[DESCRIPTION]

[Title of Invention]

HETEROCYCLIC COMPOUNDS WITH AN ROR(GAM MA)T MODULATING ACTIVITY

[Technical Field]

[0001]

The present invention relates to a heterocyclic compound which may have an RORyt modulating activity, a medicament containing the compound, and the like.

[0002]

[Background Art]

Thl7 cell and inflammatory cytokines (IL-17A, IL-17F and the like) produced thereby cause a decrease in QOL as a severe etiology cell and factor accompanying enhancement of a systemic new immune response, in various autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis and psoriasis. However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel therapeutic drug has been desired.

Involvement of T cells, inter alia, Thl7 cell and

inflammatory cytokines (IL-17A, IL-17F and the like) produced thereby, in the pathology of these immune diseases has been drawing attention in recent years.

Moreover, it has been recently clarified that a Retinoid- related Orphan Receptor (ROR) yt, which is one of the orphan nuclear receptors, plays an important role in the

differentiation of Thl7 cells and production of IL-17A/IL-17F. That is, it has been reported that RORyt is mainly expressed in Thl7 cells and functions as a transcription factor of IL-17A and IL-17F, as well as a master modulator of Thl7 cell

differentiation.

Therefore, a medicament that inhibits the action of RORyt is expected to show a treatment effect on various immune diseases by suppressing differentiation and activation of Thl7 cells. [0003]

Patent document 1 discloses the following compound having an NAMPT inhibitory action and useful as chemotherapy drugs (DNA damaging agent, .cell rescuing agent, cytotoxic agent) , a therapeutic drug for hyperproliferative disorder due to an abnormal cell proliferation action, or a prophylactic or therapeutic agent for malignant tumor, ovarian cancer, breast cancer, colorectal cancer, Hodgkin' s disease, inflammatory disease, IBS, IBD, rheumatoid arthritis and the like:

[0004]

[Chem. 1]

[0005]

wherein each symbol is as defined in the document.

Non-patent document 1 discloses the following compound having a p38α MAP kinase inhibitory action, and useful as a prophylactic or therapeutic agent for inflammatory diseases such as rheumatoid arthritis, IBD and . the like:

[0006]

[Chem. 2]

Patent document 2 discloses the following compound having a ρ-38α activity-inducing action, and useful as a prophylactic or therapeutic agent for inflammation-associated diseases (IBD, rheumatoid arthritis, Crohn's disease, Alzheimer's disease etc . ) :

[0008]

[Chem. 3]

[0009]

wherein each symbol is as defined in the document.

Patent document 3 discloses the following compound having an NMDA NR2B antagonistic action, and useful as a prophylactic or therapeutic agent for migraine, depression, anxiety,

schizophrenia, Parkinson' s disease, cerebral apoplexy and the like:

[0010]

[Chem. 4]

[0011]

wherein each symbol is as defined in the document.

Non-patent document 2 discloses the following compound

[0012]

[Chem. 5]

[0013]

Non-patent document 3 discloses the following compound:

[0014]

[Chem. 6]

[0015]

Non-patent document 4 discloses the following compound:

[0016]

[Chem. 7]

[0017]

Non-patent document 5 discloses the following compound

[0018]

[Chem. 8]

[0019]

Non-patent document 6 discloses the following compound

[0020]

[Chem. 9]

[0021]

Non-patent document 7 discloses the following compound: [0022]

[Chem. 10]

[0023]

Non-patent document 8 discloses the following compound:

[0024]

[Chem. 11]

[0025]

Non-patent document 9 discloses the following compound:

[0026]

[Chem. 12]

[0027]

Non-patent document 10 discloses the following compound

[0028]

[Chem. 13]

[0029]

Non-patent document 11 discloses the following compound

[0030] [Chem. 14]

[0031]

Non-patent document 12 discloses the following compound [0032]

[Chem. 15]

[0033]

Non-patent document 13 discloses the following compound:

[0034]

[Chem. 16]

[0035]

Non-patent document 14 discloses the following compound:

[0036]

[Chem. 17]

[0037]

Non-patent document 15 discloses the following compound:

[0038]

[Chem. 18]

[0039]

Non-patent document 16 discloses the following compound:

[0040]

[Chem. 19]

[0041]

Non-patent document 17 discloses the following compound:

[0042]

[Chem. 20]

[0043]

Non-patent document 18 discloses the following compound:

[0044]

[Chem. 21]

[0045]

non-patent document 19 discloses the following compound

[0046]

[Chem. 22]

[0047]

Non-patent document 20 discloses the following compound.

[0048]

[Chem. 23]

[0049]

Non-patent document 21 discloses the following compound:

[0050]

[Chem. 24]

[0051]

Non-patent document 22 discloses the following compound:

[0052]

[Chem. 25]

[0053]

Patent document 4 discloses the following compound useful s a prophylactic or therapeutic agent for PPARG associated diseases (diabetes, insulin resistance, obesity, inflammation etc. ) :

[0054]

[Chem. 26]

[0055]

wherein each symbol is as defined in the document.

Non-patent document 23 discloses the following compound useful as a PPARy antagonist:

[0056]

[Chem. 27]

[0057]

Patent document 5 discloses the following compound:

[0058]

[Chem. 28]

[0059]

wherein each symbol is as defined in the document. Non-patent document 24 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:

[0060]

[Chem. 29]

[0061]

Patent document 6 discloses the following compound having a modulating action on glucocorticoid receptor, AP-1, NF-KB activity, and useful as a prophylactic or therapeutic agent for inflammation, immune system disease, cancer and the like:

[0062]

[Chem. 30]

[0063]

wherein each symbol is as defined in the document.

Patent document 7 discloses the following compound having a cannabinoid receptor modulating action, and useful as a prophylactic or therapeutic agent for central nervous system pain, addiction, cancer (including melanoma) , inflammation and the like:

[0064]

[Chem. 31]

[0065]

wherein each symbol is as defined in the document.

Patent document 8 discloses the following compound:

[0066]

[Chem. 32]

[0067]

wherein each symbol is as defined in the document.

Non-patent document 25 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:

[0068]

[Chem. 33]

[0069]

Patent document 9 discloses the following compound having an RORy activity inhibitory action, and useful as a

prophylactic or therapeutic agent for immune disease,

inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, IBD etc.) and the like:

[0070]

[Chem. 34]

[0071]

wherein each symbol is as defined in the document.

Patent document 10 discloses the following compound useful as an SMYD protein inhibitor as an antitumor drug:

[0072]

[Chem. 35]

[0073]

wherein each symbol is as defined in the document.

Non-patent document 26 discloses the following compound:

[0074]

[Chem. 36]

[0075]

Non-patent document 27 discloses the following compound:

[0076]

[Chem. 37]

[0077] Non-patent document 28 discloses the following compound:

[0078]

[Chem. 38]

O

[Citation List]

[Patent Literature]

[0079]

[PTL 1] WO 2012/031197

[PTL 2] WO 2005/033072A2

[PTL 3] WO 2002/080928

[PTL 4] KR 2015110901

[PTL 5] WO 2011/073276

[PTL 6] US 2009/0075995

[PTL 7] WO 2009/012221

[PTL 8] WO 2008/021926

[PTL 9] WO 2015/083130

[PTL 10] WC 1 2016/040505

[Non Patent . Literature]

[0080]

[NPL 1] Bioorganic & Medicinal Ch

2560- -2563

[NPL 2] RN 1808757-09-6 REGISTRY

[NPL 3] RN 1808600-79-4 REGISTRY

[NPL 4] RN 1808584-22-6 REGISTRY

[NPL 5] RN 1808382-90-2 REGISTRY

[NPL 6] RN 1791070-99-9 REGISTRY

[NPL 7] RN 1790978-50-5 REGISTRY

[NPL 8] RN 1626839-07-3 REGISTRY

[NPL 9] RN 1626420-44-7 REGISTRY

[NPL 10] RN 1414842-31-1 REGISTRY

[NPL 11] RN 1414839-85-2 REGISTRY [NPL 12 RN 1320956-59-9 REGISTRY

[NPL 13 RN 1302037-83-7 REGISTRY

[NPL 14 RN 1240829-86-0 REGISTRY

[NPL 15 RN 1223212-11-0 REGISTRY

[NPL 16 RN 1197718-13-0 REGISTRY

[NPL 17 RN 1197529-23-9 REGISTRY

[NPL 18 RN 1197525-10-2 REGISTRY

[NPL 19 RN 1197511-74-2 REGISTRY

[NPL 20 RN 1147378-16-2 REGISTRY

[NPL 21 RN 1026269-51-1 REGISTRY

[NPL 22 RN 950026-22-9 REGISTRY

[NPL 23 ACS Medicinal Chemistry Letters (2015), 6(9), 998-1003 [NPL 24 ChemMedChem (2009), 4(10), 1615-1629

[NPL 25 RN 958772-68-4 REGISTRY

[NPL 26 RN 1240904-56-6 REGISTRY

[NPL 27 RN 1009913-68-1 REGISTRY

[NPL 28 RN 941202-67-1 REGISTRY

[Summary of Invention]

[Technical Problem]

[0081]

The present invention aims to provide a compound that may have an RORyt modulating action and may be useful as a

prophylactic or therapeutic agent for cancer and the like.

[Solution to Problem]

[0082]

The present inventors have found that a compound

represented by the following formula (Ι') or a salt thereof may have an RORyt modulating action based on its specific chemical structure, and may have efficacy as a prophylactic or

therapeutic agent for cancer and the like. Based on this finding, the present inventors have conducted intensive studies and completed the present invention.

[0083]

Therefore, the present invention relates to the following.

[1] A compound represented by the formula (I' ) : [0084]

Chem. 39]

[0085]

wherein

ring A is an optionally further substituted ring;

L ¹ is a bond, optionally halogenated C ₁ _ ₂ alkylene, -NH- or -0-;

R ¹ and R ² are each independently a hydrogen atom or a substituent;

R ¹ and R ² may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R ¹ and R ² may be joined together to form an oxo group;

ring D is an optionally further substituted ring;

L ² is -SO ₂ -, -S(=0)- or -S(=0) (=NR ⁴ ) - ;

R ⁴ is a hydrogen atom or a substituent;

R ³ is a substituent;

a partial structure:

[0086]

[Chem. 40]

[0087]

is

[0088]

[Chem.

[0089]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle;

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is an optionally further substituted 6-membered aromatic ring; and

Y ⁴ is =CH- or =N-, or a salt thereof (sometimes to be abbreviated as "compound (I')" in the present specification).

[2] The compound of [1] , wherein the ring A is

[0090]

[Chem. 42]

[0091]

L ¹ is a bond;

R ¹ is a hydrogen atom or a hydroxymethyl group

R ² is a hydrogen atom;

ring D is

[0092]

[Chem. 43]

[0093]

wherein

W is =CR - or =N-;

R ⁶ is a hydrogen atom, -C0 ₂ C ₂ H ₅ , -CH ₂ OH, -C0 ₂ H, -CONH ₂ or -

CN;

L is -S0 ₂ -; and

R is -CH ₃ or -C ₂ H ₅ , or a salt thereof.

[3] The compound of [1], wherein the partial structure:

[0094]

[Chem. 44]

[0095]

is

[0096]

[Chem.

[0097]

wherein

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle; Y ¹ , Y ² and Υ ³ are each independently a carbon atom or a nitrogen atom; and

ring C is an optionally further substituted 6-membered aromatic ring, or a salt thereof (sometimes to be abbreviated as "compound (I)" in the present specification).

[4] 1- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide or a salt thereof.

[5] 4- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) chromane-7-carboxamide or a salt thereof.

[6] 5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (4-

(methylsulfonyl) benzyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2- carboxamide or a salt thereof.

[7] Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl ) benzoate or a salt thereof.

[8] A medicament comprising the compound of [1] or a salt thereof .

[9] The medicament of [8], which is a RORyt modulator.

[10] The medicament of [8], which is a prophylactic or

therapeutic agent for cancer.

[11] A method of modulating RORyt in a mammal, comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.

[12] A method for the prophylaxis or treatment of cancer in a mammal, comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.

[13] The compound of [1] or a salt thereof for use in the prophylaxis or treatment of cancer.

[14] Use of the compound of [1] or a salt thereof in the production of an agent for the prophylaxis or treatment of cancer .

[Advantageous Effects of Invention]

[0098] The compound of the present invention may have an RORyt modulating action and may be useful as a prophylactic or therapeutic agent for cancer and the like.

[0099]

[Description of Embodiments]

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 "C ₁ _ 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 C ₁ _ ₆ alkyl . group" include a C ₁ _ 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 "C _2-6 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 "C ₂ - 6 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 "C _3-10 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 C _3-10 cycloalkyl group" include a C _3-10 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 "C _3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl, cycloheptenyl and cyclooctenyl .

In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.

In the present specification, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .

[0100]

In the present specification, examples of the "C ₁ _ 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 C ₁ _ ₆ alkoxy group" include a C ₁ _ ₆ 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 "C _3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In the present specification, examples of the "C ₁ _ 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 C ₁ _ ₆ alkylthio group" include a C ₁ _ 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 "C ₁ _ 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 C ₁ _ ₆ alkyl-carbonyl group" include a C ₁ _ ₆ 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 "C ₁ _ 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 "C _6-14 aryl- carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the "C _7-16 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 .

[0101]

In the present specification, examples of the "mono- or di-C ₁ _ ₆ alkyl-carbamoyl group" include methylcarbamoyl ,

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

In the present specification, examples of the "mono- or di-C _7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .

In the present specification, examples of the "C ₁ _ ₆ alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl , isopropylsulfonyl , butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .

In the present specification, examples of the "optionally halogenated C ₁ _ ₆ alkylsulfonyl group" include a C ₁ _ 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 , 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .

In the present specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .

[0102]

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 C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10

cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group and a C _7-16 aralkyl group.

[0103]

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 C ₁ _ ₆ alkoxy group,

(7) a C _6-14 aryloxy group (e.g., phenoxy, naphthoxy) ,

(8) a C _7-16 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 C ₁ _ ₆ alkyl-carbonyloxy group (e.g., acetoxy,

propanoyloxy) ,

(12) a C _6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,

(13) a C ₁ _ ₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,

(14) a mono- or di-C ₁ _ ₆ alkyl-carbamoyloxy group (e.g.,

methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,

(15) a 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 C ₁ _ ₆ alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) ,

(19) a C _6-14 arylsulfonyloxy group optionally substituted by a C ₁ _ ₆ alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy) ,

(20) an optionally halogenated C ₁ - 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 C ₁ _ ₆ alkyl-carbonyl group,

(26) a C _6-14 aryl-carbonyl group,

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

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

(29) a C ₁ _ ₆ alkoxy-carbonyl group,

(30) a C _6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl , 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,

(31) a C _7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl ) , .

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group,

(35) a C _6-14 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 C ₁ _ ₆ alkylsulfonyl group,

(39) a C _6-14 arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl ) , (41) an optionally halogenated C ₁ _ ₆ alkylsulfinyl group,

(42) a C _6-14 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-C ₁ _ ₆ alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,

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

(46) a mono- or di-C _6-14 arylamino group (e.g., phenylamino) ,

(47) a 5-: to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino) ,

(48) a C _7-16 aralkylamino group (e.g., benzylamino) ,

(49) a formylamino group,

(50) a C ₁ _ ₆ alkyl-carbonylamino group (e.g., acetylamino,

propanoylamino, butanoylamino) ,

(51) a (C ₁ _ ₆ alkyl) (C ₁ _ ₆ alkyl-carbonyl ) amino group (e.g., N- acetyl-N-methylamino) ,

(52) a C _6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,

(53) a C ₁ _ ₆ alkoxy-carbonylamino group (e.g.,

methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino) ,

(54) a C _7-16 aralkyloxy-carbonylamino group (e.g.,

benzyloxycarbonylamino) ,

(55) a C ₁ _ ₆ alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,

(56) a C _6-14 arylsulfonylamino group optionally substituted by a C ₁ _ ₆ alkyl group (e.g., phenylsulfonylamino,

toluenesulfonylamino) ,

(57) an optionally halogenated C ₁ _ ₆ alkyl group,

(58) a C _2-6 alkenyl group,

(59) a C _2-6 alkynyl group,

(60) a C _3-10 cycloalkyl group, (61) a C _3-10 cycloalkenyl group and

(62) a C _6-14 aryl group.

[0104]

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.

[0105]

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.

[0106]

In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non- aromatic heterocyclic group") include a 3- to 14-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.

[0107]

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 the "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

aforementioned 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.

[0108]

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 C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a C _7-16 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 C ₁ - 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 C ₁ _ ₆ alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C _3-1 o cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl , cycloheptanecarbonyl) , a C _3-10

cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl ) , a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a C _6-14 aryloxy-carbonyl group (e.g.,

phenyloxycarbonyl, naphthyloxycarbonyl ) , a C _7-16 aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl , phenethyloxycarbonyl ) , a carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group, a mono- or di-C _2-6 alkenyl-carbamoyl group (e.g.,

diallylcarbamoyl ) , a mono- or di-C _3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-Cs-14 aryl- carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C ₇ _ ₁₆ aralkyl-carbamoyl group, a 5- to 14-membered aromatic

heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a

thiocarbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C _2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C _3-10

cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C _6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C _7-16 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl ,

phenethylthiocarbamoyl) , a 5- to 14-membered aromatic

heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) , a sulfino group, a C ₁ _ ₆ alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl ) , a sulfo group, a C ₁ _ ₆ alkylsulfonyl group, a C ₆ - 14 arylsulfonyl group, a phosphono group and a mono- or di-C ₁ _ ₆ alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .

[0109]

In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C3-.10 cycloalkyl group, a C _6-14 aryl group, a C _7-16 aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 aryl- carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C ₁ - ₆ alkyl-carbamoyl group, a mono- or di-C _7-16 aralkyl-carbamoyl group, a C ₁ _ ₆ alkylsulfonyl group and a C _6-14 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 C ₁ _ ₆ alkyl) amino group (e.g., methylamino,

trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C _2-6 alkenylamino group (e.g., diallylamino) , a mono- or di-C ₃ -io cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino) , a mono- or di- C _6-14 arylamino group (e.g., phenylamino) , a mono- or di-C _7-16 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated C ₁ _ ₆ alkyl ) -carbonylamino group (e.g., acetylamino, propionylamino) , a mono- or di-C _6-14 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C _7-16 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-C ₁ _ 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-C ₁ - ₆ alkyl-carbamoyl ) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C _7-16 aralkyl-carbamoyl ) amino group (e.g.,

benzylcarbamoylamino) , a C ₁ _ ₆ alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C _6-14

arylsulfonylamino group (e.g., phenylsulfonylamino) , a (C ₁ _ ₆ alkyl) (C ₁ _ ₆ alkyl-carbonyl ) amino group (e.g., N-acetyl-N- methylamino) and a (C ₁ _ ₆ alkyl) (C _6-14 aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylamino) .

[0110]

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

optionally having "1 or .2 substituents selected from a C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a Ce- 14 aryl group, a C ₇ _ ₁₆ aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group and a mono- or di-C _7-16 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-C ₁ _ ₆ alkyl-carbamoyl group, a mono- or di-C _2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C _3-10 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,

cyclohexylcarbamoyl ) , a mono- or di-C _6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C _7-16 aralkyl-carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C _6-14 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,

pyridylcarbamoyl ) .

[0111]

In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a Ce- 14 aryl group, a C _7-16 aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group and a mono- or di-C _7-16 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-C ₁ _ ₆ alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C _2-6 alkenyl- thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group (e.g.,

cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C _6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl ) , a mono- or di-C _7-16 aralkyl-thiocarbamoyl group (e.g.,

benzylthiocarbamoyl , phenethylthiocarbamoyl ) , a mono- or di-C ₁ _ ₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl , propionylthiocarbamoyl) , a mono- or di-C _6-14 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl ) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl ) .

[0112]

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

optionally having "1 or 2 substituents selected from a C^g alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C ₆ - 14 aryl group, a C _7-16 aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group and " a mono- or di-C _7-16 aralkyl-carbamoyl group, each of which

optionally has 1 to 3 substituents selected from substituent group A" .

Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C ₁ _ ₆ alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl , dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl) , a mono- or di-C _2-6 alkenyl-sulfamoyl group (e.g.,

diallylsulfamoyl ) , a mono- or di-C _3-10 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl) , a mono- or di-C _6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C _7-16 aralkyl-sulfamoyl group (e.g.,

benzylsulfamoyl, phenethylsulfamoyl ) , a mono- or di-C ₁ _ ₆ alkyl- carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,

propionylsulfamoyl) , a mono- or di-C _6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) . [0113]

In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a C ₇ _ 16 aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 aryl- carbonyl group, a C _7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C ₁ _ ₆ alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C ₁ _ ₆ alkyl-carbamoyl group, a mono- or di-C _7-16 aralkyl-carbamoyl group, a C ₁ _ ₆ alkylsulfonyl group and a C _6-14 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 C ₁ _ ₆ alkoxy group, a C _2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C _3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C _6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C _7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a C ₁ _ ₆ alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C _6-14 aryl-carbonyloxy group

(e.g., benzoyloxy) , a C _7-16 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 C ₁ _ ₆ alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyridyloxy) , a carbamoyloxy group, a C ₁ _ ₆ alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a C _7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a C ₁ _ ₆ alkylsulfonyloxy group (e.g., methylsulfonyloxy,

ethylsulfonyloxy) and a C _6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .

[0114] In the present . specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from a C ₁ _ ₆ alkyl group, a C ₂ _ ₆ alkenyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a C ₇ _ i6 aralkyl group, a C ₁ _ ₆ alkyl-carbonyl group, a C _6-14 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 C ₁ _ ₆ alkylthio group, a C ₂ _ ₆ alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C _3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C _6-14 arylthio group (e.g., phenylthio, naphthylthio) , a C _7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a C ₁ _ ₆ alkyl-carbonylthio group (e.g.,

acetylthio, propionylthio, butyrylthio, isobutyrylthio,

pivaloylthio) , a C _6-14 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) .

[0115]

In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from a C ₁ _ ₆ alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group and a C _7-16 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-C ₁ _ ₆ alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .

[0116]

In the present specification, examples of the "C ₁ _ ₆ alkylene group" include -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, - (CH ₂ ) ₅ -, -(CH ₂ ) ₆ -/ -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ )-, - CH (CH (CH ₃ ) ₂ ) -/ -(CH(CH ₃ )) ₂ -/ -CH ₂ -CH (CH ₃ ) -, -CH (CH ₃ ) -CH ₂ -, -CH ₂ - CH ₂ -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -C (CH ₃ ) ₂ - and - C(CH ₃ ) ₂ -CH ₂ -CH ₂ -CH ₂ -.

In the present specification, examples of the "C ₂ _ ₆ alkenylene group" include -CH=CH-, -CH ₂ -CH=CH-, -CH=CH-CH ₂ -, - C (CH ₃ ) ₂ -CH=CH-, -CH=CH-C (CH ₃ ) ₂ -, -CH ₂ -CH=CH-CH ₂ - , -CH ₂ -CH ₂ -CH=CH-, -CH=CH-CH ₂ -CH ₂ -, -CH=CH-CH=CH-, -CH=CH-CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ - CH ₂ -CH=CH-.

In the present specification, examples of the "C ₂ _ ₆ alkynylene group" include -C≡C-, -CH ₂ -C≡C-, -C≡C-CH ₂ -, -

C (CH ₃ ) ₂ -C≡C-, -C≡C-C(CH ₃ ) ₂ -, -CH ₂ -C≡C-CH ₂ -, -CH ₂ -CH ₂ -C≡C-, -C≡ C-CH ₂ -CH ₂ -, -C≡OC≡C-, -C≡C-CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -C≡C- .

[0117]

In the present specification, examples of the

"hydrocarbon ring" include a C _6-14 aromatic hydrocarbon ring, C ₃ _ 10 cycloalkane and C _3-10 cycloalkene.

In the present specification, examples of the "C _6-14 aromatic hydrocarbon ring" include benzene and naphthalene.

In the present specification, examples of the "C _3-10 cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

In the present specification, examples of the "C _3-10 cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

In the present specification, examples of the

"heterocycle" include an aromatic heterocycle and a non- 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.

[0118]

In the present specification, examples of the "aromatic 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" 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, 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, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,

oxazolopyridine, thiazolopyridine, imidazopyrazine,

imidazopyrimidine, thienopyrimidine, furopyrimidine,

pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2, 3-b] thiophene, phenoxathiin, indole, isoindole, 1H- indazole, purine, isoquinoline, quinoline, phthalazine,

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

[0119]

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, oxazdlidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine , tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridihe, dihydrothiopyran,

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

thiomorpholine, azepane, 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 the "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.

[0120]

In the present specification, the "hydrocarbon ring" also includes a nonaromatic hydrocarbon ring. Examples of the nonaromatic hydrocarbon ring include a C _6-14 nonaromatic

hydrocarbon ring (e.g., tetrahydronaphthalene ring).

In the present specification, as the "ring" of the

"optionally further substituted ring", the above-mentioned

"hydrocarbon ring" and "heterocycle" can be mentioned and, as the substituent thereof, the above-mentioned "substituent" can be mentioned.

In the present specification, as the "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered. oxygen-containing heterocycle", a 6- or 7-membered monocyclic non-aromatic heterocycle (e.g., a dihydropyran ring, a dihydrooxazine ring, tetrahydrooxepine ring, tetrahydrooxazepine ring) containing, as a ring- constituting atom, one oxygen atom besides carbon atom, and optionally containing one more nitrogen atom can be mentioned, and as the substituent thereof, the above-mentioned

"substituent" can be mentioned.

In the present specification, as the "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring", a benzene ring and the above-mentioned 6- membered "aromatic heterocycle" can be mentioned, and as the substituent thereof, the above-mentioned "substituent" can be mentioned.

In the present specification, as the "C ₁ _ ₂ alkylene" of the "optionally halogenated C ₁ _ ₂ alkylene", the above-mentioned "C ₁ _ ₆ alkylene group" having 1 or 2 carbon atoms can be

mentioned, which may have 1 to 4 "halogen atoms" mentioned above.

[0121]

The definition of each symbol in the formula (Ι') is described in detail below.

Ring A is an optionally further substituted ring.

As the "ring" of the "optionally further substituted ring" for ring A, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned. It is preferably C _3-10

cycloalkane (e.g., cyclohexane) , C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), C _6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), 5- to 14- membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, guinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic

heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , more preferably a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring.

[0122]

The "ring" of the "optionally further substituted ring" for ring A is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents other than -L ¹ - (ring B' ) (ring C ) - group at substitutable position (s). As the substituent thereof, the above-mentioned "substituent" can be mentioned, and

preferred is (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C ₁ - ₆ alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally

substituted C _3-10 cycloalkyl group (e.g., cyclopropyl,

cyclobutyl) , (7) an optionally substituted C _3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) an optionally substituted C ₅ _ 14 aryl group (e.g., phenyl), (9) an optionally substituted C _6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14-membered nonaromatic heterocyclic group (e.g.,

oxetanyl, morpholinyl, piperazinyl) , (11) an optionally

substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl ) , (12) an optionally substituted C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyrazinyloxy) or (14) an

optionally substituted C ₁ - ₆ alkoxy-carbonyl group (e.g., tert- butoxycarbonyl) ,

more preferred is (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl)

optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkoxy group (e.g., methoxy), (5) a Cx-g alkoxy group (e.g., methoxy, ethoxy)

optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C ₃ _ ₁₀ cycloalkyl group (e.g., cyclopropyl ) , a C _6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a .C _3-10 cycloalkyl group

(e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents selected from a C ₁ - ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C _3-10 cycloalkyloxy group (e.g.,

cyclopropyloxy) , (8) a C _6-14 aryl group (e.g., phenyl)

optionally substituted by 1 - 3 substituents selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C ₁ _ ₆ alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a Ce-14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g.,

oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkyl group (e.g., methyl), (11) a 5- to 14- membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) a C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) or (14) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ,

further preferred is (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkoxy groups (e.g., methoxy), (4) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) or (5) a C _3-10 cycloalkyl group (e.g.,

cyclopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom).

[0123]

Ring A is preferably C _3-10 cycloalkane (e.g., cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C _6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an

optionally substituted C _3-10 cycloalkyloxy group (e.g.,

cyclopropyloxy) , (8) an optionally substituted C _6-14 aryl group (e.g., phenyl), (9) an optionally substituted C _6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl,

morpholinyl, piperazinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl,

pyrazolyl, pyridyl, pyrimidinyl ) , (12) an optionally

substituted C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyrazinyloxy) and (14) an

optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ,

more preferably, C _3-10 cycloalkane (e.g., cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C _6-14 nonaromatic hydrocarbon ring (e.g.,

tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran - ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkoxy group (e.g., methoxy) , (5) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C _3-10 cycloalkyl group (e.g., cyclopropyl) , a C _6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents

selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C _3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a C _6-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3 substituents selected from a C ₁ _ ₆ alkyl group (e.g., methyl ) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C ₁ _ ₆ alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a C ₆ _ 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ - ₆ alkyl group (e.g., methyl), (11) a 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) a C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (14) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ,

further preferably, a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkoxy groups (e.g., methoxy), (4) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C _3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom).

[0124]

L ¹ is a bond, optionally halogenated C ₁ _ ₂ alkylene, -NH- or -0- .

L ¹ is preferably a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -, - (CH ₂ ) ₂ - _/ -CH(CH ₃ )-), -NH- or -0-, more preferably a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -) or -NH- .

[0125]

The partial structure:

[0126]

[Chem. 46]

[0127]

is

[0128]

[Chem.

[0129]

X is a carbon atom or a nitrogen atom, n is an integer of 1 or 2, ring B is an optionally further substituted 6- or 7-membered oxygen-containing heterocycle, Y ¹ , Y ² and Y ³ are each

independently a carbon atom or a nitrogen atom, ring C is an optionally further substituted 6-membered aromatic ring, and Y ⁴ is =CH- or =N-.

The "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is preferably a dihydropyran ring (that is, X is a carbon atom, and n is 1) , a

dihydrooxazine ring (that is, X is a nitrogen atom and n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom and n is 2 ) .

[0130]

The "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents other than ring A-L ¹ - group at substitutable position (s ) . As the substituent thereof, the above-mentioned "substituent" can be mentioned, which is preferably (1) an oxo group or (2) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), more preferably (1) an oxo group or (2) a C ₁ - 6 alkyl group (e.g., methyl).

[0131]

Ring B is preferably a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an optionally substituted C ₁ _ 6 alkyl group (e.g., methyl), more preferably, a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2)

substituents selected from (1) an oxo group and (2) a C ₁ - ₆ alkyl group (e.g., methyl).

[0132]

In one embodiment of the present invention, ring B is preferably a 6- or 7-membered oxygen-containing heterocycle optionally further substituted by a methyl group, more

preferably a 6- or 7-membered oxygen-containing heterocycle not further substituted.

[0133]

The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for ring C is preferably a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (that is, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² are carbon atoms, Y ³ is a nitrogen atom) .

[0134]

The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for ring C is optionally further substituted by 1 - 3 (preferably 1 - 2, more preferably 1) substituents other than -C (=0) N (H) - group at substitutable position(s). As the substituent thereof, the above-mentioned "substituent" can be mentioned.

[0135]

Ring C is preferably a benzene. ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² are carbon atoms, Y ³ is a nitrogen atom) .

[0136]

Y ⁴ is preferably =N- . That is, in one embodiment of the present invention, the partial structure:

[0137]

[Chem. 48]

[0138]

is preferably

[0139]

[Chem. 49]

[0140]

wherein each symbol is as defined above.

[0141]

In one embodiment of the present invention, ring A is preferably [0142]

[Chem. 50]

[0143]

L ¹ is preferably a bond;

R ¹ is preferably a hydrogen atom or a hydroxymethyl group;

R ² is preferably a hydrogen atom;

ring D is preferably

[0144]

[Chem. 51]

[0145]

wherein

W is =CR ⁵ - or =N-;

R ⁵ is a hydrogen atom, -C0 ₂ C ₂ H ₅ , -CH ₂ OH, -C0 ₂ H, -CONH ₂ or

CN;

L ² is preferably -S0 ₂ -; and

R ³ is preferably -CH ₃ or -C ₂ H ₅ .

[0146]

In another embodiment of the present invention, the partial structure:

[0147]

[Chem. 52]

[0148]

is preferably

[0149]

[Chem. 53]

[0150]

wherein each symbol is as defined above.

[0151]

R ¹ and R ² are each independently a hydrogen atom or a substituent, R ¹ and R ^z may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R ¹ and R ² may be joined together to form an oxo group.

As the "substituent" for R ¹ or R ² , the above-mentioned "substituent" can be mentioned, preferably, (1) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or (2) an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl) , more preferably, (1) a C ₁ -g alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (2) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl).

As the "ring" of the "optionally further substituted ring" optionally formed by R ¹ and R ² bonded together with the adjacent carbon atom, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned, preferably, C _3-1 o

cycloalkane (e.g., cyclopropane ring). The "ring" is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents other than -C(=0)N(H)- group and R ³ -L ² -ring D- group at substitutable position (s) . As the substituent thereof, the above-mentioned "substituent" can be mentioned.

[0152]

R ¹ and R ² are preferably each independently (1) a

hydrogen atom, (2) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form an optionally further substituted C _3-10 cycloalkane (e.g., cyclopropane ring), more preferably (1) a hydrogen atom, (2) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3

substituents selected from a hydroxy group and a carboxy group or (3) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), or (4) bonded together with the adjacent carbon atom to form C _3-10 cycloalkane (e.g., cyclopropane ring), further preferably, (1) both hydrogen atoms or (2) one is a hydrogen atom and the other is a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 hydroxy groups .

[0153]

Ring D is an optionally further substituted ring.

As the "ring" of the "optionally further substituted ring" for ring D, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned, preferably, a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring) , more preferably a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring.

[0154]

The "ring" of the "optionally further substituted ring" for ring D is optionally further substituted by 1 - 4

(preferably 1 - 3, more preferably 1 or 2) substituents other than -N (H) -C (R ¹ ) (R ² ) - group and R ³ -L ² - group at substitutable position (s). As the substituent thereof, the above-mentioned "substituent" can be mentioned, preferably, a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl ) or an optionally substituted carbamoyl group, more preferably, (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl) or (6) a carbamoyl group.

[0155]

Ring D is preferably a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), a carboxyl group, an optionally substituted Cis alkoxy-carbonyl group (e.g., ethoxycarbonyl) and an optionally substituted carbamoyl group, more preferably, a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non- aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl) and (6) a carbamoyl group.

[0156]

L ² is -SO ₂ -, -S(=0)- or -S(=0) (=NR ⁴ ) -, R ⁴ is a hydrogen atom or a substituent. As the "substituent" for R ⁴ , the above-mentioned

"substituent" can be mentioned, which is preferably an

optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), more preferably a C ₁ _ ₆ alkyl group (e.g., methyl).

L ² is preferably -S0 ₂ - or -S (=0) (=NR ⁴ )- (R ⁴ is a hydrogen atom or an optionally substituted C ₁ - ₆ alkyl group (e.g., methyl)), more preferably, -S0 ₂ - or -S (=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom or a C ₁ _ ₆ alkyl group (e.g., methyl)), further preferably, -S0 ₂ - or -S (=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom).

[0157]

R ³ is a substituent.

As the "substituent" for R ³ , the above-mentioned

"substituent" can be mentioned.

R ³ is preferably an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group, more preferably a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl).

[0158]

Preferable examples of compound (Ι') are, for example, the following compounds.

[Compound A-l]

Compound (Ι') wherein

ring A is C _3-10 cycloalkane (e.g., cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C _6-14 nonaromatic hydrocarbon ring (e.g.,

tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4)- an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an optionally substituted C _3-10 cycloalkyloxy group (e.g.,

cyclopropyloxy) , (8) an optionally substituted C _6-14 aryl group (e.g., phenyl), (9) an optionally substituted C _6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) an optionally

substituted C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyrazinyloxy) and (14) an

optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ;

L ¹ is a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -, - (CH ₂ ) 2 - , ~

CH(CH ₃ )-), -NH- or -0-;

the partial structure :

[0159]

[Chem. 54]

[0160]

is [0161]

[Chem. 55]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an

optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² is a carbon atom, Y ³ is a nitrogen atom) ;

Y ⁴ is =CH- or =N-;

R ¹ and R ² are each independently (1) a hydrogen atom, (2) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C ₃ _ io cycloalkane (e.g., cyclopropane ring);

ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and an optionally substituted carbamoyl group;

L ² is -S0 ₂ - or -S(=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom or an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl)); and

R ³ is an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.

[0163]

[Compound B-l]

Compound (Ι') wherein

ring A is C _3-10 cycloalkane (e.g., cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a Ce-14 nonaromatic hydrocarbon ring (e.g.,

tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkoxy group (e.g., methoxy) , (5) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C _3-10 cycloalkyl group (e.g., cyclopropyl) , a C _6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents

selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C _3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a Ce-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3 substituents selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C ₁ _ ₆ alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a Ce- 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkyl group (e.g., methyl), (11) a 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl,

pyrimidinyl) , (12) a C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (14) a C ₁ - ₆ alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ;

L ¹ is a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -, - { Οϊ ₂ ) 2 ~ , ~

CH(CH ₃ )-), -NH- or -0-;

the partial structure:

[0164]

[Chem. 56]

[0165]

is

[0166]

[Chem. 57]

[0167]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C ₁ _ ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² is a carbon atom, Y ³ is a nitrogen atom) ;

Y ⁴ is =CH- or =N-;

R ¹ and R ² are each independently, (1) a hydrogen atom, (2) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) optionally

substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (3) a C ₁ - ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form C _3-10 cycloalkane (e.g., cyclopropane ring); ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is

optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;

L ² is -S0 ₂ - or -S(=0) (=NR ⁴ )- (R ⁴ is a hydrogen atom or a C ₁ _ ₆ alkyl group (e.g., methyl)); and

R ³ is a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl) .

[0168]

[Compound C-l]

Compound (Ι') wherein

ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkoxy groups (e.g., methoxy) , (4) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C _3-10 ^' cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom);

L ¹ is a bond, C ₁ - ₂ alkylene (e.g., -CH ₂ ~) or -NH-;

the partial structure:

[0169]

[Chem. 58]

[0170]

is

[0171]

[Chem.

[0172]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2 ;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C ₁ _ ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² are carbon atoms, Y ³ is a nitrogen atom) ;

Y ⁴ is =N-;

R ¹ and R ² are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups; ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;

L ² is -S0 ₂ - or -S(=0) (=NR ⁴ )- (R ⁴ is a hydrogen atom); and R ³ is a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl) .

[0173]

[Compound A-2]

Compound (Ι') wherein

ring A is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a Ce-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered

aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,

isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic

heterocycle (e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an optionally substituted C _3-10 cycloalkyloxy group (e.g.,

cyclopropyloxy) , (8) an optionally substituted Ce-14 aryl group (e.g., phenyl), (9) an optionally substituted C _6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl) and (12) an optionally substituted C ₁ - ₆ alkyl-carbonyl group (e.g., acetyl) ;

L ¹ is a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -, - (CH ₂ ) 2 - , ~

CH(CH ₃ )-), -NH- or -0-;

the partial structure:

[0174]

[Chem. 60]

[0177]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2 ;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an

optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² is a carbon atom, Y ³ is a nitrogen atom) ;

R ¹ and R ² are each independently (1) a hydrogen atom, (2) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted Cis alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C3- 10 cycloalkane (e.g., cyclopropane ring);

ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is

optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms (e.g., fluorine atom);

L ² is -SO2- or -S(=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom or an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl)); and

R ^3' is an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.

[0178]

[Compound B-2]

Compound (Ι') wherein

ring A is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a C _6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered

aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,

isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic

heterocycle (e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5

(preferably 1 - 3, more preferably 1 or 2) substituents

selected from (1) a halogen atom (e.g., fluorine atom,, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C ₁ - ₆ alkyl group (e.g. methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkoxy group (e.g., methoxy) , (5) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group and a carbamoyl group, (6) a C _3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl)

optionally substituted by 1 - 3 substituents selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C _3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a C _6-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3

substituents selected from a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C ₁ _ ₆ alkoxy group (e.g., methoxy) optionally

substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a C ₆ _ 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), (11) a 5- to 14^membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl) and (12) a C ₁ _ ₆ alkyl-carbonyl group (e.g., acetyl) ;

L ¹ is a bond, C ₁ _ ₂ alkylene (e.g., -(CH ₂ ) ₂ -, - CH(CH ₃ )-), -NH- or -0-;

the partial structure:

[0179]

[Chem. 62]

[0180]

is

[0181]

[Chem.

[0182]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C ₁ _ ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² is a carbon atom, Y ³ is a nitrogen atom) ;

R ¹ and R ² are each independently (1) a hydrogen atom, (2) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (3) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form C _3-10 cycloalkane (e.g., cyclopropane ring); ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is

optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms (e.g., fluorine atom);

L ² is -SO ₂ - or -S(=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom or a C ₁ _ ₆ alkyl group (e.g., methyl)); and

R ³ is a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl) .

[0183]

[Compound C-2]

Compound (Ι') wherein

ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ - ₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkoxy groups (e.g., methoxy) , (4) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C _3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) ;

L ¹ is a bond, C ₁ _ ₂ alkylene (e.g., -CH ₂ -) or -NH-; the partial structure:

[0184]

[Chem. 64]

[0185]

is

[0186]

[Chem.

[0187]

X is a carbon atom or a nitrogen atom;

n is an integer of 1 or 2;

ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C ₁ - ₆ alkyl group (e.g., methyl);

Y ¹ , Y ² and Y ³ are each independently a carbon atom or a nitrogen atom;

ring C is a benzene ring (that is, Y ¹ , Y ² and Y ³ are carbon atoms) or a pyridine ring (preferably, Y ¹ is a nitrogen atom, Y ² and Y ³ are carbon atoms or Y ¹ and Y ² is a carbon atom, Y ³ is a nitrogen atom) ;

R ¹ and R ² are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C ₁ _ ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;

ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms, (e.g., fluorine atom) ;

L ² is -S0 ₂ - or -S(=0) (=NR ⁴ ) - (R ⁴ is a hydrogen atom); and R ³ is a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl) .

[0188]

[Compound A-3]

Compound (Ι') wherein

ring A is C _3-10 cycloalkane (e.g., cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2 ) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl) , (3) an optionally substituted C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) , (4) an optionally substituted C _3-1 o cycloalkyl group (e.g.,

cyclopropyl) , (5) optionally substituted C _6-14 aryl group (e.g., phenyl), (6) an optionally substituted 3- to 14-membered nonaromatic heterocyclic group (e.g., piperazinyl) , (7) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) , (8) an optionally

substituted 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (9) an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ;

L ¹ is a bond or C ₁ _ ₂ alkylene (e.g., -CH ₂ -, -(CH ₂ )2 ^_ ) ; the partial structure:

[0189]

[Chem. 66]

[0190]

is

[0191]

[Chem.

[0192]

Y ⁴ is =CH- or =N- ;

R ¹ and R ² are each independently a hydrogen atom or an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl);

ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl), (4) a carboxyl group, (5) an optionally substituted C ₁ _ ₆ alkoxy-carbonyl group (e.g.,

ethoxycarbonyl) and (6) an optionally substituted carbamoyl group;

L ² is -SO2-; and

R ³ is an optionally substituted C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.

[0193]

[Compound B-3]

Compound (Ι') wherein

ring A is C _3-10 cycloalkane cyclohexane) , a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C ₁ _ ₆ alkoxy group (e.g., methoxy) , (3) a C ₁ _ ₆ alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a C _3-10 cycloalkyl group (e.g., cyclopropyl) and a C _6-14 aryl group

(e.g., phenyl), (4) a C ₃ _i ₀ cycloalkyl group (e.g., cyclopropyl), (5) a C _6-14 aryl group (e.g., phenyl), (6) a 3- to 14-membered nonaromatic heterocyclic group (e.g., piperazinyl) optionally substituted by 1 - 3 C ₁ _ ₆ alkyl groups (e.g., methyl), (7) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) , (8) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (9) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ;

L ¹ is a bond or C ₁ _ ₂ alkylene (e.g., -CH ₂ -, -(CH ₂ )2 ^~ ) ;

the partial structure:

[0194]

[Chem. 68]

[0195]

is

[0196]

[Chem.

[0197]

Y ⁴ is =CH- or =N-;

R ¹ and R ² are each independently a hydrogen atom or a Cis alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;

ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C ₁ - ₆ alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl) and (6) a carbamoyl group;

L ² is -SO2-; and

R ³ is a C ₁ _ ₆ alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C ₁ _ ₆ alkyl groups (e.g., methyl) .

[0198] [Compound C-3]

Compound (Ι') wherein

ring A is a pyridine ring optionally further substitut by 1 - 3 C _3-10 cycloalkyl groups (e.g., cyclopropyl) ;

L ¹ is a bond;

the partial structure:

[0199]

[Chem. 70]

[0200]

is

[0201]

[Chem.

[0202]

Y ⁴ is =N-;

R ¹ and R ² are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C ₁ - 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;

ring D is a C _6-14 aromatic hydrocarbon ring (e.g., benzene ring) or a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) , each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2)

substituents selected from (1) a cyano group, (2) a C ₁ - 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (3) a carboxyl group, (4) a C ₁ _ ₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (5) a carbamoyl group;

L ² is -SO2-; and

R ³ is a C1-6 alkyl group (e.g., methyl, ethyl).

[0203]

Specific examples of compound (Ι') include the compounds of Examples 3 - 381, among which

1- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4 ] oxazine-6-carboxamide (Example 249),

4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-

(methylsulfonyl) pyridin-2-yl) methyl) chromane-7-carboxamide (Example 290) ,

5- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2- carboxamide (Example 292) and

ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl ) -5, 6,7,8- tetrahydro-1 , 5-naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoate (Example 295)

are preferable.

[0204]

When compound (Ι') is a salt, examples of such salt include salts with inorganic base, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acids, and the like.

[0205]

Preferable examples of the salt with inorganic base include alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt,

magnesium salt and barium salt; and aluminum salt and the like.

[0206]

Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,

dicyclohexylamine, N, N' -dibenzylethylenediamine and the like.

[0207] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0208]

Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid,

benzenesulfonic acid, p-toluenesulfonic acid and the like.

[0209]

Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.

[0210]

Preferable examples of the salt with acidic amino acid include salt with aspartic acid, glutamic acid and the like.

[0211]

Of these salts, a pharmaceutically acceptable salt is preferable. As the pharmaceutically acceptable preferable salt, when the compound has a basic functional group therein,

examples of the salt thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric aid, succinic acid,

methanesulfonic acid, p-toluenesulfonic acid and the like.

When an acidic functional group is contained in the compound, examples thereof include inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt, and the like.

[0212]

Compound (Ι') may be a crystal, and both a single crystal and crystal mixtures are encompassed in the compound (I' ) .

Compound (Ι') may be a pharmaceutically acceptable

cocrystal or cocrystal salt. Here, the cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, hygroscopicity, solubility, stability etc.). The cocrystal and cocrystal salt can be produced by cocrystallization method known per se.

Compound (Ι') encompasses solvates (e.g., hydrate etc.) and non-solvates (e.g., non-hydrate etc.) within the scope thereof. A deuterium conversion form wherein ¹ H is converted to ² H(D) is also encompassed in compound (1')·

Compound (Ι') may be a compound labeled or substituted with an isotope (e.g., ³ H, ^X1 C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I). A compound labeled with or substituted by an isotope may be used, for example, as a tracer used for Positron Emission Tomography (PET) (PET tracer), and may be useful in the field of medical diagnosis and the like.

[0213]

When compound (Ι') of the present invention has an

asymmetric center, isomers such as enantiomer, diastereomer and the like may be present. Such isomers and a mixture thereof are all encompassed within the scope of the present invention. When an isomer is formed due to the conformation or tautomerism, such isomers and a mixture thereof are also encompassed in compound (Ι') of the present invention.

[0214]

The production method of the compound of the present invention is explained in the following.

[0215]

The starting materials and reagents used in each step in the following production method, and the obtained compounds each may form a salt. Examples of the salt include those similar to the aforementioned salts of the compound of the present invention and the like.

[0216]

When the compound obtained in each step is a free compound, it can be converted to a desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or a desired other kind of salt by a method known per se.

[0217]

The compound obtained in each step can also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof. Alternatively, the compound obtained in each step can be isolated and/or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like

according to a conventional method.

[0218]

When the starting materials and reagent compounds of each step are commercially available, the commercially available products can be used as they are.

[0219]

In each step, protection or deprotection reaction of a functional group is performed by the method known per se, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; "Protecting Groups 3rd Ed." (P. J. Kocienski) Thieme, 2004 and the like, or the methods described in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol and the like and a phenolic hydroxyl group include ether protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester protecting groups such as acetate ester and the like; sulfonate ester protecting groups such as methanesulfonate ester and the like; carbonate ester protecting groups such as t-butylcarbonate and the like, and the like.

Examples of the protecting group of the carbonyl group of aldehyde include acetal protecting groups such as dimethyl acetal and the like; cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like, and the like.

Examples of the protecting group of the carbonyl group of ketone include ketal protecting groups such as dimethyl ketal and the like; cyclic ketal protecting groups such as cyclic 1,3-dioxane and the like; oxime protecting groups such as 0- methyloxime and the like; hydrazone protecting groups such as N, N-dimethylhydrazone and the like, and the like.

Examples of the carboxyl protecting group include ester protecting groups such as methyl ester and the like; amide protecting groups such as N, N-dimethylamide and the like, and the like.

Examples of the thiol protecting group include ether protecting groups such as benzyl thioether and the like; ester protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.

Examples of the protecting group of an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate protecting groups such as benzyl

carbamate and the like; amide protecting groups such as

acetamide and the like; alkylamine protecting groups such as N- triphenylmethylamine and the like, sulfonamide protecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, for example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method and the like.

[0220]

The compounds and a salt thereof encompassed in the compound (Ι') of the present invention can be produced by the following Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, Method H, Method I, Method J, Method K, Method L, Method M, Method N, Method 0, Method P, Method U, Method V, Method W, Method X or Method

Compound (la) which is the compound of the present invention (Ι') wherein the partial structure:

[0221],

[Chem. 72]

[0222]

is

[0223]

[Chem.

[0224]

L ¹ is a bond, and X is a carbon atom can be produced by the following Method A.

[Method A]

[0225]

[Chem. 74]

(la)

[0226]

wherein Hal is a halogen atom, LG is a leaving group, R ⁵ is an optionally substituted hydrocarbon group, and other symbols are as defined above.

Examples of the halogen atom for Hal include chlorine atom, bromine atom and iodine atom.

As the leaving group for LG, a halogen atom (chlorine atom, bromine atom, iodine atom and the like) , a substituted sulfonyloxy group (C ₁ _ ₆ alkylsulfonyloxy group such as

methanesulfonyloxy, trifluoromethylsulfonyloxy,

ethanesulfonyloxy and the like; a C _6-14 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like; a C _7-16 aralkylsulfonyloxy group such as benzylsulfonyloxy group and the like, and the like) , an acyloxy group (acetoxy, benzoyloxy and the like) , an oxy group substituted by a

heterocyclic group or an aryl group (2, 5-dioxo-l-pyrrolidinyl, benzotriazolyl, quinolyl, 4-nitrophenyl and the like) , a heterocyclic group (imidazolyl and the like) and the like are used.

Examples of the optionally substituted hydrocarbon group for R ⁵ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like.

[0227]

(Step 1)

In this step, compound (II) or a salt thereof is

subjected to dehydration condensation with p- toluenesulfonylhydrazide to produce compound (III) .

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

The amount of p-toluenesulfonylhydrazide to be used is generally about 1 - 10 molar equivalents, preferably 1.1 molar equivalents, per 1 mol of compound (II).

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated

hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols

(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.

This step can also be performed in the presence of an acid. Examples of the acid to be used in this step include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) , organic sulfonic acid (tosylic acid, camphorsulfonic acid) and the like. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.001 - not less than 2 mol equivalents per 1 mol of compound (II) .

The reaction temperature is generally about 0 - 120°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - about 24 hr.

[0228]

(Step 2)

In this step, compound (III) or a salt thereof is coupled with compound (IV) in the presence of a Pd catalyst and a base to produce compound (V) .

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

Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,

tetrakis (triphenylphosphine ) palladium ( 0 ) ,

tris (dibenzylideneacetone) dipalladium ( 0 ) , XPHOS Pd G2 and the like, and a ligand (Xphos, triphenylphosphine, tri-t- butylphosphine, S-Phos, BINAP, 2' - (di-tert-butylphosphino) -N,N- dimethyl- [1, 1' -biphenyl] -2-amine, XANTPHOS and the like) is added as necessary. The amount of the catalyst to be used is generally about 0.0001 - 1 molar equivalent, preferably about 0.01 - 0.5 molar equivalent, per 1 mol of compound (III) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (III) .

As the base, an alkali metal salt (sodium hydrogen

carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t- butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , or alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) is added. The amount of the base to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents per 1.mol of compound (III).

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated

hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols

(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.

The reaction temperature is generally about 0 - 150°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 — 48 hr, preferably about 0.5 - about 24 hr. The reaction may be performed under microwave irradiation as necessary.

[0229]

(Step 3)

In this step, compound (V) or a salt thereof was

subjected to a catalytic hydrogenation reaction to produce compound (VI) or a salt thereof.

The catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. Examples of the catalyst include palladiums (palladium carbon, palladium carbon-ethylenediamine complex, palladium-activated carbon

Evonik Degussa type E, palladium hydroxide carbon, palladium oxide and the like), nickels (sponge nickel catalyst and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium carbon and the like) and the like. The amount thereof to be used is generally about 0.001 - about 1 molar equivalent, preferably about 0.01 - about 0.5 molar equivalent, per 1 mol of compound (V) . The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols (methanol, ethanol, propanol, butanol and the like) , hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , amides (N, N-dimethylformamide and the like), carboxylic acids (acetic acid and the like), water and a mixture thereof.

The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.

[0230]

(Step 4)

In this step, compound (VI) or a salt thereof is

subjected to a cyanation reaction to produce compound (VII) .

This reaction can be performed in the presence of a transition metal catalyst by using a cyanation reagent in a solvent that does not adversely influence the reaction.

Examples of the transition metal catalyst to be used in this reaction include palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium ( 0 ) and the like) , nickel catalyst (nickel chloride and the like) and the like, and a ligand (triphenylphosphine, tri-t- butylphosphine, S-Phos, BINAP and the like) may also be used as necessary. While the amount of the transition metal catalyst to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.001 - 1 mol equivalents, preferably about 0.1 - 0.5 molar equivalents, per 1 mol of compound (VI), and the amount of the ligand to be used is generally about 0.001 - 1 mol equivalents per 1 mol of compound (VI) . Examples of the cyanation reagent to be used in this reaction include zinc cyanide, copper cyanide and the like. While the amount thereof to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.5 - 10 molar equivalents, preferably about 0.5 - 2 molar equivalents, per 1 mol of compound (VI) .

Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl . methyl ether, tetrahydrofuran, dioxane,

dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like. Two or more kinds of these

solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -10 - 200°C. The reaction time varies depending on the kind of compound (VI), reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary.

[0231]

(Step 5)

In this step, compound (VI) or a salt thereof is

alkoxycarbonylated under a carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX) :

R ⁵ OH (CIX)

(R ⁵ is as defined above) ,

to produce compound (VIII) or a salt thereof.

Examples of the transition metal catalyst include

palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine ) palladium ( 0) and the like), nickel catalyst (nickel chloride and the like) and the like, and an organic phosphorus reagent such as triphenylphosphine, 1,1'- bis (diphenylphosphino) ferrocene (dppf) and the like can be used as necessary. The amount of the catalyst to be used varies depending on the kind of the catalyst, and is generally about 0.0001 - 1 mol, preferably about 0.01 - 0.5 mol, per 1 mol of compound (VI) , and the amount of the organic phosphorus reagent to be used is preferably about 0.01 - 2 mols.

The alcohol represented by the formula (CIX) is

preferably methanol or ethanol. The above-mentioned alcohol in this step is used in an excess amount.

This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), aprotic polar solvents (N, N-dimethylformamide, dimethyl sulfoxide and the like) and the like can be mentioned. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

In addition, this step can also be performed in the presence of a base or a salt. Examples of the base or salt include inorganic base (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate,

potassium hydrogen carbonate and the like, alkali metal

carbonates such as lithium carbonate, sodium carbonate,

potassium carbonate, cesium carbonate and the like, or organic base (amines such as trimethylamine, triethylamine,

diisopropylethylamine and the like, cyclic amine such as pyridine and the like, and the like) and the like. The amount of the base or salt to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 10 molar equivalents, per 1 mol of compound (VI) .

The reaction is generally performed under normal pressure, carbon monoxide atmosphere and can be performed under

pressurization (e.g., about 3 - 10 atm) where necessary.

The reaction temperature varies depending on the kind of the solvent, and is, for example, about -50 - 200°C, preferably about 20 - 150°C. The reaction time varies depending on the kind of compound (VI) or a salt thereof, the reaction

temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0232]

(Step 6)

In this step, compound (VII) or a salt thereof is

subjected to hydrolysis to convert same to compound (IX) or a salt thereof. This reaction can be performed by a method known per se, and generally performed, in the presence of an acid or a base and, where necessary, in a solvent that does not

adversely influence the reaction.

Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p- toluenesulfonic acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) or a mixture of two or more kinds thereof can be mentioned. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (VII), and it can also be used as a solvent.

As the base, for example, inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,

potassium hydroxide and the like, alkali metal hydrogen

carbonates such as sodium hydrogen carbonate, potassium

hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like, alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like) , organic bases (amines such as

trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine 5 and the like, and the like) and the like are used. Of these, sodium hydroxide is preferable. While the amount of the base to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.1 - 10 molar eguivalents, preferably about 1 - 5 molar equivalents, per 1

10 mol of compound (VII) .

Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,

hydrocarbons (benzene, toluene, xylene, hexane, heptane and the

15 like) , halogenated hydrocarbons (dichloromethane, chloroform

and the like) , ethers (diethyl ether, diisopropyl ether, t- butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , carboxylic acids (acetic acid and the like), amides (N, -dimethylformamide,

20 N, N-dimethylacetamide and the like), sulfoxides (dimethyl

sulfoxide and the like), water and the like. Of these, ethanol, tetrahydrofuran or water is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -50 -

25 200°C, preferably about 0 - 100°C. While the reaction time

varies depending on the kind of compound (VII) or a salt

thereof, reaction temperature and the like, it is, for example, about 0.5 min - 100 hr, preferably about 0.5 - 24 hr.

[0233]

30 (Step 7)

In this step, compound (VIII) or a salt thereof is subjected to hydrolysis to convert same to compound (IX) or a salt thereof. This step can be performed by a method according to that of Method A, Step 6.

35 [0234] (Step 8)

In this step, compound (IX) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (la) or a salt thereof.

Compound (X) or a salt thereof is commercially available or can be produced according to a method known per se or a method analogous thereto or the below-mentioned method.

The condensation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 22,

Organic Synthesis IV" and the like, or a method analogous thereto. Examples of the method include (A) a method using a condensing agent, (B) a method via a reactive derivative and the like.

[0235]

Examples of the condensing agent to be used in (A) ^M a method using a condensing agent" include (dimethylamino) -N, N- dimethyl (3H-[l,2,3]triazolo[4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (HATU) , 1- [ (1- (cyano-2-ethoxy-2- oxoethylideneaminooxy) -dimethylamino-morpholino) ] carbenium hexafluorophosphate (COMU) , 2 , 4 , 6-tripropyl-l , 3 , 5 , 2 , 4 , 6- trioxatriphosphorinane-2 , 4, 6-trioxide (T3P) ,

dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC), N-ethyl-N' -3-dimethylaminopropylcarbodiimide and hydrochlorides thereof (WSC, WSC-HC1, EDCI), benzotriazol-l-yl- tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) , ( 4-oxobenzo [d] [1, 2, 3] triazin- 3 (4H) -yl) diethyl phosphate (DETBT) , ( 3-hydroxy-3H-l , 2 , 3- triazolo [4, 5-b] pyridinato-O) tri-l-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP), Ν,Ν,Ν' ,Ν' -tetramethyl-O- (3, 4- dihydro-4-oxo-l, 2, 3-benzotriazin-3-yl ) uronium tetrafluoroborate (TDBTU) , 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4- methylmorpholinium chloride (DMT-MM) and hydrate thereof and the like. These may be used singly, or can also be used in combination with additive (e.g., N-hydroxysuccinimide, 1- hydroxybenzotriazole, 3-hydroxy-4-oxo-3, 4-dihydro-l, 2, 3- benzotriazine and the like) . The amount of the condensing agent to be used is generally about 1 - 10 molar equivalents, preferably about 1 .- 2 molar equivalents, per 1 mol of compound (IX) . The amount of the additive to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar

equivalents, per 1 mol of compound (IX) .

The above-mentioned reaction can be generally performed in a solvent that does not adversely influence the reaction, or can also be performed in the presence of a base. Examples of the solvent include hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated

hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like), aromatic amines (pyridine and the like), water and a mixture of these. Examples of the base include alkali metal hydroxides (sodium hydroxide,

potassium hydroxide and the like) , hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like) , carbonates (sodium carbonate, potassium carbonate and the like) , acetates (sodium acetate and the like) , tertiary amines

(trimethylamine, triethylamine, N-methylmorpholine,

diisopropylamine and the like) , aromatic amines (pyridine, picoline, N, N-dimethylaniline, 4-dimethylaminopyridine and the like) and the like. The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (IX) .

The reaction temperature is generally about -80 - 150°C, preferably about 0 - 50°C. The reaction time is generally about 0.5 - 48 hr, preferably 0.5 - 16 hr.

[0236]

As the reactive derivative shown in (B) "a method via a reactive derivative", a compound represented by the formula:

[0237]

[Chem. 75]

(IXa)

[0238]

wherein LG ¹ is a leaving group, and other symbols are as defined above,

(hereinafter to be referred to as compound (IXa)) or a salt thereof (e.g., acid halide, acid anhydride, mixed acid

anhydride, active ester and the like) and the like can be mentioned. Examples of the leaving group for LG ¹ include those similar to LG.

Compound (IX) can be converted to a reactive derivative

(compound (IXa)) according to a method known per se. For example, for conversion to acid halide, a method using acid halide (e.g., thionyl chloride, oxalyl chloride and the like), a method using phosphorus or phosphoric acid halide (e.g., phosphorus trichloride, phosphorus pentachloride and the like) and the like can be mentioned. The above-mentioned reaction via a reactive derivative can be performed, depending on the kind of compound (IX) , generally in a solvent that does not adversely influence the reaction, and the reaction can also be performed in the presence of a base. The kind and the amount of the solvent and base to be used in the reaction, reaction temperature and the reaction time are similar to those

described in the above-mentioned "method using a condensing agent".

[0239]

Compound (Ib-I) which is the compound of the present invention (Ι'), wherein the partial structure:

[0240]

[Chem. 76]

[0241]

is

[0242]

[Chem.

L ¹ is optionally halogenated C ₁ alkylene and X is a carbon atom, can be produced by the following Method B-1.

[Method B-1]

[0244]

[Chem. 78]

[0245]

wherein R ^5a , R ^5b and R ^5c are each independently an optionally substituted hydrocarbon group, and other symbols are as defined above .

Examples of the optionally substituted hydrocarbon group for R ^5a , R ^5b or R ^5c include those similar to R ⁵ mentioned above.

[0246]

(Step 1)

In this step, compound (II) or a salt thereof is alkoxycarbonylated under a carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX ^a ) :

R ^5a 0H (CIX ^a )

wherein the symbol is as defined above,

to produce compound (XI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0247]

(Step 2)

In this step, compound (XI) or a salt thereof and

compound (XII) or a salt thereof are subjected to a Horner- Wadsworth-Emmons reaction to produce compound (XIII) or a salt thereof .

Compound (XII) or a salt thereof to be used in this reaction may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.

This reaction can be performed in the presence of a base, in a solvent that does not adversely influence the reaction.

As the base to be used in this reaction, sodium hydride, sodium methoxide, potassium carbonate, 1,8- diazabicyclo [ 5.4.0 ] undec-7-ene (DBU) , triethylamine and the like can be mentioned. A salt such as lithium chloride and the like may also be co-present. The amount of the base to be used is generally about 0.1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XII) .

Examples of the solvent to be used in this reaction include alcohols (methanol, ethanol and the like) , ethers

(diethyl ether, dioxane, tetrahydrofuran, 1 , 2-dimethoxyethane and the like), dimethyl sulfoxide and the like, and they may also be appropriately used in a mixture.

The reaction temperature is generally about -78°C - about 150°C, preferably about 0°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.

[0248]

(Step 3)

In this step, compound (XIII) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XIV) or a salt thereof.

This step can be performed by a method according to . that of Method A, Step 3.

[0249]

(Step 4)

In this step, compound (XIV) or a salt thereof is subjected to hydrolysis to convert same to compound (XV) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0250]

(Step 5)

In this step, compound (XV) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ib-I) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0251]

Compound (Ib-II) which is the compound of the present invention (I' ) , wherein the partial ,structure :

[0252]

[Chem. 79]

[0253]

is

[0254]

[Chem. 80]

[0255]

L ¹ is optionally halogenated C ₂ alkylene, and X is a carbon atom can be produced the following Method B-2.

[Method B-2]

[0256]

[Chem. 81]

(XX) (lb-ll)

[0257]

wherein R ^5d is an optionally substituted hydrocarbon group, and other symbols are as defined above.

As the optionally substituted hydrocarbon group for R ^5d , those similar to the above-mentioned R ⁵ can be mentioned.

[0258]

(Step 1) In this step, compound (II) or a salt thereof is

subjected to a one-carbon homologation reaction to produce compound (XVI) or a salt thereof.

In this reaction, compound (II) or a salt thereof is reacted with (methoxymethylene) triphenylphosphorane in a solvent that does not adversely influence the reaction, and post-treated with water to produce compound (XVI) or a salt thereof .

Examples of the solvent to be used in this reaction include alcohols (methanol, ethanol and the like), ethers

(diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane and the like) , dimethyl sulfoxide and the like, which may also be used in a mixture as appropriate.

The amount of (methoxymethylene) triphenylphosphorane to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (II) .

The reaction temperature is generally about -78°C - about 150°C, preferably about 0°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.

[0259]

(Step 2)

In this step, compound (XVI) or a salt thereof is

subjected to alkoxycarbonylation under a carbon monoxide atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIX ^d ) :

R ^5d OH (CIX ^d )

wherein the symbol is as defined above,

to produce compound (XVII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0260]

(Step 3)

In this step, compound (XVII) or a salt thereof and compound (XII) or a salt thereof is subjected to a Horner- Wadsworth-Emmons reaction to produce compound (XVIII) or a salt thereof .

This step can be performed by a method according to that of Method B-l, Step 2.

[0261]

(Step 4)

In this step, compound (XVIII) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XIX) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 3.

[0262]

(Step 5)

In this step, compound (XIX) or a salt thereof is

subjected to hydrolysis to convert same to compound (XX) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0263]

(Step 6)

In this step, compound (XX) or a salt thereof and

compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ib- _. II) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0264]

Compound (Ic), which is the compound of the present invention (I' ) wherein the partial structure:

[0265]

[Chem. 82]

[0266]

is

[0267] ,

[Chem. 83]

[0268]

L ¹ is -NH-, and X is a carbon atom can be produced by the following Method C.

[Method C]

[0269]

[Chem. 84]

[0270]

wherein each symbol is as defined above.

[0271]

(Step 1)

In this step, compound (XI) or a salt thereof and compound (XXI) or a salt thereof are subjected to reductive amination reaction to produce compound (XXII) or a salt thereof.

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

The reductive amination reaction in this step can be performed by a method known per se. For example, it can be performed by reacting compound (XI) or a salt thereof and compound . (XXI ) or a salt thereof, and subjecting the resulting imine or iminium ion to a reduction reaction.

The amount of compound (XXI) to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 3 molar equivalents, per 1 mol of compound (XI) .

The solvent in the reaction to produce imine or iminium ion is not particularly limited as long as the reaction

proceeds. Examples of the solvent to be used in this step include hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1 , 2-dichloroethane and the like), ethers (diethyl ether,

tetrahydrofuran, dioxane and the like) , esters (ethyl acetate, t-butyl acetate and the like) , alcohols (methanol, ethanol, 2- propanol and the like) , nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the, like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.

In this step, a catalyst may be added as necessary. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc

chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agent (magnesium sulfate and the like) and the like can be mentioned. The amount of the catalyst to be used is generally about 0.01 - 50 molar equivalents,

preferably about 0.1 - about 10 mol, per 1 mol of compound (XI) .

The reaction temperature is generally about 0°C - about 200°C, preferably about 20°C - about 150°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about 24 hr.

Imine or iminium ion can be converted to compound (XXII) by various reduction reactions in a solvent inert to the

reaction. Such reduction reaction can be performed by a method known per se and, for example, a method using a metal hydride and a method by a catalytic hydrogenation reaction can be mentioned.

Examples of the metal hydride include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride,

dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catecholborane etc.) and the like, and sodium borohydride, sodium

cyanoborohydride, sodium triacetoxyborohydride and the like are preferable. The amount of the metal hydride to be used is, for example, generally about 1 - about 50 mol, preferably about 1 - about ,10 mol, per 1 mol of imine.

A reduction reaction using metal hydride can be performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptane, hexane and the like; halogenated hydrocarbons such as chloroform,

dichloromethane and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; alcohols such as

methanol, ethanol, 2-propanol, butanol, benzyl alcohol and the like; nitriles such as acetonitrile and the like; N,N- dimethylformamide; dimethyl sulfoxide and the like. These solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is generally about -80°C - about 80°C, preferably about -40°C - about 40°C, and the reaction time is generally about 5 min - about 48 hr, preferably about 1 hr - about 24 hr.

A catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. As the catalyst, palladiums such as palladium carbon, palladium

hydroxide carbon, palladium oxide and the like; nickels such as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like; and the like can be mentioned. The amount thereof to be used is generally about 0.001 - about 1 mol, preferably about 0.01 - about 0.5 mol, per 1 mol of imine or oxime .

A catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as

dichloromethane, chloroform and the like; ethers such as

diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N,N- dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.

The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.

In this step, the next reduction reaction may be

performed without isolating imine or oxime as an intermediate, and compound (XXII) may be directly obtained from compound (XI) . In this case, the pH of the reaction mixture is preferably about 4 to about 5.

[0272] (Step 2)

In this step, compound (XXII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXIII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0273]

(Step 3)

In this step, compound (XXIII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ic) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0274]

Compound ( Id) , which is the compound of the present invention (I' ) wherein the partial structure:

[0275]

[Chem. 85]

[0276]

is

[0277]

[Chem.

[0278]

L ¹ is -0-, and X is a carbon atom, can be produced by the following Method D.

[Method D]

[0279]

[Chem. 87]

(XXVI) (Id)

[0280]

wherein each symbol is as defined above.

[0281]

(Step 1)

In this step, compound (XI) is treated with a reducing agent to produce compound (CVI) .

Examples of the reducing agent to be used in this

reaction include metal hydride (e.g., sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride) and the like. The amount of the metal hydride to be used is generally about 1 - 50 molar equivalents, per 1 mol of compound (XI) .

This reaction can be performed in a solvent inert to the reaction. Examples of such solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N, N-dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.

The reaction temperature is, for example, about -50 -

200°C, preferably about 0 - 50°C. While the reaction time varies depending on the kind of compound (XI) , reaction

temperature and the like, it is, for example, about 0.1 - 100 hr, preferably about 0.1 - 6 hr.

[0282]

(Step 2)

In this step, compound (CVI) or a salt thereof is reacted with compound (XXIV) or a salt thereof in the presence of

Mitsunobu reagent and organic phosphorus reagent to produce compound (XXV) or a salt thereof.

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

While the amount of compound (XXIV) to be used varies depending on the kind of the solvent and other reaction

conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .

As the Mitsunobu reagent, azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and the like are used, of which diisopropyl

azodicarboxylate is preferable. While the amount of the

Mitsunobu reagent to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .

As the organic phosphorus reagent, organic phosphorus compounds such as tributylphosphine, triphenylphosphine and the like are used, of which triphenylphosphine is preferable.

While the amount of the organic phosphorus reagent to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .

This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, toluene or tetrahydrofuran is preferable. Two or more kinds of these solvents may be used in a mixture in an

appropriate ratio.

The reaction temperature varies depending on the kind of the solvent, and is, for example, about 0 - 200°C, preferably about 50 - 100°C. While the reaction time varies depending on the kind of compound (CVI) or a salt thereof, reaction

temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0283]

(Step 3)

In this step, compound (XXV) or a salt thereof is

subjected to hydrolysis to convert same to compound (XXVI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0284]

(Step 4)

In this step, compound (XXVI) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Id) or a salt thereof. This step can be performed by a method according to that of Method A, Step 8.

[0285]

Compound (Ie), which is the compound of the present invention (I' ) wherein the partial structure:

[0286]

[Chem. 88]

[0287]

is

[0288]

[Chem. 89

[0289]

L ¹ is a bond, and X is a nitrogen atom can be produced by the following Method E.

[Method E]

[0290]

[Chem. 90]

[0291]

wherein R ^5e is an optionally substituted hydrocarbon group, LG ² is a leaving group, Boc is t-butoxycarbonyl, and other symbols are as defined above.

Examples of the optionally substituted hydrocarbon group for R ^5e include those similar to the above-mentioned R ⁵ .

Examples of the leaving group for LG ² include those similar to the above-mentioned LG.

[0292]

(Step 1)

In this step, compound (XXVII) or a salt thereof is subjected to deprotection reaction to produce compound (XXVIII) or a salt thereof.

Such deprotection reaction can be performed according to a known method (e.g., "Protective Groups in Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts), Wiley- Interscience, 1999) . For example, while subject to variation depending on the kind of compound (XXVII), it can be generally performed in the presence of an acid and in a solvent as necessary that does not adversely influence the reaction.

Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids

(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (XXVII), and it can also be used as a solvent.

Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,

aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,

halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , carboxylic acids (acetic acid and the like) , amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed solvent thereof can be mentioned.

The reaction temperature varies depending on the kind of the solvent, and it is, for example, about -50 - 200°C,

preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (XXVII), reaction temperature and the like, it is, for example, about 0.5 - 100 hr,

preferably about 0.5 - 24 hr. [0293]

(Step 2)

In this step, compound (XXVIII) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (XXIX) or a salt thereof.

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

Examples of the transition metal catalyst to be used in this reaction include palladium catalysts (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium (0) , tris (dibenzylideneacetone ) dipalladium ( 0 ) and the like), nickel catalysts (nickel chloride and the like) and the like and, where necessary, a ligand (triphenylphosphine, tri-t- butylphosphine, S-Phos, XPhos, BINAP, 2'-(di-tert- butylphosphino) -N, N-dimethyl- [ 1 , 1 ' -biphenyl] -2-amine and the like), a base (e.g., organic amines (trimethylamine,

triethylamine, diisopropylamine , N-methylmorpholine, 1,8- diazabicyclo [5, 4 , 0] undec-7-ene, pyridine, N, N-dimethylaniline and the like), an alkali metal salt (sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like), alkali metal alkoxide (sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) may be added, or metal oxide (copper oxide, silver oxide and the like) and the like may be used as a cocatalyst. The amount of the catalyst to be used is generally about 0.0001 - 1 mol

equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the base to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the cocatalyst to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar

equivalents, per 1 mol of compound (XXVIII).

The solvent to be used may be any as long as it does not adversely influence the reaction and, for example, hydrocarbons (benzene, toluene, xylene and the like) , halogenated

hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (dimethoxyethane, tetrahydrofuran) , alcohols (methanol, ethanol and the like) , aprotic polar solvents (N, N-dimethylformamide, dimethyl

sulfoxide, hexamethylphosphoramide and the like) , water and a mixture thereof can be used.

The reaction temperature is generally about -100 - 200°C, preferably about -80 - 150°C, and the reaction time is

generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary .

[0294]

(Step 3)

In this step, compound (XXVII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXX) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0295]

(Step 4)

In this step, compound (XXVIII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXXI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6. [0296]

(Step 5)

In this step, compound (XXIX) or a salt thereof is

subjected to hydrolysis to convert same to compound (XXXII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0297]

(Step 6)

In this step, compound (XXX) or a salt thereof and

compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (XXXIII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0298]

(Step 7)

In this step, compound (XXXI) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (XXXIV) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0299]

(Step 8)

In this step, compound (XXXII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ie) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0300]

(Step 9)

In this step, compound (XXXIII) or a salt thereof is subjected to deprotection reaction to produce compound (XXXIV) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 1. [0301]

(Step 10)

In this step, compound (XXXIV) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (Ie) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 2.

[0302]

Compound (If-I), which is the compound of the present invention (Ι') wherein the partial structure:

[0303]

[Chem. 91]

[0304]

IS

[0305]

[Chem. 92]

[0306]

L ¹ is optionally halogenated C ₁ alkylene, and X is a nitrogen atom can be produced by the following Method F-1.

[Method F-1]

[0307]

[Chem. 93]

[0308]

wherein LG ³ is a leaving group, Hal ² is a halogen atom, and other symbols are as defined above.

Examples of the leaving group for LG ³ include those similar to the above-mentioned LG.

Examples of the halogen atom for Hal ² include those similar to the above-mentioned Hal.

[0309]

(Step 1)

In this step, compound (XXXVI) or a salt thereof is reacted with compound (XXXVII) or a salt thereof in the presence of a base to produce compound (XXXIX) or a salt thereof (alkylation) , or compound (XXXVI) or a salt thereof is reacted with compound (XXXVIII) or a salt thereof in the presence of a reducing agent to produce compound (XXXIX) or a salt thereof (reductive alkylation) .

Compound (XXXVI), compound (XXXVII) and compound

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

As the base to be used in "alkylation" reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium

hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),

sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, dimethylformamide is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. While the reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr.

The "reductive alkylation" reaction can be performed according to Method C, Step 1.

[0310]

(Step 2)

In this step, compound (XXXIX) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide

atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX ^e ) :

R ^5e OH (CIX ^e )

wherein the symbol is as defined above,

to produce compound (CXI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0311]

(Step 3)

In this step, in compound (XXXVI) or a salt thereof, a free amino group is protected, and the obtained compound or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX ^e ) :

R ^5e OH (CIX ^e )

wherein the symbol is as defined above,

and then the amino group is deprotected to produce compound (XXVIII) or a salt thereof.

The protecting group used for protecting a free amino group includes, for example, t-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz or Z) group, benzyl (Bn) group, 4- methoxybenzyl (PMB) group, trifluoroacetyl (CF ₃ CO) group and the like, of which Boc group is preferable.

When amino group is protected with Boc group, compound (XXXVI) or a salt thereof is reacted with di-t-butyl

dicarbonate (BOC ₂ O) in the presence of a base and in a solvent that does not adversely influence the reaction.

As the base to be used in this step, for example,

inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride, lithium hexamethyldisilazide, sodium

hexamethyldisilazide and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium

ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine , diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride, trimethylamine and sodium hexamethyldisilazide are preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .

Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,

dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- ^■ dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio. Boc ₂ 0 to be used in this step is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXXVI) .

The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

When amino group is protected with Cbz (Z) group, compound (XXXVI) or a salt thereof is reacted with benzyl chloroformate in the presence of a base and in a solvent that does not adversely influence the reaction. The base, solvent, reagent amount, reaction temperature, reaction time used in this step can be the same as those used for the above-mentioned protection of amino group with Boc group.

When amino group is protected with Bn group, compound (XXXVI) or a salt thereof is reacted with benzaldehyde in a solvent that does not adversely influence the reaction, and then treated with a reducing agent, or compound (XXXVI) or a salt thereof is reacted with benzyl bromide or benzyl chloride in the presence of a base and in a solvent that does not adversely influence the reaction.

When reacted with benzaldehyde, examples of the solvent that does not adversely influence the reaction include

hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1,2- dichloroethane and the like) , ethers (diethyl ether,

tetrahydrofuran, dioxane and the like) , esters (ethyl acetate, t-butyl acetate and the like) , alcohols (methanol, ethanol, 2- propanol and the like), nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.

Examples of the reducing agent to be used in this

reaction include metal hydrides (sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, diisobutyl aluminum hydride, aluminum hydride, lithium aluminum hydride and the like) , borane complex (borane-THF complex, catechol borane etc.) and the like. The amount of the metal hydride to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (XXXVI) .

In this reaction, a catalyst may be added as necessary to advantageous perform the reaction. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like), carboxylic acids (formic acid, acetic acid,

propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agent (magnesium sulfate and the like) and the like can be mentioned. The amount of the catalyst to be used is generally about 0.01 - 50 molar equivalents, preferably about 0.1 - 10 mol, per 1 mol of compound (XXXVI).

The amount of benzaldehyde to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar

equivalents, per 1 mol of compound (XXXVI) .

The reaction temperature is generally about 0°C - 200°C, preferably about 20°C - 150°C, and the reaction time is

generally about 0.5 hr - 48 hr, preferably about 0.5 hr - 24 hr.

When reacted with benzyl bromide or benzyl chloride, examples of the base to be used in this reaction include

inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, potassium carbonate is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .

The amount of benzyl bromide and benzyl chloride to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXXVI) .

Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,

dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, acetonitrile is

preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. While the reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr.

When amino group is protected with PMB group, compound (XXXVI) or a salt thereof is reacted with 4-methoxybenzaldehyde in a solvent that does not adversely influence the reaction, and treated with a reducing agent. The solvent, reducing agent, reagent amount, additive, reaction temperature, reaction time used in this step can be the same as those used for the above-mentioned protection of amino group with Bn group.

When amino group is protected with CF ₃ CO group, in the presence of a base, compound (XXXVI) or a salt thereof is reacted with trifluoroacetic anhydride in a solvent that does not adversely influence the reaction. The base, solvent, reagent amount, reaction temperature, reaction -time used in this step can be the same as those used for the above-mentioned protection of amino group with Boc group.

The compound or a salt thereof obtained by protecting a free amino group is subjected to alkoxycarbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the formula (CIX ^e ) , and this step can be performed according to Method A, Step 5.

The step of producing compound (XXVIII) or a salt thereof by deprotecting the amino group (deprotection) can be performed according to a known method (e.g., "Protective Groups in

Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 1999) ) .

When the protecting group is Boc group, deprotection reaction can be performed in the presence of an acid, in a solvent that does not adversely influence the reaction.

Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p- toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction

conditions, it is generally not less than about 0.1 mol

equivalent per 1 mol of the substrate, and it can also be used as a solvent.

Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,

aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,

halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , carboxylic acids (acetic acid and the like) , amides (N, -dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed

solvent thereof.

The reaction temperature is, for example, about -50 -

200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of the substrate or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

When the protecting group is Bn group, Cbz(Z) group or

PMB group, deprotection reaction can be performed by catalytic hydrogenation reaction, oxidation reaction or acid

decomposition.

The catalytic hydrogenation reaction can be performed in a hydrogen atmosphere, in the presence of a catalyst. Examples of the catalyst include palladiums such as palladium carbon, palladium hydroxide carbon, palladium oxide and the like;

nickels such as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like; and the like. The amount thereof to be used is generally about 0.001 - 1 molar

equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of the substrate.

The catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as

dichloromethane, chloroform and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N,N- dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.

The reaction is performed at a hydrogen pressure of generally about 1 - 50 atm, preferably about 1 - 10 atm. The reaction temperature is generally about 0°C - 150°C, preferably about 20°C - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

Examples of the oxidant to be used for the oxidation reaction include cerium (IV) ammonium nitrate. The amount thereof to be used is generally about 1 - about 50 molar equivalents per 1 mol of the substrate.

The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran) , amides (e.g., N,N- dimethylformamide) , water and a mixture thereof.

The reaction temperature is generally about 0°C - 150°C, preferably about 20°C - 100°C, and the reaction time is

generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

As the acid to be used for acid decomposition,

trifluoroacetic acid can be mentioned, and it can be utilized as a solvent. The reaction temperature is generally about 0°C - 150°C, preferably about 0°C - 30°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

When the protecting group is CF ₃ CO group, deprotection reaction can be performed in the presence of a base, in a solvent that does not adversely influence the reaction. Examples of the base include inorganic base (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,

potassium hydroxide and the like, alkali metal hydrogen

carbonates such as sodium hydrogen carbonate, potassium

hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like, and the like, alkoxide such as sodium methoxide, sodium ethoxide and the like, and the like) . The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 20 molar equivalents, per 1 mol of the substrate.

Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like) , halogenated hydrocarbons

(dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) water, and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -50 - 200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of the substrate or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 24 hr, preferably about 0.5 - 2 hr.

[0312]

(Step 4)

In this step, compound (XXVIII) or a salt thereof is reacted with compound (XXXVII) or a salt thereof in the

presence of a base to produce compound (CXI) or a salt thereof (alkylation) , or compound (XXVIII) or a salt thereof is reacted with compound (XXXVIII) or a salt thereof in the presence of a reducing agent to produce compound (CXI) or a salt thereof

(reductive alkylation) .

This step can be performed by a method according to that of Method F-l, Step 1.

[0313]

(Step 5)

In this step, compound (CXI) or a salt thereof is subjected to hydrolysis to be converted to compound (XL) or a salt thereof .

This step can be performed by a method according to that of Method A, Step 6.

[0314]

(Step 6)

In this step, compound (XL) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (If-I) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0315]

Compound (If-II), which is the compound of the present invention (Ι') wherein the partial structure:

[0316]

[Chem. 94]

[0317]

is

[0318]

[Chem. 95]

[0319]

L ¹ is optionally halogenated C ₂ alkylene, and X is a nitrogen atom can be produced by the following Method F-2.

[Method F-2]

[0320]

[Chem. 96]

(lf-ll)

[0321]

wherein LG ⁴ is a leaving group, Hal ³ is a halogen atom, and other symbols are as defined above.

Examples of the leaving group for LG ⁴ include those similar to the above-mentioned LG.

Examples of the halogen atom for Hal ³ include those similar to the above-mentioned Hal.

[0322]

(Step 1) In this step, compound (XXXV) or a salt thereof is reacted with compound (XLI) or a salt thereof in the presence of a base to produce compound (XLIII) or a salt thereof

(alkylation) , or compound (XXXV) or a salt thereof is reacted with compound (XLII) or a salt thereof in the presence of a reducing agent to produce compound (XLIII) or a salt thereof (reductive alkylation) .

Compound (XXXV), compound (XLI), compound (XLII) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto .

This step can be performed by a method according to that of Method F-l, Step 1.

[0323]

(Step 2)

In this step, compound (XLIII) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide

atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIX ^e ) :

R ^5e OH (CIX ^e )

wherein the symbol is as defined above,

to produce compound (XLIVI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0324]

(Step 3)

In this step, compound (XXVIII) or a salt thereof is reacted with compound (XLI) or a salt thereof in the presence of a base to produce compound (XLIVI) or a salt thereof

(alkylation), or compound (XXVIII) or a salt thereof is reacted with compound (XLII) or a salt thereof in the presence of a reducing agent to produce compound (XLIVI) or a salt thereof (reductive alkylation) .

Compound (XXVIII), compound (XLI), compound (XLII) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto .

This step can be performed by a method according to that of Method F-l, Step 1.

[0325]

(Step 4)

In this step, compound (XLIVI) or a salt thereof is subjected to hydrolysis to convert same to compound (XLV) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0326]

(Step 5)

In this step, compound (XLV) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (If-II) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0327]

Compound (Ig), which is the compound of the present invention (Ι') wherein the partial structure:

[0328]

[Chem. 97]

[0329]

is

[0330]

[Chem.

[0331]

L ¹ is -NH-, and X is a nitrogen atom can be produced by the following Method G.

[Method G]

[0332]

[Chem. 99]

(XXVIII)

[0333]

wherein each symbol is as defined above.

[0334]

(Step 1)

In this step, compound (XXVIII) or a salt thereof is subjected to a nitrosation reaction to produce compound (XLVI) or a salt thereof. The nitrosation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 20,

Organic Synthesis II" and the like, or a method analogous thereto. Examples of the method include a method using, for example, tert-butyl nitrite or sodium nitrite and the amount thereof to be used is generally 1 - 20 equivalents per 1 mol of compound (XXVIII) .

This step can be performed in a solvent that does not adversely influence the reaction. This step can also be performed in the presence of an acid. Examples of such solvent include hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , carboxylic acids (acetic acid and the like) , water or a mixture thereof. Examples of the acid include hydrochloric acid and nitric acid. The reaction temperature is generally about 0 - 150°C, preferably about 0 - 100°C, and the reaction time is generally, 5 min - 72 hr.

[0335]

(Step 2)

In this step, compound (XLVI) or a salt thereof is subjected to a reduction reaction to produce compound (XLVII) or a salt thereof.

The reduction reaction can be generally performed by using a reducing agent such as metal and metal salt, metal hydride and the like. Preferable examples of the metal and metal salt to be used include alkali metal (lithium, sodium, potassium and the like) , alkaline earth metal (magnesium, calcium and the like) , other metals (zinc, chrome, titanium, iron, samarium, selenium and the like), and metal salt (zinc- amalgam, zinc-copper alloy, aluminum-amalgam, sodium

hydrosulfite and the like) and the like. Examples of the metal hydride include lithium aluminum hydride. The amount of the reducing agent to be used is, for example, generally 1 - 50 molar equivalents per 1 mol of compound (XLVI) .

Examples of the solvent to be used for the reaction include alcohols (methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like) , amines (liquid ammonia,

methylamine, ethylamine, ethylenediamine and the like) , ethers (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid and the like) , amides (hexamethylphosphoramide) , water and the like, and these solvents can be used alone or in a mixture.

The reaction temperature is generally about -80 - 150°C, preferably about -80 - 100°C, and the reaction time is

generally, 5 min - 48 hr, preferably 1 - 24 hr.

[0336]

(Step 3)

In this step, compound (XLVII) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (XLVIII) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 2.

[0337]

(Step 4)

In this step, compound (XLVIII) or a salt thereof is subjected to hydrolysis to convert same to compound (XLIX) or a salt thereof.

This step can be performed by a method according to that of Method A,. Step 6.

[0338]

(Step 5)

In this step, compound (XLIX) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ig) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8. [0339]

Compound (In), which is the compound of the present invention (I' ) wherein the partial structure:

[0340]

[Chem. 100]

[0341]

is

[0342]

[Chem. 101]

[0343]

L ¹ is -0-, and X is a nitrogen atom can be produced by the following Method H.

[Method H]

[0344]

[Chem. 102]

[0345]

wherein R ^5f and R ^5g are each independently an optionally

substituted hydrocarbon group, LG ⁵ is a leaving group, Hal ⁴ is a halogen atom, and other symbols are as defined above.

Examples of the optionally substituted hydrocarbon group for R ^5f or R ^5g include those similar to the above-mentioned R ⁵ .

Examples of the halogen atom for Hal ⁴ include those similar to the above-mentioned Hal.

Examples of the leaving group for LG ⁵ include those similar to the above-mentioned LG.

[0346]

(Step 1)

In this step, compound (L) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LII) or a salt thereof.

Compound (L) , compound (LI) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

This step can be performed according to the method by an

"alkylation" reaction described in Method F-l, Step 1. [0347]

(Step 2)

In this step, compound (LII) is subjected to a reduction reaction using a transition metal catalyst to produce compound (LIII) or a salt thereof.

Examples of the transition metal catalyst to be used in this reaction include palladiums (palladium carbon, palladium hydroxide, palladium oxide and the like) , nickels (Raney-nickel and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium acetate, rhodium carbon and the like) and the like. The amount thereof to be used is, for example, about 0.001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (LII) .

The catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include alcohols (methanol, ethanol, propanol, butanol and the like), hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , amides

(N, N-dimethylformamide and the like), carboxylic acids (acetic acid and the like), water or a mixture thereof. The hydrogen pressure at which the reaction is performed is generally about 1 - 50 atm, preferably about 1 - 10 atm.

The reaction temperature is generally about 0 - 150°C, preferably about 20 - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 - 40 hr.

[0348]

(Step 3)

In this step, compound (LIII) or a salt thereof is reacted with compound (XXIV) or a salt thereof in the presence of a Mitsunobu reagent and an organic phosphorus reagent to produce compound (LIV) or a salt thereof.

This step can be performed by a method according to that described in Method D, Step 2. [0349]

(Step 4)

In this step, compound (LIV) or a salt thereof is

subjected to a reduction reaction to produce compound (LV) or a salt thereof.

The reduction reaction can be performed by reduction with a metal hydride in a solvent that does not adversely influence the reaction.

Examples of the metal hydride include diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catechol borane etc.) and the like. The amount of metal hydride to be used is, for example, about 1 - 50 molar equivalents per 1 mol of compound (LIV) .

The reduction reaction with metal hydride can be

generally performed in a solvent inert to the reaction.

Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbons (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide , dimethyl sulfoxide and the like. These solvent may be used in a mixture at an appropriate ratio.

While the reaction temperature varies depending on the kind of the solvent, it is generally about -80 - 80°C,

preferably about -40 - 40°C. The reaction time is generally about 5 min - 48 hr, preferably about 1 = 24 hr.

[0350]

(Step 5)

In this step, compound (LV) or a salt thereof is

subjected to alkoxycarbonylation under carbon monoxide

atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIX ^f ) :

R ^5f OH (CIX ^f )

wherein the symbol is as defined above, to produce compound (LVI) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0351]

(Step 6)

In this step, compound (LVI) or a salt thereof is subjected to hydrolysis to convert same to compound (LVII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 6.

[0352]

(Step 7)

In this step, compound (LVII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ih) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 8.

[0353]

Compound (XXVIII) or a salt thereof used in Method E, Method F-l, Method F-2, Method G can be produced by the

following Method I.

[Method I]

[0354]

[Chem. 103]

[0355]

wherein each symbol is as defined above.

[0356]

(Step 1)

In this step, compound (LVIII) or a salt thereof is subjected to a brominating reaction in the presence of a base to produce compound (LIX) or a salt thereof.

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

Examples of the brominating agent to be used for the brominating reaction include bromine, perbromides (pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide

perbromide and the like) , bromoimides (N-bromosuccinimide, N- bromophthalimide, N-bromosaccharin, dibromoisocyanuric acid and the like) , boron tribromide, phosphorus tribromide,

bromodimethylsulfonium bromide, 5 , 5-dibromomeldrum' s acid, 2, 4, 4, 6-tetrabromo-2, 5-cyclohexadienone and the like. The amount of the brominating agent to be used is, for example, about 1 - 10 molar equivalents, per 1 mol of compound (LVIII) .

The brominating reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc. ) , aliphatic hydrocarbon (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc. ) , ethers (diethyl ether, tetrahydrofuran, dioxane etc. ) , alcohols (methanol, ethanol, 2- propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide, water and the like. These solvents may be used in a mixture in an

appropriate ratio.

The reaction temperature varies depending on the kind of the solvent, and is generally about -80 - 80°C, preferably about -40 - 40°C, and the reaction time is generally about 5 min - 48 hr, preferably about 1 - 24 hr.

[0357]

(Step 2)

In this step, compound (LIX) or a salt thereof is

subjected to a demethylation reaction to produce compound (LX) or a salt there.

The demethylation reaction can be performed by a method known per se or a method analogous thereto. For example, a method using bromide or a method using Lewis acid in the presence of thiol can be mentioned.

In the method using bromide, boron tribromide, hydrogen bromide are preferably used. The amount thereof to be used is, for example, about 1 - 100 molar equivalents, per 1 mol of compound (LIX) .

The method using bromide can be generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbon (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2- propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide, water and the like. These solvents may be used in a mixture in an

appropriate ratio.

The reaction temperature varies depending on the kind of the solvent, and it is generally about -80 - 100°C, and the reaction time is generally about 5 min - 48 hr.

In the method using Lewis acid in the presence of thiol, dodecylmercaptan is preferably used as. thiol and the amount thereof to be used is, for example, about 1 - 10 molar

equivalents, per 1 mol of compound (LIX) .

As Lewis acid, aluminum chloride is preferably used. The amount thereof to be used is, for example, about 1 - 10 molar equivalents, per 1 mol of compound (LIX) .

The method using Lewis acid in the presence of thiol is generally performed in a solvent inert to the reaction.

Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbon (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents may be used in a

mixture in an appropriate ratio.

The reaction temperature varies depending on the kind of the solvent, and it is generally about -80 - 100°C, and the reaction time is generally about 5 min - 48 hr.

[0358]

(Step 3)

In this step, compound (LX) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LXI) or a salt thereof.

This step can be performed by a method by "alkylation" reaction described in Method F-l, Step 1. [0359]

(Step 4)

In this step, compound (LXI) or a salt thereof is subjected to reduction reaction to produce compound (XXXVI) or a salt thereof.

This step can be performed by a method according to that of Method H, Step 4.

[0360]

(Step 5)

In this step, compound (XXXVI) or a salt thereof is reacted with Boc ₂ 0 in the presence of a base to produce

compound (LXII) or a salt thereof.

This step can be performed according to the method described in the method of protection with Boc group in Method F-l, Step 3.

[0361]

(Step 6)

In this step, compound (LXII) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide

atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX) :

R ⁵ OH (CIX)

wherein the symbol is as defined above,

to produce compound (XXVII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 5.

[0362]

(Step 7)

In this step, compound (XXVII) or a salt thereof is subjected to deprotection reaction to produce compound (XXVIII) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 1.

[0363]

(Step 8) In this step, compound (LXIII) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LXIV) or a salt thereof.

This step can be performed according to the method by an "alkylation" reaction described in Method F-l, Step 1.

[0364]

(Step 9)

In this step, compound (LXIV) or a salt thereof is subjected to a reduction reaction to produce compound (XXVIII) or a salt thereof.

This step can be performed by a method according to the method described in Method H, Step 4.

Compound (LXII) or a salt thereof to be used in Method I can also be produced by the following Method J.

[Method J]

[0365]

[Chem. 104]

[0366]

wherein Hal ⁵ is a halogen atom, and other symbols are as defined above.

As the examples of the halogen atom for Hal ⁵ , those similar to the above-mentioned Hal can be mentioned.

[0367]

(Step 1) In this step, compound (LXV) or a salt thereof is reacted with compound (LXVI) or a salt thereof in the presence of a Mitsunobu reagent and an organic phosphorus reagent to produce compound (LXVII) or a salt thereof.

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

This step can be performed by a method according to the method described in Method D, Step 2.

[0368]

(Step 2)

In this step, compound (LXVII) or a salt thereof is subjected to deprotection reaction to produce compound (LXVIII) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 1.

[0369]

(Step 3)

In this step, compound (LXVIII) or a salt thereof is subjected to a cyclization reaction in the presence of a base to produce compound (LXIX) or a salt thereof.

As the base to be used in the cyclization reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium

hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound ( LXVI I I ) .

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether,

tetrahydrofuran, dioxane, dimethoxyethane and the like) ,

nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),

sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, dimethylformamide is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. The reaction time varies

depending on the kind of compound (LXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0370]

(Step 4)

In this step, compound (LXIX) or a salt thereof is

subjected to a brominating reaction in the presence of a base to produce compound ( XXXVI ) or a salt thereof.

This step can be performed by a method according to that of Method I, Step 1.

[0371]

(Step 5)

In this step, compound (XXXVI) or a salt thereof is reacted with Boc ₂ 0 in the presence of a base to produce

compound (LXII) or a salt thereof.

This step can be performed according to the method described in the method of protection with Boc group in Method

F-l, Step 3.

[0372]

Compound (LXXVI) , which is the compound of the present invention (Ι') wherein the partial structure:

[0373]

[Chem. 105]

[0374]

is

[0375]

[Chem. 106]

[0376]

R is a hydroxymethyl group, D is a piperidine ring, and

-SO ₂ - can be produced by the following Method K.

[Method K]

[0377]

[Chem. 107]

[0378]

wherein R ^5h is an optionally substituted hydrocarbon group, LG ⁶ is a leaving group, and other symbols are as defined above.

Examples of the optionally substituted hydrocarbon group for R ^5h include those similar to the above-mentioned R ⁵ .

Examples of the leaving group for LG ⁶ include those similar to the above-mentioned LG.

[0379]

(Step 1)

In this step, compound (LXX) or a salt thereof and compound (LXXI) or a salt thereof are subjected to a

condensation reaction to convert same to compound (LXXII) or a salt thereof.

Compound (LXX) and compound (LXXI) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

This step can be performed by a method according to that of Method A, Step 8.

[0380]

(Step 2)

In this step, compound (LXXII) or a salt thereof is subjected to deprotection reaction to produce compound (LXXIII) or a salt thereof.

This step can be performed by a method according to that of Method E, Step 1.

[0381]

(Step 3)

In this step, compound (LXXIII) or a salt thereof is reacted with sulfonylating agent (LXXIV) or a salt thereof in the presence of a base to produce compound (LXXV) or a salt thereof .

The sulfonylating agent (LXXIV) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.

As the base to be used in this step, for example,

inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride, lithium hexamethyldisilazide, sodium

hexamethyldisilazide, and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium

hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine , etc. and the like) and the like are used and, of these, sodium hydride, triethylamine and sodium hexamethyldisilazide are preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (LXXIII) .

Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,

dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The sulfonylating agent (LXXIV) is used in this step generally at about 1 - 10 molar equivalents, preferably about 1- 2 molar equivalents, per 1 mol of compound (LXXIII) .

The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (LXXIII) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0382]

(Step 4)

In this step, compound (LXXV) or a salt thereof is

treated with a reducing agent to produce compound (LXXVI) or a salt thereof.

This step can be performed by a method according to that of Method D, Step 1.

[0383]

Compound (LXXX) or a salt thereof, compound (LXXXV) or a salt thereof, compound (XC) or a salt thereof, compound (XCII) or a salt thereof used as intermediates in Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, Method H can be produced by the following Method L.

[Method L] [0384]

[Chem. 108;

[0385]

wherein R ^3a and R ^3b are each independently a hydrogen atom or a substituent of an amino group, Hal ⁶ is a halogen atom, and other symbols are as defined above.

When R ^3a and R ^3b are substituents of the amino group, they are exemplified by those similar to the substituents of the above-mentioned "optionally substituted amino group".

Examples of the halogen atom for Hal ⁶ include those similar to the above-mentioned Hal.

[0386]

(Step 1)

In this step, compound (LXXVII) or a salt thereof is reacted with compound (LXXVIII) or a salt thereof to convert same to compound (LXXIX) or a salt thereof.

Compound (LXXVII) and compound (LXXVIII) may be

commercially available products, or can also be produced

according to a method known per se or a method analogous thereto .

This step can be performed in a solvent inert to the reaction. Examples of such solvent include aromatic

hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbons (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N,N- dimethylformamide, dimethyl sulfoxide and the like. These solvent may be used in a mixture at an appropriate ratio.

Compound (LXXVIII) is used in this step at generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (LXXVII).

The reaction temperature varies depending on the kind of the solvent, and is generally about -80 - 200°C, and the

reaction time is generally about 5 min - 48 hr.

[0387]

(Step 2)

In this step, compound (LXXIX) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (LXXX) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 3.

[0388]

(Step 3)

In this step, compound (LXXVII) or a salt thereof is reacted with phenylmethanethiol in the presence of a Pd

catalyst and a base to convert same to compound (LXXXI) or a salt thereof.

Phenylmethanethiol may be a "commercially available product .

Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,

tetrakis (triphenylphosphine) palladium ( 0 ) ,

tris (dibenzylideneacetone ) dipalladium ( 0 ) , XPHOS Pd G2 and the like. Where necessary, a ligand (Xphos, triphenylphosphine, tri-t-butylphosphine, S-Phos, BINAP, 2 ' - (di-tert- butylphosphino) -N, N-dimethyl- [1, 1' -biphenyl] -2-amine, XANTPHOS and the like) is added. The amount of the catalyst to be used is generally about 0.0001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound

(LXXVII) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (LXXVII).

As the base, an organic base (triethylamine,

diisopropylethylamine and the like) , an alkali metal salt

(sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride

(potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t-butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) may be added. The amount of the base to be used is generally about 1 - 10 molar equivalents,

preferably about 1 - 2 molar equivalents, per 1 mol of compound (LXXVII) .

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated

hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols (methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.

The reaction temperature is generally about 0 - 150°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary.

[0389]

(Step 4)

In this step, compound (LXXXI) or a salt thereof is treated with N-chlorosuccinimide to convert same to compound (LXXXII) or a salt thereof.

The amount of N-chlorosuccinimide to be used is generally about 1 - about 50 molar equivalents relative to compound

(LXXXI) .

This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran) , amides (e.g., N, N-dimethylformamide) , acid (e.g., hydrochloric acid, acetic acid), water and a

mixture thereof.

The reaction temperature is generally about -80°C - 100°C, preferably about -5°C - 30°C, and the reaction time is

generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

[0390]

(Step 5)

In this step, compound (LXXXII) or a salt thereof is reacted with compound (LXXXIII) or a salt thereof in the

presence of a base to convert same to compound (LXXXIV) or a salt thereof.

Compound (LXXXIII) may be a commercially available

product, or can also be produced according to a method known per se or a method analogous thereto. The amount of compound (LXXXIII) to be used is generally about 1 - about 50 molar equivalents relative to compound

(LXXXII) .

As the base to be used in this step, for example,

inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium

ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (LXXXII) . In addition, compound

(LXXXIII) itself may be used as a base.

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , alcohol (methanol, ethanol and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides

(N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an

appropriate ratio. The reaction temperature is, for example, about -80 -

200°C, preferably about -5 - 100°C. The reaction time varies depending on . the kind of compound (LXXXII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0391]

(Step 6)

In this step, compound (LXXXIV) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (LXXXV) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 3.

[0392]

(Step 7)

In this step, compound (LXXXVI) or a salt thereof is treated with N-bromosuccinimide in the presence of potassium-t- butoxide and cyanamide to convert same to compound (LXXXVII) or a salt thereof.

The amount of potassium-t-butoxide to be used is

generally about 1 - about 10 molar equivalents relative to compound (LXXXVI) .

The amount of cyanamide to be used is generally about 1 - about 10 molar equivalents relative to compound (LXXXVI) .

The amount of N-bromosuccinimide to be used is generally about 1 - about 10 molar equivalents relative to compound

(LXXXVI) .

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , alcohol (methanol, ethanol and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -80 -

100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVI) or the salt, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0393]

(Step 8)

In this step, compound (LXXXVII) or a salt thereof is treated with an oxidant to convert same to compound (LXXXVIII) or a salt thereof.

Examples of the oxidant to be used in this reaction include m-chloroperbenzoic acid. The amount thereof to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVII) .

The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), alcohol (e.g., methanol, ethanol) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane,

tetrahydrofuran) , amides (e.g., N, N-dimethylformamide ) , water and a mixture thereof.

The reaction temperature is generally about -50°C - 100°C, preferably about -5°C - 50°C, and the reaction time is

generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

[0394]

(Step 9)

In this step, compound (LXXXVIII) or a salt thereof is treated with trifluoroacetic anhydride and subsequently treated with potassium carbonate to convert same to compound (LXXXIX) or a salt thereof.

The amount of trifluoroacetic anhydride to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVIII) .

5 This step can be performed in a solvent that does not

adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

10 hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

15 The reaction temperature is, for example, about -80 -

100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

20 The amount of potassium carbonate to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVIII) .

This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that

25 does not adversely influence the reaction include aromatic

hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , alcohol (methanol, ethanol and the like) , halogenated hydrocarbons

(dichloromethane, chloroform and the like) , ethers (diethyl

30 ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), water and the like.

Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -80 -

35 100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0395]

(Step 10)

In this step, compound (LXXXIX) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XC) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 3.

[0396]

(Step 11)

In this step, compound (LXXXIX) or a salt thereof is subjected to an alkylation reaction or a reductive alkylation reaction to produce compound (XCI) or a salt thereof.

This step can be performed by a method according to that of Method F-l, Step 1.

[0397]

(Step 12)

In this step, compound (XCI) or a salt thereof is

subjected to a catalytic hydrogenation reaction to produce compound (XCII) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 3.

[0398]

Compound (XCIV) or a salt thereof to be used as an intermediate for Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, and

Method H can be produced by the following Method M.

Of the compounds (I) of the present invention, compound

(CI) or a salt thereof and compound (CIV) or a salt thereof can be produced by the following Method M.

[Method M]

[0399]

[Chem. 109]

(XCIII) (XCIV)

[0400]

wherein R ⁵¹ is an optionally substituted hydrocarbon group, Hal ⁷ is a halogen atom, and other symbols are as defined above. Examples of the optionally substituted hydrocarbon group for R ⁵¹ include those similar to the above-mentioned R ⁵ .

Examples of the halogen atom for Hal ⁷ include those similar to the above-mentioned Hal.

[0401]

(Step 1)

In this step, compound (XCIII) or a salt thereof is reacted with hydroxylamine or a salt thereof and the obtained oxime intermediate is subjected to a reduction reaction to produce compound (XCIV) or a salt thereof.

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

The amount of hydroxylamine to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (XCIII) .

This step can be performed by a method according to that of Method C, Step 1.

[0402]

(Step 2)

In this step, compound (XCV) or a salt thereof is reacted with glyoxylic acid ester (XCVI) and diallylamine to produce compound (XCVII) or a salt thereof.

Compound (XCV) to be used in this reaction may be a commercially available product, or can also be produced

according to a method known per se or a method analogous thereto .

The amount of glyoxylic acid ester (XCVI) to be used is generally about 1 - 10 molar equivalents, per 1 mol of compound (XCV) .

The amount of diallylamine to be used is generally about

1 - 10 molar equivalents, per 1 mol of compound (XCV) .

The above-mentioned reaction can be generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent to be used include nitriles

(acetonitrile and the like) , hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like) and the like, and they may be mixed as appropriate. The reaction temperature is generally about -80 - 150°C, preferably about 0 - 10°C, and the reaction time is generally about 0.5 - 100 hr, preferably about 0.5 - 60 hr .

[0403]

(Step 3)

In this step, compound (XCVII) or a salt thereof is treated with an oxidant to convert same to compound (XCVIII) or a salt thereof.

Examples of the oxidant to be used in this reaction include m-chloroperbenzoic acid, oxone and the like. The amount thereof to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (XCVII) .

The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), alcohol (e.g., methanol, ethanol) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane,

tetrahydrofuran) , amides (e.g., N, N-dimethylformamide ) , water and a mixture thereof.

The reaction temperature is generally about -50°C - 100°C, preferably about -5°C - 50°C, and the reaction time is

generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.

[0404]

(Step 4)

In this step, compound (XCVIII) or a salt thereof is reacted with hydroxylamine or a salt thereof and the obtained oxime intermediate is subjected to a reduction reaction to produce compound (XCIX) or a salt thereof.

The amount of hydroxylamine to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (XCVIII) .

This step can be performed by a method according to that of Method C, Step 1.

[0405]

(Step 5)

In this step, compound (XCIX) or a salt thereof and compound (LXX) or a salt thereof are subjected to a

condensation reaction to convert same to compound (C) or a salt thereof.

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

This step can be performed by a method according to that of Method A, Step 8.

[0406]

(Step 6)

In this step, compound (C) or a salt thereof is treated with a reducing agent to produce compound (CI) or a salt thereof .

This step can be performed by a method according to that of Method D, Step 1.

[0407]

(Step 7)

In this step, compound (CII) or a salt thereof and compound (LXX) or a salt thereof are subjected to a

condensation reaction to convert same to compound (CIII) or a salt thereof.

Compound (CII) and compound (LXX) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.

This step can be performed by a method according to that of Method A, Step 8.

[0408]

(Step 8)

In this step, compound (CIII) or a salt thereof is reacted with sodium methanesulfinate to convert same to compound (CIV) or a salt thereof.

The amount of methanesulfonic acid to be used is

generally about 1 - about 10 molar equivalents, per 1 mol of compound (CIII).

This step can be performed by a method according to that of Method L, Step 1.

[0409]

Of compounds (XXVII) used in Method E and Method I, compound (CVIII) wherein any of Y ¹ , Y ² and Y ³ is a carbon atom, or a salt thereof can be produced by the following Method N. [Method N]

[0410]

[Chem. 110]

(CV) (CVI) (CVIII)

[0411]

wherein R ^5j is an optionally substituted hydrocarbon group, and other symbols are as defined above.

Examples of the optionally substituted hydrocarbon group for R ^5j include those similar to the above-mentioned R ⁵ .

[0412]

(Step 1)

In this step, compound (CV) or a salt thereof is reacted with B0C ₂ O in the presence of a base to produce compound (CVI) or a salt thereof.

This step can be performed according to the method described in the method of protection with Boc group in Method F-l, Step 3.

[0413]

(Step 2) In this step, compound (CVI) or a salt thereof is treated with potassium carbonate and reacted with compound (CVII) or a salt thereof to produce compound (CVIII) or a salt thereof.

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

The amount of potassium carbonate to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (CVI).

This reaction can be generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (methanol, ethanol and the like), nitriles (acetonitrile and the like) , hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane,

tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated hydrocarbons (chloroform, dichloromethane and the like), amides (N, N-dimethylformamide and the like), water and the like, and they may be mixed as appropriate. The reaction temperature is generally about -80 - 150°C, preferably about 0 - 10°C, and the reaction time is generally about 0.5 - 100 hr, preferably about 0.5 - 60 hr.

[0414]

Compound (Ij), which is the compound of the present invention (I' ) wherein the partial structure:

[0415]

[Chem. Ill]

[0416]

is

[0417]

[Chem. 112]

[0418]

ring A is

[0419]

[Chem. 113]

[0420]

L ¹ is a bond, R ¹ and R ² are each a hydrogen atom, ring

[0421]

[Chem. 114]

[0422]

(wherein W is as defined in the DESCRIPTION) , L ² is -S0 ₂ -, and R ³ is a methyl group or an ethyl group can be produced by the following Method 0.

[Method 0]

[0423]

[Chem. 115]

(CXV) (Ij)

[0424]

wherein R ⁷ is an optionally substituted hydrocarbon group, and other symbols are as defined above.

[0425]

(Step 1)

In this step, compound (CXII) or a salt thereof is coupled with compound (CXIII) or a salt thereof in the presence of a Pd catalyst and a base to produce compound (CXIV) .

Compound (CXII) or a salt thereof can be produced

according to the below-mentioned Method Q or a method analogous thereto.

Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,

tetrakis (triphenylphosphine) palladium,

tris (dibenzylideneacetone) dipalladium (0) , XPHOS Pd G2 and the like and, where necessary, a ligand (XPHOS, triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine , S-Phos, BINAP, 2' - (di-tert-butylphosphino) -N, N-dimethyl- [1, 1' -biphenyl] -2- amine, XANTPHOS and the like) is added. The amount of the catalyst to be used is about 0.0001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (CXII) , and the amount of the ligand to be used is about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (CXII) .

As the base, an alkali metal salt (sodium hydrogen

carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t- butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) are added. The amount of the base to be used is about 1

- 10 molar equivalents, preferably about 1 - 2 molar

equivalents, per 1 mol of compound (CXII).

This step is performed in a solvent that does not

adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated

hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols

(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), water and a mixture thereof.

Compound (CXIII) or a salt thereof can be produced

according to the below-mentioned Method R or a method analogous thereto. The amount of compound (CXIII) to be used is about 1

- 2 molar equivalents per 1 mol of compound (CXII) .

The reaction temperature is generally about 0 - 200°C, preferably about 60 - 150°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary. [0426]

(Step 2)

In this step, compound (CXIV) or a salt thereof is subjected to hydrolysis to convert same to compound (CXV) or a salt thereof. This reaction can be performed by a method known per se, generally in the presence of an acid or a base, and where necessary, in a solvent that does not adversely influence the reaction.

Examples of the acid to be used include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids

(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) and the like. Where necessary, two or more kinds thereof may be used in a mixture. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 molar equivalent, per 1 mol of compound (CXIV), and it can also be used as a solvent.

As the base, for example, inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,

potassium hydroxide and the like, alkali metal hydrogen

carbonates such as sodium hydrogen carbonate, potassium

hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like,

alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like) , organic bases (amines such as

trimethylamine, triethylamine , diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine and the like, and the like) and the like are used. Of these, sodium hydroxide is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 0.1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXIV) .

Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,

hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t^ butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , carboxylic acids (acetic acid and the like) , amides (dimethylformamide, dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like), water and the like. Of these, ethanol,

tetrahydrofuran or water is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

The reaction temperature is, for example, about -50 -

200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (CXIV) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 min - 100 hr, preferably about 0.5 - 24 hr.

[0427]

(Step 3)

In this step, compound (CXV) or a salt thereof and

compound (CXVI) or a salt thereof are subjected to a

condensation reaction to convert same to compound (Ij) or a salt thereof.

Compound (CXVI) or a salt thereof can be produced

according to the below-mentioned Method S or a method analogous thereto. The amount of compound (CXVI) to be used is about 1 - 2 molar equivalents, per 1 mol of compound (CXV) .

The condensation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 22,

Organic Synthesis IV" and the like, or a method analogous thereto. Examples of the method include a method using a condensing agent, a method via a reactive derivative and the like.

Examples of the condensing agent to be used in "a method using a condensing agent" include (dimethylamino) -N, N- dimethyl ( 3H- [1,2,3] triazolo [ 4 , 5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (HATU) , 1- [ (1- (cyano-2-ethoxy-2- oxoethylideneaminooxy) -dimethylamino-morpholino) ] carbenium hexafluorophosphate (COMU) , 2,4, 6-tripropyl-l , 3,5,2,4,6- trioxatriphosphorinane-2 , 4 , 6-trioxide (T3P) ,

dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) , N-ethyl-N' -3-dimethylaminoprop.ylcarbodiimide and hydrochlorides thereof (WSC, WSC-HC1, EDCI) , benzotriazol-l-yl- tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) , (4-oxobenzo [d] [1, 2, 3] triazin- 3 (4H) -yl) diethyl phosphate (DETBT) , ( 3-hydroxy-3H-l , 2 , 3- triazolo [4 , 5-b] pyridinato-O) tri-l-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP) , N, N, N' , N' -tetramethyl-O- ( 3 , 4- dihydro-4-oxo-l, 2, 3-benzotriazin-3-yl ) uronium tetrafluoroborate (TDBTU) , 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) - 4 - methylmorpholinium chloride (DMT-MM) and hydrate thereof and the like. These may be used singly, or can also be used in combination with additive (e.g., N-hydroxysuccinimide, 1- hydroxybenzotriazole, 3-hydroxy-4-oxo-3, 4-dihydro-l, 2, 3- benzotriazine and the like) . The amount of the condensing agent to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (CXV) . The amount of the additive to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (CXV) .

The above reaction is generally performed in a solvent that does not adversely influence the reaction, and a

convenient base may be added to promote the reaction. Examples of the solvent include hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated

hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like), aromatic amines (pyridine and the like) , alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) , water and the like, which may be mixed as appropriate. Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like) , hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like) , carbonates (sodium carbonate, potassium carbonate and the like) , acetates (sodium acetate and the like), tertiary amines

(trimethylamine, triethylamine, N-methylmorpholine,

diisopropylethylamine and the like) , aromatic amines (pyridine, picoline, N, N-dimethylaniline , 4-dimethylaminopyridine and the like) and the like. The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXV) .

The reaction temperature is generally about -80 - 150°C, preferably about 0 - 50°C. The reaction time is generally about 0.5 - 48 hr, preferably 0.5 - 16 hr.

As the reactive derivative in "the method via a reactive derivative", a compound represented by the formula:

[0428]

Chem. 116]

(CXVa)

[0429]

wherein LG ⁷ is a leaving group,

(hereinafter to be referred to as compound (CXVa) ) or a salt thereof (e.g., acid halide, acid anhydride, mixed acid

anhydride, active ester and the like) and the like can be mentioned . As the leaving group for LG ⁷ , for example, halogen atom (chlorine atom, bromine atom, iodine atom and the like) , substituted sulfonyloxy group (C ₁ _ ₅ alkylsulfonyloxy group such as methanesulfonyloxy, trifluoromethylsulfonyloxy,

ethanesulfonyloxy and the like; C _6-14 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like; C _7-16 aralkylsulfonyloxy group such as ^" benzylsulfonyloxy group and the like, and the like) , acyloxy group (acetoxy, benzoyloxy and the like) , oxy group substituted by heterocyclic group or aryl group (2 , 5-dioxo-l-pyrrolidinyl, benzotriazolyl, quinolyl, 4- nitrophenyl and the like) , heterocyclic group (imidazolyl and the like) and the like are used.

Compound (CXV) can be converted to a reactive derivative (compound (CXVa) ) according to a method known per se. For example, for conversion to acid halide, a method using acid halide (e.g., thionyl chloride, oxalyl chloride and the like), a method using halide of phosphorus and phosphoric acid (e.g., phosphorus trichloride, phosphorus pentachloride and the like) and the like can be mentioned. The above-mentioned reaction via a reactive derivative is generally performed in a solvent that does not adversely influence the reaction, though subject to change depending on the kind of compound (CXV) , and a convenient base may be added to promote the reaction. The kind and amount of solvent and base to be used in the reaction, reaction temperature and reaction time are similar to those described in the above-mentioned "method using a condensing agent".

[0430]

Compound (Ik), which is the compound of the present invention (Ι') wherein the partial structure:

[0431]

[Chem. 117]

[0432]

is

[0433]

[Chem. 118]

[0434]

ring A is

[0435]

[Chem. 119]

[0436]

L ¹ is a bond, ring D is [0437]

[Chem. 120]

[0438] (wherein W is as defined in the DESCRIPTION) , L ² is -S0 ₂ -, R ³ is a methyl group or an ethyl group, R ¹ is a -CH ₂ OH group, R ² is a hydrogen atom can be produced by the following Method P.

[Method P]

[0439]

[Chem. 121]

[0440]

wherein each symbol is as defined above.

[0441]

(Step 1)

In this step, compound (CXV) or a salt thereof and compound (CXVII) or a salt thereof are subjected to a

condensation reaction to convert same to compound (Ik) or a salt thereof.

Compound (CXV) or a salt thereof can be produced

according to Method 0.

Compound (CXVII) or a salt thereof can be produced according to the below-mentioned Method T or a method analogous thereto. The amount of compound (CXVII) to be used is about 1 - 2 molar equivalents per 1 mol of compound (CXV) .

This step can be performed by a method according to that of Method 0, Step 3.

[Method Q]

[0442]

[Chem. 122] de

(CXI I)

[0443]

wherein Hal ¹ is a halogen atom (chlorine atom, bromine atom, iodine atom), and other symbol is as defined above.

[0444]

(Step 1)

In this step, compound (CXVIII) or a salt thereof is reacted with di-t-butyl dicarbonate (Boc ₂ 0) in the presence of a base to convert same to compound (CXIX) or a salt thereof.

Compound (CXVIII) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

As the base to be used in this step, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like) , organic base (alkali disilazides such as lithium hexamethyldisilazide , sodium

hexamethyldisilazide and the like, amines such as

trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine , etc. and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXVIII) .

The amount of Boc ₂ 0 to be used in this step is about 1 - 10 molar equivalents, preferably, about 1 - 5 molar equivalents, per 1 mol of compound (CXVIII) .

The solvent to be used in this step includes aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether _/ t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides (dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and the like. Two or more kinds of these solvents may be used in a mixture in an

appropriate ratio.

The reaction temperature is, for example, about -80 -

100°C. While the reaction time varies depending on the kind of compound (CXVIII) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0445]

(Step 2)

In this step, compound (CXIX) or a salt thereof is subjected to carbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CXX) :

R ⁷ OH (CXX)

wherein R ⁷ is as defined above

to produce compound (CXXI) or a salt thereof.

Examples of the transition metal catalyst include

palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium and the like), nickel catalyst (nickel chloride and the like) and the like and, where necessary, an organophosphorus reagent such as

triphenylphosphine, 1, 1' -bis (diphenylphosphino) ferrocene (dppf) and the like can be used. The amount of the catalyst to be used varies depending on the kind of the catalyst, and is generally about 0.0001 ^ 1 mol, preferably about 0.01 - 0.5 mol, per 1 mol of compound (CXIX) , and the amount of the

organophosphorus reagent to be used is preferably about 0.01 - 2 mol.

The alcohol represented by the formula (CXX) is generally used in excess, and particularly, methanol or ethanol is used.

This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether,

tetrahydrofuran, dioxane, dimethoxyethane and the like) ,

nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , aprotic polar solvent (dimethylformamide, dimethyl sulfoxide and the like) and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.

In addition, the reaction can be advantageously performed by adding a base or a salt. Examples of such base or salt include inorganic bases (alkali metal hydroxides such as sodium hydroxide, potassium , hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate,

potassium hydrogen carbonate and the like, alkali metal

carbonates such as lithium carbonate, sodium carbonate,

potassium carbonate, cesium carbonate and the like, and the like) or organic bases (amines such as trimethylamine,

triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine and the like and the like) and the like. The amount of the base or salt to be used is about 1 - 100 molar equivalents, preferably about 1 - 10 molar equivalents, per 1 mol of compound (CXIX) .

While the reaction is generally performed under a carbon monoxide atmosphere at normal pressure, where necessary, it can be performed under pressurization (e.g., about 3 - 10 atm) .

The reaction temperature varies depending on the kind of the solvent and it is, for example, about -50 - 200°C,

preferably about 20 - 150°C. The reaction time varies

depending on the kind of compound (CXIX) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0446]

(Step 3)

In this step, compound (CXXI) or a salt thereof is subjected to deprotection reaction to produce compound (CXII) or a salt thereof.

Such deprotection reaction can be performed according to a known method (e.g., "Protective Groups in Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts) , Wiley- Interscience, 1999)). For example, while subject to variation depending on the kind of compound (CXXI), it is generally performed in the presence of an acid and in a solvent as necessary that does not adversely influence the reaction.

Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids

(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (CXXI), and it can also be used as a solvent.

Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) , aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,

halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl .ether.,, t.etrahydrofuran, dioxane, dimethox.y.e_thane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), carboxylic acids (acetic acid and the like), amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed solvent thereof can be mentioned.

The reaction temperature varies depending on the kind of the solvent, and it is, for example, about -50 - 200°C,

preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (CXXI), reaction temperature and the like, it is, for example, about 0.5 - 100 hr,

preferably about 0.5 - 24 hr.

[Method R]

[0447]

[Chem. 123]

(CXXI I) (CXXI 11) (CXI11)

[0448]

wherein the symbol is as defined above.

[0449]

(Step 1)

In this step, compound (CXXII) or a salt thereof is coupled with cyclopropylboronic acid in the presence of a Pd catalyst and a base to produce compound (CXXIII) .

Compound (CXXII) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

The amount of cyclopropylboronic acid to be used is about 1 - 10 molar equivalents, preferably about 1 - 5 molar

equivalents, per 1 mol of compound (CXXII) .

This step can be performed by a method according to that of Method 0, Step 1.

[0450]

(Step 2)

In this step, compound (CXXIII) or a salt thereof is subjected to a triflating reaction to produce compound (CXIII) or a salt thereof.

This reaction can be performed in the presence of a base and a triflating agent.

Examples of the base to be used in this reaction include inorganic base (alkali metal hydride such as sodium hydride, lithium hydride and the like, alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and the like) or organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo [ 5 , 4 , 0 ] undec-7-ene and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine and the like, and the like) and the like. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIII). Pyridine is sometimes used as a solvent.

As the triflating agent to be used in this reaction, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) , N-(5- chloro-2-pyridyl ) triflimide and the like can be mentioned.

While the amount of the triflating agent to be used varies depending on the kind of the solvent and other reaction

conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIII) .

This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),

sulfoxides (dimethyl sulfoxide and the like) and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio, or the base to be used in this reaction may be used as a solvent.

The reaction temperature is, for example, about -10 - 100°C. While the reaction time varies depending on the kind of compound (CXXIII) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[Method S]

[0451]

Chem. 124]

(CXXIV) (CXXV) (CXVI)

[0452]

wherein Hal ⁸ is a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) , and other symbols are as defined above .

[0453] (Step 1)

In this step, compound (CXXIV) or a salt thereof is treated with sodium sulfinate represented by the following formula (LXXVIII) :

R ³ S0 ₂ Na (LXXVIII)

wherein the symbol is as defined above,

to produce compound (CXXV) or a salt, thereof.

Compound (CXXIV) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

Sodium sulfinate (LXXVIII) may be a commercially

available product, or can also be produced according to a method known per se or a method analogous thereto. The amount of use thereof is about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIV) .

This step is performed in a solvent that does not

adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),

sulfoxides (dimethyl sulfoxide and the like) , and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio or a base to be used in this reaction may be used as a solvent.

The reaction temperature is, for example, about -10 -

200°C. The reaction time varies depending on the kind of compound (CXXIV) or a salt thereof, reaction temperature and the like and is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr .

[0454] (Step 2)

In this step, compound (CXXV) is subjected to reduction reaction by using a transition metal catalyst to produce compound (CXVI) .

Examples of the transition metal catalyst to be used in this reaction include palladiums (palladium carbon, palladium hydroxide, palladium oxide and the like), nickels. (Raney-nickel and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium acetate, rhodium carbon and the like) and the like. The amount thereof to be used is, for example, about 0.001 - 1 molar equivalent, preferably about 0.01 - 0.5 molar equivalent, per 1 mol of compound (CXXV) . The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols (methanol, ethanol, propanol, butanol and the like) , hydrocarbons (benzene, toluene, xylene and the like) ,

halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, 1,4-dioxane, tetrahydrofuran and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , carboxylic acids (acetic acid and the like), water and a mixture thereof. The reaction is performed at a hydrogen pressure of generally about 1 - 50 atm, preferably about 1 - 10 atm. The reaction temperature is generally about 0 - 150°C, preferably about 20 - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 - 40 hr.

To accelerate the reaction, an acid (hydrochloric acid and the like) may also be added. The amount thereof to be used is about 0.01 - 10 molar equivalents per 1 mol of compound (CXXV) .

[Method T]

[0455]

[Chem. 125]

[0456]

wherein each symbol is as defined above.

[0457]

(Step 1)

In this step, compound (CXXVI) or a salt thereof is reacted with acetic acid in the presence of a base to produce compound (CXXVII) or a salt thereof.

Compound (CXXVI) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.

As the base to be used in this reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodiumhydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo [5, 4, 0 ] undec-7-ene and the like, and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVI) .

The amount of acetic acid to be used in this reaction is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVI) .

This step is performed in a solvent that does not

adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated

hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, l,4^dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),

sulfoxides (dimethyl sulfoxide . and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio or a base to be used in this reaction may be used as a solvent.

The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (CXXVI) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.

[0458]

(Step 2)

In this step, compound (CXXVII) or a salt thereof is reacted with hydroxylamine or a salt thereof to produce

compound (CXXVIII) or a salt thereof.

The amount of hydroxylamine or a salt thereof to be used in this reaction is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVII) .

In this step, the reaction can be advantageously carried out by adding a catalyst as necessary. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agents (magnesium sulfate and the like) and the like can be mentioned, and these may be combined. The amount of the catalyst to be used is generally 0.01 - 50 molar

equivalents, preferably about 0.1 - about 10 mol, per 1 mol of compound (CXXVII) .

This step is performed in a solvent that does not

adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1 , 2-dichloroethane and the like), ethers (diethyl ether, tetrahydrofuran, 1,4- dioxane and the like) , esters (ethyl acetate, tert-butyl acetate and the like) , alcohols (methanol, ethanol, 2-propanol and the like) , nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N, N-dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.

The reaction temperature is generally about 0°C - about 200°C, preferably about 20°C - about 150°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about 24 hr.

[0459]

(Step 3)

In this step, compound (CXXVIII) or a salt thereof is subjected to a reduction reaction and deprotection reaction to produce compound (CXVII) or a salt thereof. The reduction reaction can be performed by various

reduction reactions in a solvent inert to the reaction. Such reduction reaction can be performed by a method known per se, which includes, for example, a method using metal hydride, and a method by a catalytic hydrogenation reaction.

Examples of the metal hydride include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyan.oboro.hydri.de, sodium triacetoxyborohydride, lithium cyanoborohydride,

dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catecholborane etc.) and the like, and sodium borohydride, sodium,

cyanoborohydride, sodium triacetoxyborohydride and the like are preferable. The amount of metal hydride to be used is, for example, about 1 - about 50 molar equivalents, preferably about 1 - about 10 molar equivalents, per 1 mol of compound (CXXVIII) .

The reduction reaction with metal hydride is generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc. ) , aliphatic hydrocarbons (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc. ) , ethers

(diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents may be used in a

mixture in an appropriate ratio.

The reaction temperature is generally about -80°C - about 80°C, preferably about -40°C - about 40°C. The reaction time is generally about 5 min - about 48 hr, preferably about 1 - about 24 hr.

The catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. Examples of the catalyst include palladiums such as palladium carbon, palladium hydroxide carbon, palladium oxide and the like; .

nickels such. as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like, and the like. The amount thereof to be used is generally about 0.001 - about 1 molar equivalent, preferably about 0.01 - about 0.5 molar equivalent, per 1 mol of (CXXVIII) .

The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of such so.lvent include alcohols (methanol, ethano.1., propanol, butanol etc.), hydrocarbons (benzene, toluene, xylene etc.),

halogenated hydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether, 1,4-dioxane, tetrahydrofuran etc.), esters (ethyl acetate etc.), amides (N, N-dimethylformamide etc.), carboxylic acids (acetic acid etc.), water and a mixture thereof .

The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.

The deprotection reaction can be performed by the method described in Method Q, Step 3, or a method analogous thereto.

[0460]

Compound (II), (Im), (In), (Io) or (Ip), which is the compound of the present invention (Ι') wherein the partial structure:

[0461]

[Chem. 126]

[0463] [Chem. 127]

[0464]

ring A is

[0465]

[Chem. 128]

[0466]

L ¹ is a bond, R ¹ and R ² are each a hydrogen atom, ring

[0467]

[Chem. 129]

[0468]

wherein W is =CR ⁶ - (R ⁶ is -COOC ₂ H ₅ , -COOH, -CONH ₂ , -CN or - CH ₂ OH) ) and L ² is -S0 ₂ - can be produced by the following Method U.

[Method U]

[0469]

[Chem. 130]

(II) CP)

[0470]

wherein the symbol is as defined above.

[0471]

(Step 1) In this step, compound (CXV) or a salt thereof and compound (CXXIX) or a salt thereof are subjected to a

condensation reaction to convert same to compound (II) or a salt thereof.

Compound (CXV) or a salt thereof can be produced

according to Method A.

Compound (CXXIX) or a salt, thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto. The amount of compound (CXXIX) to be used is. about..1 - 2 molar equivalents per 1 mol of compound (CXV) .

This step can be performed by a method according to that of Method A, Step 3.

[0472]

(Step 2)

In this step, compound (II) or a salt thereof is

subjected to hydrolysis to convert- - same to compound (Im) or a salt thereof.

This step can be performed by a method according to that of Method A, Step 2.

[0473]

(Step 3)

In this step, compound (Im) or a salt thereof and

compound (CXXX) are subjected to a condensation reaction to convert same to compound (In) or a salt thereof.

Compound (CXXX) may be a commercially available product and the amount of compound (CXXX) to be used is about 1 - 2 molar equivalents, per 1 mol of compound (Im) .

This step can be performed by a method according to that of Method 0, Step 3.

[0474]

(Step 4)

In this step, compound (In) or a salt thereof is treated with trifluoroacetic anhydride and pyridine to convert same to compound (Io) or a salt thereof. The amount of trifluoroacetic anhydride to be used is about 1 - 20 molar equivalents per 1 mol of compound (In) .

Pyridine is used as a solvent.

The reaction temperature is generally about -20°C - about 100°C, preferably about 20°C - about 50°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about .24 hr.

[0475]

(Step 5)

In this step, compound (II) or a salt thereof is

subjected to a reduction reaction to produce compound (Ip) or a salt thereof.

This step can be performed by a method according to that of Method T, Step 3, "reduction reaction with metal hydride".

[0476]

[Method V]

Compound (Iq) :

[0477]

[Chem. 131]

[0478]

wherein each symbol is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:

[0479]

[Chem. 132]

[0480] is

[0481]

[Chem. 133]

, and

[0482]

L ¹ is a bond, can be produced in the same manner as in Method and using a compound of the following formula (CXXXI) :

[0483]

[Chem. 134]

(CXXXI)

[0484]

wherein each symbol is as defined above.

[0485]

[Method W]

Compound (Ir) :

[0486]

Chem. 135]

[0487] wherein each symbol is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:

[0488]

[Chem. 136]

and

^■ 0491 ^'

L is optionally halogenated C ₁ alkylene, can be produced in the same manner as in Method F-l and using a compound of the following formula (CXXXII) :

[0492]

[Chem. 138]

(CXXXII)

[0493]

wherein each symbol is as defined above.

[0494]

[Method X]

Compound ( Is ) : [0495]

[Chem. 139]

[0496]

wherein each symbol, is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:

[0497]

[Chem. 140]

[0498]

is

[0499]

[Chem. 141]

r and [0500]

L ¹ is optionally halogenated C ₂ alkylene, can be produced in the same manner as in Method F-2 and using a compound of the following formula (CXXXII) :

[0501]

[Chem. 142]

(CXXXII)

[0502]

wherein each symbol is as defined above.

[0503]

[Method Y] . .

Compound ( It ) :

[0504]

[Chem. 143]

[0505]

wherein each symbol is as defined above, which is the compound of the present invention (Ι') wherein the partial structure:

[0506]

[Chem. 144]

[0507]

is

[0508]

[Chem. 145]

[0509]

L ¹ is -0-, can be produced in the same manner as in Method and using a compound of the following formula (CXXXIII) :

[0510]

[Chem. 146]

(CXXXIII)

[0511]

wherein each symbol is as defined above.

[0512]

When compound (I' ) has an optical isomer, a stereoisomer, a regioisomer or a rotamer, these are also encompassed in compound (I' ) , and can be obtained as a single product

according to a synthesis method and separation method known per se. For example, when compound (Ι') has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I' ) ·

[0513]

The optical isomer can be produced according to a method known per se. Specifically, the optical isomer is obtained using an optically active synthetic intermediate or by

subjecting the racemic final product to an optical resolution according to a known method.

[0514] The method of optical resolution may be a method known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method etc.

1) Fractional recrystallization method

A method wherein a salt of a racemate with an optically active compound (e.g., (t)-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.

[0515]

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-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Corporation) 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.

[0516]

3) Diastereomer method

A method wherein a racemic mixture is converted to 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 reaction and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained. For example, when compound (Ι') contains hydroxy group or primary or secondary amino group in a molecule, the compound and an optically active organic acid (e.g., MTPA [oc-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 carboxylic acid 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 reaction.

[0517]

When the compound (Ι') is obtained as a free compound, it can be converted into a desired salt by a method known per se or a modification thereof; conversely, when it is obtained as a salt, it can be converted into a free form or another desired salt by a method known per se or a modification thereof.

[0518]

Compound (Ι') may be used as a prodrug. The prodrug of compound (I/) means a compound which can be converted into compound (Ι') by reaction with an enzyme, gastric acid, or the like under physiological conditions in the living body. In other words, it means a compound which can be converted into compound (Ι') by enzymatic oxidation, reduction, hydrolysis or the like, or a compound which can be converted into compound (Ι') by hydrolysis with gastric acid or the like.

[0519]

Examples of the prodrug of compound (I' ) include a

compound in which amino of compound (Ι') is acylated, alkylated, or phosphorylated (e.g., the amino group of compound (Ι') is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-

2-oxo-l, 3-dioxolen-4-yl ) methoxycarbonylated,

tetrahydrofuranylated, pyrrolidylmethylated,

pivaloyloxymethylated, or tert-butylated) ; a compound in which hydroxyl group of compound (Ι') is acylated, alkylated, phosphorylated, or borated (e.g., a hydroxy group of compound (Ι') is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or

dimethylaminomethylcarbonylated) ; a compound in which carboxy group of compound (I' ) is esterified or amidated (e.g., a compound in which carboxy group of compound (Ι') is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5- methyl-2-oxo-l , 3-dioxolen-4-yl) methyl esterified,

cyclohexyloxycarbonylethyl esterified, or methylamidated) .

These compounds can be produced from compound (Ι') by a method known per se.

The prodrug of compound (Ι') may also be one which is converted to compound (Ι') under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of

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

[0520]

Compound (I/) may be a crystal, and both single crystal form and a crystalline mixture are encompassed in the compound (Ι') of the present invention. The crystal can be produced by crystallization by a crystallization method known per se.

[0521]

Compound (Ι') and a prodrug thereof [hereinafter

sometimes to be abbreviated as the compound of the present invention] may be useful as a safe medicament based on an RORyt modulating action. In another embodiment, since the compound of the present invention may be superior in RORyt binding capability, it may be superior in RORyt modulating activity, and may also be useful as a safe medicament based on RORyt activation action.

For example, the medicament of the present invention containing the compound of the present invention may be useful for a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as a prophylactic or

therapeutic agent for RORyt related diseases, Thl7 cell related diseases and IL-17A or IL-17F related diseases, more

specifically, the diseases described in (1) - (4) below.

(1) inflammatory diseases (e.g., rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma_, .bronchial asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD) , inflammatory bone disease, pulmonary sarcoidosis, inflammatory bowel disease, celiac disease,

Behcet's syndrome, hepatitis, alcoholic hepatic fibrosis, alcoholic hepatitis, alcoholic cirrhosis, hepatitis B viral hepatopathy, primary biliary cirrhosis (PBG), primary

sclerosing cholangitis (PSC) , transient cerebral ischemic attack (TIA) , systemic inflammatory response syndrome (SIRS) , dry eye, glaucoma, uveitis, orbital cellulitis, idiopathic orbital inflammation, age-related macular degeneration,

postoperative or posttraumatic inflammation, hepatopathy, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, autoimmune anemia, Good Basucha syndrome, Graves' disease, hashimoto' s thyroiditis, vasculitis, Basedow's disease, sinusitis, allergic rhinitis, chronic hypertrophic rhinitis etc.),

(2) autoimmune diseases (e.g., rheumatoid arthritis,

ankylopoietic spondylarthritis, psoriasis, multiple sclerosis (MS) , polymyositis, optic nervemyelitis (NMO) , chronic

inflammatory demyelinating polyneuropathy (CIDP) ,

dermatomyositis (DM), polyarteritis nodosa (PN), mixed

connective tissue disease (MCTD) , amyotrophic lateral sclerosis (ALS) , Guillain-Barre syndrome, myasthenia gravis, Parkinson's disease, spinal muscular atrophy, spinocerebellar atrophy, progressive supranuclear palsy, Fisher syndrome, central

nervous system lupus, acute disseminated encephalomyelitis, multiple system atrophy, Huntington's disease, Alzheimer's disease, cerebrovascular dementia, diffuse Lewy body disease, cerebrovascular diseases, cerebral infarction, transient

cerebral ischemic attack, cerebral hemorrhage, spinal cord vascular disorder, spinal cord infarction, polyneuritis,

Lambert-Eaton syndrome, muscular dystrophy, metabolic myopathy, inflammatory myopathy, inclusion body myositis, encephalitis, meningitis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, pemphigus, profundus lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease (IBD), ulcerative colitis (UC) , Crohn's disease, graft versus host disease, Addison's disease, abnormal immunoresponse, arthritis, dermatitis, radiodermatitis , sarcoidosis, type 1 diabetes etc . ) ,

(3) bone or joint degenerative diseases (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis etc.),

(4) neoplastic diseases [e.g., malignant tumor, angiogenesis 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 the breast cancer, cancer (e.g., colorectal cancer (e.g., familial

colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor and the like), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma and the like) , mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer and the like), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma and the like), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ,

inflammatory breast cancer and the like), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor and the like), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent prostate cancer and the like), liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer and the like), thyroid cancer (e.g., medullary thyroid carcinoma and the like), renal cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney and ureter and the like) , uterine cancer, uterine body cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma and the like) , melanoma

(melanoma) , sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic schwannoma, retinoblastoma, head and neck carcinoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gall urinary bladder cancer, penile cancer, ureter cancer, testis tumor, vulvar cancer, cervical cancer, uterine body cancer, uterus sarcoma, cholionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin' s disease,

myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary) .

[0522]

Preferably, the medicament of the present invention may be useful as a prophylactic or therapeutic agent for neoplastic disease and the like.

[0523]

In another embodiment, the medicament of the present invention may be useful as a prophylactic or therapeutic agent for preferably autoimmune disease, inflammatory disease, bone or articular disease or neoplastic disease, particularly preferably, psoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC) , Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus (SLE) , chronic obstructive pulmonary diseases, ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, head and neck carcinoma, prostate cancer or uterine . body cancer.

Here, the above-mentioned "prophylaxis" of a disease

-means, for example, administration of a medicament containing the compound of the present invention to patients who are expected to have a high risk of the onset due to some factor relating to the disease but have not developed the disease or patients who have developed the disease but do not have a subjective symptom, or administration of a medicament

containing the compound of the present invention to patients who are feared to show recurrence of the disease after

treatment of the disease.

[0524]

The medicament of the present invention is expected to show superior pharmacokinetics (e.g., a half-life of the drug in plasma), low toxicity (e.g., HERG inhibition, CYP inhibition, CYP induction) , and decreased drug interaction. The compound of the present invention may be directly used as a medicament, or as the medicament of the present invention by producing a pharmaceutical composition by mixing with a pharmaceutically acceptable carrier by a means known per se and generally used in a production method of pharmaceutical preparations. The medicament of the present invention may be orally or

parenterally administered safely to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats) .

[0525]

A medicament containing the compound of the present invention may be safely administered solely or by mixing with a pharmacologically acceptable carrier according to a method known per se (e.g., the methoc? described in the Japanese

Pharmacopoeia etc.) as the production method of a

pharmaceutical preparation, and in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal and the like) , pill, powder, granule, capsule (including soft capsule, microcapsule) , troche, syrup, liquid, emulsion, suspension, release control preparation (e.g., immediate-release

preparation, sustained-release preparation, sustained-release microcapsule), aerosol, film (e.g., orally disintegrating film, oral mucosa-adhesive 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 preparation, pulmonary preparation (inhalant), eye drop and the like, orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intraorgan,

intranasal, intradermal, instillation, intracerebral,

intrarectal, intravaginal , intraperitoneal and intratumor administrations, vicinity of tumor, and lesion) .

The content of the compound of the present invention in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament. While the dose varies depending on the subject of administration, administration route, disease and the like, for example, for an oral

preparation to a cancer patient (body weight about 60kg) , it is about 0.1 mg/kg body weight to 30 mg/kg body weight, preferably about 1 mg/kg body weight to 20 mg/kg body weight as an active ingredient (compound (I' ) ) for one day, which is administered once to several times, preferably once to 2 or 3 times per day.

The pharmacologically acceptable carrier, which may be used for the production of the medicament of the present

invention, may be exemplified by various organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, lubricant, binding agent and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations.

Furthermore, when necessary, ordinary additives such as

preservative, antioxidant, colorant, sweetening agent,

adsorbing agent, wetting agent and. the like may also be used as appropriate in an appropriate amount.

[0526]

Examples of the excipient include lactose, white sugar,

D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

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

Examples of the binding agent include crystalline

cellulose, white sugar _> D-mannitol, dextrin,

hydroxypropylcellulose, hydroxypropylmethylcellulose,

polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch,

carboxymethylcellulose, carboxymethylcellulose calcium,

carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium

carbonate, sodium citrate and the like.

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

laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like;

hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like.

[0527]

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

Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.

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

Examples of the preservative include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol,

dehydroacetic acid, sorbic acid and the like.

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

[0528]

For the prophylaxis or treatment of various diseases, the compound of the present invention may also be used together with other medicaments. In the following, a medicament to be used when the compound of the present invention is used

together with other drug is referred to as "the combination agent of the present invention".

Specifically, the compound of the present invention can be used in combination with drugs such as hormonal therapeutic agent, chemotherapeutic agent, immunotherapeutic agent or medicament inhibiting actions of cell growth factor and receptor thereof and the like. In the following, a drug that can be used in combination with the compound of the present invention is to be abbreviated as a "concomitant drug".

[0529]

As the "hormonal therapeutic agent", for example,

fosfestrol, diethylstylbestrol, chlorotrianisene,

medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol ,

gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogen (e.g., tamoxifen citrate,

toremifene citrate) , pill preparation, mepitiostane ,

testrolactone, aminoglutethimide, LH-RH agonist (e.g.,

goserelin acetate, buserelin, leuprorelin acetate) , droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitor

(e.g., fadrozole hydrochloride, anastrozole, retrozole,

exemestane, vorozole, formestane) , anti-androgen (e.g., . . flutamide, bicartamide, nilutamide, enzalutamide ) , 5a-reductase inhibitor (e.g., finasteride, epristeride, dutasteride) ,

adrenocortical hormone drug (e.g., dexamethasone, predonisolone, betamethasone, triamcinolone) , androgen synthesis inhibitor

(e.g., abiraterone) , retinoid and drugs that retard retinoid metabolism (e.g., liarozole) , thyroid gland hormone, and DDS

(Drug Delivery System) preparation thereof are used.

[0530]

As the "chemotherapeutic agent", for example, alkylating agents, metabolic antagonists, antitumor antibiotics, and plant-derived antitumor drugs may be used.

[0531]

As the "alkylating agent", for example, nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl,

cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol , melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine,

streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,

pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and DDS preparations thereof may be used.

[0532]

As the "metabolic antagonist", for example,

mercaptopurine, 6-mercaptopurine riboside, thioinosine,

methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drug (e.g.,

fluorouracil , tegafur, UFT, doxifluridine, carmofur,

gallocitabine, emitefur, capecitabine ) , aminopterin,

nelzarabine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur,

fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS preparations thereof may be used.

[0533]

As the "antitumor antibiotic", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin

hydrochloride, bleomycin sulfate, peplomycin sulfate,

daunorubicin hydrochloride, doxorubicin hydrochloride,

aclarubicin hydrochloride, pirarubicin hydrochloride,

epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof (e.g., Doxorubicin encapsulated PEG ribosome) may be used.

[0534]

As the "plant-derived antitumor drug", for example, etoposide, etoposide phosphate, vinblastine sulfate,

vincristine sulfate, vindesine sulfate, tenyposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS preparations thereof may be used.

[0535]

As the "immunotherapeutic agent", for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon,

interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody (e.g., ipilimumab,

tremelimumab) , anti-PD-1 antibody (e.g., nivolumab,

pembrolizumab) , anti-PD-Ll antibody may be used.

[0536] The "cell growth factors" in the "medicament inhibiting actions of cell growth factor and receptor thereof" may be any substance that promotes cell proliferation, which is normally peptide having not more than 20,000 molecular weight, and capable of exhibiting the activity at low concentrations by binding to a receptor, and specifically

(1) EGF (epidermal growth factor) or substances possessing substantially the same activity as EGF (e.g., TGFa) ;

(2) insulin or substances possessing substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor) -1, IGF-2),

(3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as FGF (e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10) , and

(4) other cell growth factors (e.g., GSF (colony stimulating factor), EPO (erythropoietin), IL-2 ( interleukin-2 ) , NGF (nerve growth factor) , PDGF (platelet-derived growth factor) , TGFP (transforming growth factor β) , HGF (hepatocyte growth factor) , VEGF (vascular endothelial growth factor) , heregulin,

angiopoietin) ; may be used.

[0537]

The "cell growth factor receptor" may be any receptor capable of binding to the aforementioned cell growth factors, and specifically, EGF receptor, heregulin receptor (e.g., HER3) , insulin receptor, IGF receptor-1, IGF , receptor-2 , FGF receptor- 1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (e.g., Tie2) , PDGF receptor, and the like may be used.

[0538]

As the "medicament inhibiting actions of cell growth factor and receptor thereof", for example, EGF inhibitor, TGFa inhibitor, heregulin inhibitor, insulin inhibitor, IGF

inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFp inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin

inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF

receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3

inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor,- mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1/2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK inhibitor, PI3K inhibitor, and the like are used. More specifically, anti-VEGF antibody (e.g., Bevacizumab,

Ramucurumab) , anti-HER2 antibody (e.g., Trastuzumab,

Pertuzumab) , anti-EGFR antibody (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab) , anti-HGF antibody, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib,

Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib,

Alectinib, Vismodegib, Cedirani-b,. Tivantinib, Quizartinib,

Dovitinib, Axitinib, Motesanib, Nilotinib, 6- [4- (4- ethylpiperazin-l-ylmethyl ) phenyl] -N- [1 (R) -phenylethyl] -7H- pyrrolo [2, 3-d] pyrimidin-4-amine (AEE-788), Vandetanib,

Temsirolimus , Everolimus, Enzastaurin, Tozasertib, 2- [N- [3- [4- [5- [N- ( 3-fluorophenyl ) carbamoylmethyl] -lH-pyrazol-3- ylamino] q-uinazo-lin-7—yloxy] propyl ] -N-ethylamino] ethyl phosphate (AZD-1152) , 4- [9-chloro-7- (2, 6-difluorophenyl) -5H-primido [5, 4- d] [2 ] benzazepin-2-ylamino] benzoic acid, N- [2-methoxy-5- [ (E) -2- (2,4, 6-trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na) , Volasertib, Selumetinib, Trametinib, N- [2 (R) , 3-dihydroxypropoxy] -3, 4-difluoro-2- (2-fluoro-4- iodophenylamino) benzamide (PD-0325901) , Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, and the like may be used.

[0539]

Besides the above-mentioned drugs, L-asparaginase, L- arginase, arginine deiminase, aceglatone, procarbazine

hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitor (e.g., irinotecan, topotecan, indotecan, Indimitecan) , topoisomerase II inhibitor (e.g., sobuzoxane) , differentiation-inducing factor (e.g., retinoid, vitamin D) , other angiogenesis

inhibitor (e.g., fumagillin, shark extract, COX-2 inhibitor), a-blocker (e.g., tamsulosin hydrochloride), bisphosphonic acid (e.g., pamidronate, zole.dronate) , thalidomide, lenalidomide, pomalidomide, 5-azacytidine, decitabine, proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib) , NEDD8 inhibitor (e.g., Pevonedistat) , UAE inhibitor, PARP inhibitor (e.g.,

Olaparib, Niraparib, Veliparib) , antitumor antibodies such as anti-CD20 antibody (e.g., Rituximab, Obinutuzumab) , anti-CCR4 antibody (e.g., Mogamulizumab) and the like, antibody drug complex (e.g., trastuzumab emtansine, brentuximab vedotin) , and the like may also be used as a concomitant drug.

In another embodiment, for example, when the compound of the present invention may be used as an RORyt inhibitor, Thl7 cell inhibitor, IL-17A or IL-17F inhibitor, it may be used in combination with the following drugs.

(1) non-steroidal anti-inflammatory drug (NSAIDs)

(i) 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

[0540]

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

(i) Gold preparation

aurano.fin and the like.

(ii) penicillamine

D-penicillamine .

(iii) aminosalicylic acid preparation

sulfasalazine, mesalamine, olsalazine, balsalazide.

(iv) antimalarial drug

chloroquine and the like.

(v) pyrimidine synthesis inhibitor - leflunomide and the like. -

(vi) tacrolimus

[0541]

(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) costimulatory molecule-related protein drug

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 N-F-K, NF-κΒ, IKK-!, 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 -

Belnacasan 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 (Vercirnon sodium), CCX025, N-{4-chloro-

2- [ ( l-oxidopyridin-4-yl ) carbonyl] phenyl } -4- (propan-2- yloxy) benzenesulfonamide) , MCP-1 antagonist and the like.

(ix) interleukin-2 receptor antagonist

denileukin, diftitox and the like.

(x) therapeutic vaccines

TNF-a 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-4 , interleukin-10 , soluble interleukin-1 receptor, soluble TNF-a receptor and the like,

(xii) antisense compound

ISIS-104838 and the like.

[0542]

(4) integrin inhibitor

natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like. ^. - - ^.

(5) immunomodulator (immunosuppressant)

methotrexate, cyclophosphamide, MX-68, atiprimod

dihydrochloride, Abatacept, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathioprine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like. (6) proteasome inhibitor

Velcade and the like.

(7) JAK inhibitor .

tofacitinib and the like.

(8) steroid

dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide,

fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone,

beclomethasone dipropionate, estriol and the like.

(9) angiotensin converting enzyme inhibitor

enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.

[0543]

(10) angiotensin II receptor antagonist

candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan and the like.

(11) diuretic drug

hydrochlorothiazide, spironolactone, furosemide,

indapamide, bendrofluazide, cyclopenthiazide and the like.

(12) cardiotonic drug digoxin, dobutamine and the like.

(13) β receptor antagonist

carvedilol, metoprolol, atenolol and the like.

(14) Ca sensitizer

Caldaret hydrate and the like.

(15) Ca channel antagonist

nifedipine, diltiazem, verapamil and the like.

(16) anti-platelet drug, anticoagulator

heparin, aspirin, warfarin and the like.

(17) HMG-CoA reductase inhibitor

atorvastatin, simvastatin and the like.

[0544]

(18) contraceptive

(i) sex hormone or derivatives thereof

gestagen or a derivative thereof (progesterone, 17a- hydroxyprogesterone, 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, Tosagestin, TX-525,

ethinylestradiol/TX525 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

ushercell and the like.

[0545]

(19) others

(i) T cell inhibitors (ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolate mofetil and the like.

(iii) adhesion molecule inhibitor

Alicaforsen sodium, . selectin inhibitor, ELAM-1 inhibitor, VCAM-1 inhibitor, ICAM-1 inhibitor 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, apremilast, CG-1088 and the like.

(x) ) phospholipase A ₂ inhibitor

(xi) iNOS inhibitor

VAS-203 and the like.

(xii) microtubule stimulating drug —

paclitaxel and the like.

(xiii) microtuble 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-1350 and the like.

(xix) 5-lipoxygenase inhibitor

zileuton and the like.

(xx) cholinesterase inhibitor

galanthamine and the like.

(xxi) tyrosine kinase inhibitor

Tyk2 inhibitor (WO 2010/142752) and the like.

(xxii) carepsin 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, Blisibimod and the like.

(xxxiii) CD52 inhibitor

a GT.tuzurr.ac and the like.

[0546]

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, anticoagulator, tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, muscle relaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiotonic drug, therapeutic drug for arrhythmia, vasodilator, vasoconstrictor, therapeutic drug for diabetes, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for pollakisuria/anischuria, 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 may include the following.

[0547]

(1) antibacterial agent

(i) sulfa drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine, silver sulfadiazine and the like.

(ii) quinolone antibacterial agent .

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, 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.

[0548]

(vi) 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, ampicillin, piperacillin, 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 a salt thereof, griseofulvin, lankacidin-group [Journal of Antibiotics (J.

Antibiotics), 38, 877-885(1985)], azole compound [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 .

[0549] -

(2) antifungal agent

(i) polyethylene antibiotic (e.g., amphotericin B, nystatin, trichomycin)

(ii) griseofulvin, pyrrolnitrin and the like

(iii) cytosine metabolism antagonist (e.g., flucytosine)

(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole)

(v) triazole derivative (e.g., fluconazole, 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.

[0550]

(4) antitussive and expectorant drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol

hydrochloride, ephedrine hydrochloride, methylephedrine

hydrochloride, noscapine hydrochloride, alloclamide,

chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terputaline, oxypetebanol , morphine hydrochloride, dextropethorfan hydrobromide, oxycodone

hydrochloride, dimorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine 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.

[0551]

(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) ,

(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and the like.

(7) antiulcer drug

histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrine, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.

(8) antiarrhythmic agent

(i) sodium channel blocker (e.g., quinidine, procainamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin) ,

(ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride, oxprencicl , atenolol, - acebuto-Lol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride) , (iii) potassium channel blocker (e.g., amiodarone) ,

(iv) calcium channel blocker (e.g., verapamil, diltiazem) and the like.

[0552]

(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) anticoagulator

heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor _/ antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium

citrate, 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.

[0553]

(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,

5 cisplatin, azathioprine, mercaptopurine, tegafur, carmofur,

cytarabine, methyltestosterone, testosterone propionate,

testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like. (14) hypolipidemic drug

0 clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2- phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],

pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.5 (15) muscle relaxant

pridinol, tubocurarine, pancuronium, tolperisone

hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine and the like. (16) antiepileptic drug

0 phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripethadione, carbamazepine, phenobarbital, primidone,

sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam and the like.

[0554]

5 (17) antidepressant

imipramine, clomipramine, noxiptiline; phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the0 like.

(18) antiallergic drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, - - sodium cromoglicate, tranilast, repirinast ,-.amlexanox, -.. -5 ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.

(19) cardiotonic drug

trans-n-oxocamphor, terephyllol, aminophylline, 5 etilefrine, dopamine, dobutamine, denopamine, aminophylline, vesinarine, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(20) vasodilator

10 oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.

(21) vasoconstrictor

dopamine, dobutamine denopamine and the like.

(22) hypotensive diuretic

- ^■ is hexamethonium bromide, pentolinium, mecamylamine,

ecarazine, clonidine, diltiazem, nifedipine and the like.

(23) therapeutic drug for diabetes

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon,

20 glymidine, glipuzide, phenformin, puformin, metformin and the like.

[0555]

(24) antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and 25 the like.

(25) liposoluble vitamins

(i) vitamin A: vitamin Ai, vitamin A ₂ and retinol palmitate

(ii) vitamin D: vitamin Di, D ₂ , D ₃ , D ₄ and D ₅

(iii) vitamin E: a-tocopherol, β-tocopherol, γ-tocopherol, δ -

30 tocopherol, dl-a-tocopherol nicotinate

(iv) vitamin K: vitamin Ki, ]¾, K ₃ and K ₄

(v) folic acid (vitamin M) and the like.

(26) vitamin derivative

various derivatives of vitamins, for example, vitamin D ₃ 35 derivatives such as 5 , 6-trans-cholecalciferol, 2,5- hydroxycholecalciferol, 1-a-hydroxycholecalciferol , calcipotriol and the like, vitamin D ₂ 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, predonisolone,

hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate, ciclesonide 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.

[0556]

(30) therapeutic agent for allergic rhinitis

sodium cromoglicate, chlorpheniramine maleate,

alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine, ketotifen fumarate, cetirizine hydrochloride, oxatomide, azelastine, ebastine, epinastine hydrochloride, loratadine and the like.

(31) hypertensor

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(32) others

hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins and the like.

[0557]

For combined use, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention and the concomitant drug may be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and may be appropriately selected depending on an administration subject, administration route, disease, combination and the like.

The administration form of the combined use is not particularly limited, and the compound of the present invention and a concomitant drug only need to be combined on

administration. Examples of such administration mode include the following:

(1) administration of a single preparation obtained by

simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of

preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.

The mixing ratio of the compound of the present invention and a concomitant drug in the combination agent of the present invention can be appropriately selected based on the subject of administration, administration route, disease and the like. For example, while the content of the compound of the present invention in the combination agent of the present invention varies depending on the preparation form, it is generally about 0.01 - 100 wt%, preferably about 0.1 - 50 wt%, more preferably about 0.5.. - 20 wt%, of the whole preparation.

[0558]

The content of the concomitant drug in the combination agent of the present invention varies depending on the

preparation form, and generally about 0.01 to 99.99% by weight, preferably about 0.1 to 50% by weight, further preferably about 0.5 to 20% by weight, of the entire preparation.

While the content of the additive such as a carrier and the like in the combination agent of the present invention varies depending on the form of a preparation, it is generally about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the preparation.

When the compound of the present invention and the concomitant drug are separately prepared, the same content may be adopted.

The dose varies depending on the kind of the compound of the present invention, administration route, symptom, age of patients and the like. For example, for oral administration to patients (body weight about 60 kg) with inflammatory bowel disease (IBD) , about 0.1 mg/kg body weight - about 30 mg/kg body weight, preferably about 1 mg/kg body weight - 20 mg/kg body weight, of compound (-1'-) can be administered once to several portions per day.

The dose of the medicament of the present invention as a sustained-release preparation varies depending on the kind and content of compound (Ι'), dosage form, period of sustained drug release, subject animal of administration (e.g., mammals such as mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, human and the like) , and

administration object. For example, for application by

parenteral administration, about 0.1 to about 100 mg of compound (I' ) needs to be released from the administered preparation per 1 week.

[0559]

Any amount of the concomitant drug can be adopted as long as the side effects do not cause a. problem.. The daily dosage in terms of the concomitant drug varies depending on the severity, age, sex, body weight, sensitivity ^' difference of the subject, administration period, interval, and nature,

pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly restricted, and the amount of a drug is, in the case of oral administration for example, generally about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg, per 1 kg of a mammal and this is generally

administered once to 4-times divided in a day.

When the combination agent of the present invention is administered, the compound of the present invention and the concomitant drug can be administered simultaneously, or may be administered in a staggered manner. When administered at a time interval, the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is administered within time range of from for 1 minute to 3 days, preferably from for 10 minutes to 1 day, more preferably from for 15 minutes to 1 hour, after administration of the

concomitant drug is included. When the compound of the present invention is administered first, a method in which the

concomitant drug is administered within time range of from for 1 minute to 1 day, preferably from for 10 minutes to 6 hours, more preferably from for 15 minutes to 1 hour after

administration of the compound of the present invention is included .

[Examples]

[0560] The present invention is explained in more detail in the following by referring to Examples, Formulation Examples and Experimental Examples, which are not to be construed as limitative and may be modified without departing from the scope of the invention. . ....

Unless particularly specified, the elution in column chromatography in the Examples was performed under observation by TLC (Thin Layer Chromatography) . For TLC observation,

60F254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent for column chromatography was used as a developing solvent. For detection, a UV detector was adopted. In silica gel column chromatography, NH means use of aminopropylsilane-bonded silica gel, and Di-oi means use of 3- (2 , 3-dihydroxypropoxy) propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography) , C18 means use of octadecyl-bonded silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified. The room temperature generally means a temperature about 10°C to 35°C. For drying extracts, sodium sulfate or magnesium sulfate was used.

The abbreviations in the present specification or the Examples mean as follows.

[0561]

LC: liquid chromatography

MS: mass analysis spectrum

ESI: Electrospray ionization

M: molecular weight of the compound

M: mol concentration

N: normal concentration

NMR: nuclear magnetic resonance spectrum

Hz: hertz

J: coupling constant

m: multiplet

q: quartet

t: triplet d: doublet

dd: double doublet

ddd: double double doublet

s: singlet

dt : double triplet

sxt: sextet

brs : broad singlet

quin: quintet

quant.: quantitative

tBu: tert-butyl

sat . : saturated

aq. : aqueous

AcOH: acetic acid

ADDP: 1,1'- (azodicarbonyl ) dipiperidine

Boc: tert-butyloxycarbonyl group

Boc ₂ 0: di-tert-butyl dicarbonate

CDI : carbonyldiimidazole

CPME: cyclopentyl methyl ether

DCM: dichloromethane

DIAD: diisopropyl azodicarboxylate

DIPEA: N-ethyl-N-isopropylpropan-2-amine

DMAP: 4-dimethylaminopyridine

DME: dimethoxyethane

DMF: N, N-dimethylformamide

DMSO: dimethyl sulfoxide

Et ₂ 0: diethyl ether

EtOAc, AcOEt: ethyl acetate

EtOH: ethanol

HATU: 2- (3H- [1, 2, 3] triazolo [4, 5-b] pyridin-3-yl) -1, 1, 3, 3- tetramethylisouronium hexafluorophosphate (V)

IPE: diisopropyl ether

KOtBu: potassium tert-butoxide

LiHMDS: lithium 1, 1 , 1 , 2 , 2 , 2-hexamethyldisilane

m-CPBA: m-chloroperoxybenzoic acid

MeOH: methanol MsCl : methanesulfonyl chloride

NaOMe: sodium methoxide

NaOtBu: sodium tert-butoxide

NBS : N-bromosuccinimide

nBuOH: n-butyl alcohol

nBuLi: n-butyllithium

NCS: N-chl.orosuccinimide

NMP: N-methyl-2-pyrrolidone

OXONE: potassium peroxymonosulfate

Pd (dppf) C1 ₂ -CH ₂ C1 ₂ : 1, 1' -bis (diphenylphosphino) ferrocene- palladium ( II ) dichloride-dichloromethane complex

Pd/C(en): palladium-activated carbon ethylenediamine complex (Pd:3.5-6.5%)

Pd(OAc) 2 : palladium ( II ) diacetate

Pd (PPh ₃ ) ₂ C1 ₂ : bis (triphenylphosphine ) palladium ( II ) dichloride Pd ₂ (dba) ₃ : tris (dibenzylideneacetone ) dipalladium ( 0 )

Pd-C: palladium on carbon

PdCl ₂ (dppf) : 1, 1' - bis (diphenylphosphino) ferrocenedichloropalladium ( II )

PE: petroleum ether

Ph ₃ P: triphenylphosphine

RuPhos Pd Gl, RuPhos-Pd-Gl : (RuPhos) palladium ( II )

phenethylamine chloride

Ruphos pre-catalyst : chloro (2-dicyclohexylphosphino-2 ' , 6' -di-i- propoxy-1, 1' -biphenyl) [2- (2-aminoethylphenyl) ] palladium ( II ) , methyl-t-butyl ether adduct -

Ruphos : 2-dicyclohexylphosphino-2 ' , 6' -diisopropoxy-1 , 1' - biphenyl

T3P: 1.6 M 2 , 4 , 6-tripropyl-l , 3 , 5 , 2 , 4 , 6-trioxatriphosphorinane- 2 , 4 , 6-trioxide/ethyl acetate solution or DMF solution

t-Bu ₃ P: tri-t-butylphosphine

TEA: triethylamine

Tf ₂ 0: triflic anhydride, trifluoromethanesulfonic anhydride - TFA: trifluoroacetic acid

TFAA: trifluoroacetic anhydride THF: tetrahydrofuran

TsOH*H ₂ 0: p-toluenesulfonic acid monohydrate

WSOHC1: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

hydrochlorideXANTPHOS : 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene

XPHOS Pd G2: chloro (2-dicyclohexylphosphino-2 ' , 4 ' , 6' - triisopropyl-1, 1' -biphenyl) [2- (2' -amino-1, 1' - biphenyl) ] palladium ( II )

Xphos, XPHOS: 2-dicyclohexylphosphino-2' , 4 ' , 6' - triisopropylbiphenyl

[0562]

Reference Example 1

4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl) chromane-6- carboxamide

A) 4-oxochromane-6-carboxylic acid

To a solution of 6-bromo-2 , 3-dihydro-4H-chromen-4-one

(6.0 g, 26.40 mmol) in- DMF (70 mL) and H ₂ 0 (7 mL) were added

Pd(PPh ₃ ) ₂ Cl ₂ (1.85g, 2.60 mmol) and TEA (10.7 g, 105.70 mmol).

The mixture was stirred at 80 °C for 48 h under CO atmosphere. The mixture was diluted with water. The solid was filtered, washed with MeOH, and dried in vacuo to give the title compound

(2.8 g, yield 55.1%) as white solids.

[0563]

B) methyl 4-oxochromane-6-carboxylate

To a solution of 4-oxochromane-6-carboxylic acid (400.0 mg, 2.60 mmol) in MeOH (-10 mL) was added S0C1 ₂ (569.7 mg, 4.80 mmol) dropwise. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo to give the title compound (370 mg, yield 86.2%) as white solids.

[0564]

C) methyl 4- ( (2-methoxyphenyl) amino) chromane-6-carboxylate

To a solution of methyl 4-oxochromane-6-carboxylate

(200.0 mg, 0.96 mmol) and 2-methoxyaniline (155.3 mg, 1.26 mmol) in DCM (5 mL) was added a DCM solution of TiCl ₄ (1M, 1.45 mL, 1.45 mmol). The mixture was stirred at room temperature overnight. Then, a solution of NaCNBH ₃ (121.9.0 mg, 1.94 mmol) in MeOH (2 mL) was added to the mixture and stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (250.0 mg, yield 82.2%) as grey solids.

MS (ESI+) , found 314.1 (M+H)

[0565]

D) 4- ( (2-methoxyphenyl) amino) chromane-6-carboxylic acid

To a solution of methyl 4-((2- methoxyphenyl) amino) chromane-6-carboxylate (250.0 mg, 0.80 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO ₄ , filtered and concentrated in vacuo. The white solid was washed with Et20 to afford the title compound (200.0 mg, 83.7% yield) as white solids.

[0566]

E) 4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide

To a mixture of 4- ( (2-methoxyphenyl) amino) chromane-6- carboxylic acid (180.0 mg, 0.60 mmol), HATU (240.0 mg, 0.66 mmol) and DIPEA (193.8 mg, 1.50 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide hydrochloride (133.0 mg, 0.66 mmol) . The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc and water, the organic layer was washed with brine, dried over Na2SO ₄ ,

filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (70.0 mg, 24.9% yield) . as white solids.

Prep-HPLC [Gilson-GX281] conditions

Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μπι Mobile Phase: from 65% [water + 10 mM NH ₄ HCO ₃ ] and 35% [CH ₃ CN] to 45% [water + 10 mM NH ₄ HCO ₃ ] and 55% [CH ₃ CN] in 8 min, then changed to 5% [water + 10 mM NH ₄ HCO ₃ ] and 95% [CH ₃ CN] in 0.2 min and under this condition for 3.8 min

Flow rate: 20 mL/min

Column temperature: room temperature

MS (ESI+), found 468.1 (M+H)

¹ H NMR (400 MHz , DMSO-d ₆ ) 5:2.00-2.08 (2H, m) , 3.75 (3H, s) , 4.22-4.29 (2H, m) , 4.45-4.49 (2H, m) , 4.74 (1H, t, J= 3.8 Hz), 4.92 (1H, d, J= 8.0 Hz), 6.60-6.64 (1H, m) , 6.80-6.89 (4H, m) , 7.30 (2H, s), 7.45 (2H, d, J= 8.0Hz), 7.76 (3H, d, J= 8.4Hz), 7.92 (1H, d, J= 1.2Hz), 8.98 (1H, d, J= 5.6 Hz).

[0567]

Reference Example 2

4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide

A) methyl 4-hydroxychromane-6-carboxylate

To a solution of methyl 4-oxochromane-6-carboxylate

(370.0 mg, 1.80 mmol) in DCM (5 mL) and MeOH (5 mL) was added NaBH ₄ (169.7 mg, 4.50 mmol). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (350.0 mg, yield 93.7%) as a white solid

[0568]

B) methyl 4- (2-methoxyphenoxy) chromane-6-carboxylate

To a mixture of methyl 4-hydroxychromane-6-carboxylate (150.0 mg, 0.70 mmol), 2-methoxyphenol (178.0 mg, 1.4 mmol) and t-Bu ₃ P (377.9 mg, 1.40 mmol) in THF (4 mL) was dropwise added a solution of 1, 1' - (azodicarbonyl) -dipiperidine (363.0 mg, 1.40 mmol) in THF (2 mL) . The mixture was stirred at room

temperature for 4 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/ EtOAc = 20/ 1, v/v) to afford the title compound (180.0 mg, 79.5% yield) as a

colorless oil.

MS (ESI+), found 337.2 (M+Na)

[0569]

C) 4- (2-methoxyphenoxy) chromane-6-carboxylic acid

To a solution of methyl 4- (2-methoxyphenoxy) chromane-6- carboxylate (180.0 mg, 0.6 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq. , and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ ,

filtered and concentrated in vacuo. The resulting white solid was washed with Et ₂ 0 to afford ^{^} the title, compound (160.0 mg, 93.0% yield) .

[0570]

D) 4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide

To a mixture of 4- ( 2-methoxyphenoxy) chromane-6-carboxylic acid (160.0 mg, 0.50 mmol), HATU (230.0 mg, 0.55 mmol) and DIPEA (158.4 mg, 1.23 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide (122.0 mg, 0.55 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (125.0 mg, 50.1% yield) as white solids.

Prep-HPLC [Gilson-GX281] conditions, Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μιπ; Mobile Phase: from 60% [water + 10 mM NH ₄ HCO ₃ ] and 40% [CH ₃ CN] to 40% [water + 10 itiM NH ₄ HCO ₃ ] and 60% [CH ₃ CN] in 8 min, then changed to 5% [water + 10 mM NH ₄ HCO ₃ ] and 95% [CH ₃ CN] in 0.2 min and under this condition for 3.8 min; Flow rate: 20 mL/min; Column temperature: room temperature MS (ESI+), found 469.1 (M+H)

1H NMR (400 MHz, DMSO-d ₆ ) 6:2.05-2.13 (2H, m) , 3.75 (3H, s) , 4.25-4.35 (2H, m) , 4.51 (2H, d, J= 6.0 Hz), 5.40 (1H, t, J= 1.0 Hz), 6.88-6.94 (2H, m) , 6.98-7.05 (2H, m) , 7.18-7.20 (1H, m) , 7.30 (2H, s), 7.46 (2H, d, J= 8.4 Hz), 7.78 (2H, d, J= 8.4 Hz), 7.82 (1H, d, J= 8.4 Hz), 7.95 (1H, d, J= 0.7 Hz), 9.00 (1H, t, J= 5.6 Hz).

[0571]

The compounds described in Reference Examples 1 to 2 are below (Table 1-1) .

[0572]

[Table 1-1]

[0573]

Example 3

4- ( (2-methoxyphenyl) amino) -N- (4-sulfamoylbenzyl) chromane-7- carboxamide

A) methyl 4-oxochromane-7-carboxylate

To a solution of 4-oxochromane-7-carboxylic acid (500.0 mg, 2.60 mmol) and TEA (394.9, 3.90 mmol) in MeOH (10 mL) was added S0C1 ₂ (773.9 mg, 6.50mmol) dropwise. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc . The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (450.0 mg, yield 83.9%) as grey solids.

[0574]

B) methyl 4- ( (2-methoxyphenyl) amino) chromane-7-carboxylate

To a solution of methyl 4-oxochromane-7-carboxylate

(120.0 mg, 0.58 mmol) and 2-methoxyaniline (100.3 mg, 0.81 mmol) in DCM (5 mL) was added a solution of TiCl ₄ (0.88 mL, IN, 0.88 mmol) in DCM. The mixture was stirred at room temperature overnight. Then, a solution of NaCNBH ₃ (73.0 mg, 1.16 mmol) in MeOH (2 mL) was added to the reaction. The mixture was stirred at room temperature for .1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (70.0 mg, yield 38.4%) as white solids.

MS (ESI+), found 314.3 (M+H)

[0575]

C) 4- ( (2-methoxyphenyl) amino) chromane-7-carboxylic acid.

To a solution of methyl 4- ( (2- methoxyphenyl) amino) chromane-7-carboxylate (65.0 mg, 0.20 mmol) in MeOH (4 ml) was added 4N NaOH aq. (4 mL, 16.00 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The resulting white solid was washed with Et ₂ 0 to afford the title compound (60.0 mg, 96.6% yield) as white solids.

[0576]

D) 4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl ) chromane-7- carboxamide

To a mixture of 4- ( (2-methoxyphenyl) amino) chromane-7- carboxylic acid (65.0 mg, 0.22 mmol), HATU (99.0 mg, 0.25 mmol) and DIPEA (70.0 mg, 0.54 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide hydrochloride (58.0 mg, 0.26 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc and water, the organic layer was washed with brine, dried over Na ₂ SO ₄ ,and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (31.0 mg, 30.5% yield) as white solids .

Prep-HPLC [Gilson-GX281] conditions, Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μπι; Mobile Phase: from 65% [water + 10 mM NH ₄ HCO ₃ ] and 35% [CH ₃ CN] to 45% [water + 10 mM NH ₄ HCO ₃ ] and 55% [CH ₃ CN] in 8 min, then changed to 5% [water + 10 mM NH ₄ HCO ₃ ] and 95% [CH ₃ CN] in 0.2 min and under this condition for 3.8 min; Flow rate: 20 mL/min; Column temperature: room temperature MS (ESI+), found 468.1 (M+H)

¹ H NMR (400 MHz, DMSO-d ₆ ) 5:2.00-2.09 (2H, m) , 3.76 (3H, s) , 4.21-4.29 (2H, m) ,. 4.52 (2H, d, J= 6 Hz), 4.74-4.79 (1H, m) , 4.93 (1H, d, J= 8.4 Hz), 6.60-6.64 (1H, m) , 6.77-6.86 (3H, m) , 7.31-7.41 (5H, m) , 7.47(2H, d, J= 8.4Hz), 7.78 (2H, d, J=

8.4Hz), 9.08 (1H, t, J= 5.8 Hz).

[0577]

Example 4

4- (2-methoxyphenoxy) -N- (4-sulfamoylbenzyl) chromane-7- carboxamide

A) methyl 4-hydroxychromane-7-carboxylate

To a solution of methyl 4-oxochromane-7-carboxylate

(200.0 mg, 0.97 mmol) in DCM (5 mL) and MeOH (5 mL) was added NaBH ₄ (91.7 mg, 2.42 mmol). The mixture was stirred at room temperature for 1 h. Water was added, the mixture was and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (160.0 mg, yield 79.2%) as white solids.

MS (ESI+), found 209.2 (M+H)

[0578]

B) methyl 4- (2-methoxyphenoxy) chromane-7-carboxylate

To a mixture of methyl 4-hydroxychromane-7-carboxylate (160.0 mg, 0.70 mmol), 2-methoxyphenol (190.8 mg, 1.40 mmol) and t-Bu ₃ P (310.9 mg, 1.40 mmol) in THF (4 mL) was dropwise added a solution of 1, 1' - (azodicarbonyl) -dipiperidine (387.8 mg, 1.40 mmol) in THF (2 mL) . The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc, the organic layer was washed with brine, dried over

Na ₂ SO ₄ , filtered and concentrated in vacuo. . The residue was purified by column chromatography (PE/ EtOAc = 20/ 1) to afford the title compound (170.0 mg, 70.4% yield) as a colorless oil.

MS (ESI+), found 337.1 (M+Na)

[0579]

C) 4- (2-methoxyphenoxy) chromane-7-carboxylic acid

To a solution of methyl 4- ( 2-methoxyphenoxy) chromane-7- carboxylate (170.0 mg, 0.50 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc. The organic layer was washed brine, dried over Na ₂ SO ₄ , filtered and

concentrated in vacuo. The resulting white solid was washed with Et ₂ 0 to afford the title compound (150.0 mg, 92.4% yield) as white solids.

[0580]

D) 4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-7- carboxamide

To a mixture of 4- (2-methoxyphenoxy) chromane-7-carboxylic acid (170.0 mg, 0.50 mmol), HATU (190.0 mg, 0.55 mmol) and DIPEA (193.8 mg, 1.50 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide (122.0 mg, 0.55 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (110.0 mg, 47.0% yield) as white solids.

Prep-HPLC [Gilson-GX281] conditions

Column: Waters X-Bridge C18 : 100 mm x 30 mm, 5 μηα

Mobile Phase: from 60% [water + 10 mM NH ₄ HCO ₃ ] and 40% [CH ₃ CN] to 40% [water + 10 mM NH ₄ HCO ₃ ] and 60% [CH ₃ CN] in 8 min, then changed to 5% [water + 10 mM NH ₄ HCO ₃ ] and 95% [CH ₃ CN] in 0.2 min and under this condition for 3.8 min

Flow rate: 20 mL/min

Column temperature: room temperature

MS (ESI+), found 469.1 (M+H)

2H NMR (400 MHz, DMSO-d ₆ ) δ:2.05-2.13 (2H, m) , 3.77 (3H, s) , 4.25-4.33 (2H, m) , 4.51 (2H, d, J= 5.6 Hz), 5.37 (1H, t, J= 3.6 Hz), 6.88-6.93 (1H, m) , 6.99-7.06 (2H, m) , 7.15-7.17 (1H, m) , 7.32 (2H, s), 7.38-7.43 (3H, m) , 7.48 (2H, d, J= 8.4Hz), 7.78 (2H, d, J= 8.4 Hz), 9.12 (1H, t, J= 5.6 Hz).

[0581]

Example 5

4- (2=methoxybenzyl ) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide

A) 4- (2-methoxybenzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid

A mixture of methyl 4- (2-methoxybenzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxylate (99 mg, 0.32 mmol) and 2 N NaOH (2 mL, 4.00 mmol) in MeOH (2 mL) was stirred at 40°C overnight. The mixture was acidified with 2 N HC1 and extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ and

concentrated in vacuo to give the title compound (91 mg, 0.305 mmol, 97%) as a colorless oil. This product was subjected to the next reaction without further purification.

MS (ESI+), found 300.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 6:3.46-3.55 (2H, m) , 3.86 (3H, s) , 4.25 (2H, t, J = 4.5 Hz), 4.50-4.56 (2H, m) , 6.57 (1H, dd, J = 8.9, 5.1 Hz), 6.84-6.94 (2H, m) , 7,07-7.13 (1H, m) , 7.23-7.28 (1H, m) , 7.43-7.62 (2H, m) . (A C0 ₂ H peak was omitted)

[0582]

B) 4- (2-methoxybenzyl) -N- ( (1- (methylsulfonyl) piperidin-4- yl)methyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide

To a mixture of 4- (2-methoxybenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylic acid (91.4 mg, 0.31 mmol),. (1- (methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (84 mg, 0.37 mmol) and TEA (0.128 mL, 0.92 mmol) in DMF(dry) (1 mL) was added HATU (139 mg, 0.37 mmol) . The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The

organic layer was separated, washed with brine, dried over

Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 10% MeOH in EtOAc) to give the title compound (50.2 mg, 0.106 mmol, 34.7%) as colorless foam.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.29-1.44 (2H, m) , 1.66-1.91 (3H, m) , 2.58-2.71 (2H, m) , 2.76 (3H, s) , 3.33 (2H, t, J = 6.2 Hz), 3.47-3.54 (2H, m) , 3.80 (2H, d, J = 12.1 Hz), 3.87 (3H, s), 4.23-4.30 (2H, n) , 4.51 (2H, s) , 6.05 (1H, s) , 6.58 (1H,. d, J = 8.7 Hz), 6.87-6.95 (2H, m) , 7.10 (1H, d, J = 5.7 Hz), 7.17-7.25 (3H, m) .

[0583]

Example 6

4- (2- (methoxymethyl) benzyl) -N- ( (1- (methylsulfonyl ) piperidin-4- yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-.carboxamide

A) ethyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate

To a solution of ethyl 3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (0.600 g, 2.90 mmol) in DMF(dry) (12 mL) were added NaH (60% in oil, 0.174 g, 4.34 mmol) and stirred at room

temperature for 10 min. To the mixture was added 1- ( chloromethyl ) -2- (methoxymethyl ) benzene (0.593 g, 3.47 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with AcOEt and H ₂ 0. The

organic extract was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the title compound (1.050 g, 3.08 mmol, 106%) as a light brown oil. This product was subjected to the next reaction without further purification.

[0584]

B) 4- (2- (methoxymethyl) benzyl ) -3, 4-dihydro-2H-l , 4-benzoxazine- 7-carboxylic acid

An 8N NaOH aq. (4 mL, 32.00 mmol) was added to a solution of ethyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (1.05 g, 3.08 mmol) in THF (10 mL) and EtOH (10 mL) at room temperature. The mixture was stirred at 70°C under N ₂ for 1 h. The mixture was neutralized with 6N HCl at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resultant solid was suspended in 33% EtOAc in hexane and collected by filtration to give the title compound (0.720 g, 2.298 mmol, 74.7%) as light brown solids.

[0585]

C) 4- (2- (methoxymethyl) benzyl) -N- ( ( 1- (methylsulfonyl ) piperidin- 4-yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide

To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-1, 4-benzoxazine-7-carboxylic acid (150 mg, 0.48 mmol), (1- (methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (130 mg, 0.57 mmol), HATU (221 mg, 0.58 mmol) and DMF (5 mL) was added DIPEA (0.25 mL, 1.43 mmol). After being stirred at room temperature overnight, the reaction mixture was guenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SCO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from IPE-hexane to give the title compound (125 mg, 0.256 mmol, 53.6%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:2.58-2.70 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.0 Hz), 3.30-3.35 (8H, m) , 3.42 (2H, t, J = 4.2 Hz), 3.49-3.58 (2H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.51 (2H, s), 4.59 (2H, s), 6.51 (1H, d, J = 8.7 Hz), 7.11-7.16 (1H, m) , 7.21-7.30 (4H, m) , 7.35-7.41 (1H, m) , 8.07-8.16 (1H, m) .

[0586]

Example 7

N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl ) ethyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide

A) tert-butyl 4- (2-methoxy-l- (( (4- (2- (methoxymethyl) benzyl) - 3, 4-dihydro-2H-l , 4-benzoxazin-7-yl) carbonyl) amino) -2- oxoethyl) piperidine-l-carboxylate

To a mixture of DIPEA (217 μΐ, 1.24 mmol), 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid (130 mg, 0.41 mmol) , tert-butyl 4- ( l-amino-2- methoxy-2-oxoethyl ) piperidine-l-carboxylate (169 mg, 0.62 mmol) in DMF(dry) (4149 μΐ) was added HATU (237 mg, 0.62 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo . The residue was used for next reaction without further purification.

MS (ESI+), found 568.3 (M+H)

[0587]

B) methyl ( ( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl) carbonyl) amino) (piperidin-4-yl ) acetate

hydrochloride

A mixture of tert-butyl 4- (2-methoxy-l- ( ( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazin-7- yl) carbonyl) amino) -2-oxoethyl) piperidine-l-carboxylate (233 mg, 0.41 mmol) and 4M HC1 in AcOEt (10 mL, 40.00 mmol) was stirred at room temperature under N ₂ overnight. The resultant

suspension was concentrated in vacuo. The solid was used for next reaction without further purification.

MS (ESI+), found 468.3 (M-HC1+H)

[0588]

C) methyl (( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl) carbonyl) amino) (1- (methylsulfonyl ) piperidin-4- yl) acetate

MsCl (63.9 μΐ, 0.82 mmol) and TEA (571 μΐ, 4.10 mmol) were added to a solution of methyl (((4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazin-7- yl) carbonyl) amino) (piperidin-4-yl) acetate hydrochloride (207 mg, 0.41 mmol) in THF (4100 μΐ) at room temperature. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give the title compound (50 mg, 0.092 mmol, 22.35%) as white solids.

MS (ESI+), found 546.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.36-1.66 (2H, m) , 1.69-1.89 (2H, m) , 1.93-2.11 (2H, m) , 2.56-2.71 (2H, m) , 2.72-2.77 (3H, m) , 3.41 (3H, s), 3.42-3.49 (2H, m) , 3.73-3.87 (5H, m) , 4.22-4.33 (2H, m) , 4.51 (2H, s) , 4.57-4.65 (2H, m) , 4.79-4.90 (1H, m) , 6.49- 6.61 (1H, m) , 6.61-6.75 (1Ή, m) , 7.22 (1H, s) , 7.26-7.32 (3H, m) , 7.32-7.43 (1H, m) .

[0589]

D) N- (2-hydroxy-l- (1- (methylsulfonyl ) piperidin-4-yl ) ethyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide

LiBH ₄ (3.83 mg, 0.18 mmol) was added to a solution of methyl (( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl ) carbonyl) amino) (1- (methylsulfonyl ) piperidin-4- yDacetate (48 mg, 0.09 mmol) in THF (1759 μΐ) at 0°C. The mixture was stirred at 50 °C under N2 for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The solid was

crystallized from EtOAc-hexane to give the title compound (30 mg, 0.058 mmol, 65.9%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.19-1.33 (2H, m) , 1.63-1.85 (3H, m) , 2.52-2.68 (2H, m) , 2.82 (3H, s) , 3.33 (3H, s), 3.38-3.62 (6H, m) , 3.79-3.90 (1H, m) , 4-.-20-4.30 (2H, m) , 4.51 (2H, s) , 4.60 (3H, s), 6.48-6.56 (1H, m) , 7.06-7.18 (1H, m) , 7.28 (4H, d, J = 12.1 Hz), 7.34-7.44 (1H, m) , 7.57-7.69 (1H, m) .

[0590]

Example 8

4- (2- (difluoromethoxy) benzyl) -N- ( (1- (methylsulfonyl ). piperidin- 4-yl) methyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide

A) ethyl 4- (2- (difluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate

NaH (60% in oil, 57.9 mg, 1.45 mmol) was added to a solution of ethyl 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate (150 mg, 0.72 mmol) in DMF(dry) (3 mL) at 0°C. After stirring at room temperature for 10 min, 1- (bromomethyl ) -2- (difluoromethoxy) benzene (0.166 mL, 1.09 mmol) was added to the mixture . at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, . washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title

compound (263 mg, 0.724 mmol, 100 %) as a pale yellow oil.

MS (ESI+), found 364.2 (M+H)

[0591]

B) 4- (2- (difluoromethoxy) benzyl) -N- ( il(methylsulfonyl) piperidin-4-yl) methyl) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxamide

To a solution of ethyl 4- (2- (difluoromethoxy) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxylate (263 mg, 0.72 mmol) in THF (1 mL) and MeOH (1 mL) was added 8N NaOH aq. (2 mL, 16.00 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was stirred at 70°C for 2 h. The mixture was neutralized with 2N HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. To a mixture of the residue and (1- (methylsulfonyl) piperidin-4- yl ) methanamine hydrochloride (199 mg, 0.87 mmol) in DMF (3 mL) were added HATU (413 mg, 1.09 mmol) and DIPEA (0.378 mL, 2.17 mmol) at 0°C. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room

temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) . The residue was crystallized from EtOAc-hexane to give the title compound (205 mg, 0.402 mmol, 55.6%) as off- white solids.

¹ H NMR (300 MHz , DMSO-d ₆ ) 5:1.07-1.27 (2H, m) , 1.53-1.80 (3H, m) , 2.58-2.70 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.2 Hz), 3.44-3.60 (4H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.57 (2H, s) , 6.50-6.58 (1H, m) , 7.16-7.30 (6H, m) , 7.31-7.40 (1H, m) , 8.13 (1H, t, J = 5.7 Hz) .

[0592] - Example 9

N- ( (1- (methylsulfonyl ) piperidin-4-yl ) methyl) -4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide

A) ethyl 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate

NaH (60% in oil, 34.7 mg, 1.45 mmol) was added to a solution of ethyl 3 , 4-dihydro—2H-1 , 4-benzoxazine-7-carboxylate (150 mg, 0.72 mmol) in DMF(dry) (3mL) at 0°C. After stirring at room temperature for 10 min, 1- (bromomethyl ) -2- (trifluoromethoxy) benzene (369 -mg, 1.45 mmol) was .added to the mixture at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and

concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give the title compound (250 mg, 0.656 mmol, 91%) as a colorless oil.

MS (ESI+), found 382.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.31-1.37 (3H, m) , 3.47-3.54 (2H, m) , 4.25-4.33 (4H, m) , 4.61 (2H, s) , 6.48-6.53 (1H, m), 7.20-7.36 (4H, m) , 7.50 (2H, dq, J = 4.4, 2.2 Hz).

[0593]

B) 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylic acid

2N aq.NaOH (3 mL, 6.00 mmol) was added to a solution of ethyl 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (250 mg, 0.66 mmol) in MeOH (8 mL) at room temperature. The mixture was stirred at 40 °C overnight. The mixture was neutralized with IN HC1 aq. at 0°C and diluted with water. The precipitate was collected by filtration, washed with water, dried in vacuo to give the title compound (210 mg, 0.594 mmol, 91%) as white powder.

MS (ESI+), found 354.2 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.51 (2H, t, J = 4.3 Hz), 4.25 (2H, t, J = 4.3 Hz), 4.65 (2H, s), 6.53 (1H, d, J = 8.3 Hz), 7.23 (1H, d, J = 1.9 Hz), 7.29-7.45 (5H, m) , 12.20 (1H, brs).

[0594]

C) N- ( (1- (methylsulfonyl) piperidin-4-yl) methyl) -4- (2-

(trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxamide

HATU (121 mg, 0.32 mmol) was added to a solution of 4- (2-

(trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid (80 mg, 0.23 mmol), (1-

(methylsulfonyl) piperidin-4-yl)methanamine hydrochloride (51.8 mg, 0.23 mmol) and DIPEA (0.158 mL, 0.91 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOH-water to give the title compound (84 mg, 0.159 mmol, 70.3%) as white powder.

1H NMR (300 MHz, DMSO-d ₆ ) 5:1.08-1.24 (2H, m) , 1.50-1.75 (3H, m) , 2.59-2.73 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.2 Hz), 3.45-3.57 (4H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.62 (2H, s) , 6.51 (1H, d, J = 9.1 Hz), 7.24-7.44 (6H, m) , 8.13 (1H, t, J = 5.7 Hz) .

[0595]

Example 12

4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide

HATU (136 mg, 0.36 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid (80 mg, 0.26 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (68.2 mg, 0.31 mmol) and DIPEA (145 mg, 1.12 mmol) in DMF(dry) (1 mL) at room temperature.. The mixture was, stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with60%-100%EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title compound (87 mg, 0.181 mmol, 70.8%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.33 (3H, s) , 3.44 (2H, t, J = 4.3 Hz), 4.25· (2H, t, J = 4.3 Hz), 4.43-4.55 (4H, m) , 4.61 (2H, s) , 6.53 (1H, d, J = 7.9 Hz), 7.13 (1H, dd, J = 4.5 Hz), 7.22-7.45 (9H, m) , 7.75 (2H, d, J = 7.6 Hz), 8.73 (1H, t, J = 6.0 Hz).

[0596]

Example 13

4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro-

2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

A) 7-bromo-3, 4-dihydro-2H-pyrido [3, 2-b] [l,4]oxazine

To a solution of 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine (500 mg, 3.67 mmol) in DMF (10 mL) was added NBS (719 mg, 4.04 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with sat. NaHCO ₃ aq. ' and water at 0°C and stirred at 0°C for 20 min. The precipitate was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound (549 mg, 2.55 mmol, 69.5%) as brown solids. ^{. .}

MS (ESI+), found 215.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.50-3.58 (2H, m) , 4.18-4.26 (2H, m) , 4.82 (1H, brs), 7.10 (1H, d, J = 1.9 Hz), 7.72 (1H, d, J = 2.3 Hz) . [0597]

B) 7-bromo-4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [l,4]oxazine

To a solution of 7-bromo-3, 4-dihydro-2H-pyrido [3, 2- b] [l,4]oxazine (549 mg, 2.55 mmol) in DMF(dry) (10 rtiL) was added 60% NaH in oil (123 mg, 3.06 mmol) at 0°C. The mixture was stirred at 0°C under N ₂ for 10 min. 1- ( chloromethyl ) -2- . . (methoxymethyl ) benzene (523 mg, 3.06 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title

compound (660 mg, 1.890 mmol, 74.0%) as white solids.

MS (ESI+), found 349.1 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.28-3.33 (2H, m), 3.35 (3H, s) ,

4.11-4.20 (2H, m) , 4.48 (2H, s) , 4.89 (2H,- s), 7.08 (1H, d, J = 2.3 Hz), 7.18-7.31 (3H, m) , 7.33-7.41 (1H, m) , 7.79 (1H, d, J = 1.9 Hz) .

[0598]

C) methyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [ 3 , 2-b] [1, 4] oxazine-7-carboxylate

To a solution of 7-bromo-4- (2- (methoxymethyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine (510 mg, 1.46 mmol), TEA (0.407 mL, 2.92 mmol) in DMF(dry) (23.233 mL) and MeOH (4.65 mL) was added PdCl ₂ (dppf) (107 mg, 0.15 mmol) at room

temperature. The mixture was stirred at 100 °C under CO (0.5 Mpa) for 5 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was. separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% EtOAc in hexane) to give the title compound (210 mg, 0.640 mmol, 43.8%). MS (ESI+) , found 329.1 (M+H) ¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.33 (3H, s) , 3.37-3.44 (2H, m) 3.86 (3H, s), 4.11-4.18 (2H, m) , 4.47 (2H, s), 5.00-5.08 (2H, m) ,

7.18-7.25 (1H, m) , 7.26-7.31 (2H, m) , 7.35-7.40 (1H, m) , 7.50 (1H, d, J = 1.9 Hz), 8.40-8.53 (1H, m) .

[0599]

D) 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine--7-carboxylic acid

An 8N NaOH aq. (0.4 mL, 3.20 mmol) was added to a

solution of methyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxylate (200 mg, 0.61 mmol) in EtOH (2 mL) and THF (2 mL) at room temperature. The mixture was stirred at room temperature under N ₂ for 2 h. Then, it was warmed up to 50 °C and stirred at 60 °C under N ₂ for 1 h. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (140 mg, 0.445 mmol, 73.1%) as white solids.

MS (ESI+), found 315.1 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.28 (3H, s) , 3.41-3.49 (3H, m) ,

4.17-4.25 (2H, m) , 4.43-4.56 (2H, m) , 4.88-5.04 (2H, m) , 7.12- 7.18 (1H, m) , 7.23-7.30 (2H, m) , 7.30-7.33 (1H, m) , 7.34-7.39 (1H, m) , 8.22-8.27 (1H, m) .

[0600]

E) 4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxamide

4- (Aminomethyl ) benzenesulfonamide hydrochloride (26.6 mg, 0.12 mmol), DIPEA (0.042 mL, 0.2.4 mmol) and HATU (45.4 mg, 0.12 mmol) were added to a solution of 4- (2- (methoxymethyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (25 mg, 0.08 mmol) in DMF(dry) (2 mL) at room temperature. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was quenched with water at room temperature and

extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (21 mg, 0.044 mmol, 54.7%) as white solids. ¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.29 (3H, s) , 3.39-3.50 (2H, m) , 4.15-4.26 (2H, m) , 4.45-4.53 (4H, m) , 4.92 (2H, s), 7.12-7.18

(1H, m) , 7.23-7.32 (4H, m) , 7.34-7.40 (1H, m) , 7.43-7.50 (3H, m). , 7.77 (2H, d, J = 8,5 Hz), 8.25 (1H, d, J = 1.9 Hz), 8.85

(1H, s) .

[0601]

Example 14

N- ( (5- (ethylsulfonyl) pyridin-2-yl ) methyl ) -4- (2-

(methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide hydrochloride

A) 5- (ethylsulfonyl) pyridine-2-carbonitrile

A mixture of 5-bromopicolinonitrile (14.7 g, 80.33 mmol), sodium ethanesulfinate (13.3 g, 114.54 mmol) and DMSO (100 rtiL) was stirred at 100 °C under nitrogen atmosphere for 20 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (7.74 g, 39.4 mmol, 49.1%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.14 (3H, t, J = 7.4 Hz), 3.51 (2H, q, J = 7.2 Hz), 8.36 (1H, dd, J = 8.3, 0.8 Hz), 8.56 (1H, dd, J = 8.1, 2.5 Hz), 9.20 (1H, dd, J = 2.3, 0.8 Hz).

[0602]

B) 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine hydrochloride

A mixture of 5- (ethylsulfonyl ) pyridine-2-carbonitrile (8.86 g, 45.15 mmol), 6N HC1 aq. (15 mL, 90.00 mmol), 10% Pd on carbon (50% wet, 2.39 g, 2.25 mmol) and MeOH (150 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room

temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The - - solid was suspended in EtOH, collected by filtration and dried in vacuo to give the title compound (9.65 g, 40.8 mmol, 90%) as white solids.

MS (ESI+), found 201.3 (M-HC1+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.13 (3H, t, J = 7.4 Hz), 3.46 (2H, q, J = 7.6 Hz), 4.35 (2H, brs), 7.80 (1H, d, J = 8.3 Hz), 8.38 (1H, dd, J = 8.3, 2.3 Hz), 8.57 (3H, brs), 9.05 (1H, d, J = 1.9 Hz) . - . .

[0603]

C) N- ( (5- (ethylsulfonyl) pyridin-2-yl)methyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide hydrochloride

To a solution of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-earboxylic acid (50 mg, 0.16 mmol) , 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine

hydrochloride (37.7 mg, 0.16 mmol)- in DMF (2 mL) were added HATU (72.6 mg, 0.19 mmol) and DIPEA (0.083 mL, 0.48 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at room

temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) . 4M HC1 in EtOAc (0.1 mL, 0.40 mmol) was added to the residue in MeOH (4.000 mL) at 0°C. Et ₂ 0 (abt. 10 mL) was added dropwise to the mixture and the precipitate was collected by filtration. The solid was washed with Et ₂ 0 and dried in vacuo to give the title compound (35.0 mg, 0.066 mmol, 41.3%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.05-1.18 (3H, m) , 3.29 (3H, s) , 3.32-3.53 (4H, m) , 4.23 (2H, t, J = 4.3 Hz), 4.49 (2H, s) , 4.58-5.15 (5H, m) , 7.11-7.21 (1H, m) , 7.24-7.32 (2H, m) , 7.34- 7.42 (1H, m) , 7.49-7.61 (2H, m) , 8.20-8.31 (2H, m) , 8.95 (1H, d, J = 1.9 Hz), 9.08 (1H, t, J = 5.9 Hz).

[0604]

Example 15

4- (2- (methoxymethyl) benzyl) -N- (4- (methylsulfamoyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

A) 4- (benzylsulfanyl) benzonitrile

Pd2(dba) ₃ (0.302 g, 0.33 mraol) was added to a mixture of 4-bromobenzonitrile (3 g, .16.48 mmol) , phenylmethanethiol (2.252 g, 18.13 mmol), XANTPHOS (0.381 g, 0.66 mmol) and DIPEA (5.76 mL, 32.96 mmol) in toluene (30 mL) at room temperature. The mixture was stirred at 1.00 °C under Ar overnight. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give yellow solids. The solid was washed with hexane-IPE and dried in vacuo to give the title compound (3.18 g, 14.11 mmol, 86%) as pale yellow solids.

MS (ESI-), found 224.0 (M-H)

λη NMR (300 MHz, CDC1 ₃ ) 5:4.20 (2H, s) , 7.25-7.38 (7H, m) , 7.50 (2H, d, J = 7.6 Hz) .

[0605]

B) 4-cyanobenzenesulfonyl chloride

NCS (1.778 g, 13.32 mmol) was added to a suspension of 4- (benzylsulfanyl) benzonitrile (1 g, 4.44 mmol) in AcOH (10 mL) - water (3.5 mL) at 0°C. The mixture was stirred at room

temperature for 2 h. The mixture was diluted with EtOAc and washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 20% EtOAc in hexane) to give white solids. The solids were washed with hexane and dried in vacuo to give the title compound (0.701 g, 3.48 mmol, 78%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:7.91-7.97 (2H, m) , 8.15-8.21 (2H, m) .

[0606]

C) 4-cyano-N-methylbenzenesulfonamide

A methylamine-methanol solution (1348 mg, 17.36 mmol) was added to a solution of 4-cyanobenzenesulfonyl chloride (700 mg, 3.47 mmol) in THF (30 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and neutralized with IN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO ₄ and concentrated in vacuo to give the title compound (660 mg, 3.36 mmol, 97%) as off-white solids.

MS (ESI-), found 195.0 (M-H)

λΗ NMR (300 MHz, CDC1 ₃ ) 5:2.72 (3H, d, J = 5.3 Hz), 4.47 (1H, d,J = 4.5 Hz), 7.81-7.86 (2H, m) , .7.95-8.01 (2H, m) .

[0607]

D) 4- (aminomethyl) -N-methylbenzenesulfonamide

CoCl ₂ (265 mg, 2.04 mmol) was added to a solution of 4- cyano-N-methylbenzenesulfonamide (200 mg, 1.02 mmol) in MeOH (10 mL) at 0°C. After stirring at 0°C for 5 min, NaBH ₄ (386 mg, 10.19 mmol) was added to the mixture and stirred at room

temperature overnight. The mixture was quenched with 2N HC1 aq. at room temperature and stirred for 10 min. The mixture was neutralized with 25% aq. ammonia and concentrated in vacuo.

The residue was extracted with EtOAc twice. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (115 mg, 0.574 mmol, 56.3%) as white amorphous solids.

MS (ESI+), found 201.3 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.89 (2H, brs), 2.39 (3H, s) , 3.79 (2H, s), 7.00-7.56 (3H, m) , 7.67-7.73 (2H, m) .

[0608]

E) 4- (2- (methoxymethyl ) benzyl) -N- (4- (methylsulfamoyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), 4-

(aminomethyl ) -N-methylbenzenesulfonamide (22.93 mg, 0.11 mmol) and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% -90% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title

compound (41.0 mg, 0.083 mmol, 87%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:2.39 (3H, d, J = 5.3 Hz), 3.29 (3H, s), 3.44 (2H, brs), 4.20 (2H, brs), 4.45-4.5.5 (4H, m) , 4.92 (2H, . s), 7.11-7.19 (1H, m) , 7.26 (2H, dd, J = 5.3, 3-8 Hz), 7.34- 7.53 (5H, m) , 7.73 (2H, d, J = 8.3 Hz), 8.26 (1H, d, J = 1.9 Hz), 8.86 (1H, t, J = 5.9 Hz).

[0609]

Example 16

N- ( 3-fluoro-4-sulfamoylbenzyl ) -4- (2- (methoxymethyl ) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

A) 4- (benzylsulfanyl) -3-fluorobenzonitrile

Pd ₂ (dba) ₃ (0.275 g, 0.30 mmol) was added to a mixture of 4-bromo-3-fluorobenzonitrile (3 g, 15.00 mmol),

phenylmethanethiol (2.049 g, 16.50 mmol), XANTPHOS (0.347 g, 0.60 mmol) and DIPEA (5.24 mL, 30.00 mmol) in toluene (30 mL) at room temperature. The mixture was stirred at 100 °C under Ar overnight. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give the title compound (3.82 g, 15.70 mmol, 105%) as yellow solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:4.20 (2H, s) , 7.27-7.36 (8H, m) .

[0610]

B) 4-cyano-2-fluorobenzenesulfonyl chloride

NCS (3.29 g, 24.66 mmol) was added to a suspension of 4- (benzylsulfanyl) -3-fluorobenzonitrile (2 g, 8.22 mmol) in AcOH (20 mL) - water (7 mL) at 0°C. The mixture -was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 30% EtOAc in hexane) to give the title compound (1.720 g, 7.83 mmol, 95%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:7.64-7.74 (2H, m) , 8.13 (1H, dd, J = 8.1, 7.0 Hz) .

[0611]

C) 4-cyano-2-fluorobenzenesulfonamide

An ammonia solution in MeOH (2.76 mL, 19.35 mmol) was added to a solution of 4-cyano-2-fluorobenzenesulfonyl chloride (850 mg, 3.87 mmol) in THF (30 mL) at-0°C. The mixture was stirred at room temperature for 2 ti. The mixture was diluted with water, neutralized with IN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (700 mg, 3.50 mmol, 90%) as pale yellow solids.

MS (ESI-), found 199.0 (M-H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:7.86-8.01 (4H, m) , 8.12 (1H, dd, J = 10.0, 1.3 Hz) .

[0612]

D) 4- (aminomethyl) -2-fluorobenzenesulfonamide hydrochloride

A mixture of 4-cyano-2-fluorobenzenesulfonamide (200 mg, 1.00 mmol), 10% Pd-C (50% wet, 100 mg, 0.94 mmol) in MeOH (8 mL) and cone. HC1 (80 μΐ, 0.96 mmol) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (230 mg, 0.956 mmol, 96%) as off-white solid as crude product.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:4.11 (2H, d, J = 4.9 Hz), 7.46 (1H, dd, J = 8.3, 1.5 Hz), 7.59-7.62 (1H, m) , 7.70-7.85 (3H, m) , 8.58 (3H, brs) .

[0613]

E) N- (3-fluoro-4-sulfamoylbenzyl) -4- (2- (methoxymethyl ) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxamide

HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), crude 4- (aminomethyl) -2-fluorobenzenesulfonamide hydrochloride (25.3 mg, 0.10 initial) .and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% -100% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title compound (33.0 mg, 0.066 mmol, 69.1%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ:3.29 (3H, s), 3.44 (2H, t, J = 4.3 Hz), 4.21 (2H, t, J = 4.5 Hz), 4.45-4.52 (4H, m) , 4.92 (2H, s) , 7.12-7.18 (1H, m) , 7.23-7.39 (5H, m) , 7.45 (1H, d, J = 1.9 Hz), 7.60 (2H, s) , 7.74 (1H, t, J = 7.9 Hz), 8.25 (1H, d, J = 2.3 Hz) , 8.86 (1H, t, J = 5.1 Hz) .

[0614]

Example 17

N- (3-fluoro-4- (methylsulfamoyl ) benzyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide

A) 4-cyano-2-fluoro-N-methylbenzenesulfonamide

A methylamine in MeOH (1503 mg, 19.35 mmol) was added to a solution of 4-cyano-2-fluorobenzene-l-sulfonyl chloride (850 mg, 3.87 mmol) in THF (30 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and neutralized withlN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% -45% EtOAc in hexane) to give the title compound (550 mg, 2.57 mmol, 66.3%) as off-white solids.

MS (ESI-), found 213.0 (M-H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:2.54 (3H, s), 7.88-7.97 (2H, m) , 8.05 (1H, brs), 8.15 (1H, d, J = 9.9 Hz).

[0615]

B) 4- (aminomethyl) -2-fluoro-N-methylbenzenesulfonamide CoCl ₂ (121 mg, 0.93 mmol) was added to a solution of 4- cyano-2-fluoro-N-methylbenzenesulfonamide (100 mg, 0.47 mmol) in MeOH (5 mL) at 0°C. After stirring at 0°C for 5 min, NaBH ₄ (177 mg, 4.67 mmol) was added to the mixture and stirred at room temperature overnight. The mixture was quenched with 2N HC1 aq. at room temperature and stirred for 10 min. The mixture was neutralized with 25% aq. ammonia and concentrated in vacuo. The residue was extracted with EtOAc twice. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 15% MeOH in EtOAc) to give the title compound (73.0 mg, 0.334 mmol, 71.7%) as white amorphous solids.

MS (ESI+), found 219. 3 (M+H)

¹ R NMR (300 MHz, DMSO-d ₆ ) 5:1.60-2.40 (2H, br) , 2.45-2.47 (3H, s), 3.78 (2H, s), 7.29-7.35 (1H, m) , 7;38-7.43 (1H, m) , 7.68 (1H, t, J = 7.7 Hz) . (An exchangeable proton was omitted)

[0616]

C) N- (3-fluoro-4- (methylsulfamoyl ) benzyl ) -4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide

HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-p ^' yrido [3,2- b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), 4- (aminomethyl) -2-fluoro-N-methylbenzenesulfonamide (25.00 mg, 0.11 mmol) and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give a colorless oil. The oil was triturated with IPE, and dried in vacuo to give the title compound (19.00 mg, 0.037 mmol, 38.7%) as off-white solids .

¹ H NMR (300 MHz, DMS0-d ₆ ) 5:2.48 (3H, s) , 3.29 (3H, s), 3.45 (2H, brs), 4.21 (2H, brs) , 4.45-4.54 (4H, m) , 4.92 (2H, s) , 7.16 (1H, d, J = 4.4 Hz), 7.24-7.39 (5H, m) , 7.45 (1H, d, J = 1.9 Hz), 7.63-7.76 (2H, m) , 8.26 (1H, d, J = 1.9 Hz), 8.87 (1H, s) .

[0617]

Example 18

4- ( 5-fluoro-2- (methoxymethyl ) benzyl ) -N- ( 4-sulfamoylbenzyl ) -3 , 4- dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7-carboxamide

A) tert-butyl 7-bromo-2 , 3-dihydro-4H-pyrido [3, 2--b] [ 1 , 4 ] oxazine- 4-carboxylate

To a solution of 7-bromo^3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine (1.93 g, 8.97 mmol) in THF(dry) (40 mL) was added LiHMDS (8.28 mL, 10.77 mmol) at 0°C. Boc ₂ 0 (2.500 mL, 10.77 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (2.60 g, 8.25 mmol, 92%) as a pale yellow oil.

MS (ESI+), found 258.9 (M-tBu+2H)

[0618]

B) methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7- carboxylate

To a solution of tert-butyl 7-bromo-2 , 3-dihydro-4H- pyrido [3, 2-b] [1, 4] oxazine-4-carboxylate (2.6 g, 8.25 mmol), TEA (2.300 mL, 16.50 mmol) in DMF (25 mL) /MeOH (5 mL) was added PdCl ₂ (dppf) (0.302 g, 0.41 mmol) at room temperature. The mixture was stirred at 100°C under CO (0.7 MPa) for 5 h. The mixture was quenched with water at- room temperature and

extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 30% EtOAc in hexane) to give 4-tert-butyl 7- methyl 2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-4 , 7 ( 3H) -dicarboxylate

(0.370 g, 1.257 mmol, 15.24%) as light brown solids and the title compound (1.100 g, 5.66 mmol, 68.7%) as light brown solids.

MS (ESI+), found 195.1 (M+H)

¹ R NMR (300 MHz, CDC1 ₃ ) 5:3.62 (2H, td, J = 4.5, 2.3 Hz), 3.86 (3H, s), 4.15-4.28 (2H, m) , 5.47 (1H, brs) , 7.52 (1H, d, J = 1.5 Hz), 8.37 (1H, d, J = 1.9 Hz).

[0619]

C) (2-bromo-4-fluorophenyl) methanol

To a solution of 2-bromo-4-fluorobenzoic acid (3 g, 13.70 mmol) in THF(dry) (60 mL) was added 1M Borane-tetrahydrofuran complex in THF (19.18 mL, 19.18 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 2 h. The mixture was neutralized with IN HCl at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound as a colorless oil.

[0620]

D) 2-bromo-4-fluoro-1- (methoxymethyl ) benzene

To a mixture of (2-bromo-4-fluorophenyl) methanol (1.80 g, 8.78 mmol) and DMF (30 mL) was added NaH (60% in oil, 428 mg, 10.70 mmol) at room temperature. After being stirred at room temperature for 5 min, Mel (0.82 mL, 13.11 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (1.620 g, 7.40 mmol, 84%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.46 (3H, s) , 4.48 (2H, s) , 7.04 (1H, td, J = 8.3, 2.6 Hz), 7.30 (1H, dd, J = 8.3, 2.6 Hz), 7.43 (1H, dd, J = 8.5, 6.2 Hz) . [0621]

E) 5-fluoro-2- (methoxymethyl) benzaldehyde

To a mixture of 2-bromo-4-fluoro-1- (methoxymethyl ) benzene (1.62 g, 7.40 mmol) and THF (30 mL) was added 1.6 M n-BuLi in hexane (5.6 mL, 8.96 mmol) at -78°C. After being stirred at - 78°C for 1 h, DMF (1.0 mL, 12.91 mmol) was added to the mixture. After being stirred at -78 °C for 2 h, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column .chromatography (silica gel, eluted with 1%- 10% EtOAc in hexane) to give the title compound (1.000 g, 5.95 mmol, 80%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) δ:3.46 (3H, s),.4.80 (2H, s) , 7.26-7.33 (1H, m) , 7.53-7.62 (2H, m) , 10.21 (1H, d, J = 1.5 Hz).

[0622]

F) ( 5-fluoro-2- (methoxymethyl ) phenyl ) methanol

To a mixture of 5-fluoro-2- (-methoxymethyl ) benzaldehyde (1.00 g, 5.95 mmol) and MeOH (10 mL) was added NaBH ₄ (408 mg, 10.78 mmol) at 0°C. After being stirred at room temperature for 1 h, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was subjected to the next reaction without further purification.

[0623]

G) 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene

To a mixture of (5-fluoro-2- (methoxymethyl ) phenyl ) methanol (1.01 g, 5.93 mmol) and THF (10 mL) was added S0C1 ₂ (2.0 mL, 27.40 mmol) at 0°C. After being stirred at 50 °C for 2 h, the mixture was concentrated in vacuo to give the title compound (1.280 g, 6.79 mmol, 114%) as an orange oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.35-3.42 (3H, m) , 4.42-4.70 (4H, m) , 6.90-7.05 (1H, m) , 7.11-7.18 (1H, m) , 7.28-7.36 (1H, m) .

[0624]

H) 4- (5-fluoro-2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [ 1, 4 ] oxazin.e-7-carboxylic acid

To a mixture of 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene (107 mg, 0.57 mmol) and DMF (3 mL) was added NaH (60% in oil, 17 mg, 0.43 mmol) . After being stirred at room temperature for 5 min, 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene (107 mg, 0.57 mmol) was added to the mixture. After being stirred at room temperature for 2 h, 2 M NaOH aq. (0.36 mL, 0.72 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was acidified with IN HC1 aq. and extracted with EtOAc. The

organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to the next reaction without further purification.

[0625]

I ) 4- ( 5-fluoro-2- (methoxymethyl ) benzyl ) -N- ( 4-sulfamoylbenzyl ) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

To a mixture of 4- (5-fluoro-2- (methoxymethyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (84 mg, 0.25 mmol), [4- (aminomethyl) benzenesulfonamide hydrochloride (70 mg, 0.31 mmol), HATU (123 mg, 0.32 mmol) and DMF (3 mL) was added DIPEA (0.13 mL, 0.74 mmol). After being stirred at room temperature overnight, the reaction mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 10.0% EtOAc in hexane) and then crystallized from EtOH-hexane to give the title compound (43.0 mg, 0.086 mmol, 34.0%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ:3.28 (3H, s) , 3.49 (2H, t, J = 4.3 Hz) , 4.23 (2H, t, J = 4.3 Hz), 4.44-4.53 (4H, m) , 4.90 (2H, s) , 6.93 (1H, dd, J = 10.2, 3.0 Hz), 7.07 (lH, td, J = 8.5, 2.6 Hz), 7.29 (2H, s), 7.37-7.50 (4H, m) , 7.76 (2H, d, J = 8.3 Hz), 8.24 (1H, d, J = 2.3 Hz), 8.86 (1H, t, J = 6.0 Hz).

[0626]

Example 19 4- ( ( 5-fluoro-3- (methoxymethyl ) p.yridin-2-yl ) methyl) -N- (4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7^ carboxamide

A) 2-chloro-5-fluoronicotinic acid

A mixture of Ph ₃ P (1.874 g, 7.14 mmol) , Pd(OAc) ₂ (0.802 g,

3.57 mmol) and TEA (59.7 mL, 428.59 mmol) in DMF(dry) (80 mL) was stirred at room temperature - under Ar for 20 min. To. the mixture was added formic acid (2.74 mL, 71.43 mmol), and the mixture was stirred at room temperature under Ar for 5 min. To the mixture was added 2 , 6-dichloro-5-fluoronicotinic acid (15 g, 71.43 mmol) and the mixture was stirred at 100 °C under Ar overnight. The mixture was cooled to at 0°C, added water (150 mL) , and stirred for 20 min. The mixture was filtrated through a pad of celite, that was rinsed with water. The filtrate was basified to pH 9 with 8N NaOH and washed twice with EtOAc. 35% HC1 was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (5 times) .

The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residual DMF was removed by azetropic evaporation with toluene. The precipitate was collected by filtration and washed with 50% EtOAc/Hexane to. give the title compound (8.08 g, 46.0 mmol, 64.4%) as yellow powder.

MS (ESI-), found 174.2 (M-H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:8.21 (1H, dd, J = 8.3, 3.0 Hz), 8.63 (1H, d, J = 3.0 Hz). (A C0 ₂ H peak was omitted)

[0627]

B) (2-chloro-5-fluoropyridin-3-yl) methanol

CDI (1.293 g, 7.98 mmol) was added to a solution of 2- chloro-5-fluoronicotinic acid (1 g, 5.70 mmol) in THF (23 mL) at room temperature. After stirring at room temperature for lh, the mixture was added to a solution of NaBH ₄ (0.647 g, 17.09 mmol) in water (23.00 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was

diluted with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.620 g, 3.84 mmol, 67.4%) as white solids.

MS (ESI+) , found 162.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:2.08 (1H, t, J = 5.9 Hz), 4.78 (2H, d, J = 5.7 Hz), 7.67-7.73 (1H, m) , 8.18 (1H, d, J = 3.0 Hz).

[0628]

C) 2-chloro-5-fluoro-3- (methoxymethyl) pyridine

NaH (60% in oil, 230 mg, 5.76 mmol) was added to a

solution of (2-chloro-5-fluoropyridin-3-yl ) methanol (620 mg, 3.84 mmol) in THF (dry) (8 mL) at 0°C. After stirring at room temperature for lh, Mel (599 mg, 4.22 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc and 0.5N NaOH aq. at room temperature. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title

compound (530 mg, 3.02 mmol, 79%) as a colorless oil.

MS (ESI+), found 176.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.52 (3H, s), 4.50 (2H, s), 7.59-7.65 (1H, m) , 8.17 (1H, d, J = 3.0 Hz) .

[0629]

D) methyl 5-fluoro-3- (methoxymethyl ) pyridine-2-carboxylate

A mixture of 2-chloro-5-fluoro-3- (methoxymethyl ) pyridine (100 mg, 0.57 mmol), PdCl ₂ (dppf) (83 mg, 0.11 mmol) and TEA (0.238 mL, 1.71 mmol) in MeOH (4 mL) and DMF (0.5 mL) was stirred under CO atmosphere (0.7 MPa) at 80°C for 6h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted -with 10% - 50% EtOAc in hexane) to give the title compound (107 mg, 0.537 mmol, 94%) as white solids.

MS (ESI+), found 200.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.53 (3H, s) , 3.99 (3H, s) , 4.88 (2H, s), 7.82-7.88 (lH, m) , 8.45 (1H, d, J = 2.6 _. Hz).

[0630]

E) (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methanol

LiBH ₄ (22.97 mg, 1.05 mmol) - was added to a solution of methyl 5-fluoro-3- (methoxymethyl) pyridine-2-carboxylate (105 mg, 0.53 mmol) in THF (3 mL) at room temperature. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was quenched with brine at 0°C and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SCO ₄ and concentrated in vacuo to give the title compound (80 mg, 0.467 mmol, 89%) as a pale yellow oil. .

MS (ESI+), found 172.4 (M+H)

¹ H NMR (300 MHz, CDCI ₃ ) δ:3.45 (3H, s) , 4.00-4.40 (1H, br) , 4.43 (2H, s), 4.69 (2H, s) , 7.51 (1H, dd, J = 8.7, 2.6 Hz), 8.33 (1H, d, J .= 2.6 Hz) .

[0631]

F) (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methyl

methanesulfonate

MsCl (0.040 mL, 0.51 mmol) was added to a solution of (5- fluoro-3- (methoxymethyl) pyridin-2-yl) methanol (80 mg, 0.47 mmol) and TEA (0.072 mL, 0.51 mmol) in THF (3 mL) at 0°C. The mixture was stirred at room temperature under dry atmosphere (with a CaCl ₂ tube) for 3 h. The mixture was poured into water at room temperature and extracted twice with EtOAc. The

combined organic layers were washed with brine, dried over

MgSO ₄ ^' and concentrated in vacuo to give the title compound

(60.0 mg, 0.241 mmol, 51.5%) as a purple oil.

MS (ESI+), found 250.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.06 (3H, s) , 3.48 (3H, s) , 4.58 (2H, s), 5.36 (2H, s), 7.56 (1H, dd, J = 8.7, 2.6 Hz), 8.40 (1H, d, J = 2.6 Hz).

[0632]

G) methyl 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl ) methyl ) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxylate

NaH (60% in oil, 16.05 mg, 0.40 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxylate (39.0 mg, 0.20 mmol) in DMF(dry) (2 mL) at 0°C.

After stirring at room temperature for 10 min, (5-fluoro-3-

(methoxymethyl) pyridin-2-yl ) methyl methanesulfonate (60 mg, 0.24 mmol) was added the mixture at room temperature. The mixture was stirred at room temperature under dry atmosphere

(with a CaCl ₂ tube) for 3 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 30% - 50% EtOAc in hexane) to give the title compound (55.0 mg, 0.158 mmol, 79%) as white solids.

MS (ESI+), found 348.2 (M+H) ,

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.42 (3H, s) , 3.59-3.66 (2H, m) , 3.85 (3H, s), 4.11-4.20 (2H, m) , 4.61 (2H, s) , 5.00 (2H, s) , 7.46- 7.51 (2H, m) , 8.29 (1H, d, J = 2.6 Hz), 8.41 (1H, d, J = 1.9 Hz) .

[0633]

H) 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl)methyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid

A mixture of methyl 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine-7-carboxylate (55 mg, 0.15 mmol) and 2M NaOH aq. (0.761 mL, 1.52 mmol) in MeOH (3 mL) was stirred at 50°C for 2h. The mixture was slightly acidified (pH5) by IN HC1 aq. at 0°C and diluted with water. MeOH was removed by evaporation and precipitate was collected by filtration, washed with water, . dried in vacuo to give the title compound (33.0 mg, 0.099 mmol, 65.0%) as white powder.

MS (ESI+), found 334.2 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.36 (3H, s) , 3.62 (2H, t, J = 4.5 Hz), 4.21 (2H, t, J = 4.5 Hz), 4.60 (2H, s), 4.97 (2H, s) , 7.27 (1H, d, J = 1.9 Hz), 7.67 (1H, dd, J = 9.4, 3.0 Hz), 8.17 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 3.0 Hz), 12.20-12.70 (1H, br) .

[0634] I ) 4- ( ( 5-fluoro-3- (methoxymethyl) pyri.din-2-yl ) methyl ) -N- ( 4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

HATU (47.9 mg, 0.13 mmol) was added to a mixture of 4- ( ( 5-fluoro-3- (methoxymethyl ) pyridin-2-yl ) methyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (20.04 mg, 0.09 mmol) and DIPEA (51.2 mg, 0.40 mmol) in DMF(dry) (1 mL) at room temperature. The mixture, was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% -10% MeOH in EtOAc) to give white solids. The solid was washed with EtOAc-IPE, and dried in vacuo to give the title compound (27.0 mg, 0.054 mmol, 59.8%) as off-white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.37 (3H, s), 3.62 (2H, t, J = 4.3 Hz), 4.21 (2H, t, J = 4.3 Hz), 4.48 (2H, d, J = 5.7 Hz), 4.61 . (2H, s), 4.94 (2H, s) , 7.29 (2H, s) , 7.39-7.47 (3H, m) , 7.64- 7.78 (3H, m) , 8.18 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 3.0 Hz) , 8.81 (1H, t, J = 5.8 Hz) .

[0635]

Example 21

4- (2 , 3-difluoro-6- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

A) (2-bromo-3, 4-difluorophenyl ) methanol

CDI (0.958 g, 5.91 mmol) was added to a solution of 2- bromo-3, 4-difluorobenzoic acid (1 g, 4.22 mmol) in THF (23 mL) at room temperature. After stirring at room temperature for lh, the mixture was added to a solution of NaBH ₄ (0.479 g, 12.66 mmol) in water (23.00 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was

diluted with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was .purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.820 g, 3.68 mmol, 87%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.98 (1H, t, J = 6.2 Hz), 4.74 (2H, d, J = 6.4 Hz), 7.12-7.30 (2H, m) .

[0636]

B) 2-bromo-3, 4-difluoro-1- (methoxymethyl ) benzene

NaH (60% in oil, 221 mg, 5.52 mmol) was added to a

solution of (2-bromo-3, 4-difluorophenyl) methanol (820 mg, 3.68 mmol) in THF(dry) (10 mL) at 0°C. After stirring at 0°C for 30 min, Mel (1044 mg, 7.35 mmol) was added the mixture at 0°C.

The mixture was stirred at room temperature under N ₂ for 3 days . The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column, chromatography (silica gel, eluted with 0% - 10% EtOAc in hexane) to give the title

compound (730 mg, 3.08 mmol, 84%) as a pale yellow oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.46 (3H, s), 4.49 (2H, s) , 7.10-7.26 (2H, m) .

[0637]

C) 2, 3-difluoro-6- (methoxymethyl) benzaldehyde

1.3 M n-BuLi in hexane (2.375 mL, 3.09 mmol) was added to a solution of 2-bromo-3 , 4-difluoro-1- (methoxymethyl ) benzene (610 mg, 2.57 mmol) in THF(dry) (12 mL) at -78°C. After

stirring at -78°C under Ar for 1 h, DMF (0.299 mL, 3.86 mmol) was added to the mixture and stirred at -78 °C under Ar for 2 h. The mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (260 mg, 1.397 mmol, 54.3%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.49 (3H, s) , 4.77 (2H, s) , 7.36-7.49 (2H, m) , .10.48 (1H, s) .

[0638]

D) (2, 3-difluoro-6- (methoxymethyl) phenyl) methanol

NaBH ₄ (106 mg, 2.79 mmol) was added to a solution of 2,3- difluoro-6- (methoxymethyl) benzaldehyde (260 mg, 1.40 mmol) in MeOH (3 mL) at 0°C. The mixture was stirred at room

temperature for 2 h. The mixture was quenched with sat. NH ₄ C1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (210 mg, 1.116 mmol, 80%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.15 (1H, t, J = 6.6 Hz), 3.42 (3H, s), 4.53 (2H, s), 4.74 (2H, dd, J = 6.4, 2.3 Hz), 7.03-7.13 (2H, m) .

[0639]

E) 2- (chloromethyl) -3, 4-difluoro-1- (methoxymethyl) benzene

S0C1 ₂ (0.5 mL, 6.85 mmol) was added to a solution of

(2, 3-difluoro-6- (methoxymethyl) phenyl) methanol (100 mg, 0.53 mmol) at 0°C. The mixture was stirred at room temperature under dry atmosphere (with a Si0 ₂ tube) for 3 h. The mixture was concentrated in vacuo to give the title compound (110 mg, 0.532 mmol, 100%) as a pale yellow oil. This product was subjected to the next reaction without further purification.

[0640]

F) 4- (2, 3-difluoro-6- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid

NaH (60% in oil, 35.5 mg, 0.89 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxylate (86 mg, 0.44 mmol) in DMF(dry) (2 mL) at 0°C.

After stirring at room temperature for 10 min, 2-

( chloromethyl) -3, 4-difluoro-1- (methoxymethyl) benzene (110 mg, 0.53 mmol) was added the mixture at room temperature. The mixture was stirred at room temperature -under dry atmosphere (with a CaCl ₂ tube) for 3 h. To the mixture was added 2N NaOH (1.109 mL, 2.22 mmol) and the mixture was stirred at room temperature for 3 days. The mixture was acidified by IN HC1 aq. at 0°C and concentrated in vacuo. The residue was washed with water and IPE, dried in vacuo to give the title compound (72.0 mg, 0.206 mmol, 46.3%) as light brown solids.

MS (ESI+), found 351.2 (M+H)

[0641]

G) 4- (2, 3-difluoro-6- (methoxymethyl ) benzyl) -N- (4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

HATU (109 mg, 0.29 mmol) was added to a mixture of 4-

(2, 3-difluoro-6- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7^carboxylic acid (72 mg, 0.21 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (45.8 mg, 0.21 mmol) and DIPEA (117 mg, 0.90 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give white solids.

The solid was washed with EtOAc-IPE, and dried in vacuo to give the title compound (47.0 mg, 0.091 mmol, 44.1%) as white powder. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ : 3.24 (3H, s), 3.33-3.39 (2H, m) , 4.13 (2H, t, J = 4.3 Hz), 4.46-4.55 (4H, m) , 4.95 (2H, s) ,

1.22-1. AS (7H, m) , 7.77 (2H, d, J = 8.2 Hz), 8.31 (1H, d, J = ^' 1.9 Hz), 8.88 (1H, t, J = 5.7 Hz) .

[0642]

Example 22

4- (2- (methoxymethyl) benzyl) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxamide

A) 1- (chloromethyl) -2- (methoxymethyl) benzene

NaOMe (2.037 g, 37.70 mmol) was added to a solution of 1,2-bis (chloromethyl) benzene (6.6 g, 37.70 mmol) in MeOH (120 mL) at room temperature. The mixture was stirred at 80 °C under N ₂ for 10 h and at 60 °C overnight. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 3% - 5% EtOAc in

hexane) to give the title compound (1.520 g, 8.91 mmol, 23.63%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.42 (3H, s), 4.60 (2H, s) , 4.71 (2H, s) , 7.25-7.41 (4H, m) .

[0643]

B) 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [ 1 , 4 ] oxazine-7-carboxylic acid

To a mixture of 1- (chloromethyl) -2- (methoxymethyl) benzene (629 mg, 3.69 mmol) and DMF (15 iriL) was added NaH (217 mg, 5.43 mmol) at 0°G. After being stirred at 0°C for 5 min, 1- ( chloromethyl ) -2- (methoxymethyl ) benzene (629 mg, 3.69 mmol) was added to the mixture. After being stirred at 0°C for 5 h, 2 M NaOH aq. (4.0 mL, 8.00 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was extracted with water. The aqueous layer was acidified with IN HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (629 mg, 2.002 mmol, 73.3%) as a brown oil. MS (ESI+), found 315.3 (M+H)

[0644]

C) 4- (2- (methoxymethyl) benzyl ) -N- ( ( 1- (methylsulfonyl ) piperidin- 4-yl)methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7- carboxamide

To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (101 mg, 0.17 mmol) , (1- (methylsulfonyl) piperidin-4-yl ) methanamine

hydrochloride (51 mg, 0.22 mmol), HATU (83 mg, 0.22 mmol) and DMF (3 mL) was added DIPEA (90 μΐ,, 0.52 mmol). After being stirred at room temperature for 4 h, the mixture was quenched with sat. NH ₄ CI aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ S04 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from IPE-hexane to give the title compound (30.0 mg, 0.061 mmol, 36.7%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.79-1.93 (5H, m) , 2.59-2.73 (2H, m) , 2.77 (3H, s), 3.30-3.38 (5H, m) , 3.38-3.45 (2H, m) , 3.75-3.88 (2H, m) , 4.13-4.20 (2H, m) , 4.49 (2H, s) , 5.00 (2H, s) , 6.03- 6.16 (1H, m) , 7.16-7.21 (1H, m) , 7.27-7.32 (2H, m) , 7.34-7.41 (2H, m) , 8.18 (1H, d, J = 1.9 Hz) .

[0645]

Example 23

4- (2- (methoxymethyl) benzyl) -N- ( (5- (methylsulfonyl ) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7- carboxamide

A) 5- (methylsulfonyl) pyridine-2-carbonitrile

A mixture of 5-bromopicolinonitrile (25 g, 136.61 mmol) and methanesulfinic acid, sodium salt (19.52 g, 191.25 mmol) in DMSO (200mL) was stirred at 100°C for 24h. The mixture was cooled to 50 °C and water (250 mL) was added to the mixture.

After stirring at 50 °C overnight, the precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (20.62 g, 113 mmol, 83%) as white crystals.

1H NMR (300 MHz, CDC1 ₃ ) 5:3.17 (3H, s) , 7.93 (1H, dd, J = 7.9, 0.8 Hz), 8.41 (1H, dd, J = 7.9, 2.3 Hz), 9.25 (1H, dd, J = 2.3, 0.8 Hz) .

[0646]

B) 1- (5- (methylsulfonyl)pyridin-2-yl)methanamine hydrochloride

A mixture of 5- (methylsulfonyl ) pyridine-2-carbonitrile (10 g, 54.88 mmol), 6N HC1 aq. (18.29 mL, 109.77 mmol) and 10% Pd-C (50% wet, 1 g, 9.40 mmol) in EtOH (100 mL) was

hydrogenated under middle pressure (0.45MPa) at room

temperature overnight. Water (10 mL) was added and the

catalyst was removed by filtration. The filtrate was

concentrated in vacuo to dryness. The solid was suspended in EtOH and collected by filtration, dried in vacuo to give the title compound (6.30 g, 28.3 mmol, 51.5%) as pale yellow powder. MS (ESI+), found 187.1 (M-HC1+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.37 (3H, s) , 4.33 (2H, q, J = 5.3 Hz), 7.81 (1H, d, J = 8.3 Hz), 8.41 (1H, dd, J = 8.1, 2.5 Hz), 8.70 (3H, brs) , 9.09 (1H, d, J = 1.9 Hz) .

[0647]

C) 4- (2- (methoxymethyl) benzyl) -N- ( (5- (methylsulfonyl ) pyridin-2- yl)methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

To a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (103 mg, 0.17 mmol ) , 1- ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine

hydrochloride (64 mg, 0.34 mmol), HATU (138 mg, 0.36 mmol) and DMF (3 mL) was added DIPEA (0.12 mL, 0.69 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc . The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (44.0 mg, 0.091 mmol, 53.5%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.11 (3H, s) , 3.35 (3H, s), 3.39-3.44 (2H, m) , 4.13-4.22 (2H, m) , 4.49 (2H, s) , 4.84 (2H, d, J = 5.3 Hz)-, 5.02 (2H, s), 7.12-7.23 (2H, m) , 7.27-7.30 (2H, m) , 7.34- 7.40 (1H, m) , 7.44 (1H, d, J = 1.9 Hz), 7.55 (1H, d, J = 8.7 Hz), 8.20 (1H, dd, J = 8.3, 2.3 Hz), 8.31 (1H, d, J = 2.3 Hz), 9.09 (1H, d, J = 1.5 Hz) .

[0648]

Example 25

1- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -2, 3-dihydro- lH-pyrido [2 , 3-b] [1, 4] oxazine-6-carboxamide

A) 6-bromo-2-methoxypyridin-3-amine

To a mixture of 2-methoxypyridin-3-amine (4.95 g, 39.87 mmol) and DMF (50 mL) was added NBS (7.98 g, 44.84 mmol) at 0°C. After being stirred at 0°C for 1 h, the mixture was quenched with sat. NH ₄ CI aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SCO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title

compound (4.41 g, 21.72 mmol, 54.5%) as brown solids.

MS (ESI+), found 203.0, 205.0 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.75 (2H, brs) , 3.98 (3H, s) , 6.76

(1H, d, J = 7.6 Hz), 6.87 (1H, d, J = 7.9 Hz).

[0649]

B) 3-amino-6-bromopyridin-2-ol

A mixture of 6-bromo-2-methoxypyridin-3-amine (442 mg,

2.18 mmol), 30% HBr/AcOH (5 mL, 25.50 mmol) and water (2 mL) was stirred at 80°C for 1 h. The mixture was diluted with

EtOAc and extracted with water. The organic layer was

neutralized with 8 N NaOH aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (299 mg, 1.582 mmol, 72.7%) as pale yellow solids.

MS (ESI+), found 189.0, 191.0 (M+H)

[0650]

C) 6-bromo-lH-pyrido [2, 3-b] [ 1 , 4 ] oxazin-2 ( 3H) -one

To a mixture of 3-amino-6-bromopyridin-2-ol (3.65 g,

19.31 mmol), TEA (3.5 mL, 25.11 mmol) and THF (50 mL) was added 2-bromoacetyl chloride (2.0 mL, 23.89 mmol). After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. To a mixture of the residue and DMF (50 mL) was added K ₂ GO ₃ (5.07 g, 36.68 mmol). After being stirred at 100°C for 1 h, the mixture was poured into sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (3.03 g, 13.23 mmol, 68.5%) .as white solids.

MS (ESI+), found 229.0, 230.9 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:4.81 (2H, s) , 7.15 (1H, d, J = 7.9 Hz), 7.23 (1H, d, J = 7.9 Hz), 10.94 (1H, s) .

[0651]

D) 6-bromo-2, 3-dihydro-lH-pyrido [2, 3-b] [l,4]oxazine

To a mixture of 6-bromo-lH-pyrido [2, 3-b] [1, 4] oxazin- 2(3H)-one (3.03 g, 13.23 mmol) and THF (50 mL) was added borane methylsulfide complex (3.0 mL, 31.63 mmol) under nitrogen atmosphere. After being stirred at 60 °C for 1 h, the mixture was quenched with MeOH. (50 mL) and stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexarie) to give the title compound (2.79 g, 12.97 mmol, 98%) as white solids.

MS (ESI+), found 215.2, 217.2 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.23-3.29 (2H, m) , 4.23-4.29 (2H, m) , 6.22 (1H, brs) , 6.85 (1H, d, J = 8.3 Hz), 6.92 (1H, d, J = 7.9 Hz) .

[0652]

E) tert-butyl 6-bromo-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine- 1-carboxylate

To a mixture of 6-bromo-2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4] oxazine (1.20 g, 5.58 mmol), Boc ₂ 0 (2.0 mL, 8.61 mmol) and THF (20 mL) was added LiHMDS (5.5 mL, 7.15 mmol) at 0°C. After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title compound (1.280 g, 4.06 mmol, 72.8%)- as white solids.

MS (ESI+), found 315.2, 317.1 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.54 (9H, s) , 3.86 (2H, dd, J = 5.3, 4.2 Hz), 4.38 (2H, dd, J = 5.3, 4.2 Hz), 7.07 (1H, d, J = 8.3 Hz) , 8.11 (1H, brs) .

[0653]

F) 1-tert-butyl 6-methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine-1, 6-dicarboxylate

To a mixture of tert-butyl 6-bromo-2 ,.3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-l-carboxylate (1.28 g, 4.06 mmol) , TEA (1.2 mL, 8.61 mmol), DMF (20 mL) and MeOH (5 mL) was added PdCl ₂ (dppf) (151 mg, 0.21 mmol) . After being stirred at 100°C under CO (0.7 MPa) for 7 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (1.020 g, 3.47 mmol, 85%) as white solids.

MS (ESI+), found 295.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.56 (9H, s), 3.90-3.94 (2H, m) , 3.94 (3H, s), 4.37-4.44 (2H, m) , 7.78 (lH, d, J = 8.3 Hz), .8.46 (1H, d, J = 8.3 Hz) .

[0654]

G) methyl 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6- carboxylate hydrochloride

To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (113 mg, 0.38 mmol) and MeOH (5 mL) was added 4 M HCl/EtOAc (5 mL, 20.00 mmol) . After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was subjected to the next reaction without further purification.

[0655]

H) 1- (2- (methoxymethyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid

To a mixture of 1- (chloromethyl) -2- (methoxymethyl) benzene (90 mg, 0.53 mmol) and DMF (5 mL) was added NaH (60% in oil, 38 mg, 0.95 mmol) at 0°C. After being stirred at 0°C for 5 min, 1- (chloromethyl) -2- (methoxymethyl) benzene (90 mg, 0.53 mmol.) was added to the mixture. After being stirred at room temperature for 7 h, 2 M NaOH aq. (0.60 mL, 1.20 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was extracted with water. The aqueous layer was acidified with IN HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to the next reaction without further purification.

MS (ESI+), found 315.3 (M+H)

[0656]

I) 1- (2- (methoxymethyl) benzyl) -N- (4-sulfamoylbenzyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide

To a mixture of 1- (2- (methoxymethyl) benzyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (121 mg, 0.38 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (118 mg, 0.53 mmol), HATU (195 mg, 0.51 mmol) and DMF (5 mL) was added DIPEA (0.20 mL, 1.15 mmol). After being stirred at room

temperature for 3 h, the reaction mixture was quenched with sat. NH ₄ C1 aq. and _, extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) and then crystallized from EtOAc-hexane to give the title compound (15.00 mg, 0.031 mmol-, 8.08%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) δ:3.39 (3H, s), 3.44-3.50 (2H, m) ,

4.43-4.48 (2H, m) , 4.49 (2H, s) , 4.62 (2H, s), 4.66 (2H, d, J = 6.4 Hz), 4.74 (2H, s) , 6.89 (1H, d, J = 7.9 Hz), 7.15-7.21 (1H, m) , 7.29-7.41 (3H, m) , 7.48 (2H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.04-8.12 (1H, m) .

-[-0657]

Example 26

4- (3-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide

A) methyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate

To a solution of methyl 4-amino-3-hydroxybenzoate (10 g, 59.82 mmol) and NaHCO ₃ (5.53 g, 65.80 mmol) in EtOAc (50 mL) and water (50 mL) was added 2-chloroacetyl chloride (4.7.6 mL, 59.82 mmol) at 0°C. The mixture was stirred at room

temperature for 0.5 h, diluted with EtOAc and THF to become solution, and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ , and evaporated. To a solution of the residue in NMP (50 mL) was added K ₂ CO ₃ (8.27 g, 59.82 mmol) at room temperature. The mixture was stirred at room temperature overnight, cooled to 0°C, diluted with water. The precipitates were collected by filtration, washed with water, and dried to give the title compound (11.80 g, 57.0 mmol, 95%) as off-white solids.

[0658]

B) methyl 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate

A mixture of methyl 3-oxo-3 , 4-dihydro-2H-l , 4-benzoxazine- 7-carboxylate (1 g, 4.83 mmol) and boron trifluoride ether complex (1.273 mL, 10.14 mmol) in THF (20 mL) was stirred at 0°C for 20 min. To the mixture was. added NaBH ₄ (0.383 g, 10.14 mmol), which was stirred at 0°C at 1 h and room temperature overnight. EtOAc (ca. 1 mL) was added, followed by IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (0.916 g, 4.74 mmol,. 98%) as pale yellow solids.

[0659]

C) methyl 4- ( 3-methoxyphenyl ) -3 , 4-dihydro-2H-l , 4-benzoxazine-7- carboxylate

Pd ₂ (dba) ₃ (35.5 mg, 0.04 mmol) and XPHOS (37.0 mg, 0.08 mmol) were added to a mixture of methyl 3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-3- methoxybenzene (218 mg, 1.16 mmol) and K ₃ PO ₄ (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ . and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give white solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (90 mg, 0.301 mmol, 38.7%) as a light brown oil.

MS (ESI+), found 300.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.72-3.75 (2H, m) , 3.80 (3H, s) , 3.85 (3H, s), 4.28-4.35 (2H, m), 6.72-6.87 (4H, m) , 7.19-7.36 (1H, m) , 7.42 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 1.9 Hz).

[0660]

D) 4- (3-methoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid

2N NaOH aq. (1.503 mL, 3.01 mmol) was added to a solution of methyl 4- (3-methoxyphenyl) -3, 4~dihydro-2H-l, 4-benzoxazine-7- carboxylate (90 mg, 0.30 mmol) in MeOH (4 mL) at room

temperature. The mixture was stirred at room temperature overnight. The mixture was acidified by IN HC1 aq. at 0°C (pH4.0) and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give the title compound (60.0 mg, 0.210 mmol, 69.9%) as pale orange powder.

MS (ESI+) , found 286.3 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 6:3.68-3.79 (5H, m) , 4.24-4.35 (2H, m) , 6.75-6.82 (2H, m) , 6.85-6.94 (2H, m) , 7.25-7.41 (3H, m) , 12.35 (1H, s) .

[0661]

E) 4- (3-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide

HATU (56.0 mg, 0.15 mmol) was added to a solution of 4- ( 3-methoxyphenyl ) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylic acid (30 mg, 0.11 mmol), 4- (aminomethyl ) benzenesulfonamide hydrochloride (25.8 mg, 0.12 mmol) and DIPEA (59.8 mg, 0.46 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a colorless oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (24.00 mg, 0.053 mmol, 50.3%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.69-3.79 (5H, m) , 4.29 (2H, brs) , 4.48 (2H, d, J = 5.7 Hz), 6.73-6.90 - (4H, m) , 7.27-7.47 (7H, m) , 7.76 (2H, d, J = 8.3 Hz) , 8.81-8.88 (1H, m) .

[0662]

Example 27

4- (3-ethoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide

A) methyl 4- (3-ethoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate

Pd ₂ (dba) ₃ (35.5 mg, 0.04 mmol) and XPHOS (37.0 mg, 0.08 mmol) were added to a mixture of methyl 3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-3- ethoxybenzene (234 mg, 1.16 mmol) and K ₃ PO ₄ (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 20% EtOAc in hexane) to give white solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (88 mg, 0.281 mmol, 36.2%) as orange amorphous solids.

MS (ESI+), found 314.2 (M+H) -

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.41 (3H, t, J = 7.0 Hz), 3.70-3.76 (2H, m) , 3.85 (3H, s) , 3.95-4.08 (2H, m) , 4.29-4.35 (2H, m) , 6.70-6.87 (4H, m) , 7.22-7.33 (1H, m) , 7.42 (1H, dd, J = 8.7, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz).

[0663]

B) 4- (3-ethoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid

2N NaOH aq. (1.404 mL, 2.81 mmol) was added to a solution of methyl 4- ( 3-ethoxyphenyl ) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylate (88 mg, 0.28 mmol) in MeOH (4 mL) at room

temperature. The mixture was stirred at room temperature overnight. The mixture was acidified by IN HC1 aq. at 0°C and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give an oil. The oil was crystallized from EtOAc-hexane to give the title compound (68.0 mg, 0.227 mmol, 81%) as pale orange powder.

MS (ESI+), found 300.3 (M+H)

XH NMR (300 MHz, DMSO-d ₆ ) 5:1.32 (3H, t, J = 7.0 Hz), 3.70-3.78 (2H, m) , 4.03 (2H, q, J = 6.9 Hz), 4.25-4.34 (2H, m) , 6.75-6.90 (4H, m) , 7.28-7.36 (3H, m) , 12.38 (1H, brs).

[0664]

C) 4- (3-ethoxyphenyl) -N- ( 4-sulfamoylbenzyl ) -3 , 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide

HATU (53.4 mg, 0.14 mmol) was added to a solution of 4- ( 3-ethoxyphenyl) -3, 4-dihydro-2H-l , 4-benzoxazine-^7-carboxylic acid (30 mg, 0.10 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (24.55 mg, 0.11 mmol) and DIPEA (57.0 mg, 0.44 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 90% EtOAc in hexane) to give a pale pink oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (32.0 mg, 0.068 mmol, 68.3%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.32 (3H, t, J = 6.6 Hz), 3.73 (2H, brs), 4.02 (2H, d, J - 7.2 Hz), 4.29 (2H, brs), 4.48 (2H, d, J

= 4.5 Hz), 6.71-6.92 (4H, m) , 7.28-7.55 (7H, m) , 7.76 (2H, d, J

= 7.6 Hz), 8.84 (1H, brs) .

[0665]

Example 29

4- (2- (methoxymethyl) benzyl) -N- (1- (4- (methylsulfon.yl ) phenyl) cyclopropyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide

A) N- (1- (4-bromophenyl) cyclopropyl) -4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide

To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (420 mg, 0.69 mmol) , 1- (4-bromophenyl) cyclopropanamine (402 mg, 1.90 mmol) , HATU (786 mg, 2.07 mmol) and DMF (10 mL) was added DIPEA (0.50 mL, 2.86 mmol) . After being stirred at room temperature

overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (259 mg, 0.509 mmol, 73.3%) as white solids.

MS (ESI+), found 508.2, 510.1 (M+H) -

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.34 (4H, dt, J = 7.5, 1.9 Hz), 3.35 (3H, s), 3.37-3.42 (2H, m) , 4.13-4.19 (2H, m) , 4.48 (2H, s) , 5.00 (2H, s), 6.57 (1H, s) , 7.14-7.21 (3H, m) , 7.27-7.32 (2H, m) , ^' 7.35-7.43 (4H, m) , 8.19 (1H, d, J = 2.3 Hz).

[0666]

B) 4- (2- (methoxymethyl) benzyl) -N- (1- (4-

(methylsulfonyl) phenyl) cyclopropyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide

To a mixture of N- ( 1- ( 4-bromophenyl ) cyclopropyl ) -4- ( 2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide (230 mg, 0.45 mmol),

methanesulfinic acid sodium salt (94 mg, 0.92 mmol), L-proline (11 mg, 0.10 mmol), NaOH (8 mg, 0.20 mmol) and DMSO (10 mL) was added copper(I) iodidel (9 mg, 0.05 mmol). After being stirred at 110 °C under nitrogen atmosphere for 30 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane and_MH silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (24.00 mg, 0.047 mmol, 10.4%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.31-1.42 (4H, m) , 3.17 (3H, s) , 3.29 (3H, s), 3.45 (2H, t, J = 4.0 Hz), 4.21 (2H, t, J = 4.3 Hz), 4.49 (2H, s), 4.92 (2H, s) , 7.10-7.18 (lH,_m), 7.23-7.31 (2H, m) , 7.33-7.41 (3H, m) , 7.46 (1H, d, J = 1.9 Hz), 7.76-7.84 (2H, m) , 8.26 (1H, d, J = 1.9 Hz) ,- 9.01 (1H, s).

[0667]

Example 31

4- (4-methoxyphenyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxamide

A) methyl 4- (4-methoxyphenyl) -3, 4-dihydro-2H-l ,.4-benzoxazine-7- carboxylate

Pd2(dba)3 (35.5 mg, 0.04 mmol) was added to a mixture of methyl 3 , 4-dihydro-2H-l , 4-benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-4-methoxybenzene (218 mg, 1.16 mmol), Xphos (37.0 mg, 0.08 mmol) and K ₃ PO ₄ (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room

temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give white solids. The solid was washed with EtOAc-IPE and dried in vacuo to give the title compound (65.0 mg, 0.217 mmol, 28.0%) as a light brown oil.

MS (ESI+), found 300.3 (M+H)

[0668]

B) 4- (4-methoxyphenyl) -3, 4=dihydro-2H-l, 4-benzoxazine-7- carboxylic acid

2N NaOH aq. (0.543 mL, 1.09 mmol) was added to a solution of methyl 4- (4-methoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (65 mg, 0.22 mmol) in MeOH (3 mL) at room

temperature. The mixture was stirred at room temperature for 3 days. To the mixture were added MeOH (2 mL) and 2N NaOH aq. (0.543 mL, 1.09 mmol) and the mixture was stirred at 50°C for 5 h. The mixture was acidified by IN HC1 aq. at 0°C (pH5.0) and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give the title compound (22.00 mg, 0.077. mmol, 35.5%) as pale orange powder.

MS (ESI+), found 286.3 (M+H)

[0669]

C) 4- (4-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide

HATU (41.0 mg, 0.11 mmol) was added to a solution of 4- ( 4-methoxyphenyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxylic acid (22 mg, 0.08 mmol), 4- (aminomethyl ) benzenesulfonamide hydrochloride (17.2 mg, 0.08 mmol) and DIPEA (43.9 mg, 0.34 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc . The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale pink oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (11.00 mg, 0.024 mmol, 31.5%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.63-3.70 (2H, m) , 3.78 (3H, s) , 4.27-4.34 (2H, m) , 4.47 (2H, d, J = 5.7 Hz), 6.50 (1H, d, J = 8.7 Hz), 7.01 (2H, d, J = 9.1 Hz), 7.22-7.32 (5H, m) , 7.36-7.46 (3H, m) , 7.76 (2H, d, J = 7.5 Hz), 8.79 (1H, t like).

[0670]

Example 37

1- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3-" dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) methyl 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6- carboxylate

To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4 ] oxazine-1, 6-dicarboxylate (905 mg, 3.08 mmol) and MeOH. (_5 mL) was added 4.M .HCl/EtOAc (10 mL, 40.00 mmol) . After being stirred at room temperature overnight, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and Amberlyst A26 (937 mg, 3.08 mmol) was added to the mixture. After being stirred at room temperature for 1 h, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give the title compound (605 mg, 3.12 mmol,- 101%) as yellow solids.

[0671]

B) methyl 1- ( 3-cyclopropylphenyl ) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate

A mixture of methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4] oxazine-6-carboxylate (193 mg, 0.99 mmol), l-bromo-3- cyclopropylbenzene (380 mg, 1.93 mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol), XPHOS (52 mg, 0.11 mmol), K ₃ PO ₄ (423 mg, 1.99 mmol) and toluene (10 mL) was stirred under nitrogen atmosphere at 100°C for 16 h. After being cooled^ the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (133 mg, 0.429 mmol, 43.1%) as pale yellow solids.

MS (ESI+), found 311.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.66-0.75 (2H, m) , 0.98-1.09 (2H, m) , 1.83-1.97 (1H, m) , 3.74-3.80 (2H, m) , 3.92 (3H, s) , 4.49-4.55 (2H, m) , 6.92-6.98 (2H, m) , 6.99-7.07 (2H, m) , 7.29-7.38 (1H, m) , 7.60 (1H, d, J = 7.9 Hz) .

[0672]

C) 1- (3-cyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6=carboxylic acid

To a mixture of methyl 1- ( 3-cyclopropylphenyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (129 mg, 0.42 mmol) and MeOH (5 mL) was added 2 M NaOH aq. (1.0 mL, 2.00 mmol) . After being stirred at 60 °C for 1 h, the mixture was acidified with 1 N HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give an oil. The oil was crystallized from EtOAc- hexane to give the title compound (113 mg, 0.381 mmol, 92%) . MS (ESI+), found 297.3 (M+H)

[0673]

D) 1- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3- dihydro-lH-pyrido [2 , 3--b] [1,4] oxazine-6-carboxamide

To a mixture of 1- ( 3-cyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxylic acid (59 mg, 0.20 mmol), (4- (methylsulfonyl ) phenyl ) methanamine hydrochloride (54 mg,

0.24 mmol), DIPEA (0.18 mL, 1.03 mmol), DMAP (26 mg, 0.21 mmol) and EtOAc (3 mL) was added T3P in EtOAc (0.24 mL, 0.41 mmol). After being stirred at 60°C overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SCO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile

containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated. The residue was crystallized from EtOAc- hexane to give the title compound (50.0 mg, 0.108 mmol, 54.2%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.65-0.76 (2H, m) , 0.97-1.07 (2H, m) , 1.84-1.98 (1H, m) , 3.03 (3H, s) , 3.74-3.80 (2H, m) , 4.50-4.57 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.90-6.98 (2H, m) , 6.99-7.05 (1H, m) , 7.11 (1H, d, J = 8.3 Hz), 7.28-7.37 (1H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz) , 8.11 (1H, t, J = 6.2 Hz) .

[0674]

Example 51

4- (4-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide

A) 4-tert-butyl 7-methyl 2 , 3-dihydro-4H-l , 4-benzoxazine-4 , 7- dicarboxylate A mixture of methyl 3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (10.07 g, 52.13 mmol), Boc ₂ 0 (14:52 mL, 62.56 mraol), TEA (8.72 mL, 62.56 mmol) and DMAP (3.18 g, 26.07 mmol) in THF (200 mL) was stirred at 50°C for 3 h. The mixture was quenched with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over

MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%- 30% EtOAc in hexane) to give the title compound (9.90 g, 33.8 mmol, 64.7%) as white solids.

[0675]

B) 4- (tert-butoxycarbonyl ) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid

A mixture of 4-tert-butyl 7-methyl 2 , 3-dihydro-4H-l , 4- benzoxazine-4 , 7-dicarboxylate (6.9 g, 23.52 mmol) and lithium hydroxide (23.52 mL, 94.10 mmol) in THF (20 mL) and MeOH (20.00 mL) was stirred at 50 °C for 2 h. The mixture was quenched with IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over

MgSO ₄ and concentrated in vacuo. The residue was washed with IPE-hexane to give the title compound (5.38 g, 19.26 mmol, 82%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.50 (9H, s), 3.70-3.94 (2H, m) , 4.16-4.33 (2H, m) , 7.35 (1H, d, J = 1.9 Hz), 7.41-7.49 (1H, m) , 7.93 (1H, d, J = 8.7 Hz), 12.76 (1H, brs).

[0676]

C) tert-butyl 7- (( 4- (methylsulfonyl ) benzyl ) carbamoyl ) -2H-1 , 4- benzoxazine-4 (3H) -carboxylate

HATU (7.08 g, 18.62 mmol) was added to a mixture of 4- (tert-butoxycarbonyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-^

carboxylic acid (4 g, 14.32 mmol), (4-

(methylsulfonyl) phenyl ) methanamine (2.92 g, 15.75 mmol) and DIPEA (11.01 mL, 63.02 mmol) in DMF (20mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (4.49 g, 10.06 mmol, 70.2%) as off-white solids. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluted with 50% - 90% EtOAc in hexane) to give the title compound (0.800 g, 1.792 mmol, 12.51%) as white amorphous solids.

MS (ESI+), found 447.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.55 (9H, s) , 3.04 (3H, s) , 3.85-3.91 (2H, m) , 4.23-4.29 (2H, m) , 4.72 (2H, d, J = 6.0 Hz), 6.52 (1H, t, J = 6.0 Hz), 7.27-7.36 (2H, m) , 7.53 (2H, d, J = 5.1 Hz), 7.87-7.97 (3H, m) . .

[0677]

D) N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine- 7-carboxamide

4N HC1 in EtOAc (-29.4 mL, 117 _^ 58 mmol) was added to a suspension of tert-butyl 7-((4-

(methylsulfonyl) benzyl) carbamoyl) -2H-1, 4-benzoxazine-4 (3H) - carboxylate (5.25 g, 11.76 mmol) in EtOAc (90 mL) at 0°C. The mixture was stirred at room temperature for 2 h. To the

mixture was added TFA (20 mL, 259.60 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with IN NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was crystallized from EtOAc-IPE to give the title compound (4.06 g, 11.72 mmol, 100%) as off-white solids.

MS (ESI+), found 347.2 (M+H)

1ti NMR (400 MHz, DMSO-d ₆ ) 5:3.18 (3H, s), 3.31-3.35 (2H, m, overlapped by H ₂ 0) , 4.11 (2H, t, J = 4.3 Hz), 4.49 (2H, d, J = 5.9 Hz), 6.39 (1H, s) , 6.56 (1H, d, J = 8.3 Hz), 7.25 (1H, s) , 7.29 (1H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 8.73 (1H, t, J = 6.0 Hz).

[0678] E) 4- (4-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4- dihydro-2H-l , 4- ^~ benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-

1 , 4-benzoxazine-7-carboxamide (100 mg, 0.29 mmol.) , l-bromo-4- cyclopropylbenzene (85 mg, 0.43 mmol), Ruphos pre-catalyst

(21.04 mg, 0.03 mmol) , - NaOtBu (83 mg, 0.87 mmol) and DME (3 mL) was heated at 120 °C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo.

The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (55.0 mg, 0.119 mmol, 41.2%) as off-white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.62-0.72 (2H, m) , 0.89-1.00 (2H, m) , 1.85-2.00 (1H, m) , 3.18 (3H, s) , 3.64-3.75 (2H, m) , 4.24-

4.35 (2H, m) , 4.51 (2H, d, J = 5.7 Hz), 6.66 (1H, d, J = 8.7 Hz), 7.09-7.23 (4H, m) , 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.39

(1H, d, J = 1.9 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J =

8.7 Hz), 8.86 (1H, t, J = 5.9 Hz).,-

[0679]

Example 52

4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide

A) 2-ethoxy-4-fluorobenzaldehyde

A mixture of K ₂ CO ₃ (8878 mg, 64.23 mmol), ethyliodide (2.226 mL, 27.83 mmol) and 4-fluoro-2-hydroxybenzaldehyde (3000 mg, 21.41 mmol) in DMSO (30 mL) was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title compound (3270 mg, 19.45 mmol, 91%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.50 (3H, t, J = 7.0 Hz), 4.13 (2H, q, J = 6.8 Hz), 6.61-6.77 (2H, m) , 7.86 (1H, dd, J = 8.5, 7.0 Hz), 10.39 (1H, s) .

[0680] B) (2-ethoxy-4-fluorophenyl ) methanol

NaBH ₄ (956 mg, 25.28 mmol) was added to a solution of 2- ethoxy-4-fluorobenzaldehyde (3270 mg, 19.45 mmol) in THF (40 mL) and MeOH (10.0 mL) at room temperature. The mixture was stirred with water bath for 90 min. The mixture was quenched with water at room temperature, and evaporated to remove excess amount of THF-MeOH. The residue was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title

compound (3316 mg, 19.49 mmol, 100%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.45 (3H, t,. J = 7.0 Hz), 2.21 (1H, t, J = 6.6 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 6.8 Hz), 6.56-6.66 (2H, m) , 7.21 (1H, t, J = 7.4 Hz).

[0681]

C) 1- ( chloromethyl ) -2-ethoxy-4-fluorobenzene

A mixture of (2-ethoxy-4-fluorophenyl) methanol (1.6 g, 9.40 mmol), S0C1 ₂ (0.686 mL, 9.40 mmol) and CH ₃ CN (30 mL) was stirred at room temperature for 15min. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO ₄ and concentrated in vacuo to give the title compound (1.790 g, 9.49 mmol, 101%) as a colorless oil. This product was subjected to the next reaction without further purification.

¹ ti NMR (300 MHz, CDC1 ₃ ) 5:1.46 (3H, t, J = 7.0 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.62 (2H, s), 6.56-6.67 (2H, m) , 7.30 (1H, dd, J = 8.1, 6.6 Hz) .

[0682]

D) 4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl ) - 3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-

1 , 4-benzoxazine-7-carboxamide (100 mg, 0.29 mmol), 1- ( chloromethyl) -2-ethoxy-4-fluorobenzene (65.3 mg, 0.35 mmol), sodium iodide (43.3 mg, 0.29 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol) in DMF (3 mL) was stirred at 50 °C overnight. The mixture was quenched with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over. MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (53.0 mg, 0.106 mmol, 36.8%) as off-white solids.

λΗ NMR (300 MHz, DMSO-d ₆ ) 5:1.36 (3H, t, J = 7.0 Hz), 3.17 (3H, s), 3.47 (2H, t, J = 4.3 Hz), 4.09 (2H, q, . J = 7.1 Hz), 4.21 (2H, t, J = 4.2 Hz), 4.39-4.55 (4H, m) , 6.57-6.76 (2H, m) , 6.93 (1H, dd, J = 11.3, 2.6 Hz), 7.13 (1H, dd, J = 8.3, 7.2 Hz), 7.27-7.37 (2H, m) , 7.52 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.77 (1H, t, J = 5.9 Hz).

[0683]

The compounds described in Examples 3 to 53 are below (Table 2- 1 - Table 2-8) . ^{. . .}

[0691]

[Table 2-8]

[0692]

5 The compounds described in Examples 10, 11, 20, 24, 28,

30, 32-36 and 38-50 were synthesized in the same manner as in the reaction and purification described in the Examples.

[0693]

Example 53

0 4- (4-isopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -3 , 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , l-bromo-4- isopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg,5 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol), NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under

microwave irradiation. The reaction mixture was diluted with AoOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous 0 layer was extracted with EtOAc (2 mL) . The combined organic

- ^■■ layer was evaporated by blowing away with the air at 60 °C. -The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at5 60°C to afford the title compound (18.2 mg, 0.0392 mmol, 49%).

[0694]

Example 57 4- (3-ethoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxa.zine-7-carboxami.de. .... . .. . . ..

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , 3- bromophenetole (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by. blowing away with the air at 60°C to afford the title compound (22.9 mg, 0.0491 mmol, 64%).

[0695]

Example 68

4- (3-ethoxy-4-methoxyphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), 4-bromo-2- ethoxy-l-methoxybenzene (37 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, ,0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60°C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (22.9 mg, 0.0461 mmol, 58%).

[0696] Example 75

4- ( 3-isopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), l-bromo-3- isopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol), NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5 : 95→100 : ^→ 0 ) . Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (21.9 mg, 0.0471 mmol, 59%) .

[0697]

Example 77

N- (4- (methylsulfonyl) benzyl) -4- (4- (1-

(trifluoromethyl) cyclopropyl) phenyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), (l-bromo-4- (1- (trifluoromethyl) cyclopropyl) benzene (32 mg, 0.160 mmol),

RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The

combined organic layer was evaporated by blowing away with the air at 60°C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→ 100:0). Pure fractions were combined and concentrated by blowing away with the air at 60 °C to afford the title compound (22.2 mg, 0.0.4.18 mmol, 52%).

[0698]

Example 78

4- (3, 5-diethylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -3, 4-dihydro-2H-

1.4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), 1-bromo-

3.5-diethylbenzene (34 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (23 mg, 0.0481 mmol, 60%).

[0699]

Example 79

4- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) -3,4- dihydro-2H-l , 4-benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-

1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), l-bromo-3- cyclopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μιτιοΐ) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentxated by blowing away with the air at 60°C to afford the title compound (19.8 mg, 0.0428 mmol, 54%).

[0700]

The compounds described in Examples 54 to 104 , are below (Table 3-1 - Table 3-8) .

[0708]

[Table 3-8]

[0709]

The compounds described in Examples 54-56, 58-67, 69-74,

76, and 80-104 were synthesized in the same manner as in the reaction and purification described in the Examples.

[0710]

Example 105

N- (4- (methylsulfonyl ) benzyl) -4- (quinoxalin-6-yl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , 6- bromoquinoxaline (33 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μηαοΐ) , NaOtBu (0.023 g, 0.240 mmol) and D E (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 itiM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (18.3 mg, 0.0368 mmol, 48%).

[0711]

The compounds described in Examples 105 to 141 are below [0717]

[Table

[0718]

The compounds described in Examples 106-141 were

synthesized in the same manner as in the reaction and

purification described in the Examples.

[0719]

Example 145

1- (4-cyclopropylphenyl) -N- (2-fluoro-4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) (E) -2-fluoro-4- (methylsulfonyl ) benzaldehyde oxime

To a mixture of 2-fluoro-4- (methylsulfonyl ) benzaldehyde (305 mg, 1.51 mmol) and MeOH (10 mL) was added hydroxylamine hydrochloride (205 mg, 2.95 mmol) . After being stirred at room temperature for 1 h, 10% Pd-C (50% wet, 154 mg, 0.14 mmol) was added to the mixture. After being stirred at room temperature under hydrogen atmosphere overnight, the insoluble material was filtered off. TEA was added to the filtrate and the mixture was concentrated. The residue was suspended in EtOAc. The insoluble material was filtered off and the filtrate was

concentrated. The residue was purified by column

chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title .compound (218 mg, 1.004 mmol, 66.5%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₅ ) 5:3.29 (3H, s) , 7.79 (1H, dd, J = 8.3, 1.5 Hz), 7.86 (1H, dd, J = 9.8, 1.9 Hz), 7.96-8.05 (1H, m) , 8.29 (1H, s) , 12.04 (1H, s) .

[0720]

B) 1- (2-fluoro-4- (methylsulfonyl) phenyl) methanamine

hydrochloride

To a mixture of (E) -2-fluoro-4-

(methylsulfonyl ) benzaldehyde oxime (217 mg, 1.00 mmol), 2 M HC1 in MeOH (1.0 mL, 2.00 mmol) and MeOH (5 mL) was added 10% Pd-C (50% wet, 100 mg, 0.09 mmol). After being stirred at room temperature under hydrogen atmosphere overnight, the insoluble material was filtered off and the filtrate was concentrated in vacuo to give the title compound (162 mg, 0.676 mmol, 67.7%) as white solids.

MS (ESI+), found 204.3 (M-HC1+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.30 (3H, s) , 4.17 ^' (2H, s), 7.78- 7.93 (3H, m) , 8.28 (3H, brs).

[0721]

C) methyl 1- ( 4-cyclopropylphenyl ) -2, 3-d : hydro- ^" : H-pyr i do [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate

A mixture of methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate (51 mg, 0.26 mmol), l-bromo-4- cyclopropylbenzene (70 μL, 0.52 mmol), Pd ₂ (dba) ₃ (13 mg, 0.01 mmol), XPHOS (12 mg, 0.03 mmol), K ₃ PO ₄ (113 mg, 0.53 mmol) and toluene (5 mL) was stirred under nitrogen atmosphere at 100°C for 16 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (31.0 mg, 0.100 mmol, 38.0%) as pale yellow solids.

MS (ESI+), found 311.3 (M+H)

[0722]

D) 1- (4-cyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid

To a mixture of methyl 1- (4-cyclopropylphenyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (30 mg, 0.10 mmol) in THF (1 mL) and MeOH (3 mL) was added 2 M NaOH aq.

(0.15 mL, 0.30 mmol). After being stirred at 60°C overnight, the mixture was acidified with 1 M HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was subjected to the next reaction without further purification.

[0723]

E) 1- ( 4-cyclopropylphenyl ) -N- (2-fl-uoro-4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a mixture of 1- ( 4-cyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (29 mg, 0.10 mmol), 1- (2-fluoro-4- (methylsulfonyl ) phenyl) methanamine hydrochloride (29 mg, 0.12 mmol), HATU (62 mg, 0.16 mmol) and DMF (3 mL) was added DIPEA (70 μL, 0.40 mmol) . After being stirred at room temperature for 3 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat.

NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated. The residue was suspended in IPE and collected by filtering to give the title compound (19.00 mg, 0.039 mmol, 40.3%) as white solids .

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.67-0.77 (2H, m) , 0.96-1.07 (2H, m) , 1.86-1.99 (1H, m) , 3.03 (3H, s) , 3.72-3.78 (2H, m) , 4.51-4.57 (2H, m) , 4.72 (2H, d, J = 6.4 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.10-7.18 (4H, m) , 7.58-7.71 (4H, m) , 8.08 (1H, t, J = 6.2 Hz).

[0724]

Example 146

1- (3-cyclopropyl-5-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide

A) 1- (tert-butoxycarbonyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid

To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-1 , 6-dicarboxylate (1.52 g, 5.16 mmol) , THF (5 mL) and MeOH (15 mL) was added 2 M NaOH aq. (5.0 mL, 10.00 mmol). After being stirred at room temperature overnight, the mixture was acidified with 1 M HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over

Na ₂ SCO ₄ and concentrated to give the title compound as crude product, which was subjected to the next reaction without further purification.

[0725]

B) tert-butyl 6- (( 4- (methylsulfonyl ) benzyl ) carbamoyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-l-carboxylate

To a mixture of 1- (tert-butoxycarbonyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (1.45 g, 5.17 mmol), ( 4- (methylsulfonyl ) phenyl ) methanamine (1.15 g, 6.21 mmol), HATU (2.95 g, 7.76 mmol) and DMF (30 mL) was added DIPEA (2.7 mL, 15.50 mmol). After being stirred at room temperature overnight, the mixture, was poured into water and extracted with EtOAc.

The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (2.220 g, 4.96 mmol, 96%) as white solids.

MS (ESI+), found 448.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.56 (9H, s), 3.03 (3H, s) , 3.90-3.97 (2H, m) , 4.39-4.46 (2H, m) , 4.70 (2H,. d, J = 6.4 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.83-7.94 (3H, m) , 8.17 (1H, t, J = 5.5 Hz), 8.45 (1H, d, J = 8.7 Hz) .

[0726]

C) N- (4- (methylsulfonyl) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a mixture of tert-butyl 6-((4- (methylsulfonyl) benzyl) carbamoyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4] oxazine-l-carboxylate (2.22 g, 4.96 mmol) and MeOH (10 mL) was added 4 M HC1 in EtOAc (10 mL, 40.00 mmol) . After being stirred at 60°C for 2 h, the mixture was concentrated. The residue was dissolved in water, basified with sat. NaHCCO ₃ aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was washed with IPE to give the title compound (1.300 g, 3.74 mmol, 75%) as pale yellow solids.,

MS (ESI+), found 348.1 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.17 (3H, s), 3.33-3.38 (2H, m) , 4.26-4.34 (2H, m) , 4.50 (2H, d, J = 6.4 Hz), 6.94 (1H, d, J = 7.9 Hz), 7.46 (1H, d, J = 7.9 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.82 (1H, t, J = 6.4 Hz). (An

exchangeable proton was omitted)

[0727] ^{" '"}

D) 3-cyclopropyl-5-methylphenol

To a solution of 3-bromo-5-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),

tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium

phosphate (1702 mg,. 8..02 mmol) in toluene .(10 mL) /water (2.00 mL) was added Pd(OAc) ₂ (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over

MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (144 mg, 0.972 mmol,

36.3%) as a pale orange oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.62-0.70 (2H, m) , 0.86-0.97 (2H, m) , 1.74-1.87 (1H, m) , 2.26 (3H, s) , 4.57 (1H, s), 6.33 (1H, s) , 6.43 (1H, s) , 6.49 (1H, s) .

[0728]

E) 3-cyclopropyl-5-methylphenyl trifluoromethanesulfonate

To a solution of 3-cyclopropyl-5-methylphenol (144 mg, 0.97 mmol) in pyridine (3 mL) was added Tf ₂ 0 (0.197 mL, 1.17 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 20% EtOAc in hexane) to give the title compound (227 mg, 0.810 mmol, 83%) as a colorless oil.

¹ R NMR (300 MHz, CDC1 ₃ ) 5:0.64-0.74 (2H, m) , 0.96-1.05 (2H, m) , 1.82-1.94 (1H, m) , 2.34 (3H, s) , 6.74 (1H, s), 6.84 (1H, s), 6.88 (1H, s) .

[0729]

F) 1- ( 3-cyclopropyl-5-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (70 mg, 0.20 mmol), 3- cyclopropyl-5-methylphenyl trifluoromethanesulfonate (120 mg, 0.43 mmol), Ruphos pre-catalyst (15 mg, 0.02 mmol), NaOtBu (55 mg, Q.57 mmol) and DME (3 mL) was stirred at 120 °C for 2 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) , suspended in IPE and collected by

filtering to give the title compound (22.00 mg, 0.046 mmol, 22.86%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.64-0.73 (2H, m) , 0.94-1.04 (2H, m) , 1.80-1.92 (1H, m) , 2.33 (3H, s) , 3.03 (3H, s) , 3.71-3.79 (2H, m) , 4.49-4.56 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.72-6.78 (2H, m) , 6.83 (1H, s) , 7.09 (1H, d, J = 7.9 Hz), 7.54 (2H, d, J = 8.7 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.7 Hz), 8.11 (1H, t, J = 6.4 Hz) .

[0730]

Example 147

1- (3-cyclopropyl-4-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide A) 3-cyclopropyl-4-methylphenol

To a solution of 3-bromo-4-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),

tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium

phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(0Ac) ₂ (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over

MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (361 mg, 2.436 mmol, 91%) as an orange oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 6:0.54-0.66 (2H, m) , 0.86-0.97 (2H, m) , 1.79-1.92 (1H, m) , 2.33 (3H, s) , 4.51 (1H, s) , 6.45 (1H, d, J = 2.6 Hz) , 6.56 (1H, dd, J = 8.1, 2.8 Hz) , 6.99 (1H, d, J = 7.9 Hz) .

[0731]

B) 3-cyclopropyl-4-methylphenyl trifluoromethanesulfonate

To a solution of 3-cyclopropyl-4-methylphenol (361 mg,

2.44 mmol) in pyridine (7 mL) was added Tf ₂ 0 (0.494 mL, 2.92 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2%- 20% EtOAc in

hexane) to give the title compound (576 mg, 2.055 mmol, 84%) as a colorless oil.

[0732]

C) 1- ( 3-cyclopropyl-4-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (70 mg, 0.20 mmol), 3- cyclopropyl-4-methylphenyl trifluoromethanesulfonate (113 mg, 0.40 mmol) , Ruphos pre-catalyst (14.68 mg, 0.02 mmol), NaOtBu (58.1 mg, 0.60 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (70.0 mg, .0.14.7. mmol , 72.7%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.56-0.67 (2H, m) , 0.84-0.98 (2H, m) , 1.86-1.98 (1H, m) , 2.39 (3H, s) , 3.18 (3H, s) , 3.67-3.77 (2H, m) , 4.42-4.57 (4H, m) , 6.87-6.98 (2H, m) , 7.05 (1H, dd, J = 7.9, .2.3 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.94 (1H, t, J = 6.4 Hz) .

[0733]

Example 148

1- ( 5-cyclopropyl-2-methylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxami.de

A) 5-cyclb.propyl-2-methylphenol

To a solution of 5-bromo-2-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),

tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium

phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added diacetoxypalladium (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar

overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in- hexane) to give the title compound (192 mg, 1.296 mmol, 48.5%) as a pale yellow oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.57-0.70 (2H, m) , 0.85-0.98 (2H, m) , 1.81 (1H, tt, J = 8.4, 5.2 Hz), 2.20 (3H, s) , 4.58 (1H, s) , 6.49 (1H, d, J = 1.5 Hz), 6.59 (1H, dd, J = 7.7, 1.7 Hz), 6.99 (1H, d, J = 7.6 Hz) . [0734]

B) 5-cyclopropyl-2-methylphenyl trifluoromethanesulfonate

To a solution of 5-cyclopropyl-2-methylphenol (106 mg, 0.72 mmol) in pyridine (2 mL) was added Tf ₂ 0 (0.145 mL, 0.86 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 20% EtOAc in hexane) to give the title compound (113 mg, 0.403 mmol, 56.4%) as a colorless oil.

[0735]

C) 1- ( 5-cyclopropyl-2-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2 , 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (70 mg, 0.20 mmol), 5- cyclopropyl-2-methylphenyl trifluoromethanesulfonate (113 mg, 0.40 mmol), Ruphos pre-catalyst (14.68 mg, 0.02 mmol), NaOtBu (58.1 mg, 0.60 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (85 mg, 0.178 mmol, 88%) as yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.59-0.73 (2H, m) , 0.84-0.99 (2H, m) , 1.83-1.95 (1H, m) , 2.08 (3H, s) , 3.17 (3H, s) , 3.50-3.62

(1H, m) , 3.74-3.87 (1H, m) , 4.43-4.61 (4H, m) , 6.34 (1H, d, J = 8.3 Hz), 6.99 (1H, dd, J = 7.9, 1.9 Hz), 7.06 (1H, d, J = 1.9 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz) , 7.81-7.91 (2H, m) , 8.92 (1H, t, J = 6.4 Hz) .

[0739]

The compounds described in Examples 142-144 and 149-151 were synthesized in the same manner as in the reaction and purification described in the Examples.

[0740]

Example 152

5- ( 4-isopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide

The mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (0.029 g, 0.08 mmol) , l-bromo-4-isopropylbenzene (0.032 g, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 pmol) , RuPhos (3.73 mg, 8.00 pmol), NaOtBu

(0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was

diluted with AcOEt (3 mL) and quenched with H ₂ O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The

combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC

(Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO3 aq. 5:95 → 100:0). Pure fractions were combined and concentrated by blowing away with the air at 60 °C to afford the title compound (8.7 mg, 0.0182 mmol, 22.7%).

[0741]

Example 162

5- ( 4-fluoro-3-methoxyphenyl ) -N- (4- (methylsulfonyl) benzyl) - 2,3,4, 5-tetrahydro-l, 5-benzoxazepine-8-carboxamide

A) methyl 4- (bis (tert-butoxycarbonyl) amino) -3- ( (tert- butoxycarbonyl ) oxy) benzoate

A mixture of methyl 4-amino-3-hydroxybenzoate (30 g,

179.47 mmol) and Boc ₂ 0 (125 mL, ^' 538.40 mmol) in THF (400 mL) was stirred at room temperature for 3 days. The mixture was concentrated, in vacuo to give the title compound (85 g, 182 mmol, 101%) as a light brown oil. This product was subjected to the next reaction without further purification.

[0742]

B) 5-tert-butyl 8-methyl 3, 4-dihydro-l, 5-benzoxazepine-5, 8 (2H) - dicarboxylate

K ₂ CO ₃ (75 g, 545.44 mmol) was .added, to a solution of methyl 4- (bis (tert-butoxycarbonyl) amino) -3- ( (tert- butoxycarbonyl ) oxy) benzoate (85 g, 181.81 mmol) in MeOH (500 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo.. The residue was diluted with acetone (200 mL) . To the

suspension were added 1 , 3-dibromopropane (44.0 g, 218.18 mmol) and K ₂ CO ₃ (25.1 g, 181.81 mmol), and the mixture was stirred at 50 °C overnight. After cooling, the mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 15% EtOAc in hexane) to give pale yellow solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (13.10 g, 42.6 mmol, 23.44%) as white powder.

MS (ESI+), found 208.3 (M+H) ¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.39 (9H, s), 1.90-2.02 (2H, m) , 3.64 (2H, brs), 3.83 (3H, s) , 4.09 (2H, t, J = 5.3 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 2.3 Hz), 7.59 (1H, dd, J = 8.3, 1.9 Hz) .

[0743]

C) 5- (tert-butoxycarbonyl) -2, 3, 4, 5-tetrahydro-l , 5- benzoxazepine-8-carboxylic acid ..

2N aq. NaOH (56.9 mL, 113.88 mmol) was added to a

solution of 5-tert-butyl 8-methyl 3 , 4-dihydro-l , 5- benzoxazepine-5, 8 (2H) -dicarboxylate (7 g, 22.78 mmol) in MeOH (105 mL) -THF (21 mL) at room temperature. The mixture was stirred at 40°C for 1 h. The mixture was acidified by IN HC1 aq. at 0°C and diluted with water. Precipitates were collected by filtration, washed with water and dried in vacuo to give the title compound (6.46 g, 22.02 mmol, 97%) as white powder.

MS (ESI+), found 194.4 (M-Boc+2H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.39 (9H, brs), 1.89-2.01 (2H, m) , 3.64 (2H, brs), 4.08 (2H, t, J = 5.1 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.48... (1H, d, J = 1.9 Hz), 7.57 (1H, dd, J - 8.3, 2.3 Hz), 13.00 (1H, brs) .

[0744]

D) tert-butyl 8- ( (4- (methylsulfonyl ) benzyl) carbamoyl) -3, 4- dihydro-1, 5-benzoxazepine-5(2H) -carboxylate

HATU (7.26 g, 19.09 mmol) was added to a mixture of 5- (tert-butoxycarbonyl ) -2 , 3 , 4 , 5-tetrahydro-l , 5-benzoxazepine-8- carboxylic acid (4 g, 13.64 mmol), (4-

(methylsulfonyl ) phenyl ) methanamine (2.78 g, 15.00 mmol) and DIPEA (10.48 mL, 60.00 mmol) in DMF (25mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtQAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70%- 95% EtOAc in hexane) to give the title compound (6.63 g, 14.40 mmol, 106%) as white solids. MS (ESI+), found 361.2 (M-Boc+2H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.45 (9H, brs) , 2.04-2.13 (2H, m) , 3.04 (3H, s), 3.75 (2H, brs), 4.08-4.20 (2H, m) , 4.72 (2H, d, J = 6.0 Hz), 6.55 (1H, brs), 7.33-7.44 (3H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz.)..

[0745]

E) N- (4- (methylsulfonyl) benzyl) -2 , 3 , 4 , 5-tetrahydro-l , 5- benzoxazepine-8-carboxamide

TFA (20 mL, 259.60 mmol) was added to a suspension of tert-butyl 8- ( (4- (methylsulfonyl ) benzyl) carbamoyl) -3, 4-dihydro- 1, 5-benzoxazepine-5 (2H) -carboxylate (5.3 g, 11.51 mmol) in EtOAc (90 mL) at 0°C. The mixture was stirred at room

temperature overnight. To the mixture was added TFA (30 mL, 389.39 mmol) at room temperature. The mixture was stirred at room temperature overnight. TFA (20 mL, 259.60 mmol) was added to the mixture at room temperature and stirred for 5h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over .Mg.SO ₄ and concentrated in vacuo to give the title compound (4.37 g, 12.12 mmol, 105%) as off-white solids .

MS (ESI+), found 361.2 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.90 (2H-, t, J = 5.5 Hz), 3.15-3.21 (5H, m) , 4.05 (2H, t, J = 5.7 Hz), 4.50 (2H, d, J = 5.7 Hz), 5.90 (1H, s), 6.77 (1H, d, J = 8.3 Hz), 7.35-7.39 (2H, m) ,

7.50-7.56 (2H, m) , 7.84-7.89 (2H, m) , 8.81 (1H, t, J = 5.9 Hz).

[0746]

F) 5- (4-fluoro-3-methoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide

-■■ The mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), 2-fluoro-5-bromoanisole (33 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 pmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (5.7 mg, 0.0118 mmol, 15%).

[0747]

Example 166

5- (3-ethoxy-4-methoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l, 5-benzoxazepine-8-carboxamide

A mixture of N- ( 4- (methylsulfonyl) benzyl ) -2, 3, 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), 4-bromo-2-ethoxy-l-methoxybenzene (37 mg, 0.160 mmol), RuPhos- Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched. with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5 : 95→100 : 0 ) .. Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (7.4 mg, 0.0145 mmol, 18%).

[0748]

Example 167

5- (3, 5-dimethoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine=8-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), l-bromo-3, 5-dimethoxybenzene (35 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (10.1 mg, 0.0203 mmol, 15%).

[0749]

Example 175

5- (3, 5-diethylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), l-bromo-3, 5-diethylbenzene (34 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq. 5 : 95→100 : 0 ) . Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (14.4 mg, 0.0292 mmol, 37%).

[0750]

The compounds described in Examples 152 to 192 are below (Table 6-1 - Table 6-6) .

[0757]

The compounds described in Examples 153-161, 163-165,

168-174, and 176-192 were synthesized in the same manner as in the reaction and purification described in the Examples.

[0758]

Example 194

1- ( 4-cyclopropyl-3-methylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide A) 4-cyclopropyl-3-methylphenol

To a solution of 4-bromo-3-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol) ,

tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium

phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(0Ac)2 (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over

MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (300 mg, 2.024 mmol, 76%) as an orange oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.50-0.59 (2H, m) , 0.81-0.91 (2H, m) , 1.71-1.85 (1H, m) , 2.37 (3H, s) , 4.55 (1H, s), 6.57 (1H, dd, J = 8.3, 2.6 Hz), 6.64 (1H, d, J = 2.6 Hz), 6.88 (1H, d, J = 8.3 Hz) .

[0759]

B) 4-cyclopropyl-3-methylphenyl trifluoromethanesulfonate

To a solution of 4-cyclopropyl-3-methylphenol (300 mg,

2.02 mmol) in pyridine (3 mL) was added Tf ₂ 0 (0.410 mL, 2.43 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO ₄ and concentrated in vacuo to give the title compound (510 mg, 1.820 mmol, 90%) as a yellow oil. The obtained oil was used for next reaction without further purification.

[0760]

C) 1- (4-cyclopropyl-3-methylphenyl). -N- (4- · -

(methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol), 4- cyclopropyl-3-methylphenyl trifluoromethanesulfonate (97 mg, 0.35 mmol) , Ruphos pre-catalyst (12.59 mg, 0.02 mmol) , NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) and (NH silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (52.0 mg, 0.109 mmol, 63.0%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.56-0.66 (2H, m) , 0.87-0.98 (2H, m) , 1.84-1.96 (1H, m) , 2.31-2.43 (3H, m) , 3.17 (3H, s), 3.68- 3.79 (2H, m) , 4.42-4.58 (4H, m) , 6.95-7.10 (3H, m) , 7.14 (1H, d, J = 1.9 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.94 (1H, t, J = 6.4 Hz).

[0761]

The compounds described in Examples 193 to 195 are below

(Table 7) .

[0762]

[Table 7]

[0763]

The compounds described in Examples 193 and 195 were synthesized in the same manner as in the reaction and

purification described in the Examples. [0764]

Example 196

N- (4- (methylsulfonyl) benzyl) -5- (quinoxalin-6-yl ) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide

The mixture of N- ( 4- (methylsulfonyl ) benzyl) -2 , 3, 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (0.029 g, 0.08 mmol) , 6-bromoquinoxaline (0.033 g, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 pmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under

microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H ₂ 0 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL ) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus. Triart C18, eluted with MeCN/10 mM NH ₄ HCO ₃ aq . 5:95 → 100:0) . Pure

fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (5.6 mg, 0.0115 mmol, 14.3%) . .

[0765]

The compounds described in Examples 196 to 220 are below (Table 8-1 - Table 8-4) .

[0769]

[Table 8-4]

[0770]

The compounds described in Examples 197 and 220 were synthesized in the same manner as in the reaction and

purification described in the Examples.

[0771]

Example 223

N- (4- (methylsulfonyl) benzyl) -4- (2-phenylethyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide

To a solution of N- (4- (methylsulfonyl) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide (50 mg, 0.14 mmol) and 2-phenylacetaldehyde (0.024 mL, 0.22 mmol) in AcOH (0.1 mL) and MeOH (1 mL) was added borane-2-picoline complex (23.16 mg, 0.22 mmol) at room temperature. The mixture was stirred at 60 °C under N ₂ overnight. The mixture was neutralized with sat.

NaHCO ₃ aq. at 0°C and extracted with EtOAc . The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. . The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (55.0 mg, 0.122 mmol, 85 %) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:2.83 (2H, t, J = 7.4 Hz),, 3.18 (3H, s), 3.27-3.33 (2H, m) , 3.51-3.63 (2H, m) , 4.09 (2H, t, J = 4.3 Hz), 4.52 (2H, d, J = 5.7 Hz), 6.80 (1H, d, J = 8.7 Hz), 7.17- 7.34 (6H, m) , 7.42 (1H, dd, J = 8.5, 2.1 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz) , 8.80 (1H, t, J = 6.0 Hz) .

[0772]

Example 227

4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl) -3-oxo- 3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide

A) ethyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate

A suspension of 3-oxo-3 , 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid (1000 mg, 5.18 mmol) and H ₂ SO ₄ (0.276 mL, 5.18 mmol) in EtOH (25 mL) was refluxed overnight. After being cooled to rt, the reaction mixture was evaporated. The mixture was poured into sat. NaHCO ₃ aq. at room temperature and

extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was suspended in IPE and filtered to give the title compound (487 mg, 2.202 mmol, 42.5%) as brown solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.29 (3H, t, J = 7.0 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.64 (2H, s), 6.98 (1H, d, J = 7.9 Hz), 7.43

(1H, d, J = 1.9 Hz), 7.58 (1H, dd, J = 8.1, 1.7 Hz), 11.06 (1H, s) -

[0773]

B) ethyl 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate

NaH (60% in oil, 26.3 mg, 0.66 mmol) was added to a solution of ethyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (112 mg, 0.50 mmol) and 1- (chloromethyl) -2-ethoxy- 4-fluorobenzene (100 mg, 0.53 mmol) in DMF(dry) (4 mL) at room temperature. The mixture was stirred at room temperature for 3 days. The mixture was poured into water . and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The

residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give the title

compound (94 mg, 0.252 mmol, 49.9%) as off-white solids.

MS (ESI+), found 374.3 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.28 (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.27 (2H, q, J = 6.9 Hz), 4.85 (2H, s) , 5.04 (2H, s) , 6.67 (1-H-, -td, J = 8.5, 2.3 Hz), 6.93 (1H, dd, J = 11.1, 2.5 Hz), 6.99-7.09 (2H, m) , 7.48 (1H, d, J = 1.5 Hz), 7.56 (1H, dd, J = 8.3, 1.9 Hz).

[0774]

C) 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylic acid

• 2N NaOH (0.378 mL, 0.76 mmol) was added to a solution of ethyl 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylate (94 mg, 0.25 mmol) in MeOH (0.8 mL) and THF (1.600 mL) at room temperature. The mixture was

stirred at room temperature for 4h. The mixture was slightly acidified with IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (91 mg, 0.264 mmol, 105%) as white solids.

[0775]

D) 4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl) -3- ■oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide

(4- (methylsulfonyl) phenyl )methanamine (53.7 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol) and DIPEA (0.092 mL, 0.53 mmol) were added to a solution of 4- (2-ethoxy-4--fluorobenzyl) -3-oxo- 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylic acid (91 mg, 0.26 mmol) in DMF(dry) (3.0 mL) . The mixture was stirred at room temperature overnight. The mixture was poured into sat NaHCO ₃ aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give off-white solids. The solids were crystallized from EtOAc- hexane to give the title compound (62.0 mg, 0.121 mmol, 45.9%) as off-white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.37 (3H, t, J = 7.0 Hz), 3.17 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.53 (2H, d, J = 6.0 Hz), 4.83 (2H, s), 5.04 (2H, s) , 6.67 (1H, td, J = 8.5, 2.6 Hz), 6.94 (1H, dd, J = 11.3, 2.3 Hz), 6.99-7.10 (2H, m) , 7.47-7.60 (4H, m) , 7.87 (2H, d, J = 8.3 Hz), 9.09 (1H, t, J = 6.0 Hz).

[0776]

Example 229

1- (4-fluoro-3-isopropyl-5-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) 2- ( 5-bromo-2-fluoro-3-methylphenyl ) propan-2-ol

1.6 M n-BuLi in hexane (7.94 mL, 12.70 mmol) was added to a solution of bis ( isopropyl ) amine (2.246 mL, 15.87 mmol) in THF(dry) (10 mL) at -78 °C. The mixture was stirred at -7.8 °C under Ar for 30 min. The solution of 4-bromo-l-fluoro-2- methylbenzene (1.338 mL, 10.58 mmol) in THF was added. The mixture was stirred at -78 °C under Ar for 1 h. Propan-2-one (0.935 mL, 12.70 mmol) was added. The mixture was stirred at - 78°C under Ar for 2 h. The mixture was poured into IN HC1 aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 3% - 12% EtOAc in hexane) to give the title

compound (1.780 g, 7.20 mmol, 68.1%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.-46 (6H, d, J = 1.1 Hz), 2.21 (3H, d, J = 2.6 Hz), 5.39 (1H, s), 7.32-7.42 (1H, m) , 7.55 (1H, dd, J = 6.8, 2.6 Hz) .

[0777]

B) 5-bromo-2-fluoro-1-isopropyl-3-methylbenzene

To a mixture of 2- ( 5-bromo-2-fluoro-3- methylphenyl)propan-2-ol (300 mg, 1.21 mmol) in TFA (5000 μΐ, 64.90 mmol) was added triethylsilane (580 μΐ, 3.64 mmol) at 0°C, and the mixture was stirred for 4h. The reaction mixture was concentrated at reduced pressure, diluted with water, and

5 extracted with EtOAc. The extract was washed with saturated

aqueous NaHCCO ₃ and brine, then dried over Na ₂ SO ₄ and

concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%- 5%EtOAc in hexane) to give the title compound (217 mg, 0.939 mmol, 77%) l-o as a colorless oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.19 (6H, d, J = 7.2 Hz), 2.21 (3H, d, J = 2.3 Hz), 3.13 (1H, spt, J = 6.9 Hz), 7.27-7.39 (2H, m) .

[0778]

C) 1- (4-fluoro-3-isopropyl-5-methylphenyl) -N- (4-

15 (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol), 5- bromo-2-fluoro-l-isopropyl-3-methylbenzene (59.9 mg, 0.26 mmol).,..

20 chloro (2-dicyclohexylphosphino-2' , 6' -di-i-propoxy-1 , 1' - biphenyl) [2- (2-aminoethylphenyl )] palladium ( II ) , methyl-t-butyl ether adduct (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (2mL) was heated at 120 °C for 1 h under microwave

irradiation. The mixture was filtered through celite and

25 concentrated in vacuo. The residue was purified by column

chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to white solids. The solids were crystallized from

EtOAc-hexane to give the title compound (34.0 mg, 0.068 mmol, 39.6%) as white solids.

30 ¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.25 (6H, d, J = 6.8 Hz), 2.28 (3H, d, J = 1.9 Hz), 3.03 (3H, s) , 3.24 (1H, dt, J = 13.7, 6.9 Hz),

3.67-3.81 (2H, m) , 4.48-4.60 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.83-7.02 (3H, m) , 7.54 (2H, d, J = 7.9 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.10 (1H, t, J = 6.6 Hz).

35 [0779] Example 232

1- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3- dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide

A) 3 , 5-dicyclopropylphenol

A mixture of 3 , 5-dibromophenol (1 g, 3.97 mmol) , 3,5- dibromophenol (1 g, 3.97 mmol), cyclopropylboronic acid (1.705 g, 19.85 mmol), tricyclohexylphosphine (0.223 g, 0.79 mmol) and K3PO4 (2.53 g, 11.91 mmol) in toluene (20 mL) and water (4.0 mL) was stirred at 100°C overnight. The mixture was filtered, the filtrate was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (512.8 mg, 2.94 mmol, 74.1%) as white amorphous solids.

MS (ESI-), found 173.0 (M-H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.62-0.71 (4H, m) , 0.87-0.97 (4H, m) , 1.75-1.87 (2H, m) , 4.72 (1H, s), 6.27-6.33 (2H, m) , 6.42-6.47 (1H, m) . ... .

[0780]

B) 3 , 5-dicyclopropylphenyl trifluoromethanesulfonate

To a solution of 3 , 5-dicyclopropylphenol (510 mg, 2.93 mmol) in pyridine (10 mL) was added Tf ₂ 0 (0.593 mL, 3.51 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 0% - 20% EtOAc in hexane) to give the title compound (680 mg, 2.22 mmol, 75.7%) as a colorless oil.

¹ H NMR (300 MHz, CDCI ₃ ) 5:0.65-0.75 (4H, m) , 0.95-1.07 (4H, m) , 1.80-1.96 (2H, m) , 6.67-6.73 (2H, m) , 6.80-6.85 (1H, m) .

[0781]

C) 1- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 3 , 5-dicyclopropylphenyl trifluoromethanesulfonate (58.2 mg, 0.19 mmol), Ruphos pre-catalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 1 h under microwave irradiation. The mixture was quenched with water and extracted with EtOAc. The organic layer was

separated and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% E-tOAc in hexane) to -give the title

compound (36.4 mg, 0.072 mmol, 41.8%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.63-0.72 (4H, m) , 0.87-0.98 (4H, m) , 1.82-1.94 (2H, m) , 3.17 (3H, s) , 3.67-3.79 (2H, m) , 4.40- 4.49 (2H, m) , 4.52 (2H, d, J = 6.4 Hz), 6.66 (1H, s) , 6.79 (2H, d, J = 1.5 Hz) , 7.01 (1H, d, J = 8.3 Hz), 7.46 (1H, d, J = 7.9 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.95 (1H, t, J = 6.4 Hz) .

[0782]

Example 233

1- ( 4-fluoro-3-isopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) 4-fluoro-3- (prop-l-en-2-yl ) phenol

To a solution of 3-^bromo-4-fluorophenol (1- g, 5.24 mmol), prop-l-en-2-ylboronic acid (0.755 mL, 7.85 mmol),

tricyclohexylphosphine (0.294 g, 1.05 mmol) and potassium phosphate (3.33 g, 15.71 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(OAc) ₂ (0.118 g, 0.52 mmol) at room temperature. The mixture was stirred at 100°C under Ar overnight. The mixture was quenched with water at room temperature and

extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title

compound (0.423 g, 2.78 mmol, 53.1%) as a pale yellow oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:2.12 (3H, d, J = 0.8 Hz), 4.67 (1H, brs), 5.23 (2H, s) , 6.62-6.70 (1H, m) , 6.71-6.79 (1H, m) , 6.85- 6.96 (1H, m) .

[0783]

B) 4-fluoro-3-isopropylphenol

A mixture of 4-fluoro-3- (prop-l-en-2-yl) phenol (423 mg,

2.78 mmol) and 10% Pd-C (50% wet, 296 mg, 0.28 mmol) in THF (5 mL) /MeOH (5.00 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by

filtration and the filtrate was concentrated in vacuo. A mixture of the residue and 10% Pd-C (50% wet, 296 mg, 0.28 mmol) in THF (5 mL) /MeOH (5.00 mL) was hydrogenated under balloon pressure again at room temperature overnight. The catalyst was removed by filtration and the filtrate was

concentrated in vacuo. The residue was purified by column chromatography (NH■ silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (307 mg, 1.991 mmol, 71.6%) as a colorless oil.

^X H NMR (300 MHz, CDC1 ₃ ) 5:1.23 (6H, d, J = 6.8 Hz), 3.10-3.26 (1H, m)., 4.66. (lH, s) , 6.54-6.62 (IE, m) , 6.70 (1H, dd, J = 5.9, 3.2 Hz), 6.86 (1H, dd, J = 9.8, 8.7 Hz).

[0784]

C) 4-fluoro-3-isopropylphenyl trifluoromethanesulfonate

To a solution of 4-fluoro-3-isopropylphenol (307 mg, 1.99 mmol) in pyridine (3 mL) was added Tf ₂ 0 (0.404 mL, 2.39 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO^ and

concentrated in vacuo. The residue was purified by column chromatography (si-lica gel, eluted with 2% - 10% EtOAc in hexane) to give the title compound (292 mg, 1.020 mmol, 51.2%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.26 (6H, d, J = 6.8 Hz), 3.18-3.33 (1H, m) , 7.05-7.10 (2H, m) , 7.11-7.17 (1H, m) .

[0785] D) 1- (4-fluoro-3-isopropylphenyl) -N- (4- (methylsulfonyl) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 4- fluoro-3-isopropylphenyl trifluoromethanesulfonate (99 mg, 0.35 mmol), Ruphos pre-catalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3.5 mL) was heated at 120 °C for 3 h under microwave irradiation. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (35.0 mg, 0.072 mmol, 41.9%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.23 (6H, d, J = 6.8 Hz), 3.11-3.25 (4H, m) , 3.71-3.82 (2H, m) , 4.45-4.58 (4H, m) , 6.96 (1H, d, J = 8.3 Hz), 7.18-7.28 (2H, m) , 7.29-7.36 (1H, m) , 7.43-7.58 (3H, m) , 7.87 (2H, d, J = 8.7 Hz), 8.96 (1H, t, J = 6.4 Hz).

[0786] .. .

Example 234

4- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

A) 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid

4 N lithium hydroxide (3.86 mL, 15.45 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine- 7-carboxylate (1 g, 5.15 mmol) in MeOH (10 mL) - THF (10 mL) at room temperature. After being stirred at 60 °C for overnight, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO ₄ and concentrated in -vacuo to give crystals, which were collected by filtration and washed with IPE-hexane to give the title compound (692.9 mg, 3.85 mmol, 74.7%) as white powder. This product was subjected to the next reaction without further purification.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.41-3.50 (2H, m) , 4.11 (2H, t, J = 4.5 Hz), 7.23-7.26 (1H, m) , 7.61 (1H, brs), 8.16 (1H, d, J =

1.9 Hz) , 12.43 (1H, brs) .

[0787]

B) N- (4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide

To a solution of 3 , 4-dihydro-2H-pyrido [ 3 , 2- b] [1, 4] oxazine-7-carboxylic acid (690 mg, 3.83 mmol) , (4- (methylsulfonyl ) phenyl ) methanamine (780 mg, 4.21 mmol) and

DIPEA (1.309 mL, 7.66 mmol) in DMF (14 mL) was added 2- OH[1,2,3] triazolo [4 , 5-b] pyridin-3-yl) -1, 1,3,3- tetramethylisouronium hexafluorophosphate (V) (1747 mg, 4.60 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water to give the title compound (112 mg, 0.322 mmol, 8.42%) as white solids.

MS (ESI+), found 348.2 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.18 (3H, s), 3.37-3.49 (2H, m) , 4.06-4.16 (2H, m) , 4.51 (2H, d, J = 5.7 Hz}., .7.33-7.43 (2H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.18 (1H, d, J = 1.9 Hz), 8.84 (1H, t, J = 6.0 Hz).

[0788]

C) 4- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -

3.4-dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxamide (110 mg, 0.32 mmol),

3.5-dicyclopropylphenyl trifluoromethanesulfonate (107 mg, 0.35 mmol), Ruphos pre-catalyst (23.07 mg, 0.03 mmol), NaOtBu (91 mg, 0.95 mmol) and DME (5 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% -80% EtOAc in hexane) to give the title compound (2.3. mg, 4.57 μmol, 1.4%) as a colorless viscous oil. ¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.65-0.72 (4H, m) , 0.91-0.99 (4H, m) , 1.81-1.93 (2H, m) , 3.04 (3H, s) , 3.86-3.93 (2H, m) , 4.30-4.37 (2H, m) , 4.72 (2H, d, J = 6.0 Hz) , 6.45 (1H, t, J = 6.2 Hz) , 6.64-6.68 (1H, m) , 6.83 (2H, d, J = 2.3 Hz), 7.48-7.56 (3H, m) , 7.91 (2H, d, J = 8.7 Hz), 8.16 (1H, d, J = 2.3 Hz).

[0789]

Example 235

1- (3, 5-dicyclopropylphenyl) -N- (4-sulfamoylbenzyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) methyl 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-6-carboxylate

A mixture of methyl 2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4 ] oxazine-6-carboxylate (98 mg, 0.50 mmol) , 3,5- dicyclopropylphenyl trifluoromethanesulfonate (173 mg, 0.56 mmol), Pd ₂ (dba) ₃ (24 mg, 0.03 mmol), XPHOS (25 mg, 0.05 mmol),

K3PO ₄ (201 mg, 0.95 mmol) and toluene (5 mL) was stirred at

120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc.

The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (46.0 mg, 0.131 mmol, 26.0%) as pale yellow solids.

MS (ESI+), found 351.2 (M+H)

[0790]

B) 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid

To a mixture of methyl 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (46 mg, 0.13 mmol) and MeOH (3 mL) was added 2 M NaOH aq. (0.30 mL, 0.60 mmol) . After being stirred at 50°C for 3 h, the mixture was acidified with 1 N HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to the next reaction without further purification. [0791]

C) 1- (3, 5-dicyclopropylphenyl) -N- ( 4-sulfamoylbenzyl ) -2, 3- dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide

To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (44 mg, 0.13 mmol) , 4- (aminomethyl) benzenesulfonamide hydrochloride (46 mg, 0.21 mmol), HATU (74 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (70 μΕ, 0.40 mmol). After being stirred at room

temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) and then by preparative HPLC (L- Column 2 ODS, eluted with H ₂ 0 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (42.0 mg, 0.083 mmol, 63.6%) as white solids.

¹ H NMR (300 MHz, DMSQ-d ₆ ) 5:0.64-0.73 (4H,_ m) , 0.88-0.98 (4H, m) , 1.83-1.95 (2H, m) , 3.69-3.77 (2H, m) , 4.43-4.52 (4H, m) , 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.29 (2H, s), 7.41-7.50 (3H, m) , 7.75 (2H, d, J = 8.3 Hz), 8.89 (1H, t, J = 6.4 Hz) .

[0792]

Example 244

1- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl) pyridin-2- yl)methyl) =2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide

To a solution of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (25 mg, 0.07 mmol) , (5- (methylsulfonyl) pyridin-2-yl ) methanamine

hydrochloride (18.21 mg, 0.08 mmol) and DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (33.9 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (22.8 mg, 0.045 mmol, 60.8%) as pale-yellow amorphous solids .

¹ ti NMR (300 MHz, DMSO-d ₆ ) δ:0.64-0.73 (4H, m) , 0.88-0.97 (4H, m) , 1.83-1.95 (2H, m) , 3.30 (3H, s) , 3.70-3.80 (2H, m) , 4.42- 4.52 (2H, m) , 4.65 (2H, d, J = 6.0 Hz), 6.67 (1H, s), 6.80 (2H, d, J = 1.5 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.43-7.54 (2H, m) , 8.27 (1H, dd, J = 8.3, 2.3 Hz), 8.92-9.04 (2H, m) .

[0793]

Example 246

1- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl ) pyrimidin-2- yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6- carboxamide

A) 5- (methylsulfonyl ) pyrimidine-2-carbonitrile

A mixture of 5-bromopyrimidine-2-carbonitrile (1.00 g, 5.43 mmol), sodium methanesulfinate (844 mg, 8.27. mmol) and DMSO (10 mL) was stirred at 100 °C under nitrogen atmosphere for 20 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) , followed by suspending in IPE. The precipitate was collected by filtration and dried in vacuo to give the title compound (0.572 g, 3.12 mmol, 57.5%) as pale yellow solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.23 (3H, s), 9.34 (2H, s) .

[0794]

B) 1- (5- (methylsulfonyl ) pyrimidin-2-yl ) methanamine

hydrochloride

A mixture of 5- (methylsulfonyl) pyrimidine-2-carbonitrile (566 mg, 3.09 mmol), 6N HC1 aq. (1.0 mL, 6.00 mmol), 10% Pd-C (50% wet, 180 mg, 0.17 mmol) and MeOH (15 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 30 min. The insoluble material was removed by filtration and washed with water. The filtrate was concentrated in vacuo. The solid was suspended in MeOH, collected by filtration and dried in vacuo to give the title compound (490 mg, 2.191 mmol, 70.9%) as white solids.

MS (ESI+) , found 188.3 (M-HC1+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.47 (3H, s) , 4.47 (2H, s), 8.59 (3H, brs) , 9.37 (2H, s) .

[0795]

C) 1- (3, 5-dicyclopropylphenyl ) -N- ( (5- (methylsulfonyl ) pyrimidin- 2-yl)methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide

To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (31 mg, 0.09 mmol ) , 1- ( 5- (methylsulfonyl ) pyrimidin-2-yl ) methanamine

hydrochloride (54 mg, 0.24 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 μΤ, 0.46 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel eluted with 10% - 30% EtOAc in hexane) and crystallized from EtOH-hexane to give the title compound (11.00 mg, 0.022 mmol, 23.61%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.64-0.74 (4H, m) , 0.88-0.98 (4H, m) , 1.82-1.96 (2H, m) , 3.40 (3H, s) , 3.75 (2H, t, J = 4.3 Hz), 4.48 (2H, t, J = 4.2 Hz), 4.78 (2H, d, J = 5.9 Hz), 6.67 (1H, s), 6.81 (2H, d, J = 1.5 Hz), 7.02 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 8.1 Hz), 8.-83 (1H, t, J = 5.9 Hz), 9.23 (2H, s).

[0796]

Example 247

1- (3, 5-dicyclopropylphenyl) -N- (4- (ethylsulfonyl ) benzyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

To a solution of 1- ( 3, 5-dicyclopropylphenyl) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.09 mmol) , ( 4- (ethylsulfonyl) phenyl) methanamine hydrochloride

(23.13 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room

temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with

EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (21.7 mg, 0.042 mmol, 47.0%) as colorless amorphous solids.

1H NMR (300 MHz, DMSO-d ₆ ) 5:0.64-0.72 (4H, m) , 0.88-0.97 (4H, m) , 1.08 (3H, t, J = 7.6 Hz), 1.82-1.95 (2H, m) , 3.25 (2H, q, J = 7.6 Hz), 3.68-3.77 (2H, m) , 4.42-4.49 (2H, m) , 4.53 (2H, d, J = 6.8 Hz), 6.64-6.68 (1H, m) , 6.79 (2H, d, J = 1.5 Hz), 7.01

(1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz) , 7.82 (2H, d, J = 8.3 Hz), 8.95 (1H, t, J = 6.4 Hz) .

[0797]

Example 248

methyl ( ( ( 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4- (methylsulfonyl ) phenyl) acetate

A) (diallylamino) ( 4- (methylsulfanyl ) phenyl ) acetic acid

A mixture of (4- (methylthio) phenyl) boronic acid (3.5 g, 20.83 mmol), 2-oxoacetic acid hydrate (1.917 g, 20.83 mmol) and diallylamine (2.57 mL, 20.83 mmol) in CH ₃ CN (25 mL) was stirred at 80°C for 8h. The mixture was cooled to room temperature and white precipitates were collected using IPE to give the title compound (5.41 g, 19.50 mmol, 94%).

MS (ESI+) , found 278.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:2.48 (3H, s) 3.12 - 3.23 (2H, m) 3.25 - 3.37 (2H, m) 4.46 (1H, s) 5.11 - 5.26 (4H, m) 5.73 - 5.94 (2H, m) 7.20 (2H, d, J=8.69 Hz) 7.35 (2H, d, J=8.31 Hz). (The C0 ₂ H peak was omitted)

[0798] B) methyl (diallylamino) ( 4- (methylsulfanyl ) phenyl ) acetate

To a mixture of (diallylamino) (4- (methylsulfanyl ) phenyl) acetic acid (1.63 g, 5.88 mmol) in MeOH (10 mL) and toluene (25 mL) was added

(diazomethyl ) trimethylsilane in hexanes (14.69 mL, 8.81 mmol) at 5°C. After the mixture was stirred at room temperature for 14 hrs and concentrated in vacuo. The residue was purified by Si0 ₂ column chromatography (hexane/EA=95/5 to 80/20) to give the title compound (1.70 g, 5.83 mmol, 99%) as a colorless oil. MS (ESI+) , found 292.1 (M+H)

[0799]

C) methyl 2- (diallylamino) -2- (4- (methylsulfinyl) phenyl) acetate m-CPBA (1334 mg, 5.41 mmol) was added to a solution of methyl (diallylamino) (4- (methylsulfanyl ) phenyl) acetate (1051 mg, 3.61 mmol) in EtOAc (20 mL) at 0°C and the reaction mixture was stirred overnight at room temperature. The reaction mixture was passed through NH silica gel pad (EtOAc) and concentrated in vacuo to give the title compound (1085 mg, 3.53 mmol, 98%) as a. pale yellow oil. „

[0800]

D) methyl (4- (methylsulfonyl) phenyl) (oxo) acetate

To a mixture of methyl 2- (diallylamino) -2- (4- (methylsulfinyl ) phenyl ) acetate (1085 mg, 3.53 mmol) in MeOH (10.00 mL) , water (10.00 mL) and THF (10 mL) was added OXONE (4340 mg, 7.06 mmol) at 5°C. After the mixture was stirred at room temperature overnight, the mixture was made basic with aqueous NaHCO ₃ , and extracted with EtOAc. The organic layer was separated and washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by S1O ₂ column chromatography (hexane/EA=20/80 to 50/50) to give the title compound (264 mg, 1.090 mmol, 30.9%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.04 (3H, s) , 3.31-3.51 (2H, m) ,

3.54-3.70 (2H, m) , 3.74 (3H, s), 5.11-5.27 (4H, m) , 5.33 (1H, s)_, 5.83-6.01 (2H, m) , 7.57-7.66 (2H, m) , 7.87-7.96 (2H, m) .

[0801] E) methyl (hydroxyimino) ( 4- (methylsulfonyl ) phenyl ) acetate

Hydroxylamine hydrochloride (89 mg, 1.29 mmol) was added to a solution of methyl ( 4- (methylsulfonyl ) phenyl ) (oxo) acetate (260 mg, 1.07 mmol) in pyridine (3 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 0. IN HC1 and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 60% EtOAc in hexane) to give the title compound (247 mg, 0.960 mmol, 89.7%) as white solids.

[0802]

F) methyl amino ( 4- (methylsulfonyl ) phenyl ) acetate

A mixture of methyl (hydroxyimino) (4- (methylsulfonyl ) phenyl) acetate (240 mg, 0.93 mmol) and 10% Pd-C (50% wet, 99 mg, 0.93 mmol) in MeOH (6 mL) and THF (2.00 mL) was hydrogenated under balloon pressure at room temperature for 4 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to gi_ve__.the title compound (235 mg, 0.966 mmol, 104%) as a pale yellow oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.97 (2H, brs), 3.05 (3H, s), 3.73 (3H, s), 4.74 (1H, brs), 7.60-7.66 (2H, m) , 7.91-7.98 (2H, m) .

[0803]

G) methyl ( ( (1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4-

(methylsulfonyl ) phenyl) acetate

To a solution of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (100 mg, 0.30 mmol), methyl amino ( 4- (methylsulfonyl ) phenyl ) acetate (80 mg, 0.33 mmol) and DIPEA (0.152 mL, 0.89 mmol) in DMF (2.0 mL) was added HATU (136 mg, 0.36 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (145.8 mg, 0.260 mmol, 87%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.63-0.72 (4H, m) , 0.87-0.96 (4H, m) , 1.82-1.94 (2H, m) , 3.22 (3H, s) , 3.69 (3H, s) , 3.71-3.80 (2H, m) , 4.40-4.53 (2H, m) , 5.80 (1H, d, J = 7.6 Hz), 6.65-6.69 (1H, m) , 6.79 (2H, d, J = 1.5 Hz), 7.00 (1H, d, J = 8.3 Hz),

7.44 (1H, d, J = 7.6 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.93 (2H, d,

J = 8.3 Hz), 8.87 (1H, d, J = 7.6 Hz).

[0804]

Example 249

1- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) 2 , 6-dicyclopropylpyridin-4-ol

A mixture of 2 , 6-dibromopyridin-4-ol (1.06 g, 4.19 mmol), cyclopropylboronic acid (1.76 g, 20.49 mmol), Pd(OAc)2 (99 mg, 0.44 mmol), tricyclohexylphosphine (235 mg, 0.84 mmol) and

K3PO4 (2.76 g, 13.00 mmol) in toluene (10 mL) and water (2.0 mL) was stirred at 100°C overnight. After being cooled, the mixture was poured into water and extracted with 2-butanone. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 0%- 20% MeOH in EtOAc) to give the title compound (0.305 g, 1.741 mmol, 41.5%) as pale yellow solids.

MS (ESI+), found 176.4 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 6:0.75-0.81 (8H, m) , 1.80-1.89 (2H, m) , 6.38 (2H, s) , 10.11 (1H, s) .

[0805]

B) 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate

To a mixture of 2, 6-dicyclopropylpyridin^4-ol (305 mg, 1.74 mmol) and pyridine (10 mL) was added Tf ₂ 0 (0.35 mL, 2.07 mmol) at 0°C. After being stirred at room temperature under N ₂ overnight, the mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was washed with citric acid aq. and brine and dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (373 mg, 1.214 mmol, 69.7%) as a colorless oil. MS (ESI+), found 308.0 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.85-1.02 (8H, m) , 2.07-2.20 (2H, m) , 7.25 (2H, s) .

[0806]

C) 1- (2, 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (45 mg, 0.13 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (77 mg, 0.25 mmol), Ruphos pre-catalyst (10 mg, 0.01 mmol) and NaOtBu (33 mg, 0.34 mmol) in DME (3 mL) was stirred at 120°C for 1 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (..silica gel, eluted with 20% - 80% EtOAc in hexane and then NH silica gel, eluted with 20% - 50% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (27.0 mg, 0.054 mmol, 41.3%) as white solids. ¹ ti NMR (300 MHz, DMSO-d ₆ ) 5:0.80-0.90 (8H, m) , 1.90-2.02 (2H, m) , 3.18 (3H, s) , 3.83 (2H, t, J = 4.2 Hz), 4.45 (2H, t, J = 4.2 Hz), 4.54 (2H, d, J = 6.4 Hz), 6.93 (2H, s), 7.51-7.59 (3H, m) , 7.60-7.67 (1H, m) , 7.87 (2H, d, J = 8.7 Hz) , 9.08 (1H, t, J = 6.4 Hz) .

[0807]

Example 250

1- ( 3 , 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl ) pyridin-2- yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide

To a mixture of 1- ( 3, 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-.6-c.a.rb.oxylic acid (30 mg, 0.09 mmol) and 1- ( 5- (ethylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride (25.3 mg, 0.11 mmol). in DMF (3.000 mL) were added HATU (50.9 mg, 0.13 mmol) and DIPEA (0.047 mL, 0.27 mmol) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at room temperature and

extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (45.0 mg, 0.087 mmol, 97%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.62-0.74 (4H, m) , 0.86-1.00 (4H, m) , 1.12 (3H, t, J = 7.4 Hz), 1.83-1.96 (2H, m) , 3.39 (2H, q, J = 7.2 Hz), 3.69-3.82 (2H, m) , 4.48 (2H, t, J = 4.3 Hz), 4.67 (2H, d, J = 6.0 Hz), 6.67 (1H, s) , 6.81 (2H, d, J = 1.5 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.43-7.57 (2H, m) , 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.91-9.04 (2H, m) .

[0808]

Example 251

1- (3, 5-dicyclopropylphenyl ) -N- ( 2-hydroxy-l- (4- (methylsulfonyl ) phenyl) ethyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a stirred solution of methyl (((l-(3,5- dicyclopropylphenyl ) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazin-6- yl) carbonyl) amino) (4- (methylsulfonyl ) phenyl) acetate (130 mg, 0.23 mmol) in MeOH (3.0 mL) was added NaBH ₄ (43.8 mg, 1.16 mmol) at room temperature. ^" After being stirred at room

temperature for 1 h, the mixture was quenched with sat NaHCO ₃ aq. and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized with EtOAc-hexane to give the title compound (86.2 mg, 0.162 mmol, 69.8%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.63-0.72 (4H, m) , 0.87-0.97 (4H, m) , 1.81-1.94 (2H, m) , 3.18 (3H, s) , 3.68-3.83 (4H, m) , 4.42- 4.52 (2H, m) , 4.99-5.11 (1H, m) , 5.14-5.22 (1H, m) , 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.59 (1H, d, J = 7.9 Hz).

[0809]

Example 252

1- (2-cyano-5-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) 4-cyclopropyl-2-hydroxybenzonitrile

A mixture of 4-bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) , cyclopropylboronic acid (0.651 g, 7.58 mmol) ,

tricyclohexylphosphine (0.283 g, 1.01 mmol), Pd(OAc) ₂ (0.113 g, 0.51 mmol) and K ₃ PO ₄ (3.22 g, 15.15 mmol) in DME (10 mL) -water (2 mL) was heated at 100°C for 10 h under microwave irradiation. After cooling, the mixture was partitioned between EtOAc and IN HC1. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 40% EtOAc in hexane) to give the title compound (0.560 g, 3.52 mmol, 69.7%) as off-white solids.

[0810]

B) 2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate

To a solution of 4-cyclopropyl-2-hydroxybenzonitrile (560 mg, 3.52 mmol) in pyridine (10 mL) was added Tf ₂ 0 (0.713 mL, 4.22 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ for 4 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 15% EtOAc in hexane) to give the title compound (190 mg, 0.652 mmol, 18.54%) as a colorless oil.

MS (ESI-), found 289.9 (M-H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.79-0.87 (2H, m) , 1.14-1.26 (2H, m) , 1.95-2.05 (1H, m) , 7.11 (1H, s) , 7.14 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 7.9 Hz) .

[0811]

C) 1- ( 2-cyano-5-cyclopropylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol), 2- cyano-5-cyclopropylphenyl trifluoromethanesulfonate (75 mg, 0.26 mmol), RuPhos precatalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 20% - 100% EtOAc in hexane) to give a colorless oil. The oil was precipitated from EtOAc-IPE to give the title compound (16.00 mg, 0.033 mmol, 18.96%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.77-0.88 (2H, m) , 1.05-1.12 (2H, m) , 1.98-2.09 (1H, m) , 3.17 (3H, s) , 3.81 (2H, brs), 4.47-4.58 (4H, m) , 6.81 (1H, d, J = 8.3 Hz), 7.20 (1H, dd, J = 8.1, 1.7 Hz), 7.35 (1H, d, J = 1.5 Hz), 7.47-7.57 (3H, m) , 7.79-7.89 (3H, m) , 9.03 (1H, t, J = 5.9 Hz) .

[0812]

Example 253

1- (3, 5-dicyclopropylphenyl) -N—( (1- (methylsulfonyl ) piperidin-4- yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide

To a solution of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (30 mg, 0.09 mmol), ( 1- (methylsulfonyl ) piperidin-4-yl ) methanamine

hydrochloride (22.44 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (37.2 mg, 0.073 mmol, 82%) as colorless amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.63-0.73 (4H, m) , 0.87-0.97 (4H, m) , 1.09-1.26 (2H, m) , 1.58-1.77 (3H, m) , 1.81-1.94 (2H, m) , 2.58-2.71 (2H, m) , 2.83 (3H, s) , 3.13-3.21 (2H, m) , 3.46-3.60 (2H, m) , 3.67-3.78 (2H, m) , 4.38-4.50 (2H, m) , 6.66 (1H, s) , 6.78 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.45 (1H, d, J = 7.9 Hz), 8.26 (1H, t, J = 6.4 Hz).

[0813]

Example 254

5- (2-cyano-5-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3, 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (60 mg, 0.17 mmol), 2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate (72.7 mg, 0.25 mmol), RuPhos precatalyst (12.13 mg, 0.02 mmol), NaOtBu (48.0 mg, 0.50 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 20% - 100% EtOAc in hexane) to give a colorless oil. The oil was purified by column chromatography (silica gel, eluted with.70% - 100% EtOAc in hexane) to give the title compound (6.00 mg, 0.012 mmol, 7.19%) as a pale yellow oil.

[0814]

Example 259

4- (3, 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl) pyridin-2- yl ) methyl ) -3 , 4-dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7- carboxamide

A) methyl 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylate A mixture of methyl 3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4 ] oxazine-7-carboxylate (500 mg, 2.57 mmol), 3,5- dicyclopropylphenyl trifluoromethanesulfonate (946 mg, 3.09 mmol), XPHOS Pd G2 (203 mg, 0.26 mmol), XPHOS (123 mg, 0.26 mmol), Cs2C03 (1678 mg, 5.15 mmol) and DME (20 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (692.5 mg, 1.976 mmol, 77%) as white amorphous solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.66-0.73 (4H, m) , 0.91-0.99 (4H, m) , 1.81-1.93 (2H, m) , 3.87 (3H, s) , 3.88-3.92 (2H, m) , 4.28-4.37 (2H, m) , 6.64-6.69 (IH, m) , 6.84 (2H, d, J = 1.9 Hz), 7.59 (IH, d, J = 1.9 Hz), 8.40 (IH, d, J = 1.9 Hz).

[0815]

B) 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxylic acid

4 N lithium hydroxide (2.461 mL, 9.85 mmol) was added to a solution of methyl 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylate (690 mg, 1.97 mmol) in MeOH (6.9 mL) - THF (6.9 mL) at room temperature. After being stirred at 60 °C for lh, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc- THF. The organic layer was dried over MgSO ₄ and concentrated in vacuo to give crystals, which were collected by filtration and washed with IPE-hexane to give the title compound (578.8 mg, 1.721 mmol, 87%) as white powder.

[0816]

C) 4- (3, 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

To a solution of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro- 2H-pyrido [ 3 , 2-b] [1, 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , 1- (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (23.22 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc- The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (21.6 mg, 0.042 mmol, 46.7%) as white amorphous solids.

[0817]

Example 260

4- (3, 5-dicyclopropylphenyl ) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

To a solution of 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , (1- (methylsulfonyl ) piperidin-4-yl ) methanamine

hydrochloride (22.44 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (27.5 mg, 0.054 mmol, 60.4%) as white amorphous solids. ¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.61-0.70 (4H, m) , 0.86-0.96 (4H, m) , 1.08-1.27 (2H, m) , 1.54-1.69 (1H, m) , 1.70-1.80 (2H, m) , 1.81-1.92 (2H, m) , 2.58-2.72 (2H, m) , 2.83 (3H, s) , 3.14 (2H, t, J = 6.2 Hz), 3.47-3.61 (2H, m) , 3.80-3.92 (2H, m) , 4.22-4.34 (2H, m) , 6.59 (1H, s) , 6.84 (2H, d, J = 1.9 Hz), 7.49 (1H, d, J = 1.9 Hz), 8.12 (1H, d, J = 1.9 Hz), 8.31 (1H, t, J = 5.7 Hz) .

[0818]

Example 261 4- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide

To a solution of 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , (5- (methylsulfonyl ) pyridin-2-yl ) methanamine

hydrochloride (21.85 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (25.7 mg, 0.051 mmol, 57.1%) as white amorphous solids.

[0819]

Example 262

1- ( 3-cyclopropyl-5-methoxyphenyl) -N- (4- (methylsulfonyl) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A) 1- (benzyloxy) -3-bromo-5-methoxybenzene

To a mixture of 3-bromo-5-methoxyphenol (1.00 g, 4.93 mmol) and K ₂ CO ₃ (0.681 g, 4.93 mmol) in DMF (5 mL) was added (bromomethyl ) benzene (0.702 mL, 5.91 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs and poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by purified by column chromatography (Si0 ₂ , eluted with 0% - 10% EtOAc in hexane) to give the title

compound (1.29 g, 4.40 mmol, 89%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) δ : ppm 3.76 (3H, s) 5.01 (2H, s) 6.46

(1H, t, J=2.27 Hz) 6.65 - 6.70 (1H, m) 6.73 - 6.78 (1H, m) 7.29

- 7.45 (5H, m) .

[0820]

B) 1- (benzyloxy) -3-cyclopropyl-5-methoxybenzene

A mixture of 1- (benzyloxy) -3-bromo-5-methoxybenzene (1.26 g, 4.30 mmol), K ₃ PO ₄ (1.368 g, 6.45 mmol) and

cyclopropylboronic acid (1.108 g, 12.89 mmol) in toluene (10 mL) and H ₂ 0 (2 mL) was degassed with Ar and then Pd(OAc) ₂

(0.096 g, 0.43 mmol) was added thereto. The mixture was

stirred at 100 °C under Ar for 14 hrs and poured into water and EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%- 10% EtOAc in hexane) to give the title compound (1.05 g, 4.13 mmol, 96%) as a pale brown oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.63 - 0.76 (2H, m) 0.87 - 1.00 (2H, m) 1.77 - 1.93 (1H, m) 3.76 (3H, s) 5.02 (2H, s) 6.26 (1H, s) 6.32 (1H, s) 6.34 (1H, d, J=2.27 Hz) 7.28 - 7.47 (5H, m) .

[0821]

C) 3-cyclopropyl-5-methoxyphenol

A mixture of 1- (benzyloxy) -3-cyclopropyl-5-methoxybenzene (1.03 g, 4.05 mmol) and 10% Pd-C (50% wet, 0.259 g, 0.12 mmol) in EtOH (25 mL) was stirred under H ₂ (1 atm) at room

temperature for 24 hrs. The catalyst was removed by filtration. The filtrate was concentrated and then the residue was purified by column chromatography (silica gel, eluted with 2%- 15% EtOAc in hexane) to give the title compound (0.30 g, 1.827 mmol,

45.1%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:ppm 0.61 - 0.72 (2H, m) 0.87 - 1.00 (2H, m) 1.71 - 1.88 (1H, m) 3.76 (3H, s) 4.65 (1H, s) 6.12 - 6.16 (1H, m) 6.20 (1H, s) 6.22 - 6.26 (1H, m) .

[0822]

D) 3-cyclopropyl-5-methoxyphenyl trifluoromethanesulfonate

To a cold mixture of 3-cyclopropyl-5-methoxyphenol (0.29 g, 1.77 mmol) in pyridine (5 mL) was added Tf ₂ 0 (0.358 mL, 2.12 mmol) at 5°C. After stirring at the same temperature for 30 min, the reaction mixture was quenched with 10% aqueous citric acid and then the product was extracted with EtOAc. The

extract was washed with 10% aqueous citric acid and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5%- 20% EtOAc in hexane) to give the title compound (0.423 g, 1.428 mmo ^' l, 81%) as a colorless oil.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.64 - 0.77 (2H, m) 0.95 - 1.07 (2H, m) 1.82 - 1.96 (1H, m) 3.80 (3H, s) 6.55 (1H, d, J=1.51 Hz) 6.56 - 6.59 (1H, m) 6.60 - 6.65 (1H, m) .

[0823]

E) 1- (3-cyclopropyl-5-methoxyphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 3- cyclopropyl-5-methoxyphenyl trifluoromethanesulfonate (61.4 mg, 0.21 mmol), NaOtBu (16.60 mg, 0.17 mmol) and Ruphos pre- catalyst (12.59 mg, 0.02 mmol) in DME (3 mL) was heated at

120°C for lhr under microwave irradiation. More Ruphos pre- catalyst (12.59 mg, 0.02 mmol) was added thereto, and the mixture was heated again at 120 °C for lhr under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with aq. NH ₄ C1 and brine, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5- 95% EtOAc in hexane) to give a crude product, which was further purified by preparative HPLC to give the title compound (20 mg, 0.041 mmol, 23.46%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.65 - 0.75 (2H, m) 1.00 (5H, d,

J=6.42 Hz) 1.87 (1H, s) 3.73 - 3.77 (2H, m) 3.79 (3H, s) 4.49 - 4.56 (2H, m) 4.69 (2H, d, J=6.42 Hz) 6.46 - 6.51 (1H, m) 6.53 - 6.59 (2H, m) 7.16 (1H, d, J=8.31 Hz) 7.54 (2H, d, J=8.31 Hz) 7.68 (1H, d, J=8.31 Hz) 7.89 (2H, d, J=8.31 Hz) 8.07 - 8.16 (1H, m) .

[0824]

Example 263

5- (6-cyclopropyl-l-methyl-lH-indazol-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3, 4, 5-tetrahydro-l , 5-benzoxazepine-8- carboxamide

A) 4-bromo-2-fluoro-6-methoxybenzaldehyde

A solution of 28% NaOMe in MeOH (9.60 g, 49.77 iranol) in MeOH (50.0 mL) was added dropwise to a suspension of 4-bromo- 2, 6-difluorobenzaldehyde (10 g, 45.25 mmol) in MeOH (50 mL) at 0°C. The mixture was stirred at 50°C under N ₂ for 10 h. After cooling, the mixture was concentrated in vacuo and the residue was suspended in water. The mixture was acidified by IN HC1 and extracted with EtOAc twice. The combined organic layers were dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 15% EtOAc in hexane) to give the title compound (6.51 g, 27.9 mmol, 61.7%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.94 (3H, s) , 6.91-6.99 (2H, m) ,

10.36 (1H, d, J = 1.1 Hz) .

[0825]

B) 6-bromo-4-methoxy-lH-indazole

A mixture of 4-bromo-2-fluoro-6-methoxybenzaldehyde (6.5 g, 27.89 mmol) and hydrazine monohydrate (27.9 g, 557.86 mmol) in ethylene glycol (30 mL) was stirred at 95°C under N ₂

overnight. After cooling, the mixture was quenched with water (200 mL) at 0°C and precipitate was collected by filtration, washed with water. The obtained solid was dissolved in EtOAc and dried over MgSO ₄ . Insoluble material was removed off by filtration and the filtrate was concentrated in vacuo to give the title compound (5.90 g, 26.0 mmol, 93%)- as off-white solids. MS (ESI+), found 227.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.96 (3H, s) , 6.62 (1H, d, J = 1.1 Hz), 7.24-7.29 (1H, m) , 8.10 (1H, d, J = 0.8 Hz)-, 10.19 (1H, brs) .

[0826]

C) 6-bromo-4-methoxy-l-methyl-lH-indazole

NaH (60% in oil, 0.194 g, 4.84 mmol) was added to a solution of 6-bromo-4-methoxy-lH-indazole (1 g, 4.40 mmol) in DMF (dry) (5 mL) at 0°C. After stirring at room temperature for 10 min, Mel (0.413 mL, 6.61 mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.570 g, 2.36 mmol, 53.7 mmol) .

MS (ESI+) , found 241.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.95 (3H, s), 3.99 (3H, s), 6.58 (1H, d, J = 1.1 Hz), 7.16 (1H, t, J = 1.1 Hz), 7.98 (1H, d, J = 0.8 Hz) .

[0827]

D) 6-cyclopropyl-4-methoxy-1-methyl-lH-indazole

A mixture of 6-bromo-4-methoxy-l-methyl-lH-indazole (570 mg, 2.36 mmol), cyclopropylboronic acid (305 mg, 3.55 mmol), tricyclohexylphosphine (133 mg, 0.47 mmol), Pd(OAc) ₂ (53.1 mg, 0.24 mmol) and K ₃ PO ₄ (1506 mg, 7.09 mmol) in toluene (10 mL) and water (0.5 mL) was heated at 100 °C for 3 h under microwave irradiation. After cooling, the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% -40% EtOAc in hexane) to give the title

compound (420 mg, 2.077 mmol, 88%) as pale yellow solids.

MS (ESI+), found 203.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.75-0.82 (2H, m) , 0.93-1.05 (2H, m) , 1.98-2.08 (1H, m) , 3.93-4.01 (6H, m) , 6.22 (1H, s) , 6.66 (1H, s) , 7.94 (1H, d, J = 0.8 Hz) .

[0828]

E) 6-cyclopropyl-l-methyl-lH-indazol-4-ol

Aluminum chloride (237 mg, 1.78 mmol) was added to a solution of 6-cyclopropyl-4-methoxy-l-methyl-lH-indazole (120 mg, 0.59 mmol) and dodecyl mercaptan (0.426 mL, 1.78 mmol) in toluene (3 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with IN HC1 aq. at room temperature and adjusted pH 5 by sat. NaHCCO ₃ aq. The mixture was extracted with EtOAc, washed with brine, and dried over MgSCO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 60% EtOAc in hexane) to give the title compound (80 mg, 0.425 mmol, 71.6%) as white solids.

MS (ESI+) , found 189.4 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.65-0.73 (2H, m) , 0.90-0.98 (2H, m) , 1.89-1.99 (1H, m) , 3.91 (3H, s), 6.13 (1H, d, J = 0.8 Hz), 6.71 (1H, s), 7.88 (1H, d, J = 0.8 Hz), 9.97 (1H, s) .

[0829]

F) 6-cyclopropyl-1 -methyl-lH-indazol -4 -yl

trifluoromethanesulfonate

To a solution of 6-cyclopropyl-l-methyl-lH-indazol-4-ol

(80 mg, 0.43 mmol) in pyridine (2 mL) was added Tf ₂ 0 (0.086 mL, 0.51 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted withl0% - 50% EtOAc in hexane) to give the title compound (110 mg, 0.343 mmol, 81%) as a pale orange oil.

MS (ESI+), found 321.2 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.75-0.85 (2H, m) , 1.04-1.13 (2H, m) , 2.02-2.12 (1H, m) , 4.04-4.09 (3H, m) , 6.79 (1H, s) , 7.10 (1H, s) , 7.96 (1H, s) .

[0830]

G) 5- ( 6-cyclopropyl -1 -methyl-IH-indazol-4 -yl) -N- (4-

(methylsulfonyl) benzyl) -2, 3, 4, 5-tetrahydro-l, 5-benzoxazepine-8- carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3, 4, 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (60 mg, 0.17 mmol), 6-cyclopropyl- 1-methyl-lH-indazol-4 -yl trifluoromethanesulfonate (53.3 mg, 0.17 mmol), RuPhos

precatalyst (24.26 mg, 0.03 mmol) and NaOtBu (48.0 mg, 0.50 mmol) in DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give a brown oil. The oil was purified by column chromatography (NH silica gel, eluted with 80% - 100% EtOAc in hexane) to give white amorphous solids, which was recrystallized from EtOAc-IPE to give the title compound (9.00 mg, 0.017 mmol, 10.19%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.78 (2H, d, J = 4.9 Hz), 0.92-0.99 (2H, m) , 1.90-2.03 (3H, m) , 3.19 (3H, s) , 3.90 (3H, s), 4.00 (2H, brs), 4.22 (2H, s) , 4.54 (2H, d, J = 5.3 Hz);, 6.58 (1H, s) , 6.76-6.88 (3H, m) , 7.40 (1H, d, J = 4.4 Hz), 7.54-7.61 (3H, m) , 7.89 (2H, d, J = 7.5 Hz), 9.08 (1H, s) .

[0831]

Example 264

1- ( 6-cyclopropyl-l-methyl-lH-indazol-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol), 6- cyclopropyl-l-methyl-lH-indazol-4-yl trifluoromethanesulfonate (55.3 mg, 0.17 mmol), RuPhos precatalyst (25.2 mg, 0.03 mmol) and NaOtBu (49.8 mg, 0.52 mmol) in DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane then 0% - 5% MeOH in EtOAc) to give pale yellow

amorphous solids, which was recrystallized from EtOAc-IPE to give the title compound (31.0 mg, 0.060 mmol, 34.7%) as off- white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.76-0.89 (2H, m) , 0.98-1.02 (2H, m) , 2.03-2.13 (1H, m) , 3.18 (3H, s) , 3.90 (2H, brs), 4.02 (3H, s), 4.48-4.60 (4H, m) , 6.83-6.89 (2H, m) , 7.24 (1H, s) , 7.43 (1H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.73 (1H, s), 7.87 (2H, d, J = 8.3 Hz), 9.00 (1H, t, J = 6.4 Hz).

[0832]

Example 265

1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-

(methylsulfonyl) pyridin-2-yl) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) methyl 1- (2, 6-dicyclopropylpyridin-4-yl ) -2, 3-dihydro-lH- pyrido [2 , 3-b] [1,4] oxazine-6-carboxylate

A mixture of methyl 2 , 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate (165 mg, 0.85 mmol), 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (287 mg, 0.93 mmol), Pd ₂ (dba) ₃ (38.9 mg, 0.04 mmol), XPHOS (40.5 mg, 0.08 mmol), K ₃ PO ₄ (361 mg, 1.70 mmol) and DME (3.0 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (184.3 mg, 0.524 mmol, 61.7%) as pale yellow solids.

[0833]

B) 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid

4 N lithium hydroxide (0.647 mL, 2.59 mmol) was added to a solution of methyl 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (182 mg, 0.52 mmol) in MeOH (2.0 mL) - THF (2.0 mL) at room temperature. After being stirred at 60°C for lh, the reaction mixture was quenched with water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO ₄ and concentrated in vacuo to give the title compound (152.7 mg, 0.453 mmol, 87%) as pale yellow amorphous solids. This product was subjected to the next reaction without further purification.

[0834]

C) 1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-

(methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a solution of 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (20 mg, 0.06 mmol) , ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine

hydrochloride (14.52 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (15.7 mg, 0.031 mmol, 52.4%) as pale yellow amorphous solids .

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.80-0.92 (8H, m) , 1.91-2.02 (2H, m) , 3.30 (3H, s) , 3.80-3.90 (2H, m) , 4.41-4.51 (2H, m) , 4.67

(2H, d, J = 6.0 Hz), 6.94 (2H, s) , 7.48-7.69 (3H, m) , 8.27 (1H, dd, J = 8.3, 2.3 Hz), 9.01 (1H, d, J = 1.9 Hz), 9.11 (1H, t, J

= 6.0 Hz) .

[0835]

Example 266

1- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (ethylsulfonyl) pyridin-

2-yl ) methyl) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6- carboxamide

To a solution of 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3- dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxylic acid (20 mg, 0.06 mmol), 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine

hydrochloride (15.44 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (20.7 mg, 0.040 mmol, 67.2%) as pale yellow amorphous solids .

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.79-0.91 (8H, m) , 1.09-1.15 (3H, m) , 1.89-2.02 (2H, m) , 3.39 (2H, q, J = 7.6 Hz), 3.80-3.90 (2H, m) , 4.42-4.51 (2H, m) , 4.68 (2H, d, J = 6.2 Hz), 6.94 (2H, s) , 7.49-7.68 (3H, m) , 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.11 (1H, t, J = 6.2 Hz).

[0836]

Example 267

1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (1- (methylsulfonyl) piperidin-4-yl) methyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

To a solution of 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (20 mg, 0.06 mmol), ( 1- (methylsulfonyl ) piperidin-4-yl) methanamine hydrochloride (14.92 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title

compound (16.8 mg, 0.033 mmol, 55.4%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.79-0.91 (8H, m) , 1.10-1.28 (2H, m) , 1.63-1.77 (3H, m) , 1.89-2.02 (2H, m) , 2.59-2.74 (2H, m) , 2.83 (3H, s), 3.14-3.25 (2H, m) , 3.47-3.60 (2H, m) , 3.77-3.87 (2H, m) , 4.38-4.47 (2H, m) , 6.92 (2H, s) , 7.50-7.66 (2H, m) , 8.39 (1H, t, J = 5.7 Hz) .

[0837]

Example 268 1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( 2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) methyl ( ( ( 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4-

(methylsulfonyl) phenyl) acetate

To a solution of 1- (2, 6-dicyclopropylpyridin-4-yl ) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (70 mg, 0.21 mmol), methyl 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) acetate (55.5 mg, 0.23 mmol) and DIPEA (0.106 mL, 0.62 mmol) in DMF

(2.0 mL) was added HATU (95 mg, 0.25 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 40% - 70% EtOAc in hexane) to give the title compound (94.0 mg, 0.167 mmol, 81%) as white amorphous solids.

MS (ESI+) , found 563.2

1H NMR (300 MHz, CDC1 ₃ ) 5:0.85-0.95 (4H, m) , 0.95-1.04 (4H, m) , 1.82-1.96 (2H, m) , 3.04 (3H, s) , 3.74-3.85 (5H, m) , 4.48-4.56 (2H, m) , 5.85 (1H, d, J = 7.2 Hz), 6.73 (2H, s), 7.55 (1H, d, J = 7.9 Hz), 7.65-7.74 (3H, m) , 7.94 (2H, d, J = 8.7 Hz), 8.66 (1H, d, J = 7.2 Hz) .

[0838]

B) 1- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a mixture of methyl ( ( (1- (2, 6-dicyclopropylpyridin-4- yl) -2, 3-dihydro-lH-pyrido [2, 3-b] [ 1 , 4 ] oxazin-6- yl ) carbonyl ) amino) ( 4- (methylsulfonyl ) phenyl ) acetate (90 mg, 0.16 mmol) in MeOH (3 mL) was added NaBH ₄ (30.3 mg, 0.80 mmol) at room temperature. After being stirred at room temperature for 1 h, the mixture was quenched with sat. NaHCO ₃ aq. and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (64.2 mg, 0.120 mmol, 75%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.79-0.90 (8H, m) , 1.89-2.02 (2H, m) , 3.19 (3H, s) , 3.73-3.90 (4H, m) , 4.39-4.52 (2H, m) , 5.02- 5.12 (1H, m) , 5.16-5.24 (1H, m) , 6.93 (2H, s) , 7.49-7.55 (1H, m) , 7.58-7.67 (3H, m) , 7.88 (2H, d, J = 8.7 Hz), 8.71 (1H, d, J = 7.6 Hz) .

[0839]

Example 269

1- (3, 5-dicyclopropylphenyl) -N- (4- (S- methylsulfonimidoyl ) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) ( (E) - (4-cyanophenyl) (methyl) ^ ⁴ -sulfanylidene) cyanamide

To a mixture of 4- (methylthio) benzonitrile (3.01 g, 20.17 mmol), cyanamide (1.02 g, 24.26 mmol), KOtBu (2.70 g, 24.06 mmol) and MeOH (60 mL) was added NBS (5.33 g, 29.95 mmol).

After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was subjected to the next reaction without further purification .

[0840]

B) ((4-cyanophenyl) (methyl ) oxido^ ⁴ -sulfanylidene ) cyanamide

To a mixture of ( (E) -( 4-cyanophenyl ) (methyl) -λ ⁴ - sulfanylidene) cyanamide (3.82 g, 20.19 mmol), K ₂ CO ₃ (5.52 g, 39.94 mmol) and EtOH (50 mL) was added m-CPBA (5.94 g, 24.10 mmol) at 0°C. After being stirred at room temperature

overnight, the mixture was quenched with Na ₂ S ₂ O ₃ aq. and

extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (0.825 g, 4.02 mmol, 19.91%) as a light brown oil.

MS (ESI+) , found 206.1

¹ H NMR (300 MHz, CDC1 ₃ ) 5:3.39 (3H, s), 7.96-8.03 (2H, m) , 8.12-8.19 (2H, m) .

[0841]

C) 4- (S-methylsulfonimidoyl) benzonitrile

To a mixture of ( (4-cyanophenyl) (methyl ) oxido-λ ⁴ - sulfanylidene) cyanamide (825 mg, 4.02 mmol) and THF (30 mL) was added TFAA (1.7 mL, 12.04 mmol) at 0°C. After being stirred at room temperature for 3 h, the mixture was concentrated. The residue was dissolved in MeOH (30 mL) and K ₂ CO ₃ (2.69 g, 19.46 mmol) was added to the mixture. After being stirred at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (275 mg, 1.526 mmol, 38.0%) as white solids.

MS (ESI+) , found 181.1

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:3.13 (3H, d, J = 1.1 Hz), 4.52 (1H, s) , 8.10 (4H, s) .

[0842]

D) 1- ( 4- (S-methylsulfonimidoyl) phenyl ) methanamine hydrochloride

A mixture of 4- ( S-methylsulfonimidoyl ) benzonitrile (55 mg, 0.31 mmol), 6N HC1 aq. (0.10 mL, 0.60 mmol), 10% Pd-C (50% wet, 19 mg, 0.02 mmol) and MeOH (5 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 4 h. The

insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to the next reaction without further purification.

[0843]

E) 1- (3, 5-dicyclopropylphenyl) -N- (4- (S- methylsulfonimidoyl ) benzyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (31 mg, 0.09 mmol) , 1- ( 4- (S-methylsulfonimidoyl) phenyl ) methanamine

hydrochloride (67 mg, 0.30 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 μΐ,, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile

containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (21.00 mg, 0.042 mmol, 45.3%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.64-0.74 (4H, m) , 0.88-0.97 (4H, m) , 1.82-1.95 (2H, m) , 3.03 (3H, s) , 3.73 (1H, t, J = 3.8 Hz), 4.16 (1H, brs), 4.4.6 (2H, t, J = 3.8 Hz), 4.51 (2H, d, J = 6.4 Hz), 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.47 (3H, dd, J = 8.3, 3.8 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.91 (1H, t, J = 6.6 Hz). (An exchangeable proton was omitted)

[0844]

Example 270

1- ( 3-cyclopropyl-5- ( 1-methoxyethyl ) phenyl) -N- ( 4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) 1 , 3-dibromo-5- ( 1-ethoxyethoxy) benzene

To a mixture of 3 , 5-dibromophenol (2.04 g, 8.10 mmol), ethyl vinyl ether (1.5 mL, 15.69 mmol) and THF (20 mL) was added TsOH-H ₂ 0 (75 mg, 0.39 mmol). After being stirred at room temperature for 5 h, the mixture was quenched with sat. NaHCCO ₃ aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (2.050 g, 6.33 mmol, 78%) as a yellow oil. ^X R NMR (300 MHz , CDC1 ₃ ) 5:1.21 (3H, t, J = 7.0 Hz), 1.49 (3H, d, J = 5.3 Hz), 3.53 (1H, dq, J = 9.3, 7.1 Hz), 3.75 (1H, dq, J = 9.2, 7.1 Hz), 5.35 (1H, q, J = 5.4 Hz), 7.10-7.12 (2H, m) , 7.29 (1H, t, J = 1.5 Hz) .

[0845]

B) 1- ( 3-bromo-5- (1-ethoxyethoxy) phenyl ) ethanol

To a mixture of 1, 3-dibromo-5- ( 1-ethoxyethoxy) benzene (2.05 g, 6.33 mmol) and THF (20 mL) was added 1.6 M n-BuLi in hexane (4.3 mL, 6.88 mmol) under nitrogen atmosphere at -78 °C. After being stirred at -78 °C for 1 h, acetaldehyde (2.5 mL,

12.50 mmol) was added to the mixture. After being stirred at - 78 °C for 2 h, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30%

EtOAc in hexane) to give the title compound (0.608 g, 2.103 mmol, 33.2%) as a yellow oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.10 (3H, t, J = 7.2 Hz), 1.29 (3H, d, J = 6.4 Hz), 1.38 (3H, d, J = 5.3 Hz), 3.49 (1H, dq, J = 9.5, 7.2 Hz), 3.65 (1H, dq, J = 9.4, 7.1 Hz), 4.61-4.73 (1H, m) , 5.27 (1H, d, J = 4.5 Hz), 5.49 (1H, q, J = 5.0 Hz), 6.95 (1H, s), 7.05 (1H, t , J = 2.1 Hz), 7.13 (1H, s).

[0846]

C) l-bromo-3- (1-ethoxyethoxy) -5- ( 1-methoxyethyl ) benzene

To a mixture of 1- ( 3-bromo-5- ( 1- ethoxyethoxy) phenyl ) ethanol (608 mg, 2.10 mmol), Mel (0.40 mL, 6.40 mmol) and THF (10 mL) was added NaH (60% in oil, 101 mg, 2.53 mmol). After being stirred at room temperature for 1 h, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (579 mg, 1.910 mmol, 91%) as a pale yellow oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.09 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.39 (3H, d, J = 5.3 Hz), 3.13 (3H, s) , 3.50 (1H, dq, J = 9.2, 7.1 Hz), 3.65 (1H, dq, J = 9.5, 7.2 Hz), 4.23-4.34 (1H, m) , 5.52 (1H, q, J = 5.2 Hz), 6.91-6.96 (1H, m) , 7.07-7.14 (2H, m) .

' [0847]

D) l-cyclopropyl-3- ( 1-ethoxyethoxy) -5- ( 1-methoxyethyl) benzene

A mixture of l-bromo-3- ( 1-ethoxyethoxy) -5- ( 1- methoxyethyl ) benzene (578 nag, 1.91 mmol) , cyclopropylboronic acid (322 mg, 3.75 mmol), Pd(OAc) ₂ (44 mg, 0.20 mmol),

tricyclohexylphosphine (111 mg, 0.40 mmol) and K3PO4 (1.23 g, 5.79 mmol) in toluene (20 mL) and water (4 mL) was stirred under nitrogen atmosphere at 100 °C overnight. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1%- 5% EtOAc in hexane) to give the title compound (485 mg, 1.835 mmol, 96%) as a yellow oil.

λΗ NMR (300 MHz, DMSO-d ₆ ) 5:0.61-0.69 (2H, m) , 0.88-0.98 (2H, m) , 1.09 (3H, t, J = 7.0 Hz), 1.28 (3H, d, J = 6.8 Hz), 1.37

(3H, d, J = 4.9 Hz), 1.81-1.94 (1H, m) , 3.10 (3H, s) , 3.41-3.55 (1H, m) , 3.58-3.71 (1H, m) , 4.16-4.27 (1H, m) , 5.38-5.49 (1H, m) , 6.54 (1H, s) , 6.62-6.70 (2H, m) .

[0848]

E) 3-cyclopropyl-5- ( 1-methoxyethyl) phenol

To a mixture of l-cyclopropyl-3- ( 1-ethoxyethoxy) -5- ( 1- methoxyethyl) benzene (485 mg, 1.83 mmol) and THF (15 mL) was added HC1 (2.7 mL, 5.40 mmol). After being stirred at room temperature for 3 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 20%

EtOAc in hexane) to give the title compound (340 mg, 1.768 mmol, 96%) as a yellow oil.

MS (ESI+), found 191.1 ¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.55-0.63 (2H, m) , 0.85-0.94 (2H, m) , 1.26 (3H, d, J = 6.4 Hz), 1.75-1.87 (1H, m) , 3.08 (3H, s), 4.14 (1H, q, J = 6.4 Hz), 6.31 (1H, t, J = 2.1 Hz), 6.42-6.48 (2H, m) , 9.20 (1H, s) .

[0849]

F) 3-cyclopropyl-5- (1-methoxyethyl ) phenyl

trifluoromethanesulfonate

To a mixture of 3-cyclopropyl-5- ( 1-methoxyethyl) phenol (340 mg, 1.77 mmol) and pyridine (10 mL) was added Tf ₂ 0 (0.36 mL, 2.13 mmol) at 0°C. After being stirred at room temperature under N ₂ overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with 0. IN HC1 and brine and dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (484 mg, 1.492 mmol, 84%) as a colorless oil.

MS (ESI+) , found 323.0

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.68-0.77 (2H, m) , 1.00-1.11 (2H, m) , 1.40 (3H, d, J = 6.4 Hz), 1.87-2.00 (1H, m) , 3.23 (3H, s) , 4.27 (1H, q, J = 6.4 Hz), 6.81-6.85 (1H, m) , 6.97-7.00 (1H, m) , 7.01-7.05 (1H, m) .

[0850]

G) 1- ( 3-cyclopropyl-5- (1-methoxyethyl) phenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (59 mg, 0.17 mmol), 3- cyclopropyl-5- ( 1-methoxyethyl ) phenyl trifluoromethanesulfonate (115 mg, 0.35 mmol), Ruphos pre-catalyst (14 mg, 0.02 mmol) and NaOtBu (35 mg, 0.36 mmol) in DME (3 mL) was stirred at 120°C for 2 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (54.0 mg, 0.104 mmol, 61.0%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.66-0.75 (2H, m) , 0.91-1.00 (2H, m) , 1.33 (3H, d, J = 6.4 Hz), 1.88-2.02 (1H, m) , 3.14 (3H, s) , 3.17 (3H, s), 3.77 (2H, t, J = 4.0 Hz), 4.28 (1H, q, J = 6.2 Hz), 4.44-4.50 (2H, m) , 4.53 (2H, d, J = 6.4 Hz), 6.89 (1H, s) , 6.93 (1H, s), 7.02 (1H, s) , 7.07 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz) , 8.97 (1H, t, J = 6.6 Hz).

[0851]

Example 271

1- (3, 5-dicyclopropylphenyl) -N- (4- (N, S- dimethylsulfonimidoyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) 4- (N, S-dimethylsulfonimidoyl) benzonitrile

To a mixture of 4- ( S-methylsulfonimidoyl ) benzonitrile (109 mg, 0.60 mmol) and formic acid (3 mL, 0.60 mmol) was added paraformaldehyde (55 mg, 1.83 mmol) . After being stirred at 100°C overnight, the mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (30.0 mg, 0.154 mmol, 25.5%) as white solids.

MS (ESI+), found 195.1 (M+H)

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:2.46 (3H, s) , 3.20 (3H, s), 7.97- 8.04 (2H, m) , 8.08-8.16 (2H, m) .

[0852]

B) 1- ( 4- (N, S-dimethylsulfonimidoyl ) phenyl ) methanamine

hydrochloride

A mixture of 4- (N, S-dimethylsulfonimidoyl ) benzonitrile (29 mg, 0.15 mmol), 6N HC1 aq. (50 \iL, 0.30 mmol), 10% Pd-C (50% wet, 10 mg, 9.40 μmol) and MeOH (5 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 6 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to the next reaction without further purification.

MS (ESI+), found 199.1 (M-HC1+H)

[0853]

C) 1- (3, 5-dicyclopropylphenyl) -N- (4- (N, S- dimethylsulfonimidoyl) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [1, 4] oxazine-6-carboxamide

To a mixture of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.09 mmol ) , 1- ( 4- (N, S-dimethylsulfonimidoyl ) phenyl) methanamine hydrochloride (35 mg, 0.15 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 yL, 0.46 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc . The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile

containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (20.00 mg, 0.039 mmol, 43.4%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.63-0.73 (4H, m) , 0.88-0.98 (4H, m) , 1.83-1.95 (2H, m) , 2.45 (3H, s) , 3.07 (3H, s) , 3.73 ^' (2H, t, J = 4.2 Hz), 4.43-4.49 (2H, m) , 4.52 (2H, d, J = 6.4 Hz), 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.1 Hz), 7.44-7.55 (3H, m) , 7.76 (2H, d, J = 8.3 Hz), 8.93 (1H, t, J = 6.4 Hz) .

[0854]

Example 272

5- (2 , 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (100 mg, 0.28 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (102 mg, 0.33 mmol) , Ruphos pre-catalyst (20.22 mg, 0.03 mmol) , NaOtBu

(80 mg, 0.83 mmol) and DME (3.5 mL) was heated at 120°C for 1 h under microwave irradiation. The mixture was diluted with

EtOAc and filtered through celite. The filtrate was evaporated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 10% - 100% EtOAc in hexane) and column chromatography (NH, silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (33.0 mg, 0.064 mmol,

22.98%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.69-0.82 (8H, m) , 1.80 (2H, brs) , 1.95-2.09 (2H, m) , 3.19 (3H, s) , 3.89 (2H, brs), 4.00-4.11 (2H, m) , 4.56 (2H, d, J = 6.0 Hz), 6.46 (2H, s), 7.49-7.64 (5H, m) , 7.82-7.92 (2H, m) , 9.17 (1H, s) .

[0855]

Example 273

1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-fluoro-4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

To a mixture of 1- ( 2 , 6-dicyclopropylpyridin-4-yl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (25 mg, 0.07 mmol), (2-fluoro-4- (methylsulfonyl ) phenyl ) methanamine hydrochloride (26 mg, 0.11 mmol), HATU (54 mg, 0.14 mmol) and DMF (2 mL) was added DIPEA (40 μΐ^ 0.23 mmol). After being stirred at room temperature overnight, the reaction mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq.

and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (20.00 mg, 0.038 mmol, 51.6%) as white solids. ¹ R NMR (300 MHz, DMSO-d ₆ ) 5:0.80-0.90 (8H, m) , 1.91-2.03 (2H, m) , 3.25 (3H, s) , 3.80-3.89 (2H, m) , 4.42-4.49 (2H, m) , 4.57 (2H, d, J = 6.0 Hz), 6.93 (2H, s), 7.50-7.60 (2H, m) , 7.61-7.68 (1H, m) , 7.71-7.81 (2H, m) , 9.05 (1H, t, J = 6.0 ,Hz).

[0856] .

Example 274

1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl ) ethyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide (shorter retention time)

Optical resolution of 1- ( 2 , 6-dicyclopropylpyridin-4-yl ) -

N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl) ethyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.11 mmol) was performed by preparative chiral HPLC. The factions with a shorter retention time gave the title compound (23.8 mg, 39.7%) as white amorphous solids.

Preparative chiral HPLC condition, Column : CHIRALPAK AD

(NF001); Column Size : 50 mmID x 500 mmL; Eluent :

Hexane/EtOH=200/800 (v/v) ; Flow rate : 60 mL/min; Pressure : 0.2 Mpa; Detector & sens. : UV 220 nm; Temperature :30°C

[0857]

Example 275

1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide (longer retention time)

Optical resolution of 1- (2, 6-dicyclopropylpyridin-4-yl) -

N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.11 mmol) was performed by preparative chiral HPLC. The factions with a longer retention time gave the title compound (26.0 mg, 43.3%) as white amorphous solids. The preparative chira;l HPLC

condition was the same as described in Example 274.

[0858]

Example 276

4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl ) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide

A) methyl 4- (2, 6-dicyclopropylpyridin-4-yl ) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxylate

A mixture of methyl 3 , 4-dihydro-2H-pyrido [ 3 , 2- b] [1, 4] oxazine-7-carboxylate (240 mg, 1.24 mmol) , 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (418 mg, 1.36 mmol), XPHOS Pd G2 (97 mg, 0.12 mmol), XPHOS (58.9 mg, 0.12 mmol), Cs ₂ CO ₃ (805 mg, 2.47 mmol) and DME (5.0 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was dried over MgSCu and

concentrated. The residue was purified by column

chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (346.3 mg, 0.985 mmol, 80%) as pale yellow amorphous solids. This product was subjected to the next reaction without further purification.

MS (ESI+) , found 352.3

[0859]

B) 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxylic acid

4 N lithium hydroxide (1.227 mL, 4.91 mmol) was added to a solution of methyl 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylate (345 mg, 0.98 mmol) in MeOH (3.5 mL) - THF (3.5 mL) at room temperature. After being stirred at 60°C for 1 h, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO ₄ and

concentrated in vacuo to give the title compound (276.7 mg, 0.820 mmol, 84%) as pale yellow amorphous solids.

MS (ESI+), _. found 338.2

- ¹ H MR (300 MHz, DMSO-d ₆ ) 5:0.82-0.89 (8H, m) , 1.89-2.04 (2H, m) , 3.91-4.01 (2H, m) , 4.27-4.38 (2H, m) , 7.13 (2H, s) , 7.51 (1H, d, J = 1.9 Hz), 8.29 (1H, d, J = 1.9 Hz), 12.85 (1H, brs) .

[0860]

C) 4- ( 2 , 6-dicyclopropylpyridin-4-yl ) -N- ( ( 5- (methylsulfonyl) pyridin-2-yl) methyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide

To a solution of 4- (2 , 6-dicyclopropylpyridin-4-yl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) , (5- (methylsulfonyl ) pyridin-2-yl) methanamine

hydrochloride (14.52 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (19.1 mg, 0.038 mmol, 63.7%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.83-0.89 (8H, m) , 1.88-2.01 (2H, m) , 3.31 (3H, s) , 3.91-4.01 (2H, m) , 4.28-4.38 (2H, m) , 4.65 (2H, d, J = 5.7 Hz), 7.13 (2H, s), 7.58 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 8.34 (1H, d, J = 2.3 Hz), 9.00 (1H, d, J = 1.9 Hz), 9.16 (1H, t, J = 5.9 Hz) .

[0861]

Example 277

4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (ethylsulfonyl) pyridin- 2-yl) methyl) -3 , 4-dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7- carboxamide

To a solution of 4- (2 , 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), 1- (5- (ethylsulfonyl) pyridin-2-yl) methanamine

hydrochloride (15.44 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at. room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (25.8 mg, 0.050 mmol, 84%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.80-0.90 (8H, m) , 1.12 (3H, t, J = 7.6 Hz), 1.90-2.01 (2H, m) , 3.39 (2H, q, J = 7.6 Hz), 3.91-4.00 (2H, m) , 4.30-4.38 (2H, m) , 4.66 (2H, d, J = 6.0 Hz), 7.13 (2H, s), 7.59 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.25 (1H, dd, J = 8.3, 1.9 Hz), 8.34 (1H, d, J = 1.9 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.16 (1H, t, J = 6.0 Hz).

[0862]

Example 278

4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (1- (methylsulfonyl ) piperidin-4-yl) methyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), ( 1- (methylsulfonyl) piperidin-4-yl ) methanamine hydrochloride (14.92 mg, 0.07 mmol) and DIPEA (0.030 rtiL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSC^ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (17.1 mg, 0.033 mmol, 56.4%) as white crystals .

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.79-0.90 (8H, m) , 1.11-1.28 (2H, m) , 1.57-1.71 (1H, m) , 1.71-1.83 (2H, m) , 1.88-1.99 (2H, m) , 2.58-2.74 (2H, m) , 2.83 (3H, s) , 3.12-3.20 (2H, m) , 3.48-3.61 (2H, m) , 3.88-3.99 (2H, m) , 4.27-4,37 (2H, m) , 7.12 (2H, s),

7.60 (1H, d, J = 1.9 Hz), 8.27 (1H, d, J = 1.9 Hz), 8.42 (1H, t,

J = 5.7 Hz) .

[0863]

Example 279

4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) , (4- (methylsulfonyl) phenyl) methanamine (12.08 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50 - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (25.2 mg, 0.050 mmol, 84%) as white crystals.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.86 (8H, s) , 1.89-1.99 (2H, m) , 3.19 (3H, s), 3.91-3.99 (2H, m) , 4.29-4.38 (2H, m) , 4.56 (2H, d, J = 6.0 Hz), 7.13 (2H, s) , 7.56 (2H, d, J = 8.7 Hz), 7.64 (1H, d, J = 1.9 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.32 (1H, d, J = 1.9 Hz) , 9.07 (1H, t, J = 6.0 Hz) .

[0864]

Example 280

4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-fluoro-4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxamide

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [ 3 , 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), 4- (2, 6-dicyclopropylpyridin-4-yl ) -3, 4-dihydro-2H- pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was ^' stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and ^■ concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (17.8 mg, 0.034 mmol, 57.5%) as white crystals.

1H NMR (300 MHz, DMSO-d ₆ ) 5:0.77-0.93 (8H, m) , 1.87-2.00 (2H, m) , 3.26 (3H, s) , 3.90-4.00 (2H, m) , 4.27-4.38 (2H, m) , 4.56 (2H, d, J = 5.7 Hz), 7.13 (2H, s) , 7.56-7.67 (2H, m) , 7.71-7.82 (2H, m) , 8.32 (1H, d, J = 2.3 Hz), 9.05 (1H, t, J = 5.7 Hz).

[0865]

Example 281

4- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl) ethyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxamide

A) methyl ( ( (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazin-7-yl) carbonyl) amino) (1- (methylsulfonyl) piperidin-4-yl ) acetate

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (60 mg, 0.18 mmol), methyl 2-amino-2- ( 1- (methylsulfonyl ) piperidin-4- yl)acetate hydrochloride (56.1 mg, 0.20 mmol) and DIPEA (0.091 mL, 0.53 mmol) in DMF (2.0 mL) was added HATU (81 mg, 0.21 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 50 - 100% EtOAc in hexane) to give the title compound (93.5 mg, 0.164 mmol, 92%) as white amorphous solids.

MS (ESI+) , found 570.2

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.77-0.91 (8H, m) , 1.25-1.51 (2H, m) , 1.65-1.86 (2H, m) , 1.87-2.02 (3H, m) , 2.62-2.75 (2H, m) , 2.85 (3H, s) , 3.52-3.64 (2H, m) , 3.66 (3H, s), 3.91-4.00 (2H, m) , 4.27-4.45 (3H, m) , 7.14 (2H, s) , 7.65 (1H, d, J = 1.9 Hz), 8.33 (1H, d, J = 1.9 Hz), 8.57 (1H, d, J = 7.6 Hz).

[0866]

B) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl ) ethyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxamide

To a mixture of methyl 2- ( 4- (2 , 6-dicyclopropylpyridin-4- yl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamido) -2- (1- (methylsulfonyl) piper.idin-4-yl ) acetate (90 mg, 0.16 mmol) in MeOH (3 mL) was added NaBH ₄ (29.9 mg, 0.79 mmol) at room

temperature. After being stirred at room temperature for 2 h, the mixture was quenched with sat. NaHCO ₃ aq. and extracted with EtOAc. The organic layer was separated and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (68.7 mg, 0.127 mmol, 80%) as white amorphous solids.

[0867]

Example 282

4- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4-

(methylsulfonyl) phenyl) ethyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide

A) methyl ( ( (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazin-7-yl) carbonyl) amino) (4- (methylsulfonyl) phenyl) acetate

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (70 mg, 0.21 mmol), methyl 2-amino-2- (4- (methylsulfonyl) phenyl) acetate (55.5 mg, 0.23 mmol) and DIPEA (0.106 mL, 0.62 mmol) in DMF (2.0 mL) was added HATU (95 mg, 0.25 mmol) at room temperature. The mixture was stirred at room temperature for lh. The

mixture was quenched with sat. NaHCO ₃ aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (92.6 mg, 0.165 mmol, 79%) as white amorphous solids.

MS (ESI+) , found 563.2

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.79-0.91 (8H, m) , 1.88-1.98 (2H, m) , 3.23 (3H, s) , 3.68 (3H, s), 3.90-3.99 (2H, m) , 4.28-4.38 (2H, m) , 5.84 (1H, d, J = 7.2 Hz), 7.13 (2H, s), 7.67 (1H, d , J = 1.9 Hz), 7.75 (2H, d, J = 8.3 Hz), 7.95 (2H, d , J = 8.3 Hz), 8.34 (1H, d, J = 1.9 Hz ) , 9.23 (1H, d, J = 7.2 Hz) .

[0868]

B) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( 2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxamide

To a mixture of methyl 2- (4- (2, 6-dicyclopropylpyridin-4- yl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamido) -2- (4- (methylsulfonyl ) phenyl) acetate (90 mg, 0.16 mmol) in MeOH (3.0 mL) was added NaBH ₄ (30.3 mg, 0.80 mmol) at room

temperature. After being stirred at room temperature for 2 h, the mixture was quenched with sat. NaHCO ₃ aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (72.3 mg, 0.135 mmol, 85%) as white amorphous solids.

[0869]

Example 283

5- ( 6-cyclopropyl-l-methyl-IH-pyrazolo [ 3 , 4-b] pyridin-4-yl ) -N- ( 4- (methylsulfonyl) benzyl) -2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8- carboxamide

A) 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-ol

A mixture of l-methyl-lH-pyrazol-5-amine (200 mg, 2.06 mmol) and ethyl 3-cyclopropyl-3-oxopropanoate (322 mg, 2.06 mmol) in AcOH (3 mL) was stirred at 100°C overnight. The mixture was concentrated in vacuo. The residue was washed with EtOAc-IPE and dried in vacuo to give the title compound (65.0 mg, 0.344 mmol, 16.68%) as off-white solids.

MS (ESI+) , found 190.4

¹ H NMR (400 MHz, DMSO-d ₆ ) δ : 0.93-0.99 (2H, m) , 1.07-1.13 (2H, m) , 2.15 (1H, s), 3.84 (3H, s), 5.90 (1H, brs) , 7.90 (1H, s), 10.90-11.90 (1H, br) .

[0870] B) 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-yl trifluoromethanesulfonate

Tf ₂ 0 (0.070 mL, 0.41 mmol) was added to a solution of 6- cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-ol (65 mg, 0.34 mmol) in pyridine (2 mL) at 0°C. The mixture was stirred at room temperature under N ₂ for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (92 mg, 0.286 mmol, 83%) as a colorless oil.

MS (ESI+) , found 322.2

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.09-1.21 (2H, m) , 1.23-1.37 (2H, m) , 2.29 (1H, tt, J = 8.3, 4.9 Hz), 4.07 (3H, s) , 6.48 (1H, s), 8.08 (1H, s) .

[0871]

C) 5- ( 6-cyclopropyl-l-methyl-IH-pyrazolo [3 , 4-b] pyridin-4-yl ) -N- (4- (methylsulfonyl ) benzyl) -2,3,4, 5-tetrahydro-l, 5- benzoxazepine-8-carboxamide

A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (65 mg, 0.18 mmol), 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-yl

trifluoromethanesulfonate (87 mg, 0.27 mmol), Ruphos

precatalyst (13.14 mg, 0.02 mmol) and NaOtBu (52.0 mg, 0.54 mmol) in DME (3 mL) was stirred under microwave irradiation at 120°C for 3h. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give a colorless oil. The oil was triturated with EtOAc-IPE and the precipitates were dried in vacuo to give the title compound (21.00 mg, 0.040 mmol, 21.90%) as white powder.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.84-0.90 (2H, m) , 1.01-1.08 (2H, m) , 2.03-2.11 (3H, m) , 3.19 (3H, s) , 3.88 (3H, s) , 4.05-4.21 (4H, m) , 4.57 (2H, d, J = 6.0 Hz), 6.13 (1H, s), 7.39 (1H, d, J = 8.3 Hz), 7.56-7.65 (4H, m) , 7.86-7.92 (3H, m) , 9.19 (1H, s) .

[0872]

Example 284

(2S) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5-

(methylsulfonyl) pyridin-2-yl ) methyl ) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) tert-butyl ( (2S) -1- ( (3-bromopyridin-2-yl) oxy) propan-2- yl ) carbamate

ADDP (10.88 g, 43.10 mmol) was added to a solution of 3- bromopyridin-2-ol (5 g, 28.74 mmol), ( S ) -tert-butyl (1- hydroxypropan-2-yl ) carbamate (6.04 g, 34.48 mmol) and BU3P

(10.64 mL, 43.10 mmol) in THF (dry) (96 mL) at room temperature. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was concentrated in vacuo to half volume, filtered with washing with IPE and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (5.46 g, 16.49 mmol, 57.4%) as a colorless oil.

1R NMR (300 MHz, CDC1 ₃ ) 5:1.26-1.33 (3H, m) , 1.44 (9H, s) , 4.12 (1H, q, J = 6.9 Hz), 4.25-4.40 (2H, m) , 4.82 (1H, brs) , 6.78 (1H, dd, J = 7.6, 4.9 Hz), 7.81(1H, dd, J = 7.7, 1.7 Hz), 8.02- 8.13 (1H, m) .

[0873]

B) ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2-amine

To tert-butyl ( ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2- yl) carbamate (5000 mg, 15.10 mmol) was added TFA (15 mL, 194.70 mmol). The mixture was stirred at room temperature for 10 min, concentrated in vacuo. The residue was neutralized with sat. NaHCO ₃ aq. and extracted with EtOAc-THF (twice.) . The organic layer was separated, washed with water and brine, dried over MgSCO ₄ and concentrated in vacuo to give the title compound

(3500 mg, 15.15 mmol, 100%) as a colorless oil. This product was subjected to the next reaction without further purification.

¹ H NMR (300 MHz, CDC1 ₃ ) 6:1.43 (3H, d, J = 6.8 Hz), 3.75 (1H, td, J = 6.7, 3.6 Hz), 4.35-4.46 (1H, m) , 4.49-4.61 (1H, m) , 6.84 (1H, dd, J = 7.6, 4.9 Hz), 7.83 (1H, d, J = 7.6 Hz), 8.06 (1H, d, J = 4.2 Hz). (The NH ₂ proton was omitted.)

[0874]

C) (3S) -3-methyl-3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine

To a solution of ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan- 2-amine (3500 mg, 15.15 mmol) , t-Bu ₃ P (613 mg, 3.03 mmol) and KOtBu (3399 mg, 30.29 mmol) in THF (dry) (15 mL)- was added

Pd2(dba) ₃ (1387 mg, 1.51 mmol) at room temperature. The mixture was stirred at 70°C under Ar for 3 h. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (1070 mg, 7.12 mmol, 47.0%) as light brown solids.

MS (ESI+) , found 151.0 (M+H)

[0875]

D) (2S) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine

NBS (1.395 g, 7.84 mmol) was added to a solution of (S)-

2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine (1.07 g, 7.12 mmol) in DMF (11.87 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc (twice) . The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 60% EtOAc in hexane) to give the title

compound (1.010 g, 4.41 mmol, 61.9%) as pale yellow solids. MS (ESI+) , found 229.0

¹ H NMR (300 MHz, CDC1 ₃ ) δ:1.20 (3H, d, J = 6.4 Hz), 3.50-3.62 (1H, m) , 3.75 (1H, brs) , 3.92 (1H, dd, J = 10.8, 8.1 Hz), 4.34 (1H, dd, J = 10.8, 2.8 Hz), 6.73(1H, d, J = 7.9 Hz), 6.90 (1H, d, J = 7.9 Hz) .

[0876]

E) tert-butyl (2S) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4 ] oxazine-l-carboxylate

DMAP (539 mg, 4.41 mmol) was added dropwise to a solution of (S) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2,3- b] [1, 4] oxazine (1010 mg, 4.41 mmol) and Boc ₂ 0 (1.536 mL, 6.61 mmol) in THF (14.70 mL) at 0°C. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 15% - 50% EtOAc in hexane) to give the title compound (1170 mg, 3.55 mmol, 81%) as a pale yellow oil. MS (ESI+), found 329.0 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.23 (3H, d, J = 6.8 Hz), 1.55 (9H, s), 4.18-4.30 (2H, m) , 4.57-4.70 (1H, m) , 7.07 (1H, d, J = 8.3 Hz) , 8.23 (1H, d, J = 8.3 Hz) .

[0877]

F) 1-tert-butyl 6-methyl (2S) -2-methyl-2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate

A mixture of tert-butyl (2S) -6-bromo-2-methyl-2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (1.1695 g, 3.55 mmol), Pd (dppf) C1 ₂ -CH ₂ C1 ₂ (0.145 g, 0.18 mmol) and TEA (0.990 mL, 7.11 mmol) in DMF (13.16 mL) and MeOH (22.37 mL) was stirred under CO atmosphere (0.5 MPa) at 100°C for 5h. After cooling, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The

residue was purified by column chromatography (silica gel, eluted with 15% -60% EtOAc in hexane) to give the title

compound (0.940 g, 3.05 mmol, 86%) as a pale yellow oil.

MS (ESI+), found 309.1 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.24-1.30 (3H, m) , 1.52-1.60 (9H, m) , 3.90-3.98 (3H, m) , 4.21-4.34 (2H, m) , 4.64 (1H, q, J = 6.8 Hz), 7.74-7.82 (1H, m) , 8.55(1H, d, J = 8.3 Hz).

[0878]

G) (2S) -1- (tert-butoxycarbonyl) -2-methyl-2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid

A mixture of 1-tert-butyl 6-methyl ( 2S ) -2-methyl-2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (110 mg, 0.36 initio1) and 2N NaOH (0.535 mL, 1.07 mmol) in THF (2 mL) and MeOH (1 mL) was stirred at room temperature for 3h. The

mixture was acidified with IN HC1 aq. at 0°C and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO ₄ and concentrated in vacuo to give the title compound (103 mg, 0.350 mmol, 98%) as pale yellow amorphous solids.

MS (ESI+), found 295.3 (M+H)

1R NMR (300 MHz, CDC1 ₃ ) 5:1.22-1.37 (3H, m) , 1.58 (9H, s) , 4.33 (2H, dd, J = 4.9, 1.9 Hz), 4.70 (1H, dt, J = 7.0, 1.8 Hz), 7.85 (1H, d, J = 8.3 Hz), 8.64 (1H, d, J = 8.3 Hz). (The C0 ₂ H peak was omitted. )

[0879]

H) tert-butyl (2S) -2-methyl-6- (( (5- (methylsulfonyl) pyridin-2- yl ) methyl ) carbamoyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine- 1-carboxylate

HATU (186 mg, 0.49 mmol) was added to a solution of (2S)- 1- (tert-butoxycarbonyl) -2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid (103 mg, 0.35 mmol), (5-

(methylsulfonyl) pyridin-2-yl ) methanamine hydrochloride (78 mg, 0.35 mmol) and DIPEA (199 mg, 1.54 mmol) in DMF (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (120 mg, 0.259 mmol, 74.1%) as off-white amorphous solids.

MS (ESI+) , found 463.2

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.28 (3H, d, J = 6.9 Hz), 1.57 (9H, s), 3.09 (3H, s), 4.27-4.36 (2H, m) , 4.68 (1H, d, J = 7.2 Hz), 4.85 (2H, d, J = 6.4 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.86 (1H, d, J = 8.3 Hz), 8.17 (1H, dd, J = 8.1, 2.5 Hz), 8.46-8.59 (2H, m) , 9.10 (1H, d, J = 2.7 Hz).

[0880]

I) (2S) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl) methyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide

A mixture of tert-butyl (2S) -2-methyl-6- ( ( (5-

(methylsulfonyl ) pyridin-2-yl ) methyl) carbamoyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (120 mg, 0.26 mmol) and TFA (1 mL, 12.98 mmol) in EtOAc (0.5 mL) was stirred at room temperature for 3h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (95 mg, 0.262 mmol, 101%) as white solids.

MS (ESI+) , found 363.2

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.09-1.20 (3H, d, J = 6.6 Hz), 3.30 (3H, s), 3.53 (1H, brs) ^' , 3.87 (1H, dd, J = 11.0/ 7.6 Hz), 4.33 (1H, dd, J = 10.6, 1.5 Hz), 4.63 (2H, d, J = 6.0 Hz), 6.81-6.88 (1H, m) , 6.95 (1H, d, J = 7.9 Hz), 7.49 (2H, t, J = 8.1 Hz), 8.26 (1H, dd, J = 8.3, 2.3 Hz), 8.87 (1H, t, J = 6.0 Hz), 8.99 (1H, d, J = 2.5 Hz) .

[0881]

J) (2S) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of ( 2S ) -2-methyl-N- (( 5- (methylsulfonyl ) pyridin-

2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6- carboxamide (60 mg, 0.17 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (153 mg, 0.50 mmol), Ruphos

precatalyst ^' (12.06 mg, 0.02 mmol), Ruphos (7.73 mg, 0.02 mmol) and NaOtBu (47.7 mg, 0.50 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling,

insoluble material was removed off by filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 10% MeOH in EtOAc) and column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale yellow amorphous solid, which was washed with EtOAc-IPE and dried in vacuo to give the title compound (3.00 mg, 5.77 μmol, 27.3%) as white amorphous solids .

1H NMR (300 MHz, CDC1 ₃ ) 5:0.85-1.05 (8H, m) , 1.39 (3H, d, J = 6.8 Hz), 1.82-1.92 (2H, m) , 3.09 (3H, s) , 4.01-4.10 (1H, m) , 4.36 (2H, d, J = 2.3 Hz), 4.86 (2H, d, J = 6.4 Hz), 6.72 (2H, s), 7.48 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 8.3 Hz), 8.17 (1H, dd, J = 8.3, 2.3 Hz), 8.45 (1H, t, J = 6.0 Hz), 9.11 (1H, d, J = 1.9 Hz).

[0882]

Example 285

1- (2-cyano-5-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) - 1,2,3, 4-tetrahydropyrido [2 , 3-b] [1,4] oxazepine-7-carboxamide

A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3, 4, 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (35 mg, 0.10 mmol) ,

2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate (42.4 mg, 0.15 mmol), Ruphos precatalyst (7.08 mg, 9.71 pmol) and NaOtBu (28.0 mg, 0.29 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (3.00 mg, 5.97 μmol, 6.15%) as pale yellow amorphous solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.74-0.94 (2H, m) , 1.07-1.19 (2H, m) , 1.87-1.96 (1H, m) , 2.18 (2H, t, J = 6.0 Hz), 3.03 (3H, s) , 4.04-4.12 (2H, m) , 4.63-4.72 (4H, m) , 6.85-6.91 (2H, m) , 6.98 (1H, d, J = 1.5 Hz), 7.54 (3H, dd, J = 8.1, 5.1 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.90 (2H, d, J = 7.6 Hz), 8.17 (1H, t, J = 6.2 Hz) .

[0883]

Example 286

4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) chromane-7-carboxamide A) 4-oxochromane-7-carbonitrile

A mixture of 7-bromochroman-4-one (1.99 g, 8.76 mmol) , zinc cyanide (1.23 g, 10.48 mmol), Pd(Ph ₃ P) ₄ (295 mg, 0.26 mmol) and DMF (20 mL) was stirred at 80°C under nitrogen atmosphere overnight. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (0.236 g, 1.363 mmol, 15.55%) as pale yellow solids.

[0884]

B) N' - ( (4E) -7-cyano-2, 3-dihydro-4H-chromen-4-ylidene) -4- methylbenzenesulfonohydrazide

To a mixture of 4-oxochromane-7-carbonitrile (230 mg, 1.33 mmol) and EtOH (15 mL) was added p-toluenesulfonyl hydrazide (259 mg, 1.39 mmol) . After being stirred at 90°C for 3 h, the mixture was concentrated. The residue was washed with Et ₂ 0 and dried in vacuo to give the title compound (299 mg, 0.876 mmol, 65.9%) as pale orange solids.

MS (ESI+) , found 342.1

[0885]

C) 4- (2, 6-dicyclopropylpyridin-4-yl ) -2H-chromene-7-carbonitrile

To a mixture of 2 , 6-dicyclopropylpyridin-4-yl

trifluoromethanesulfonate (497 mg, 1.62 mmol), N'-((4E)-7- cyano-2, 3-dihydro-4H-chromen-4-ylidene) -4- methylbenzenesulfonohydrazide (499 mg, 1.46 mmol), Pd ₂ (dba) ₃ (67 mg, 0.07 mmol), Xphos (139 mg, 0.29 mmol) and CPME (30 mL) was added lithium t-butoxide (272 mg, 3.40 mmol). After being stirred under nitrogen atmosphere at 90 °C for 1 h, the mixture was poured into sat. NH ₄ C1 aq _r and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (NH silica gel, eluted with 1% - 5% EtOAc in hexane and silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (374 mg, 1.190 mmol, 81%) as yellow solids .

MS (ESI+) , found 315.1

[0886]

D) 4- (2, 6-dicyclopropylpyridin-4-yl) chromane-7-carbonitrile To a mixture of 4- ( 2 , 6-dicyclopropylpyridin-4-yl ) -2H- chromene-7-carbonitrile (374 mg, 1.19 mmol) and MeOH (15 mL) was added Pd/C (en) (259 mg, 0.12 mmol). After being stirred under hydrogen atmosphere at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by column

chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (138 mg, 0.436 mmol, 36.7%) as white solids.

MS (ESI+) , found 317.1

[0887]

E) 4- (2, 6-dicyclopropylpyridin-4-yl ) chromane-7-carboxylic acid

To a mixture of 4- (2 , 6-dicyclopropylpyridin-4- yl) chromane-7-carbonitrile (138 mg, 0.44 mmol) and nBuOH (10 mL) was added 8 M NaOH aq. (-0.50 mL, 4.00 mmol). After being stirred at 90°C overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was subjected to the next reaction without further purification .

[0888]

F) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) chromane-7-carboxamide

To a mixture of 4- ( 2 , 6-dicyclopropylpyridin-4- yl ) chromane-7-carboxylic acid (24 mg, 0.07 mmol), (5- (methylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride (28 mg, 0.13 mmol), HATU (54 mg, 0.14 mmol) and DMF (1 mL) was added DIPEA (0.12 mL, 0.69 mmol). After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SCO ₄ and concentrated. The residue was purified by preparative HPLC (L-Column 2 ODS, eluted with H ₂ 0 in

acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO ₃ aq. and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (32.0 mg, 0.064 mmol, 89%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.81-0.86 (8H, m) , 1.94 (2H, quin, J = 6.3 Hz), 2.00-2.13 (1H, m) , 2.20-2.32 (1H, m) , 3.31 (3H, s) , 4.14-4.25 (3H, m) , 4.64 (2H, d, J = 5.7 Hz), 6.80 (2H, s) , 6.87 (1H, s), 7.33-7.44 (2H, m) , 7.57 (1H, d, J = 8.3 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 9.00 (1H, d, J = 1.9 Hz), 9.19 (1H, t, J = 5.9 Hz) .

[0889]

Example 28.7

(R) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A) tert-butyl ( ( 2R) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2- yl ) carbamate

ADDP (4.35 g, 17.24 mmol) was added to a solution of 3- bromopyridin-2-ol (2 g, 11.49 mmol), Bu ₃ P (4.25 mL, 17.24 mmol) and (R) -tert-butyl ( l-hydroxypropan-2-yl ) carbamate (2.014 g, 11.49 mmol) in THF (dry) (100 mL) at room temperature. The mixture was stirred at room temperature under N ₂ overnight.

The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 30% EtOAc in hexane) to give the title

compound (2.52 g, 7.61 mmol, 66.2%) as a colorless oil.

MS (ESI+), found 331.2 (M+H)

λΕ NMR (300 MHz, CDC1 ₃ ) 5:1.30 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 4.06-4.17 (1H, m) , 4.32 (2H, dd, J = 4.5, 1.5 Hz), 4.70- 5.00 (1H, br), 6.79 (1H, dd, J = 7.6, 4.9 Hz), 7.81 (1H, dd, J = 7.7, 1.7 Hz), 8.06 (1H, dd, J = 4.9, 1.9 Hz) .

[0890] B) tert-butyl (2R) -2-methyl-2 , 3-dihydro-lH-pyrido [ 2 , 3- b] [1, 4 ] oxazine-l-carboxylate

A mixture of tert-butyl ( (2R) -1- ( (3-bromopyridin-2- yl) oxy) propan-2-yl) carbamate (2.52 g, 7.61 mmol), N^N ² - dimethylethane-1, 2-diamine (0.335 g, 3.80 mmol), copper(I) iodide (0.725 g, 3.80 mmol) and cesium carbonate (4.96 g, 15.22 mmol) in THF (150 mL) was stirred at 70°C under Ar overnight. After cooling, insoluble material was removed off by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 50% EtOAc in hexane) to give the title compound ^{^} (0.080 g, 0.320 mmol, 4.20%) as a pale orange oil.

MS (ESI+), found 251.4 (M+H)

λΕ NMR (300 MHz, CDC1 ₃ ) 5:1.25 (3H, d, J = 6.9 Hz), 1.55 (9H, s), 4.21-4.32 (2H, m) , 4.53-4.69 (1H, m) , 6.85-6.95 (1H, m) , 7.87-7.98 (1H, m) , 8.33 (1H, d, J = 7.9 Hz).

[0891]

C) (2R) -2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [l,4]oxazine

TFA (1.2 mL, 15.58 mmol) was added to a solution of tert- butyl (2R) -2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-l- carboxylate (80 mg, 0.32 mmol) in EtOAc (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted five times with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (50.0 mg, 0.333 mmol, 104%) as light brown solids.

MS (ESI+), found 151.4 (M+H)

[0892]

D) (2R) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine

NBS (65.2 mg, 0.37 mmol) was added to a solution of (2R)- 2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine (50 mg, 0.33 mmol) in DMF (1 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was quenched with water at 0°C and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound

(35.0 mg, 0.153 mmol, 45.9%) as pale yellow solids.

MS (ESI+), found 229.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.20 (3H, d, J = 6.4 Hz), 3.55 (1H, ddd, J = 8.0, 6.3, 3.0 Hz), 3.65-3.88 (1H, br) , 3.92 (1H, dd, J = 10.8, 8.1 Hz), 4.29-4.37 (1H, m) , 6.69-6.78 (1H, m, J = 7.9 Hz), 6.87-6.93 (1H, m, J = 7.9 Hz).

[0893]

E) tert-butyl (2R) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3- b] [ 1 , 4 ] oxazine-l-carboxylate

DMAP (18.67 mg, 0.15 mmol) was added dropwise to a

solution of (2R) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4] oxazine (35 mg, 0.15 mmol) and Boc ₂ 0 (0.053 mL, 0.23 mmol) in THF (1 mL) at 0°C. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title

compound (38.0 mg, 0.115 mmol, 76%) as a colorless oil.

MS (ESI+), found 329.2 (M+H)

¹ H NMR (300 MHz, CDCI ₃ ) 5:1.23 (3H, d, J = 6.8 Hz), 1.55 (9H, s), 4.20-4.31 (2H, m) , 4.63 (1H, dt, J = 6.9, 2.0 Hz), 7.08 (1H, d, J = 8.3 Hz), 8.23 (1H, d, J = 7.9 Hz).

[0894]

F) 1-tert-butyl 6-methyl (2R) -2-methyl-2 , 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-1, 6-dicarboxylate

A mixture of tert-butyl (2R) -6-bromo-2-methyl-2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (38 mg, 0.12 mmol), Pd(dppf)Cl ₂ 'CH ₂ Cl2 (4.71 mg, 5.77 pmol) and TEA (0.032 mL, 0.23 mmol) in DMF (1 mL) and MeOH (3 mL) was stirred under CO atmosphere (0.5 MPa) at 100°C for 6h. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 60% EtOAc in hexane) to give the title compound (32.0 mg, 0.104 mmol, 90%) as a pale yellow oil.

MS (ESI+), found 309.3 (M+H)

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.28 (3H, d, J = 6.8 Hz), 1.57 (9H, s), 3.95 (3H, s), 4.28 (2H, dd, J = 4.5, 2.3 Hz), 4.64 (1H, d, J = 6.8 Hz), 7.79 (1H, d, J = 8.3 Hz), 8.56 (1H, d, J = 8.3 Hz).

[0895]

G) (2R) -1- (tert-butoxycarbonyl) -2-methyl-2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid

A mixture of 1-tert-butyl 6-methyl (2R) -2-methyl-2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (32 mg, 0.10 mmol) and 2N NaOH (0.156 mL, 0.31 mmol) in THF (1 mL) and MeOH (0.5 mL) was stirred at room temperature for 3h. The mixture was acidified with IN HC1 aq. at 0°C and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (30.0 mg,

0.102 mmol, 98%) as pale yellow amorphous solids.

MS (ESI+), found 295.3 (M+H)

[0896]

H) tert-butyl (2R) -2-methyl-6- ((( 5- (methylsulfonyl ) pyridin-2- yl) methyl) carbamoyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine- 1-carboxylate

HATU (54.3 mg, 0.14 mmol) was added to a solution of

(2R) -1- (tert-butoxycarbonyl) -2-methyl-2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.10 mmol), (5- (methylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride

(22.70 mg, 0.10 mmol) and DIPEA (58.0 mg, 0.45 mmol) in DMF (0.7 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (35.0 mg, 0.076 mmol, 74.2%) as white amorphous solids .

MS (ESI+), found 463.2 (M+H)

[0897]

I) (2R) -2-methyl-N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of tert-butyl (2R) -2-methyl-6- ( ( (5- (methylsulfonyl) pyridin-2-yl) methyl) carbamoyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (35 mg, 0.08 mmol) and TFA (1 mL, 12.98 mmol) in EtOAc (0.5 mL) was stirred at room temperature for 3h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO ₄ and concentrated in vacuo to give the title compound (25.00 mg, 0.069 mmol, 91%) as white solids.

MS (ESI+), found 363.2

[0898]

J) (R) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide

A mixture of ( 2R) -2-methyl-N- (( 5- (methylsulfonyl ) pyridin-

2-yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6- carboxamide (25 mg, 0.07 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (63.6 mg, 0.21 mmol), Ruphos

precatalyst (5.03 mg, 6.90 μmol) , Ruphos (3.22 mg, 6.90 μmol) and NaOtBu (19.89 mg, 0.21 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling, insoluble material was removed off by filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale yellow amorphous solid, which was washed with IPE and dried in vacuo to give the title compound (4.00 mg, 7.70 μmol, 11.16%) as pale yellow amorphous solids.

1H NMR (300 MHz, CDC1 ₃ ) 5:0.82-1.05 (8H, m) , 1.39 (3H, d, J = 6.4 Hz), 1.75-2.00 (2H, brs) , 3.09 (3H, s) , 3.98-4.16 (1H, m) , 4.36 (2H, d, J = 2.3 Hz), 4.86 (2H, d, J = 6.0 Hz), 6.70 (2H, s), 7.50 (1H, d, J = 8.3 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.78

(1H, d, J = 7.9 Hz), 8.17 (1H, dd, J = 8.1, 2.5 Hz), 8.38-8.51 (1H, m) , 9.10 (1H, d, J = 1.9 Hz).

[0899]

Example 288

5- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) -2, 3,4,5- tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxamide

A) 3- ( (2-bromopyridin-3-yl) oxy) propan-l-amine

To a solution of 2-bromopyridin-3-ol (3 g, 17.24 mmol) ,

3-aminopropan-l-ol (1.439 mL, 18.97 mmol) and PPh ₃ (5.43 g, 20.69 mmol) in THF (dry) (120 mL) was added DIAD (4.02 mL, 20.69 mmol) at 0°C. The mixture was stirred at room

temperature under N ₂ for 3 days. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (2.72 g, 11.77 mmol, 68.3%) as brown solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:1.74-1.87 (2H, m) , 2.72 (2H, t, J =

6.6 Hz), 3.22-3.48 (2H, m) , 4.16 (2H, t, J = 6.2 Hz), 7.39 (1H, dd, J = 8.3, 4.5 Hz), 7.46-7.73 (1H, m) , 7.95 (1H, dd, J = 4.7,

1.7 Hz) .

[0900]

B) 2, 3, 4, 5-tetrahydropyrido [3, 2-b] [ 1 , 4 ] oxazepine

To a solution of 3- ( ( 2-bromopyridin-3-yl ) oxy) propan-1- amine (738 mg, 3.19 mmol), t-Bu ₃ P (129 mg, 0.64 mmol) and KOtBu (717 mg, 6.39 mmol) in THF (dry) (32 mL) was added Pd ₂ (dba) ₃ (292 mg, 0.32 mmol) at room temperature. The mixture was stirred at 70°C under Ar overnight. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (195 mg, 1.298 mmol, 40.7%) as light brown solids.

1H NMR (300 MHz, DMSO-d ₆ ) 5:1.90 (2H, quin, J = 5.8 Hz), 3.16- 3.26 (2H, m) , 4.02-4.10 (2H, m) , 6.04 (1H, brs), 6.60 (1H, dd, J = 7.7, 4.7 Hz), 7.10 (1H, dd, J = 7.7, 0.9 Hz), 7.70 (1H, dd, J = 4.9, 1.5 Hz) .

[0901]

C) 8-bromo-2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2-b] [ 1 , 4 ] oxazepine

To a solution of 2, 3, 4, 5-tetrahydropyrido [3, 2- b] [1, 4] oxazepine (102 mg, 0.68 mmol) in DMF (3 mL) was added NBS (127 mg, 0.71 mmol) at 0°C. The mixture was stirred at 0°C for 3 h. The mixture was neutralized with sat. NaHCO ₃ aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (84 mg, 0.367 mmol, 54.0%) as off-white solids.

¹ H NMR (300 MHz, CDCi ₃ ) 5:1.99-2.10 (2H, m) , 3.37 (2H, td, J = 5.8, 3.6 Hz), 4.13-4.20 (2H, m) , 4.72 (1H, brs), 7.27-7.30 (1H, m) , 7.83 (1H, d, J = 1.9 Hz).

[0902]

D) tert-butyl 8-bromo-3, 4-dihydropyrido [3, 2-b] [1, 4 ] oxazepine- 5 (2H) -carboxylate

To a solution of 8-bromo-2 , 3, 4 , 5-tetrahydropyrido [ 3 , 2- b] [1, 4] oxazepine (84 mg, 0.37 mmol) and DMAP (44.8 mg, 0.37 mmol) in THF (4 mL) was added Boc ₂ 0 (0.102 mL, 0.44 mmol) at room temperature. The mixture was stirred at 50 °C overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (101 mg, 0.307 mmol, 84%) as white solids.

[0903]

E) 5-tert-butyl 8-methyl 3 , 4-dihydropyrido [ 3 , 2- b] [1,4] oxazepine-5 , 8 (2H) -dicarboxylate

To a mixture of tert-butyl 8-bromo-3 , 4-dihydropyrido [ 3 , 2- b] [ 1 , 4 ] oxazepine-5 (2H) -carboxylate (101 mg, 0.31 mmol) and TEA (0.086 mL, 0.61 mmol) in DMF (8 mL, 0.31 mmol) and MeOH (2 mL, 49.44 mmol) was added PdCl ₂ (dppf) (22.45 mg, 0.03 mmol). After being stirred at 100°C under CO (0.5 MPa) for 5 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 80% EtOAc in hexane) to give the title

compound (86 mg, 0.279 mmol, 91%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ) 5:1.47 (9H, s) , 2.11 (2H, quin, J = 5.8 Hz), 3.81 (2H, t, J = 5.9 Hz), 3.94 (3H, s) , 4.17-4.24 (2H, m) , 7.90 (1H, d, J = 1.9 Hz), 8.76 (1H, d, J = 1.9 Hz).

[0904]

F) methyl 2, 3, 4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8- carboxylate

To a solution of 5-tert-butyl 8-methyl 3,4- dihydropyrido [ 3 , 2-b] [1, 4] oxazepine-5, 8 (2H) -dicarboxylate (86 mg, 0.28 mmol) in MeOH (1 mL) was added 4M HC1 in EtOAc (1 mL, 2.00 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture concentrated in vacuo.

Amberlyst A21 (500 mg) was added to the mixture of the residue in MeOH (3.0 mL) , and the mixture was stirred at room

temperature for 20 min. The mixture was filtered and the filtrate was evaporated in vacuo to give the title compound

(58.0 mg, 0.279 mmol, 100%) as a pale yellow oil.

MS (ESI+), found 209.2 (M+H)

[0905]

G) methyl 5- (2, 6-dicyclopropylpyridin-4-yl) -2, 3, 4, 5- tetrahydropyrido [3 , 2-b] [1,4] oxazepine-8-carboxylate

A mixture of methyl 2 , 3 , 4 , 5-tetrahydropyrido [3 , 2- b] [ 1 , 4 ] oxazepine-8-carboxylate (58 mg, 0.28 mmol), 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (103 mg, 0.33 mmol), XPHOS Pd G2 (21.92 mg, 0.03 mmol), XPHOS (13.28 mg, 0.03 mmol) and Cs ₂ CO ₃ (182 mg, 0.56 mmol) in DME (5.0 mL) was stirred at 120°C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (100 mg, 0.274 mmol, 98%) as pale yellow solids .

¹ H NMR (300 MHz, CDC1 ₃ ) 5:0.75-0.86 (4H, m) , 0.92-1.00 (4H, m) , 1.75-1.89 (2H, m) , 2.13 (2H, quin, J = 6.0 Hz), 3.93 (3H, s), 4.05 (2H, t, J = 6.0 Hz), 4.23 (2H, t, J = 6.0 Hz), 6.65 (2H, s), 7.84 (1H, d, J = 1.9 Hz), 8.63 (1H, d, J = 1.9 Hz).

[0906]

H) 5- (2, 6-dicyclopropylpyridin-4-yl) -2,3,4,5- tetrahydropyrido [ 3 , 2-b] [ 1 , 4 ] oxazepine-8-carboxylic acid

To a solution of methyl 5- (2 , 6-dicyclopropylpyridin-4- yl ) -2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxylate (100 mg, 0.27 mmol) in MeOH (1 mL) and THF (1 mL) was added 2 M NaOH aq. (0.137 mL, 0.27 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc . The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (85 mg, 0.242 mmol, 88%) as pale yellow solids.

MS (ESI+) , found 352.3 (M+H)

[0907]

I) 5- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-

(methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3, 2-b] [1,4] oxazepine-8-carboxamide

To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) -

2,3,4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8-carboxylic acid (42 mg, 0.12 mmol), ( 5- (methylsulfonyl ) pyridin-2-yl) methanamine (26.7 mg, 0.14 mmol) and DI ^' PEA (0.063 mL, 0.36 mmol) in DMF (3 mL) was added HATU (68.2 mg, 0.18 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and

extracted with EtOAc/THF (1:1). The organic layer was

separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (47.0 mg, 0.090 mmol, 76%) as pale yellow solids. ¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.90 (8H, brs) , 1.19-1.31 (3H, m) , 1.88-2.13 (4H, m) , 4.06 (2H, brs), 4.19 (2H, t, J = 5.9 Hz), 4.68 (2H, d, J = 5.7 Hz), 6.74 (2H, s), 7.52 (1H, dd, J = 8.5, 4.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.29 (1H, dd, J = 8.1, 2.5 Hz), 8.49-8.79 (2H, m) , 9.02 (1H, d, J = 1.9 Hz), 9.38 (1H, t, J = 5.9 Hz).

[0908]

Example 289

5- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8-carboxamide

To a solution of 5- (2 , 6-dicyclopropylpyridin-4-yl) - 2,3,4, 5-tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxylic acid (42 mg, 0.12 mmol), ( 4- (methylsulfonyl ) phenyl) methanamine (26.6 mg, 0.14 mmol) and DIPEA (0.063 mL, 0.36 mmol) in DMF (3 mL) was added HATU (68.2 mg, 0.18 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (51.0 mg, 0.098 mmol, 82%) as off-white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ) 5:0.71-0.89 (8H, m) , 1.78-1.92 (2H, m) , 2.05 (2H, t, J = 5.9 Hz), 3.19 (3H, s) , 4.01 (2H, t, J = 5.7 Hz), 4.17 (2H, t, J = 5.9 Hz), 4.58 (2H, d, J = 6.0 Hz), 6.75 (2H, s) , ^' 7.59 (2H, d, J = 8.3 Hz), 7.82-7.93 (3H, m) , 8.53 (1H, d, J = 2.3 Hz), 9.25 (1H, t, J = 5.9 Hz).

[0909]

Example 290

4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-

(methylsulfonyl ) pyridin-2-yl ) methyl ) chromane-7-carboxamide

(shorter retention time)

[0910]

Example 291 4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-

(methylsulfonyl) pyridin-2-yl ) methyl ) chromane-7-carboxamide (longer retention time)

4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl ) chromane-7-carboxamide

(24.7 mg) was subjected to optical resolution by chiral column chromatography. The fraction having a shorter retention time was concentrated to give the compound of Example 290 (7 mg,>99.9%ee) and the fraction having a longer retention time was concentrated to give the compound of Example 291 (7 mg, 99.3%ee) .

purification condition by chiral column chromatography column: CHIRALPAK IB (MB001) 20 x 250 mm, 5 μιη

mobile phase: CO ₂ /MeOH=600/400 (v/v)

pressure: 100 bar

flow Rate: 50 mL/min

temperature: 35°C

detection: UV 220 nm

concentration: 1 mg/mL (MeOH/TFE=l/l , v/v)

injection volume: 2 mL

load: 2 mg

solubility: 1 mg/ (MeOH/TFE=l/l, v/v)

[0911]

The compounds described in Examples 221 to 291 are below (Table 9-1 - Table 9-11) .

[0922]

[Table 9-11]

[0923]

The compounds described in Examples 221-222, 224-226, 228,

230-231, 236-243, 245, and 255-258 were synthesized in the same manner as in the reaction and purification described in the Examples .

[0924]

Example 292

5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 5,6,7, 8-tetrahydro-l, 5-naphthyridine-2-carboxamide

A) 2 , 6-Dicyclopropylpyridin-4-ol

A mixture of 2 , 6-dibromopyridin-4-ol (1.06 g, 4.19 mmol) , cyclopropylboronic acid (1.76 g, 20.49 mmol), Pd(0Ac)2 (99 mg, 0.44 mmol), tricyclohexyl phosphine (235 mg, 0.84 mmol), K ₃ PO ₄ (2.76 g, 13.00 mmol) in toluene (10 mL) and water (2 mL) was stirred at 100 °C overnight. After being cooled, the mixture was poured into water and extracted with 2-butanone. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column

chromatography (silica gel, eluted with 0%- 20% MeOH in EtOAc) to give the title compound (0.305 g, 1.741 mmol, 42%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.75-0.81 (8H, m) , 1.80-1.89 (2H, m) , 6.38 (2H, s) , 10.11 (1H, s).

MS m/z 176.4 [M+H] ⁺ .

[0925]

B) 2 , 6-Dicyclopropylpyridin-4-yl trifluoromethanesulfonate

To a mixture of 2 , 6-dicyclopropylpyridin-4-ol (305 mg,

1.74 mmol) and pyridine (10 mL) was added Tf ₂ 0 (0.35 mL, 2.07 mmol) at 0°C. After being stirred at room temperature under N ₂ overnight, the mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was washed with aqueous citric acid and brine and dried over Na ₂ SO ₄ :and

concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (373 mg, 1.214 mmol, 70%) as a colorless oil.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.85-1.02 (8H, m) , 2.07-2.20 (2H, m) , 7.25 (2H, s) .

MS m/z 308.0 [M+H] ⁺ .

[0926]

C) tert-Butyl 6-Bromo-3, 4-dihydro-l, 5-naphthyridine-l (2H) - carboxylate

To a mixture of 6-bromo-l , 2 , 3 , 4-tetrahydro-l , 5- naphthyridine (2 g, 9.39 mmol), Boc ₂ 0 (2.62 mL, 11.26 mmol) and THF (40 mL) was added 1.3 M LiHMDS in THF (8.66 mL, 11.26 mmol) at 0°C. After being stirred at room temperature overnight, the mixture was quenched with sat. NH ₄ C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (2.37 g, 7.57 mmol, 81%) as pale yellow solids.

¹ H NMR (300 MHz, CDC1 ₃ ):5 1.53 (9H, s), 1.92-2.06 (2H, m) ,

2.92-2.98 (2H, m) , 3.68-3.76 (2H, m) , 7.24 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.7 Hz) .

MS m/z 313.2, 315.2[M+H] ⁺ .

[0927]

D) 1-tert-Butyl 6-methyl 3 , 4-dihydro-l , 5-naphthyridine-l , 6 ( 2H) - dicarboxylate

To a mixture of tert-butyl 6-bromo-3, 4-dihydro-l, 5- naphthyridine-1 (2H) -carboxylate (8.70 g, 27.78 mmol) and TEA (7.75 mL, 55.56 mmol) in a mixture of DMF (80 mL) and MeOH (80 mL) was added PdCl ₂ (dppf) (1.016 g, 1.39 mmol) . The mixture was stirred at 100°C under CO, 0.5 MPa (0.00 mmol) for 6 hrs . MeOH was removed by evaporation, and then the residue was poured into water and 10% aqueous citric acid, and extracted with EtOAc, and then the extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was passed through a pad of Si0 ₂ (ca. 200 g) using EtOAc. The eluent was concentrated in vacuo, and then the precipitate was collected by IPE, which was recrystallized from EtOAc-IPE. All of the filtrates were purified by column chromatography (silica gel, eluted with 5% - 60% EtOAc in hexane) to give white solids. The precipitates and the white solids were mixed together to give the title compound (6.74 g, 23.1 mmol, 83%) as white solids .

¹ R NMR (300 MHz, CDC1 ₃ ):5 1.55 (9H, s) 1.96-2.09 (2H, m) 2.97- 3.12 (2H, m) 3.71-3.81 (2H, m) 3.98 (3H, s) 7.90-7.98 (1H, m) 8.29 (1H, d, J=8.69 Hz) .

MS m/z 293.0 [M+H] ⁺ .

[0928]

E) Methyl 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylate To a mixture of 1-tert-butyl 6-methyl 3, 4-dihydro-l, 5- naphthyridine-1, 6 (2H) -dicarboxylate (3.00 g, 10.26 mmol) in MeOH (25 mL) was added 4N HCl/EtOAc (25.7 mL, 102.62 mmol). The mixture was stirred at 60 °C for 1 hr. MeOH was removed by evaporation, and then the residue was poured into water and made slightly basic with 8N NaOH (ca. 13 mL) and extracted with EtOAc-THF. The extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (1.67 g, 8.69 mmol, 85%) as pale brown solids.

¹ H NMR (300 MHz, CDC1 ₃ ):5 1.93-2.15 (2H, m) 2.95-3.08 (2H, m) 3.31-3.45 (2H, m) 3.93 (3H, s) 4.27-4.48 (1H, m) 6.70 (1H, d, J=8.31 Hz) 7.79 (1H, d, J=8.31 Hz).

MS m/z 193.0 [M+H] ⁺ .

[0929]

F) Methyl 5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8-tetrahydro- 1, 5-naphthyridine-2-carboxylate A mixture of methyl 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine- 2-carboxylate (219 mg, 1.14 mmol) , 2 , 6-dicyclopropylpyridin-4- yl trifluoromethanesulfonate (350 mg, 1.14 mmol), Pd ₂ (dba) ₃ (52.1 mg, 0.06 mmol), XPHOS (54.3 mg, 0.11 mmol), K ₃ PO ₄ (484 mg, 2.28 mmol) in DME (5 mL) was stirred at 120°C under microwave irradiation for 2 hrs . After being cooled, the mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was purified by column chromatography

(silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (380 mg, 1.087 mmol, 95%) as a light brown oil. ¹ tt NMR (300 MHz, CDC1 ₃ ):5 0.83-0.92 (4H, m) , 0.94-1.04 (4H, m) , 1.87 (2H, tt, J = 8.0, 4.9 Hz), 2.09-2.20 (2H, m) , 3.10 (2H, t, J = 6.4 Hz), 3.65-3.74 (2H, m) , 3.96 (3H, s), 6.73 (2H, s), 7.33 (1H, d, J = 8.7 Hz), 7.80 (ΙΗ, ^' d, J = 8.7 Hz) .

MS m/z 350.2 [M+H] ⁺ .

[0930]

G) 5- (2, 6-Dicyclopropylpyridin~4-yl ) -5,6,7, 8-tetrahydro-l, 5- naphthyridine-2-carboxylic acid

To a solution of methyl 5- (2, 6-dicyclopropylpyridin-4- yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylate (380 mg,

1.09 mmol) in THF (4 mL) was added 4N LiOH (1.36 mL, 5.44 mmol) at room temperature. The mixture was stirred at 60 °C for 2 hrs.

The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (299 mg, 0.891 mmol, 82%) as a pale yellow oil.

MS m/z 336.1 [M+H] ⁺ .

[0931]

H) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4-

(methylsulfonyl) benzyl) -5,6,7, 8-tetrahydro-l, 5-naphthyridine-2- carboxamide

To a solution of 5- (2 , 6-dicyclopropylpyridin-4-yl) - 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), (4- (methylsulfonyl ) phenyl) methanamine (91 mg, 0.49 mmol), DIPEA (0.229 mL, 1.34 mmol) in DMF (4 mL) was added HATU (204 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr . The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10 % - 60% EtOAc in hexane) to give a gum, which was solved again in EtOAc, washed with water and brine (for removing DMF) , dried over MgSO ₄ , concentrated in vacuo and crystallized from EtOAc-IPE to give the title compound (150 mg, 0.298 mmol, 67%) as white solids. ¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.79-0.89 (8H, m) 1.88-1.97 (2H, m) 2.00-2.11 (2H, m) 2.96 (2H, s) 3.18 (3H, s) 3.70 (2H, s) 4.55- 4.61 (2H, m) 6.89 (2H, s) 7.44-7.51 (1H, m) 7.52-7.60 (2H, m) 7.67-7.77 (1H, m) 7.83-7.92 (2H, m) 9.09 (1H, t, J=6.23 Hz). MS m/z 503.3 [M+H] ⁺ .

[0932]

Example 293

5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) -5,6,7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide

A) 5- (Methylsulfonyl) pyridine-2-carbonitrile

A mixture of 5-bromopicolinonitrile (25.0 g, 136.61 mmol) and sodium methanesulfinate (19.52 g, 191.25 mmol) in DMSO (200 mL) was stirred at 100°C for 24 hrs . The mixture was cooled to 50°C and water (250 mL) was added thereto. After stirring at 50°C overnight, the precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (20.6 g, 113 mmol, 83%) as white crystals.

1H NMR (300 MHz, CDC1 ₃ ):5 3.17 (3H, s) , 7.93 (1H, dd, J = 7.9, 0.8 Hz), 8.41 (1H, dd, J = 7.9, 2.3 Hz), 9.25 (1H, dd, J = 2.3, 0.8 Hz) .

[0933]

B) (5- (Methylsulfonyl) pyridin-2-yl) methanamine hydrochloride A mixture of 5- (methylsulfonyl ) pyridine-2-carbonitrile (10 g, 54.88 mmol) , 6N HC1 (18.29 mL, 109.77 mmol) and 10% Pd-C (50% wet, 1.00 g, 9.40 mmol) in EtOH (100 mL) was hydrogenated under middle pressure (0.45 MPa) at room temperature overnight.

Water (10 mL) was added thereto and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to dryness.

The solid was suspended in EtOH and collected by filtration, dried in vacuo to give the title compound (6.30 g, 28.3 mmol,

52%) as pale yellow powders.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 3.37 (3H, s) , 4.33 (2H, q, J = 5.3 Hz), 7.81 (1H, d, J = 8.3 Hz), 8.41 (1H, dd, J = 8.1, 2.5 Hz), 8.70 (3H, brs), 9.09 (1H, d, J = 1.9 Hz).

MS m/z 187.1 [M+H] ⁺ .

[0934]

C) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl ) pyridin-2-yl) methyl) -5,6,7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide

To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (25 mg, 0.070 mmol), ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine

hydrochloride (18.3 mg, 0.08 mmol), DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (34.0 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (19.1 mg, 0.038 mmol, 51%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.75-0.92 (8H, m) , 1.88-2.00 (2H, m) , 2.01-2.12 (2H, m) , 2.98 (2H, t, J = 6.4 Hz), 3.30 (3H, s), 3.72 (2H, t, J = 5.7 Hz), 4.70 (2H, d, J = 6.4 Hz), 6.90 (2H, s), 7.48 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.7 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 9.01 (1H, d, J = 2.3 Hz), 9.14 (1H, t, J = 5.7 Hz).

MS m/z 504.3 [M+H] ⁺ . [0935]

Example 294

5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (ethylsulfonyl) pyridin- 2-yl) methyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2-carboxamide A) 5- (Ethylsulfonyl) pyridine-2-carbonitrile

To a stirred solution of 5-bromopicolinonitrile (3.60 g, 19.68 mmol) in DMSO (25 mL) were added sodium ethanesulfinate (3.20 g, 27.6 mmol), and the reaction mixture was stirred at 100°C under Ar atmosphere for 16 hrs. The filtrate was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give white solids. The residue was crystallized from EtOAc-hexane to give the title compound (2.69 g, 13.71 mmol, 70%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ):5 1.35 (3H, t, J = 7.6 Hz), 3.21 (2H, q, J = 7.3 Hz), 7.92 (1H, dd, J = 8.1, 0.9 Hz), 8.37 (1H, dd, J = 7.9, 2.3 Hz), 9.20 (1H, dd, J = 2.3, 0.8 Hz).

[0936]

B) ( 5- (Ethylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride

A mixture of 5- (ethylsulfonyl ) pyridine-2-carbonitrile

(528 mg, 2.69 mmol), 6N HC1 aq. (1.0 mL, 6.00 mmol), 10% Pd-C (50% wet, 180 mg, 0.17 mmol) and MeOH (15 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 30 min.

The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in

EtOH, collected by filtration and dried in vacuo to give the title compound (516 mg, 2.180 mmol, 81%) as white solids.

¹ R NMR (300 MHz, DMSO-d ₆ ):5 1.13 (3H, t, J = 7.4 Hz), 3.46 (2H, q, J = 7.2 Hz), 4.35 (2H, brs), 7.80 (1H, d, J = 8.3 Hz), 8.38 (1H, dd, J = 8.3, 2.3 Hz), 8.54 (3H, brs), 9.06 (1H, d, J = 1.9

Hz) .

MS m/z 201.3 [M+H] ⁺ .

[0937]

C) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (ethylsulfonyl)pyridin-2-yl)methyl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide

To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (25 mg, 0.070 mmol) , ( 5- (ethylsulfonyl ) pyridin-2-yl) methanamine

hydrochloride (19.41 mg, 0.08 mmol), DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (34.0 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in. vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (25.8 mg, 0.050 mmol, 67%) as white amorphous solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.79-0.88 (8H, m) , 1.12 (3H, t, J = 7.2 Hz), 1.88-2.00 (2H, m) , 2.00-2.12 (2H, m) , 2.98 (2H, t, J = 5.9 Hz), 3.38 (2H, q, J = 7.2 Hz), 3.71 (2H, t, J = 5.9 Hz), 4.70 (2H, d, J = 6.4 Hz), 6.90 (2H, s) , 7.48 (1H, d, J = 8.3 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.15 (1H, t, J = 6.0 Hz) .

MS m/z 518.3 [M+H] ⁺ .

[0938]

Example 295

Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6,7,8- tetrahydro-1 , 5-naphthyridin-2-yl ) carbonyl) amino) methyl ) -5- (methylsulfonyl ) benzoate

A) Ethyl 2-cyano-5- (methylsulfonyl) benzoate

To a solution of ethyl 2-cyano-5-fluorobenzoate (1.00 g, 5.18 mmol) in DMSO (10 mL) was added sodium methanesulfinate (0.581 g, 5.69 mmol) at room temperature. The. mixture was stirred 130 °C overnight. The mixture was quenched with water at 0°C and the precipitate was collected by filtration. The solid was washed with water and dried in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (0.920 g, 3.63 mmol, 70%) as white solids.

¹ H NMR (300 MHz, CDC1 ₃ ):5 1.48 (3H, t, J = 7.2 Hz), 3.13 (3H, s), 4.53 (2H, q, J = 7.2 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.23 (1H, dd, J = 8.3, 1.9 Hz), 8.69 (1H, d, J = 1.9 Hz).

[0939]

B) Ethyl 2- (aminomethyl) -5- (methylsulfonyl) benzoate

hydrochloride

A mixture of ethyl 2-cyano-5- (methylsulfonyl ) benzoate (920 mg, 3.63 mmol), 6N HC1 (2 mL, 12.00 mmol), 10% Pd-C (50% wet, 387 mg, 0.36 mmol) in MeOH (20 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 3 hrs . The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in EtOH/Et ₂ 0, collected by filtration and dried in vacuo to give the title compound (921 mg, 3.14 mmol, 86%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 1.38 (3H, t, J = 7.2 Hz), 3.32 (3H, s), 4.34-4.48 (4H, m) , 7.88 (1H, d, J = 8.3 Hz), 8.26 (1H, dd, J = 8.1, 2.1 Hz), 8.36 (3H, brs) , 8.44 (1H, d, J = 1.9 Hz). MS m/z 258.1 [M+H] ⁺ .

[0940]

C) Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridin-2-yl ) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoate

To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), ethyl 2- (aminomethyl) -5- (methylsulfonyl ) benzoate hydrochloride (158 mg, 0.54 mmol) and DIPEA (0.391 mL, 2.24 mmol) in DMF (3 mL) was added HATU (204 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with sat. NaHCO ₃ aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (204 mg, 0.355 mmol, 79%) as pale yellow solids. ^λ Η NMR (300 MHz, DMSO-d ₆ ):5 0.79-0.89 (8H, m) , 1.39 (3H, t, J = 7.2 Hz), 1.88-1.99 (2H, m) , 2.05 (2H, quin, J = 6.1 Hz), 2.97 (2H, t, J = 6.4 Hz), 3.25 (3H, s) , 3.71 (2H, t, J = 5.9 Hz), 4.42 (2H, q, J = 7.1 Hz), 4.85 (2H, d, J = 6.0 Hz), 6.89 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.69 (2H, t, J = 9.3 Hz), 8.07- 8.14 (1H, m) , 8.32 (1H, d, J = 1.9 Hz), 9.01 (1H, t, J = 6.4 Hz) .

MS m/z bib.2 [M+H] ⁺ .

[0941]

Example 296

5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2- (hydroxymethyl ) -4- (methylsulfonyl ) benzyl ) -5 , 6, 7 , 8-tetrahydro-l , 5-naphthyridine-2- carboxamide

To a solution of ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin- 4-yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridin-2- yl) carbonyl) amino) methyl ) -5- (methylsulfonyl) benzoate (40 mg, 0.070 initio1) in EtOH (2.3 mL) was added NaBH ₄ (5.27 mg, 0.14 mmol) at room temperature. The mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (27.0 mg, 0.051 mmol, 73%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.73-0.92 (8H, m) , 1.87-2.12 (4H, m) , 2.96 (2H, t, J = 6.2 Hz), 3.17 (3H, s) , 3.70 (2H, t, J = 5.7 Hz), 4.56 (2H, d, J = 6.0 Hz), 4.72 (2H, d, J = 5.3 Hz), 5.50 (1H, t, J = 5.3 Hz), 6.89 (2H, s) , 7.48 (2H, dd, J = 8.3, 4.5 Hz), 7.75 (2H, dd, J = 17.9, 8.1 Hz), 7.97 (1H, s), 9.00 (1H, t, J = 6.0 Hz).

MS m/z 533.3 [M+H] ⁺ .

[0942]

Example 297

2- ( ( ( (5- (2 , 6-Dicyclopropylpyridin-4-yl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoic acid

To a solution of ethyl 2- ( ( ( ( 5- ( 2 , 6-dicyclopropylpyridin-

4-yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridin-2- yl) carbonyl) amino) methyl) -5- (methylsulfonyl ) benzoate (164 mg, 0.29 mmol) in THF (1 mL) and EtOH (1 mL) was added 2N NaOH (2.0 mL, 4.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hrs . The mixture was neutralized with AcOH at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was washed with EtOAc to give the title compound (38.0 mg, 0.070 mmol, 24%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 0.79-0.89 (8H, m) , 1.88-1.98 (2H, m) , 2.05 (2H, quin, J = 5.9 Hz), 2.96 (2H, t, J = 6.4 Hz), 3.24 (3H, s), 3.71 (2H, t, J = 5.9 Hz), 4.87 (2H, d, J = 6.4 Hz), 6.89 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 8.06 (1H, dd, J = 8.1, 2.1 Hz), 8.35 (1H, d, J = 2.3 Hz), 9.05 (1H, t, J = 6.2 Hz), 13.66 (1H, brs) .

MS m/z 547.2 [M+H] ⁺ .

[0943]

Example 298

5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl ) -5 , 6, 7 , 8-tetrahydro-l , 5- naphthyridine-2-carboxamide

A) 2- (4- (Methylsulfonyl) phenyl) -2-oxoethyl acetate

To a solution of TEA (0.553 mL, 3.97 mmol) in DMF (8 mL) was added AcOH (0.227 mL, 3.97 mmol) at room temperature. The mixture was stirred at room temperature for 5 min. A solution of 2-bromo-l- ( 4- (methylsulfonyl ) phenyl ) ethanone (1.00 g, 3.61 mmol) in DMF (7.00 mL) was added to the mixture dropwise at room temperature. The mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water at room

temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was washed with EtOAc/hexane (1:1, v/v) and dried in vacuo to give the title compound (0.806 g, 3.15 mmol, 87%) as pale yellow solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 2.16 (3H, s), 3.30 (3H, s), 5.52 (2H, s), 8.07-8.14 (2H, m) , 8.16-8.22 (2H, m) .

[0944]

B) 2- (Hydroxyimino) -2- ( 4- (methylsulfonyl ) phenyl ) ethyl acetate

To a solution of 2- (4- (methylsulfonyl) phenyl) -2-oxoethyl acetate (800 mg, 3.12 mmol) and hydroxylamine hydrochloride (260 mg, 3.75 mmol) in- EtOH was added AcOK (368 mg, 3.75 mmol) at room temperature. The mixture was stirred at 70°C overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the title compound (884 mg, 3.26 mmol, quantitative) as a pale yellow oil as a crude product, which was used in the next step without further purification.

MS m/z 272.0 [M+H] ⁺ .

[0945] .

C) 2-Amino-2- (4- (methylsulfonyl ) phenyl) ethyl acetate

hydrochloride and 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride

A mixture of 2- (hydroxyimino) -2- ( 4- (methylsulfonyl) phenyl) ethyl acetate (88.4 mg, 3.26 mmol), 6N HC1 (1 mL, 6.00 mmol), 10% Pd-C (50% wet, 347 mg, 0.33 mmol) and MeOH (20 mL) was stirred under hydrogen atmosphere (3 atm) at room temperature for 5 hrs . The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in EtOH/Et20, collected by filtration and dried in vacuo to give a mixture of the title compounds (647 mg) as white solids, which was used in the next step without further purification.

MS m/z 258.1 [M+H] ⁺ and 216.1 [M+H] ⁺ .

[0946] D) tert-Butyl (2-hydroxy-l- ( 4-

(methylsulfonyl) phenyl) ethyl) carbamate

To a solution of a mixed 2-amino-2- ( 4- (methylsulfonyl) phenyl) ethyl acetate hydrochloride and 2-amino- 2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (647 mg) and TEA (1.54 mli, 11.01 mmol) in THF (6 mL) and MeOH (6 rtiL) was added B0C ₂ O (0.614 mL, 2.64 mmol) at room temperature. The mixture was stirred at room temperature for 3 days . The

mixture was quenched with water at room temperature and

extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (323 mg, 1.02 mmol, 47%) as white solids.

1H NMR (300 MHz, CDC1 ₃ ):5 1.43 (9H, brs), 1.86-1.95 (1H, m) ,

3.05 (3H, s), 3.75-4.01 (2H, m) , 4.84 (1H, brs), 5.42 (1H, d, J = 5.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.7 Hz).

[0947]

E) 2-Amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride

To a solution of tert-butyl (2-hydroxy-l- ( 4-

(methylsulfonyl ) phenyl) ethyl) carbamate (323 mg, 1.02 mmol) in MeOH (2 mL) was added 4M HC1 in EtOAc (2 mL, 8.00 mmol) at room temperature. The mixture was stirred at room temperature for 3 hrs. The mixture was diluted with IPE (4.0 mL) and the

precipitating solid was collected by filtration. The solid was washed with IPE and dried in vacuo to give the title compound

(212 mg, 0.842 mmol, 82%) as white solids.

¹ H NMR (300 MHz, DMSO-d ₆ ):5 3.24 (3H, s), 3.65-3.85 (2H, m) , 4.44 (1H, t, J = 5.7 Hz), 5.58 (1H, t, J = 4.9 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.99 (2H, d, J = 8.3 Hz), 8.64 (3H, brs). (An exchangeable proton was omitted. )

MS m/z 216.1 [M+H] ⁺ .

[0948]

F) 5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -5,6,7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide

To a mixture of 5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), DIPEA (0.094 mL, 0.54 mmol) and 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride (135 mg, 0.54 mmol) in EtOH (2.24 mL) was added 4- (4, 6- dimethoxy [1.3.5] triazin-2-yl ) -4-methylmorpholinium chloride hydrate (186 mg, 0.67 mmol) . After being stirred at room temperature overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 80% EtOAc in hexane) to give the title

compound (66.6 mg, 0.125 mmol, 28%) as white colorless foam.

[0949]

Example 299

5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl ) ethyl ) -5 , 6, 7 , 8-tetrahydro-l , 5- naphthyridine-2-carboxamide ( shorter retention time)

Example 300

5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide (longer retention time)

Optical resolution of 5- (2, 6-dicyclopropylpyridin-4-yl) - N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridine-2-carboxamide (66.6 mg) was

performed by preparative chiral HPLC. The factions with a shorter retention time gave Example 299 (24.1 mg, 0.045 mmol, 10%) as white solids. The factions with a longer retention time gave Example 300 (19.4 mg, 0.036 mmol, 8%) as white solids. Preparative chiral HPLC condition

Column : CHIRALPAK AD (JG001)

Column Size : 50 mmID x 500 mmL

Eluent : Hexane/2-propanol=450/550 (v/v)

Flow rate : 60 mL/min Pressure : 0.3 Mpa

Detector & sens. : UV 220 nm

Temperature :30°C

Example 299

[a] _D ²⁵ -16.4 (c 0.2520, MeOH)

¹ H NMR (300 MHz, CDC1 ₃ ):5 0.82-0.92 (4H, m) , 0.94-1.01 (4H, m) , 1.86 (2H, tt, J = 7.9, 4.9 Hz), 2.14 (2H, quin, J = 6.1 Hz), 2.54 (1H, brs), 2.94-3.07 (5H, m) , 3.63-3.74 (2H, m) , 4.00-4.10

(2H, m) , 5.23-5.34 (1H, m) , 6.71 (2H, s) , 7.40 (1H, d, J = 8.3 Hz), 7.63 (2H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.94

(2H, d, J = 8.3 Hz), 8.61 (1H, d, J = 7.6 Hz).

MS m/z 533.2

Example 300

[a] _D ²⁵ +16.2 (c 0.2520, MeOH)

¹ H NMR (300 MHz, CDC1 ₃ ) : δ 0.82-0.92 (4H, m) , 0.94-1.01 (4H, m) , 1.86 (2H, tt, J = 7.9, 4.9 Hz), 2.14 (2H, quin, J = 6.1 Hz), 2.54 (1H, brs), 2.94-3.07 (5H, m) , 3.63-3.74 (2H, m) , 4.00-4.10 (2H, m) , 5.23-5.34 (1H, m) , 6.71 (2H, s) , 7.40 (lH, d, J = 8.3 Hz), 7.63 (2H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.3 Hz), 8.61 (1H, d, J = 7.6 Hz).

MS m/z 533.2

[0950]

Example 301

N- (2-Carbamoyl-4- (methylsulfonyl) benzyl) -5- (2, 6- dicyclopropylpyridin-4-yl ) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide

To a solution of 2- ( ( ( ( 5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5,6,7, 8-tetrahydro-l, 5-naphthyridin-2- yl ) carbonyl ) amino) methyl ) -5- (methylsulfonyl ) benzoic acid (135 mg, 0.25 mmol) , lH-benzo[d] [1, 2, 3] triazol-l-ol, ammonium salt (113 mg, 0.74 mmol) and TEA (0.172 mL, 1.23 mmol) in DMF (3 mL) was added WSOHC1 (95 mg, 0.49 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with sat. NaHCO ₃ aq.. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (67.0 mg, 0.123 mmol, 50%) as white solids.

1H NMR (300 MHz , DMSO-d ₆ ):5 0.78-0.89 (8H, m) , 1.86-2.11 (4H, m)., 2.95 (2H, t, J = 6.4 Hz), 3.22 (3H, s) , 3.70 (2H, t, J = 5.9 Hz), 4.69 (2H, d, J = 6.4 Hz), 6.89 (2H, s), 7.46 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.66-7.79 (2H, m) , 7.90- 8.01 (2H, m) , 8.25 (1H, s) , 9.06 (1H, t, J = 6.2 Hz).

MS m/z 546.3 [M+H] ⁺ .

[0951]

Example 302

N- (2-Cyano-4- (methylsulfonyl ) benzyl) -5- (2, 6- dicyclopropylpyridin-4-yl ) -5, 6, 7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide

To a solution of N- (2-carbamoyl-4- (methylsulfonyl ) benzyl ) -5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxamide (51 mg, 0.090 mmol) in pyridine (2 mL) was added TFAA (0.053 mL, 0.37 mmol) at 0°C. The mixture was stirred at room temperature under N ₂ for 3 hrs . The mixture was neutralized with sat.

NaHCCO ₃ aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (33.0 mg, 0.063 mmol, 67%) as off-white solids.

¹ ti NMR (300 MHz, DMSO-d ₆ ):5 0.78-0.89 (8H, m) , 1.88-1.99 (2H, m) , 2.06 (2H, quin, J = 6.1 Hz), 2.98- (2H, t, J = 6.4 Hz), 3.29 (3H, s), 3.71 (2H, t, J = 5.9 Hz), 4.74 (2H, d, J = 6.0 Hz), 6.90 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.71 (2H, dd, J = 8.5, 2.5 Hz), 8.18 (1H, dd, J = 8.3, 1.9 Hz), 8.39 (1H, d, J = 1.9 Hz) , 9.25 (1H, t, J = 6.0 Hz) .

MS m/z 528.2 [M+H] ⁺ .

[0952] The compounds of the Examples are shown in the following tables (Table 9-12 - Table 9-13) . In these tables, MS

represents an observed molecular ion (found) .

[0953]

[Table 9-12]

[0954]

[Table 9-13]

[0955]

The compounds of Examples 303 to 381 are below (Table 9-

14 - Table 9-25) . The compounds of Examples 303 to 381 below were synthesized in the similar manner as in the reaction and purification described in the Examples 1-302.

[0967]

[Table 9-25]

[0968]

Experimental Example 1

RORyt binding test using fluorescent-labeled synthetic ligand

The binding activity of the test compound to RORyt was measured by a time resolved fluorescence resonance energy transfer method (TR-FRET) utilizing histidine-tagged RORyt, the fluorescent-labeled synthetic ligand and terbium-labeled anti- histidine tag antibody ( Invitrogen) .

First, 4 μΐ, of a test compound diluted with an assay buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA) was added to a 384 well plate.

Then, 4 μΐ, of the mixture of RORyt and the terbium- labeled anti-histidine tag antibody diluted with the assay buffer were added so that their final concentrations were 2 nM and 1 nM, respectively. Finally, 4 μΐι of the fluorescent- labeled synthetic ligand diluted with the assay buffer was added to make the final concentration of 120 nM. The mixture .was incubated at room temperature for 120 min, and fluorescence .intensity (excitation wavelength 320 nm, fluorescence

wavelength 520 nm) was measured by Envision ( PerkinElmer) . The results (% of inhibition of the fluorescent-labeled synthetic ligand binding to RORyt by a test compound at 1 μΜ ) measured by the above-mentioned method are shown in Table 10.

The fluorescent-labeled synthetic ligand: 5- ( (2Z) -2- ( (1- (difluoroboryl) -3, 5-dimethyl-lH-pyrrol-2-yl) methylene) -2H- pyrrol-5-yl) -N- (2- ( ( 3 , 5-difluoro-4-

^' (trimethylsilyl) phenyl) amino) -1- (4- (methoxymethyl) phenyl) -2- oxoethyl ) pentanamide

[0969]

Experimental Example 1 has shown that the compound of the present invention has a binding capability to RORyt .

[0970]

Experimental Example 2

Jurkat reporter test

A human IL-17 ROR response element was inserted into the .upstream of luciferase of pGL 4.28 reporter vector (Promega) iand RORyt sequence was inserted into the downstream of CMV promoter. Jurkat cells (Clontech Laboratories, Inc) used for the reporter test were generated by stably introducing reporter vector and RORgt expression vector. The cells were cultured in a culture medium (RPMI-1640 ( Invitrogen) , 10% FCS (AusGeneX) , ,100 U/mL penicillin, 100 pg/mL streptomycin) . On the day of the test, frozen cells were collected by a centrifugal

operation (1000 rpm, 5 min) and suspended in PBS (phosphate buffered saline) (Invitrogen) .

The cells were suspended in a cholesterol-depleted reaction medium (RPMI-1640, 10% Lipid reduced FCS (HyClone) , 10 mM HEPES (pH 7.5), 100 U/mL penicillin, 100 pg/mL streptomycin, 5 μΜ lovastatin) or a normal medium (RPMI-1640, 10% FCS (AusGeneX) , 10 mM HEPES (pH 7.5), 100 U/mL penicillin, 100 μg/mL

streptomycin). After doxycycline (final concentration, 1.25 μg/mL) was added to cell suspension of 1X10 ⁶ cells/mL, cells .were seeded into a 384 well plate by 20 μL (final density, .20, 000 cells/well) . After that, a test compound diluted with the reaction medium was added by 5 yL, and the cells were cultured overnight in an incubator. Bright-Glo (Promega) was .added by 25 μL, and the mixture was stirred at room temperature for 10 min, and the luminescence level was measured by Envision (PerkinElmer) . The results (% of control of the luminescence level of a test compound at 3 μΜ) measured by the above- mentioned method are shown in Table 10.

[0971]

Experimental Example 2 has shown that the compound of the present invention has an activity to modulate transcription of RORyt .

[0972]

[Table 10-1]

[0975]

Experimental Example 3

Mouse Thl7 cell differentiation test

CD4 positive naive T cells were collected from the spleen cells of BALB/c mice (female, 8-llw, Charles River Laboratories Japan, Inc.) using CD4+CD62L+ T Cell Isolation kit II (Miltenyi

Biotec) . The CD4 positive naive T cells in a 96 well plate (3xl0 ⁵ cells/well) were stimulated (37 °C for culture) with anti-mouse CD3e antibody (Bio X cell) (10 yg/mL, solid phase) and anti-CD28 antibody (Bio X cell) (5 yg/mL) for 4 days in the presence of anti-IFN-γ antibody (BioLegend) , anti-IL-4 antibody (BioLegend) , anti-IL-2 antibody (BioLegend) , IL-6, TGF-β and IL-23 to differentiate into Thl7 cells. The compound was dissolved in DMSO and then added thereto. The cells were cultured under these conditions for 4 days, and differentiation of the Thl7 cells was evaluated by using the concentration of IL-17A, which was measured by ELISA, in the culture supernatant obtained by centrifugation .

The results (% of control of a test compound at 3 μΜ) evaluated by the above-mentioned method are shown in Table 11.

[0976]

Experimental Example 3 has shown that the compound of the present invention has an activity to modulate IL-17A production in cells derived from mouse spleen.

[0977]

[Table 11-1]

1), 2), 3) and 4) are mixed and filled in a gelatin capsule .

[0981]

Formulation Example 2 (production of tablet) 1) compound of Example 1 : 30 g

2) lactose : 50 g

3) cornstarch : 15 g

4) carboxymethylcellulose calcium : 44 g

5) magnesium stearate : 1 g

1000 tablets total 140 g

The total amount of 1), 2) and 3) and 4) (30 g) is kneaded with water, vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and 5) (1 g) , and the mixture is punched by a tableting machine, whereby 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

[0982]

Formulation Example 3

(1) the compound of Example 1 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

The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) are granulated in aqueous solution (70 mL) of soluble starch (7.0 g as soluble starch) and then dried, the resulting mixture is mixed with lactose (70.0 g) and cornstarch (50.0 g) (lactose, cornstarch, soluble starch and magnesium stearate are all products in compliance with Japanese Pharmacopoeia 14 ^th Edition). The mixture compressed to give tablets.

[Industrial Applicability]

[0983]

The compound of the present invention may have an RORyt modulating action, and useful as an agent for the prophylaxis or treatment of cancer and the like.

This application is based on provisional patent

application Nos. 62/372,522 and 62/485,170 filed in the USA, the contents of which are incorporated in full herein.