid (0.017 g, 19.7%); HPLC- MS: m/z 473.2 [M⁺+l] .

1HNMR (400 MHz, DMSO-d₆) : δ 1.32 (d, J = 6.8 Hz, 6H) , 2.03 (d, J = 12.8 Hz, 2H) , 2.24-2.28 (m, 2H) , 2.89-3.01 (m, 1H) , 3.02- 3.22 (m, 4H) , 3.42 (t, J = 13.2 Hz, 4H) , 3.45-3.48 (m, 1H) , 3.78 (t, J = 11.2 Hz, 2H) , 3.95-3.99 (m, 2H) , 4.32 (s, 2H) , 5.39 (s, 2H) , 7.27 (d, J = 7.6 Hz, 1H) , 7.43-7.48 (m, 3H) ,

7.55-7.58 (m, 2H) , 7.80 (d, J = 8.8 Hz, 1H) , 8.17 (s, 1H) , 10.50 (br.s, 1H) , 10.90 (br.s, 1H)

[0443]

Example A94 : 7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8-methyl- 2- (morpholinomethyl) -4H-imidazo [2, 1-c] [ 1 , 4 ] benzoxazine

[0445]

Step I: [7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8-methyl-4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2-yl] methanol (A-1)

A solution of Intermediate 3-VI (0.100 g, 1.33 mmol) ,

Intermediate l-II (0.134 g, 0.40 mmol) and K₂C0₃ (0.116 g, 8.84 mmol) in a mixture of dioxane/water (4:1, 5 mL) was degassed in a stream of argon for 15 minutes. To this mixture was added 1-bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.027 g, 0.033 mmol) and the mixture was degassed for additional 15 minutes. After stirring at 90°C for 12 hours, the reaction mixture was diluted with water (15 mL) followed by extraction with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (25 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product A-1 as a dark brown solid (0.06 g, 42%); LCMS: m/z 210.2 [M⁺/2+l] . [0446]

Step II: 2- ( chloromethyl ) -7- [4- ( 4-isopropylpipe^'razin-l- yl) phenyl] -8-methyl-4H-imidazo [2, 1-c] [ 1 , 4 ] benzoxazine (A-2)

To a solution of A-l (0.06 g, 0.14 mmol) and Et₃N (0.05 mL, 0.35 mmol) in dichloromethane (5 mL) was added S0C1₂ (0.0.2 mL, 0.28 mmol) at 0°C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL) and water (15 mL) . The layers were separated and the organic, layer was washed with brine (25 mL) , dried over anhydrous Na₂S0 and concentrated to dryness to give the desired product A-2 as a brown solid (0.06 g, 99% crude) . The desired crude product A-2 was used in the next step^' without purification.

[0447]

Step III: 7- [4- ( 4-isopropylpiperazin-l-yl) phenyl] -8-methyl-2- (morpholinomethyl) -4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine (Example A94)

To a solution of A-2 (0.06 g, 0.13 mmol) in DMF (3 mL)^' were added dropwise DIPEA (0.06 mL, 0.34 mmol) and morpholine (0.02 mL, 0.27 mmol) at room temperature and heated at 60°C for 12 hours. The volatiles were removed by evaporation and the obtained residue was diluted with water (20 mL) and EtOAc (20 mL) . The organic layer was separated and the aqueous layer was back extracted using EtOAc (10 mL x 2) . The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example A94. The product was dissolved in 4M HC1 in dioxane and the solution was stirred at room

temperature for 2 hours. The volatiles were removed under reduced pressure to give 2HC1 salt of Example A94 (0.023 g, 30%) as an off-white solid; HPLC-MS: m/z 488.3 [M⁺+l].

1HNMR (400 MHz, DMSO-d₆) : δ 1.12 (d, J = 6.8 Hz, 6H) , 2.27 (s, 3H) , 2.56-2.58 (m, 4H) , 2.73 (t, J = 4.0 Hz_y_4H), 2.75-2.79 (m, 1H) , 3.28 (t, J = 5.6 Hz, 4H) , 3.55 (S, 2H) , 3.75 (t, J = 4.8 Hz, 4H) , 5.22 (s, 2H) , 6.95-6.97 (m, 3H) , 7.12 (s, 1H) , 7.20

(d, J = 8.8 Hz, 2H) , 7.29 (s, 1H), 10.92 (br.s, 2H)

The compounds of Examples A95 and A96 as shown in Table

14 were prepared according to analogous sequence of procedures as used for the synthesis of Example A94.

[0448]

Table 14:

yl) phenyl] -8- 3.08-3.19 (m, 4H) , methyl-2- 3.37-3.40 (m, 2H) , (morpholinomethyl ) 3.45-3.51 (m, 2H) , -4H-imidazo [2, 1- 3.55-3.59 (m, 2H) , c] [ 1 , 4 ] benzoxazine 3.65-3.75 (m, 4H) ,

3.87-3.97 (m, 4H) ,

4.30 (s, 2H) , 5.31 (s,

2H) , 6.95 (s, 1H) , 7.07 (d, J = 8.8 Hz,

2H) , 7.27 (d, J = 8.8

Hz, 2H), 7.63 (s, 1H) ,

8.12 (s, 1H) , 10.82 (br.s, 1H) , 10.86 (br.s, 1H)

[0449]

Example A97 : (4-isopropylpiperazin-l-yl) - [4- [2- (morpholinomethyl) -4H-imidazo [2, 1-c] [1,4] benzoxazin-7- yl] phenyl] methanone

[0450]

Intermediate 3-1 A-3

Step I: 4- [2- (morpholinomethyl ) -4H-imidazo [2, 1- c] [1, ] benzoxazin-7-yl] benzoic acid (A-3)

A- mixture of Intermediate 3-1 (0.3 g, 0.85 mmol) , 4- boronobenzoic acid (0.15 g, 0.94 mmol) and Na₂C0₃ (0.22 g, 2.14 mmol) in acetonitrile-water (4:1, 5 mL) was degassed under^' argon for 30 minutes. Pd (PPh₃)₄ (0.099 g, 0.085 mmol) was added thereto and degassing was continued for another 10 minutes. The resulting reaction mixture was heated at 90°C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The volatiles were removed under reduced pressure, and the crude product was taken into minimum amount of water and neutralized with IN HC1 to adjust the pH to ~5. The resulting solution was

concentrated to dryness. The obtained residue was suspended in 5% eOH in dichloromethane (100 mL) and the inorganic material was removed by filtration. The filtrate was concentrated under reduced pressure to give crude product, which was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product A-3 (0.33 g, 98%) as a yellow solid; LCMS: m/z 392.1 [M⁺+l] .

[0452]

Step II: ( 4-isopropylpiperazin-l-yl ) - [4- [2- (morpholinomethyl) - 4H-imidazo [2,1-c] [1,4] benzoxazin-7-yl] phenyl] methanone

(Example A97)

To a solution of A-3 (0.165 g, 0.42 mmol) in DMF (5 mL) were added 1-isopropylpiperazine (0.07 g, 0.54 mmol) and

diisopropylethylamine (0.109 g, 0.84 mmol) at room temperature. After 10 minutes, HATU (0.24 g, 0.63 mmol) was added thereto and stirring was continued for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example A97 as an off-white solid. The product was dissolved in 3M HC1 in MeOH (3 ^'mL) and the solution was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure to give 2HC1 salt of Example A97 (0.160, 66%) as an off-white solid; HPLC-MS: m/z 502.4

[M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 1.28 (d, J = 6.8 Hz, 6H) , 2.85-2.92 (m, 4H) , 3.12-3.29 (m, 5H) , 3.32-3.58 (m, 4H) , 3.65-3.71 (m, 4H) , 4.32 (s, 2H) , 5.40 (s, 2H) , 7.55 (dd, J = 2.4 Hz, 3.6 Hz, 2H) , 7.59 (d,J = 8.4 Hz, 2H) , 7.82 (d, J = 8.8 Hz, 3H) , 8.16 (s, 1H) , 9.38 (br.s, 1H) , 10..62 (br.s, 1H)

[0453]

The compound of Example A98 as shown in Table 15 was prepared from Intermediate 3-1 according to analogous sequence of procedures as used for the synthesis of Example A97.

[0454]

Table 15:

[0455]

Example Bl : 7- [4- (4-isopropylpiperazin-l-yl) phenyl]

morpholinoethyl ) -4H-imidazo [2,1-c] [1,4] benzoxazine

[0456]

[0457]

A mixture of Intermediate 5-1 (0.35 g, 0.958 mmol) ,

Intermediate l-II (0.475 g, 1.15 mmol) and K₂C0₃ (0.396 g, 2.87 mmol) in a mixture of dioxane-water (4:1, 5 mL) was degassed for 30 minutes with argon. PdCl₂dpp . DCM (0.02 g, 0.023 mmol) was added thereto and the reaction mixture was heated at 100°C for 18 hours. After completion of the reaction (monitored by TLC) , the reaction mixture was taken into water (20 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with water (20 mL) followed by brine (20 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 10% MeOH in dichloromethane as solvent system to give the desired product Example Bl . The product was dissolved in 4M HC1 in dioxane and the solution was stirred at room

temperature for 2 hours. The volatiles were removed under reduced pressure to give 2HC1 salt of Example Bl (0.017 g, 38%) as an off-white solid; HPLC-MS: m/z 488.2 [M⁺+l].

1HNMR (400 MHz, DMSO-d₆) : δ 1.33 (d, J = 6.4 Hz, 6H) , 3.09-3.20 (m, 5H) , 3.27 (t, J = 12 Hz, 4H) , 3.88-3.56 (m, 6H) , 3.93-3.94 (m, 6H) , 5.44 (s, 2H) , 7.00 (d, J = 8.4 Hz, 2H) , 7.44-7.47 (m, 2H) , 7.65 (d, J = 8.8 Hz, 2H) , 7.75 (d, J = 8 Hz, 1H) , 8.10 (s, 1H), 11.0 (br.s, 1H) , 11.65 (br.s, 1H)

[0458]

The compounds of Examples B2 and B3 as shown in Table 16 were prepared according to similar procedure as used for the synthesis of Example Bl . [0459]

c] [ 1 , 4 ] benzoxazine water signal, 2H) ,

5.33 (s, 2H), 7.09

(d, J = 8.4 Hz,

2H) , 7.40 (s, IH) ,

7.43 (s, IH) , 7.63

(d, J = 9.2 Hz,

2H) , 7.68 (d, J =

8.4 Hz, IH) , 7.88

(s, IH) , 10.50

(br.s, IH), 10.82

(br.s, IH)

[0460]

Example B4 : tert-butyl 4- [3-methyl-4- [2- (2-morpholinoethyl) - 4H-imidazo [2,1-c] [1,4] benzoxazin-7-yl] phenyl] piperazine-1- carboxylate

[0461

Intermediate 5-1 Example B4

[0462]

A mixture of Intermediate 5-1 (0.30 g, 0.822 mmol),

Intermediate 1-XV (0.662 g, 1.64 mmol) and K₂C0₃ (0.341 g, 2.47 mmol) in a mixture of dioxane-water (4:1, 13 mL) was degassed for 30 minutes with argon. PdCl₂dppf . DCM (0.033 g, 0.0412 mmol) was added thereto and the reaction mixture was heated at

100°C for 18 hours. After completion of the reaction

(monitored by TLC) , the reaction mixture was taken into water (20 mL) and ethyl acetate (25 mL) . The organic layer was separated and washed with water (20 mL) followed by brine (25 mL) , dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography using 5% MeOH in dichloromethane as solvent system to give the desired product Example B4 (0.320 g, 72%) as an off-white solid; LCMS : m/z 252.7 [M⁺-^tBu/2+l] . .

""^"HNMR (400 MHz , DMSO-d₆) : δ 1.42 (s, 9H) , 2.23 (s, 3H) , 2.42 (br.s, 4H) , 2.54-2.60 (m, 2H) , 2.68-2.72 (m, 2H) , 3.12 (t, J = 5.6 Hz, 4H) , 3.46 (t, J = 5.2 Hz, 4H) , 3.59 (t, J = 4.0 Hz, 4H) , 5.27 (s, 2H), 6.83 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H) , 6.87 (d, J = 1.6 Hz, 1H) , 7.02-7.03 (m, 2H) , 7.08 (d, J = 8.8 Hz, lH) , 7.60 (d, J = 8.0 Hz, 1H) , 7.67 (s, 1H)

[0463]

The compounds of Examples B5 to B8 as shown in the Table 17 were prepared according to similar procedure as used for the preparation of Example B4.

[0464]

LC S: m/z 252.7

[M⁺-^tBu/2+l]

1HNMR (400 MHz, DMSO-de) :

tert-butyl 4- [ [4- [2- 5 1.45 (s, 9H) , ( 2-morpholinoethyl ) - 2.41 (t, J = 4.8 4H-imidazo [2 , 1- Hz, 4H) , 2.56 (t, c] [1, 4 ] benzoxazin-7- J = 4.4 Hz, 4H) , yl ] phenyl ] methyl ] pip 2.76 (t, J = 8.4 erazine-1- Hz, 2H), 2.86 (t,

B6 5-1 and 1-XX

■ carboxylate J = 8.4 Hz, 2H) ,

3.44 (t, J = 4.8 Hz, 4H), 3.55 (s, 2H) , 3.76 (t, J = 4.4 Hz, 4H) , 5.27 (s, 2H), 7.18 (s, 1H) , 7.29-7.31 (m, 3H) , 7.39 (d, J = 8 Hz, 2H) , 7.52 (d, J = 8 Hz, 2H)

tert-butyl 4- [4- [2- LCMS: m/z 561.3 [M⁺

B7 5-1 and 1-XXI

( 2-morpholinoethyl ) - + 1]

4H-imidazo [2, 1- c] [1, 4 ] benzoxazin-7- yl] phenoxy] piperidin

e-l-carboxylate

LCMS: m/z 576.3

B8 5-1 and 1-XVI

[M⁺+l] tert-butyl 4-[3- methoxy-4- [2- (2- morpholinoethyl) -4H- imidazo [2,1- c] [1, 4 ] benzoxazin-7- yl ] phenyl ] piperazine

-1-carboxylate

[0465]

Example B9 : 2- (2-morpholinoethyl) -7- [4- ( 4- piperidyloxy) phenyl] -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0466

Example B7 Example B9

[0467]

To a solution of Example B7 (0.290 g, 0.510 mmol) in dioxane (2 mL) was added dropwise 4M HC1 in dioxane (5.1 mL) at 0°C. After complete addition, the reaction mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure and saturated aqueous NaHCC>3 solution (15 mL) was added thereto. The mixture was

concentrated to dryness, the residue so obtained was suspended in 10% MeOH in dichloromethane (50 mL) and the insoluble

inorganic material was removed by filtration. The filtrate was concentrated to dryness to give the desired product Example B9 (0.205 g, 86%) as a brown solid; LCMS : m/z 231.3 [M⁺/2+l] .

1HNMR (400 MHz, CDC1₃) : δ 1.65-1.71 (m,- merged in CDC1₃ water signal, 3H) , 2.02-2.05 (m, 2H) , 2.55 (t, J = 4.8 Hz, 4H) ,

2.71-2.77 (m, 4H) , 2.85 (t, J = 8.4 Hz, 2H) , 3.13-3.18 (m, 2H) , 3.75 (t, J = 4.8 Hz, 4H) , 4.41 (quin., 1H) , 5.26 (s, 2H) , 6.98 (d, J = 8.8 Hz, 2H) , 7.17 (s, 1H) , 7.24 (d, J = 1.2 Hz, 2H) , 7.26 (m, merged with CDC1₃, 1 H ) , 7.48 (d, J = 8.0 Hz, 2H)

[0468]

The compounds of Examples BIO to B13 as shown in Table were prepared according to similar procedure as used for the synthesis of Example B9.

[0469]

Table 18:

[0470]

Example B14: 7- [3-methyl-4- (4-methylpiperazin-l-yl) phenyl] -2- (2-morpholinoethyl) -4H-imidazo [2, 1-c] [1,4] benzoxazine

[0471]

Example B12 Example B14

[0472]

The compound of Example B14 was prepared from the compound of Example B12 according to similar procedure as used for the synthesis of the compound of Example A57 from the compound of Example A47 ; HPLC-MS: m/z 474.1 [M⁺+l] . ¹HN R (400 MHz , DMSO-d₆) : δ 2.33 (s, 3H) , 2.83 (d, J = 4.8 Hz, 3H) , 3.09-3.32 (m, 10H) , 3.41-3.56 (m, 5H) , 3.66-3.71 (m, 1H) , 3.90 (br.s, 4H), 5.41 (s, 2H) ,· 7.12 (d, J = 8.4 Hz, 1H) , 7.42- 7.43 (m, 1H) , 7.46 (d, J = 1.6 Hz, 1H) , 7.53 (d, J = 8.0 Hz, 1H) , 7.56 (d, J = 1.6 Hz, 1H) , 7.74 (d, J = 8.0 Hz, 1H) , 8.02 (s, 1H) , 10.91 (br.s, 1H) , 11.25 (br.s, lH)

[0473]

The compounds of Examples B15 to B17 as shown in Table 19 were prepared according to similar procedure as used for the synthesis of Example B14.

[0474]

Table 19:

(d, J =.1.2 Hz, 1H) ,

7.43 (s, 1H) , 7.64- 7.71 (m, 3H) , 7.92 (s, 1H), 10.58

(br.s, 1H) , 11.05 (br.s, 1H)

[0475]

Example B18: 7- [4- (4-ethylpiperazin-l-yl) -3-methylphenyl] -2- (2-morpholinoethyl) -4H-imidazo [2, 1-c] [1,4] benzoxazine

[0476]

Example B12 Example B18

[0477]

The compound of Example B18 was synthesized from the compound of Example B12 according to similar procedure as used for the synthesis of the compound of Example A89 from the compound of Example A41 ; HPLC-MS: m/z 488.1 [M⁺+l] .

1HNMR (400 MHz, DMSO-d₆) : δ 1.30 (t, J = 7.6 Hz, 3H) , 2.34 (s, 3H) , 3.10-3.25 (m, 10H) , 3.35-3.50 (m, 4H) , 3.66-3.75 (m, 4H) , 3.91 (br.s, 4H) , 5.39 (s, 2H) , 7.12 (d, J = 8.4 Hz, 1H) , 7.42 (s, 1H) , 7.45 (d, J = 1.6 Hz, 1H) , 7.53 (d, J = 8.4 Hz, 1H) ,

7.56 (d, J = 1.6 Hz, 1H) , 7.73 (d, ^"J = 8 Hz, 1H) , 7.98 (s, 1H) ,

10.80 (br.s, 1H) , 11.20 (br.s, 1H)

[0478]

The compound of Example B19 as shown in Table 20 was prepared according to similar procedure as used for the

synthesis of Example B18.

[0479] Table 20:

[0480]

Example B20: 7- [ 4- ( 4-isopropylpiperazin-l-yl ) -3-methylphenyl ] - 2- (2-morpholinoethyl) -4H-imidazo [2, 1-c] [ 1, 4 ] benzoxazine

[0481]

[0482]

The compound of Example B20 was prepared from the compound of Example B12 according to similar procedure as used for the synthesis of the compound of Example A72 from the compound of Example A47; HPLC-MS: m/z 502.1 [M⁺+L] .

XHNMR (400 MHz, ^" DMSO-d₆) : δ 1.35 (d, J = 7.2 Hz, 6H) , 2.34. (s, 3H) , 3.08-3.12 (m, 2H) , 3.17-3.24 (m, 7H) , 3.31-3.53 (m, 8H) , 3.90-4.06 (m, merged in DMSO moisture, 4H) 5.37 (s, 2H) , 7.12 (d, J = 8 Hz, 1H) , 7.42 (s, 1H) , 7.45 (d, J = 2 Hz, 1Ή) , 7.53 (d, J = 8 Hz, 1H) , 7.56 (d, J = 2 Hz, 1H) , 7.72. (d, J = 8 Hz, 1H) , 7.95 (s, 1H) , 10.60 , (br. s, ^' 1H) , 11.10 (br.s, 1H)

[0483] ^{' ·' ''}

The compounds of Examples B21 to B24 as shown in Table 21 were prepared according to- similar procedure as used for the synthesis of Example B20.

[0484]

Table 21:

c] [1, ] benzoxazine 2H) , 6.65 (d, J =

8.8 Hz, IH) , 6.71

(d, J = 1.6 Hz, IH) ,

7.21-7.25 (m, 3H) ,

7.64 (d, J = 8.8 Hz,

IH), 7.90 (br.s,

IH), 10.65 (br.s,

IH), 10.95 (br.s,

IH)

[0485]

Example B25: 7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8-:

2- (2-morpholinoethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

[0486]

Intermediate 3-VI B-1 B-2

[0487]

Step I: 7-bromo-8-methyl-4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine-2- carbaldehyde (B-1)

B-1 was prepared from Intermediate 3-VI according to the procedure described for the synthesis of 3-10 from 3-8.

[0488]

Step II: 7-bromo-2- [ (E, Z) -2-methoxyvinyl] -8-methyl-4H- imidazo [2, 1-c] [ 1 , 4 ] enzoxazine (B-2)

B-2 was prepared from B-1 according to the procedure described in the synthesis of 5-1 from 3-10.

[04-89]

Step III: 7- [4- (4-isopropylpiperazin-l-yl) phenyl] -2- [ (E, Z) -2- methoxyvinyl] -8-methyl-4H-imidazo [2, 1-c] [ 1 , 4 ] benzoxazine (B-3) A mixture of B-2 (0.400 g, 1.24 mmol) , Intermediate l-II (0.493 g, 1.49 mmol) and K₂C0₃ (0.429 g, 3.11 mmol) in 4:1 mixture of dioxane/water (10 mL) was degassed in a stream of argon for 15 minutes. To this mixture was added 1- bis (diphenylphosphino) ferrocenepalladium ( II ) dichloride dichloromethane complex (0.101 g, 0.12 mmol) and the mixture was degassed for additional 15 minutes. After stirring at 90°C for 12 hours, the reaction mixture. as diluted with water (15 mL) followed by extraction with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (25 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The crude product so obtained was purified -by combiflash using 5% MeOH in dichloromethane as eluent to give the desired, product B-3 as a yellow solid (0.25 g, 45%); LCMS : m/z 223.2 [M⁺/2+l] .

[0490]

Step IV: 2- [7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8-methyl- 4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2-yl ] acetaldehyde (B-4)

A stirred solution of B-3 (0.25 g, 0.56 mmol) in THF (2 mL) was treated with 6N aqueous HC1 (2 mL) at room temperature and heated to 60°C for 2 hours. The reaction mixture was taken in ethyl acetate (15 mL) and neutralized with saturated aqueous NaHC0₃ solution (15 mL) . The organic layer was

separated, washed with brine (15 mL) and dried over anhydrous Na₂S0₄. The solvent was evaporated under reduced pressure and the desired crude product B-4 (0.25g, 99% crude) so obtained was used in the next step without purification.

[0491]

Step V: 2- [7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8-methyl- 4H-imidazo [2, 1-c] [1, 4] benzoxazin-2-yl] ethanol (B-5)

To a stirred solution of B-4 (0.250 g, 0.58 mmol) in a mixture of THF/MeOH/water (3:2:1, 10 mL) was added NaBH₄ (0.109 g, 2.90 mmol) portion wise. The reaction mixture was stirred for 3 hours at room temperature. After completion of the reaction, saturated NH₄C1 solution (15 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (15 mL X 2) . The organic layer was separated and washed with brine (15 mL) and dried over anhydrous Na₂S0₄. The organic layer was evaporated under reduced pressure and the crude product so obtained was purified by Combiflash using 2% methanol in dichloromethane to give the desired product B-5

(0.110 g, 45%) as pale brown oil; LCMS : m/z 217.2 [M⁺/2+l] .

[0492]

Step VI: 2- [7- [4- (4-isopropylpiperazin-l-yl) phenyl] -8 -methyl- 4H-imidazo [2 , 1-c] [ 1 , 4 ] benzoxazin-2-yl] ethyl methanesulfonate

(B-6)

To a solution of B-5 (0.100 g, 0.23 mmol) in CH₂C1₂ (5 mL) were added methanesulfonyl chloride (0.02 mL, 0.27 mmol) and DIPEA (0.1 mL, 0.57 mmol) at 0°C. After stirring for 1 hour, the reaction mixture was diluted with CH₂C1₂ (10 mL) and washed with saturated NaHC0₃ solution (15 mL) . The organic layer was separated and washed with 'brine (15 mL) , dried over anhydrous Na₂S0₄, and concentrated^' under reduced pressure to give desired crude product B-6 (0.100 g, 84%) as a pale yellow liquid that was used for next step as such without

purification; LCMS: m/z 256.2 [M/2+1].

[0493]

Step VII: 7- [ 4- ( 4-isopropylpiperazin-l-yl ) phenyl ] -8-methyl-2- (2-morpholinoethyl) -4H-imidazo [2, 1-c] [ 1 , 4 ] benzoxazine (Example B25)

To a mixture of B-6 (0.100 g, 0.19 mmol) in anhydrous DMF (3 mL) were added morpholine (0.025 g, 0.29 mmol) and N,N- diisopropylethylamine (0.050 g, 0.39 mmol) at room temperature. After stirring at 60°C for 16 hours, the excess solvent was removed in vacuo, and the obtained residue was diluted with ice water followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The- crude product so obtained was purified by

preparative HPLC to give the desired product Example B25. To the solution of Example B25 in dioxane (0.5 mL) , 4M HC1 in dioxane (1 mL) was added thereto at 0°C. After stirring for 2 hours at room temperature, the volatiles were removed by evaporation and the obtained solid was dried under vacuum to give 2HC1 salt of Example B25 (0.025 g, 25%) as a white solid; HPLC-MS: m/z 502.2 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 1.33 (d, J = 6.4 Hz, 6H) , 2.25 (s,

3H) , 3.08-3.22 (m, 7H) , 3.25-3.37 (m, 2H) , 3.42 (t, J = 8.0 Hz,

2H) , 3.49-3.53 (m, 4H) , 3.66-3.72 (m, 2H) , 3.88-3.91 (m, 4H) , 5.30 (s, 2H) , 6.93 (s, 1H) , 7.07 (d, J = 8.8 Hz, 2H) , 7.27 (d,

J = 8.8 Hz, 2H) , 7.59 (s, 1H) , 7.88 (br.s, 1H) , 10.45 (br.s,

1H) , 10.85 (br.s, 1H)

The compound of Example B26 as shown in Table 22 was prepared according to analogous sequence of procedures as used for the synthesis of Example B25.

[0494]

Table 22:

J = 8.8 Hz, 2H) ,

7.26 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H) , 7.89 (s, 1H) , 10.52 (br.s, 1H) , 10.92 (br.s, 1H)

[0495]

Example B27: ( 4-isopropylpiperazin-l-yl ) - [4- [2- (2- morpholinoethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazin-7- yl] phenyl ]methanone

[0496]

Intermediate 5-1 B-7 Example B27

[0497]

Step I: 4- [2- (2-morpholinoethyl) -4H-imidazo [2, 1- c] [1, 4 ] benzoxazin-7-yl] benzoic acid (B-7)

A mixture of Intermediate 5-1 (0.2 g, 0.54 mmol) , 4- boronobenzoic acid (0.10 g, 0.60 mmol) and Na₂C0₃ (0.145 g, 1.37 mmol) in a mixture of acetonitrile-water (4:1, 5 mL) was degassed under argon for 30 minutes. Pd (PPh₃)₄ (0.063 g, 0.054 mmol) was added thereto and degassing was continued for another 10 minutes. The resulting reaction mixture was heated at 90°C for 18 hours. After the reaction was complete, the reaction mixture was cooled down to room temperature and the volatiles were removed under reduced pressure. The crude product so obtained was taken into minimum amount of water and neutralized with IN HC1 to pH ~5, concentrated to dryness and the residue so obtained was suspended in 5% MeOH in

dichloromethane (100 mL) . The inorganic material was removed by filtration and the filtrate was concentrated under reduced pressure to give crude product, which was purified by

preparative TLC using 10% MeOH in dichlorometh.ane as solvent system to give the desired product B-7 (0.12 g, 54%) as a yellow solid; LC S : m/z 406.2 [M⁺+l] .

[0498] ·

Step II: ( 4-isopropylpiperazin-l-yl ) - [4- [2- (2- morpholinoethyl) -4H-imidazo [2, 1-c] [1, 4 ] benzoxazin-7- yl] phenyl] methanone (Example B27)

To a solution of B-7 (0.12 g, 0.42 mmol) in DMF (5 mL) were added 1-isopropylpiperazine (0.05 g, 0.38 mmol) and

diisopropylethylamine (0.076 g, 0.59 mmol) at room temperature. After 10 minutes, HATU (0.17 g, 0.44 mmol) was added thereto and the reaction mixture was stirred for 18 hours. The

reaction mixture was diluted with water and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were dried over anhydrous Na₂S04 and concentrated under reduced pressure. The crude product so obtained was purified by

preparative TLC to give the desired product Example B27 as an off-white solid. To the solution of Example B27 in dioxane (1 mL) , 3M HC1 in dioxane (2 mL) was added thereto at 0°C. After stirring for 2 hours at room temperature, the volatiles were removed by evaporation and the obtained solid was dried under vacuum to give 2HC1 salt of Example B27 (0.045 g, 26%) as an off-white solid; HPLC-MS: m/z 516.4 [M⁺+l] .

¹HNMR (400 MHz, DMSO-d₆) : δ 1.29 (d, J = 6.4 Hz, 6H) , 3.05-3.10 (m, 4H) , 3.20-3.59 (m, 12H) , 3.82-3.99 (m, 5H) , 5.37 (s, 2H) , 7.53 (d, J = 6.8 Hz, 3.6 Hz, 2H) , 7.58 (d, J = 8.0 Hz;, 2H) , 7.76 (d, J = 8.8 Hz, 1H) , 7.81 (d,J = 8.4 Hz, 2H) , 7.92 (s, 1H) , 10.92 (br.s, 2H)

[0499]

Example CI: 7- [4- (4-isopropylpiperazin-l-yl) phenyl] -2- (3- morpholinopropyl ) -4H-imidazo [2, 1-c] [1,4] benzoxazine

[0500]

[0501]

A mixture of Intermediate 6-1 (0.03 g, 0.07 mmol),

Intermediate l-II (0.031 g, 0.09 mmol) and K₂C0₃ (0.033 g, 0.23 mmol) in a mixture of dioxane-water (4:1, 6 mL) was degassed for 30 minutes with argon. PdCl₂dppf . DCM (0.002 g, 0.0019 mmol) was added thereto and the reaction mixture was refluxed for 18 hours. After completion of the reaction (monitored by TLC) , the reaction mixture was taken into water (10 mL) and ethyl acetate (10 mL) . The organic layer was separated and washed with water (10 mL) followed by brine (10 mL) , dried over anhydrous a₂S04 and concentrated under reduced pressure. The crude product so obtained was purified by preparative TLC using 10% eOH in dichloromethane to give the desired product Example CI. To the solution of Example CI in dioxane (1 mL) , 3M HC1 in dioxane (2 mL) was added thereto at 0°C. After stirring for 2 hours at room temperature, the volatiles were removed by evaporation and the obtained solid was dried under vacuum to give 2HC1 salt of Example CI (0.017 g, 38%) as a creamy white solid; HPLC-MS : m/z 502.2 [M⁺+l] .

¹HN R (400 MHz, DMSO-d₆) : δ 1.30 (d, J = 8.4 Hz, 6H) , 2.08

(quin., 2H) , 2.64-2.66 (m, 2H) , 3.14-3.23 (m, 7H) , 3.41-3.51 (m, 6H) , 3.90-3.93 (m, 6H) , 5.36 (s, 2H) , 7.00 (d, J = 8.8 Hz, 2H) , 7.41 (s, 1H) , 7.44 (d, J = 2 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 2H) , 7.69 (d, J = 8 Hz, 1H) , 7.89 (s, 1H) , 10.55 (br.s, 1H) , 11.90 (br.s, 1H)

[0502]

The following compounds as shown in Table 23 can also be prepared according to Schemes 1-10 or in the same manner as in the above mentioned examples.

[0503]

Table 23:

4- [ [7- [4- (4-isopropylpiperazin-l^ N—> yl) phenyl] -4H-imidazo [2,1- c] [1, 4 ] benzoxazin-2- yl] methyl] morpholin-2-ol

7- [4- ( 4-isopropylpiperazin-l-

N. yl) phenyl] -2- ( 6-oxa-3- azabicyclo [3.1.1] heptan-3- ylmethyl) -4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazine

[7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2, 1- c] [1, 4 ] benzoxazin-2-yl] - morpholino-methanone

1- [7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2, 1- c] [1, 4]benzoxazin-2-yl] -2- morpholino-ethanone

7- [4- (4-isopropylpiperazin-l- yl) phenyl] -2- ( 1-methyl-l- morpholinoethyl) -4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazine

7- [4- ( 4-isopropylpiperazin-l- yl ) henyl ] -2- (morpholinomethyl ) - 4H- [1, 2, 4] triazolo [5, 1- c] [ 1 , 4 ] benzoxazine

7- [4- ( l-isopropyl-4- piperidyl) phenyl] -2- (morpholinomethyl ) -4H- [1, 2, 4] triazolo [5, 1- c] [1,4] benzoxazine

7- [4- ( l-isopropyl-4- piperidyl) phenyl] -2- (morpholinomethyl) -4H- pyrazolo [5, 1-c] [1,4] benzoxazine

7- [4- ( l-isopropyl-4-piperidyl ) - phenyl] -2- (morpholinomethyl ) -4H- 5-oxa-3, 8, 9b-triaza- cyclopenta [a] naphthalene

7- [4- (l-methyl-4- piperidyl ) phenyl ] -2- (morpholinomethyl ) -4H-5- 3,8, 9b-triaza- cyclopenta [a] naphthalene

7 - [4- (l-ethyl- 47- piperidyl) phenyl] -2- (morpholinomethyl) -4H-5-oxa- 3, 8 , 9b-triaza- cyclopenta [a] naphthalene

7- [4- ( 4-methylpiperazin-l- yl) phenyl] -2- (morpholinome

4H-5-oxa-3, 8, 9b-triaza- cyclopenta [a] naphthalene

7- [4- ( 4-isopropylpiperazin-l- yl) henyl] -2- (morpholinomethyl ) - 4H-5-oxa-3, 8, 9b-triaza- cyclopenta [a] naphthalene

7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 9, 9b-triaza- cyclopenta [a] naphthalene

7- [4- ( 4-methylpiperazin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 9, 9b-triaza- cyclopenta [a] naphthalene

7- [4- ( 4-methylpiperazin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 8, 9, 9b-tetraaza- cyclopenta [a] naphthalene

/—\

0 N—v 7- [4- ( 4-isopropylpiperazin-l- yl ) phenyl ] -2- (morpholinomethyl ) - 4H-5-oxa-3, 8, 9, 9b-tetraaza- cyclopenta [a] naphthalene

7- [4- (4-methylpiper.azin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 6, 9, 9b-tetraaza- cyclopenta [a] naphthalene

7- [4- (4-isopropylpiperazin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 6, 9, 9b-tetraaza- cyclopenta [a] naphthalene

—\

N— 7- [4- (4-isopropylpiperazin-l- yl) phenyl] -2- (morpholinomethyl) - 4H-5-oxa-3, 6, 8, 9b-tetraaza- cyclopenta [a] naphthalene

7- [4- (4-methylpiperazin-l- yl ) phenyl ] -2- (morpholinomethyl ) -

N

4H-5-oxa-3, 6, 8, 9b-tetraaza- cyclopenta [a] naphthalene

5- (4-isopropylpiperazin-l-yl) -2- [2- (morpholinomethyl) -4H- imidazo [2, 1-c] [1,4] benzoxazin-7- yl] benzamide

5- (4-methylpiperazin-l-yl) -2- [2- (morpholinomethyl ) -4H-

^NT^{N H2} imidazo [2, 1-c] [1,4] benzoxazin-7- yl ] benzamide

1- [ [7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2, 1- c] [1, 4] benzoxazin-2- yl] methyl] pyrrolidin-3-ol

CO, e methyl 1- [ [7- [4- (4- isopropylpiperazin-l-yl ) phenyl] -

N u 4H-imidazo [2, 1-c] [1, 4 ] benzoxazin- 2-yl] methyl] pyrrolidine-2- carboxylate

C0₂H 1- [ [7- [4- ( 4-isopropylpiperazin-l- yl ) phenyl] -4H-imidazo [2,1- c] [1, 4 ] benzoxazin-2- yl] methyl] pyrrolidine-2- carboxylic acid

7- [4- (4-isopropylpiperazin-l-yl) - 2-methylphenyl ] -8-methyl-2- (morpholinomethyl) -4H- imidazo [2, 1-c] [ 1 , 4 ] benzoxazine

/—\ 8-fluoro-7- [4- (4- isopropylpiperazin-l-yl ) -2- methylphenyl] -2- (morpholinomethyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine 7- [2-fluoro-4- (4- isopropylpiperazin-l-yl) phenyl] -

8-methyl-2- (morpholinomethyl) -4H- imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4- ( 4-isopropyl-3- methylpiperazin-l-yl) phenyl] -2- (morpholinomethyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

6, 8-difluoro-7- [4- (4- isopropylpiperazin-l-yl) phenyl] - 2- (morpholinomethyl) -4H- imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine

6-fluoro-7- [4- (4- isopropylpiperazin-l-yl) phenyl] - 8-methyl-2- (morpholinomethyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

9-fluoro-7- [4- (4- isopropylpiperazin-l-yl ) phenyl] 2- (morpholinomethyl) -4H- imidazo [ 2 , 1-c] [1, 4] benzoxazine

7- [6- [ ( l-isopropyl-4- piperidyl) oxy] -3-pyridyl] -2- (morpholinomethyl) -4H-

imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine 7- [6- (4-isopropylpiperazin-l-yl) - 4-methoxy-3-pyridyl] -2-

Χ₀Χ)Λ (morpholinomethyl) -4H- imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4-methoxy-6- (4- methylpiperazin-l-yl ) -3-pyridyl] - 2- (morpholinomethyl ) -4H- imidazo [2, 1-c] [ 1 , 4 ] benzoxazine

7- [4-methyl-5- ( 4-methylpiperazin- 1-yl) -2-pyridyl] -2- (morpholinomethyl) -4H- imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4-methoxy-5- (4- methylpiperazin-l-yl ) -2-pyridyl] - 2- (morpholinomethyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -2- [ (2-methyl-7- azaspiro [3.5] nonan-7-yl) methyl] - 4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

7- [ [7- [4- (4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2,1- c] [1, 4 ] benzoxazin-2-yl] methyl] -7- azaspiro [3.5] nonan-2-ol

7- [4- (3-methyl-3, 9- diazaspiro [5.5] undecan-9- yl) phenyl] -2- (morpholinomethyl ) -

4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

2- (morpholinomethyl) -7- [4- (2-oxa- 7-azaspiro [3.5] nonan-7- yl) phenyl] -4H-imidazo [2,1- c] [ 1 , 4 ] benzoxazine

7- [4- ( l-isopropyl-4- piperidyl) phenyl] -2- (2-oxa-7- azaspiro [ 3.5 ] nonan-7-ylmethyl ) - 4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

2- [ ( 4-fluoro-l-piperidyl ) methyl] -

N . 7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2, 1- c] [1, 4] benzoxazine

1- [ [7- [4- ( 4-isopropylpiperazin-l-

N. yl) phenyl] -4H-imidazo [2, 1- c] [ 1 , 4 ] benzoxazin-2- yl] methyl] piperidin-4-ol

2- [ (4, 4-difluoro-l- piperidyl) methyl] -7- [4- (4- isopropylpiperazin-l-yl ) phenyl ] - 4H-imidazo [2 , 1-c] [1,4] benzoxazine

4-fluoro-l- [ [7- [4- (4- isopropylpiperazin-l-yl ) phenyl] - 4H-imidazo [ 2 , 1-c] [ 1 , 4 ] benzoxazin- 2-yl]methyl] piperidin-4-ol

7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4-methyl-2- (morpholinomethyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4, 4-dimethyl-2- (morpholinomethyl ) imidazo [2, 1- c] [1, 4] benzoxazine

7- [4- ( -isopropylpiperazin-l- yl) phenyl] -2- ( 1-morpholinoethyl ) -

4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

7- [4- ( 6-isopropyl-3, 6- diazabicyclo [3.1.1] heptan-3- yl') phenyl] -2- (morpholinomethyl) - 4H-imidazo [2, 1-c] [1,4] benzoxazine

7- [4- ( 4-tert-butylpiperazin-l- yl) henyl] -2- (morpholinomethyl) - 4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

1- [A- ( 4-methylpiperazin-l- yl) sulfonylphenyl] -2- (morpholinomethyl) -4H- imidazo [2, 1-c] [1,4] benzoxazine

4- [ [7- [4- ( 4-isopropylpiperazin-l- yl) phenyl] -4H-imidazo [2,1- c] [1,4] benzoxazin-2-yl] methyl] - 1, -thiazinane 1,1-dioxide

4- [ [7- [4- ( 4-methylpiperazin-l- yl) phenyl] -4H-imidazo [2, 1- c] [1, 4 ] benzoxazin-2-yl] methyl] - 1 , 4-thiazinane 1,1-dioxide

7- [4- ( l-methylpyrrolidin-3- yl) phenyl] -2- (morpholinomethyl) -

4H-imidazo [2 , 1-c] [1,4] benzoxazine

2- (morpholinomethyl) -7- (4- (pyrrolidin-3-yl) phenyl) -4H- imidazo [2 , 1-c] [ 1 , 4 ] benzoxazine

7- [4- ( l-methylazetidin-3- yl) phenyl] -2- (morpholinomethyl) -

4H-imidazo [2, 1-c] [1, 4 ] benzoxazine

7- [4- [ (l-methylazetidin-3- yl) methyl] phenyl] -2- (morpholinomethyl ) -4H- imidazo [2, 1-c] [ 1 , 4 ] benzoxazine

[0504]

Experimental Example 1

hTLR9 antagonism (SEAP inhibition assay) in HEK293 cell lines:

The SEAP reporter gene in HEK-Blue™-hTLR9 cells is placed under the control of the IFN-b minimal promoter fused to five NF-kB and AP-1 binding sites. The stimulation with a TLR9 ligand (ODN-2006) activates NF-kB and AP-1 which induces the production of SEAP. Levels of SEAP are determined with QUANTI- Blue™ detection medium that turns purple/blue in the presence of alkaline phosphatase. Decrease in the levels of SEAP production as indicated by reduction in absorbance at 650nm is directly co-related with the TLR9 inhibitory activity of the antagonist (NCE) .

HEK-Blue™-hTLR9 cells were maintained in DMEM with 10%

FBS, 1% Penicillin /Streptomycin/Amphotericin (complete growth medium) and 0.2% Normocin. For the assay, cells were

dissociated by washing in IX PBS and re-suspended in complete DMEM. Cells were seeded at a density of 20000 cells per well; (40μ1 per well) in a 384 well assay plate.

5μ1 of 10X antagonist (NCE) was added to the cells in triplicates for each concentration. The plate was incubated for half an hour at 37°C with 5% C0₂. 5μ1 of agonist (ODN- 2006) was added and the plate was incubated overnight for 18 hours at 37°C with 5% C0₂.- 5μ1 of supernatant was- transferred to a 384 well reading plate and to this 45μ1 of Quanti-Blue™ detection reagent was added. The plate was then incubated for an hour at 37°C. SEAP activity in the supernatant was

indicated by change in the pink color of Quanti-Blue™

detection reagent to purple/blue and the absorbance was read at 650 nm in the end point mode.

[0505]

Experimental Example 2

mTLR7 antagonism (cytokine release assay) in mouse

splenocytes:

[0506]

Materials :^■

Splenocytes isolated from male C57/BL6 mice

TLR7 ligand R0006 (IDT, 5'- rU*rU*rG*rU*rU*rG*rU^rU*rG*rU*rU*rG*rU*rU*rG*rU*rU*rG*rU*rU- 3'), Liposomal transfection reagent - DOTAP (Roche, Cat.

No.11202375001) , TLR9 ligand CpG ODN2006 (Sequence: *=phosphorothioate )

DMSO (Sigma, D2650), RPMI Powder (Sigma, R6504), Fetal Bovine Serum (Gibco, 10270), Dulbecco' s Phosphate Buffered Saline (Sigma, D1408), 96 well plate (Flat bottom, Costar 3599), ELISA kit for IL-6 (EBioscience, 88-7064-77 and TNF

(EBioscience, 88-7346-88 ), MACS Buffer (AutoMACS Rinsing Solution (Miltenyl Biotec, 130-091-222) + 0.05% BSA) , RBC lysis buffer (0.85% NH4C1) , 40μπι cell strainer (BD Falcon, 352340)

[0507]

Method: A. Isolation of mouse splenocytes

Mouse spleen was isolated from C57BL6 mouse and stored in IX chilled PBS buffer until further processed. Spleen was transferred to a sterile petriplate and chopped in to 5-6 pieces in presence of MACS buffer (ΙΟΟμΙ) with the help of fresh surgical blade and crushed with flat plunger of a

sterile syringe. A uniform suspension was prepared by passing cells through a 40 μπι cell strainer. Cells were- centrifuged at 450xg for 5 minutes at 4°C, supernatant was discarded and pellet dislodged gently, resuspended in 2 ml of pre-warmed

(37°C) RBC lysis buffer at room temperature with continuous gentle mixing with 1 ml pipette. Lysis buffer was neutralized with 12 ml of chilled MACS buffer and cells were passed

through 40 μπι cell strainer. Cell suspension was collected in 15 ml MACS buffer and centrifuged at 450xg for 5 minutes at 4°C. Pellet was resuspended in 15 ml MACS buffer and centrifuged at 400xg for 5 minutes. Cells were resuspended in 10 ml of RPMI complete medium and viability was estimated by Trypan blue method.

Expected yield: 60-70 million cells from single mouse spleen.

[0508]

mTLR7 antagonism (IL-6 and TNF-a release assay) :

1 mg/ml stock of R0006 was prepared in sterile,

endotoxin-free water. R0006 stock was diluted 10 fold with DOTAP and incubated for 30 minutes to form liposome complex

(100 μg/ml of R0006) . This complex was further diluted 10 fold with incomplete RPMI media (10 μg/ml of R0006) to achieve the final agonist concentration of 1 μg/mϊ. DOTAP alone was

diluted 10 fold in incomplete RPMI media. NCEs were added in a concentration range of 30 μΜ to 1 nM in respective wells of assay plate, assay medium containing 0.3% DMSO were added to control wells. 0.2 million splenocytes were added to all the wells and incubated at 37°C in 5% C0₂ incubator for 30 minutes. 1 μg/ml of respective agonist was added to all the wells

except those were assigned as negative controls and mixed thoroughly. DOTAP was added to negative control wells and incubated overnight at 37°C / 5% C0₂. The plate was

centrifuged at 450xg for 5 minutes at room temperature and the supernatant was collected. ELISA was performed as per

manufacturer's protocol. S/B Ratio, % Activity and %

Inhibition was calculated using MS Excel. IC₅₀ and inhibition . curve was generated using Graph Pad Prism.

hTLR9 %inhibition and mTLR7 IL-6 and TNF-a

release %inhibition at 1 μΜ and 300 nM concentrations

respectively are given in Table 24 b

[0509]

Table 24:

A94 96.8 28.44 15.55

A95 100 29.12 23.15

A96 96.2 22.44 -2.0

A98 66.1 ND ND

Bl 89.8 75.38* 78.80*

B2 96.9 82.84 98.7

B3 98.2 81.68 99.2

B14 98.8 77.06 94.35

B15 93 39.18 15.85

B16 100 85.87 85.70

B17 100 92.88 94.70

B18 98.8 76.05 94.80

B19 98 ND ND

B20 100 81.3 98.25

B21 99.3 62.74 50.5

B22 99.4 84.21 77.65

B23 98.4 94.47 95.25

B24 91.3 87.44 85.75

B25 94 70.36 84.45

B26 90.1 50.59 30.85

B27 98.1 66.33 45.95

CI 98.5 85.77 97.15

*% inhibition at 150 nM concentration ^' of compound

ND: Not Determined

[0510]

Experimental Example 3

Collagen Antibody Induced Arthritis (CAIA) model in mice

On day 0, Male DBA/1J mice (-6-8 weeks age, n - 6-9 per group) were injected intra-peritoneally with collagen antibody cocktail. A booster intra-peritoneal injection of LPS was given on day 3 and animals were segregated in different treatment groups. Animals were dosed with TLR-7/9 antagonist (Example Al) in a prophylactic fashion orally once a day (QD) from Day 3 to Day 14 at 1, 3, 10 and 30 mg/kg doses. Evaluation of disease severity:

Animals were evaluated for clinical symptoms and scored accordingly for inflamed paws and erythema. The scorer was blind to the treatments groups. Key findings for Example Al in the mouse arthritis disease model are as follows [See Fig. 1] . Mice treated with Example Al showed 10, 14, 53 and 66%

reduction in arthritic scores at 1, 3, 10 and 30 mg/kg doses, QD compared to vehicle treatment at the end of the study period. ED50 was 11.4 mg/kg.

[0511]

Formulation Example 1

(1) Compound of Example Al 10.0 g

(2) Lactose 70.0 g

(3) Cornstarch 50.0 g

(4) Soluble starch 7.0 g

(5) Magnesium stearate 3.0 g

After 10.0 g of the compound of Example Al 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, and 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 14^th Edition) . The mixture is

compressed to obtain a tablet.

Industrial Applicability

[0512]

According to the present invention, a heterocyclic compound a TLR7 and/or TLR9 and/or TLR-7/8/9 and/or TLR-7/8 and/or TLR-7/9 inhibitory action, which may be useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases and the like, in particular, acute decompensated heart failure, non-alcoholic

steatohepatitis (NASH) , IgA nephropathy, Duchenne muscular dystrophy (DMD) , systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, type 1 diabetes, myasthenia gravis,

hematopoietic disfunction, B-cell malignancies, transplant rejection and graft-versus-host disease, hepatocellular carcinoma (HCC) , can be provided.

[0513]

This application is based on patent application No. 2707/DEL/2015 filed on August 28, 2015 in India, the contents of which are encompassed in full herein.

Claims

1. A compound represented by the formula (I) :

wherein

Ring A is an optionally further substituted 5-membered

nitrogen-containing aromatic heterocycle,

aromatic ring,

Ring C is an optionally substituted heterocycle,

Ring D is an optionally further substituted aromatic ring, 2 is a bond or a linker, and

Ring E is an optionally substituted heterocycle,

or a salt thereof.

2. The compound or salt of claim 1, wherein

Ring A is

(1) imidazole (X¹ is a carbon atom and X² is a nitrogen atom), or

(2) triazole (X¹ is a nitrogen atom and X² is a nitrogen atom) ; R¹ and R² are both hydrogen atoms;

Ring B is

(1) benzene optionally further substituted by 1 to 3

substituents selected from (a) a halogen atom, and

(b) a Ci-6 alkyl group, or

(2) pyridine (Z¹ is a nitrogen atom, Z² is a carbon atom and Z³ is a carbon atom) ;

W¹ is -C¾-, -(CH₂)₂- ox -(CH₂)₃-;

Ring C is

(1) morpholine optionally substituted by 1 to 3 Ci-₆ alkyl groups ,

(2) piperazine optionally substituted by 1 to 3 Ci_₆ alkyl groups, or

(3) piperidine;

Ring D is

(1) benzene optionally further substituted by 1 to 3

substituents selected from

(a) a halogen atom,

(b) an optionally halogenated Ci_₆ alkyl group,

(c) a Ci-6 alkoxy group, and

(d) a carbamoyl group,

(2) pyridine, or

(3) pyrazole;

W² is a bond, -CH₂-, -C (=0) - o ^' -0-; and

Ring E is

(1) piperidine optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a Ci-6 alkoxy group, and

(c) a Ci-6 alkoxy-carbonyl group,

(2) piperazine optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom, (ii) a hydroxy group,

(iii) a Ci-6 alkoxy group, and

(iv) a 5- to 1 -membered aromatic heterocyclic group, (b) a C3-.10 cycloalkyl group,

(c) a Ci-6 alkoxy-carbonyl group, and

(d) a 3- to 14-membered non-aromatic heterocyclic group, or (3) tetrahydropyridine optionally substituted by 1 to 3 substituents selected from

(a) a Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and

(b) a Ci-6 alkoxy-carbonyl group.

3. 7- [4 - ( 4-Isopropylpiperazin-l-yl ) henyl] -2-

(morpholinomethyl) -4H-imidazo [2, 1-c] [ 1 , 4 ] benzoxazine or a salt thereof .

4. 7- [4- [ (4-Isopropylpiperazin-l-yl)methyl]phenyl] -2- (morpholinomethyl) -4H-imidazo [2, 1-c] [ 1 ,_.4 ] benzoxazine or a salt thereof.

5. A medicament comprising the compound or salt of claim 1.

6. The medicament of claim 5, which is a TLR7, TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9 inhibitor.

7. The medicament of claim 5, which is an agent for the prophylaxis or treatment of autoimmune diseases and/or

inflammatory diseases.

8. The medicament of claim 7, wherein the autoimmune diseases and/or inflammatory diseases is selected from systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis., psoriasis and inflammatory bowel disease.

9. The compound or salt of claim 1 for use in the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.

10. The compound or salt of claim 9, wherein the autoimmune diseases and/or inflammatory diseases is selected from

systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis and inflammatory bowel disease.

11. A method of inhibiting TLR7 , TLR9, TLR-7/8, TLR-7/9 or TLR-7/8/9 in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal . -

12. A method for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.

13. The method of claim 12, wherein the- autoimmune diseases and/or inflammatory diseases is selected from systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis and inflammatory bowel disease.

14. Use of the compound or salt of claim 1 for the production of an agent for the prophylaxis or treatment of autoimmune diseases and/or- inflammatory diseases.

15. Use of claim 14, wherein the autoimmune diseases and/or inflammatory diseases is selected from systemic lupus

erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis and inflammatory bowel disease.