Technical Field
[0001]
The present invention relates to a phenyldifluoromethyl-substituted prolinamide compound that has a cathepsin S inhibitory effect and is expected to be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for preventing and/or treating autoimmune disease including systemic lupus erythematosus (SLE) and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue.
Background Art
[0002]
Cathepsin S is a lysosomal cysteine protease expressed mainly in antigen-presenting cells such as dendritic cells, macrophages, and B cells, and is responsible for the degradation of the invariant chain bound to major histocompatibility complex class II (MHC class II) molecules at the time of generation. The MHC class II molecules bind to a self or non-self peptide incorporated extracellularly, and induces secretion of various cytokines by presenting the self peptide or the non-self peptide to CD4-positive T cells. It was confirmed that inhibition or deletion of the cathepsin S inhibits loading of an antigenic peptide to the MHC class II molecules, and furthermore, suppression of antigen presentation to the CD4-positive T cells lowers immune response against foreign antigens ("Immunity", 1999, vol. 10, No. 2, p. 207-217). It is considered that in a case of autoimmune disease such as SLE, the above-described antigen presentation occurs with respect to a pathogenic self peptide, and therefore it is considered that there is a high possibility of a cathepsin S inhibitor being useful for treating autoimmune disease ("Journal of Clinical Investigation", 1998, Vol. 101, No. 11, p. 2351-2363).
[0003]
Accordingly, it is expected that the cathepsin S inhibitor is promising as an agent for preventing and/or treating autoimmune disease including SLE and lupus nephritis, or an agent for preventing and/or treating allergies, or graft rejection of an organ, bone marrow or tissue.
[0004]
Patent Document 1 discloses that a compound of the formula (A) exhibits the cathepsin S inhibitory effect and is useful for treating various metabolic disease or immune disease such as SLE.

(Refer to this publication for the symbols in the formula.)
Patent Document 2 discloses that a compound of the formula (B) exhibits the
cathepsin S inhibitory effect and is useful for treating various metabolic disease or immune
disease such as SLE. [Chem. 2]
R5 **
(Refer to this publication for the symbols in the formula.)
0 Non-Patent Document 1 discloses that a compound of the formula (C) interferes
with the progression of SLE and lupus nephritis. [Chem. 31
Patent Document 3 discloses that a compound of the formula (D) exhibits the cathepsin S inhibitory effect and is useful for treating diabetes and the like. [Chem. 4]

(Refer to this publication for the symbols in the formula.) Patent Document 4 discloses that a compound of the formula (E) exhibits the cathepsin S inhibitory effect and is useful for treating diabetes and the like. [Chem. 5]
(Refer to this publication for the symbols in the formula.)
Related Art Patent Document
[0005]
[Patent Document 1] WO 2010/121918
[Patent Document 2] WO 2012/059507
[Patent Document 3] WO 2010/142650
[Patent Document 4] WO 2017/144483 Non-Patent Document
[0006]
[Non-Patent Document 1] "Annals of the Rheumatic Diseases", 2015, Vol. 74, p. 452-463
Disclosure of Invention
Problems to Be Solved by the Invention
[0007]
Provided is a compound that has a cathepsin S inhibitory effect and is expected to be useful as an active ingredient of a pharmaceutical composition, for example, a

pharmaceutical composition for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue.
Means for Solving the Problems
I [0008]
As a result of intensive studies on the compound having the cathepsin S inhibitory
effect, the inventors of the present invention have found that a phenyldifluoromethyl-
substituted prolinamide compound has the cathepsin S inhibitory effect, thereby
completing the present invention.
> That is, the present invention relates to a compound of the formula (I) or a salt
thereof, and relates to a pharmaceutical composition comprising the compound of the
formula (I) or a salt thereof and one or more excipients. [Chem. 6]
(In the formula, R1 is lower alkyl or halogeno-lower alkyl, R2 is a halogen or halogeno-lower alkyl, L is a bond or -CH2-, AisCHorN, R3 is H or lower alkyl,
R4 and R5 are the same as or different from each other, and are H or lower alkyl, and R6 and R7 are the same as or different from each other, and are H, lower alkyl, or a halogen.)
Unless described otherwise, in a case where symbols in the chemical formulae in the present specification are also used in other chemical formulae, the same symbols have the same meaning.
[0009]

The present invention further relates to a pharmaceutical composition for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue, comprising the compound of the formula (I) or a salt thereof. The pharmaceutical composition includes an agent for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue, comprising the compound of the formula (I) or a salt thereof.
The present invention still further relates to:
(1) the compound of the formula (I) or a salt thereof, which is a cathepsin S inhibitor;
(2) the compound of the formula (I) or a salt thereof, for use as the cathepsin S inhibitor;
(3) the cathepsin S inhibitor comprising the compound of the formula (I) or a salt thereof;
(4) use of the compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue;
(5) use of the compound of the formula (I) or a salt thereof for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue;
(6) the compound of the formula (I) or a salt thereof, for use in preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue; and
(7) a method for preventing and/or treating autoimmune disease including SLE
and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue, the
method comprising administering to a subject an effective amount of the compound of the
formula (I) or a salt thereof.
The "subject" refers to humans or other animals in need of prevention or treatment of the disease, and in one embodiment, the subject refers to humans in need of prevention or treatment of the disease.
Effects of the Invention
[0010]
The compound of the formula (I) or a salt thereof has the cathepsin S inhibitory effect, and can be used as an agent for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue.

Embodiments for Carrying Out the Invention
[0011]
Hereinafter, the present invention will be described in detail.
[0012]
The term "lower alkyl" refers to a linear or branched alkyl having carbon atoms of 1 to 6 (hereinafter also referred to as Ci-6) such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl, and refers to C1-4 alkyl in one embodiment, methyl or ethyl in one embodiment, and methyl in one embodiment.
[0013]
The term "halogen" means F, CI, Br, and I.
[0014]
The term "halogeno-lower alkyl" is C1-6 alkyl substituted with one or more halogens, and refers to C1-6 alkyl substituted with 1 to 5 halogens in one embodiment and refers to CF3 in one embodiment.
[0015]
Some aspects of the present invention are shown below.
(1) A compound or a salt thereof, in which the formula (I) is represented by the following formula (la).
[Chem. 7]
(2) A compound or a salt thereof, in which the formula (I) is represented by the following formula (lb). [Chem. 8]

(3) A compound or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl; a compound or a salt thereof, in which R1 is halogeno-lower alkyl; a compound or a salt thereof, in which R1 is lower alkyl; a compound or a salt thereof, in which R1 is methyl or CF3; or a compound or a salt thereof, in which R1 is methyl.
(4) A compound or a salt thereof, in which R2 is a halogen or halogeno-lower alkyl; a compound or a salt thereof, in which R2 is a halogen; a compound or a salt thereof, in which R2 is halogeno-lower alkyl; or a compound or a salt thereof, in which R2 is CF3.
(5) A compound or a salt thereof, in which A is CH or N; a compound or a salt thereof, in which A is CH; or a compound or a salt thereof, in which A is N.
(6) A compound or a salt thereof, in which L is a bond or -CH2-; a compound or a salt thereof, in which L is a bond; or a compound or a salt thereof, in which L is -CH2-.
(7) A compound or a salt thereof, in which R3 is H or lower alkyl; a compound or a salt thereof, in which R3 is H; a compound or a salt thereof, in which R3 is lower alkyl; a compound or a salt thereof, in which R3 is methyl or ethyl; or a compound or a salt thereof, in which R3 is methyl.
(8) A compound or a salt thereof, in which R4 is H or lower alkyl; a compound or a salt thereof, in which R4 is lower alkyl; or a compound or a salt thereof, in which R4 is H.
(9) A compound or a salt thereof, in which R5 is H or lower alkyl; a compound or a salt thereof, in which R5 is lower alkyl; or a compound or a salt thereof, in which R5 is H.

(10) A compound or a salt thereof, in which R6 is H, lower alkyl, or a halogen; a compound or a salt thereof, in which R6 is lower alkyl; a compound or a salt thereof, in which R6 is a halogen; or a compound or a salt thereof, in which R6 is H.
(11) A compound or a salt thereof, in which R7 is H, lower alkyl, or a halogen; a compound or a salt thereof, in which R7 is lower alkyl; a compound or a salt thereof, in which R7 is a halogen; or a compound or a salt thereof, in which R7 is H.
(12) A compound or a salt thereof which is represented by two or more non-contradictory combinations among the embodiments described in (1) to (11).
[0016]

Examples of the compound or a salt thereof of the present invention represented by the combinations in the above embodiment (12) include the following embodiments.
(13) A compound of the formula (I) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is a halogen or halogeno-lower alkyl, L is a bond or -CH2-, A is CH or N, R3 is H or lower alkyl, R4 is H or lower alkyl, R5 is H or lower alkyl, R6 is H, and R7 is H.
(14) A compound of the formula (la) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is a halogen or halogeno-lower alkyl, L is a bond or -CH2-, A is CH or N, R3 is H or lower alkyl, R4 is H or lower alkyl, R5 is H or lower alkyl, R6 is H, lower alkyl, or a halogen, and R7 is H, lower alkyl, or a halogen.
(15) A compound of the formula (I) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is a halogen or halogeno-lower alkyl, L is -CH2-, A is CH or N, R3 is H or lower alkyl, R4 is H or lower alkyl, R5 is H or lower alkyl, R6 is H, lower alkyl, or a halogen, and R7 is H, lower alkyl, or a halogen.
(16) A compound of the formula (I) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is halogeno-lower alkyl, L is -CH2-, A is N, R3 is lower alkyl, R4 is H, R5 is H, R6 is H, and R7 is H.
(17) A compound of the formula (la) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is halogeno-lower alkyl, L is -CH2-, A is N, R3 is lower alkyl, R4 is H, R5 is H, R6 is H, and R7 is H.
(18) A compound of the formula (lb) or a salt thereof, in which R1 is lower alkyl or halogeno-lower alkyl, R2 is halogeno-lower alkyl, L is -CH2-, A is N, R3 is lower alkyl, R4 is H, R5 is H, R6 is H, and R7 is H.
[0017]
Specific examples of the compounds included in the present invention include compounds or a salt thereof selected from the following group:
(4R)-N-( 1 -cyanocyclopropyl)-4-(difluoro {4- [(4-methylpiperazin-1 -yl)methyl] -2-(trifluoromethyl)phenyl} methyl)-1 - [(1 -methylcyclopropyl)carbonyl] -L-prolinamide,
(4R)-N-( 1 -cyanocyclopropyl)-4-(difluoro {4- [(4-methylpiperazin-1 -yl)methyl] -2-(trifluoromethyl)phenyl} methyl)-1 - {[ 1 -(trifluoromethyl)cyclopropyl] carbonyl} -L-prolinamide,
(4R)-N-( 1 -cyanocyclopropyl)-4- [ {4- [(4-ethylpiperazin-1 -yl)methyl] -2-(trifluoromethyl)phenyl} (difluoro)methyl]-1 - {[ 1 -(trifluoromethyl)cyclopropyl] carbonyl} -
L-prolinamide, and
(4R)-N-(l-cyanocyclopropyl)-4-[{4-[(4-ethylpiperazin-l-yl)methyl]-2-(trifluoromethyl)phenyl} (difluoro)methyl]-1 -[(1 -methylcyclopropyI)carbonyl]-L-prolinamide.
[0018]

Specific examples of the compounds included in the present invention include a compound or a salt thereof, which is a crystal containing (4R)-N-(l-cyanocyclopropyl)-4-(difluoro {4- [(4-methylpiperazin-1 -yl)methyl] -2-(trifluoromethyl)phenyl} methyl)-1 - [(1 -methylcyclopropyl)carbonyl]-L-prolinamide (hereinafter, referred to as "Compound A" in some cases) and succinic acid in a molar ratio of 1:2, and which is characterized by any one of the following aspects.
(1) The compound has peaks near 29(°) 2.7, 5.3, 9.8, 10.4, 13.5, 14.0, 15.1, 16.6, 17.4, and 24.4 by powder X-ray diffraction.
(2) The compound characteristically has peaks near 20(°) 5.3, 9.8, 15.1, 16.6, and 24.4 by powder X-ray diffraction.
(3) The compound has an endothermic peak near 134.3°C by differential scanning calorimetry (DSC analysis).
The crystal containing Compound A and succinic acid in a molar ratio of 1:2 also include a crystal of a disuccinate of Compound A, and a co-crystal of a succinic acid and a monosuccinate of Compound A.
[0019]
Tautomers and geometric isomers may exist in the compound of the formula (I) depending on the types of the substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes isomers other than that, and includes a form obtained by separating isomers, or a mixture thereof.
In addition, the compound of the formula (I) may have an asymmetric center or an axis chirality in some cases, and enantiomers (optical isomers) based thereon may exist. The compound of the formula (I) or a salt thereof includes any of an isolated individual enantiomer such as (R) form or (S) form, and a mixture thereof (including a racemic mixture or a non-racemic mixture). In one embodiment, the enantiomer is "stereochemically pure". The term "stereochemically pure" refers to a degree of purity that those skilled in the art can recognize that an enantiomer is substantially stereochemically pure. In another embodiment, the enantiomer is, for example, a compound having stereochemical purity of 90% ee (enantiomeric excess) or more, 95% ee or more, 98% ee or more, or 99%) ee or more.
[0020]
The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and depending on the types of substituents, an acid addition salt may be formed in some cases. Specific examples thereof include an acid addition salt of inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic

acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, and the like. In addition, the salt of the compound of the formula (I) also include a co-crystal of the compound of the formula (I) and an acid.
[0021]
The present invention further includes substances having crystalline polymorphism, various hydrates and solvates of the compound of the formula (I) and a salt thereof. The present invention still further includes the compound of the formula (I) or a salt thereof, which is pharmaceutical^ acceptable and is labeled with one or more radioactive or non-radioactive isotopes. Examples of suitable isotopes used for isotopic labeling of the compound of the present invention include isotopes such as hydrogen (2H, 3H, and the like), carbon (nC, 13C, 14C, and the like), nitrogen (13N, 15N, and the like), oxygen (150,170,180, and the like), fluorine (18F and the like), chlorine (36C1 and the like), iodine (1231,125I, and the like), phosphorus (32P and the like), and sulfur (35S and the like).
The isotope-labeled compound of the present invention can be used for research and the like on tissue distribution of drugs and/or substrates. For example, radioactive isotopes such as tritium (3H) and carbon 14 (14C) can be used for this purpose from the viewpoint of the ease of labeling and the convenience of detection.
Substitution by heavier isotopes, for example, substitution of hydrogen by deuterium (2H), is advantageous in terms of treating by improving metabolic stability in some cases (for example, increase in in vivo half-life, decrease in required dose, decrease in interaction between drugs).
Substitution by positron emission isotopes (nC, 18F, 150,13N, and the like) can be used in a positron-emission tomography (PET) test for testing occupancy of a substrate receptor.
The isotope-labeled compound of the present invention can be generally produced by methods of the related art known to those skilled in the art, or by the same preparation method as in examples or preparation examples by using suitable reagents which is isotopic labeled in place of unlabeled reagents.
[0022]
(Preparation Method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthetic methods using the basic structure thereof or the characteristics based on the types of substituents. Depending on the types of functional groups, it is effective for production technique in some cases, to replace the functional group with an appropriate protective group (a group which can be easily converted to the functional group) in advance at a stage from a starting material to an intermediate. Examples of

such a protective group include a protective group and the like described in "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)" by Wuts (P.GM. Wuts) and Greene (T.W. Greene). The protective group may be appropriately selected and used according to these reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group to carry out the reaction, and then removing the protective group if necessary.
A pharmaceutical^ acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of a group forming the prodrug include a group described in Prog. Med., 5, 2157-2161 (1985) and "Pharmaceutical Research and Development, Drug Design, Hirokawa Publishing Company" (Hirokawa-Shoten Ltd., 1990), Vol. 7, Molecular Design 163-198.
In addition, similarly to the protective group, a prodrug of the compound of the formula (I) can be produced by introducing a specific group at a stage from a starting material to an intermediate, or further carrying out the reaction using the obtained compound of the formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as general esterification, amidation, and dehydration.
Hereinafter, a representative method for preparing the compound of the formula (I) is described. Each preparation method can also be carried out with reference to the reference document attached to the explanation. The preparation method of the present invention is not limited to the examples shown below.
[0023]
In the present specification, the following abbreviations may be used.
DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetate, MeOH = methanol, MeCN = acetonitrile, THF = tetrahydrofuran, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine, NMM = N-methylmorpholine, XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, HATU = 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, brine = saturated sodium chloride aqueous solution, MgSCU = anhydrous magnesium sulfate.
[0024]
In the structural formulae and groups in the present specification, the following abbreviations may be used.
Ac = acetyl, BOC = tert-butoxycarbonyl, t-Bu = tert-butyl, Me = methyl, Et = ethyl, CF3 = trifluoromethyl, Ms = methanesulfonyl, Ts = p-toluenesulfonyl, Tf= trifluoromethanesulfonyl, Ph = phenyl.

(In the formula, RB represents -BF3"Y+, -B(OR)3, and the like. Lv represents a leaving group. Y represents an alkali metal such as Na or K. R may be H or lower alkyl, or two Rs may form lower alkylene together.)
The compound of the formula (I) can be obtained by a coupling reaction between Compound (1) and Compound (2). Examples of the leaving group include a halogen, TfO, and the like.
In this reaction, Compound (1) and Compound (2) are used in equivalent amounts, or either thereof in an excess amount. A mixture thereof is stirred in a solvent inert during the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux, in one embodiment, from room temperature to 150°C, usually for 0.1 hours to 5 days.
Examples of the solvent include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, EtOAc, MeCN, H2O, and a mixed solvent thereof. As examples of the base, an inorganic base such as CS2CO3, EC3PO4, K2CO3, Na2C03, and KOH is preferable. Examples of the palladium catalyst include a palladium catalyst adjusted in the system by palladium acetate and a phosphine ligand such as XPhos and RuPhos, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1' -bis(diphenylphosphino)ferrocene-palladium(II) dichloride, and the like.
[Document]
Edited by A. d. Meijere and F. Diederich, "Metal-Catalyzed Cross-Coupling Reactions", 1st edition, VCH Publishers Inc., 1997
Edited by The Chemical Society of Japan, "5th Edition, Courses in Experimental Science (Vol. 14)", Maruzen, 2005
[0026]
(Preparation Method 2)
[Chem. 10]

(3) (4) (1-1)
(In the formula, the compound of the formula (1-1) is the compound of the formula (I) in which L is CH2 and A is N.)
The compound of the formula (1-1) can be obtained by introducing a leaving grour. to Compound (3), and then allowing the reaction with Compound (4).
In this reaction, a compound obtained by allowing the reaction of Compound (3) with a halogenated sulfonyl compound such as MsCl or TsCl in a solvent inert during the reaction in the presence of a base, and Compound (4) are used in equivalent amounts, or either thereof in an excess amount. A mixture thereof is stirred in a solvent inert during the reaction in the presence of a base under ice cooling to heating under reflux, preferably at 0°C to 120°C, usually for 0.1 hours to 5 days.
Examples of the solvent include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, EtOAc, MeCN, and a mixed solvent thereof Examples of the base include an organic base such as TEA, DIPEA, and NMM, an inorganic base such as K2CO3, Na^CCb, and KOH, and the like.
The compound of the formula (I) can be obtained by an amidation reaction between Compound (5) and Compound (6). In this reaction, Compound (5) and Compound (6) are used in equivalent amounts, or either thereof in an excess amount. A mixture thereof is stirred in a solvent inert during the reaction in the presence of a condensing agent under cooling to heating, preferably at -20°C to 60°C, usually for 0.1

hours to 5 days. Examples of the solvent include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, EtOAc, MeCN, and a mixed solvent thereof. Examples of the condensing agent include HATU, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a hydrochloride thereof, dicyclohexylcarbodiimide, l,l'-carbonyldiimidazole, diphenylphosphoryl azide, and the like. In some cases, it is preferable to use an additive (for example, 1-hydroxybenzotriazole) for the reaction. In some cases, it is advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, and NMM, or an inorganic base such as K2CO3, Na2C03, and KOH, and the like in order to allow the reaction to proceed smoothly.
Furthermore, a method in which Compound (5) is converted into a reactive derivative, and then the reaction with Compound (6) is allowed can be used. Examples of the reactive derivative of a carboxylic acid include an acid halide obtained by reaction with a halogenating agent such as phosphorus oxychloride and thionyl chloride, a mixed acid anhydride obtained by reaction with isobutyl chloroformate or the like, an active ester obtained by condensing with 1-hydroxybenzotriazole or the like, and the like. The reaction between these reactive derivatives and Compound (6) is carried out in a solvent inert during the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, or the like under cooling to heating, preferably at -20°C to 60°C.
[Document]
S.R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd Edition, Vol. 1, Academic Press, Inc., 1991
Edited by The Chemical Society of Japan, "Courses in Experimental Chemistry (5th Edition)", Vol. 16 (2005) (Maruzen)
[0028]
(Starting Material Synthesis 1)
[Chem. 12]

(In the formula, Lv is a leaving group, Pgi and Pg2 are protective groups, and X is a halogen. Crossed double bonds in Compound (13) represent a mixture of geometric isomers.)
Examples of Pgi include a BOC group and the like, and examples of Pg2 include a t-Bu group, an Et group, a Me group, and the like.
Steps represented by Step 1-1 to Step 1-3 are a reaction for obtaining Compound (15) used as a Wittig reagent (phosphorus ylide) from Compound (17), and a reaction for obtaining Compound (13) by the Wittig reaction of Compound (15) and Compound (14), respectively. In Step 1-1 and Step 1-2, Compound (17) is allowed to react with a halogenating agent such as N-bromosuccinimide or bromine so to form Halide (16), and then a mixture with triphenylphosphine is stirred in a solvent inert during the reaction under cooling to heating under reflux, in one embodiment, at 0°C to 120°C, usually for 0.1 hours to 5 days. In a case of being dihalogenated during the halogenation reaction, Monoharide (16) can be obtained by reacting with diethyl phosphonate. In Step 1-3, a mixture of Compound (14) and Compound (15) is stirred in a solvent inert during the reaction in the presence of a base under cooling to heating under reflux, preferably at 0°C to 100°C, usually for 0.1 hours to 10 days. Examples of the solvent include aromatic

hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, EtOAc, MeCN, and a mixture thereof. Examples of the base include an organic base such as sodium methoxide, potassium tert-butoxide, n-butyl lithium, lithium hexamethyldisilazide, an inorganic base such as K2CO3, Na2C03, and KOH, and the like.
[Document]
Wittig, G. et al., U. Ber., 1954, Vol. 87, p.1318
A step represented by Step 1-4 is a reaction for obtaining Compound (12) by oxidation reaction that occurs after hydroboration of alkene of Compound (13). In this reaction, a reactant which is obtained by stirring a mixture of Compound (13) and a borane-THF complex, 9-borabicyclo[3.3.1]nonane, disiamylborane, thexylborane, or the like in a solvent inert during the reaction, preferably at 10°C to 80°C usually for 0.1 hours to 3 day is processed with an equivalent amount or an excess amount of an oxidizing agent in a solvent inert during the reaction in the presence of a base under cooling to heating under reflux, preferably at -20°C to 80°C, usually for 0.1 hours to 3 days, and thereby Compound (12) can be obtained.
Examples of the solvent include aromatic hydrocarbons, ethers such as THF, halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN, and a mixture thereof. Examples of the base include NaOH, K2CO3, Na2C03, and KOH, and the like. Examples of the oxidizing agent include hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone, activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.
[Document]
J. Am. Chem., Soc, 1956, Vol. 78, p.5694-5695
J. Org. Chem., 1986, Vol. 51, p.439-445
A step represented by Step 1-5 is a reaction for obtaining Compound (11) by the oxidation reaction of Compound (12). In this reaction, Compound (12) is processed with an equivalent amount or an excess amount of an oxidizing agent, in a solvent inert during the reaction under cooling to heating, preferably at -20°C to 80°C, usually for 0.1 hours to 3 days. In this reaction, DMSO oxidation such as tetrapropylammonium perruthenate (TPAP) oxidation, or Swern oxidation, or oxidation using Dess-Martin reagent is suitably used. In the TPAP oxidation, Compound (12) is processed in the presence of tetrapropylammonium perruthenate which is an oxidation catalyst, molecular sieve 4A which is a dehydrating agent, and N-methylmorpholin-N-oxide (NMMO) which is a reoxidant. Examples of the solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, EtOAc, MeCN, and a mixture thereof. Examples of other oxidizing agents include hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone, activated

manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.
[Document]
J. Chem. Soc, Chem. Commun., 1987, p. 1625-1627
Edited by The Chemical Society of Japan, "5th Edition, Courses in Experimental Science (Vol. 14)", Maruzen, 2005
A step represented by Step 1-6 is a reaction for deprotecting the protective group Pgi of Compound (11) and then condensing with Compound (10), and thereby obtaining Compound (9). The step can be carried out in the same manner as in Preparation Method 3 after carrying out deprotection reaction with reference to the method described in "Greene's Protective Groups in Organic Synthesis", 4th edition, 2006, and the like.
A step represented by Step 1-7 is a reaction for obtaining Compound (8) by fluorination of Compound (9). In this reaction, Compound (9) is stirred in a solvent inert during the reaction in the presence of a fluorinating agent under cooling to heating, preferably at -20°C to 120°C, usually for 0.1 hours to 10 days. Examples of the solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, EtOAc, MeCN, and a mixture thereof. Examples of the fluorinating agent include 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, hydrogen fluoride, diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride (SF4), bis(2-methoxyethyl)aminosulfur trifluoride, and the like.
[Document]
J. Am. Chem. Soc, 2010, Vol. 132, p.18199-18205
A step represented by Step 1-8 is a reaction for obtaining Compound (7) by deprotection of Compound (8). This reaction can be referred to, for example, the method described in "Greene's Protective Groups in Organic Synthesis", 4th edition, 2006, and the like.
A step represented by Step 1-9 is a reaction for obtaining Compound (1) by condensing Compound (7) and Compound (6). The step can be carried out by the same method as Preparation Method 3.
[0029]
(Starting Material Synthesis 2)
[Chem. 13]

Examples of Pg3 include 2,4,6-trichlorophenyl.
A step represented by Step 2-1 is a reaction for obtaining Compound (18) by the reaction between Compound (1) and Compound (19). The step can be carried out in the same method as Preparation Method 1 except that Compound (19) is used in place of Compound (2).
As the solvent, toluene or benzotrifluoride is preferable. As the base, TEA or tributylamine is preferable. As the palladium catalyst, a palladium catalyst adjusted in situ by palladium acetate and a phosphine ligand such as XantPhos is preferable.
[Document]
Organic Letters, 2012, Vol. 14, No. 20, pp. 5370-5373.
A step represented by Step 2-2 is a reaction for obtaining Compound (3) by the reduction reaction of Compound (18). In this reaction, Compound (18) is processed with an equivalent amount or an excess amount of a reducing agent, in a solvent inert during the reaction under cooling to heating, preferably at -20°C to 80°C, usually for 0.1 hours to 3 hours. Examples of the solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as MeOH, DMF, DMSO, EtOAc, MeCN, and a mixture thereof. Examples of the reducing agent include hydride reducing agents such as sodium borohydride and lithium borohydride.
[Document]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd Edition (ACS Monograph: 188)," ACS, 1996
R.C. Larock, "Comprehensive Organic Transformations", 2nd Edition, VCH Publishers, Inc., 1999
T.J. Donohoe "Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)", Oxford Science Publications, 2000
Edited by The Chemical Society of Japan, "Courses in Experimental Chemistry (5th Edition)", Vol. 14 (2005) (Maruzen)
[0030]
(Starting Material Synthesis 3)
[Chem. 14]

A step shown in Step 3-1 is a reaction for obtaining Compound (20) by a coupling reaction between Compound (8) and Compound (2), and can be carried out by the same method as in Preparation Method 1.
A step represented by Step 3-2 is a reaction for obtaining Compound (5) by deprotection of Compound (20), and can be carried out by the same method as Step 1-8 of Starting Material Synthesis 1.
[0031]
The compound of the formula (I) is isolated as a free form compound, a salt thereof, a hydrate, a solvate, or a substance having crystalline polymorphism, and purified. The salt of the compound of the formula (I) can also be prepared by subjecting the compound to a salt formation reaction of a general method.
Isolation and purification are carried out by applying usual chemical operations such as extraction, fractional crystallization, and various fractionation chromatography.
Various isomers can be prepared by selecting an appropriate starting compound or :an be separated by using a difference in physicochemical properties between isomers. For example, the optical isomer can be obtained by a general optical resolution method of racemic form (for example, fractional crystallization leading to a diastereomeric salt with an optically active base or an acid, chromatography using a chiral column or the like, and the like), or can be prepared from an appropriate optically active starting compound.
[0032]
The pharmacological activity of the compound of the formula (I) can be confirmed oy the following tests or well-known improved tests.
[0033]
Test Example 1: Measurement of in vitro Human Cathepsin S Inhibitory Activity
To a 96-well plate, 5 uL of human cathepsin S enzyme (R&D 1183-CY-010) was idded so as to be 20 ng/well. Next, with assay buffer (50 mM sodium acetate, 250 mM sodium chloride, and 5 mM dithiothreitol (DTT), pH = 4.5), a test compound (10 mM DMSO solution) was diluted 10-fold dilution series with 5 steps so that a final concentration becomes 0.1 nM to 1 uM or diluted 3-fold dilution series with 7 steps so that i final concentration becomes 0.01 nM to 10 nM, and 10 uL thereof was added to the well [final DMSO concentration was 0.1%), followed by addition of 25 uL of synthetic substrate VVR-AMC (Peptide Institute 3211-V) so that a final concentration becomes 40 j,M, and thereby an enzymatic reaction was initiated. The fluorescence intensity [excitation wavelength: 380 nm, fluorescence wavelength: 460 nm) was measured at 37°C for 5 to 10 minutes from the start of the reaction using a spectrofluorophotometer [SPECTRAMAX GEMINI, Molecular Devices), and a reaction rate when linearity was recognized (5 minutes) was obtained for each concentration of the test compound. An inhibition rate at each concentration was defined by suppressing a reaction rate at the time

of non-addition of an enzyme without adding the test compound and a reaction rate at the time of addition of an enzyme without adding the test compound by 100% inhibition and 0% inhibition, respectively, and therefore an IC50 value was calculated by a sigmoid Emax nonlinear regression method. The results are shown in Table 1. In the table, Ex represents Example compound No., and Datl represents the IC50 value (nM) of human cathepsin S inhibitory activity.
[0035]
Test Example 2: Evaluation of Inhibitory Effect on in vitro MHC class II Expression Using Mouse Splenocytes (Cell Evaluation System)
In antigen-presenting cells, inhibition of cathepsin S suppresses expression of MHC class II molecules. As a result, suppression of antigen presentation to CD4-positive T cells causes a deterioration in the immune response to foreign antigens. In regard to an increase in MHC class II expression in B cells, the inhibitory effect of the compound of the formula (I) was examined.
Splenocytes collected from male C57BL/6J mice (Charles River Laboratories Japan, Inc.) were seeded in a 96-well plate by 1 x 105 cells/well. With RPMI1640 medium (containing 10% fetal bovine serum (FCS), 5 x 10"5 M 2-mercaptoethanol, 50 IU/mL penicillin, and 50 ug/mL streptomycin), 10 mM DMSO solution of the test compound was diluted 5-fold dilution series with 9 steps so that a final concentration becomes 0.026 nM to 10 uM, or diluted 5-fold dilution series with 12 steps so that a final concentration becomes 0.205 pM to 10 uM (final DMSO concentration is 0.1%), and added. At the same time, LPS (Sigma L4005) was added to the well so that the final concentration becomes 2 ug/mL, and the cells were cultured at 37°C under 5% CO2 for 48 hours. After culturing, the cells were stained with biotin-labeled YAe antibody (EBIOSCIENCE 13-5741-85) at 4°C for 20 minutes, and washed. The cells were further stained with FITC fluorochrome labeled anti-mouse B220 antibody (BD BIOSCIENCES 553088) and PE fluorochrome labeled streptavidin (BD BIOSCIENCES 554061) for 20 minutes at 4°C. Therefore, an expression level (fluorescence intensity of YAe-biotin/streptavidin-PE) of MHC class II bound to the Ea peptide in B220 positive B cells was measured by using a flow cytometry system (Guava EasyCyte Plus System,

Millipore). An inhibition rate at each concentration was defined by suppressing a value at the time of non-stimulation of LPS without addition of the test compound and a value at the time of stimulation of LPS without addition of the test compound by 100% inhibition and 0% inhibition, respectively, and therefore an IC50 value was calculated by the sigmoid Emax nonlinear regression method. The results are shown in Table 2. In the table, Ex represents Example compound No., and Dat2 represents the IC50 value (nM).
[0037]
Test Example 3: Evaluation of ex vivo MHC class II Expression Inhibitory Effect Using Mouse Peripheral Blood
The expression inhibitory effect of MHC class II molecules was evaluated in an ex vivo system.
The test compound was orally administered to male C57BL/6J mice (Charles River Laboratories Japan, Inc.), and an inhibition effect with respect to an increase in the expression of MHC class II in B cells of peripheral blood after oral administration was examined. That is, 10 mL/kg of the test compound dissolved in a vehicle [30% propylene glycol solvent {propylene glycol: hydrogenated castor oil (HCO40): Tween 80 = 4:2:1}/HC1 (2 equivalents to the test compound)/water] was orally administered to male C57BL/6J mice (dose: 0.3 mg/kg, 4 subjects per group), and peripheral blood was recovered after 6 hours. To 90 uL of the peripheral blood, 10 uL of PBS or 10 uL (final concentration 100 |ag/mL) of LPS (Sigma L4005) was added, and the culturing was carried out at 37°C under 5% CO2 for 15 hours. After culturing, the cells were stained with FITC fluorochrome labeled anti-mouse I-A/I-E antibody (BD BIOSCIENCES 553623) and PE fluorochrome labeled anti-mouse B220 antibody (BD BIOSCIENCES 553090) for 30 minutes under refrigeration, and then hemolysis and fixation were carried out for 11 to 12 minutes at 37°C using a buffer (BD BIOSCIENCES Phosflow Lyse/Fix Buffer 558049). After washing, using the flow cytometry system (FACSCanto II, BD BIOSCIENCES), an expression level of MHC class II on a surface of B220 positive B cells was measured with an average fluorescence intensity of FITC (hereinafter referred to as MFI) as an index. A difference between MFI of LPS stimulation and MFI of no stimulation was defined as AMFI, and therefore, an inhibition rate of AMFI according to the administration of the test

compound was calculated by setting AMFI of mice administered with 10 mL/kg of the vehicle to 1.
[0038]
In this test, the compound of Example 8 showed 41% inhibition (0.3 mg/kg), which inhibited the increase in expression of MHC class II.
[0039]
Test Example 4: Evaluation of Inhibitory Effect on SLE-Like Disease Onset in Spontaneous Onset Model Using NZB/W Fl Mice
NZB/W Fl mice (Japan SLC, Inc.) is used as a model of SLE spontaneously developing a disease condition close to humans ("JAMA", 1966, Vol. 195, p. 145; "Advances in Immunology", 1985, Vol. 37, p. 269-390; "Journal of Biomedicine and Biotechnology", 2011, Vol. 2011, 271694).
NZB/W Fl female mice were divided into groups according to urine protein values (creatinine corrected value), anti-double stranded DNA (dsDNA) antibody value (IgG) in plasma, an expression level of MHC class II in B cells of peripheral blood, and body weight at age of 19 weeks. At this time, individuals with urine protein values (creatinine corrected value) of 3 or more were excluded. From age of 20 weeks, the test compound was orally administered twice a day, and then urine collection and blood collection were performed over time. The change in urine protein value and anti-dsDNA antibody value over time were evaluated.
In the above test, anti-dsDNA IgG antibody value in plasma generated in association with SLE-like disease was measured by ELISA method (ALPHA DIAGNOSTIC 5120). In geometric mean values of the antibody value at age of 28 weeks and age of 32 weeks of each individual, a geometric mean value of 10 vehicle-administered subjects was 216662 U/mL, whereas a geometric mean value of 10 subjects administered with 1 mg/kg b.i.d. of the compound of Example 2 was 26827 U/mL, which is a low value having a significant difference (P value = 0.0009, Dunnett's multiple comparison). In addition, urine protein values (creatinine corrected value) at age of 40 weeks were measured. A geometric mean value of the 10 vehicle-administered subjects was 13.0, whereas a geometric mean value of the 10 subjects administered with 1 mg/kg b.i.d. of the compound of Example 2 was 0.7, which is a low value having a significant difference (P value = 0.0005, Dunnett's multiple comparison). Based on this, it was confirmed that the compound of Example 2 has the effect of suppressing the SLE-like disease onset in NZB/W Fl female mice.
[0040]
Test Example 5: Evaluation of Therapeutic Effect on SLE-Like Disease in Poly (I:C) Induced Onset Model Using NZB/W Fl Mice

The poly (I:C), which is a ligand for Toll-like receptor 3, is administered to NZB/W Fl mice (Japan SLC, Inc.), and therefore, it is possible to accelerate an increase in proteinuria associated with SLE-like disease. Administration of the test compound is started from the state where proteinuria is induced by poly (I:C) administration, and then a therapeutic effect of SLE-like disease is evaluated.
200 jug of poly (I:C) (InvivoGen tlrl-picw-250) is administered to 22-weeks-old NZB/W Fl mice three times a week for 4 weeks, which is a total of 12 times. In the following 2 weeks, individuals whose urine protein value (creatinine corrected value) has become 2 to 50 in principle are incorporated in the test and allocated based on the urine protein value. After grouping, the test compound is orally administered twice a day for 5 weeks, urine is collected over time, and therefore the change in urine protein value over time is evaluated.
[0041]
Based on the above results, the compound of the formula (I) or a salt thereof is expected to be used as an agent for preventing and/or treating autoimmune disease including SLE and lupus nephritis, allergies, or graft rejection of an organ, bone marrow or tissue.
[0042]
A pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient can be prepared by using an excipient generally used in this field, that is, a pharmaceutical excipient, a pharmaceutical carrier, and the like, according to methods generally used.
Administration may be in any form of oral administration with tablets, pills, capsules, granules, powders, solutions, and the like, injections such as intra-articular, intravenous, and intramuscular injections, and parenteral administration by suppository, eye drops, eye ointment, transdermal solution, ointment, transdermal patch, transmucosal solution, transmucosal patch, inhaler, and the like.
[0043]
As a solid composition for oral administration, tablets, powders, granules, and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain inactive additives such as lubricants and disintegrants, stabilizers, and solubilizing agents according to general methods. The tablets or pills may be coated with a sugar coating or a film of stomach-soluble or enteric substance, if necessary.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and include inert diluents generally used, such as purified water or ethanol. The liquid composition may contain a

solubilizing agent, a wetting agent, an adjuvant such as a suspending agent, a sweetening agent, a flavor, an aromatic, and a preservative in addition to the inert diluent.
[0044]
The injections for parenteral administration contain sterile aqueous or nonaqueous solutions, suspensions, or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of the nonaqueous solvents include alcohols such as ethanol. Such a composition may further include a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria-retaining filter, and blending of a sterilizing agent or irradiation. These can also be used by preparing a sterile solid composition and dissolving or suspending the composition in sterile water or a sterile injectable solvent before use.
[0045]
Examples of external preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. Generally used ointment base, lotion base, aqueous or nonaqueous solutions, suspensions, emulsions, and the like are included therein.
[0046]
Transmucosal agents such as inhalers and transnasal preparations are solid, liquid, or semisolid, and can be manufactured according to known methods of the related art. For example, well-known excipients, and furthermore, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, and the like may be appropriately added. For administration, a device for proper inhalation or insufflation can be used. For example, using a known device such as metered-dose inhaler device, or a nebulizer, the compound can be administered alone or as a powder of the formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler and the like may be a device for single or multiple administrations, and a dry powder or a powder-containing capsule may be used. Alternatively, the administration form may be a suitable ejection agent such as a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane or carbon dioxide.
[0047]
In a case of the oral administration, a daily dose is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg per body weight, which are suitable, and this dose is administered once or divided into 2 to 4 doses. In a case of intravenous administration, a daily dose is suitably about 0.0001 to 10 mg/kg per body weight, and this dose is administered once to several doses a day. In regard to a transmucosal agent, about 0.001 to 100 mg/kg per body weight is administered once to

several doses a day. The dose is appropriately decided according to individual cases in consideration of symptoms, age, sex, and the like.
[0048]
The pharmaceutical composition of the present invention contains 0.01% to 100% by weight, and 0.01% to 50% by weight in one embodiment, of one or more compounds of the formula (I) or a salt thereof, which is an active ingredient, although the weight thereof may vary depending on the route of administration, dosage form, site of administration, types of excipients and additives.
[0049]
The compound of the formula (I) can be used in combination with various agents for treating or agents for preventing diseases on which the compound of the formula (I) is considered to exhibit efficacy. The combination may be administered simultaneously, or separately in succession, or at a desired time interval. An agent for simultaneous administration may be a compounding agent or may be separately formulated. [Examples]
[0050]
Hereinafter, a preparation method of the compound of the formula (I) will be explained in more detail based on examples. The present invention is not limited to compounds described in the following examples. In addition, each preparation method of a starting compound is shown in preparation examples. Furthermore, the preparation method of the compound of the formula (I) is not limited only to preparation methods of the specific examples shown below. The compound of the formula (I) can be prepared according to a combination of these preparation methods, or methods which are obvious for those skilled in the art.
[0051]
An onset temperature of a DSC curve obtained by measurement under the following conditions is shown in the following tables as a melting point.
The DSC measurement was performed using an aluminum sample pan in a state of not covering the sample pan under conditions of a measurement range of temperature: room temperature to 300°C, an increase rate of temperature: 10°C/min, and a flow rate of nitrogen: 50 mL/min by using DSC Q2000 (manufactured by TA Instruments.).
[0052]
Powder X-ray diffraction was performed by using RINT-TTRII (manufactured by RIGAKU Corporation) under conditions of a tube: Cu, a tube current: 300 mA, a tube voltage: 50 kV, a sampling width: 0.020°, a scanning speed: 47min, a wavelength: 1.5418 A, a measured range of diffraction angle: (26): 2.5 to 40°.
In regard to a pattern of the powder X-ray diffraction, because of the nature of data thereof, crystal lattice space and overall patterns are important in identification of crystal

network, each value indicating duration of barring of access to a corresponding network type of network, wherein
if each of the at least one value is a valid value, the access barring timer is started, and network access barring duration of the access barring timer is set to a smallest or greatest one of the at least one value, and
if at least one of the at least one value is an invalid value, the access barring timer is not started.
6. The method according to claim 1, wherein
the multiple pieces of access control information are broadcast in the same or different system information.
7. User equipment (UE), comprising:
a transceiver, configured to receive, from a base station, multiple pieces of access control information respectively corresponding to multiple network types;
a checking unit, configured to use the received multiple pieces of access control information to respectively perform an access control check for the multiple network types of networks;
a starting unit, configured to start an access barring timer according to an access control check result; and
an informing unit, configured to, if the access barring timer times out, inform an upper layer of the UE that barring of access is removed.
8. The UE according to claim 7, wherein
the starting unit is further configured to: if the check result indicates that access to at least one network type of network is barred, respectively start at least one access barring timer provided for the at least one network type of network, each access barring timer indicating duration of barring of access to a corresponding network type of network.
9. The UE according to claim 8, wherein
the informing unit is further configured to:
if one of the at least one access barring timer times out, inform the upper layer of the UE that barring of access to a corresponding network type of network is removed; or,
if each of the at least one access barring timer times out, inform the upper layer of the UE that barring of access to the corresponding network type of network is removed.
10. The UE according to claim 8, further comprising