JP2010510211A - 7-substituted purine derivatives for immunosuppression - Google Patents

Abstract

III
で示される。The present invention provides novel prinones and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory diseases, mast cell mediated diseases and graft rejection. The compound has the general formula III:

III
Indicated by

Description

  The present invention relates to a prinone derivative useful as an immunosuppressant.

  Immunosuppression is an important clinical approach in the treatment of autoimmune diseases and the prevention of organ and tissue rejection. Although clinically available immunosuppressive drugs such as azathioprine, cyclosporine and tacrolimus are effective, they often cause undesirable side effects such as nephrotoxicity, hypertension, gastrointestinal disorders and gingivitis. Inhibitors of tyrosine kinase Jak3 are known to be useful as immunosuppressants (see US Pat. No. 6,313,129).

Members of the Janus kinase (Jak) family of non-receptor intracellular tyrosine kinases are components of cytokine signaling. Four family members have been identified: Jak1, Jak2, Jak3 and Tyk2. The Jak group plays an important role in intracellular signaling mediated by cytokine receptors. When cytokines to their receptor binding, Jak group is activated, the receptor phosphorylated other signaling molecules, in particular, signal transducer and activator of transcription (STAT: s ignal t ransducer and a ctivator of t ranscription) Generate docking sites for the family. Jak1, Jak2 and Tyk2 expression is relatively ubiquitous, and Jak3 expression is temporally and spatially regulated. Jak3 is mainly expressed in hematopoietic cells; it is constitutively expressed in natural killer (NK) cells and thymocytes and induced in T cells, B cells and bone marrow cells (Ortmann et al., 1999 and Yamaoka). Et al., 2004). Jak3 is also expressed in mast cells and its enzymatic activity is enhanced by IgE receptor / FcεRI cross-linking (Malaviya and Uckun, 1999).

  CP-690,550, a specific orally effective Jak3 inhibitor, has been shown to act as an effective immunosuppressant and prolong animal survival in heart transplanted mouse models and kidney transplanted primate models ( Changelian et al. 2003).

  Furthermore, abnormal Jak3 activity has been implicated in leukemia types of cutaneous T-cell lymphoma (Sezary syndrome) and acute lymphoblastic leukemia (ALL), the most common forms of childhood cancer. The identification of Jak3 inhibitors provides the basis for new clinical approaches in targeting leukemia and lymphoma (reviewed in Uckun et al., 2005). Two dimethoxyquinazoline derivatives, WHI-P131 (JANEX-1) and WHI-P154 (JANEX-2) have been reported to be selective inhibitors of Jak3 in leukemia cells (Sudbeck et al., 1999).

  Jak3 has also been shown to play a role in mast cell-mediated allergic reactions and inflammatory diseases and to serve as a target in indications such as asthma and anaphylaxis.

  Thus, compounds that inhibit Jak3 are useful for indications such as leukemia and lymphoma, organ and bone marrow transplant rejection, mast cell mediated allergic reactions and inflammatory diseases and disorders.

III
の化合物が、Jak3の強力かつ選択的なインヒビターであることが見出された。
これらの化合物において、
Q₁およびQ₂は独立して、CX₁、CX₂および窒素から選ばれ(ここで、Q₁およびQ₂は、両方が水素ではない)；
Q₃は、NまたはCHであり；
X₁およびX₂は独立して、水素、(C₁-C₆)アルキル、シアノ、ハロ、ハロ(C₁-C₆)アルキル、ヒドロキシル、(C₁-C₆)アルコキシ、ハロ(C₁-C₆)アルコキシおよびニトロから選ばれ；
R₁は独立して、水素および(C₁-C₆)アルキルから選ばれ；
yは、0または1、2および3から選ばれる整数であり；
R₂およびR₃は、(CR₂R₃)の存在毎に独立して、水素および(C₁-C₆)アルキルから選ばれ；
R₄は、アルキル、ヘテロシクリル、アリール、ヘテロアリール、置換アルキル、置換ヘテロシクリル、置換アリール、置換ヘテロアリールから選ばれ；および
R₅は独立して、アルキル、ヘテロシクリル、置換ヘテロシクリルおよびC₁-C₆アルキルから選ばれる(ここで、
(a)1または2個のCH₂は、NHおよびN(アルキル)から選ばれる基で置換されるか；
(b)1または2個のCH₂は、Oで置換されるか；
(c)1または2個のCH₂は、(C＝O)で置換されるか；
(d)2個のCH₂は、CH＝CHまたはC≡Cで置換されるか；または
(e)(a)、(b)、(c)および(d)のいずれかの化学的に安定な組み合わせ；
であり、ここで、0〜3個の水素は、
(a)ハロゲン、ヒドロキシ、シアノ、低級アルキルスルホニル、低級アルキルスルホニルオキシ、アミノ、低級アルキルアミノ、ジ低級アルキルアミノ、アルコキシアミノ、スルホニルアミノ、アシルアミノ、アリールアミノ、低級アルコキシ；
(b)ヘテロシクリルならびにハロゲン、ヒドロキシ、アルコキシ、アルキルおよびアルコキシカルボニルから選ばれる1〜3個の置換基で置換されたヘテロシクリル；
(c)フェニルならびにハロゲン、ヒドロキシ、アルコキシ、アルキル、アシルアミノ、シアノ、カルボキシ、アルコキシカルボニル、ハロアルキルおよびヘテロシクリルから選ばれる1〜3個の置換基で置換されたフェニル；および
(d)ヘテロアリールならびにハロゲン、ヒドロキシ、アルコキシ、アルキルおよびアルコキシカルボニルから選ばれる1〜3個の置換基で置換されたヘテロアリール；
から選ばれる置換基で置換される)。 (Summary of the Invention)
Currently, the general formula III:

III
Were found to be potent and selective inhibitors of Jak3.
In these compounds,
Q ₁ and Q ₂ are independently selected from CX ₁ , CX ₂ and nitrogen (where Q ₁ and Q ₂ are not both hydrogen);
Q ₃ is N or CH;
X ₁ and X ₂ are independently hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halo, halo (C ₁ -C ₆ ) alkyl, hydroxyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) selected from alkoxy and nitro;
R ₁ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl;
y is 0 or an integer selected from 1, 2 and 3;
R ₂ and R ₃ are independently selected from hydrogen and (C ₁ -C ₆ ) alkyl for each occurrence of (CR ₂ R ₃ );
R ₄ is selected from alkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl; and
R ₅ is independently selected from alkyl, heterocyclyl, substituted heterocyclyl and C ₁ -C ₆ alkyl (wherein
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from:

These members of the genera are useful for inhibiting Jak3 activity and as such are useful in the treatment of indications and blood cancer where clinical immunosuppression is desirable. The compounds are more selective for Jak3 than the corresponding compound Aurora A kinase where R ₅ is hydrogen.

  In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of general formula III or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

  In another embodiment, the present invention relates to a method for treating a disease by altering a response mediated by Jak3 tyrosine kinase. The method includes contacting at least one compound of general formula III with Jak3.

  In yet another aspect, the invention relates to a method of suppressing the immune system in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of general formula III.

  In a further aspect, the present invention comprises administering to a patient a therapeutically effective amount of at least one compound of general formula III in a patient in need thereof, an autoimmune disease, an inflammatory disease, a mast cell mediated disease And a method for treating a disease or disorder selected from hematological malignancy and organ transplant rejection.

  Suppression of immune system activity is desirable for the prevention or treatment of tissue or organ rejection after transplant surgery and the prevention and treatment of abnormal activity of the immune system, particularly autoimmune disorders and diseases resulting from the disorder. Exemplary autoimmune disorders include graft-versus-host disease (GVHD), insulin-dependent diabetes mellitus (type I), Hashimoto's thyroiditis and Graves' disease, pernicious anemia, Addison's disease, chronic active hepatitis, Crohn's disease, ulcerative colon Inflammation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, scleroderma and myasthenia gravis.

The compounds of the present invention are useful for the prevention and treatment of diseases and disorders associated with mast cell-mediated allergic reactions such as dry keratoconjunctivitis and inflammation.
Other indications where Jak3 inhibitors are useful include leukemia and lymphoma.

(Detailed description of the invention)
Throughout this specification, substituents are defined when introduced and retain that definition.

III
で示されるプリノンおよびイミダゾピリジノンに関する。 In a first embodiment, the present invention provides a compound of general formula III:

III
In relation to prinone and imidazopyridinone.

Type III members can be divided into subgeneras for convenience based on the meaning of Q. When Q ₁ is nitrogen and Q ₂ is carbon, the subclasses prionone and imidazo [4,5-b] pyridinone with bound imidazo [4,5-c] pyridine are produced. When Q ₁ is carbon and Q ₂ is nitrogen, the subclasses prionone and imidazo [4,5-b] pyridinone with bound imidazo [5,4-c] pyridine are produced. When both Q ₁ and Q ₂ are carbon, the subclasses prionone and imidazo [4,5-b] pyridinone with attached benzimidazole are generated. Type, based on the Q _3, it can be divided in the same manner. When Q ₃ is nitrogen, subclasses of prinones with bound imidazo [4,5-c] pyridine, imidazo [5,4-c] pyridine or benzimidazole are produced. When Q ₃ is carbon, a subclass of imidazo [4,5-b] pyridinone with bound imidazo [4,5-c] pyridine, imidazo [5,4-c] pyridine or benzimidazole results. The structural formulas for these subtypes are as follows:

In certain embodiments, X ₁ and X ₂ are selected from hydrogen, cyano, chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methyl; in other embodiments, R ₁ is H. In one subdivision, y is 0; in another subdivision, y is 1 or 2, and R ₂ and R ₃ are hydrogen or methyl. Examples of R ₄ are cyclopentyl, cyclohexyl, piperidine, oxepane, benzoxepane, dihydrocyclopentapyridine, phenyl, benzyl, tetralin, indane, tetrahydropyran, tetrahydrofuran, tetrahydroindole, isoquinoline, tetrahydroisoquinoline, quinoline, tetrahydroquinoline, chroman, pyridine , Pyrimidine, pyrazine, dihydropyran, dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, furan, dihydropyrano [2,3-b] pyridine (see Examples below), tetrahydroquinoxaline, tetrahydrothiopyran (thian), thiochroman (dihydrobenzo) Thiine) or halogen, methyl, methoxy, trifluoromethyl, cyano, hydroxy, oxo, oxide and And any of the above rings having 1-3 additional substituents such as acetyl. Further examples where R ₄ is alkyl or substituted alkyl include the subclass where R ₄ is oxaalkyl (alkoxyalkyl).

である表示によって記載されてもよい。 In certain embodiments of Type III, y is 1 or 2; R ₂ and R ₃ are hydrogen or methyl and R ₄ is phenyl, quinoline, pyridine, pyrazine or substituted phenyl, quinoline, pyridine or pyrazine . In other embodiments of type III, y is 0 and R ₄ is cyclopentyl, cyclohexyl, phenyl, indane, piperidine, oxepane, benzoxepane, dihydrocyclopentapyridine, tetralin, tetrahydropyran, tetrahydrofuran, tetrahydroindole, isoquinoline, tetrahydroisoquinoline , Quinoline, tetrahydroquinoline, chromane, pyridine, pyrimidine, dihydropyran, dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, furan, dihydropyrano [2,3-b] pyridine, tetrahydroquinoxaline, tetrahydrothiopyran (thian), thiochroman (dihydro Benzothiin) or a substituted ring from the above list. In a further embodiment, (a) y is 0 and R ₄ is cyclohexyl, oxepane, tetralin, indane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano [2,3-b ] Selected from pyridine and tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo or halogen; or (b) y is 1 or 2, R ₂ and R ₃ are hydrogen or methyl, R ₄ Is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen. When y is 0, R ₄ is tetrahydropyran-4-yl, 4-hydroxycyclohexyl, 4-oxocyclohexyl, oxepan-4-yl, chroman-4-yl; 3,4-dihydronaphthalene-1 (2H) -On-4-yl; 2,3-dihydroinden-1-on-4-yl and their fluoro substituted counterparts. Although both enantiomers are active, it appears that compounds with the (R) configuration at the 4-position carbon of chroman have stronger drag. Certain of the above subtypes where y is 0, R ₄ is

May be described by a display.

は、その対応する(S)エナンチオマーよりも効力が強いように思われる。他の実施態様として、yが1であり、R₄がジフルオロフェニル、フルオロフェニル、クロロフェニル、クロロフルオロフェニル、ピリジン-3-イルおよびピラジン-3-イルから選ばれる化合物が挙げられる。 According to this notation, W is CH ₂ , C═O or O; p is 1, 2 or 3; and A is a 6-membered heteroaromatic ring containing 1 or 2 nitrogens or 1 or 2 A benzene ring optionally substituted with one fluorine. The wavy line means the connection point to the prinon. Compounds in which the carbon marked with an asterisk is in the (R) configuration:

Seems to be more potent than its corresponding (S) enantiomer. Other embodiments include compounds wherein y is 1 and R ₄ is selected from difluorophenyl, fluorophenyl, chlorophenyl, chlorofluorophenyl, pyridin-3-yl and pyrazin-3-yl.

In certain embodiments of Type III, X ₁ and X ₂ are selected from hydrogen, cyano, chloro, fluoro, trifluoromethyl, trifluoromethoxy and methyl. In a more narrowly defined embodiment, X ₁ is selected from hydrogen, cyano and fluoro; Q ₁ and Q ₂ are CX ₁ ; Q ₃ is N and R ₁ is H. In some embodiments, y is 0 and R ₄ is cyclohexyl, tetralin, indane, oxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano [2,3-b ] Selected from pyridine and tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo or halogen. In other embodiments, y is 1 or 2, R ₂ and R ₃ are hydrogen or methyl, R ₄ is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen.

であり、1つのCH₂がC＝Oで置換された2-(4-モルホリニル)エチルとみなされてもよい。1つの実施態様(d)において、2個のCH₂は、CH＝CHまたはC≡Cで置換される。このようなのR₅例は、3-メチルブト-2-エン-1-イル： [-CH₂CH＝C(CH₃)₂]である。さらなる実施態様(e)として、(a)、(b)、(c)および(d)の化学的に安定な組み合わせが挙げられる。このようなR₅の例として、-CH₂CH₂CH₂NHC(＝O)CH₂CNが挙げられ、1つのCH₂がNHで置換され、1つのCH₂がC＝Oで置換された6-シアノヘキサンとみなされてもよい。用語「化学的に安定な」は、化学業界における当業者によって容易に理解される。それは、単離および精製されてもよい化合物ならびに水溶液中で生理的pHにおいて測定可能な程度には分解しないか、または周囲温度にて1時間後に＞99%が残る速度で分解する化合物を包含する。これらの化合物のすべてにおいて、0〜3個の水素が、以下から選ばれる置換基で置換されてもよい：
(a)ハロゲン、ヒドロキシ、シアノ、低級アルキルスルホニル、低級アルキルスルホニルオキシ、アミノ、低級アルキルアミノ、ジ低級アルキルアミノ、アルコキシアミノ、スルホニルアミノ、アシルアミノ、アリールアミノ、低級アルコキシ；
(b)ハロゲン、ヒドロキシ、アルコキシ、アルキルおよびアルコキシカルボニルから選ばれる1〜3個の置換基で置換されたヘテロシクリルおよびヘテロシクリル；
(c)ハロゲン、ヒドロキシ、アルコキシ、アルキル、アシルアミノ、シアノ、カルボキシ、アルコキシカルボニル、ハロアルキルおよびヘテロシクリルから選ばれる1〜3個の置換基で置換されたフェニルおよびフェニル。 In certain embodiments, R ₅ is C ₁ -C ₆ alkyl with certain substitutions or substitutions. In one embodiment (a), 1 or 2 CH ₂ can be replaced by NH or N (alkyl). These residues are also referred to as azaalkyls. An example of such R ₅ is —CH ₂ CH ₂ CH ₂ N (CH 3) CH ₂ CN, which may be regarded as 5-cyanopentane in which one CH ₂ is substituted with N (CH ₃ ). In one embodiment (b), 1 or 2 CH ₂ may be replaced by O. These residues are also referred to as oxaalkyl. In one embodiment (c), 1 or 2 CH ₂ may be substituted with (C═O). An example of such R ₅ is

And one CH ₂ may be regarded as 2- (4-morpholinyl) ethyl substituted with C═O. In one embodiment (d), two CH ₂ are substituted with CH═CH or C≡C. An example of such R ₅ is 3-methylbut-2-en-1-yl: [—CH ₂ CH═C (CH ₃ ) ₂ ]. Further embodiments (e) include chemically stable combinations of (a), (b), (c) and (d). An example of such R ₅ is —CH ₂ CH ₂ CH ₂ NHC (═O) CH ₂ CN, where one CH ₂ is replaced with NH and one CH ₂ is replaced with C═O. It may be considered 6-cyanohexane. The term “chemically stable” is readily understood by those skilled in the chemical arts. It includes compounds that may be isolated and purified as well as compounds that do not degrade measurable in aqueous solution at physiological pH, or degrade at a rate that remains> 99% after 1 hour at ambient temperature. . In all of these compounds, 0 to 3 hydrogens may be substituted with a substituent selected from:
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl.

。 Some examples of substituents for the aforementioned C ₁ -C ₆ alkyl include, but are not limited to:

.

In certain embodiments of Type III, Q ₁ is CX ₁ , Q ₂ is CX ₂ , X ₁ is hydrogen, X ₂ is a substituent at the 6-position of benzimidazole, and X ₂ is hydrogen. , Fluoro and cyano.

  All compounds included in the aforementioned parent genera and its subclasses are useful as Jak3 inhibitors.

(Definition)
For convenience and clarity, certain terms employed in the specification, examples and claims are set forth herein.
Alkyl is intended to include linear, branched or cyclic hydrocarbon structures and combinations thereof. Lower alkyl means an alkyl group consisting of 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl. Preferred alkyl groups are those of C ₂₀ or lower; more preferably C ₁ -C ₈ alkyl. Cycloalkyl is part of alkyl and includes cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

As C ₁ -C ₂₀ hydrocarbon, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.

Alkoxy or alkoxyl means a group consisting of 1 to 8 carbon atoms of straight, branched, cyclic configuration and combinations thereof attached to the parent structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy means a group containing 1 to 4 carbons. The term oxaalkyl is intended to be understood in the art (see Naming and Indexing of Chemical Substances for Chemical Abstracts , published by the American Chemical Society, paragraph 196 without limitation in paragraph 127 (a)), ie Means a compound in which oxygen is bonded to its adjacent atoms through a single bond (forms an ether bond); it does not mean a double-bonded oxygen such as found in a carbonyl group.

  Acyl means a group consisting of 1 to 8 carbon atoms of linear, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof linked to the parent structure via a carbonyl function. . As long as the point of attachment to the parent remains at the carbonyl, one or more carbons in the acyl residue may be substituted with nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl means a group containing 1 to 4 carbons.

  Aryl and heteroaryl are 5- or 6-membered aromatic or heteroaromatic rings containing 0 to 3 heteroatoms selected from O, N or S; 0 to 3 heteroaryls selected from O, N or S Bicyclic 9 or 10 membered aromatic or heteroaromatic ring system containing atoms; or Tricyclic 13 or 14 membered aromatic or hetero containing 0 to 3 heteroatoms selected from O, N or S Means an aromatic ring system. Examples of aromatic 6- to 14-membered carbocyclic rings include, for example, benzene and naphthalene, and for the purposes of the present invention, tetrahydro, where one or more rings are aromatic but not all aromatic Condensation moieties such as naphthalene (tetralin), indane and fluorine are mentioned. Examples of 5- to 10-membered aromatic heterocyclic rings include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

  Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include pyridinylmethyl, pyrimidinylethyl and the like.

  Heterocycle means cycloalkyl in which 1 to 3 carbons are replaced by a heteroatom selected from N, O and S. Nitrogen and sulfur heteroatoms may optionally be oxidized. In some situations other than this application, the term heterocycle may be construed to include heteroaryl; for purposes of this application, a heterocycle is a saturated heterocycle and does not include heteroaryl. Where heteroaryl is intended, it is clearly named. Examples of the heterocyclic ring include pyrrolidine, morpholine, dioxane, tetrahydrofuran and the like. Examples of heterocyclyl residues further include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 4-piperidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, quinuclidinyl, tetrahydro And furyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. A nitrogen-containing heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens as well as other heteroatoms.

  In substituted alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc., up to 3 H atoms in each residue are halogen, haloalkyl, hydroxy, lower alkoxy, hydroxy lower alkyl, carboxy, carboalkoxy (also referred to as alkoxycarbonyl). ), Carboxamide (also called alkylaminocarbonyl), heterocyclylcarbonyl, cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, lower alkoxyamino, arylaminocarbonyl, mercapto, alkylthio, sulfoxide, sulfoxideamino, sulfone , Acylamino, amidino, alkenyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, phenoxy, benzenesulfonyl, benzi Means alkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl substituted with ruoxy or heteroaryloxy; Where the parent is a heterocycle that allows such substitution, the term also includes oxides such as, for example, pyridine-N-oxide, thiopyran sulfoxide and thiopyran-S, S-dioxide. As mentioned above, two hydrogens on one carbon can be replaced with carbonyl to form an oxo derivative. Notable oxo-substituted aryl residues include tetralone (3,4-dihydronaphthalen-1 (2H) -one) and indanone (2,3-dihydroinden-1-one).

  The terms “halogen” and “halo” mean fluorine, chlorine, bromine or iodine. Some of the compounds described herein can contain one or more asymmetric centers, and thus as (R)-or (S)-in terms of enantiomers, diastereomers, and their absolute stereochemistry Other stereoisomers can be generated that can be determined. The present invention is also intended to encompass all such possible isomers. Optionally, active (R)-and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described in the present invention contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, it is intended that the compound contain both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; therefore, the carbon arbitrarily depicted herein as trans The carbon double bond can be Z, E or a mixture thereof in any ratio.

  As used herein, racemic, ambiscalemic and scalemic or enantiomerically pure compounds are described in Maehr J. et al. Chem. Ed. 62, 114-120 (1985): filled wedges and broken wedges are used to display the absolute configuration of chiral elements; wavy lines were able to produce the bonds they represent Indicates the negation of any stereochemical relationship; filled and broken bold lines are geometric descriptors that show the indicated relative configuration but do not imply racemic properties; And dotted or dashed lines mean enantiomerically pure compounds of absolute configuration that cannot be determined.

The compound of the present invention may exist in a radiolabel, that is, the compound of the present invention may contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Will be understood. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, chlorine and iodine include ³ H, ¹⁴ C, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I, respectively. Compounds containing these radioisotopes and / or other radioisotopes of other atoms are within the scope of this invention. Tritiated hydrogen, ie ³ H, and carbon-14, ie, ¹⁴ C radioisotope are particularly preferred because they are easy to produce and highly detectable. The radiolabeled compound of the present invention can generally be produced by methods known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by performing the procedures disclosed in the examples by replacing readily available radiolabeled reagents with non-radiolabeled reagents. Because of its high affinity for the JAK3 enzyme active site, the radiolabeled compounds of the present invention are useful in JAK3 assays.

および

などのピペリジン、ピリジン、ピラジン、ピリミジン、ピリジン、キノリン、イソキノリン、テトラヒドロキノリン、テトラヒドロイソキノリンおよびそれらの様々に置換された誘導体が挙げられる。 In one embodiment, R ₄ is a heterocycle. Heterocycles that appear in the examples are monocyclic and bicyclic heterocycles or monocyclic and bicyclic heterocycles substituted with 1 or 2 substituents. When y is not 0, heteroaryl is a preferred subset of heterocyclyl for R ₄ . Exemplary nitrogen-containing heterocycles include:

and

And piperidine, pyridine, pyrazine, pyrimidine, pyridine, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline and their various substituted derivatives.

などのテトラヒドロピラン、クロマンおよびそれらの様々に置換された誘導体が挙げられる。 An oxygen-containing heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygen as well as other heteroatoms. Exemplary oxygenated heterocycles include:

Tetrahydropyran, chromane and their various substituted derivatives.

(Chemical synthesis)
Terms relating to “protecting”, “deprotecting” and “protected” functionalities appear throughout this application. Such terms are well understood by those skilled in the art and are used in processes involving sequential treatment with a series of reagents. In such a situation, a protecting group refers to a group that reacts if not protected but is used to mask a functional group during a processing step where the reaction is undesirable. The protecting group prevents reaction in such a step, but can be subsequently removed to expose the original functional group. Removal or “deprotection” occurs after completion of the reaction or reactions that the functional group interferes with. Thus, if a series of reagents are identified in the course of the present invention, those skilled in the art can readily predict such groups that are suitable as “protecting groups”. Suitable groups for such purposes are Protective Groups in Organic Synthesis by TW. Discussed in standard textbooks in the field of chemistry such as Greene [John Wiley & Sons, New York, 1991]. This is incorporated herein by reference.

A comprehensive list of abbreviations used by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry . The list typically presented in the table entitled “Standard List of Abbreviations” is incorporated herein by reference in its entirety.

  In general, the compounds of the present invention are produced, for example, by methods such as those shown in the general reaction schemes described below or modifications thereof using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to use variants that are known per se but are not mentioned here. The starting materials are commercially available, for example in the case of appropriately substituted benzimidazole ring compounds, may be synthesized as described in the examples or may be obtained by methods well known to those skilled in the art.

  The present invention further provides pharmaceutical compositions comprising a compound described herein as an active agent.

  As used herein, a “pharmaceutical composition” is derived from one or more compounds described herein or physiologically acceptable salts thereof and other chemical components such as physiologically suitable carriers and excipients. Is a formulation.

  Accordingly, a pharmaceutical composition for use in accordance with the present invention is one or more physiologically acceptable comprising excipients and adjuvants that facilitate processing the active compound into a pharmaceutically usable formulation. It may be formulated in a conventional manner using a carrier. Proper formulation is dependent upon the route of administration chosen.

  A compound that inhibits Jak- is formulated as a pharmaceutical composition and human in various forms compatible with the selected route of administration, i.e. oral or parenteral, intravenous, intramuscular, topical, transdermal or subcutaneous route, etc. It can be administered to a mammalian patient such as a patient.

  For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such a carrier makes it possible to prepare the compound of the present invention as a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension or the like for oral intake by a patient. Using solid excipients, optionally crushing the resulting mixture, adding appropriate adjuvants if necessary, then processing the granule mixture to obtain tablets or dragee cores, pharmacology for oral use A pharmaceutical preparation can be produced. Suitable excipients are specifically fillers such as sugars such as lactose, sucrose, mannitol or sorbitol; for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl Cellulose products such as methylcellulose, sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

  In addition, enteric coatings are useful when it is desirable to prevent exposure of the compounds of the invention to the stomach environment.

  Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-in capsules contain the active ingredient as a mixture with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer.

  In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

  For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution, or physiological saline buffer. For transmucosal and transdermal administration, penetrants appropriate to the barrier to be permeated may be used in the composition. For example, such penetrants such as DMSO or polyethylene glycol are known in the art.

  For administration by inhalation, the compounds for use in accordance with the present invention are pressurized packs or nebulizers using a suitable high pressure gas such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. Conveniently delivered in the form of an aerosol spray jet from. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. For example, capsules or cartridges such as gelatin for use in an inhaler can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

  Pharmaceutical compositions for parenteral administration include aqueous solutions of active ingredients in water-soluble form. In addition, suspensions of the active compounds as appropriate oily suspension injections may be prepared. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty oils such as ethyl oleate, triglycerides or liposomes. Aqueous suspension injections may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers, or agents that increase the solubility of the compound, allowing the production of highly concentrated solutions.

  The compounds of the present invention may be formulated in rectal compositions such as suppositories or retention enemas, using, eg, conventional suppository bases such as cocoa butter or other glycerides.

  Depending on the severity and responsiveness of the condition being treated, dosing may be a sustained release composition as a course of treatment lasting days to weeks or until healing is achieved or a reduction in disease state is achieved. It can also be a single administration of the product. The amount of composition administered will, of course, depend on many factors, such as the patient being treated, the severity of the affliction, the dosage form, the judgment of the prescribing physician, and the like. The compound of the present invention may be administered orally or by injection at a dose of 0.001 to 2500 mg / kg / day. The dose range for adult humans is generally 0.005 mg to 10 g / day. Administration of tablets or other forms provided in discrete units is effective at such doses or in multiple doses, for example, units containing 5 mg to 500 mg, usually about 10 mg to 200 mg An amount of the compound of the present invention can be conveniently included. The exact amount of compound administered to the patient will be determined by the attending physician. However, the dose used will depend on many factors such as the age and sex of the patient, such as the details of the disorder being treated and its severity. Also, the route of administration will vary depending on the condition and severity.

  As used herein and as understood by one of skill in the art, the description of “compound” is intended to include salts, solvates and inclusion complexes of the compound. The term “solvate” means a compound of formula I or II in the solid state in which molecules of the appropriate solvent are incorporated into the crystal lattice. Suitable solvents for therapeutic administration are those that are physiologically tolerable at the dosage administered. Examples of suitable solvents suitable for therapeutic administration are ethanol and water. When water is the solvent, the solvate is called a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate using cooling or antisolvent. Solvates are typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, pages 176-177, which is incorporated herein by reference. The most commonly used inclusion complexes are complexes with cyclodextrins, and all synthetic and natural cyclodextrin complexes are expressly included in the claims.

  The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic salts or bases such as inorganic acids and bases and organic acids and bases. When the compound of the present invention is basic, salts are prepared from pharmaceutically acceptable non-toxic acids, such as inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, Hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucin acid, nitric acid, pamonic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfone Examples include acid salts. When the compound of the present invention contains an acidic side chain, a metal salt prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc as a suitable pharmaceutically acceptable base addition salt for the compound of the present invention Alternatively, organic salts produced from lysine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine can be mentioned.

  As used herein, the term “preventing” means administering a medicament to prevent or blunt the disease in advance. One of ordinary skill in the medical arts to which the present method claims relate will recognize that the term “prevent” is not an absolute expression. In the medical industry, it is understood to mean prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition, and this is the meaning intended herein.

  In addition to the ingredients specifically mentioned above, it should be understood that the formulations of the present invention may include other agents customary in the art that take into account the type of formulation in question, eg, oral Formulations suitable for administration can include flavoring agents.

  The composition may be provided in a packaging means or dispenser that may contain one or more unit doses containing the active ingredients. Examples of packaging means include metal or plastic foils such as blister packs and nebulizers for inhalation. The packaging means or dispenser may be accompanied by instructions for administration. A composition comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may be placed in a suitable container and labeled for treatment of the indication.

(Indication)
The compound of the present invention is useful in inhibiting the activity of Jak3 or inhibiting Jak3-mediated activity, and is useful as an immunosuppressant for tissue and organ transplantation such as bone marrow transplantation. Useful in the treatment of complications.

  Hyperacute, acute and chronic organ transplant rejection can be treated. Hyperacute rejection occurs within minutes of transplantation. Acute rejection generally occurs within 6 to 12 months after transplantation. Hyperacute and acute rejection are typically reversible and are treated with immunosuppressive agents. Chronic rejection, characterized by the gradual loss of organ function, is a continuing concern for graft transplant patients that can occur anytime after transplantation.

  There are about 75 different autoimmune diseases that have been shown to be categorized into two types: organ-specific (primarily for one organ) and non-organ-specific (which affects many organs).

  Examples of organ-specific autoimmune diseases include insulin-dependent diabetes mellitus (type I) affecting the pancreas, Hashimoto's thyroiditis and Graves' disease affecting the thyroid, pernicious anemia affecting the stomach, and Cushing affecting the adrenal gland Disease and Addison's disease, chronic active hepatitis affecting the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and ankylosing spondylitis.

  Examples of non-organ-specific autoimmune diseases include rheumatoid arthritis, multiple sclerosis, systemic lupus and myasthenia gravis.

  Type I diabetes follows the selective attack of autoreactive T cells on the insulin-secreting beta cells of the islets of Langerhans. Jak3 targeting in this disease is based on the observation that a number of cytokines that signal through the Jak pathway are known to participate in T cell-mediated autoimmune destruction of beta cells. In fact, JANEX-1, a Jak3 inhibitor, has been shown to prevent spontaneous autoimmune diabetes from occurring in NOD mice with type I diabetes.

  Graft-versus-host disease (GVHD) is a pathological condition initiated by donor T cells that often follows allogeneic bone marrow transplantation (BMT). Many experimental and clinical studies have demonstrated that donor T cells are the main mediators and effectors of GVHD. Jak3 played an important role in the induction of GVHD, and the Jak3 inhibitor JANEX-1 was shown to reduce the severity of GVHD (reviewed in Cetkovic-Cvrlje and Ucken, 2004).

  Mast cells express Jak3, which is an important regulator of IgE-mediated mast cell responses such as the release of inflammatory mediators. Jak3 has been shown to be an effective target in the treatment of mast cell-mediated allergic reactions.

  Allergic diseases with mast cell activation include allergic rhinitis (withered fever), allergic urticaria (urticaria papules), angioedema, allergic asthma and anaphylaxis, ie anaphylactic shock Sexual reaction is mentioned. These diseases are treated or prevented by inhibition of Jak3 activity, such as by administration of a Jak3 inhibitor, according to the present invention.

  In accordance with the present invention, the Jak3 inhibitor may be administered prophylactically, ie before or after the onset of an acute allergic reaction, or at both time points.

  Tissue and organ inflammation occurs in a wide range of disorders and diseases, and in some variations is due to activation of the cytokine family of receptors. Examples of inflammatory disorders involving Jak3 activation include, but are not limited to, radiation-induced dermatitis, asthma, allergic inflammation and chronic inflammation.

  The Jak3 inhibitors of the present invention are also useful for several malignancies such as skin cancer and hematological malignancies such as lymphoma and leukemia.

  The following examples further illustrate the invention, but are used for purposes of illustration only and should not be construed as limiting the invention disclosed.

The following abbreviations and terms have the indicated meanings throughout the specification.
Ac = acetyl
Bu = Butyl
DCM = Dichloromethane = methylene chloride = CH ₂ Cl ₂
DEAD = diethyl azodicarboxylate
DIC = diisopropylcarbodiimide
DIEA = N, N-diisopropylethylamine
DMF = N, N-dimethylformamide
DMSO = dimethyl sulfoxide
EA (EtOAc) = ethyl acetate
GC = gas chromatography
h = time
HOAc = acetic acid
HOBt = Hydroxybenzotriazole
Me = methyl
Pd (dppf) ₂ Cl ₂ = dichloro [1,1'-bis (diphenylphosphinoferrocene] palladium
Ph = phenyl
PhOH = phenol
RT = room temperature
sat'd = saturation
s- = second level
t- = 3rd class
TBDMS = t-butyldimethylsilyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TMOF = trimethyl orthoformate
TMS = tilmethylsilyl
tosyl ＝ p-toluenesulfonyl
Trt = Triphenylmethyl Examples 1-15 describe the synthesis of several precursors and intermediates of the present invention.

エタノール(80 mL)中の、4-アミノ-3-ニトロベンゾニトリル(1)(3.0 g)の溶液を5分間窒素で処理する。パラジウム／炭素(10%、300 mg)を加え、混合物に水素を飽和させる。混合物を水素バルーン下で7時間撹拌する。混合物を窒素で処理し、セライトで濾過する。濾液を濃縮して、標記化合物、3,4-ジアミノベンゾニトリル(2)を得る。 Synthesis of 3,4-diaminobenzonitrile

A solution of 4-amino-3-nitrobenzonitrile (1) (3.0 g) in ethanol (80 mL) is treated with nitrogen for 5 minutes. Palladium / carbon (10%, 300 mg) is added to saturate the mixture with hydrogen. The mixture is stirred under a hydrogen balloon for 7 hours. The mixture is treated with nitrogen and filtered through celite. Concentrate the filtrate to give the title compound, 3,4-diaminobenzonitrile (2).

Synthesis of 3H-benzo [d] imidazole-5-carbonitrile
A mixture of 3,4-diaminobenzonitrile (2) (1.0 g) and (ethoxymethylene) malononitrile (1.4 g) is refluxed in 50 mL of isopropyl alcohol for 16 hours. Concentrate the mixture to give the title compound, 3H-benzo [d] imidazole-5-carbonitrile (3).

4
6-(トリフルオロメトキシ)-1H-ベンゾ[d]イミダゾール(4)を、4-アミノ-3-ニトロベンゾニトリル(1、実施例1、2)から3H-ベンゾ[d]イミダゾール-5-カルボニトリル(3)を製造するのに用いた手順と同様の手順を用いて、二段階で、2-ニトロ-4-(トリフルオロメトキシ)アニリン(5)から製造する。 Synthesis of 6- (trifluoromethoxy) -1H-benzo [d] imidazole

Four
6- (Trifluoromethoxy) -1H-benzo [d] imidazole (4) was converted from 4-amino-3-nitrobenzonitrile (1, Example 1, 2) to 3H-benzo [d] imidazole-5-carbohydrate. Prepared from 2-nitro-4- (trifluoromethoxy) aniline (5) in two steps using a procedure similar to that used to prepare nitrile (3).

30 mLのTHF中の4,5-ジフルオロ-2-ニトロアニリン(6)(1.0 g)の溶液を、30 mLの水中の6 gのNa₂S₂O₄および3 gのNaHCO₃を含む溶液で処理する。混合物が均質になるように該水溶液を加えた後、メタノール(10 mL)を加える。混合物を2時間撹拌し、次いで、100 mLの酢酸エチルおよび100 mLの水で希釈する。有機層を分離し、水層を100 mLの塩化メチレンで再度抽出する。有機層を合わせ、乾燥(硫酸ナトリウム)し、濾過し、濃縮して、粗中間体4,5-ジフルオロベンゼン-1,2-ジアミン(7)を得る。中間体を、25 mLのイソプロピルアルコール中の(エトキシメチレン)マロノニトリル(1.1 g)とともに16時間還流する。混合物を減圧濃縮し、得られる粗生成物を水に懸濁し、濾過する。沈澱を水で洗浄し、風乾して、380 mgの5,6-ジフルオロ-1H-ベンゾ[d]イミダゾール(8)を得る。 Synthesis of 5,6-difluoro-1H-benzo [d] imidazole

A solution of 4,5-difluoro-2-nitroaniline (6) (1.0 g) in 30 mL THF containing 6 g Na ₂ S ₂ O ₄ and 3 g NaHCO ₃ in 30 mL water Process with. The aqueous solution is added so that the mixture is homogeneous, followed by methanol (10 mL). The mixture is stirred for 2 hours and then diluted with 100 mL ethyl acetate and 100 mL water. The organic layer is separated and the aqueous layer is extracted again with 100 mL of methylene chloride. The organic layers are combined, dried (sodium sulfate), filtered and concentrated to give the crude intermediate 4,5-difluorobenzene-1,2-diamine (7). The intermediate is refluxed with (ethoxymethylene) malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 hours. The mixture is concentrated under reduced pressure and the resulting crude product is suspended in water and filtered. The precipitate is washed with water and air dried to give 380 mg of 5,6-difluoro-1H-benzo [d] imidazole (8).

マイクロウェーブ中、220℃にて4,5-ジメトキシ-1,2-フェニレンジアミンジヒドロクロリド(9)を加熱し、次いで、減圧濃縮することによって、標記化合物、5,6-ジメトキシ-1H-ベンゾ[d]イミダゾール(10)を製造する。 Synthesis of 5,6-dimethoxy-1H-benzo [d] imidazole

By heating 4,5-dimethoxy-1,2-phenylenediamine dihydrochloride (9) in a microwave at 220 ° C. and then concentrating under reduced pressure, the title compound, 5,6-dimethoxy-1H-benzo [ d] Imidazole (10) is produced.

11 12 Synthesis of 6-fluoro-1H-benzo [d] imidazole (11) and 6- (trifluoromethyl) -1H-benzo [d] imidazole (12) US Patent Publication 2004/0087601 by some inventors The title compound is prepared as described in

11 12

13 14 15 16 Benzimidazole (13), 5-Azabenzimidazole (14), 6-Chloro-5-fluorobenzimidazole (15) and 5-Methylbenzimidazole (16)
The title compound is commercially available.

13 14 15 16

ラニーニッケル触媒が湿っているのを確実にしながら、THFおよびメタノールで注意深く洗浄する。湿った触媒の重量は、洗浄後2.5 gである。この物質を7N メタノール性アンモニア(120 mL)中のピラジンカルボニトリル(17)(3.0 g)の溶液に加える。水素雰囲気下、50 p.s.iにて1.5時間混合物を振とうする。混合物を濾過し、濾液を濃縮して、粗標記化合物を得る。塩化メチレン中の過剰のジ-tert-ブチルジカーボネートで処理して、粗アミンをtert-ブチルカルバメートに変換することによって精製する。カラムクロマトグラフィー(70：27：3 ヘキサン：酢酸エチル：メタノール)により、0.50 gの純粋なtert-ブチルピラジン-2-イルメチルカルバメートを得る。カルバメートを1：1 TFA／CH₂Cl₂で脱保護して、純粋なピラジン-2-イルメタンアミン(18)をTFA塩として得る。 Synthesis of primary amine, pyrazin-2-ylmethanamine

Carefully wash with THF and methanol ensuring the Raney nickel catalyst is wet. The wet catalyst weight is 2.5 g after washing. This material is added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). Shake the mixture for 1.5 hours at 50 psi under hydrogen atmosphere. The mixture is filtered and the filtrate is concentrated to give the crude title compound. Purify by treatment with excess di-tert-butyl dicarbonate in methylene chloride to convert the crude amine to tert-butyl carbamate. Column chromatography (70: 27: 3 hexane: ethyl acetate: methanol) gives 0.50 g of pure tert-butylpyrazin-2-ylmethylcarbamate. The carbamate is deprotected with 1: 1 TFA / CH ₂ Cl ₂ to give pure pyrazin-2-ylmethanamine (18) as a TFA salt.

丸底フラスコに0.3g(2.46mM)の3-シアノ-2-フルオロピリジン(19)を入れ、次いで、20mL EtOHで希釈する。溶液をアルゴンでフラッシュし、次いで、アルゴンブランケット下、60mgの10% Pd/C(20重量％)を加える。次いで、系をセプタムで密封し、減圧下に置く。次いで、水素バルーンを加え、反応物を3時間撹拌する(次いでTLC)。次いで、反応物を再度減圧下に置き、次いで、空気に曝露し、濾過する(触媒は湿った状態に保つ)。得られる溶液を乾燥し、蒸発して、0.28g(90%)の標記化合物、3-アミノメチル-2-フルオロピリジン(20)を得る。 Synthesis of 3-aminomethyl-2-fluoropyridine

A round bottom flask is charged with 0.3 g (2.46 mM) of 3-cyano-2-fluoropyridine (19) and then diluted with 20 mL EtOH. The solution is flushed with argon and then 60 mg of 10% Pd / C (20 wt%) is added under an argon blanket. The system is then sealed with a septum and placed under vacuum. A hydrogen balloon is then added and the reaction is stirred for 3 hours (and then TLC). The reaction is then placed again under reduced pressure and then exposed to air and filtered (the catalyst remains moist). The resulting solution is dried and evaporated to give 0.28 g (90%) of the title compound, 3-aminomethyl-2-fluoropyridine (20).

21 22 23 Synthesis of 3-aminomethyl-6-methoxypyridine (21), 3-aminomethyl-6-methylpyridine (22) and 3-aminomethylquinoline (23)
The title amine is obtained from the corresponding nitrile using a procedure similar to that used to obtain 3-aminomethyl-2-fluoropyridine (20) from 3-cyano-2-fluoropyridine (see Example 9). .

21 22 23

丸底フラスコに、0.44g(3.23mM)の2-メトキシ-3-ピリジンカルボキシアルデヒド(24)、1.24g(16.15mM)の酢酸アンモニウムおよび0.61g(19.69mM)のシアノ水素化ホウ素ナトリウムを入れる。次いで、フラスコをアルゴンでフラッシュし、次いで、シリンジにて50mLの無水MeOHを加える。反応物を2日間撹拌した時点で、MeOHを蒸発する。25mLの水を加え、濃HClで混合物をpH2にする。これをEtOAcで2回抽出して、アルコール副産物を除去する。水酸化ナトリウムペレットで混合物をpH10にし、NaClで飽和させ、DCMで2回、EtOAcで1回抽出する。有機層を合わせ、乾燥し、蒸発して、0.31g(69%)の3-アミノメチル-2-メトキシピリジン(25)を得る。 Synthesis of 3-aminomethyl-2-methoxypyridine

A round bottom flask is charged with 0.44 g (3.23 mM) 2-methoxy-3-pyridinecarboxaldehyde (24), 1.24 g (16.15 mM) ammonium acetate and 0.61 g (19.69 mM) sodium cyanoborohydride. The flask is then flushed with argon and then 50 mL of anhydrous MeOH is added via syringe. When the reaction is stirred for 2 days, MeOH is evaporated. Add 25 mL of water and bring the mixture to pH 2 with concentrated HCl. This is extracted twice with EtOAc to remove the alcohol byproduct. The mixture is brought to pH 10 with sodium hydroxide pellets, saturated with NaCl, extracted twice with DCM and once with EtOAc. The organic layers are combined, dried and evaporated to give 0.31 g (69%) of 3-aminomethyl-2-methoxypyridine (25).

2-メトキシ-3-ピリジンカルボキシアルデヒド(２４；実施例１１参照)から3-アミノメチル-2-メトキシピリジンを得るために用いた手順と同様の手順を用いて、対応するケトンから標記アミンを得る。 Synthesis of 3- (α-aminoethyl) -2-chloropyridine (26)

The title amine is obtained from the corresponding ketone using a procedure similar to that used to obtain 3-aminomethyl-2-methoxypyridine from 2-methoxy-3-pyridinecarboxaldehyde (24; see Example 11). .

27 28
丸底フラスコに、0.45g(3.30mM)の4-メチルニコチンアミド(27)を入れる。フラスコをアルゴンでフラッシュし、50mLの無水THFをシリンジにて加える。得られる溶液を0℃に冷却し、2.5mL(4.96mM)の2Mボラン-ジメチルスルフィド錯体溶液(THF)を加える。バブラーを設置し、溶液を室温に一夜温める。溶液にMeOHを加えて反応を停止し、乾燥し、蒸発して、0.38g(95%)の3-アミノメチル-4-メチルピリジン(28)を得る。 Synthesis of 3-aminomethyl-4-methylpyridine

27 28
In a round bottom flask is placed 0.45 g (3.30 mM) of 4-methylnicotinamide (27). The flask is flushed with argon and 50 mL of anhydrous THF is added by syringe. The resulting solution is cooled to 0 ° C. and 2.5 mL (4.96 mM) of 2M borane-dimethyl sulfide complex solution (THF) is added. Install a bubbler and warm the solution to room temperature overnight. The solution is quenched with MeOH, dried and evaporated to give 0.38 g (95%) of 3-aminomethyl-4-methylpyridine (28).

4-(2-フルオロフェニル)ブタン酸メチル(2-(4-メチルブタノエート)フルオロベンゼン、30)
ラバーセプタムで丸底フラスコを密封し、アルゴンでフラッシュし、次いで、5.32mLの3-ブタン酸メチル(29)および100mLの9-BBNの0.5M THF溶液を入れる。溶液を室温にて3時間撹拌する。二口丸底フラスコにコンデンサーを設置し、アルゴンでフラッシュし、次いで、7.36gのナトリウムメトキシドおよび1.11gのPd(dppf)₂Cl₂を入れる。この混合物に20mLの無水THFおよび5.22mLの1-フルオロ-2-ヨードベンゼンを加える。カニューレを介して、ヒドロホウ素化溶液を加え、得られる混合物を16時間還流する。溶液を室温に冷却し、150mLの水で希釈し、エーテルで3回抽出する。有機層を合わせ、食塩水で洗浄し、乾燥し、蒸発する。カラムクロマトグラフィー(5% EtOAc/ヘキサン)により、1.79 gの4-(2-フルオロフェニル)ブタン酸メチル(30)を得る。 Synthesis of 5-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine

Methyl 4- (2-fluorophenyl) butanoate (2- (4-methylbutanoate) fluorobenzene, 30)
The round bottom flask is sealed with a rubber septum and flushed with argon, then charged with 5.32 mL of methyl 3-butanoate (29) and 100 mL of 9-BBN in 0.5 M THF. The solution is stirred at room temperature for 3 hours. Place a condenser in a two-neck round bottom flask and flush with argon, then charge 7.36 g sodium methoxide and 1.11 g Pd (dppf) ₂ Cl ₂ . To this mixture is added 20 mL anhydrous THF and 5.22 mL 1-fluoro-2-iodobenzene. Via the cannula, the hydroboration solution is added and the resulting mixture is refluxed for 16 hours. The solution is cooled to room temperature, diluted with 150 mL water and extracted three times with ether. The organic layers are combined, washed with brine, dried and evaporated. Column chromatography (5% EtOAc / hexanes) gives 1.79 g of methyl 4- (2-fluorophenyl) butanoate (30).

4- (2-Fluorophenyl) butanoic acid (31)
A round bottom flask is charged with 1.79 g of 2- (4-methylbutanoate) fluorobenzene and dissolved in 17 mL of MeOH. To this solution is added a solution of 1 g sodium hydroxide. The resulting mixture is stirred at room temperature for 20 hours. The solvent is evaporated and the crude material is diluted with 15 mL of 0.5 M HCl. Extraction with DCM three times gives 1.17 g (92%) of 4- (2-fluorophenyl) butanoic acid (31).

5-Fluoro-3,4-dihydronaphthalene-1 (2H) -one (32)
In a round bottom flask, place 0.15 g of 4- (2-fluorophenyl) butanoic acid, dissolve in 20 mL DCM and cool to 0 ° C. Oxalyl chloride is added followed by a drop of DMF. A drying tube is installed and the solution is stirred at 0 ° C. for 2 hours. Aluminum chloride (0.121 g) is added and the solution is slowly warmed overnight at room temperature. Pour water into the mixture and extract three times with DCM. Combine the organic layers and wash with 0.5 M NaOH and brine. The organic phase was dried, evaporated and purified by column chromatography (eluting with 20% EtOAc / hexanes) to give 0.07 g (53%) of 5-fluoro-3,4-dihydronaphthalene-1 (2H) -one. Get (32).

5-Fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (34)
A round bottom flask is charged with 0.5 g of 5-fluoro-3,4-dihydronaphthalen-1 (2H) -one, 0.28 g hydroxylamine hydrochloride and 0.34 g sodium acetate. A condenser is installed and the flask is purged with argon. 20 mL of absolute EtOH is added and the mixture is stirred at reflux for 18 hours. The solution is cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was dried (sodium sulfate) and evaporated to give 0.5 g of intermediate 5-fluoro-3,4-dihydronaphthalene-1 (2H) -one oxime (33), Pd / C and hydrogen in EtOH (50 psi) to give 0.43 g (86%) of 5-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (34).

3-(2-フルオロフェノキシ)プロパン酸(36)
2-フルオロフェノール(35)(15 g)、3-ブロモプロパン酸(20 g)およびNaOH(11 g)の混合物を50mLの水中で還流する。溶液を室温に冷却し、3M HClでpH2に酸性化する。得られる沈澱を濾過により単離して、9.27 gの標記化合物を白色固体で得る。濾液をEtOAcで3回抽出して、2.5gの純度の低い化合物(36)を得る。 Synthesis of 8-fluorochroman-4-amine

3- (2-Fluorophenoxy) propanoic acid (36)
A mixture of 2-fluorophenol (35) (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) is refluxed in 50 mL of water. The solution is cooled to room temperature and acidified to pH 2 with 3M HCl. The resulting precipitate is isolated by filtration to give 9.27 g of the title compound as a white solid. The filtrate is extracted 3 times with EtOAc to give 2.5 g of impure compound (36).

8-Fluorochroman-4-one (37)
To an ice-cold solution of 3- (2-fluorophenoxy) propanoic acid (9.27 g) in DCM (50 mL) is added oxalyl chloride (8.79 mL) and a drop of DMF. The solution is stirred at 0 ° C. for 2 hours, aluminum chloride (7.39 g, 55.42 mM) is added and the solution is stirred at room temperature for 16 hours. Pour water into the mixture and extract three times with DCM. The organic layers were combined, washed with 0.5M NaOH and brine, dried, evaporated and purified by column chromatography (eluting with 20% EtOAc / hexanes) to give 8-fluorochroman-4-one (37) (37). 8.20 g, 98%).

8-Fluorochroman-4-amine (39)
A round bottom flask is charged with 8-fluorochroman-4-one (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser is installed, the flask is purged with argon, absolute EtOH (20 mL) is added, and the mixture is stirred at reflux for 18 hours. The solution is cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was dried and evaporated to give the intermediate 8-fluorochroman-4-one oxime (38), reduced at 50 PSI with Raney nickel in EtOH to give the title amine (39) (4.69 g, 57%).

要するに、無水tert-ブチルメチルエーテル(75mL)中の8-フルオロクロマン-4-アミン(3.40 g)、2-メトキシ酢酸メチル(2.44 g)およびノボザイム435(アルドリッチ、0.68 g)の混合物をアルゴン下で2時間加熱還流する(この時点で、HPLCによるアシル化対非アシル化生成物の比は、1：1である)。冷却により形成する固体を濾過して集め、EtOAcに溶解する。混合物を濾過して、生体触媒を除去し、0.5M HClで1回洗浄して、残留している(S)-アミンを除去する。溶媒を蒸発し、tert-ブチルメチルエーテルから生成物を再結晶して、(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.78 g)を得る。反応溶媒および再結晶母液を0.5 M HClで3回洗浄し、濃縮して、さらなる(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.83 g)を得る。酸性層を合わせ、NaOHで塩基性にし、DCMで抽出して、(S)-8-フルオロクロマン-4-アミン(39a)(1.6 g)を得る。8M HCl/EtOH(50 mL)中の(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.78 g)の溶液を、4時間加熱還流する。冷却した反応混合物から溶媒を除去し、得られる固体に50 mLの0.5M NaOHを加え、NaCl(s)で塩析し、DCMで4回抽出して、(R)-8-フルオロクロマン-4-アミン(0.48 g(87%))(39b)を得る。キラルHPLCを介してee(鏡像体過剰率)％をチェックする：キラルセルOD-H(0.46 x 25 cm分析用カラム、ダイセル化学工業)、方法：アイソクラティック 5 %(0.05% TFA/EtOH) 95 %(0.05 % TFA/ヘキサン)、Rt＝7.2分(S)-エナンチオマー、Rt＝9.2分(R)-エナンチオマー。 Resolution of 8-fluorochroman-4-amine

In short, a mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) under argon. Heat to reflux for 2 hours (at this point the ratio of acylated to unacylated product by HPLC is 1: 1). The solid that forms upon cooling is collected by filtration and dissolved in EtOAc. The mixture is filtered to remove the biocatalyst and washed once with 0.5M HCl to remove residual (S) -amine. The solvent is evaporated and the product is recrystallized from tert-butyl methyl ether to give (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.78 g). The reaction solvent and recrystallized mother liquor are washed 3 times with 0.5 M HCl and concentrated to give additional (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.83 g). The acidic layers are combined, basified with NaOH and extracted with DCM to give (S) -8-fluorochroman-4-amine (39a) (1.6 g). A solution of (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.78 g) in 8M HCl / EtOH (50 mL) is heated to reflux for 4 hours. Remove the solvent from the cooled reaction mixture and add 50 mL of 0.5 M NaOH to the resulting solid, salt out with NaCl (s), extract 4 times with DCM, and (R) -8-fluorochroman-4. -Amine (0.48 g (87%)) (39b) is obtained. Check ee (enantiomeric excess)% via chiral HPLC: Chiralcel OD-H (0.46 x 25 cm analytical column, Daicel Chemical Industries), Method: isocratic 5% (0.05% TFA / EtOH) 95 % (0.05% TFA / hexane), Rt = 7.2 min (S) -enantiomer, Rt = 9.2 min (R) -enantiomer.

2-(1H-ベンゾ[d]イミダゾール-1-イル)-N-((R)-8-フルオロクロマン-4-イル)-5-ニトロピリミジン-4-アミン
(R)-8-フルオロクロマン-4-アミン(60 mg、実施例15)を、THF(5 mL)中の2,4-ジクロロ-5-ニトロピリミジン(70 mg)およびDIEA(0.14 mL)の溶液に-78℃にて加える。反応混合物を-78℃にてさらに15分間撹拌し、次いで、冷却浴を除去し、室温にする。ベンズイミダゾールのナトリウム塩の1モル溶液(0.7 ml、THF中のベンズイミダゾール溶液に水素化ナトリウムを添加して調製した貯蔵液)を、反応中間体((R)-2-クロロ-N-(8-フルオロクロマン-4-イル)-5-ニトロピリミジン-4-アミン)に加え、得られる混合物を室温にて一夜撹拌する。カラムクロマトグラフィー(1 MeOH/DCMで溶離)で精製することにより、標記化合物(120 mg)を得る、MH^＋＝407。 Synthesis of 2- (1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purin-8 (9H) -one

2- (1H-Benzo [d] imidazol-1-yl) -N-((R) -8-fluorochroman-4-yl) -5-nitropyrimidin-4-amine
(R) -8-Fluorochroman-4-amine (60 mg, Example 15) was added to 2,4-dichloro-5-nitropyrimidine (70 mg) and DIEA (0.14 mL) in THF (5 mL). Add to solution at -78 ° C. The reaction mixture is stirred at −78 ° C. for a further 15 minutes, then the cooling bath is removed and brought to room temperature. A 1 molar solution of sodium salt of benzimidazole (0.7 ml, a stock solution prepared by adding sodium hydride to a benzimidazole solution in THF) was added to the reaction intermediate ((R) -2-chloro-N- (8 -Fluorochroman-4-yl) -5-nitropyrimidin-4-amine) and the resulting mixture is stirred overnight at room temperature. Purification by column chromatography (eluting with 1 MeOH / DCM) affords the title compound (120 mg), MH ⁺ = 407.

2- (1H-Benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purin-8 (9H) -one Freshly prepared H ₂ O A solution of sodium dithionite (tech, 0.5 g) and sodium bicarbonate (0.25 g) in (5 mL) is added to a solution of the above nitro compound (120 mg) in THF (10 mL). The mixture was stirred vigorously for 30 min then extracted with EtOAc (2 x) and DCM (2 x) and the organic layers were combined, washed with brine, dried, filtered and concentrated to give intermediate 2- (1H-Benzo [d] imidazol-1-yl) -N ⁴ -((R) -8-fluorochroman-4-yl) pyrimidine-4,5-diamine is obtained and used as such in the next step.

To a solution of the above amine in THF (10 mL) is added carbonyldiimidazole (0.2 g).
The resulting mixture is stirred at room temperature overnight, silica gel is added, then the solvent is removed in vacuo and purified by column chromatography eluting with 5% MeOH / DCM to give the title product (28 mg), MH ⁺ = 403, ¹ H NMR (CDCl ₃ ) δ 10.6 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (m, 2H), 7.3 (m, 2H), 7.0 (m , 1H), 6.7 (m, 1H), 5.9 (dd, 1H), 4.7 (m, 1H), 4.4 (t, 1H), 2.7 (m, 1H), 2.3 (m, 1H) ppm, ¹⁹ F NMR δ -135.7 (m). Chiral HPLC-no trace of other enantiomers, method; Chiralcel OD-H (0.46 x 25 cm analytical column, Daicel Chemical Industries) Isocratic 15% (0.05% TFA / EtOH) 85% (0.05% TFA / hexane) , Rt = 19.5 min (R) -enantiomer, Rt = 22.4 min (S) -enantiomer.

2-クロロ-5-ニトロ-N-(ピリジン-3-イルメチル)ピリミジン-4-アミン(41)
塩化メチレン(60 mL)中の2,4-ジクロロ-5-ニトロピリミジン(40)(5 g)の溶液を、-78℃に冷却し、3-(アミノメチル)ピリジン(2.8 g)で処理する。混合物を-78℃にて6時間撹拌し、室温にて減圧濃縮して、粗2-クロロ-5-ニトロ-N-(ピリジン-3-イルメチル)ピリミジン-4-アミン(41)を得、さらに精製することなく用いる。 Benzimidazole purinone derivatives: 5-nitro-N- (pyridin-3-ylmethyl) -2- (6- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine (42 ) And 5-nitro-N- (pyridin-3-ylmethyl) -2- (5- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine (44) Specific synthesis

2-Chloro-5-nitro-N- (pyridin-3-ylmethyl) pyrimidin-4-amine (41)
A solution of 2,4-dichloro-5-nitropyrimidine (40) (5 g) in methylene chloride (60 mL) is cooled to -78 ° C. and treated with 3- (aminomethyl) pyridine (2.8 g). . The mixture was stirred at −78 ° C. for 6 hours and concentrated in vacuo at room temperature to give crude 2-chloro-5-nitro-N- (pyridin-3-ylmethyl) pyrimidin-4-amine (41). Used without purification.

5-Nitro-N- (pyridin-3-ylmethyl) -2- (6- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine (42) and 5-nitro- N- (Pyridin-3-ylmethyl) -2- (5- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine (44)
A suspension of crude 2-chloro-5-nitro-N- (pyridin-3-ylmethyl) pyrimidin-4-amine (52 mg) in acetonitrile (10 mL) was dissolved in 6- (trifluoromethoxy) -1H-benzo [d] Treat with imidazole (40 mg) and potassium carbonate (0.5 g) and heat at 80 ° C. for 5 hours. The mixture is diluted with water and extracted with methylene chloride. The organic layer is separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. By column chromatography (70: 22: 8 methylene chloride: ethyl acetate: methanol) 12 mg of 5-nitro-N- (pyridin-3-ylmethyl) -2- (5- (5- ( (Trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine and as the second eluting isomer, 15 mg 5-nitro-N- (pyridin-3-ylmethyl) -2- (6- (Trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) pyrimidin-4-amine is obtained.
High R _f isomer: ¹ H-NMR (CDCl ₃ ) δ 9.2 (s, 1H), 8.9 (s, 1H), 8.8 (m, 1H), 8.6 (s, 1H), 8.5 (d, 1H), 8.2 (d, 1H, attribution: H-7 of benzimidazole ring), 7.6 (d, 1H), 7.6 (s, 1H, attribution: H-4 of benzimidazole ring), 7.2 (dd, 1H), 4.9 ( d, 2H).
Low R _f isomer: ¹ H-NMR (CDCl ₃ ) δ 9.2 (s, 1H), 8.9 (s, 1H), 8.8 (m, 1H), 8.6 (s, 1H), 8.5 (d, 1H), 8.2 (s, 1H, attribution: H-7 of the benzimidazole ring), 7.7 (d, 1H, attribution: H-4 of the benzimidazole ring), 7.6 (d, 1H), 7.2 (dd, 1H), 7.1 ( d, 1H), 4.9 (d, 2H).

Benzimidazole purinone derivatives: 9- (pyridin-3-ylmethyl) -2- (6- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) -7H-purine-8 (9H) -one (43) and 9- (Pyridin-3-ylmethyl) -2- (5- (trifluoromethoxy) -1H-benzo [d] imidazol-1-yl) -7H-purin-8 (9H) -one (45 Non-regiospecific synthesis of
(R) -2,4-dimethoxybenzyl (5-nitro-6- (1- (pyridin-3-yl) ethylamino) pyridin-2-yl) carbamate tert-butyl (R) -2,4- Dimethoxybenzyl (2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-yl) carbamate tert-butyl ( 67; 5-nitro-N- (pyridin-3-ylmethyl) -2- (6- (trifluoromethoxy) -1H-benzoate, using a method similar to that used to convert to Example 22) below [d] imidazol-1-yl) pyrimidin-4-amine (42) and 5-nitro-N- (pyridin-3-ylmethyl) -2- (5- (trifluoromethoxy) -1H-benzo [d] imidazole The title compound is synthesized from 1-yl) pyrimidin-4-amine (44).
6-trifluoromethoxy isomer (non-salt): ¹ H-NMR (CD ₃ OD) δ 9.3 (s, 1H), 8.8 (br s, 1H), 8.6 (s, 1H, attribution: H of benzimidazole ring -7), 8.6 (m, 1H), 8.4 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H, attribution: H-4 of the benzimidazole ring), 7.5 (dd, 1H), 7.4 (dd, 1H), 5.4 (s, 2H).
5-trifluoromethoxy isomer (non-salt): ¹ H-NMR (CD ₃ OD) δ 9.3 (s, 1H), 8.8 (s, 1H), 8.7 (d, 1H, attribution: H- of benzimidazole ring 7), 8.5 (d, 1H), 8.3 (s, 1H), 7.9 (d, 1H), 7.6 (s, 1H, attribution: H-4 of the benzimidazole ring), 7.4 (dd, 1H), 7.3 ( dd, 1H), 5.3 (s, 2H).

6-(1H-ベンゾ[d]イミダゾール-1-イル)-3-ニトロ-N-(ピリジン-3-イルメチル)ピリジン-2-アミン(48)
アセトニトリル(20 mL)中の2,6-ジクロロ-3-ニトロピリジン(46)(0.5 g)の溶液を、0℃に冷却し、トリエチルアミン(0.36 mL)、次いで、3-(アミノメチル)ピリジン(0.26 mL)で処理する。混合物を0℃にて30分間および室温にて8時間撹拌する。中間体6-クロロ-3-ニトロ-N-(ピリジン-3-イルメチル)ピリジン-2-アミン(47)を含んでいる得られる溶液を、ベンズイミダゾール(0.84 g)および炭酸カリウム(3 g)を含む密封管に移し、70℃にて16時間加熱する。混合物を冷却し、濾過する。沈澱を水で洗浄し、風乾して、239 mgの標記化合物(48)を得る。 Oxoimidazopyridine and imidazopyridine derivatives: 5- (1H-benzo [d] imidazol-1-yl) -3- (pyridin-3-ylmethyl) -1H-imidazo [4,5-b] pyridine-2 (3H) -Non-regiospecific synthesis of on (50)

6- (1H-Benzo [d] imidazol-1-yl) -3-nitro-N- (pyridin-3-ylmethyl) pyridin-2-amine (48)
A solution of 2,6-dichloro-3-nitropyridine (46) (0.5 g) in acetonitrile (20 mL) was cooled to 0 ° C., triethylamine (0.36 mL), then 3- (aminomethyl) pyridine ( 0.26 mL). The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 8 hours. The resulting solution containing the intermediate 6-chloro-3-nitro-N- (pyridin-3-ylmethyl) pyridin-2-amine (47) was added benzimidazole (0.84 g) and potassium carbonate (3 g). Transfer to a sealed tube containing it and heat at 70 ° C. for 16 hours. Cool the mixture and filter. The precipitate is washed with water and air dried to give 239 mg of the title compound (48).

5- (1H-benzo [d] imidazol-1-yl) -3- (pyridin-3-ylmethyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (50) and 5- (1H-Benzo [d] imidazol-1-yl) -3- (pyridin-3-ylmethyl) -3H-imidazo [4,5-b] pyridine (51)
A solution of 6- (1H-benzo [d] imidazol-1-yl) -3-nitro-N- (pyridin-3-ylmethyl) pyridin-2-amine (48) (50 mg) in 1 mL DMSO Treat with a solution of Na ₂ S ₂ O ₄ (300 mg) in 1 mL of water. The mixture is stirred for 2 hours and diluted with 50 mL of ethyl acetate. The mixture was washed with three 50 mL aliquots of saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo to give intermediate 6- (1H-benzo [d] imidazol-1-yl) -N2 -(Pyridin-3-ylmethyl) pyridine-2,3-diamine (49) is obtained. Half of the intermediate is dissolved in methylene chloride (2 mL) and treated with 1,1′-carbonyldiimidazole (46 mg) at room temperature for 16 hours. The resulting crude mixture was purified by preparative TLC (1000 micron, 5% MeOH / CH ₂ Cl ₂ ) to give 7.1 mg of 5- (1H-benzo [d] imidazol-1-yl) -3- (pyridine -3-ylmethyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (50) is obtained: ¹ H-NMR (CDCl ₃ ) δ 10.0 (br s, 1 H), 8.9 (s , 1H), 8.6 (d, 1H), 8.5 (s, 1H), 7.9 (m, 2H), 7.8 (m, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 7.4 (m, 1H), 7.3 (d, 1H), 5.2 (s, 2H).

N²-(2,4-ジメトキシベンジル)-N⁴-(2,6-ジフルオロベンジル)-5-ニトロピリミジン-2,4-ジアミン(53)
-78℃に設定した冷却浴において、THF中の2,4-ジクロロ-5-ニトロピリミジン(40)(0.388 g)およびDIEA(0.77 mL)の溶液に、2,6-ジフルオロベンジルアミン(0.24 mL)を1分間かけて滴下する。反応混合物を-78℃にてさらに15分間撹拌し、次いで、冷却浴から外し、放置して室温に温める。反応中間体(N-(2,6-ジフルオロベンジル)-2-クロロ-5-ニトロピリミジン-4-アミン)(52)に、DIEA(0.77 mL)、次いで、2,4-ジメトキシベンジルアミン(0.30 mL)を加え、得られる混合物を室温にて一夜撹拌する。カラムクロマトグラフィー(1および2.5 % MeOH/DCMで溶離)により精製して、N²-(2,4-ジメトキシベンジル)-N⁴-(2,6-ジフルオロベンジル)-5-ニトロピリミジン-2,4-ジアミン(53)(0.80 g)、MH^＋＝432を得る。 Regiospecific synthesis: 3- (9- (2,6-difluorobenzyl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile

N ² - (2,4-dimethoxybenzyl) -N ⁴ - (2,6-difluorobenzyl) -5-nitropyrimidine-2,4-diamine (53)
In a cooling bath set at −78 ° C., a solution of 2,4-dichloro-5-nitropyrimidine (40) (0.388 g) and DIEA (0.77 mL) in THF was added to 2,6-difluorobenzylamine (0.24 mL). ) Is added dropwise over 1 minute. The reaction mixture is stirred at −78 ° C. for a further 15 minutes, then removed from the cooling bath and allowed to warm to room temperature. Reaction intermediate (N- (2,6-difluorobenzyl) -2-chloro-5-nitropyrimidin-4-amine) (52) was added to DIEA (0.77 mL) and then 2,4-dimethoxybenzylamine (0.30 mL) and the resulting mixture is stirred at room temperature overnight. Purification by column chromatography (eluted with 1 and 2.5% MeOH / DCM), N 2 - (2,4- dimethoxybenzyl) -N ⁴ - (2,6-difluorobenzyl) -5-nitro-pyrimidin-2, 4-diamine (53) (0.80 g), MH ⁺ = 432 is obtained.

2- (2,4-Dimethoxybenzylamino) -9- (2,6-difluorobenzyl) -7H-purine-8 (9H) -one (55)
THF N ² of (50 mL) in - (2,4-dimethoxybenzyl) -N ⁴ - To a solution of (2,6-difluorobenzyl) -5-nitropyrimidine-2,4-diamine (0.80 g), argon Add Raney Nickel under flash. The suspension is degassed and filled with hydrogen (balloon) and stirred for 16 hours. The resulting mixture was filtered through a plug of Celite, rinsed completely with THF and MeOH, N ² - (2,4- dimethoxybenzyl) -N ⁴ - (2,6-difluorobenzyl) pyrimidine-2,4,5 Triamine (54) is obtained and used as such in the next reaction.

THF (20 mL) in N ² - (2,4-dimethoxybenzyl) -N ⁴ - To a solution of (2,6-difluorobenzyl) pyrimidine-2,4,5-triamine (54), carbonyldiimidazole ( 0.93 g) is added and the resulting mixture is stirred overnight at room temperature, then the solvent is removed in vacuo, EtOAc is added and washed three times with water. The organic layer was dried, filtered, evaporated and purified by column chromatography eluting with 2.5 and 4% MeOH / DCM to give 2- (2,4-dimethoxybenzylamino) -9- (2,6-difluoro (Benzyl) -7H-purin-8 (9H) -one (55) (0.58 g), MH ⁺ = 428 is obtained.

Tert-Butyl 9- (2,6-difluorobenzyl) -2-amino-8-oxo-8,9-dihydropurine-7-carboxylate (57)
2- (2,4-Dimethoxybenzylamino) -9- (2,6-difluorobenzyl) -7H-purin-8 (9H) -one (55) (0.58 g) was mixed with TFA / DCM (10 mL). Add 1: 1 solution and stir for 30 minutes, then add triethylsilane (2 mL) and stir the mixture for another 4 hours. The solvent was removed under reduced pressure, a minimum amount of MeOH added to the residue, triturated with Et ₂ O, 9- (2,6- difluorobenzyl) -2-amino -7H- purin -8 (9H) - one (56 ) (0.55 g) of the TFA salt, MH ⁺ = 278, as a salmon solid.

9- (2,6-difluorobenzyl) -2-amino-7H-purin-8 (9H) -one (0.55 g) was dissolved in a mixture of MeOH / ACN / DCM (40 mL) and Et ₃ N ( 2 mL) and di-tert-butyl dicarbonate (0.61 g) are added and the mixture is stirred overnight at room temperature. The reaction solvent was removed and DCM was added to the crude material, washed with H ₂ O, evaporated and purified by column chromatography eluting with 2 and 3% MeOH / DCM to give the title product (57) (0.36 g ), MH ⁺ = 378, MH ⁺ -Boc = 278 (main). (M + Na) ⁺ = 400 and (2M + Na) ⁺ = 777 are also observed.

Tert-butyl 9- (2,6-difluorobenzyl) -2- (5-cyano-2-nitrophenylamino) -8-oxo-8,9-dihydropurine-7-carboxylate (58)
Tert-Butyl 9- (2,6-difluorobenzyl) -2-amino-8-oxo-8,9-dihydropurine-7-carboxylate (57) (191 mg) and 3-M in DMF (5 mL) To a solution of fluoro-4-nitrobenzonitrile (415 mg), sodium hydride (88 mg, 95%) is added at −40 ° C. under an argon flush. The reaction mixture is warmed to −20 ° C. over 3 hours, then quenched with saturated aqueous NH ₄ Cl once at room temperature, and the mixture is diluted with EtOAc and separated. The organic layer was washed with brine (3 x), dried, filtered, evaporated and purified by column chromatography (eluting with DCM and 1 and 2.5% MeOH / DCM) to give 9- (2,6- Difluorobenzyl) -2- (5-cyano-2-nitrophenylamino) -8-oxo-8,9-dihydropurine-7-carboxylate tert-butyl (58) (288 mg), MH ⁺ = 524 is obtained. .

Tert-butyl 9- (2,6-difluorobenzyl) -2- (6-cyano-1H-benzo [d] imidazol-1-yl) -8-oxo-8,9-dihydropurine-7-carboxylate ( 60)
The nitro compound in THF (10 mL) (58) To a solution of (288 mg), freshly sodium dithionite in the prepared _{H 2 O (10 mL) (} tech, 1 g) and sodium bicarbonate (0.5 Add the solution of g). The mixture was stirred vigorously for 5 minutes, extracted with DCM (3 x), the organic layers combined, washed with brine, dried, filtered and concentrated to intermediate 9- (2,6-difluorobenzyl). Tert-Butyl-2- (2-amino-5-cyanophenylamino) -8-oxo-8,9-dihydropurine-7-carboxylate (59) is obtained and used as such in the next step.

To a solution of the above amine intermediate and trimethyl orthoformate (3 mL) in MeOH (10 mL) is added a catalytic amount of paratoluenesulfonic acid monohydrate. After 1 hour, the crude material was adsorbed onto silica gel and purified by column chromatography (eluting with 1 and 2% MeOH / DCM) to give 9- (2,6-difluorobenzyl) -2- (6-cyano-1H -Benzo [d] imidazol-1-yl) -8-oxo-8,9-dihydropurine-7-carboxylate tert-butyl (60) (164 mg), MH ⁺ = 504 and MH ⁺ -BOC = 404.

3- (9- (2,6-Difluorobenzyl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile (61)
Tert-butyl 9- (2,6-difluorobenzyl) -2- (6-cyano-1H-benzo [d] imidazol-1-yl) -8-oxo-8,9-dihydropurine-7-carboxylate ( 60) Add a 1: 1 solution of TFA / DCM (10 mL) and stir for 1 hour. The solvent is removed in vacuo and the resulting solid is triturated with Et ₂ O and suspended in 6N HCl. The solvent was removed under reduced pressure and the resulting solid was triturated with Et ₂ O to give the title compound (61) (68 mg) as the HCl salt. MH ⁺ = 404, ¹ H NMR (d ₆ -DMSO) δ 11.8 (s, 1H), 9.2 (s, 1H), 8.8 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (Broad s, 1H), 7.4 (d, 1H), 7.4 (Five, 1H), 7.1 (m, 2H), 5.2 (s, 2H) ppm, ¹⁹ F NMR δ-114.3 (m).

62
3-(9-(2,6-ジフルオロベンジル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル(61、実施例20)の合成のために記載した手順と同様にして、標記化合物を合成することができる。
¹H NMR(d₆-DMSO)11.71(s、1H)、9.34(s、1H)、8.94(d、J＝1.5 Hz、1H)、8.38(s、1H)、8.00(d、J＝8.1 Hz、1H)、7.79(dd、J＝8.1、1.5 Hz、1H)、4.57(m、1H)、4.04(m、2H)、3.50(m、2H)、2.59(m、2H)、1.79(m、2H)；質量(MH＋)362.1。 3- (8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile (62 )

62
3- (9- (2,6-Difluorobenzyl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile (61, Examples The title compound can be synthesized analogously to the procedure described for the synthesis of 20).
¹ H NMR (d ₆ -DMSO) 11.71 (s, 1H), 9.34 (s, 1H), 8.94 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 8.00 (d, J = 8.1 Hz , 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 4.57 (m, 1H), 4.04 (m, 2H), 3.50 (m, 2H), 2.59 (m, 2H), 1.79 (m, 2H); mass (MH +) 362.1.

(R)-N6-(2,4-ジメトキシベンジル)-3-ニトロ-N2-(1-(ピリジン-3-イル)エチル)ピリジン-2,6-ジアミン(64)
THF(20 mL)中の2,6-ジクロロ-5-ニトロピリジン(46)(0.5 g)の溶液を、0℃に冷却し、1.6 mL トリエチルアミン、次いで、(R)-1-ピリジン-3-イル-エチルアミン(300 μL)で処理する。混合物を1.5時間撹拌し、次いで、室温に温め、さらに20時間撹拌する。2,4-ジメトキシベンジルアミン(0.8 mL)を加え、混合物を50℃にて5時間加熱する。混合物を酢酸エチルで希釈し、飽和塩化ナトリウム溶液で2回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、濃縮する。カラムクロマトグラフィー(50→100% 酢酸エチル／ヘキサン)により、761 mgの(R)-N6-(2,4-ジメトキシベンジル)-3-ニトロ-N2-(1-(ピリジン-3-イル)エチル)ピリジン-2,6-ジアミン(64)を得る。 Oxoimidazopyridine derivative: 3- (2-oxo-3-((R) -1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridine-5 Regiospecific synthesis of -yl) -3H-benzo [d] imidazole-5-carbonitrile

(R) -N6- (2,4-Dimethoxybenzyl) -3-nitro-N2- (1- (pyridin-3-yl) ethyl) pyridine-2,6-diamine (64)
A solution of 2,6-dichloro-5-nitropyridine (46) (0.5 g) in THF (20 mL) was cooled to 0 ° C., 1.6 mL triethylamine, then (R) -1-pyridine-3- Treat with yl-ethylamine (300 μL). The mixture is stirred for 1.5 hours, then warmed to room temperature and stirred for a further 20 hours. 2,4-Dimethoxybenzylamine (0.8 mL) is added and the mixture is heated at 50 ° C. for 5 hours. The mixture is diluted with ethyl acetate and washed twice with saturated sodium chloride solution. The organic layer is separated, dried (sodium sulfate), filtered and concentrated. By column chromatography (50 → 100% ethyl acetate / hexane), 761 mg of (R) -N6- (2,4-dimethoxybenzyl) -3-nitro-N2- (1- (pyridin-3-yl) ethyl ) Pyridine-2,6-diamine (64) is obtained.

2,4-Dimethoxybenzyl (5-nitro-6- (1- (pyridin-3-yl) ethylamino) pyridin-2-yl) carbamic acid ((R) -tert-butyl 65)
) (R) -N6- (2,4-dimethoxybenzyl) -3-nitro-N2- (1- (pyridin-3-yl) ethyl) pyridine-2,6-diamine (20 mL) in methylene chloride 64) (367 mg) is treated with di-tert-butyl dicarbonate (1.0 g) and 4-dimethylaminopyridine (22 mg). The mixture is stirred for 16 hours and concentrated in vacuo. By column chromatography (50 → 100% ethyl acetate / hexane), 500 mg of 2,4-dimethoxybenzyl (5-nitro-6- (1- (pyridin-3-yl) ethylamino) pyridin-2-yl) Carbamate (R) -tert-butyl (65) is obtained.

2,4-Dimethoxybenzyl (2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-yl) carbamic acid (R) -tert-Butyl (67)
2,4-Dimethoxybenzyl (5-nitro-6- (1- (pyridin-3-yl) ethylamino) pyridin-2-yl) carbamic acid (R) -tert-butyl (500) in THF (25 mL) mg) is treated with an aqueous solution of 2 g Na ₂ S ₂ O ₄ and 1 g NaHCO ₃ in 20 mL of water followed by 1 mL of methanol. The mixture is stirred for 30 minutes, then diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was separated, dried (sodium sulfate), filtered and concentrated to give intermediate 2,4-dimethoxybenzyl (5-amino-6- (1- (pyridin-3-yl) ethylamino) pyridine- 2- (yl) carbamic acid (R) -tert-butyl (66) is obtained. The intermediate is dissolved in THF (50 mL) and treated with 1,1′-carbonyldiimidazole (0.5 g) at 50 ° C. for 20 hours. The mixture was concentrated and purified by column chromatography (2 → 5% MeOH in methylene chloride) to give 413 mg of 2,4-dimethoxybenzyl (2-oxo-3- (1- (pyridin-3-yl) ethyl ) -2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-yl) carbamic acid (R) -tert-butyl (67).

5-Amino-2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5-b] pyridine-1-carboxylic acid (R) -tert-butyl ( 69)
2,4-Dimethoxybenzyl (2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] in methylene chloride (15 mL) A solution of pyridin-5-yl) carbamic acid (R) -tert-butyl is treated with TFA (15 mL) and triethylsilane (1.0 mL) for 1 hour. The mixture was concentrated to give intermediate (R) -5-amino-3- (1- (pyridin-3-yl) ethyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one ( 68) is obtained, dissolved in acetonitrile (50 mL) and stirred vigorously with di-tert-butyl dicarbonate (1.0 g) and potassium carbonate (3.0 g) for 2 hours. Methylene chloride (200 mL) and water (100 mL) are added and the organic layer is separated. Extract the aqueous layer with an additional 100 mL of methylene chloride. The organic layers are combined, separated, dried (sodium sulfate), filtered and concentrated. By column chromatography (2 → 3 → 4% MeOH / methylene chloride), 235 mg of 5-amino-2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [ 4,5-b] pyridine-1-carboxylic acid (R) -tert-butyl (69) is obtained.

5- (5-cyano-2-nitrophenylamino) -2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5-b] pyridine-1- Carboxylic acid (R) -tert-butyl (70)
5-amino-2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5-b] pyridine-1-carboxylic acid (6 mL) in DMF (6 mL) A solution of R) -tert-butyl (94 mg) and 3-fluoro-4-nitrobenzonitrile (225 mg) was cooled to -25 ° C and treated with NaH (60% w / w mineral oil solution, 75 mg). And slowly warm to -15 ° C. The mixture is stirred at −20 ° C. to −15 ° C. for 4 hours, then diluted with EtOAc and quenched with saturated ammonium chloride solution. The organic phase is washed 3 times with brine, separated, dried (sodium sulfate), filtered and concentrated. By column chromatography (2% MeOH in methylene chloride), 100 mg of 5- (5-cyano-2-nitrophenylamino) -2-oxo-3- (1- (pyridin-3-yl) ethyl) -2 3,3-Dihydroimidazo [4,5-b] pyridine-1-carboxylic acid (R) -tert-butyl (70) is obtained.

5- (6-Cyano-1H-benzo [d] imidazol-1-yl) -2-oxo-3-((R) -1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [ 4,5-b] tert-butyl pyridine-1-carboxylate (72)
5- (5-Cyano-2-nitrophenylamino) -2-oxo-3- (1- (pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5 in THF (5 mL) -b] Treat a solution of pyridine-1-carboxylic acid (R) -tert-butyl (70) (100 mg) with 5 mL of an aqueous solution containing 0.5 g Na ₂ S ₂ O ₄ and 0.25 g NaHCO ₃ . The mixture quickly turns from red to yellow, indicating reduction of the nitro gas. Dilute the mixture with and wash with ethyl acetate, saturated sodium chloride solution. The organic layer is separated, dried (sodium sulfate), filtered and concentrated to the intermediate (R) -tert-butyl 5- (2-amino-5-cyanophenylamino) -2-oxo-3- ( 1- (Pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5-b] pyridine-1-carboxylic acid (71) is obtained. The intermediate is dissolved in THF (5 mL), DMF (1 mL) and trimethyl orthoformate (2 mL). The mixture is treated with 10 mg p-toluenesulfonic acid and stirred for 20 hours. The mixture is diluted with ethyl acetate and washed once with saturated sodium bicarbonate and twice with saturated NaCl solution. The organic layer is separated, dried (sodium sulfate), filtered and concentrated. By column chromatography (2% MeOH / methylene chloride), 57 mg of 5- (6-cyano-1H-benzo [d] imidazol-1-yl) -2-oxo-3-((R) -1- ( Pyridin-3-yl) ethyl) -2,3-dihydroimidazo [4,5-b] pyridine-1-carboxylate tert-butyl (72) is obtained.

3- (2-oxo-3-((R) -1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-yl) -3H -Benzo [d] imidazole-5-carbonitrile (73)
5- (6-Cyano-1H-benzo [d] imidazol-1-yl) -2-oxo-3-((R) -1- (pyridin-3-yl) ethyl) in methylene chloride (1 mL) A solution of tert-butyl (72) (57 mg) -2,3-dihydroimidazo [4,5-b] pyridine-1-carboxylate is treated with TFA (1 mL) for 1 hour. The mixture is concentrated, dissolved in 5 mL EtOH, 0.5 mL of concentrated HCl is added, and then the resulting TFA salt is converted to the HCl salt by concentrating the solution under reduced pressure. The process is repeated and the resulting residue is dissolved in a minimum amount of methanol and triturated with the addition of ethyl ether. After trituration three times, 3- (2-oxo-3-((R) -1- (pyridin-3-yl) ethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridine- 5-yl) -3H-benzo [d] imidazole-5-carbonitrile (73) HCl salt (39 mg) is obtained as a tan solid: ¹ H-NMR (CD ₃ OD) δ 9.9 (br s, 1H) , 9.2 (s, 1H), 9.0 (m, 2H), 8.5 (s, 1H), 8.3 (m, 1H), 8.2 (m, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 6.3 (q, 1H), 2.3 (d, 3H).

(No original)

2-クロロ-N-(cis-3-メチル-テトラヒドロ-2H-ピラン-4-イル)-5-ニトロピリミジン-4-アミン。THF(10 mL)中の0.24 gのcis-3-メチル-テトラヒドロ-2H-ピラン-4-アミン(WO 2004/041161)の塩酸塩およびDIEA(1.5 mL)の懸濁液に、2,4-ジクロロ-5-ニトロピリミジン(0.72 g)を-78℃にて加える。混合物をゆっくりと室温に到らせ、16時間撹拌する。混合物をEtOAcで希釈し、食塩水で3回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、減圧濃縮する。カラムクロマトグラフィー(20→40% EtOAc／ヘキサン)により、289 mgの標記化合物を得る。 Synthesis of 2- (1H-benzo [d] imidazol-1-yl) -9- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one

2-Chloro-N- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -5-nitropyrimidin-4-amine. To a suspension of 0.24 g cis-3-methyl-tetrahydro-2H-pyran-4-amine (WO 2004/041161) hydrochloride and DIEA (1.5 mL) in THF (10 mL), 2,4- Dichloro-5-nitropyrimidine (0.72 g) is added at -78 ° C. The mixture is slowly brought to room temperature and stirred for 16 hours. The mixture is diluted with EtOAc and washed 3 times with brine. The organic layer is separated, dried (sodium sulfate) and concentrated in vacuo. Column chromatography (20 → 40% EtOAc / hexanes) gives 289 mg of the title compound.

2- (1H-benzo [d] imidazol-1-yl) -N- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -5-nitropyrimidin-4-amine in acetonitrile (5 mL) Of 2-chloro-N- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -5-nitropyrimidin-4-amine (115 mg) with potassium carbonate (300 mg) and benzimidazole (150 mg) is added. The mixture is stirred at 70 ° C. for 2.5 hours. After diluting with 70 mL EtOAc, the mixture is washed with brine, dried (sodium sulfate) and concentrated in vacuo. Column chromatography (50 → 100% EtOAc / hexanes) gives 99 mg of the title compound.

2- (1H-Benzo [d] imidazol-1-yl) -9- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -7H-purine-8 (9H) -one
2- (1H-benzo [d] imidazol-1-yl) -N- (cis-3-methyl-tetrahydro-2H-pyran-4-yl) -5-nitropyrimidine-4-in THF (10 mL) To a solution of amine (51 mg) is added a solution of sodium dithionite (300 mg) and sodium bicarbonate (150 mg) in water (10 mL). The mixture temporarily turns blue and then becomes colorless. Add methanol (1 mL) to maintain homogeneity of the solution. The mixture is diluted with 70 mL EtOAc and washed twice with brine. The aqueous washes were extracted with an additional 50 mL of EtOAc, then the organic layers were combined, dried (sodium sulfate), concentrated in vacuo, and 2- (1H-benzo [d] imidazol-1-yl) -N4- ( cis-3-Methyl-tetrahydro-2H-pyran-4-yl) pyrimidine-4,5-diamine is obtained. The diamine intermediate is dissolved in THF (5 mL) and treated with 1,1′-carbonyldiimidazole (80 mg) at 50 ° C. for 16 hours. The mixture is diluted with 50 mL EtOAc and washed 3 times with brine. The organic layer is separated, dried (sodium sulfate) and concentrated in vacuo. Column chromatography (2 → 4% MeOH / DCM) gives 19.3 mg of the title compound. ¹ H-NMR (300 MHz, 5% CD ₃ OD in CDCl ₃ ) δ 8.9 (s, 1H), 8.5 (d, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.4 (t, 1H), 7.3 (t, 1H), 4.7 (m, 1H), 4.2 (d (br), 1H), 3.9 (d, 1H), 3.7 (d, 1H), 3.5 (m, 2H), 2.3 ( t (br), 1H), 1.8 (d (br), 1H), 1.2 (d, 3H).

2-(5,6-ジクロロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-8-フルオロクロマン-4-イル)-7H-プリン-8(9H)-オン
アセトニトリル中の(R)-2-クロロ-N-(8-フルオロクロマン-4-イル)-5-ニトロピリミジン-4-アミンの溶液を5,6-ジクロロベンズイミダゾールおよび炭酸カリウムで処理する。混合物を6時間還流撹拌し、室温に冷却し、150 mLのEtOAcで希釈し、30 mL部の水で2回洗浄する。有機層を分離し、乾燥(硫酸マグネシウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(2% MeOH/DCM)により精製して、中間体ニトロピリミジンアミンを得る。実施例24の手順により、中間体ニトロピリミジンアミンから標記化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.7(s、1H)、8.3(s、1H)、8.2(s、1H)、7.8(t、1H)、7.0(t、1H)、6.6(m、2H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、3.0(m、1H)、2.3(m、1H)。

2- (5,6-Dichloro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purine-8 (9H) -one acetonitrile A solution of (R) -2-chloro-N- (8-fluorochroman-4-yl) -5-nitropyrimidin-4-amine in it is treated with 5,6-dichlorobenzimidazole and potassium carbonate. The mixture is stirred at reflux for 6 hours, cooled to room temperature, diluted with 150 mL EtOAc, and washed twice with 30 mL portions of water. The organic layer is separated, dried (magnesium sulfate), filtered and concentrated under reduced pressure. Purify by column chromatography (2% MeOH / DCM) to obtain the intermediate nitropyrimidineamine. The title compound is synthesized from the intermediate nitropyrimidineamine by the procedure of Example 24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 7.8 (t, 1H), 7.0 (t, 1H), 6.6 (m , 2H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.0 (m, 1H), 2.3 (m, 1H).

2-(5,6-ジメチル-1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-8-フルオロクロマン-4-イル)-7H-プリン-8(9H)-オン
実施例25に記載の手順により、5,6-ジクロロベンズイミダゾールから標記化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 9.6(s、1H)、8.8(s、1H)、8.3(s、1H)、8.0(s、1H)、7.6(s、1H)、7.0(t、1H)、6.7(m、1H)、5.9(t、1H)、4.7(m、1H)、4.5(m、1H)、3.2(m、2H)、2.4(d、6H)。

2- (5,6-Dimethyl-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purin-8 (9H) -one The title compound is synthesized from 5,6-dichlorobenzimidazole by the procedure described in Example 25. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.6 (s, 1H), 8.8 (s, 1H), 8.3 (s, 1H), 8.0 (s, 1H), 7.6 (s, 1H), 7.0 (t , 1H), 6.7 (m, 1H), 5.9 (t, 1H), 4.7 (m, 1H), 4.5 (m, 1H), 3.2 (m, 2H), 2.4 (d, 6H).

9-((R)-8-フルオロクロマン-4-イル)-2-(6-(トリフルオロメチル)-1H-ベンゾ[d]イミダゾール-1-イル)-7H-プリン-8(9H)-オンおよび9-((R)-8-フルオロクロマン-4-イル)-2-(5-(トリフルオロメチル)-1H-ベンゾ[d]イミダゾール-1-イル)-7H-プリン-8(9H)-オン
実施例25に記載の手順により、5-トリフルオロメチルベンズイミダゾール(US 2004/0087601)から標記化合物を合成する。カラムクロマトグラフィー(2% MeOH/DCM)により精製して、6-トリフルオロメチル異性体(¹H-NMR(300 MHz、CDCl₃)δ 8.8(d、2H)、8.4(s、1H)、7.9(d、1H)、7.6(d、2H)、7.0(t、1H)、6.7(m、2H)、5.9(t、1H)、4.7(m、1H)、4.4(m、1H)、3.0(m、1H)、2.4(m、1H)が最初に溶出し、次いで5-トリフルオロメチル異性体(¹H-NMR(300 MHz、CDCl₃)δ 9.0(s、1H)、8.4(s、1H)、8.1(s、1H)、8.0(d、1H)、7.6(d、2H)、7.0(m、1H)、6.8(m、2H)、5.9(t、1H)、4.7(m、1H)、4.4(m、1H)、2.9(m、1H)、2.4(m、1H)が溶出する。

9-((R) -8-Fluorochroman-4-yl) -2- (6- (trifluoromethyl) -1H-benzo [d] imidazol-1-yl) -7H-purine-8 (9H)- ON and 9-((R) -8-fluorochroman-4-yl) -2- (5- (trifluoromethyl) -1H-benzo [d] imidazol-1-yl) -7H-purine-8 (9H ) -One The title compound is synthesized from 5-trifluoromethylbenzimidazole (US 2004/0087601) by the procedure described in Example 25. Purification by column chromatography (2% MeOH / DCM), 6- trifluoromethyl isomer ^{(1 H-NMR (300 MHz} , CDCl 3) δ 8.8 (d, 2H), 8.4 (s, 1H), 7.9 (d, 1H), 7.6 (d, 2H), 7.0 (t, 1H), 6.7 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.0 ( m, 1H), 2.4 (m , 1H) eluted first, followed by 5-trifluoromethyl isomer ^{(1 H-NMR (300 MHz} , CDCl 3) δ 9.0 (s, 1H), 8.4 (s, 1H ), 8.1 (s, 1H), 8.0 (d, 1H), 7.6 (d, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H) , 4.4 (m, 1H), 2.9 (m, 1H), 2.4 (m, 1H) are eluted.

N-((R)-8-フルオロクロマン-4-イル)-2-(3H-イミダゾ[4,5-c]ピリジン-3-イル)-5-ニトロピリミジン-4-アミンおよびN-((R)-8-フルオロクロマン-4-イル)-2-(1H-イミダゾ[4,5-c]ピリジン-1-イル)-5-ニトロピリミジン-4-アミン
実施例25に記載の手順により、5-アザベンズイミダゾールから標記化合物を合成する。カラムクロマトグラフィー(1% MeOH／DCM)により精製して、N-((R)-8-フルオロクロマン-4-イル)-2-(3H-イミダゾ[4,5-c]ピリジン-3-イル)-5-ニトロピリミジン-4-アミンを第１溶出異性体として得る：(¹H-NMR(300 MHz、CDCl₃)δ 9.8(s、1H)、9.4(s、1H)、9.2(s、1H)、8.9(d、1H)、8.6(d、1H)、7.8(d、1H)、7.1(m、2H)、6.9(m、1H)、5.8(q、1H)、4.6(m、1H)、4.4(m、1H)、2.6(m、1H)、2.4(m、1H))。N-((R)-8-フルオロクロマン-4-イル)-2-(1H-イミダゾ[4,5-c]ピリジン-1-イル)-5-ニトロピリミジン-4-アミンが２番目に溶出する：(¹H-NMR(300 MHz、CDCl₃)δ 9.4(s、1H)、9.2(s、1H)、9.1(s、1H)、8.9(d、1H)、8.6(d、1H)、8.4(d、1H)、7.1(m、2H)、6.9(m、1H)、5.7(q、1H)、4.5(m、1H)、4.4(m、1H)、2.6(m、1H)、2.4(m、1H))。

N-((R) -8-fluorochroman-4-yl) -2- (3H-imidazo [4,5-c] pyridin-3-yl) -5-nitropyrimidin-4-amine and N-(( R) -8-Fluorochroman-4-yl) -2- (1H-imidazo [4,5-c] pyridin-1-yl) -5-nitropyrimidin-4-amine According to the procedure described in Example 25, The title compound is synthesized from 5-azabenzimidazole. Purified by column chromatography (1% MeOH / DCM) to give N-((R) -8-fluorochroman-4-yl) -2- (3H-imidazo [4,5-c] pyridin-3-yl ) -5-nitropyrimidin-4-amine is obtained as the first eluting isomer: ( ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.8 (s, 1 H), 9.4 (s, 1 H), 9.2 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 7.8 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.8 (q, 1H), 4.6 (m, 1H ), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H)). N-((R) -8-fluorochroman-4-yl) -2- (1H-imidazo [4,5-c] pyridin-1-yl) -5-nitropyrimidin-4-amine elutes second To: ( ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.4 (s, 1H), 9.2 (s, 1H), 9.1 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 8.4 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.7 (q, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H)).

9-((R)-8-フルオロクロマン-4-イル)-2-(3H-イミダゾ[4,5-c]ピリジン-3-イル)-7H-プリン-8(9H)-オン
実施例24に記載の手順により、N-((R)-8-フルオロクロマン-4-イル)-2-(3H-イミダゾ[4,5-c]ピリジン-3-イル)-5-ニトロピリミジン-4-アミンから標記化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 9.8(s、1H)、9.4(s、1H)、8.6(d、1H)、8.3(m、2H)、7.0(t、1H)、6.7(m、2H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、2.8(m、1H)、2.4(m、1H)。

9-((R) -8-Fluorochroman-4-yl) -2- (3H-imidazo [4,5-c] pyridin-3-yl) -7H-purin-8 (9H) -one Example 24 N-((R) -8-fluorochroman-4-yl) -2- (3H-imidazo [4,5-c] pyridin-3-yl) -5-nitropyrimidine-4- The title compound is synthesized from the amine. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.8 (s, 1H), 9.4 (s, 1H), 8.6 (d, 1H), 8.3 (m, 2H), 7.0 (t, 1H), 6.7 (m , 2H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H).

9-((R)-8-フルオロクロマン-4-イル)-2-(1H-イミダゾ[4,5-c]ピリジン-1-イル)-7H-プリン-8(9H)-オン
実施例24に記載の手順により、N-((R)-8-フルオロクロマン-4-イル)-2-(1H-イミダゾ[4,5-c]ピリジン-1-イル)-5-ニトロピリミジン-4-アミンから標記化合物を合成する。¹H-NMR(300 MHz、CDCl δ 9.3(d、2H)、8.4(d、1H)、8.3(d、2H)、7.0(t、1H)、6.7(m、2H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、2.8(m、1H)、2.4(m、1H)。

9-((R) -8-Fluorochroman-4-yl) -2- (1H-imidazo [4,5-c] pyridin-1-yl) -7H-purin-8 (9H) -one Example 24 N-((R) -8-fluorochroman-4-yl) -2- (1H-imidazo [4,5-c] pyridin-1-yl) -5-nitropyrimidine-4- The title compound is synthesized from the amine. ¹ H-NMR (300 MHz, CDCl δ 9.3 (d, 2H), 8.4 (d, 1H), 8.3 (d, 2H), 7.0 (t, 1H), 6.7 (m, 2H), 5.9 (t, 1H ), 4.6 (m, 1H), 4.4 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H).

4-(2,4-ジメトキシベンジルアミノ)-3-ニトロベンゾニトリル
THF(100 mL)中の4-フルオロ-3-ニトロベンゾニトリル(5.0 g)の溶液を、DIEA(6.3 mL)および2,4-ジメトキシベンジルアミン(5.0 mL)で処理し、次いで、24時間撹拌する。溶媒を蒸発し、粗混合物をEtOAc(100 mL)に溶解する。溶液を、1 M HClで1回および飽和水性NaCl(100 mL each)で2回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(20% EtOAc／DCM)により、9.25 gの標記化合物を得る。 3- (9-((R) -6,8-Difluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5 -Synthesis of carbonitrile

4- (2,4-Dimethoxybenzylamino) -3-nitrobenzonitrile
A solution of 4-fluoro-3-nitrobenzonitrile (5.0 g) in THF (100 mL) was treated with DIEA (6.3 mL) and 2,4-dimethoxybenzylamine (5.0 mL) and then stirred for 24 hours. To do. The solvent is evaporated and the crude mixture is dissolved in EtOAc (100 mL). The solution is washed once with 1 M HCl and twice with saturated aqueous NaCl (100 mL each). The organic layer is separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. Column chromatography (20% EtOAc / DCM) gives 9.25 g of the title compound.

4-(2,4-ジメトキシベンジルアミノ)-3-アミノベンゾニトリル
THF(400 mL)中の4-(2,4-ジメトキシベンジルアミノ)-3-ニトロベンゾニトリル(4.54 g)の溶液を、蒸留水(350 mL)中の亜ジチオン酸ナトリウム(20 g)および重炭酸ナトリウム(10 g)の溶液で処理する。十分なメタノールをただちに加えて、均質な溶液を維持する。15分後、EtOAc(500 mL)および飽和水性NaCl(500 mL)を加え、有機層を分離する。水性層を400 mLのEtOAcで再度抽出する。有機層を合わせ、飽和水性NaCl(500 mL)で洗浄し、分離する。有機相を乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮して、4.33 gの標記化合物を得る。

4- (2,4-Dimethoxybenzylamino) -3-aminobenzonitrile
A solution of 4- (2,4-dimethoxybenzylamino) -3-nitrobenzonitrile (4.54 g) in THF (400 mL) was added to sodium dithionite (20 g) and heavy water in distilled water (350 mL). Treat with a solution of sodium carbonate (10 g). Sufficient methanol is added immediately to maintain a homogeneous solution. After 15 minutes, EtOAc (500 mL) and saturated aqueous NaCl (500 mL) are added and the organic layer is separated. Extract the aqueous layer again with 400 mL of EtOAc. Combine the organic layers and wash with saturated aqueous NaCl (500 mL) and separate. The organic phase is dried (sodium sulfate), filtered and concentrated in vacuo to give 4.33 g of the title compound.

4-(2,4-ジメトキシベンジルアミノ)-3-(5-ニトロ-4-チオシアナトピリミジン-2-イルアミノ)ベンゾニトリル
アセトニトリル(100 mL)中の4-(2,4-ジメトキシベンジルアミノ)-3-アミノベンゾニトリル(3.9 g)の溶液を、0℃に冷却し、炭酸カリウム(6.3 g)、次いで、アセトニトリル(50 mL)中に3 gの2-クロロ-5-ニトロ-4-チオシアナトピリミジンを含む溶液(WO 2003/032994)で処理する。混合物を0℃にて30分間および室温にて30分間撹拌すると沈澱が形成する。混合物に、4%酢酸(150 mL)を0℃にて加えて反応を停止し、濾過する。沈澱を100 mLのアセトニトリル中で旋回させ、再度濾過する。沈澱をアセトニトリルで洗浄すると、生成物がゆっくりと濾液に溶解する。風乾後、1.5 gの標記化合物が沈澱ケーキとして残る。濾液をEtOAcで抽出し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(0→20% EtOAc／DCM)およびアセトニトリルからの再結晶により、0.415 gの追加の標記化合物を得る。

4- (2,4-Dimethoxybenzylamino) -3- (5-nitro-4-thiocyanatopyrimidin-2-ylamino) benzonitrile 4- (2,4-dimethoxybenzylamino) in acetonitrile (100 mL) A solution of -3-aminobenzonitrile (3.9 g) was cooled to 0 ° C. and 3 g 2-chloro-5-nitro-4-thiol in potassium carbonate (6.3 g) followed by acetonitrile (50 mL). Treated with a solution containing Ocyanatopyrimidine (WO 2003/032994). The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 30 minutes and a precipitate forms. The mixture is quenched with 4% acetic acid (150 mL) at 0 ° C. and filtered. The precipitate is swirled in 100 mL acetonitrile and filtered again. When the precipitate is washed with acetonitrile, the product slowly dissolves in the filtrate. After air drying, 1.5 g of the title compound remains as a precipitated cake. The filtrate is extracted with EtOAc, dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (0 → 20% EtOAc / DCM) and recrystallization from acetonitrile gives 0.415 g of the additional title compound.

(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(4-(6,8-ジフルオロクロマン-4-イルアミノ)-5-ニトロピリミジン-2-イルアミノ)ベンゾニトリル
40 mLのアセトニトリル中の4-(2,4-ジメトキシベンジルアミノ)-3-(5-ニトロ-4-チオシアナトピリミジン-2-イルアミノ)ベンゾニトリル(415 mg)の一部懸濁液を、DMSO(10 mL)中の(R)-6,8-ジフルオロクロマン-4-アミン HCl salt(320 mg)の溶液、次いで、炭酸カリウム(1.0 g)で処理する。混合物を24時間撹拌し、次いで、EtOAc(200 mL)で希釈する。混合物を飽和水性塩化アンモニウム(200 mL)で1回および飽和水性NaCl(200 mL each)で3回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(20→40% EtOAc／ヘキサン)により、358 mgの標記化合物を得る。

(R) -4- (2,4-Dimethoxybenzylamino) -3- (4- (6,8-difluorochroman-4-ylamino) -5-nitropyrimidin-2-ylamino) benzonitrile
A partial suspension of 4- (2,4-dimethoxybenzylamino) -3- (5-nitro-4-thiocyanatopyrimidin-2-ylamino) benzonitrile (415 mg) in 40 mL of acetonitrile was added. Treat with a solution of (R) -6,8-difluorochroman-4-amine HCl salt (320 mg) in DMSO (10 mL) followed by potassium carbonate (1.0 g). The mixture is stirred for 24 hours and then diluted with EtOAc (200 mL). The mixture is washed once with saturated aqueous ammonium chloride (200 mL) and three times with saturated aqueous NaCl (200 mL each). The organic layer is separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. Column chromatography (20 → 40% EtOAc / hexanes) gives 358 mg of the title compound.

(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(9-(6,8-ジフルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イルアミノ)ベンゾニトリル
THF(25 mL)中の(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(4-(6,8-ジフルオロクロマン-4-イルアミノ)-5-ニトロピリミジン-2-イルアミノ)ベンゾニトリル(358 mg)の溶液を、20 mLの蒸留水中の亜ジチオン酸ナトリウム(1.5 g)および重炭酸ナトリウム(1.5 g)の溶液で処理する。メタノール(5 mL)を加えて、均質な溶液を維持する。15分後、混合物をEtOAc(100 mL)で希釈し、飽和水性NaCl(2 X 100 mL)で洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮して、中間体(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(5-アミノ-4-(6,8-ジフルオロクロマン-4-イルアミノ)ピリミジン-2-イルアミノ)ベンゾニトリルを得る。中間体をTHF(5 mL)に溶解し、カルボニルジイミダゾール(0.55 g)で16時間処理する。混合物をEtOAc(100 mL)で希釈し、飽和水性NaCl(2 X 100 mL)で2回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(2→3% MeOH／DCM)により、230 mgの標記化合物を得る。

(R) -4- (2,4-Dimethoxybenzylamino) -3- (9- (6,8-difluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purine-2- (Ilamino) benzonitrile
(R) -4- (2,4-Dimethoxybenzylamino) -3- (4- (6,8-difluorochroman-4-ylamino) -5-nitropyrimidin-2-ylamino) in THF (25 mL) A solution of benzonitrile (358 mg) is treated with a solution of sodium dithionite (1.5 g) and sodium bicarbonate (1.5 g) in 20 mL of distilled water. Methanol (5 mL) is added to maintain a homogeneous solution. After 15 minutes, the mixture is diluted with EtOAc (100 mL) and washed with saturated aqueous NaCl (2 X 100 mL). The organic layer was separated, dried (sodium sulfate), filtered and concentrated in vacuo to give intermediate (R) -4- (2,4-dimethoxybenzylamino) -3- (5-amino-4- (6 , 8-difluorochroman-4-ylamino) pyrimidin-2-ylamino) benzonitrile. The intermediate is dissolved in THF (5 mL) and treated with carbonyldiimidazole (0.55 g) for 16 hours. The mixture is diluted with EtOAc (100 mL) and washed twice with saturated aqueous NaCl (2 X 100 mL). The organic layer is separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. Column chromatography (2 → 3% MeOH / DCM) gives 230 mg of the title compound.

3-(9-((R)-6,8-ジフルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
DCM(5 mL)中の(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(9-(6,8-ジフルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イルアミノ)ベンゾニトリル(230 mg)の溶液を、TFA(5 mL)およびトリエチルシラン(1 mL)で16時間処理する。混合物を減圧濃縮して、中間体(R)-4-アミノ-3-(9-(6,8-ジフルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イルアミノ)ベンゾニトリルを得る。中間体を5 mL THFに溶解し、3 mLのオルトギ酸トリメチル、次いで、p-トルエンスルホン酸(3 mg)で処理する。1時間後、混合物をEtOAc(100 mL)で希釈し、飽和水性重炭酸ナトリウム(100 mL)で1回洗浄する。有機層を分離し、乾燥(硫酸ナトリウム)し、濾過し、減圧濃縮する。カラムクロマトグラフィー(50→100% EtOAc／ヘキサン)により、78 mgの標記化合物を得る。¹H-NMR(300 MHz、5% CD₃OD in CDCl₃)δ 8.8(s、1H)、8.7(s、1H)、8.2(s、1H)、7.8(d、1H)、7.6(dd、1H)、6.8(td、1H)、6.4(dd、1H)、5.8(dd、1H)、4.6(m、1H)、4.4(td、1H)、2.9(m、1H)、2.3(m、1H)。

3- (9-((R) -6,8-Difluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5 -Carbonitrile
(R) -4- (2,4-Dimethoxybenzylamino) -3- (9- (6,8-difluorochroman-4-yl) -8-oxo-8,9-dihydro in DCM (5 mL) A solution of -7H-purin-2-ylamino) benzonitrile (230 mg) is treated with TFA (5 mL) and triethylsilane (1 mL) for 16 hours. The mixture was concentrated under reduced pressure to give intermediate (R) -4-amino-3- (9- (6,8-difluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purine-2. -Ilamino) benzonitrile is obtained. The intermediate is dissolved in 5 mL THF and treated with 3 mL trimethylorthoformate followed by p-toluenesulfonic acid (3 mg). After 1 hour, the mixture is diluted with EtOAc (100 mL) and washed once with saturated aqueous sodium bicarbonate (100 mL). The organic layer is separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. Column chromatography (50 → 100% EtOAc / hexanes) gives 78 mg of the title compound. ¹ H-NMR (300 MHz, 5% CD ₃ OD in CDCl ₃ ) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (dd, 1H), 6.8 (td, 1H), 6.4 (dd, 1H), 5.8 (dd, 1H), 4.6 (m, 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.3 (m, 1H ).

3-(9-((R)-クロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例26に記載の手順により、(R)-クロマン-4-アミンから標記化合物を合成する。¹H-NMR(300 MHz、5% CD₃OD in CDCl₃)δ 8.8(s、1H)、8.5(s、1H)、8.2(s、1H)、7.8(d、1H)、7.5(dd、1H)、7.1(m、2H)、6.8(d、1H)、6.7(td、1H)、5.8(dd、1H)、4.5(m、1H)、4.3(td、1H)、2.8(m、1H)、2.3(m、1H)。

3- (9-((R) -chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile Examples The title compound is synthesized from (R) -chroman-4-amine by the procedure described in 26. ¹ H-NMR (300 MHz, 5% CD ₃ OD in CDCl ₃ ) δ 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.5 (dd, 1H), 7.1 (m, 2H), 6.8 (d, 1H), 6.7 (td, 1H), 5.8 (dd, 1H), 4.5 (m, 1H), 4.3 (td, 1H), 2.8 (m, 1H ), 2.3 (m, 1H).

3-[9-(8-フルオロ-クロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル。実施例26に記載の手順により、(R)-8-フルオロクロマン-4-アミンから標記化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.6(s、1H)、8.2(s、1H)、7.8(d、1H)、7.6(d、1H)、7.0(t、1H)、6.6(m、2H)、5.8(t、1H)、4.6(m、1H)、4.4(m、1H)、2.8(m、1H)、2.4(m、1H)。

3- [9- (8-Fluoro-chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile. The title compound is synthesized from (R) -8-fluorochroman-4-amine by the procedure described in Example 26. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.0 (t , 1H), 6.6 (m, 2H), 5.8 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H).

3-(9-((R)-6-フルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例26に記載の手順により、(R)-6-フルオロクロマン-4-アミンから標記化合物を合成する。¹H NMR(300 MHz、CDCl₃＋5%CD₃OD)：δ 8.86(s、1H)、8.41(s、1H)、8.18(s、1H)、7.72(d、1H)、7.51(d、1H)、7.0-7.1(m、1H)、6.8-6.9(m、1H)、6.49(dd、1H)、5.76(br t、1H)、4.4-4.5(m、1H)、4.24(br t、1H)、2.7-2.9(m、1H)、2.2-2.3(m、1H)。クロマニルアミンの導入のための条件を以下の通り改良する。

3- (9-((R) -6-Fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbo Nitrile The title compound is synthesized from (R) -6-fluorochroman-4-amine by the procedure described in Example 26. ¹ H NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD): δ 8.86 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.72 (d, 1H), 7.51 (d, 1H ), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 1H), 6.49 (dd, 1H), 5.76 (br t, 1H), 4.4-4.5 (m, 1H), 4.24 (br t, 1H) ), 2.7-2.9 (m, 1H), 2.2-2.3 (m, 1H). The conditions for introduction of chromanamine are improved as follows.

(R)-4-(2,4-ジメトキシベンジルアミノ)-3-(4-(6-フルオロクロマン-4-イルアミノ)-5-ニトロピリミジン-2-イルアミノ)ベンゾニトリル
無水DMSO(3 mL)中の4-(2,4-ジメトキシベンジルアミノ)-3-(5-ニトロ-4-チオシアナトピリミジン-2-イルアミノ)ベンゾニトリル(139 mg)の溶液を、無水DMSO(3 mL)およびDIEA(0.21 mL)中の(R)-6-フルオロクロマン-4-アミン塩酸塩(79 mg)の溶液に加え、得られる暗赤色をアルゴン雰囲気下、溶液が黄色に変わるまで室温にて撹拌する。反応完了後、混合物を氷浴で0℃に冷却し、水(25 mL)を加える(発熱)。得られる黄色固体を濾過して集め、さらなる水で洗浄し、風乾し、次いで、CH₂Cl₂に溶解し、有機溶液を乾燥(硫酸マグネシウム)し、濾過し、蒸発して、標記化合物(定量的)を得る、NMR CDCl₃ ¹H δ 9.0(s、1H)、8.6(d、1H)、7.7(br s、1H)、7.4(dd、1H)、7.1(d、1H)、7.0-6.8(m、4H)、6.5-6.4(m、2H)、5.2(br s、1H)、4.3(s、2H)、4.2(br s、2H)、3.8(s、6H)、2.2(br s、1H)、1.8(br s、1H)；¹⁹F δ -123 ppm；MH^＋＝572。

(R) -4- (2,4-Dimethoxybenzylamino) -3- (4- (6-fluorochroman-4-ylamino) -5-nitropyrimidin-2-ylamino) benzonitrile in anhydrous DMSO (3 mL) A solution of 4- (2,4-dimethoxybenzylamino) -3- (5-nitro-4-thiocyanatopyrimidin-2-ylamino) benzonitrile (139 mg) in anhydrous DMSO (3 mL) and DIEA ( To a solution of (R) -6-fluorochroman-4-amine hydrochloride (79 mg) in 0.21 mL) and stir the resulting dark red at room temperature under argon until the solution turns yellow. After the reaction is complete, the mixture is cooled to 0 ° C. with an ice bath and water (25 mL) is added (exothermic). The resulting yellow solid was collected by filtration, washed with additional water, air dried and then dissolved in CH ₂ Cl ₂ and the organic solution was dried (magnesium sulfate), filtered and evaporated to give the title compound (quantitative). NMR CDCl ₃ ¹ H δ 9.0 (s, 1H), 8.6 (d, 1H), 7.7 (br s, 1H), 7.4 (dd, 1H), 7.1 (d, 1H), 7.0-6.8 (m, 4H), 6.5-6.4 (m, 2H), 5.2 (br s, 1H), 4.3 (s, 2H), 4.2 (br s, 2H), 3.8 (s, 6H), 2.2 (br s, 1H), 1.8 (br s, 1H); ¹⁹ F δ −123 ppm; MH ⁺ = 572.

3-(9-((R)-7-フルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例26に記載の手順により、(R)-7-フルオロクロマン-4-アミンから標記化合物を合成する。¹H NMR(300 MHz、CDCl₃＋5%CD₃OD)：δ 8.86(s、1H)、8.58(s、1H)、8.19(s、1H)、7.79(d、1H)、7.56(d、1H)、6.7-6.9(m、2H)、6.4-6.5(m、1H)、5.78(br t、1H)、4.5-4.6(m、1H)、4.32(br t、1H)、2.7-2.9(m、1H)、2.2-2.4(m、1H)。 This material was treated similarly to the procedure outlined in Example 26 to give 3- (9-((R) -6-fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purine. -2-yl) -3H-benzo [d] imidazole-5-carbonitrile is obtained.

3- (9-((R) -7-Fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbo Nitrile The title compound is synthesized from (R) -7-fluorochroman-4-amine by the procedure described in Example 26. ¹ H NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD): δ 8.86 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 7.79 (d, 1H), 7.56 (d, 1H ), 6.7-6.9 (m, 2H), 6.4-6.5 (m, 1H), 5.78 (br t, 1H), 4.5-4.6 (m, 1H), 4.32 (br t, 1H), 2.7-2.9 (m , 1H), 2.2-2.4 (m, 1H).

3-[9-(5,8-ジフルオロ-クロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
実施例26に記載の手順により、(R)-5,8-ジフルオロクロマン-4-アミンから標記化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.7(s、1H)、8.2(s、1H)、7.8(d、1H)、7.6(d、1H)、7.0(m、1H)、6.4(m、1H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、2.5(m、2H)。

3- [9- (5,8-Difluoro-chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile Example 26 The title compound is synthesized from (R) -5,8-difluorochroman-4-amine by the procedure described in 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.0 (m , 1H), 6.4 (m, 1H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.5 (m, 2H).

4-フルオロ-2-ニトロ-フェニル ジ-tert-ブチルイミドジカーボネート
触媒量のDMAPを、DCM(20 mL)中の4-フルオロ-2-ニトロベンゼンアミン(0.78 g)およびジ-tert-ブチルジカーボネート(2.18 g)の混合物に加え、室温にて15時間撹拌する。混合物をH₂Oで希釈し、DCMで2回抽出し、有機層を合わせ、乾燥し、濾過し、蒸発して、bis-BOC物質(定量的)を得る。¹H-NMR(300 MHz、CDCl₃)δ 7.8(dd、1H)、7.3(m、2H)、1.4(s、18H)。 Synthesis of 2- (6-fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluoro-chroman-4-yl) -7H-purin-8 (9H) -one

4-Fluoro-2-nitro-phenyl di-tert-butylimidodicarbonate Catalytic amount of DMAP was added to 4-fluoro-2-nitrobenzenamine (0.78 g) and di-tert-butyldicarbonate in DCM (20 mL). Add to the mixture (2.18 g) and stir at room temperature for 15 hours. The mixture is diluted with H ₂ O and extracted twice with DCM, the organic layers are combined, dried, filtered and evaporated to give the bis-BOC material (quantitative). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.8 (dd, 1H), 7.3 (m, 2H), 1.4 (s, 18H).

Tert-Butyl 4-fluoro-2-nitrophenylcarbamate
(Procedure: Connell, RD; Rein, T .; Akermark, B .; Helquist, PJ; J. Org. Chem. 1988, 53, 3845)
To a stirred solution of Bis-BOC material in DCM (20 mL) is added TFA (0.58 mL). After 3 h, the reaction is quenched with aqueous NaHCO ₃ (5 mL), brine is added, the mixture is separated and extracted with additional DCM. The organic layers are combined, evaporated and purified by column chromatography (eluting with 7.5% EtOAc / hexanes) to give the title product (1.12 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.5 (br 1H), 8.5 (dd, 1H), 7.9 (dd, 1H), 7.3 (m, 1H), 1.5 (s, 9H).

Tert-Butyl 2-amino-4-fluorophenylcarbamate
A solution of tert-butyl 4-fluoro-2-nitrophenylcarbamate (0.34 g) in THF (30 mL) was added to sodium dithionite (2 g) and sodium bicarbonate (1 g) in water (50 mL). Add the premixed solution. To aid the mixture solution, MeOH (10 mL) is also added, stirred at room temperature for 30 minutes, and sodium chloride is added to saturate the solution. The resulting mixture is extracted with EtOAc (2x). The organic layers are combined, dried, filtered and evaporated to give the title compound (quantitative) that is used as such in the next step. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.5 (dd, 1H), 6.6 (dd, 1H), 6.5 (m, 1H), 6.4 (br 1H), 4.7 (br 2H), 1.5 (s, 9H ); MH ⁺ = 227 (minor) 127 (-BOC), 171 (-tBu).

2-クロロ-5-ニトロ-4-チオシアナトピリミジン(公知化合物、たとえば、WO 2003/032994など)
チオシアン酸カリウム(0.97 g、10 mM)を、氷浴で0℃に冷却したEtOH(40 mL)中の2,4-ジクロロ-5-ニトロピリミジン(1.94 g 10、mM)の溶液に加える。溶液を0℃にて30分間撹拌し、次いで、浴を除去し、得られる懸濁液を60分間かけて室温にし、水(100 mL)を加える。沈澱を濾過により集め、氷冷水で洗浄し、DCMに溶解し、乾燥(硫酸マグネシウム)し、濾過し、蒸発して、標記化合物(1.7 g)を得る。¹H-NMR(300 MHz、CDCl₃)δ 9.4(s、1H)。

2-Chloro-5-nitro-4-thiocyanatopyrimidine (known compounds such as WO 2003/032994)
Potassium thiocyanate (0.97 g, 10 mM) is added to a solution of 2,4-dichloro-5-nitropyrimidine (1.94 g 10, mM) in EtOH (40 mL) cooled to 0 ° C. in an ice bath. The solution is stirred at 0 ° C. for 30 minutes, then the bath is removed, the resulting suspension is brought to room temperature over 60 minutes and water (100 mL) is added. The precipitate is collected by filtration, washed with ice cold water, dissolved in DCM, dried (magnesium sulfate), filtered and evaporated to give the title compound (1.7 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.4 (s, 1H).

4-fluoro-2- (5-nitro-4-thiocyanatopyrimidin-2-ylamino) phenylcarbamate tert-butyl potassium carbonate (207 mg) in 2-chloro-5-nitro in ACN (5 mL) Add 4-thiocyanatopyrimidine (108 mg) and 4-fluoro-2-nitrophenylcarbamic acid (113 mg) to a stirred solution of tert-butyl and stir for 15 hours. The solution is diluted with brine and extracted with EtOAc (2x). The organic layers are combined, evaporated and purified by column chromatography (eluting with 30% EtOAc / hexanes) to give the title compound (144 mg, 71% yield). ¹ H-NMR (300 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.3 (br s, 1H), 8.9 (br s, 1H), 7.7-7.4 (m, 2H), 7.1 (br s , 1H), 1.5 (s, 9H), 1.5 (s, 9H); MH ⁺ = 407, 307 (-BOC), 351 (-tBu).

4-フルオロ-2-(4-(8-フルオロクロマン-4-イルアミノ)-5-ニトロピリミジン-2-イルアミノ)フェニルカルバミン酸(R)-tert-ブチル
DMSO(2 mL)中の(R)-8-フルオロクロマン-4-アミン塩酸塩(104 mg)の溶液および炭酸カリウム(141 mg)を、ACN(10 mL)中の4-フルオロ-2-(5-ニトロ-4-チオシアナトピリミジン-2-イルアミノ)フェニルカルバミン酸tert-ブチル(140 mg)の撹拌溶液に加える。混合物を室温にて15時間撹拌し、次いで、食塩水およびEtOAcに分配し、分離する。水性層をさらなるEtOAcで洗浄し、有機層を合わせ、蒸発し、20-30 % EtOAc/Hで溶離するカラムクロマトグラフィーにより精製して、標記生成物を83 %収率で得る。¹H-NMR(300 MHz、CDCl₃)δ 9.1(s、1H)、8.7(m、1H)、8.2(br s、1H)、7.7(m、1H)、7.3(m、1H)、7.3-6.8(m、4H)、6.5(s、1H)、5.5(br s,1H)、4.4(m 2H)、2.4(m、1H)、2.2(m、1H)、1.5(s、9H)；MH^＋＝515、459(-tBu)。

4-Fluoro-2- (4- (8-fluorochroman-4-ylamino) -5-nitropyrimidin-2-ylamino) phenylcarbamic acid (R) -tert-butyl
A solution of (R) -8-fluorochroman-4-amine hydrochloride (104 mg) in DMSO (2 mL) and potassium carbonate (141 mg) were added to 4-fluoro-2- ( Add to a stirred solution of tert-butyl 5-nitro-4-thiocyanatopyrimidin-2-ylamino) phenylcarbamate (140 mg). The mixture is stirred at room temperature for 15 hours, then partitioned between brine and EtOAc and separated. The aqueous layer is washed with additional EtOAc, the organic layers are combined, evaporated and purified by column chromatography eluting with 20-30% EtOAc / H to give the title product in 83% yield. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.1 (s, 1H), 8.7 (m, 1H), 8.2 (br s, 1H), 7.7 (m, 1H), 7.3 (m, 1H), 7.3- 6.8 (m, 4H), 6.5 (s, 1H), 5.5 (br s, 1H), 4.4 (m 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H); MH ⁺ = 515, 459 (-tBu).

4-Fluoro-2- (9- (8-fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-ylamino) phenylcarbamic acid (R) -tert-butyl
4-Fluoro-2- (4- (8-fluorochroman-4-ylamino) -5-nitropyrimidin-2-ylamino) phenylcarbamic acid (R) -tert-butyl (141 mg) in THF (20 mL) To this solution is added a premixed solution of sodium dithionite (0.6 g) and sodium bicarbonate (0.3 g) in water (50 mL). To maintain dissolution of the mixture, MeOH (5 mL) is also added and stirred at room temperature for 30 minutes before sodium chloride is added to saturate the solution. The resulting mixture is extracted with EtOAc (2x) and the organic layers are combined, dried, filtered and evaporated to 2- (5-amino-4- (8-fluorochroman-4-ylamino) pyrimidine-2- (Ilamino) -4-fluorophenylcarbamic acid (R) -tert-butyl is obtained and used as such in the next step. MH ⁺ = 485.

To a stirred solution of the above material in THF (5 mL) is added CDI (131 mg). After 15 hours, brine and EtOAc are added and the mixture is separated. The aqueous layer was washed with more EtOAc, the organic layers were combined, evaporated and purified by column chromatography (eluting with 3% MeOH / DCM) to give the title product (86 mg, 62% yield over 2 steps). obtain. ^{1 H-NMR (300 MHz,} 5% CD 3 OD in CDCl 3) δ 7.9 (s, 1H), 7.4 (dd, 1H), 7.3 (m, 1H), 6.9 (dd, 1H), 6.7-6.5 ( m, 3H), 5.7 (dd, 1H), 4.6 (m 1H), 4.3 (td, 1H), 2.9 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H); MH ⁺ = 511 , 411 (-BOC), 455 (-tBu).

2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purine-8 (9H) -one
A freshly prepared solution of 30% TFA / DCM (5 mL) was added to 4-fluoro-2- (9- (8-fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purine. 2-ylamino) phenylcarbamic acid (R) -tert-butyl was added and the solution was stirred at room temperature for 60 minutes, then the solvent was removed in vacuo to give (R) -2- (2-amino-5- Fluorophenylamino) -9- (8-fluorochroman-4-yl) -7H-purin-8 (9H) -one is obtained and used as such. MH ⁺ = 411.

To the diamine is added MeOH (2 mL), trimethyl orthoformate (2 mL) and p-TsOH (catalyst). The mixture is stirred at room temperature for 60 minutes, then the solvent is reduced and the resulting material is partitioned between DCM and brine and separated. The crude product is purified by column chromatography (eluting with 4% MeOH / DCM) to give the title compound (46 mg). ¹ H-NMR (300 MHz, 5% CD ₃ OD in CDCl ₃ ) δ 8.7 (s, 1H), 8.1 (s, 1H), 7.5 (m, 2H), 6.9 (m, 2H), 6.6 (m, 2H), 5.8 (dd, 1H), 4.6 (m1H), 4.3 (td, 1H), 2.8 (m, 1H), 2.3 (m, 1H); MH ⁺ = 421.

2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-6-フルオロクロマン-4-イル)-7H-プリン-8(9H)-オン
実施例27に記載の手順により、(R)-6-フルオロクロマン-4-アミンから標記化合物を合成する。¹H NMR(300 MHz、CDCl₃＋5%CD₃OD)：δ 8.72(s、1H)、8.16(s、1H)、7.5-7.7(m、2H)、6.9-7.0(m、2H)、6.8-6.9(m、1H)、6.54(dd、1H)、5.78(br t、1H)、4.4-4.5(m、1H)、4.26(m、1H)、2.7-2.8(m、1H)、2.2-2.3(m、1H)。

2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -6-fluorochroman-4-yl) -7H-purin-8 (9H) -one Example 27 The title compound is synthesized from (R) -6-fluorochroman-4-amine by the procedure described in 1. ¹ H NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD): δ 8.72 (s, 1H), 8.16 (s, 1H), 7.5-7.7 (m, 2H), 6.9-7.0 (m, 2H), 6.8 -6.9 (m, 1H), 6.54 (dd, 1H), 5.78 (br t, 1H), 4.4-4.5 (m, 1H), 4.26 (m, 1H), 2.7-2.8 (m, 1H), 2.2- 2.3 (m, 1H).

2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-(テトラヒドロ-2H-ピラン-4-イル)-7H-プリン-8(9H)-オン
実施例27に記載の手順により、4-アミノテトラヒドロピランから標記化合物を合成する。¹H NMR(d₆-DMSO)δ 11.65(s、1H)、9.13(s、1H)、8.34(s、1H)、8.28(m、1H)、7.82(m、1H)、7.25(td、J＝9.0、2.4 Hz、1H)、4.56(m、1H)、4.03(dd、J＝11.1、3.9 Hz、2H)、3.50(t、J＝11.1 Hz、2H)、2.59(m、2H)、1.78(m、2H)。

2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one described in Example 27 According to the procedure, the title compound is synthesized from 4-aminotetrahydropyran. _{^{1 H NMR (d 6 -DMSO)}} δ 11.65 (s, 1H), 9.13 (s, 1H), 8.34 (s, 1H), 8.28 (m, 1H), 7.82 (m, 1H), 7.25 (td, J = 9.0, 2.4 Hz, 1H), 4.56 (m, 1H), 4.03 (dd, J = 11.1, 3.9 Hz, 2H), 3.50 (t, J = 11.1 Hz, 2H), 2.59 (m, 2H), 1.78 (m, 2H).

2-(6-クロロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-8-フルオロクロマン-4-イル)-7H-プリン-8(9H)-オン
実施例27に記載の手順により、(R)-8-フルオロクロマン-4-アミンおよび4-クロロ-2-ニトロベンゼンアミンから標記化合物を合成する。¹H NMR(300 MHz、CDCl₃＋5%CD₃OD)：δ 8.7(s、1H)、8.2(s、1H)、8.1(s、1H)、7.6(d、1H)、7.2(dd、1H)、6.9(td、1H)、6.7-6.5(m、2H)。5.8(dd、1H)、4.6(m 1H)、4.4(td、1H)、2.9(m、1H)、2.3(m、1H)。

2- (6-Chloro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purin-8 (9H) -one Example 27 The title compound is synthesized from (R) -8-fluorochroman-4-amine and 4-chloro-2-nitrobenzenamine by the procedure described in 1. ¹ H NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD): δ 8.7 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.6 (d, 1H), 7.2 (dd, 1H ), 6.9 (td, 1H), 6.7-6.5 (m, 2H). 5.8 (dd, 1H), 4.6 (m 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.3 (m, 1H).

N-(2,4-ジメトキシベンジル)-5-フルオロ-2-ニトロベンゼンアミン
THF(40 mL)中の2,4-ジフルオロ-1-ニトロベンゼン(1.1 mL)、2,4-ジメトキシベンジルアミン(1.5 mL)およびDIEA(5.2 mL)の溶液を、60℃にて60分加熱し、室温に冷却し、EtOAcおよびH₂Oに分配し、分離し、乾燥(硫酸マグネシウム)し、濾過し、蒸発して、標記生成物を黄色固体(3.14 g)で得る。¹H-NMR(300 MHz、CDCl₃)δ 8.5(br s、1H)、7.2(dd、1H)、7.2(d、1H)、6.6-6.4(m、3H)、6.3(m、1H)、4.3(d、2H)、3.9(s、3H)、3.8(s、3H)。 Synthesis of 2- (5-fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purin-8 (9H) -one

N- (2,4-Dimethoxybenzyl) -5-fluoro-2-nitrobenzenamine
A solution of 2,4-difluoro-1-nitrobenzene (1.1 mL), 2,4-dimethoxybenzylamine (1.5 mL) and DIEA (5.2 mL) in THF (40 mL) was heated at 60 ° C. for 60 minutes. Cool to room temperature, partition between EtOAc and H ₂ O, separate, dry (magnesium sulfate), filter and evaporate to give the title product as a yellow solid (3.14 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.5 (br s, 1H), 7.2 (dd, 1H), 7.2 (d, 1H), 6.6-6.4 (m, 3H), 6.3 (m, 1H), 4.3 (d, 2H), 3.9 (s, 3H), 3.8 (s, 3H).

N ^1- (2,4-Dimethoxybenzyl) -5-fluorobenzene-1,2-diamine Under an argon flush, a catalytic amount of an aqueous solution of Raney nickel was added to N- (2,4-dimethoxy) in THF (20 mL). Add to a solution of (benzyl) -5-fluoro-2-nitrobenzenamine (0.5 g). The flask is stoppered with a septum and degassed under hydrogen added via house vacuum and balloon. After stirring the resulting suspension at room temperature for 16 hours, the H ₂ balloon is removed and the mixture is degassed, filtered through a celite plug, rinsed thoroughly with THF and MeOH to give the title diamine, which is used as is. .

(R)-2-クロロ-N-(8-フルオロクロマン-4-イル)-5-ニトロピリミジン-4-アミン
DCM(10 mL)中の(R)-8-フルオロクロマン-4-アミン塩酸塩(1.02 g)およびDIEA(2.6 mL)の溶液を、THF(25 mL)中の2,4-ジクロロ-5-ニトロピリミジン(0.97 g)の溶液に-78℃にてゆっくりと加える。反応混合物を-78℃にて30分間撹拌し、次いで、室温に一夜温める。反応物に飽和NH₄Cl(1 mL)を加えて反応を停止し、溶媒の体積を減圧下で減少させ、得られる混合物をにEtOAcおよび水分配し、 次いで、分離する。粗物質を、30 % EtOAc/ヘキサンで溶離するカラムクロマトグラフィーにより精製して、標記生成物(1.43 g)を得る。¹H-NMR(300 MHz、CDCl₃)δ 9.1(s、1H)、8.6(br d、1H)、7.1-6.8(m、3H)、5.6(dd,1H)、4.4(m 1H)、4.3(m、1H)、2.4(m、1H)、2.2(m、1H)。

(R) -2-Chloro-N- (8-fluorochroman-4-yl) -5-nitropyrimidin-4-amine
A solution of (R) -8-fluorochroman-4-amine hydrochloride (1.02 g) and DIEA (2.6 mL) in DCM (10 mL) was added to 2,4-dichloro-5- in THF (25 mL). Slowly add to a solution of nitropyrimidine (0.97 g) at -78 ° C. The reaction mixture is stirred at −78 ° C. for 30 minutes and then warmed to room temperature overnight. The reaction is quenched with saturated NH ₄ Cl (1 mL), the solvent volume is reduced under reduced pressure, the resulting mixture is partitioned between EtOAc and water, and then separated. The crude material is purified by column chromatography eluting with 30% EtOAc / hexanes to give the title product (1.43 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.1 (s, 1H), 8.6 (br d, 1H), 7.1-6.8 (m, 3H), 5.6 (dd, 1H), 4.4 (m 1H), 4.3 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H).

^{(R) -N 2 - (2-} (2,4- dimethoxybenzyl) -4- fluorophenyl) -N ⁴ - (8- fluorochroman-4-yl) -5-nitropyrimidine-2,4-diamine
(R) -2-Chloro-N- (8-fluorochroman-4-yl) -5-nitropyrimidin-4-amine (32 mg) in ACN, N ^1- (2,4-dimethoxybenzyl) -5 A mixture of -fluorobenzene-1,2-diamine (28 mg) and KCO ₃ (41 mg) was heated at 65 ° C. for 3 h, cooled to room temperature, diluted with brine and extracted with EtOAc (2 ×) To do. The organic layers are combined, evaporated and purified by column chromatography (eluting with 30% EtOAc / hexanes) to give the title product (21 mg). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.0 (s, 1H), 8.6 (br d, 1H), 7.2-6.8 (m, 6H), 6.5-6.3 (m, 4H), 4.4-4.2 (m , 4H), 3.8 (s, 6H), 2.3-2.2 (m, 2H).

(R) -2- (2- (2,4-Dimethoxybenzylamino) -4-fluorophenylamino) -9- (8-fluorochroman-4-yl) -7H-purine-8 (9H) -one argon atmosphere, a solution of a catalytic amount of Raney nickel, in ^{THF (R) -N 2 - (} 2- (2,4- dimethoxybenzyl) -4- fluorophenyl) -N ⁴ - (8- fluorochroman - Add to a solution of 4-yl) -5-nitropyrimidine-2,4-diamine (21 mg). The flask is stoppered with a septum and degassed under hydrogen added via house vacuum and balloon. After stirring the resulting suspension at room temperature for 2 hours, the H ₂ balloon was removed, the mixture was degassed, filtered through a celite plug, rinsed thoroughly with THF and MeOH, and (R) -N ^2- (2- (2,4-dimethoxybenzyl) -4- fluorophenyl) -N ⁴ - (8- fluorochroman-4-yl) pyrimidine-2,4,5-triamine, used directly. To a stirred solution of the above material in THF (5 mL) is added CDI (12 mg). After 18 hours, brine and EtOAc are added and the mixture is separated. The organic layer is evaporated and purified by column chromatography (eluting with 4% MeOH / DCM) to give the title product (14 mg). ¹ H NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD): δ 7.8 (s, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.9 (m, 2H), 6.7-6.2 (m , 6H), 5.7 (dd, 1H), 4.5 (m 1H), 4.2 (m, 1H), 4.1 (s, 2H), 3.8 (s, 3H), 3.7 (s, 3H), 2.8 (m, 1H ), 2.2 (m, 1H).

2- (5-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purine-8 (9H) -one
(R) -2- (2- (2,4-dimethoxybenzylamino) -4-fluorophenylamino) -9- (8-fluorochroman-4-yl) -7H-purin-8 (9H) -one ( After stirring a mixture of 14 mg) and TFA (1 mL) for 60 min, triethylsilane (0.5 mL) is added. The resulting solution was stirred at room temperature for 16 hours, then the solvent was removed in vacuo to give (R) -2- (2-amino-4-fluorophenylamino) -9- (8-fluorochroman-4-yl ) -7H-purin-8 (9H) -one is obtained and used as such.

A catalytic amount of p-TsOH is added to a solution of the above amine in trimethylorthoformate (2 mL). The mixture is stirred at room temperature for 15 hours, then the solvent is reduced and the resulting material is partitioned between DCM and brine and separated. The crude product is purified by column chromatography (eluting with 5% MeOH / DCM) to give the title compound (9 mg). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.0 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (dd, 1H), 7.4 (d, 1H), 7.1 (m , 2H), 6.8 (m, 2H), 5.9 (dd, 1H), 4.7 (m1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.4 (m, 1H).

3-(2-フルオロフェノキシ)プロパン酸
2-フルオロフェノール(15 g)、3-ブロモプロパン酸(20 g)およびNaOH(11 g)の混合物を50mLの水中で還流する。溶液を室温に冷却し、3 M HClでpH2に酸性化する。得られる沈澱を濾過により単離して、9.27 gの標記化合物を白色固体で得る。濾液をEtOAcで3回抽出して、2.5gの純度の低い化合物を得る。 Synthesis and resolution of 8-fluorochroman-4-amine

3- (2-Fluorophenoxy) propanoic acid
A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) is refluxed in 50 mL of water. Cool the solution to room temperature and acidify to pH 2 with 3 M HCl. The resulting precipitate is isolated by filtration to give 9.27 g of the title compound as a white solid. The filtrate is extracted 3 times with EtOAc to give 2.5 g of impure compound.

8-Fluorochroman-4-one
To an ice-cold solution of 3- (2-fluorophenoxy) propanoic acid (9.27 g) in DCM (50 mL) is added oxalyl chloride (8.79 mL) and 1 drop of DMF. The solution is stirred at 0 ° C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) is added and the solution is stirred at room temperature for 16 hours. Pour ice water into the mixture and extract three times with DCM. The organic layers are combined and washed with 0.5 M NaOH and brine, then dried, evaporated and purified by column chromatography (eluting with 20% EtOAc / hexanes) to give the title compound (8.20 g, 98%). .

8-Fluorochroman-4-amine A round bottom flask is charged with 8-fluorochroman-4-one (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser is installed, the flask is purged with argon, absolute EtOH (20 mL) is added, and the mixture is stirred at reflux for 18 hours. The solution is cooled to room temperature, diluted with EtOAc and washed with water. The organic phase is dried and evaporated to give the intermediate 8-fluorochroman-4-one oxime and reduced with Raney nickel in EtOH at 50 PSI to give the title amine (4.69 g, 57%).

8-フルオロクロマン-4-アミンの分割(US0157739に基づく手順)
無水tert-ブチルメチルエーテル(75mL)中の8-フルオロクロマン-4-アミン(3.40 g)、2-メトキシ酢酸メチル(2.44 g)およびノボザイム435(Aldrich、0.68 g)の混合物を、アルゴン下で2時間加熱還流する(この時点で、アシル化対非アシルば生成物のHPLCによる比は、1：1である)。冷却によって形成される固体を濾過により集め、EtOAcに溶解する。混合物を濾過して、生体触媒を除去し、0.5M HClで1回洗浄して、残存する(S)-アミンを除去する。溶媒を蒸発し、tert-ブチルメチルエーテルから生成物を再結晶して、(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.78 g)を得る。反応溶媒および再結晶母液を0.5 M HClで3回洗浄し、濃縮して、さらなる(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.83 g)を得る。合わせた酸性水層をNaOHによって塩基性にし、DCMで抽出して、(S)-8-フルオロクロマン-4-アミン(1.6g)を得る。EtOH(50mL)中の8M HCl中の(R)-N-(8-フルオロクロマン-4-イル)-2-メトキシアセトアミド(0.78g)の溶液を、4時間加熱還流する。冷反応混合物から溶媒を除去し、得られる固体に50 mLの0.5M NaOHを加え、NaCl_(s)で塩析し、DCMで4回抽出して、(R)-8-フルオロクロマン-4-アミン(0.48 g(87%))を得る。キラルHPLCにより、% eeをチェックする：キラルセル OD-H(0.46 x 25 cm分析用カラム、ダイセル化学工業)方法：アイソクラティック 5 %(0.05% TFA/EtOH)95 %(0.05 % TFA/ヘキサン)、Rt＝7.2分(S)-エナンチオマー、Rt＝9.2分(R)-エナンチオマー。

Resolution of 8-fluorochroman-4-amine (procedure based on US0157739)
A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was added under argon. Reflux for hours (at this point the ratio of acylated to non-acylated product by HPLC is 1: 1). The solid formed on cooling is collected by filtration and dissolved in EtOAc. The mixture is filtered to remove the biocatalyst and washed once with 0.5M HCl to remove residual (S) -amine. The solvent is evaporated and the product is recrystallized from tert-butyl methyl ether to give (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.78 g). The reaction solvent and recrystallized mother liquor are washed 3 times with 0.5 M HCl and concentrated to give additional (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.83 g). The combined acidic aqueous layers are basified with NaOH and extracted with DCM to give (S) -8-fluorochroman-4-amine (1.6 g). A solution of (R) -N- (8-fluorochroman-4-yl) -2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) is heated to reflux for 4 hours. Remove the solvent from the cold reaction mixture, add 50 mL of 0.5 M NaOH to the resulting solid, salt out with NaCl _(s) , extract 4 times with DCM, and (R) -8-fluorochroman-4- The amine (0.48 g (87%)) is obtained. Check% ee by chiral HPLC: Chiralcel OD-H (0.46 x 25 cm analytical column, Daicel Chemical Industries) Method: 95% isocratic (0.05% TFA / EtOH) 95% (0.05% TFA / hexane) , Rt = 7.2 min (S) -enantiomer, Rt = 9.2 min (R) -enantiomer.

8-フルオロクロマン-4-アミンの合成のための実施例29に記載の手順により、これらのアミンを調製する。対応するクロマン-4-オンは、クロマン-4-アミン、6-フルオロクロマン-4-アミン、6-クロロクロマン-4-アミン、6-メチルクロマン-4-アミンおよび6-メトキシクロマン-4-アミンの合成のための改良型中間体として市販されている。5-フルオロクロマン-4-アミンの合成のために、GB 2355264に記載の手順を用いて中間体5-フルオロクロマン-4-オンが得られ、7-フルオロクロマン-4-オンも得られる。7-フルオロクロマン-4-オンは、7-フルオロクロマン-4-アミンの合成に用いることができる。8-フルオロクロマン-4-アミンの分割のための実施例29記載の手順により、クロマン-4-アミン、5-フルオロクロマン-4-アミン、6-フルオロクロマン-4-アミン、7-フルオロクロマン-4-アミン、5,8-ジフルオロクロマン-4-アミンおよび6,8-ジフルオロクロマン-4-アミンを分割する。 Chroman-4-amine, 5-fluorochroman-4-amine, 6-fluorochroman-4-amine, 6-chlorochroman-4-amine, 6-methylchroman-4-amine, 6-methoxychroman-4-amine 7-fluorochroman-4-amine, 5,8-difluorochroman-4-amine and 6,8-difluorochroman-4-amine

These amines are prepared by the procedure described in Example 29 for the synthesis of 8-fluorochroman-4-amine. The corresponding chroman-4-ones are chroman-4-amine, 6-fluorochroman-4-amine, 6-chlorochroman-4-amine, 6-methylchroman-4-amine and 6-methoxychroman-4-amine Are commercially available as improved intermediates for the synthesis of For the synthesis of 5-fluorochroman-4-amine, the procedure described in GB 2355264 is used to give the intermediate 5-fluorochroman-4-one and also 7-fluorochroman-4-one. 7-Fluorochroman-4-one can be used for the synthesis of 7-fluorochroman-4-amine. According to the procedure described in Example 29 for resolution of 8-fluorochroman-4-amine, chroman-4-amine, 5-fluorochroman-4-amine, 6-fluorochroman-4-amine, 7-fluorochroman- Resolution of 4-amine, 5,8-difluorochroman-4-amine and 6,8-difluorochroman-4-amine.

8-フルオロクロマン-4-オンから8-フルオロクロマン-4-アミンを得るために用いる実施例29に記載の手順により、1-メチル-6,7-ジヒドロ-1H-インドール-4(5H)-オン(ヘテロ環(1984)、22、2313)から標記化合物を得る。 1-methyl-4,5,6,7-tetrahydro-1H-indole-4-amine.

The procedure described in Example 29 used to obtain 8-fluorochroman-4-amine from 8-fluorochroman-4-one gives 1-methyl-6,7-dihydro-1H-indole-4 (5H)- The title compound is obtained from ON (heterocycle (1984), 22, 2313).

3-(2-ブロモ-4,5-ジフルオロフェノキシ)プロパン酸
5 mLの水中の1.68 gのNaOH(42 mmol)の溶液を、2.29 mL(20 mmol)の2-ブロモ-4,5-ジフルオロフェノールおよび3.07 g(20 mmol)の3-ブロモプロピオン酸の懸濁液にゆっくりと加える。混合物を油浴中で100℃にて5時間加熱し、次いで、室温に放冷する。水を加えて固体物質を完全に溶解し、濃HClで反応混合物を酸性にする。生成物をエーテル(3回)に抽出し、有機層を合わせ、乾燥(硫酸ナトリウム)し、蒸発して、3.7 g(66%)の標記化合物を淡褐色固体で得る。¹H NMR(300 MHz、CDCl₃)： δ 7.4(t、1H)、6.8(q、1H)、4.3(t、2H)、2.9(t、2H)。 Synthesis of 5,6-difluorochroman-4-amine

3- (2-Bromo-4,5-difluorophenoxy) propanoic acid
A solution of 1.68 g NaOH (42 mmol) in 5 mL water was suspended in 2.29 mL (20 mmol) 2-bromo-4,5-difluorophenol and 3.07 g (20 mmol) 3-bromopropionic acid. Slowly add to the liquid. The mixture is heated in an oil bath at 100 ° C. for 5 hours and then allowed to cool to room temperature. Water is added to completely dissolve the solid material and the reaction mixture is acidified with concentrated HCl. The product is extracted into ether (3 times) and the organic layers are combined, dried (sodium sulfate) and evaporated to give 3.7 g (66%) of the title compound as a light brown solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.4 (t, 1H), 6.8 (q, 1H), 4.3 (t, 2H), 2.9 (t, 2H).

8-Bromo-5,6-difluoro-2,3-dihydrochromen-4-one
To a solution of 2.8 g (10 mmol) 3- (2-bromo-4,5-difluorophenoxy) -propanoic acid in 40 mL anhydrous DCM was added oxalyl chloride (1.7 mL, 20 mmol), then DMF. Add a drop. After 1.5 hours, install a drying tube and cool the solution in an ice-water bath. AlCl ₃ (1.5 g, 11 mmol) is added and the dark red solution is allowed to slowly reach room temperature with stirring for 16 hours. Put ice in the mixture and separate the organic layer. Extract the aqueous layer twice with DCM. The organic layers are combined and washed with 0.5N NaOH and brine, then dried (sodium sulfate) and concentrated. Column chromatography of this residue with hexane and EtOAc yields 1.9 g of the title compound as an off-white solid (73%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.6 (t, 1H), 4.65 (t, 2H), 2.85 (t, 2H).

8-Bromo-5,6-difluoro-2,3-dihydrochromen-4-one oxime
To a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one (7.2 mmol) in 40 mL of ethanol was added hydroxylamine hydrochloride (0.55 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol). The mixture is heated to reflux for 20 hours. The mixture is cooled, diluted with EtOAc, washed with water and brine, then dried (sodium sulfate). Concentrate the solvent to give the title compound as a white solid (1.9 g). ¹ H NMR (300 MHz, 10% CD ₃ OD in CDCl ₃ ): δ 7.3 (t, 1H), 4.2 (t, 2H), 2.9 (t, 2H).

5,6-Difluoro-3,4-dihydro-2H-chromen-4-amine
To a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one oxime (1.9 g) in 200 mL MeOH is added Rani-Ni (5 mL slurry / water). The mixture is hydrogenated at 50 psi for 24 hours to give 8-bromo-5,6-difluoro-3,4-dihydro-2H-chromen-4-amine. Pd / C (0.3 g) is added to the mixture and hydrogenation is performed again at 50 psi for 4 hours. After filtration and concentration in vacuo, the title compound is obtained. ¹ H NMR (300 MHz, 10% CD ₃ OD in CDCl ₃ ): δ 7.15 (q, 1H), 6.6 (m, 1H), 4.6 (bm, 1H), 4.25 (bm, 2H), 2.2-2.4 ( m, 2H).

4-アミノ-3,4-ジヒドロ-2H-クロメン-8-カルボニトリル
10 mLのメタノール中の260 mgの4-オキソ-3,4-ジヒドロ-2H-クロメン-8-カルボニトリル(実施例29に記載の手順により、2-ヒドロキシベンゾニトリルから調製)、酢酸アンモニウム(1.2 g)および3オングストロームモレキュラーシーブス(1.5 g)の混合物を5日間撹拌する。混合物をセライトで濾過し、濾液を減圧濃縮する。粗残渣を100 mLの1 M HClで処理し、エチルエーテル(3 X 100 mL)で抽出する。飽和NaOHで水性層をpH10の塩基性にし、DCM(3 X 100 mL)で抽出する。合わせたDCM層を食塩水で洗浄し、乾燥(硫酸マグネシウム)し、減圧濃縮して、150 mgの標記化合物を得る。 Synthesis of 4-amino-3,4-dihydro-2H-chromene-8-carbonitrile

4-Amino-3,4-dihydro-2H-chromene-8-carbonitrile
260 mg 4-oxo-3,4-dihydro-2H-chromene-8-carbonitrile (prepared from 2-hydroxybenzonitrile by the procedure described in Example 29), ammonium acetate (1.2 ml) in 10 mL methanol. A mixture of g) and 3 Angstrom molecular sieves (1.5 g) is stirred for 5 days. The mixture is filtered through celite and the filtrate is concentrated in vacuo. The crude residue is treated with 100 mL of 1 M HCl and extracted with ethyl ether (3 X 100 mL). Basify the aqueous layer with saturated NaOH to pH 10 and extract with DCM (3 X 100 mL). The combined DCM layers are washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give 150 mg of the title compound.

4-アミノ-3,4-ジヒドロ-2H-クロメン-6-カルボニトリル
実施例33に記載の手順と同様にして、6-シアノ-4-クロマノン(Syntech)から標記化合物を製造する。

4-Amino-3,4-dihydro-2H-chromene-6-carbonitrile The title compound is prepared from 6-cyano-4-chromanone (Syntech) analogously to the procedure described in Example 33.

4-アミノ-1,2,3,4-テトラヒドロナフタレン-1-イルアセテート
実施例33に記載の手順と同様にして、4-オキソ-1,2,3,4-テトラヒドロナフタレン-1-イルアセテート(Tetrahedron：Asymmetry 2001、12、2283)から標記化合物を製造する。

4-Amino-1,2,3,4-tetrahydronaphthalen-1-yl acetate In analogy to the procedure described in Example 33, 4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl acetate The title compound is prepared from (Tetrahedron: Asymmetry 2001, 12, 2283).

6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-5-アミン
WO 03/045924に記載のとおり、標記化合物を製造する。

6,7-Dihydro-5H-cyclopenta [b] pyridin-5-amine
The title compound is prepared as described in WO 03/045924.

アセチル(5,6,7,8-テトラヒドロキノキサリン-5-イル)カルバミン酸(R)-tert-ブチル
アセトニトリル(20 mL)中の483 mgの(R)-N-(5,6,7,8-テトラヒドロキノキサリン-5-イル)アセトアミド(J. Org. Chem. (2003)、68、3546)を含む溶液を、Boc₂O(3 g)およびDMAP(5 mg)で処理する。混合物を60℃にて1.5時間加熱し、次いで、減圧濃縮する。カラムクロマトグラフィー(50% EtOAc／ヘキサン)により、293 mgの標記化合物を得る。 Synthesis of (R) -5,6,7,8-tetrahydroquinoxaline-5-amine

483 mg (R) -N- (5,6,7,8 in acetyl (5,6,7,8-tetrahydroquinoxalin-5-yl) carbamic acid (R) -tert-butyl acetonitrile (20 mL) A solution containing -tetrahydroquinoxalin-5-yl) acetamide (J. Org. Chem. (2003), 68, 3546) is treated with Boc ₂ O (3 g) and DMAP (5 mg). The mixture is heated at 60 ° C. for 1.5 hours and then concentrated under reduced pressure. Column chromatography (50% EtOAc / hexanes) gives 293 mg of the title compound.

5,6,7,8-Tetrahydroquinoxalin-5-ylcarbamic acid (R) -tert-butyl Acetyl (5,6,7,8-tetrahydroquinoxalin-5-yl) carbamic acid in methanol (10 mL) A solution of R) -tert-butyl (293 mg) is treated with hydrazine hydrate (0.5 mL) for 1.5 hours. The mixture is diluted with EtOAc and washed twice with saturated aqueous sodium chloride. The organic layer is separated, dried (sodium sulfate) and concentrated in vacuo to give 238 mg of the title compound.

(R) -5,6,7,8-Tetrahydroquinoxaline-5-amine
A solution of 5,6,7,8-tetrahydroquinoxalin-5-ylcarbamic acid (R) -tert-butyl (238 mg) in 10 mL 1: 1 TFA / DCM is stirred for 30 minutes. The mixture is concentrated to give the title compound as a TFA salt.

1-(フェニルスルホニル)-4-オキソ-4,5,6,7-テトラヒドロインドール
1,2-ジクロロエタン(250 mL)中のNaOH(4.44 g)の懸濁液に、4-オキソ-4,5,6,7-テトラヒドロインドール(5.0 g)を加える。次いで、混合物を0℃に冷却し、30分間撹拌し、次いで、1,2-ジクロロエタン(50 mL)中の塩化フェニルスルホニル(5.7 mL)の溶液を30分間にわたって滴下する。30分間撹拌した後、反応混合物を室温まで放冷し、一夜撹拌する反応物に蒸留水(100 mL)を加えて反応を停止する。有機層を分離し、水性層をジクロロメタン(3 × 50 mL)で抽出する。合わせた有機抽出物を蒸留水で洗浄して中和し、乾燥(硫酸マグネシウム)し、減圧濃縮して、7.0 gの標記化合物を得る。 Synthesis of 2- (1H-benzo [d] imidazol-1-yl) -9- (4,5,6,7-tetrahydro-1H-indol-4-yl) -7H-purin-8 (9H) -one

1- (Phenylsulfonyl) -4-oxo-4,5,6,7-tetrahydroindole
To a suspension of NaOH (4.44 g) in 1,2-dichloroethane (250 mL) is added 4-oxo-4,5,6,7-tetrahydroindole (5.0 g). The mixture is then cooled to 0 ° C. and stirred for 30 minutes, then a solution of phenylsulfonyl chloride (5.7 mL) in 1,2-dichloroethane (50 mL) is added dropwise over 30 minutes. After stirring for 30 minutes, the reaction mixture is allowed to cool to room temperature and quenched with distilled water (100 mL) to the reaction stirred overnight. The organic layer is separated and the aqueous layer is extracted with dichloromethane (3 x 50 mL). The combined organic extracts are neutralized by washing with distilled water, dried (magnesium sulfate) and concentrated in vacuo to give 7.0 g of the title compound.

1- (Phenylsulfonyl) -4,5,6,7-tetrahydro-1H-indole-4-amine
The procedure described in Example 29 used to obtain 8-fluorochroman-4-amine from 8-fluorochroman-4-one gives 1- (phenylsulfonyl) -4-oxo-4,5,6,7- The title compound is obtained from tetrahydroindole.

2- (1H-Benzo [d] imidazol-1-yl) -9- (1- (phenylsulfonyl) -4,5,6,7-tetrahydro-1H-indol-4-yl) -7H-purine-8 (9H) -one The title compound is obtained from 1- (phenylsulfonyl) -4,5,6,7-tetrahydro-1H-indole-4-amine by the procedure described in Example 24.

2- (1H-Benzo [d] imidazol-1-yl) -9- (4,5,6,7-tetrahydro-1H-indol-4-yl) -7H-purin-8 (9H) -one
2- (1H-benzo [d] imidazol-1-yl) -9- (1- (phenylsulfonyl) -4,5,6,7-tetrahydro-1H-indol-4-yl in MeOH (1 mL) To a solution of) -7H-purin-8 (9H) -one (50 mg) is added 4N NaOH (1 mL) and the mixture is refluxed overnight and cooled. Volatiles are removed under reduced pressure and the resulting material is neutralized with 4N HC. The white precipitate is filtered, washed with a small amount of water and dried in vacuo to give 36 mg of the title compound. ¹ H NMR (d ₆ -DMSO) δ 11.6 (s, 1H), 10.7 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.33 (m, 2H), 6.53 (t, J = 2.4 Hz, 1H), 5.64 (t, J = 2.4 Hz, 1H), 5.54 (m, 1H), 2.72 (m, 2H), 2.30 (m, 1H), 2.07 (m, 2H), 1.84 (m, 1H).

and

2-フルオロ-6-メトキシベンゾイルクロリド
5 mLの無水CH₂Cl₂中の1.0 g(5.9 mmol)の2-フルオロ-6-メトキシ安息香酸の溶液に、塩化オキサリル(0.56 mL、6.4 mmol)を加える。次いで、一滴のDMFを加える。1時間後、泡立ちが終わったとき、揮発物を減圧除去して、1.1 g(95%)の酸塩化物をで薄黄色液体で得る。
¹H NMR(300 MHz、CDCl₃)： δ 7.45(q、1H)、6.7-6.8(m、2H)、3.9(s、3H)。 Examples 36 and 37 (dihydrobenzofuran): 2- (1H-benzo [d] imidazol-1-yl) -9- (2,3-dihydrobenzofuran-3-yl) -7H-purine-8 (9H)- ON and 2- (1H-benzo [d] imidazol-1-yl) -9- (4-fluoro-2,3-dihydrobenzofuran-3-yl) -7H-purine-8 (9H) -one

2-Fluoro-6-methoxybenzoyl chloride
To a solution of 1.0 g (5.9 mmol) 2-fluoro-6-methoxybenzoic acid in 5 mL anhydrous CH ₂ Cl ₂ is added oxalyl chloride (0.56 mL, 6.4 mmol). A drop of DMF is then added. After 1 hour, when bubbling ceased, the volatiles were removed in vacuo to give 1.1 g (95%) of the acid chloride as a pale yellow liquid.
¹ H NMR (300 MHz, CDCl ₃ ): δ 7.45 (q, 1H), 6.7-6.8 (m, 2H), 3.9 (s, 3H).

4-Fluorobenzofuran-3 (2H) -one
To 0.57 g (3.0 mmol) of the above acid chloride, yellow (trimethylsilyl) diazomethane ether solution (2.0 M, 3.7 mL) is added with stirring. After 3 hours, the solvent is evaporated. Dissolve the yellow residue in 3 mL acetic acid (strong gas and heat release, use water bath to cool flask briefly) and stir at room temperature for 15 minutes. The solvent is removed under reduced pressure and 2 mL CH ₂ Cl ₂ is added to the red residue, washed twice with water and then with brine and dried (sodium sulfate). The crude product is purified by column chromatography (eluting with 10% EtOAc / hexanes) to give 0.24 g (53%) of 4-fluorobenzofuran-3 (2H) -one as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (m, 1H), 6.92 (br d, 1H), 6.71 (t, 1H), 4.65 (s, 2H).

(Z) -4-fluorobenzofuran-3 (2H) -one oxime The above ketone (0.70 g, 4.6 mmol) was dissolved in 5 ml of ethyl alcohol, then 0.64 g (9.2 mmol) of hydroxylamine hydrochloride and 0.75 g (9.2 mmol) sodium acetate is added. The suspension is refluxed for 1 hour. Cool the mixture to room temperature and add 4 mL of water to dissolve excess reagent. Filter with suction and then wash the solid cake with a small amount of cold water to give 0.48 g (63%) of the desired oxime as white needles.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.38 (s, 1H), 7.38 (q, 1H), 6.6-6.8 (m, 2H), 5.21 (s, 2H).

4-Fluoro-2,3-dihydrobenzofuran-3-amine The above oxime (0.48 g) is dissolved in 40 mL of anhydrous THF under argon. Freshly prepared aluminum amalgam (2% HgCl ₂ aqueous solution, water, and finally by sequentially immersing 1 g of polished aluminum foil in THF) is quickly added and the mixture is refluxed under argon for 24 hours. Shiny mercury beads appear at the bottom of the flask. Cool the mixture to room temperature and filter through a celite pad. The flask and solid cake are washed 3 times with THF and then 3 times with methanol. The combined filtrates are rotoevaporated to give 0.41 g of a yellow solid with about 20% of the desired amine and 80% of the starting oxime mixture (determined by NMR). This mixture is used in the next step without purification.
¹ H NMR (300 MHz, CDCl ₃ ): δ 7.18 (q, 1H), 6.5-6.7 (m, 2H), 4.8-4.9 (m, 1H), 4.69 (t, 1H), 4.2-4.3 (m, 1H).

上記ラセミ2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-(2,3-ジヒドロベンゾフラン-3-イル)-7H-プリン-8(9H)-オンは、85：15 ヘキサン：エタノール(両者とも0.1% ジエチルアミンで)で溶離するキラルキラルセル OD-Hカラム(5μMシリカゲル基質上のセルロース トリス(3,5-ジメチルフェニルカルバメート))により、分離することができる。一方のエナンチオマーは、保持時間25分であり、他方は、33.5分である。

The racemic 2- (1H-benzo [d] imidazol-1-yl) -9- (2,3-dihydrobenzofuran-3-yl) -7H-purin-8 (9H) -one is 85:15 hexane: Separation can be achieved with a chiral chiral cell OD-H column (cellulose tris (3,5-dimethylphenylcarbamate) on a 5 μM silica gel substrate) eluting with ethanol (both with 0.1% diethylamine). One enantiomer has a retention time of 25 minutes and the other is 33.5 minutes.

Procedure and NMR data for 7-alkylated prinone analogs

2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7-methyl-7H-purine-8 (9H)- on
2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7H-purine-8 (1 mL) in ACN (1 mL) 9H) -one (5 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine / polystyrene (30 mg, 2.2 mM / g) and iodomethane (5 μL ) Is stirred at room temperature for 1 hour, then filtered through a short plug of celite and rinsed thoroughly with MeOH. Evaporate the solvent and chromatograph on silica gel (eluting with 4% MeOH / DCM) to give the title compound (4 mg). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.2 (s, 1H), 7.7 (m, 2H), 7.0 (m, 2H), 6.7 (m, 2H), 5.9 (dd , 1H), 4.7 (m 1H), 4.4 (td, 1H), 3.6 (s, 3H), 2.9 (m, 1H), 2.4 (m, 1H).

3- [9-chroman-4-yl-7- (2-methoxy-ethyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile acetonitrile 3- (9-((R) -chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole in (10 mL) A solution of 5-carbonitrile (10 mg) was added to 2-bromoethyl methyl ether (23 μL) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine / polystyrene. Treat with (500 mg, 2.2 mmol base / g). The mixture is stirred at room temperature for 16 hours and then filtered through celite. Celite is washed with acetonitrile and methanol, then the collected filtrate is dried (magnesium sulfate) and concentrated in vacuo. Purify by column chromatography (1% MeOH / DCM) to give 4 mg of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.2 (m , 2H), 6.9 (d, 1H), 6.8 (d, 1H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.4 (s, 3H), 2.8 (m, 1H), 2.4 (m, 1H).

2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -6-fluorochroman-4-yl) -7- (2-hydroxyethyl) -7H-purine- 8 (9H) -ON
5 mg 2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -9-((R) -6-fluorochroman-4-yl) -7H-purine in 1 mL anhydrous acetonitrile -8 (9H) -one in a solution of 50 mg (excess) 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine / polystyrene (2.2 mmol base / g Fluka), then 10 μL (excess) of 2-iodoethanol. The mixture is stirred at room temperature for 24 hours. Column chromatography with 3% MeOH / CH ₂ Cl ₂ followed by preparative HPLC yields 3 mg of the desired product as a TFA salt. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.14 (s, 1H), 8.40 (s, 1H), 7.7-7.9 (m, 2H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 6.59 (dd, 1H), 5.88 (br t, 1H), 4.5-4.6 (m, 1H), 4.32 (t, 1H), 4.0-4.2 (m, 4H ), 2.7-2.9 (bs + m, 2H), 2.2-2.3 (m, 1H).

3- [9-Chroman-4-yl-7- (2-dimethylamino-ethyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile 3- (9-((R) -chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole in acetonitrile (10 mL) A solution of -5-carbonitrile (65 mg) was added to 2-chloro-N, N-dimethylethylamine hydrochloride (25 mg) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1, Treat with 3,2-diazaphospholine / polystyrene (325 mg, 2.2 mmol base / g). The mixture is stirred at room temperature for 16 hours and then filtered through celite. Celite is washed with acetonitrile and methanol, then the collected filtrate is dried (magnesium sulfate) and concentrated in vacuo. Purify by column chromatography (2% MeOH / DCM) to give 21 mg of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.9 (s, 1H), 8.5 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H), 7.60 (d, 1H), 7.2 (m , 2H), 6.9 (d, 1H), 6.8 (d, 1H), 5.9 (t, 1H), 4.4 (m, 4H), 3.6 (m, 3H), 3.0 (s, 6H), 2.2 (m, 1H).

3- (9-chroman-4-yl-7-cyanomethyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzimidazole-5-carbonitrile in acetonitrile (10 mL) 3- (9-((R) -chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile (10 mg) solution of bromoacetonitrile (17 μL) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine / polystyrene (500 mg, 2.2 mmol base / g) Process with. The mixture is stirred at room temperature for 16 hours and then filtered through celite. Celite is washed with acetonitrile and methanol, then the collected filtrate is dried (magnesium sulfate) and concentrated in vacuo. Purify by column chromatography (1% MeOH / DCM) to give 11 mg of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.5 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.2 (m , 2H), 6.8 (m, 2H), 5.9 (t, 1H), 5.0 (s, 2H), 4.6 (m, 1H), 4.4 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H).

2- (2- (6-Cyano-1H-benzo [d] imidazol-1-yl) -9-((R) -6,8-difluorochroman-4-yl) -8-oxo-8,9- Dihydropurin-7-yl) methyl acetate 3- (9-((R) -6,8-difluorochroman-4-yl) -8-oxo-8,9-dihydro-7H- in acetonitrile (2 mL) Purin-2-yl) -3H-benzo [d] imidazole-5-carbonitrile (10 mg) was diluted with methyl bromoacetate (90 mg) and 2-tert-butylimino-2-diethylamino-1,3- Treat with dimethyl-perhydro-1,3,2-diazaphospholine / polystyrene (100 mg, 2.2 mmol base / g). The mixture is stirred at room temperature for 48 hours and then filtered. The collected filtrate is concentrated under reduced pressure. Purification by preparative TLC (5% MeOH / DCM) followed by column chromatography gives 6 mg of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.94 (s, 1H), 8.78 (m, 1H), 8.21 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.1, 1.2 Hz, 1H), 6.83 (m, 1H), 6.42 (m, 1H), 5.89 (m, 1H), 4.77 (s, 2H), 4.68 (m, 1H), 4.41 (m, 1H) 3.87 (s, 3H), 2.98 (m, 1H), 2.40 (m, 1H).

2- (2- (6-Cyano-1H-benzo [d] imidazol-1-yl) -9-((R) -6,8-difluorochroman-4-yl) -8-oxo-8,9- Dihydropurin-7-yl) acetic acid
2- (2 (6-Cyano-1H-benzo [d] imidazol-1-yl) -9-((R) -6,8-difluorochroman-4) in MeOH (0.75 mL) and THF (0.25 mL) -Il) -8-oxo-8,9-dihydropurin-7-yl) methyl acetate (4 mg) in solution of lithium hydroxide (2 mg) in water (0.25 mL) at 0 ° C. Add. The reaction is allowed to warm to room temperature and stirred for 2 hours. After concentration in vacuo, the residue is diluted with water and acidified with 2N HCl to pH 4. The precipitated solid is filtered, washed with a small amount of cold water, treated with 1N HCl in MeOH (0.5 mL) and concentrated in vacuo to give 2 mg of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 8.75 (m, 1H), 8.46 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 1.5 Hz, 1H), 6.92 (m, 1H), 6.70 (m, 1H), 5.97 (m, 1H), 4.77 (s, 2H), 4.63 (m, 1H), 4.44 (m, 1H) 2.91 (m, 1H), 2.42 (m, 1H).

トリフェニルホスフィン結合樹脂(264 mg、2.15 mM/g、Argonaut)および4-ヒドロキシピペリジン-1-カルボン酸tert-ブチル6(24 mg)を、ジクロロエタン(6 mL)中の2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-(テトラヒドロ-2H-ピラン-4-イル)-7H-プリン-8(9H)-オンに加え、アゾジカルボン酸ジイソプロピル(64 μL)を加えた後、混合物を10分間撹拌する。18時間後、物質を濾過し、ACNおよびMeOHで樹脂を完全に濯ぎ、有機層を合わせ、蒸発し、RP-HPLCにより精製して(TFAが蒸発においてBocを除去)、標記化合物をTFA塩で得る(16 mg)。¹H-NMR(300 MHz、CDCl₃ ＋5% CD₃OD)δ 9.0(s、1H)、8.6(s、1H)、8.3(dd、1H)、7.7(dd、1H)、7.1(td、1H)、4.7-4.4(m、2H)、4.2(dd、2H)、3.6(t,2H)、3.3(br d、2H)、2.9-2.7(m、4H)、2.4-2.2(m、4H)、2.9(m、1H)、1.9(d、2H)、1.8(d、2H)；¹⁹F δ -76、-117 ppm；MH^＋＝438；IR(CDCl₃)1726(C＝O ストレッチ)。 2- (6-Fluoro-1H-benzo [d] imidazol-1-yl) -7- (piperidin-4-yl) -9- (tetrahydro-2H-pyran-4-yl) -7H-purine-8 ( Synthesis of (9H) -one

Triphenylphosphine-conjugated resin (264 mg, 2.15 mM / g, Argonaut) and tert-butyl 4-hydroxypiperidine-1-carboxylate 6 (24 mg) were added to 2- (6-fluoro-) in dichloroethane (6 mL). In addition to 1H-benzo [d] imidazol-1-yl) -9- (tetrahydro-2H-pyran-4-yl) -7H-purin-8 (9H) -one, add diisopropyl azodicarboxylate (64 μL) After that, the mixture is stirred for 10 minutes. After 18 hours, the material was filtered, the resin was rinsed thoroughly with ACN and MeOH, the organic layers were combined, evaporated and purified by RP-HPLC (TFA removed Boc on evaporation) and the title compound was washed with TFA salt. Obtain (16 mg). ¹ H-NMR (300 MHz, CDCl ₃ + 5% CD ₃ OD) δ 9.0 (s, 1H), 8.6 (s, 1H), 8.3 (dd, 1H), 7.7 (dd, 1H), 7.1 (td, 1H ), 4.7-4.4 (m, 2H), 4.2 (dd, 2H), 3.6 (t, 2H), 3.3 (br d, 2H), 2.9-2.7 (m, 4H), 2.4-2.2 (m, 4H) 2.9 (m, 1H), 1.9 (d, 2H), 1.8 (d, 2H); ¹⁹ F δ −76, −117 ppm; MH ⁺ = 438; IR (CDCl ₃ ) 1726 (C═O stretch).

2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-8-フルオロクロマン-4-イル)-7-メチル-7H-プリン-8(9H)-オン
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.2(s、1H)、8.1(m、1H)、7.8(m、2H)、7.3(m、2H)、7.0(m、1H)、6.7(m、2H)、5.9(t、1H)、4.7(m 1H)、4.4(td、1H)、3.6(s、3H)、2.9(m、1H)、2.4(m、1H)。

2- (1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7-methyl-7H-purin-8 (9H) -one Example 38 This compound is synthesized by the method described in 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.2 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.3 (m, 2H), 7.0 (m , 1H), 6.7 (m, 2H), 5.9 (t, 1H), 4.7 (m 1H), 4.4 (td, 1H), 3.6 (s, 3H), 2.9 (m, 1H), 2.4 (m, 1H ).

2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-(6-フルオロクロマン-4-イル)-7-メチル-7H-プリン-8(9H)-オン
実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.80(s、1H)、8.19(s、1H)、7.96(d、1H)、7.78(d、1H)、7.2-7.4(m、2H)、6.8-7.1(m、2H)、6.61(dd、1H)、5.88(br t、1H)、4.54(m、1H)、4.32(m、1H)、3.56(s、3H)、2.84(m、1H)、2.30(m、1H)。

2- (1H-Benzo [d] imidazol-1-yl) -9- (6-fluorochroman-4-yl) -7-methyl-7H-purin-8 (9H) -one Method described in Example 38 To synthesize this compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.80 (s, 1H), 8.19 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.2-7.4 (m, 2H), 6.8 -7.1 (m, 2H), 6.61 (dd, 1H), 5.88 (br t, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 3.56 (s, 3H), 2.84 (m, 1H) 2.30 (m, 1H).

2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-5,8-ジフルオロクロマン-4-イル)-7-メチル-7H-プリン-8(9H)-オン
実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.7(s、1H)、8.2(s、1H)、8.0(d、1H)、7.9(d、1H)、7.4(m、2H)、7.0(t-d、1H)、6.5(t-d、1H)、6.0(t、1H)、4.6(m、1H),4.4(m、1H)、3.5(s、3H)、2.6(m、1H)、2.5(m、1H)。

2- (1H-Benzo [d] imidazol-1-yl) -9-((R) -5,8-difluorochroman-4-yl) -7-methyl-7H-purin-8 (9H) -one This compound is synthesized by the method described in Example 38. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.7 (s, 1H), 8.2 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.0 (td , 1H), 6.5 (td, 1H), 6.0 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.5 (s, 3H), 2.6 (m, 1H), 2.5 (m, 1H).

2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-5,8-ジフルオロクロマン-4-イル)-7-エチル-7H-プリン-8(9H)-オン
ヨードエタンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.8(s、1H)、8.2(s、1H)、8.0(d、1H)、7.9(d、1H)、7.4(m、2H)、7.0(t-d、1H)、6.5(t-d、1H)、6.0(t、1H)、4.6(m、1H),4.4(m、1H)、4.0(m、2H)、2.6(m、1H)、2.5(m、1H)、1.5(t、3H)。

2- (1H-Benzo [d] imidazol-1-yl) -9-((R) -5,8-difluorochroman-4-yl) -7-ethyl-7H-purine-8 (9H) -one iodoethane This compound is synthesized by the method described in Example 38. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.8 (s, 1H), 8.2 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.0 (td , 1H), 6.5 (td, 1H), 6.0 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 2H), 2.6 (m, 1H), 2.5 (m, 1H), 1.5 (t, 3H).

2-(1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-5,8-ジフルオロクロマン-4-イル)-7-プロピル-7H-プリン-8(9H)-オン
ヨードプロパンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 9.8(s、1H)、8.2(s、1H)、8.0(d、1H)、7.9(d、1H)、7.4(m、2H)、7.0(t-d、1H)、6.5(t-d、1H)、6.0(t、1H)、4.6(m、1H),4.4(m、1H)、4.0(m、2H)、2.6(m、1H)、2.5(m、1H)、1.9(m、2H)、1.0(t、3H)。

2- (1H-Benzo [d] imidazol-1-yl) -9-((R) -5,8-difluorochroman-4-yl) -7-propyl-7H-purine-8 (9H) -one iodo This compound is synthesized by the method described in Example 38 using propane. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.8 (s, 1H), 8.2 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.0 (td , 1H), 6.5 (td, 1H), 6.0 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 2H), 2.6 (m, 1H), 2.5 (m, 1H), 1.9 (m, 2H), 1.0 (t, 3H).

9-((R)-5,8-ジフルオロクロマン-4-イル)-2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-7-メチル-7H-プリン-8(9H)-オン
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.7(s、1H)、8.0(m、1H)、7.7(dd、1H)、7.1(m、2H)、6.5(td、1H)、5.9(dd、1H)、4.6(m 1H)、4.5(m、1H)、3.5(s、3H)、2.6(m、1H)、2.5(m、1H)。

9-((R) -5,8-Difluorochroman-4-yl) -2- (6-fluoro-1H-benzo [d] imidazol-1-yl) -7-methyl-7H-purine-8 (9H ) -On This compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.0 (m, 1H), 7.7 (dd, 1H), 7.1 (m, 2H), 6.5 (td, 1H), 5.9 (dd , 1H), 4.6 (m 1H), 4.5 (m, 1H), 3.5 (s, 3H), 2.6 (m, 1H), 2.5 (m, 1H).

9-((R)-5,8-ジフルオロクロマン-4-イル)-2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-7-(2-メトキシエチル)-7H-プリン-8(9H)-オン
実施例39に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.7(s、1H)、8.4(s、1H)、8.0(m、1H)、7.8(dd、1H)、7.2-7.0(m、2H)、6.5(td、1H)、6.0(t、1H)、4.6(m 1H)、4.5(m、1H)、4.1(t、2H)、3.7(t、2H)、3.4(s、3H)、2.7(m、1H)、2.4(m、1H)。

9-((R) -5,8-Difluorochroman-4-yl) -2- (6-fluoro-1H-benzo [d] imidazol-1-yl) -7- (2-methoxyethyl) -7H- Purin-8 (9H) -one This compound is synthesized by the method described in Example 39. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.4 (s, 1H), 8.0 (m, 1H), 7.8 (dd, 1H), 7.2-7.0 (m, 2H), 6.5 (td, 1H), 6.0 (t, 1H), 4.6 (m 1H), 4.5 (m, 1H), 4.1 (t, 2H), 3.7 (t, 2H), 3.4 (s, 3H), 2.7 (m , 1H), 2.4 (m, 1H).

9-((R)-5,8-ジフルオロクロマン-4-イル)-7-(2-(ジメチルアミノ)エチル)-2-(6-フルオロ-1H-ベンゾ[d]イミダゾール-1-イル)-7H-プリン-8(9H)-オン
実施例41に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 9.2(s、1H)、8.5(s、1H)、7.9(m、1H)、7.8(dd、1H)、7.2(td、1H)、7.1(td、1H)、6.5(td、1H)、5.9(t、1H)、4.6(m 1H)、4.5(m、3H)、3.6(m、2H)、3.0(s、6H)、2.7(m、1H)、2.5(m、1H)。

9-((R) -5,8-Difluorochroman-4-yl) -7- (2- (dimethylamino) ethyl) -2- (6-fluoro-1H-benzo [d] imidazol-1-yl) -7H-purin-8 (9H) -one This compound is synthesized by the method described in Example 41. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (m, 1H), 7.8 (dd, 1H), 7.2 (td, 1H), 7.1 (td , 1H), 6.5 (td, 1H), 5.9 (t, 1H), 4.6 (m 1H), 4.5 (m, 3H), 3.6 (m, 2H), 3.0 (s, 6H), 2.7 (m, 1H ), 2.5 (m, 1H).

2-(6-クロロ-1H-ベンゾ[d]イミダゾール-1-イル)-9-((R)-8-フルオロクロマン-4-イル)-7-メチル-7H-プリン-8(9H)-オン
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.7(s、1H)、8.3(m、1H)、8.2(s、1H)、7.7(d、1H)、7.3(dd、1H)、7.0(td、1H)、6.8-6.6(m、2H)、5.9(dd、1H)、4.7(m 1H)、4.5(td、1H)、3.6(s、3H)、3.0(m、1H)、2.4(m、1H)。

2- (6-Chloro-1H-benzo [d] imidazol-1-yl) -9-((R) -8-fluorochroman-4-yl) -7-methyl-7H-purine-8 (9H)- On The compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.3 (m, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.3 (dd, 1H), 7.0 (td , 1H), 6.8-6.6 (m, 2H), 5.9 (dd, 1H), 4.7 (m 1H), 4.5 (td, 1H), 3.6 (s, 3H), 3.0 (m, 1H), 2.4 (m , 1H).

３-(7-メチル-8-オキソ-9-(テトラヒドロ-2H-ピラン-4-イル)-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 9.37(s、1H)、8.90(m、1H)、8.58(s、1H)、8.00(d、J＝8.4 Hz、1H)、7.79(dd、J＝8.4、1.5 Hz、1H)、4.63(m、1H)、4.03(m、2H)、3.51(m、2H)、3.44(s、3H)、2.58(m、2H)、1.80(m、2H)。

3- (7-Methyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5- Carbonitrile The compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.37 (s, 1H), 8.90 (m, 1H), 8.58 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.4, 1.5 Hz, 1H), 4.63 (m, 1H), 4.03 (m, 2H), 3.51 (m, 2H), 3.44 (s, 3H), 2.58 (m, 2H), 1.80 (m, 2H) .

３-(9-クロマン-4-イル-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾイミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.5(s、1H)、8.2(s、1H)、7.8(d、1H)、7.6(d、1H)、7.2(m、2H)、6.9(d、1H)、6.8(d、1H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、3.6(s、3H)、2.8(m、1H)、2.4(m、1H)。

3- (9-chroman-4-yl-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzimidazole-5-carbonitrile The method described in Example 38 To synthesize this compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.2 (m , 2H), 6.9 (d, 1H), 6.8 (d, 1H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.6 (s, 3H), 2.8 (m, 1H), 2.4 (m, 1H).

３-[9-(8-フルオロ-クロマン-4-イル)-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(d、2H)、8.2(s、1H)、7.8(d、1H)、7.6(d、1H)、7.0(t、1H)、6.6(m、2H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、3.6(s、3H)、2.8(m、1H)、2.4(m、1H)。

3- [9- (8-Fluoro-chroman-4-yl) -7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile This compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (d, 2H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.0 (t, 1H), 6.6 (m , 2H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.6 (s, 3H), 2.8 (m, 1H), 2.4 (m, 1H).

３-(9-((R)-6-フルオロクロマン-4-イル)-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.90(s、1H)、8.52(s、1H)、8.21(s、1H)、7.84(d、1H)、7.59(d、1H)、7.1-7.2(m、1H)、6.9-7.0(m、1H)、6.59(dd、1H)、5.89(br t、1H)、4.5-4.6(m、1H)、4.34(br t、1H)、3.59(s、3H)、2.8-2.9(m、1H)、2.3-2.4(m、1H)。

3- (9-((R) -6-Fluorochroman-4-yl) -7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole -5-carbonitrile The compound is synthesized by the method described in Example 38. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.90 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.1-7.2 (m, 1H), 6.9-7.0 (m, 1H), 6.59 (dd, 1H), 5.89 (br t, 1H), 4.5-4.6 (m, 1H), 4.34 (br t, 1H), 3.59 (s , 3H), 2.8-2.9 (m, 1H), 2.3-2.4 (m, 1H).

３-(9-((R)-7-フルオロクロマン-4-イル)-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.90(s、1H)、8.62(s、1H)、8.19(s、1H)、7.84(d、1H)、7.59(d、1H)、6.8-7.0(m、2H)、6.4-6.6(m、1H)、5.86(br t、1H)、4.5-4.6(m、1H)、4.36(br t、1H)、3.59(s、3H)、2.8-2.9(m、1H)、2.3-2.4(m、1H)。

3- (9-((R) -7-Fluorochroman-4-yl) -7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole -5-carbonitrile The compound is synthesized by the method described in Example 38. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.90 (s, 1H), 8.62 (s, 1H), 8.19 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 6.8-7.0 (m, 2H), 6.4-6.6 (m, 1H), 5.86 (br t, 1H), 4.5-4.6 (m, 1H), 4.36 (br t, 1H), 3.59 (s, 3H), 2.8-2.9 (m, 1H), 2.3-2.4 (m, 1H).

３-(9-((R)-6,8-ジフルオロクロマン-4-イル)-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.9(s、1H)、8.8(s、1H)、8.2(s、1H)、7.9(d、1H)、7.6(dd、1H)、6.8(td、1H)、6.4(dd、1H)、5.9(dd、1H)、4.7(m、1H)、4.4(td、1H)、3.6(s、3H)、3.0(m、1H)、2.4(m、1H)。

3- (9-((R) -6,8-Difluorochroman-4-yl) -7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d Imidazole-5-carbonitrile This compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.9 (s, 1H), 8.8 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.6 (dd, 1H), 6.8 (td , 1H), 6.4 (dd, 1H), 5.9 (dd, 1H), 4.7 (m, 1H), 4.4 (td, 1H), 3.6 (s, 3H), 3.0 (m, 1H), 2.4 (m, 1H).

３-[9-(5,8-ジフルオロ-クロマン-4-イル)-7-メチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.7(s、1H)、8.2(s、1H)、7.8(d、1H)、7.6(d、1H)、7.0(m、1H)、6.5(m、1H)、5.9(t、1H)、4.5(m、2H)、3.5(s、3H)、2.5(m、2H)。

3- [9- (5,8-Difluoro-chroman-4-yl) -7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbo Nitrile The compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.0 (m , 1H), 6.5 (m, 1H), 5.9 (t, 1H), 4.5 (m, 2H), 3.5 (s, 3H), 2.5 (m, 2H).

３-[7-エチル-9-(8-フルオロ-クロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
ヨードエタンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、2H)、8.2(s、1H)、7.9(d、1H)、7.6(d、1H)、7.0(t、1H)、6.7(m、2H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、4.0(q、2H)、2.9(m、1H)、2.4(m、1H)、1.4(t、3H)。

3- [7-Ethyl-9- (8-fluoro-chroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbonitrile iodoethane This compound is synthesized by the method described in Example 38. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 2H), 8.2 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.0 (t, 1H), 6.7 (m , 2H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (q, 2H), 2.9 (m, 1H), 2.4 (m, 1H), 1.4 (t, 3H).

３-(7-エチル-9-((R)-7-フルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
ヨードエタンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.88(s、1H)、8.62(s、1H)、8.21(s、1H)、7.84(d、1H)、7.59(d、1H)、6.8-7.0(m、2H)、6.4-6.6(m、1H)、5.86(br t、1H)、4.5-4.6(m、1H)、4.36(br t、1H)、4.0-4.1(m、2H)、2.8-2.9(m、1H)、2.3-2.4(m、1H)、1.48(t、3H)。

3- (7-Ethyl-9-((R) -7-fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole This compound is synthesized by the method described in Example 38 using -5-carbonitrile iodoethane. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.88 (s, 1H), 8.62 (s, 1H), 8.21 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 6.8-7.0 (m, 2H), 6.4-6.6 (m, 1H), 5.86 (br t, 1H), 4.5-4.6 (m, 1H), 4.36 (br t, 1H), 4.0-4.1 (m, 2H), 2.8 -2.9 (m, 1H), 2.3-2.4 (m, 1H), 1.48 (t, 3H).

３-(9-((R)-6,8-ジフルオロクロマン-4-イル)-7-エチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
ヨードエタンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.9(s、1H)、8.8(s、1H)、8.2(s、1H)、7.9(d、1H)、7.6(dd、1H)、6.8(td、1H)、6.4(dd、1H)、5.9(dd、1H)、4.7(m、1H)、4.4(td、1H)、4.1(q、2H)、3.0(m、1H)、2.4(m、1H)、1.5(t、3H)。

3- (9-((R) -6,8-Difluorochroman-4-yl) -7-ethyl-8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [d This compound is synthesized by the method described in Example 38 using imidazole-5-carbonitrile iodoethane. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.9 (s, 1H), 8.8 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.6 (dd, 1H), 6.8 (td , 1H), 6.4 (dd, 1H), 5.9 (dd, 1H), 4.7 (m, 1H), 4.4 (td, 1H), 4.1 (q, 2H), 3.0 (m, 1H), 2.4 (m, 1H), 1.5 (t, 3H).

３-[9-(5,8-ジフルオロ-クロマン-4-イル)-7-エチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
ヨードエタンを用い、実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.8(s、1H)、8.7(s、1H)、8.2(s、1H)、7.9(d、1H)、7.6(d、1H)、7.0(m、1H)、6.4(m、1H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、4.0(q、2H)、2.5(m、2H)、1.4(t、3H)。

3- [9- (5,8-Difluoro-chroman-4-yl) -7-ethyl-8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazole-5-carbo Nitrile This compound is synthesized by the method described in Example 38 using iodoethane. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.0 (m , 1H), 6.4 (m, 1H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (q, 2H), 2.5 (m, 2H), 1.4 (t, 3H).

３-[9-(5,8-ジフルオロ-クロマン-4-イル)-7-isoブチル-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル]-3H-ベンゾイミダゾール-5-カルボニトリル
ヨウ化イソブチルを用い、実施例38に記載の方法によって、本化合物を合成する。¹H-NMR(300 MHz、CDCl₃)δ 8.9(s、1H)、8.8(s、1H)、8.2(s、1H)、7.9(d、1H)、7.6(d、1H)、7.1(m、1H)、6.5(m、1H)、5.9(t、1H)、4.6(m、1H)、4.4(m、1H)、3.8(q、2H)、2.7(m、1H)、2.5(m、1H)、2.3(q、1H)、1.0(s、6H)。

3- [9- (5,8-Difluoro-chroman-4-yl) -7-isobutyl-8-oxo-8,9-dihydro-7H-purin-2-yl] -3H-benzimidazol-5- Carbonitrile The compound is synthesized by the method described in Example 38 using isobutyl iodide. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.9 (s, 1H), 8.8 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.1 (m , 1H), 6.5 (m, 1H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.8 (q, 2H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (q, 1H), 1.0 (s, 6H).

３-(7-ベンジル-8-オキソ-9-(テトラヒドロ-2H-ピラン-4-イル)-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
ベンジルブロミドを用い、実施例38に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 9.30(s、1H)、9.01(m、1H)、8.23(s、1H)、7.89(m、1H)、7.66(dd、J＝8.1、1.5 Hz、1H)、7.40-7.32(m、5H)、5.16(s、2H)、4.75(m、1H)、4.18(m、2H)、3.63(m、2H)、2.81(m、2H)、1.90(m、2H)。

3- (7-Benzyl-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8,9-dihydro-7H-purin-2-yl) -3H-benzo [d] imidazole-5- The compound is synthesized by the method described in Example 38 using carbonitrile benzyl bromide. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.30 (s, 1H), 9.01 (m, 1H), 8.23 (s, 1H), 7.89 (m, 1H), 7.66 (dd, J = 8.1, 1.5 Hz , 1H), 7.40-7.32 (m, 5H), 5.16 (s, 2H), 4.75 (m, 1H), 4.18 (m, 2H), 3.63 (m, 2H), 2.81 (m, 2H), 1.90 ( m, 2H).

３-(9-(6,8-ジフルオロクロマン-4-イル)-7-(3-ヒドロキシプロピル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
3-ヨードプロパノールを用い、実施例40に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.92(s、1H)、8.77(m、1H)、8.38(s、1H)、7.90(d、J＝8.4 Hz、1H)、7.62(dd、J＝8.4、1.5 Hz、1H)、6.83(m、1H)、6.38(m、1H)、5.88(m、1H)、4.67(m、1H)、4.41(m、1H)、4.19(t、J＝6.5 Hz、2H)、3.74(t、J＝5.6 Hz、2H)、2.93(m、1H)、2.40(m、1H)、2.08(m、2H)。

3- (9- (6,8-Difluorochroman-4-yl) -7- (3-hydroxypropyl) -8-oxo-8,9-dihydro-7H-purin-2-yl) -3H-benzo [ d] imidazole-5-carbonitrile
The compound is synthesized by the method described in Example 40 using 3-iodopropanol. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.92 (s, 1H), 8.77 (m, 1H), 8.38 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.5 Hz, 1H), 6.83 (m, 1H), 6.38 (m, 1H), 5.88 (m, 1H), 4.67 (m, 1H), 4.41 (m, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 2.93 (m, 1H), 2.40 (m, 1H), 2.08 (m, 2H).

３-(7-(2-(ジエチルアミノ)エチル)-9-((R)-7-フルオロクロマン-4-イル)-8-オキソ-8,9-ジヒドロ-7H-プリン-2-イル)-3H-ベンゾ[d]イミダゾール-5-カルボニトリル
2-クロロ-N,N-ジエチルエチルアミン塩酸塩を用い、実施例41に記載の方法によって、本化合物を合成する。¹H NMR(300 MHz、CDCl₃)：δ 8.91(s、1H)、8.64(s、1H)、8.28(s、1H)、7.84(d、1H)、7.59(d、1H)、6.8-7.0(m、2H)、6.4-6.6(m、1H)、5.86(br t、1H)、4.5-4.7(m、1H)、4.3-4.4(m、1H)、4.0-4.1(m、2H)、2.8-3.0(m、3H)、2.58(q、4H)、2.3-2.4(m、1H)、0.96(t、6H)。

3- (7- (2- (diethylamino) ethyl) -9-((R) -7-fluorochroman-4-yl) -8-oxo-8,9-dihydro-7H-purin-2-yl)- 3H-Benzo [d] imidazole-5-carbonitrile
This compound is synthesized by the method described in Example 41 using 2-chloro-N, N-diethylethylamine hydrochloride. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.91 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 6.8-7.0 (m, 2H), 6.4-6.6 (m, 1H), 5.86 (br t, 1H), 4.5-4.7 (m, 1H), 4.3-4.4 (m, 1H), 4.0-4.1 (m, 2H), 2.8-3.0 (m, 3H), 2.58 (q, 4H), 2.3-2.4 (m, 1H), 0.96 (t, 6H).

Jak3 kinase assay Human Jak3 cDNA is amplified by PCR. A fragment encoding the catalytic domain (508aa to 1124aa) of Jak3 is ligated with GST at the 5 ′ end. This fused GST-Jak3 DNA fragment is cloned into the EcoRI site of the donor plasmid pFastBac 1 (Life Technologies # 10359-016). Insect cells (Sf9) are transformed, translocated and transfected according to the instructions for use. Cell lysates containing recombinant GST-Jak3 are used for kinase assays. Anti-GST antibody (10 μg / ml, Sigma # G1417) is coated on a 384 well plate and placed at 4 ° C. overnight. A cell lysate containing GST-Jak3 (1: 100 dilution) is added to the anti-GST coating plate, and GST-Jak3 is captured by immobilized anti-GST antibody. Test compound and substrate mixture (50 mM HEPES, pH 7, 0.5 mM Na ₃ VO ₄ , 25 mM MgCl ₂ , 1 mM DTT, 0.005% BSA, 1 μM ATP and 4.5 μg / ml biotinyl poly-Glu, Ala, Tyr) Is added to the plate to initiate the reaction. After incubation for 60 minutes, the reaction was stopped with 4 mM EDTA, using homogeneous time-resolved fluorescence (HTRF) technology, 17 μg / ml Cy5-streptavidin (Amersham, # PA92005) and 2.7 μg / ml europium-conjugated anti-phosphotyrosine antibody (PerkinElmer # AD0069) is used to detect phosphorylation of biotinyl poly-Glu, Ala, Tyr.

Jak3 Cell Assay The mouse F7 pre-B lymphocyte cell line is used for the cell Jak3 assay. Human IL-2Rβc cDNA is stably expressed in F7 cells (Kawahara et al., 1995). F7 cells are maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum + IL-3. For cell proliferation assay, cells in serum free medium (30,000 cells / well) are seeded in 96 well plates. Test compound is added to the cells, followed by IL-2 (final concentration 20 ng / ml). After 24 hours of incubation, the number of viable cells is determined by CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, # G7573) according to the instructions.

Test results of typical chemical species are shown below. The compounds in Table 1 exhibited an IC ₅₀ of 100 nM or less. The compounds in Table 2 exhibited an IC ₅₀ between 101 nM and 1 μM.

Test results of typical chemical species are shown below. The compounds in Table 1 exhibited an IC ₅₀ of 100 nM or less. The compounds in Table 2 exhibited an IC ₅₀ between 101 nM and 1 μM.

IL-2 induced IFN-γ purification in mice Due to cytokine NK secretion, IL-2 administration causes an increase in serum IFN-γ in mice (Thornton S, Kuhn KA, Finkelman FD and Hirsch R., “NK cells”). secrete high levels of IFN-γ in response to in vivo administration of IL-2 ”, Eur J Immunol 2001 31: 3355-3360). Experiments are performed essentially according to the procedure of Thornton et al. And test compounds are administered to determine the level of inhibition achieved. In summary, female BALB / c mice are fasted for 12-18 hours before the experiment, but always have free access to water. Test compounds are administered by gavage 1 hour prior to intraperitoneal injection of IL-2 and capture antibody. At the end of the experiment, mice are sacrificed by carbon dioxide inhalation, and terminal blood samples are collected by cardiac puncture to produce serum. Serum is stored frozen until assayed for IFN-γ as described in the kit manufacturer's instructions (BD Pharmingen ™, San Diego, CA).

  Using the above method, the compounds of Examples 16, 28 and Examples 501, 504 and 505 in Table 1 inhibited IL-2 induced IFN-γ production> 40% in in vivo mice at 30 mg / kg. To be revealed. Reference compound CP690550 exhibits 96% inhibition at 30 mg / kg in this screen.

  7-substituted prinones show increased sensitivity to Jak3 compared to 7-unsubstituted homologues.

  Aurora A kinase assay is performed using a fluorescence polarization format. Fluorescein-labeled FAM PKAtide (Molecular Devices) 100 nM solution, Aurora A substrate (Upstate Biotechnology) together with Aurora A (80 ng / ml) and 30 mM ATP at room temperature in the presence of appropriate concentrations of test inhibitors Incubate for hours. Add IMAP Progressive Binding reagent mixture according to the instructions (Molecular Devices) to complete the reaction. Is used to detect the polarization signal using Aquest (Molecular Devices).

Some comparative examples are shown below. On the left is the ratio of Jak3 to Aurora A inhibition, expressed as 7-unsubstituted compound and “x-fold” selectivity. The right side shows the 7-substituted homologues and their selectivity. All IC ₅₀ for Jak3 is 100 nM or less.

  Although the foregoing invention has been described in some detail for purposes of illustration, it will be readily apparent to those skilled in the art that changes and modifications can be made without departing from the scope of the invention described herein. I will.

Claims (44)

Formula III:

III
[Where:
Q ₁ and Q ₂ are independently selected from CX ₁ , CX ₂ and nitrogen (where Q ₁ and Q ₂ are not both hydrogen);
Q ₃ is N or CH;
X ₁ and X ₂ are independently hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halo, halo (C ₁ -C ₆ ) alkyl, hydroxyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) selected from alkoxy and nitro;
R ₁ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl;
y is 0 or an integer selected from 1, 2 and 3;
R ₂ and R ₃ are independently selected from hydrogen and (C ₁ -C ₆ ) alkyl for each occurrence of (CR ₂ R ₃ );
R ₄ is selected from alkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl; and
R ₅ is independently selected from alkyl, heterocyclyl, substituted heterocyclyl and C ₁ -C ₆ alkyl (wherein
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from
A compound represented by formula:

The compound of Claim 1 shown by these. formula:

The compound of Claim 2 shown by these. formula:

The compound of Claim 2 shown by these. formula:

The compound of Claim 1 shown by these. formula:

The compound of Claim 5 shown by these. formula:

The compound of Claim 5 shown by these. formula:

The compound of Claim 1 shown by these. formula:

The compound of Claim 8 shown by these. formula:

The compound of Claim 8 shown by these. Independently X ₁ and X ₂ is hydrogen, cyano, chloro, fluoro, methyl, A compound according to any one of claims 1-10 selected from trifluoromethyl and trifluoromethoxy. The compound according to any one of claims 1 to 10, wherein R ₁ is H. The compound according to any one of claims 1 to 10, wherein y is 1 or 2, and R ₂ and R ₃ are hydrogen or methyl. The compound according to claim 13, wherein R ₄ is selected from phenyl, quinoline, pyridine, pyrazine and substituted products thereof.   The compound according to any one of claims 1 to 10, wherein y is 0. R ₄ is cyclopentyl, cyclohexyl, phenyl, indane, tetralin, piperidine, oxepane, benzoxepane dihydrocyclopentapyridine, tetrahydropyran, tetrahydrofuran, tetrahydroindole, isoquinoline, tetrahydroisoquinoline, quinoline, tetrahydroquinoline, chroman, pyridine, pyrimidine, dihydropyran , Dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, furan, dihydropyrano [2,3-b] pyridine, tetrahydroquinoxaline, tetrahydrothiopyran (thian), thiochroman (dihydrobenzothiin) and substituted products thereof The described compound. (a) y is 0 and R ₄ is cyclohexyl, tetralin, indane, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano [2,3-b] pyridine And tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo or halogen; or
(b) y is 1 or 2, R ₂ and R ₃ are hydrogen or methyl, R ₄ is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen The compound in any one of. y is 0 and R ₄ is chroman-4-yl; 3,4-dihydronaphthalen-1 (2H) -on-4-yl; 2,3-dihydroinden-1-one-4-yl and its fluoro The compound according to claim 17, which is selected from substituents. The compound according to claim 18, wherein R ₄ is chroman-4-yl, and the carbon at the 4-position of chroman is in the (R) configuration. y is 0 and R ₄ is

In which W is CH ₂ , C═O or O; p is 1, 2 or 3; A is a 6-membered heteroaromatic ring containing 1 or 2 nitrogens or 1 or 2 A benzene ring optionally substituted with fluorine; and the wavy line is the point of attachment to prinone]
The compound according to claim 17, wherein Formula where the carbon marked with an asterisk is in the (R) configuration:

The compound of Claim 20 shown by these. y is 1, R ₄ is difluorophenyl, fluorophenyl, chlorophenyl, chlorofluorophenyl, compound of claim 17 selected from pyridin-3-yl and pyrazin-3-yl. y is 0, 4 R ₄ is tetrahydropyran-yl, 4-hydroxycyclohexyl, compound of claim 17 selected from 4-oxo cyclohexyl and oxepan-4-yl. Independently X ₁ and X ₂ is hydrogen, cyano, selected from chloro and fluoro A compound according to claim 10 R ₁ is H. (a) y is 0 and R ₄ is cyclohexyl, tetralin, indane, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano [2,3-b] pyridine And tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo or halogen; or
25. The method of claim 24, wherein (b) y is 1 or 2, R ₂ and R ₃ are hydrogen or methyl, R ₄ is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen. Compound. R ₅ is C ₁ -C ₆ alkyl [where:
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from
26. A compound according to claim 25. y is 0 and R ₄ is

[Wherein the carbon marked with an asterisk is in the (R) configuration, W is CH ₂ , C═O or O; p is 1, 2 or 3; A is 1 or 2 A 6-membered heteroaromatic ring containing 1 nitrogen or a benzene ring optionally substituted with 1 or 2 fluorines; and the wavy line is the point of attachment to the prinone]
27. A compound according to claim 26. X ₁ is hydrogen, a substituent X ₂ is at the 6-position of the benzimidazole compound according to claim 27, X ₂ is selected from hydrogen, fluoro and cyano. The compound according to any one of claims 1 to 10, wherein R ₅ is C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl. y is 0 and R ₄ is

[Wherein the carbon marked with an asterisk is in the (R) configuration, W is CH ₂ , C═O or O; p is 1, 2 or 3; A is 1 or 2 A 6-membered heteroaromatic ring containing 1 nitrogen or a benzene ring optionally substituted with 1 or 2 fluorines; and the wavy line is the point of attachment to the prinone]
30. The compound of claim 29. R ₅ is C ₁ -C ₆ alkyl, wherein 0 to 3 hydrogens are hydroxy, carboxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxy The compound according to any one of claims 1 to 10, which is substituted with a substituent selected from amino, sulfonylamino, acylamino, arylamino and lower alkoxy. y is 0 and R ₄ is

[Wherein the carbon marked with an asterisk is in the (R) configuration, W is CH ₂ , C═O or O; p is 1, 2 or 3; A is 1 or 2 A 6-membered heteroaromatic ring containing 1 nitrogen or a benzene ring optionally substituted with 1 or 2 fluorines; and the wavy line is the point of attachment to the prinone]
32. The compound of claim 31 which is   34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claims 1-32. Therapeutically effective amount of formula III:

III
[Where:
Q ₁ and Q ₂ are independently selected from CX ₁ , CX ₂ and nitrogen (where Q ₁ and Q ₂ are not both hydrogen);
Q ₃ is N or CH;
X ₁ and X ₂ are independently hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halo, halo (C ₁ -C ₆ ) alkyl, hydroxyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) selected from alkoxy and nitro;
R ₁ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl;
y is 0 or an integer selected from 1, 2 and 3;
R ₂ and R ₃ are independently selected from hydrogen and (C ₁ -C ₆ ) alkyl for each occurrence of (CR ₂ R ₃ );
R ₄ is selected from alkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl; and
R ₅ is independently selected from alkyl, heterocyclyl, substituted heterocyclyl and C ₁ -C ₆ alkyl (wherein
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from
A method of treating a disorder dependent on the inhibition of Janus kinase 3, comprising administering to a patient in need of treatment a compound according to Therapeutically effective amount of formula III:

III
[Where:
Q ₁ and Q ₂ are independently selected from CX ₁ , CX ₂ and nitrogen (where Q ₁ and Q ₂ are not both hydrogen);
Q ₃ is N or CH;
X ₁ and X ₂ are independently selected from hydrogen, cyano, chloro and fluoro;
R ₁ is hydrogen;
y is 0 or an integer selected from 1, 2 and 3;
R ₂ and R ₃ are independently selected from hydrogen and (C ₁ -C ₆ ) alkyl for each occurrence of (CR ₂ R ₃ );
R ₄ is selected from alkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl; and
R ₅ is independently selected from alkyl, heterocyclyl, substituted heterocyclyl and C ₁ -C ₆ alkyl (wherein
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from
A method for the treatment of a disorder dependent on the inhibition of Janus kinase 3, comprising administering to a patient in need of treatment a compound represented by   36. The method of claim 34 or 35, wherein the disorder is selected from autoimmune diseases, inflammatory diseases, mast cell mediated diseases, hematological malignancies and organ transplant rejection.   40. The method of claim 36, wherein the disorder is bone marrow transplant rejection.   37. The method of claim 36, wherein the hematological malignancy is selected from leukemia and lymphoma.   40. The method of claim 36, wherein the disorder is asthma.   The method according to claim 36, wherein the autoimmune disease is selected from organ-specific and non-organ-specific autoimmune diseases.   37. The method of claim 36, wherein the disorder is dry keratoconjunctivitis.   The method according to claim 36, wherein the hematological malignancy is chronic myeloid leukemia.   36. The method of claim 34 or 35, wherein the disorder is selected from cutaneous T-cell lymphoma and leukemia type of acute lymphoblastic leukemia. Therapeutically effective amount of formula III:

III
[Where:
Q ₁ and Q ₂ are independently selected from CX ₁ , CX ₂ and nitrogen (where Q ₁ and Q ₂ are not both hydrogen);
Q ₃ is N or CH;
X ₁ and X ₂ are independently hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halo, halo (C ₁ -C ₆ ) alkyl, hydroxyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) selected from alkoxy and nitro;
R ₁ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl;
y is 0 or an integer selected from 1, 2 and 3;
R ₂ and R ₃ are independently selected from hydrogen and (C ₁ -C ₆ ) alkyl for each occurrence of (CR ₂ R ₃ );
R ₄ is selected from alkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl; and
R ₅ is independently selected from alkyl, heterocyclyl, substituted heterocyclyl and C ₁ -C ₆ alkyl (wherein
(a) 1 or 2 CH ₂ is substituted with a group selected from NH and N (alkyl);
(b) 1 or 2 CH ₂ or is substituted with O;
(c) 1 or 2 CH ₂ are replaced by (C═O);
(d) two CH ₂ are replaced by CH═CH or C≡C; or
(e) a chemically stable combination of any of (a), (b), (c) and (d);
Where 0 to 3 hydrogens are
(a) halogen, hydroxy, cyano, lower alkylsulfonyl, lower alkylsulfonyloxy, amino, lower alkylamino, di-lower alkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, lower alkoxy;
(b) heterocyclyl and heterocyclyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
(c) phenyl and phenyl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and
(d) heteroaryl and heteroaryl substituted with 1 to 3 substituents selected from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;
Substituted with a substituent selected from
A method for treating a disorder selected from autoimmune diseases, inflammatory diseases, mast cell mediated diseases, hematological malignancies and organ transplant rejection, comprising administering a compound according to the compound represented by the above to a patient in need of treatment: .