TW201121970A - New fused pyrimidine derivatives - Google Patents

Abstract

The invention relates to a medicament for preventing and/or treating autoimmune disease, immunodeficiency or neurodegenerative disease, especially sepsis, comprising a new fused pyrimidine derivative.

Description

201121970 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a condensation biting derivative which can be used as a medicine. In more detail, it is related to the effective prevention and/or treatment of the condensation of the disease transmitted through the terminal receptor a〇ii_iikei*eeep_’TLR (IV). Specifically, it is a self-immune-related disease (sepsis, inflammation, allergy, asthma, graft rejection, graft versus host disease, infectious disease, cancer), New Zealand or God, degenerative disease (Az A condensed mouth bite derivative of a preventive and/or therapeutic drug for Haimo® and Parkinson's disease. [Prior Art] Stimulation of the immune system in vivo can bring a protective physiological response to the host or a harmful physiological response thereto. In recent years, the mechanisms for such natural immunity (innate immunity) have received increasing attention. In particular, recently discovered TLRs have reported that they are involved in natural immunity and are receptors for identifying pathogenic microorganisms. TLR is a highly preserved pattern recognition receptor (pattern)

φ recognition receptors) and received attention. To date, human TLRs have identified 10 species, named TLR1 to TLR10. Individual TLRs can identify the cell wall components of pathogenic microorganisms or pathogen-associated molecular patterns (PAMPs), which induce DNA immune responses in the host (Nature Reviews Immunology, 2001, 1, 135-145). For example, TLR2 transmits signals such as peptidoglycan and yeast zymosan, which are components of microbial cell wall. TLR4 transmits the signal of lipopolysaccharide (LPS), which is a component of the cell wall of Gram-negative bacteria, from the host cell to the cell (Nature 3 322543 201121970

Immunology, 2001, 2, 675-680). In addition, it has been reported that the TLR9 expressed by the endosome in the host cell recognizes the MA or CpGDNA of the pathogenic microorganism and is particularly noticed (Nature, 2000, 408, 740-745 or Proceedings of the National Academy of Sciences). , 2001, 98, 9237-9242). Therefore, the agent and/or composition for effectively controlling the natural immunity through the TLR can be an autoimmune-related disease (sepsis, inflammation, allergy, asthma, graft rejection, graft versus host disease, infection) as shown below. , cancer, immunodeficiency or neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.) preventive drugs and / or therapeutic drugs. "Self-immune disease" is a disease in which antibodies or lymphocytes that react with components that constitute self-organization continue to proliferate in the body and cause tissue damage. They can be broadly classified into the following categories: (1) Organ-specific autoimmune Disease; (2) organ non-specific self-immune disease (systemic autoimmune disease).

(1) Organ-specific autoimmune diseases: Hashimoto (s thyroiditis), primary myxedema, thyrotoxicosis, pernicious anemia, ancient bus deer syndrome (Good-pasture's syndrome), rapid progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid , Tengdaosu resistant diabetes, juvenile diabetes, type I diabetes (Typel 4 322543 201121970 diabetes), Addison, s disease, atrophic gastritis, male infertility, Early onset menopause, rheology-induced uveitis, multiple sclerosis, ulcerative colitis, primary biliary cirrhosis, chronic active hepatitis Active hepatitis), autoimmune blood disease (eg autoimmune hemolytic deprivation) (autoiujjjjune hemolytic anemia), idiopathic thrombocytopenia, etc., paroxysmal nodules (par0XySmai hemoglobinuria), primary biiiary cirrhosis, green/bally syndrome ( Guiiiain-Barre syndrome), Basedow, s disease, idiopathic thrombocytopenic purpura, intersstitial lung fibrosis, and chronic discoid lupus erythematosus (chronic discoid lupus erythematosus) ° (2) organ non-specific autoimmune disease (systemic autoimmune disease): rheumatoid arthritis, systemic lupus erythematosus, Hugh's syndrome (Sjogren's syndrome), polyneuritis, cutaneous inflammatory disease, systemic sclerosis, polyarteritis nodosa, allergic granulomatous vasculitis, sc 1 eroderma And mixed connective tissue disease (mi xed connective-tissue dis Ease) ° 322543 5 201121970 On the other hand, 'sepsis is defined as systemic Inflammatory Response Syndrome (SIRSKChest, 1992, 101, 1644-1655). The cause of the disease is thought to be an excessive production of inflammatory mediators induced by pathogenic microorganisms and their toxins, which are related to the incidence of septic shock, the accompanying organ failure, and It is related to the induction of anti-inflammatory mediators.

In recent years, agents for inhibiting inflammatory mediators such as nitric oxide (No) or cytokines have been developed in the above-mentioned context, and their effectiveness has been confirmed in the animal stage, and inflammatory mediators have been administered to patients with severe sepsis. Clinical trials of targeted drug therapies. However, so far, the effect of filling the knife / σ treatment has not been obtained, and only the inflammatory media that form a complex network structure can be suppressed. "The - part of the substance" cannot be expected to have a high effect.

Medical Bulletin, 1999, 55, 212-225) The inflammatory mediators and anti-inflammatory mediators of the sputum immune response, the severe disease of sepsis, septic shock, and sputum The onset of the disease, caused by two infections. Therefore, control: two = tr, _ this = and = two: P preparation can be expected to be caused by pathogenic microorganisms = = selective _ 彳. Ingredients, τ ^ should be combined with inhibitors, 龃ΤΤΡ 4 J can also be used in combination with TLR2 (10) or with TLR2 inhibitors and sputum, which can be expected as the fundamental treatment of new sepsis 322543 6 201121970 treatment. It is also expected to achieve further effects on sepsis-related diseases by combining the existing sepsis treatments such as existing antibacterial agents and blood coagulants. The gasified quinine (a) developed as an antimalarial drug can also be used for the treatment of various autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.) and can also be used as an anti-inflammatory drug. It has recently been reported that the mechanism of action of quinacrine (b) for this self-immune disease chlorinated quinine and its analogues is due to the antagonism of TLR9 (European Journal of

Immunology, 2004, 34, 2541-2550).

Other than this, although there has been a recent disclosure of a TLR9 inhibitor, it is different from the structure of the compound of the present invention (Patent Document 1). Further, the compound having the TLR7, TLR and TLR antagonism has revealed the following representative compound (c)', but it is different from the compound of the present invention (Patent Document 2).

Patent Document 1: International Publication No. 2000/076982 7 322543 201121970 Patent Document 2: International Publication No. 2008/030455 SUMMARY OF INVENTION Technical Problem The object of the present invention is to prevent and/or treat an autoimmune disease, specifically To provide an autoimmune-related disease (inflammation, allergies, asthma, graft rejection, graft versus host disease, infection, cancer), 'free

Epidemic = pre-treatment and/or therapeutic drugs for whole or neurodegenerative diseases (Alzheimer's, Parkinson's, etc.). In addition, the present invention provides an effective pharmaceutical product in terms of 4 syndromes and/or treatments for finding the possible (4) flaws. In order to solve the problem, it has been found that the following formula (1) shows a potent TLR inhibitory action, and it is a useful medicine for the treatment of severe sepsis, and the present invention has been completed. The root time r "/ provides a condensation money derivative represented by the following formula (1) (hereinafter, the temple is referred to as a compound of the present invention). In other words, the invention is as follows.趟之趟,1] A compound represented by the following formula (1) or a pharmaceutically acceptable substance thereof Α1 Ν^〇[ΑΙΚ1)η1 A2Wli)n2 (丨) [wherein, A1 and A2 represent the following formula (1) or (8) , · 322543 8 201121970 R3 ~-N~Alk3-~X-.Qi (A) (B) 〇2—Aik4—Y-Ar. When tAl is of formula (4), A2 represents equation (8); when ^ is equation (8), A2 represents the formula (1);

R1 and substituted 4 to 1G shell nitrogen-containing saturated heterocyclic ring, or -fresh; = are independent of each other, and the substituted Gh. a 4- to 10-membered saturated heterocyclic group which is substituted with 4 alkyl groups or may be substituted; a bond or a ?8 alkyl group which may be substituted by a wire;

Represents a single bond CO-, -nr6c〇-, -c〇2-, -coco-, -c〇NR6-, a 0C_6_, ~NR6C〇2',, 6(10)R7-, -(CRWo- or -NR6_; - this Where 'Q1 is a replaceable 4 to 1 () nitrogen-containing saturated heterocyclic ring (the carbon atom forming a ring in the soil is bonded to the ruthenium), and the fool 3 is a single bond or can pass through the Cl-3 Substituted methylene cyclin, X represents a single bond, -C0-, -NR6C0- or -coco-;, Q1 is a 4 to 10 member nitrogen-containing saturated heterocyclic ring which can be substituted (the ring forms a ring) When the nitrogen atom is bonded to the X bond or the state ^^, and Alk3 is a C2-8 extendable group which can be substituted by C! 3 alkyl, X represents a single bond, _c〇_, _C〇2_, _c〇C〇 -, -C0NR6- or -(cr6r7)2〇-; when Q1 is a 4 to 1 member nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to X) or -NyR2, And when Alk3 is a single bond or a fluorenylene group which may be substituted by a Cl-3 group, X represents -C0- or -COCO-; R3 represents a hydrogen atom, a C1M which may be substituted, an alkyl group or a substituted c3- 8 9 322543 201121970 裱alkyl, which may also form a substituted 4 to 1 employee saturated heterocyclic ring with the carbon atom of r1 or Alk3i; * ^ indicates 4 to 1 member of the nitrogen-containing saturated heterocyclic ring, or -NR4R5; R and R are each independently, which represents a hydrogen atom, a substituted 匕!. alkyl group, a substituted C3-8 cycloalkyl group or a substituted 4 to 10 membered saturated heterocyclic ring; Aik represents a single bond or a stretched alkyl group which may be substituted with a Ci 3 alkyl group;

Ar is an unsubstituted aryl group or a substituted heteroaryl group; Y represents a single bond, -CO-, _NR8C0-, -C〇2-, -COCO-, -C0NR8-, -〇C〇 NR8-, -NR8C〇2-, -NR8C0NR9-, -NR8-, -C0(CR8R9)0-, -NR8S〇2-, -s〇2nr8- or -s-; Here, when Q2 is replaceable 4 to 1 member of a nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to Aik4) or -NR4R5, Aik4 is a Gw alkyl group which may be substituted by a Ci_3 alkyl group, and Ar (the Ar represents Pyrrole, imidazole 'pyrazole, triazole, hydrazine, oxazole, benzimidazole, porphyrin, tetrahydroquinoline, 3,4-di-argon-211-benzo[1)][1,4]噚When cultivating or 111-吼 并 [2,3-13> than φ biting) the nitrogen atom on the ring is bonded to Y, Y represents a single bond -C0-, -nr8co-, -coco- or -NR8S〇2- When Q is a 4 to 10 member nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to Aik4) or -NR4R5, Aik4 is a single bond or a substitutable Cm-substituted When the carbon atom on the Ar ring is bonded to γ, γ represents a single bond, -C0-, -C〇2-, -COCO-, -C0NR8-, -C0(CR8R9)0_ or -S〇2NR8- ; when Q2 is 4 to 10 members that can be replaced Saturated heterocyclic nitrogen (nitrogen form a ring system with the atom bonded to the ring Aik4) or -NR4R5, Aik4 is a single bond or may be 322 543 10 201 121 970

Substituted by a Ci-3 alkyl group, and ^ (the αγ represents 吼洛, 嗤, 0 sits on the previous 0, ° 引α木, 丨〇 丨〇 sit, 苯〇米〇 sit, bow Dylin, tetrahydrogenin, 3' 4-dihydro-2Η-benzo[b][l,4] 噚 or lH-n 咯[2, 3-b> pyridine) When an atom is bonded to a γ bond, γ represents _c〇 or _c〇c〇_ ; Z represents a single bond, -0-, -S(0)m2- or -N(Rlfl)_;

Aik1 and Aik2 are each independently, and represent Cm which may be substituted by halogen, hydroxyl, carboxyl, and substituted. An alkyl group (here, when two of the alkyl groups are substituted with an anthracene φ group, two of the alkyl groups may also be bonded to each other to form a ring), a substituted Cm alkoxy group, a substituted ο-ring An alkyl group, a substituted aryl group, a substituted heteroaryl group, _C_11R12, a substituted & calcined carbonyl group, and a substituted Cu calcined oxycarbonyl group in the same or different groups 1 to 2 substituent-substituted methylene; or carbonyl; in and in are each independently 'indicate an integer from 〇 to 2; η and η are each independently' denotes an integer from 1 to 3; R10 represents an argon atom, Substituted Cl, an alkyl group, a substituted c3 8 fluorene group, a substituted aryl group 匕 ( 1 (alkyl), a substituted 4 to 1 member saturated heterocyclic group, may be substituted An aryl group, a substituted heteroaryl group, a substituted C!-5 alkylcarbonyl group, a substituted C5 alkoxycarbonyl group, _c〇nr13rU or -S〇2R13; 〆1^, 1^7, The inverse 8, 1^, 1^, 1^, ]^ and 1^ are each independently represent a hydrogen atom or a substituted Chg alkyl group]. [Item 2] The compound of Item 1, or a pharmaceutically acceptable salt thereof, wherein: C^ which may be substituted. An alkyl group, a substituted alkoxy group, a substituted Cm alkylcarbonyl group, a substituted Ci-alkoxycarbonyl group, and a substituted group 322543 11 201121970 grouped below aryl-Cl-oxime. The alkyl moiety of each group in the refining group may be substituted with one or five substituents selected from the same or different ones: (1) a tooth atom, (2) a hydroxyl group, (3) a cyano group, and (4) a carboxyl group. (5) C3-8 cycloalkyl substituted by hydrazine,

(6) aryl substituted aryl, (7) substituted heteroaryl, (8) 〇5 alkoxy, (9) substituted Cw cycloalkoxy, (10) Cl-5 Oxygen group, (11)-NR15R16, (12)-C0NR15R16, and (13) a 4 to 1 member saturated heterocyclic ring which may be substituted (here, a group represented by the above (6) and (7), Substituents which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: (a) a meridine, (b) a halogen, (c) may be substituted with from 1 to 5 fluorine atoms Cl_1()alkyl, (d) Cl_5 alkoxy which may be substituted with 1 to 5 fluorine atoms, (e) chaotic, (decyl carboxyl group, (g)~NR15R16. 12 322543 201121970 (h)-C0NR15R16, and (nc^ alkane carbonyl; the same or different 1 to (a) hydroxyl group, (b) halogen, (c) 1 to 5 fluorine in the group shown by (5), (9) and (13) Atomic replacement

The base may not be substituted by a group of five substituents selected from the group consisting of C1-1. a pyridyl group, a Cl-5 alkoxy group, (d) (h)-CONR15R16) substituted with 1 to 5 fluorine atoms; (a), (b), 1 to 5 substituents And a saturated heterocyclic group means a group which may be substituted by the same or different substituents selected from the group consisting of (c), (d) and (h); exocyclic group - heteroaryl group, aryl group, heteroaryl group And the aryl group U-based soil 4 is not substituted by the same or different one to five substituents selected from the group consisting of the above (4) to (1); R15 and R16 are each independently represent a hydrogen atom, a hospital group substituted by 5 fluorodimers of the summer solstice or a 4 to 1 (s) saturated heterocyclic ring which may be substituted: when R15 and R16 are bonded to the same nitrogen atom, they may also form a 4 to 1 employee. Saturated heterocycle. [Item 3] The compound of Item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the Q form is not the same or different from the group selected from the group consisting of halogen, hydroxy, -C0NR15Ru&Cb6 alkyl i to 3 substituents substituted by 4 to 1 member of the nitrogen-containing saturated heterocyclic ring HR2; R1 and R2 are each independently, representing hydrogen 13 322543 201121970 'Atom, which may be grouped by fluorine atom, via group and -CONR15R16 C3-8 substituted by the same or different 1 to 3 substituents in the group, C3-8 which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and a hydroxyl group a cycloalkyl group, or a 4 to 7 membered saturated heterocyclic ring which may be substituted with a C 6 alkyl group; Aik3 represents a single bond or a C1-6 stretching group; X represents a single bond, _C0_, -NR6C0- or; R3 represents a hydrogen atom Or a Cw alkyl group which may be substituted with the same or different one to three substituents selected from the group consisting of a fluorine atom and a hydroxyl group; φ q2 represents a group selected from a hydroxyl group, a fluorine atom, a Ch alkyl group, and C0NR15R16 The same or different 1 to 3 substituents in the group are substituted with 4 to 10 members of a gas-saturated heterocyclic ring, or -NR4R5; R4 and R5 are each independently, and represent a hydrogen atom, which may be selected from a Cl_6 alkyl or cycloalkyl group substituted with the same or different 1 to 3 substituents in the group of Ci-5, NR15R16 and -C0NR15R16, or may be passed through G-6 a 4- to 7-membered saturated heterocyclic ring substituted with an alkyl group;

Aik4 represents a single bond or a Ci-3 alkyl group which may be substituted by a C 2 alkyl group; ring γ represents a single bond, -0---NR8C0---C0NR8---NR8C0NR9-, -NR8-, -CO(CR8R9) 〇—or —SO2NR8-;

Ar represents the same or different in a group selected from the group consisting of dentate, Cl-6, which may be substituted with 1 to 3 fluorine atoms, and Cl_5, which may be substituted with 1 to 3 fluorine atoms. 1 to 3 substituents substituted by a phenyl group, or may be selected from a Ci-e alkyl group which may be substituted by 1 to 3 fluorine atoms and a Ci-s alkoxy group which may be substituted by 1 to 3 fluorine atoms a heteroaryl group containing 1 to 2 nitrogen atoms substituted by the same or different 1 to 3 substituents in a group; 14 322543 201121970 Z represents a single bond, -ο-, -s- or -N ( R1(>)-;

Aik1 and Aik2 are each independently, and represent 1 to 2 Ch alkyl groups (the G-6 alkyl group may be substituted by the same or different 1 to 2 substituents selected from the group consisting of a hydroxyl group and a Cm alkoxy group). Substituted) substituted fluorenylene, or carbonyl; m1 represents 0 or 1; η1 and η2 are each independently, meaning 1 or 2; R10 represents a hydrogen atom, which may be grouped by a fluorine atom and a Cl_5 alkoxy group. Cm substituted by the same or different 1 to 3 substituents. An alkyl group which may be substituted with the same or different 1 to 3 substituents in the group of Ci-e alkyl groups which may be substituted by 1 to 3 fluorine atoms - Ci- a 6- to 10-membered saturated heterocyclic ring which may be substituted with 1 to 3 Ci-6 alkyl groups, may be grouped by a Cl-6 alkyl group selected from halogen and substituted by 1 to 3 fluorine atoms. An aryl group substituted with the same or different 1 to 3 substituents, which may be the same or different in the group of Ci_3 alkyl groups substituted by halogen and < 1 to 3 fluorine atoms a heterocyclic group substituted to three substituents, a Ci-3 alkylcarbonyl group which may be substituted with the same or different one to three substituents selected from the group consisting of φ fluorine atom and —NR11Rl2; —conr13r14 or — S〇2R13; V, R8, R9, R", R12, R13, R14, R15 and R16 are each independently represent a nitrogen atom or a C1-6 alkyl group. [Claim 4] The compound according to any one of items 1 to 3, wherein the Aik1 and Aik2 are each independently an anthracene group or a singular. The compound of any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein x represents a single bond, -C0- or -(CRWo-, Alk3 table = single bond or Cw stretch group. The compound of any one of the items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein γ is a single bond, _〇-,-----(3)-CO(CR8Rg)〇~. The compound of any one of items 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Z represents a single bond or -N(R, -. ^), the compound of any one of items 1 to 7 or A pharmaceutically acceptable salt, wherein R1° represents a hydrogen atom, which may be substituted with 1 to 3 fluorine atoms, may be substituted with a Cl_6 group which may be substituted with 1 to 3 fluorine atoms. The same or different 1 to 3 substituent-substituted aromatic clays of 6 6 groups, 4 to 10 membered saturated moles, which may be substituted by 1 to 3 G-6 alkyl groups, may be selected from An aryl group substituted with the same or different 1 to 3 substituents in a group of 1 to 3 fluorine-substituted Cl-6 groups, or may be red selected from the group consisting of 1 to 3 fluorine atoms substituted by g-6 alkyl groups in the same or different groups The compound of any one of items 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Z represents _〇_. [Item 10] The compound of any one of the above items, or a pharmaceutically acceptable salt thereof, wherein + R3 represents a hydrogen atom or a Cw alkyl group which may be substituted with a hexyl group. [Item u] A compound or a pharmaceutically acceptable salt thereof, wherein A1 is a compound of the formula (A), A, or (8), or a pharmaceutically acceptable salt thereof. The compound of any one of the items 1 to 5, or the pharmaceutically acceptable salt thereof, wherein the Q2 represents -NR4r5, wherein the compound is a compound of the formula (8). The compound according to any one of 1 to 12, wherein the q2 is the same or different from the group selected from the group consisting of a trans group, a gas atom, a & 6 alkyl group and a C0NRR The compound of any one of items 1 to 14 or a pharmaceutically acceptable salt thereof, wherein both Alkl and Aik2 are sub-substituted. Methyl. [Item 16] as items 1 to 15 A compound according to any one of them, or a pharmaceutically acceptable salt thereof, wherein Ar is a C, 6-yard group which may be substituted with 1 to 3 fluorine atoms, and may be substituted by 3 gas atoms a compound which is substituted by the same or a different one or three substituents in the group of alkoxy groups, or a pharmaceutically acceptable compound thereof. a salt in which red is the same or different in the group of C, _5 alkoxy groups which may be substituted with 1 to 3 fluorine atoms selected from the group which can be substituted by a gas atom! The heteroaryl group of the atom substituted to three substituents. The compound of any one of items 1 to κ, or a pharmaceutically acceptable salt thereof, wherein Q 丨 represents - qing. ^Sub-item [item 19] such as item 1 to work T5 tm # ^ Y a member of the compound or its pharmacy 4 orphan 'its" means that it can be replaced by the same or different ones selected from the middle, The base is substituted with 4 to 10 shells of a nitrogen-containing saturated heterocyclic ring. [20] A pharmaceutical composition, which contains items! A compound according to the formula or a pharmaceutically acceptable salt thereof. And a pharmaceutically acceptable salt of the compound of any one of items 1 to 19, or a pharmaceutically acceptable salt thereof, as a therapeutic agent and/or a prophylactic agent for a disease related to a Toll-Like receptor-related disease. Active ingredients. [Claim 22] The therapeutic and/or prophylactic agent according to Item 21, wherein the steroid-related disease is sepsis, an autoimmune disease or a neurodegenerative disease. [Claim 23] The therapeutic and/or prophylactic agent according to Item 21, wherein the steroid-related disease is cancer. EFFECT OF THE INVENTION The compound of the present invention can be used for the prevention and/or treatment of an autoimmune disease, in particular, as an autoimmune-related disease (inflammation, allergy, asthma, graft rejection, graft versus host disease, infection, cancer) , preventive and/or therapeutic drugs for immunodeficiency or neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.). Further, the present invention has been found to be an effective pharmaceutical for the prevention and/or treatment of sepsis, particularly in the prevention and/or treatment of severe sepsis, since it has been found to selectively inhibit TLR inhibitors of TLR. In addition, since the present invention finds a TLR inhibitor which can selectively inhibit TLR, it is expected to have an effect of inhibiting cancer proliferation and/or an effect of inducing cancer cell death, and can also be effective as an effective prevention and/or treatment for cancer. Pharmaceutical products. [Embodiment] Hereinafter, the present invention will be described in further detail. In the following description, the compound represented by the formula (I) is referred to as the compound (I). Other compounds of the formula number are also referred to in the same manner. Further, the number of the substituents in the "substituted" group in the present specification is not particularly limited as long as it can be substituted unless otherwise specified, and is 1 or 2 18 322543 201121970 or more. The group not specifically described in the description in the present specification means an unsubstituted group. Unless otherwise stated, the description of each group is also consistent with the fact that the group is part of another group or a substituent. The compound of the present invention may also exist in the form of a hydrate and/or a solvate. Therefore, the hydrazine hydrate and/or solvate is also included in the compound of the present invention. The compound (I) may have one or more than one asymmetric carbon atom in some cases and sometimes undergoes geometric isomerism or palmarity, so that several stereoisomers sometimes exist. In the present invention, the stereoisomers, the mixtures, and the racemates are included in the compound (丨) of the present invention. Further, a ruthenium converter in which one or two or more of the compounds (I) are converted into H (D) is also contained in the compound (I) of the present invention. (i) the known alkyl group, which is a straight-chain or branched-type saturated hydrocarbon group. For example, the so-called "Ch-yard" or "Cl_10 yard-based" means that the number of carbon atoms is j to 6 or 1 to 1 respectively. Substituent. Specific examples of the "匕6 alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a third butyl group, a pentyl group, an isopentyl group, and the like. The "Cho alkyl group" such as a neopentyl group, a third amyl group, a hexyl group or an isohexyl group may, for example, be a heptyl group, an octyl group, an isooctyl group, a decyl group or a fluorenyl group. Among them, a "^ base" is preferable. ▲ (11) The term "ring-burning group" means a cyclic saturated hydrocarbon group. For example, the so-called "C" cycloalkyl group" S means a 3- to 8-membered cyclic saturated hydrocarbon. Illustrative: cyclopropyl, cyclobutyl, cyclofilament , cyclohexyl, cycloheptyl, coco and the like. Preferably, a 5- to 7-member cycloalkyl group is mentioned. (in) The "aryl group" includes a monocyclic ring of 6 to 14 members, and a 2 ring 322543 19 201121970-type, 3-ring aryl group. Specific examples thereof include a phenyl group and a naphthyl group. Preferably, a monocyclic ring having a carbon number of 6 or "anthracene, an aryl group, or an aryl group is mentioned, and examples thereof include a phenyl group and a phenyl group or a 2-naphthyl group. 2. The so-called "stretching aryl group" means the above. The divalent group of "aryl" is preferably a group as exemplified above. Further, the term "heteroaryl" as used in the case of "iv" is exemplified by a group selected from a group consisting of a nitrogen atom, an oxygen group and a sulfur atom, and a group of 5 to 4? The monocyclic Μ(tetra)yl group of the cyclamate, the 2-ring aromatic heterocyclic group of 9 to 11 Å or the 3-ring aromatic heterocyclic group of 12 to 15 members. Specifically, it may be exemplified by: (4) a base, a thiol group, a benzyl group, a phenanthrene group, a 2-position oxybenzoyl group, a benzotrisene group, a benzofluorenyl group, a ketone group, a fluorenyl group, Benzene (tetra), benzo-2-yl, benzodiyl, (tetra)yl 1 silk, iso (tetra)yl, sulfonium, heterogeneous base" Taixian, ρ Naiji, turn county, scaleline, quinoxaline The group, the α-octyl group, the pyridinium is a salivary group, the ms • group can be derived from the earth, the K group, the porphinyl group, the group, and the like. Preferably, the 5-ring or 6-membered monocyclic aromatic cyclic heterocyclic group of the bovine, specifically "= bei: 1 〇 2 of the sulphate, oxime, t, and hetero. , 味 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Other bonds at the time of base bonding (v) The so-called "dentin" means fluoro and "takes: various atoms of chlorine, bromine or iodine. 322543 20 201121970 Preferably, various atoms of fluorine, chlorine or bromine are mentioned. (vi) The term "alkoxy" means a group having a linear or branched saturated hydrocarbon group bonded through an oxygen atom, for example, a so-called rCl_s alkoxy group means an alkane having 1 to 5 carbon atoms. Oxygen. Specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, a pentyloxy group, and an isopenic group. An oxy group, a neopentyloxy group, a third pentyloxy group or the like. Among them, "Cl_3 alkoxy group" is preferable. (vii) "Alkylcarbonyl" means a group in which a linear group or a branched alkyl group is directly bonded to a carbonyl group. For example, the so-called "Cl_5 calcination group" means an alkylcarbonyl group having a total of 1 to 5 carbon atoms. . Specific examples thereof include an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group, an isobutyl fluorenyl group, a pentamidine group, an isopentenyl group, a trimethylethyl fluorenyl group, a pentylcarbonyl group, an isopentylcarbonyl group, a neopentylcarbonyl group and the like. Preferably, "0-4 alkylcarbonyl group" is mentioned. (viii) "Alkoxycarbonyl" means a group in which a linear or branched alkoxy group is directly bonded to a carbonyl group, for example, a so-called "Cl_5 alkoxycarbonyl group" has a degree of 1 to An alkoxy group of 5 alkoxy groups. Specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a second butoxycarbonyl group, a third butoxycarbonyl group, a pentyloxycarbonyl group, and an isopenic group. An oxycarbonyl group, a neopentyloxycarbonyl group, a third pentyloxycarbonyl group or the like. More preferably, "Cl-3 alkoxycarbonyl group" is mentioned. (ix) The "4 to 10 member saturated heterocyclic ring" means a ring of 4 to 1 G atoms other than a carbon atom and further containing a group selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom to 3 hetero atoms. A single ring or a 2-ring saturated ring. Specific examples include aziridine, pyrrolidinyl, piperidinyl, morpholinyl, 322543 21 201121970 high thiol, (tetra), high D thiophene, tetrahydro π fil, tetrahydro cucurbit π south A group, a tetrahydrothiophenyl group, a tetrahydrothiopiperidyl group, a pendant oxytetrahydrothiopiperidyl group, a di-oxytetrahydrothiopiperidyl group, and the like. It is preferably a 4- to 7-membered saturated heterocyclic ring. Specifically, nitrogen butyl is mentioned. A pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a ketone group, a (tetra) group, a tetrahydro group, and a tetrahydro(tetra) group. The "4 to 10 member nitrogen-containing saturated heterocyclic ring" means a saturated ring composed of 4 to 1 G atoms other than a carbon atom and having 1 to 2 nitrogen atoms (here, the saturated ring)

One of the carbs is Kejin (10) oxidant or (10) substituting). It is preferably a 4- to 7-membered nitrogen-containing saturated heterocyclic ring. (X) "alkylene group" means a linear divalent hydrocarbon group (the group may also form a cyclic hydrocarbon chain), for example, "% 4 stretched wire" or "Ci8 stretched base" means a carbon atom The number is a hydrocarbon chain of 12 to 3 or 1 to 8. Specific examples of the alkylene group include a methylene group, an ethyl group, a propyl group, and a butyl group. The "Ch wire" may be, for example, a stretched wire or a stretched base. Among them, "Cl_4 alkylene group" is preferable. _Can be replaced by G, silk, "can be substituted & oxy", can be taken through the base", "G 5 silk can be hoofed" and: take green silk" The filament fractions of the respective groups are selected from the same or different U 5 substituents in the following group: 322543 22 1 tooth atom, 2 channel group, 3 carboxyl group, 4 cyano group, 201121970 (5) Substituted C3-8 cycloalkyl, (6) substituted aryl, (7) substituted heteroaryl, (8) C!-5 alkoxy, (9) substituted C3 -8 cycloalkoxy, (10) 〇5 alkoxycarbonyl, (11) -NR15R16, (12) -CONR15R16, and (13) a 4 to 10 membered saturated heterocyclic ring which may be substituted; The groups represented by (6) and (7) represent a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: (a) a hydroxyl group, (b) a halogen, (c) Ci-i substituted by 1 to 5 fluorine atoms, (d) Ci-5 alkoxy group substituted by 1 to 5 fluorine atoms, ^(e)cyano group, .(f)carboxyl group (g) -NR15R16 ' (h) -C0NR15R16, and (nc^oxycarbonyl); (5), (9) and (13), which may be selected from Substituents of the same or different 1 to 5 substituents in the next group: (a) hydroxy, (b) halogen, 23 322543 201121970 (c) Ch which may be substituted with 1 to 5 fluorine atoms. An alkyl group, (d) a Ch alkoxy group which may be substituted with 1 to 5 fluorine atoms, (h)-C0NR15R16); wherein (1), (2), (8), (11), (12) are preferred. Or a substituent of (13), more preferably a fluorine atom, (2) or no substitution (8). The substituents of the "substitutable C3-8 cycloalkyl group" and the "substitutable 4 to 10 member (nitrogen-containing) saturated heterocyclic ring" may be selected from the above (a), (b), and (c). , (d) and (h) the same or different 1 to 5 substituents in the group. Preferred among them are (a), (b), (c) or (h), and more preferably (a), a gas atom or (c). "Substitutable aryl group", "Substitutable heteroaryl group", "Substitutable aryl group", "Substitutable heteroaryl group" and "Substitutable aryl group-Ci- The substituent of the aryl group of the ioalkyl group may be the same or different one to five substituents selected from the group consisting of the above (a) to (i). Among them, preferred are the substituents of (a) to (e), and more preferably a fluorine atom, (c) or (d). φ The pharmaceutically acceptable salt of the compound (I) may, for example, be a mineral acid salt such as a hydrochloride, a hydrobromide, a nitrate, a sulfate or a phosphate; a benzenesulfonate, a benzoate, or a screw Acid addition of an acid salt such as citrate, fumarate, gluconate, lactate, maleate, malate, oxalate, sulfonate or tartrate Salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salts and calcium salts; metal salts such as aluminum salts and zinc salts; ammonium salts such as ammonium and tetra-ammonium; morpholine addition salts and piperidine addition salts; An organic amine addition salt such as a salt; or an amino acid addition salt such as a glycine acid addition salt, a phenylalanine addition salt, an lysine addition salt, an aspartic acid addition salt or a glutamic acid addition salt; . 24 322543 201121970 Among the compounds of the present invention represented by the formula (I), A1, A2, X to Z,

The preferred groups or numbers of each of Qi, Q2, Ar, AlV to Aik4 and Ri to R16, and mi, m2, η1 and n2 are as follows, but the present invention is not limited to the following Compound. A compound wherein A1 is a formula (A) and A2 is a formula (I) of the formula (B) is preferred. Z preferably exemplifies a single bond, -0-, -S- or -NCR10)-, more preferably a single bond, -0- or -N(R1())-, and most preferably -N(R1 ())-. Preferably, Aik1 and Aik2 may be the same or different from 1 to 2 Ci-6 alkyl groups (the 0-6 alkyl group may be selected from the group consisting of a hydroxyl group and a 0-5 alkyl oxy group). Substituted to a substituted group of two substituents, or a carbonyl group. More preferably, an anthracene group or a carbonyl group is mentioned, and a methylene group is preferable. R10 is preferably a hydrogen atom, a C?g alkyl group which may be substituted by the same or a different one to three substituents selected from the group consisting of a fluorine atom and a fluoren-5 alkoxy group, and may be selected from Halogen and aryl φ-G-6 alkyl which may be substituted by 1 to 3 fluorine atoms (1-6 substituents in the group of ^-6 alkyl groups), may be subjected to 1 a 4 to 10 membered saturated heterocyclic ring substituted with 3 Ch alkyl groups, which may be the same or different in the group selected from the group consisting of ii and substituted with 1 to 3 fluorine atoms 1 to 3 substituent-substituted aryl groups, or 1 to 3 substituents which may be the same or different in a group selected from a halogen and a G-3 alkyl group which may be substituted by 1 to 3 fluorine atoms The heteroaryl group is substituted. More preferably, it may be a hydrogen atom, a G-! alkyl group, an aryl-Cw alkyl group, a saturated heterocyclic ring, an aryl group or a heteroaryl group. Particularly preferred are a hydrogen atom and an aryl-G- group. The aryl group or the aryl group is preferably an aryl-Ch alkyl group. η1 and η2 are preferably 1 or 2. 25 322543 201121970 When Q1 is -nFr2, R1 R2 is preferably a hydrogen atom. The same or different in the group selected from the group consisting of a fluorine atom, a hydroxyl group, and -c〇Nr15ri6 a cycloalkyl group substituted with three substituent-substituted Ci_e alkyl groups, which may be substituted with the same or different J to three substituents selected from the group consisting of a fluorine atom and a hydroxyl group: or may be substituted by a Ch alkyl group a 4- to 7-membered saturated heterocyclic ring. More preferably a calamine hydrogen atom, a g 6 alkyl group which may be substituted by a base group, a Gy cycloalkyl group which may be substituted by a base group, or a 5 i 6 member which may be substituted by an α3 alkyl group. a saturated heterocyclic ring, particularly preferably a fluorenyl fluorenyl group, a G3_8 cycloalkyl group or a 5 to 6 M saturated heterocyclic ring. Preferably, a hydrogen atom or a Cle alkyl group is used. The base and the propyl group are preferred. When Q is a 4 to 10 member nitrogen-containing saturated heterocyclic ring, preferred examples of the ring include the ring of the following structure.

26 322543 201121970 [wherein R represents a substituent of a substituted saturated heterocyclic ring (a), (b), (c), (d) or (h) ' R18 represents (c), (d) , (h) or a hydrogen atom, R represents an integer from 0 to 5. Preferably, q^a, q%, id, q, 屮一f, ql_g, q -h, q -i, q -j, q丨-k, q丨-1, qLm, q1-! !, q1-. , q丨_p, q, and Q1-1, more preferably enumerated q, qi_c, qi_d, qi_e, ql_f, ☆g, Vh, q'-i, q1-』·, qi_k, qI_m, q! _n, ql 〇 and Q1-q.

Aik1 and Aik2 are preferably each independently, and may exemplify one or two alkyl groups which may be the same or different (here, when two alkyl groups are substituted with a methylene group, two alkyl groups may also be bonded to each other) The knot forms a ring) substituting a subunit. Preferably, a single bond and a Ci-6 stretched wire are used, and a single bond and a c2-6 stretch wire are more preferable, and a C2 5 stretched wire is particularly preferable, and an alkyl group is preferable. Preferably, X is a single bond, _C〇_, _ 〇 _ and _ (CR6R7) ml 〇-, more preferably a single bond, -c 〇 - and - ((10) Vo-, preferably one single bond and - C0-, wherein x represents "_" of each substituent, χ on the left side is linked to Alk, and on the right side of X is the name of "_" and Ql. R3 is preferably a hydrogen atom or a group t The same or different from the three substituent groups to form a better base or may be taken from 1 to 3 fluorine atoms to obtain a dibasic group, preferably a hydrogen material, or a Gi e sulphide. In addition, R3 may also It is preferable to form a carbon atom together with R1 or Aik3, a star-substituted 4 to 1 member saturated heterocyclic ring, and one of them may be exemplified by the following structure: 322543 27 201121970

R3-f r3-g r3-h r3-i r3^

R3-p r3-q r3-r r3-s r3-t ΛΛΛ/ ^y(R19)p

R3-k r3-l r3-m r3-n r3-o

R3-u [wherein R19 represents the above (a), (b), (c), (d) or (h) of the substituent of the substituted saturated heterocyclic ring, and R2Q represents (c), (d) , (h) or a hydrogen atom, p represents an integer from 0 to 5. Preferred examples thereof include r3-a, r3-b, r3-c, r3-d, r3-e, r3-f, r3-g, r3-h, r3-i, r3-k, r3-n, and r3. -s, more preferably r3-a, r3-c, r3-e, r3-f, r3-h, r3-k and r3-s. When Q2 is -NR4R5, R4 and R5 are preferably a hydrogen atom, which may be selected from 28 322543 201121970 from the group of fluorine atoms, hydroxyl groups, Cl_5 alkoxy groups, _NR"R16 and _C0NR15R16. a 1 to 3 substituent-substituted Ch alkyl group or a c3-8 decyl group, or a 4 to 7 membered saturated heterocyclic ring which may be substituted by a Cl_e alkyl group. More preferably, a ruthenium atom and an axis-substitutable Gi channel may be cited. a C3-8 ring filament substituted with a fluorenyl group or a C3-8 ring filament which may be substituted by a Ci 3 alkyl group, and a hydrogen atom, C, a cycline, a k cycloalkane, etc. The base, the ethyl group or the propyl group is preferably a ring of the following structure when the methyl group is a 4 to 10 shell nitrogen-containing saturated heterocyclic ring.

322543 29 201121970 [wherein R21 represents the above-mentioned (a), (b), (c), (d) or (h) of the substituent of the substituted saturated heterocyclic ring, and R22 represents (c), (d) , (h) or a hydrogen atom, o represents an integer from 0 to 5. Among them, preferred are q2-a, q2-c, q2-d, q2-f, q2-g, q2-i, q2-j, q2_k, q2-l, q2-m, q2-n, q2-〇 And q2-p or, more preferably, q2-a, q2-c, q2-d, q2-f, q2-g, q2-i, q2-j, q2-k or q2-n.

Aik4 is preferably a single bond, a methylene group, an ethylidene group or a propyl group.

Ar preferably exemplified by the same group selected from the group consisting of a halogen, a Ci-e alkyl group which may be substituted by 1 to 3 fluorine atoms, and a Ci-5 methoxy group which may be substituted by 1 to 3 fluorine atoms. Or a heterophenyl substituted with 1 to 3 substituents, or a C alkyl group selected from a C alkyl group which may be substituted with 1 to 3 fluorine atoms and a Cm alkoxy group which may be substituted with 1 to 3 fluorine atoms The same or different j to 3 substituents in the group are substituted with a heteroaryl group containing fluorene to 2 nitrogen atoms. More preferably, it may be a phenyl group which may be substituted by the same or different one to three substituents selected from the group consisting of halogen, Cl_e alkyl and Ci 5 alkoxy group, or may be selected from C! The same or different in the group of the aryl group and the Cl_5 oxime group, the group substituted 丨 to 2 nitrogen atoms 3 == heteroaryl group, the base group and the _ group can be exemplified below = * ^ The bonding of the substituted positions is preferred. 322543 30 201121970

Ar-a ar-b ar-c ar*d ar-e ar-f

丨〆(R^ ar-n ar-o ar-p ar-q ar-r (R23), ar-m

Ar-s ar-t ar-u ar-v ar-w ar-x

Ar-y ar~z ar-aa ar-ab ar-ac

Ar-af ar-ag ar-ah

Ar-ak

Ar-al

Ar>am

[wherein, R23 represents the above (a) to (i) of the substituent of the heteroaryl group which may be substituted, and q represents an integer of 0 to 4]. Among them, ar-b, ar-c, ar-d, ar-e, ar-i, ar-n, ar-o 'ar-y 'ar-z 'ar-aa 'ar-ab' ar are preferred. -ac 'ar-ad 'ar-ae ' 31 322543 201121970 ar-af, ar-ai, ar_al, ar-(10), nge (four). . Y is preferably a single bond, +, wisdom (3)...c_8... The "-" indicates that it is bonded to Ar, and the "_" on the right side of γ indicates the connection with the coffee-H (the tender H-face 8_. More preferably Keys, such as -N^ and side 8♦ cans 8r9)q_, can be listed as a single key or as the most, can be ♦ single button. Here, γ represents "_" of each substituent, and Y on the left side of Y is preferably 〇 or 1 „ m2 is preferably 0 or 2. More preferably, 〇

R6, R7, R8, R9, R11, R12, π, Rl4, Rl5 and R16 are preferably a hydrogen atom or a c1-6 alkyl group. More preferably, it is a hydrogen atom or a Ci 4 alkyl group. In addition, in order to simplify the description in this specification, the following abbreviations are sometimes used. P- : para—, t- : tert_, s_ : sec_, THF: tetrahydrofuran, DME: ethylene glycol dimethyl ether, MF: N,N-dimethyl decylamine, DMA. Amine, NMP: N-methyl π piroxicam, dce: 1 2-diethylene bromide, DMS0: dimethyl sulfoxide, CDCI3: deuterated chloroform, DMS〇_d6 : dimethylated Yashifeng, 〇Ms: 醯 醯 醯, 〇 Ts : 曱 醯 醯 、 、, OTf: trifluoromethyl methoxy, S: single J | r (singlej:), d: double peak (dUblet t: triplet, m: multiplet, Boc: third butoxycarbonyl, BINAT (registered trademark): 2,2'-bis(diphenylphosphino, dinaphthyl, DPE-Phos (registered trademark): bis(2-diphenylphosphinophenyl)ether, 八八町-?^1〇5 (registered trademark): 9,9-dimethyl-4,5-bis(diphenylphosphino) Astragalus, S-Phos (registered trademark): 2-dicyclohexylphosphino-2,6,-dimethoxy-1,1'-binaphthyl, X-Phos (registered trademark): 2- Cyclohexylphosphino-2',4',6'-triisopropylbiphthalene. 32 322543 201121970 The process for the production of the compound (I) of the present invention is as follows. Compound (la), (lb), Ic), (Id) , (Ie), (If), (Ig), Uh), (Ii), (Ij), (Ik), (II), (Im), (In), and (I) are included in the compound (I) a compound in ). The compound (I) can be produced by the method shown in the following Production Methods 1 to 11 or the method following the same. The compound in the reaction formula contains a case where a salt is formed. The salt is, for example, the same as the salt of the compound (I). Production Method 1 : Among the compounds (I), A1 is a compound of the formula (A), A2 is a compound of the formula (B) (Ia), and A1 is a compound of the formula (B), and A2 is a compound (lb) of the formula (A). It can be produced by the manufacturing method shown below.

Ο H2N NH2 [Step 1] 0 HN 〇人

Alk1)n1 'AJk2)n2 (III)

Hal [Step 2]

R3,. Ik3 N Η (V) alkali [Step 3]

Q2, W<〇Rl>) 2 (VII)

(la) Supply and reaction [Step 4]

(lb) Y, z, Ar, η1 and substituted alkyl, (wherein Q1, Q2, R3, Alk) to Alk4, χ, η2 are synonymous with the above. Ra and Rb represent a hydrogen atom or may be represented by Hal Chlorine or bromine atom). 322543 33 201121970 [Step 1] The compound (II) is used in the solvent in the presence of 2 to 10 equivalents (preferably 3 to 5 equivalents) of a base and 1 to 20 equivalents (preferably 2 to 10 equivalents). The urea is reacted, whereby the compound (III) can be obtained. The compound (II) can be produced by a commercially available product or by a known method [for example, Journal of American

Chemical Society, 5779 (1958), Journal of Medicinal Chemistry, 40, 2474-2482 (1997), Journal of Organic Chemistry, 60, 1665-1673 (1995), W02004/26864, EP1552842] or synthesized according to the method thereof. The solvent used in the reaction may be any one which is inert to the reaction, and is not particularly limited. It can be used alone, for example, THF, 1,4-dioxane, DME, stupid, toluene, dioxane, DMF, DMA, surface P. Methanol, ethanol, propanol, L propanol, etc., or the like, wherein methanol or ethanol is preferred.

And (4) (4), for example, various tests such as A-, B-, and T-butanol, or alkaline earth metal-sintered oxides, among which sodium methoxide or ethanol is preferred. The temperature of the reaction is from 50 to 100 ° C' from room temperature to the boiling point of the solvent used, usually for 1 to 60 hours. [Step 2] It is preferred to prepare the compound (1) [) obtained in the first step to obtain the compound OV with an excessive amount (preferably 3 to 丨. equivalent). (4) The agent enters the 仃 reaction. = Solvents such as oxygenated scales, phosphorus pentoxide, and oxygen desertification can be used as long as they are inert to the reaction, and there is no special use such as DCE, Cao, 1,4-HDME, 322543 34 201121970 Trichloromethane, benzene, toluene, xylene, ethyl acetate, triethylamine, pyridyl, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylamine Etc., or use them in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent or the toothing agent, preferably from 50 to 140 ° C, usually for from 1 to 24 hours. [Step 3] The compound (iv) obtained in the step 2 is used in a solvent in the presence of 1 to 5 equivalents (preferably 1.5 to 2 equivalents) of a base and 1 to 5 equivalents (preferably • 丨. The compound (VI-a) and/or (VI-b) can be obtained by reacting 2 to 3 equivalents of the compound (V). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, hydrazine, 4-dioxane, anthracene, alum, benzene, xylene, DMF, DMA, NMP, methanol, Ethanol, propanol, 2-propanol, or the like, or a mixture thereof, wherein hydrazine, 4-dioxane, p- or 2-propanol is preferred. • Alkali salts such as sodium carbonate, potassium carbonate, carbonic acid planer, and sodium acetate; inorganic bases such as sodium hydroxide and potassium hydroxide; pyridine, dipyridamole 4 aromatic amines, diethylamine, etc. Dipropylamine, tributylamine, cyclohexyldiamine, 4-monoamidopyridine, N,N-diisopropylethylamine, n,n-didecylphenylamine, n-methylpyramine, N-fluorenyl Also mouth. A tertiary amine such as N-fluorenyl phenazine; an alkali metal hydride such as sodium nitride or potassium hydride; and among them, triethylamine or dipyridylethylamine is preferred. The reaction temperature is from room temperature to the point of use of the solvent, preferably from 5 to 18 (TC 'usually carried out for 5 to 24 hours. 322543 35 201121970 [Step 4] The compound obtained in the step 3 ( Vi-a) or the compound (yj-b) in a solvent and in an amount of 1 to 10 equivalents (preferably 2 to 4 equivalents), and 〇. 〇i to 1 equivalent (preferably 0.05 to 〇· 2 equivalents of palladium catalyst, 〇. 5 to 〇. 2 equivalents of the phosphine ligand in the presence (or absence) and 1 to 5 equivalents (preferably 1.1 to 2 equivalents) of the compound ( VH) The reaction is carried out, whereby the compound (la) or the compound (lb) can be obtained. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1, 4 - Diterpenoid, DME, benzene, methyl, monograph, DMF, water, or a combination thereof, wherein DME and water or a mixed solvent of 1,4-dioxane and water are preferred. As the palladium catalyst, for example, tetravalent (triphenylphosphine) palladium, bis(t-butylphosphine) palladium, tris(dibenzylideneacetone) dipalladium or the like, or bis(triphenylphosphine) II may be used. chlorine A divalent catalyst such as palladium, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, wherein tetrakis(triphenylphosphine)palladium or palladium acetate is preferred. The φ base may, for example, be sodium carbonate or potassium carbonate. Alkaline salts such as carbonic acid planer and sodium acetate, or inorganic tests such as bismuth oxide, hydrogen peroxide, and hydrazine, among which sodium hydride, carbonic acid or sodium hydroxide is preferred. For the base time, a single-site coordination type phosphine such as triphenylphosphine, triphenylphosphine, triterpenoid 11 phosphine, dibutylphosphonium, S-Phos, X-Phos, or BINAP, 2,2-di (Diphenylphosphinyl χ γ _ binaphthyl, DpE_ph〇s, XANT-Phos and other two coordination phosphines, of which s_ph〇s is preferred. The reaction temperature is from room temperature to the boiling point of the solvent used, Preferably, it is carried out under heating of 5 Torr to 180 ° C or under microwave irradiation, usually for 5 to 24 hours. 322543 36 201121970 Production Method 2: Among the compounds (I), A* is a formula (A), A^ (8), 4 and ¥ are a single bond UNW or a compound containing a nitrogen-containing saturated heterocyclic ring bonded by a nitrogen atom ((6), which can be produced by the compound (VI_a) by the following production method .

x-Q, R\.., Alk3 N<^y(AI, k1)n1 Hal, ArB(0Ra)2 (VIII) Hal^N^AIk2)n2 (Vl-a) Supply Reaction [Step 5]

Coupling reaction [Step 6] q2-h (χ) X u R3, ... person Ik3

(wherein Q1, Q2, R3, Aik1 to Aik3, X, Z, Ar, ni and n2 are synonymous with the above. Ra represents a hydrogen atom or a substituted alkyl group, and a hydrogen atom or a bromine atom is shown in the table) . [Step 5] The compound (vi-a) obtained in the step 3 is subjected to a test in a solvent to § (preferably 2 to 4 equivalents), and 1 to 1 equivalent (preferably 0.05 to 〇. 2 equivalents) in the presence of palladium catalyst! The compound (IX) can be obtained by reacting with 5 equivalents (preferably 1.1 to 2 equivalents) of the compound (μ). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, L4-dioxane, DME, benzene, methyl 322543 37 201121970 benzene, dimethyl strepene, DMF, water, etc. Or, these may be used in combination, and it is preferable to use a mixed solvent of DME and water or 1,4-diaster and water. The palladium catalyst may be, for example, tetrakis(triphenylphosphine)palladium, bis(t-butylphosphine), bis(dibenzylideneacetone) or the like, or bis(triphenylphosphine) II. A divalent catalyst such as palladium vapor, palladium acetate or bis(diphenylphosphinoferrocene) di-palladium oxide, wherein tetrakis(triphenylphosphine)palladium is preferred. The test may, for example, be an inorganic salt such as sodium carbonate, carbonic acid, barium carbonate or sodium acetate, which is preferably replaced by sodium carbonate or carbonic acid. The reaction temperature is from room temperature to the boiling point of the solvent used, preferably from 50 to 180 ° C under heating or under microwave irradiation, usually for 5 to 24 hours. [Step 6] The compound (jx) obtained in the step 5 is used in a solvent in an amount of 1 to 10 equivalents (preferably 3 to 5 equivalents) of a base, and 〇. 〇1 to 1 equivalent (preferably 〇· 05 to 〇. 2 equivalents of the phosphine ligand, and 〇. 1 to 1 equivalent (preferably 0. 05 to 0.2 equivalent) in the presence of a palladium catalyst and 1 to 5 equivalents (better than φ The compound (Ic) can be obtained by reacting 1 to 2 equivalents of the compound (X). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, or the like, or may be used in combination. Further, it is preferably toluene or hydrazine, 4- to 1%. As the phosphine ligand, a single-site coordination type phosphine such as triphenylphosphine, triphenylphosphine, trifuranphosphine or tri-tert-phosphine can be used, or BINAP, 2, 2,-bis (diphenylphosphinyl). Γ-binaphthyl, DPE-Phos, XANT-Phos, etc. 2 coordination type 38 322543 201121970 phosphine, which is better by binap. Palladium catalyst can be used, for example, tetrakis(triphenylphosphine) palladium, double (third a valent catalyst such as phosphine palladium or tris(dibenzylideneacetone) dipalladium, or bis(triphenylphosphine) palladium dichloride, palladium acetate, bis(diphenylphosphinoferrocene)palladium dichloride Such as a divalent catalyst, wherein palladium or palladium acetate is preferably used as tris(dibenzylideneacetone). For example, carbonate salts, potassium carbonate, carbonic acid planer, sodium acetate and the like can be used; sodium methoxide, A variety of alkali or alkaline earth metal alkoxides such as sodium ethoxide or potassium t-butoxide, among which carbonic acid planing or potassium t-butoxide is preferred. The reaction temperature is preferably from room temperature to the boiling point of the solvent used. 5至24小时。 In addition, A1 is a formula (B), A2 is a compound of formula (A) can also be used for heating at a temperature between 50 and 180 ° C or under microwave irradiation. The compound (VI-b) obtained in the step 3 is obtained by the same production method. Production method 3: Among the compounds (I), A1 is a formula (A), A2 is a formula (B), and Y is -0-, -C〇2---C0NR8---NR8---C0(CR8R9)0- or -S〇2NR8- compound φ (Id), which can be produced by the compound (VI-a) by the following manufacturing method Got it.

Alk1)n1 (XI) supply reaction [Step 7]

Mitochondrial reaction, alkylation or deuteration (Vl-a) (XII) [Step 8] 201121970 (where Q1, Q2, R3, Aik1, Aik2, Aik3, Aik4, X, Y, Z, Ar, n1 and n2 It is synonymous with the above. R' represents a hydrogen atom or a substitutable alkyl group, and L- represents a chlorine atom, a desert atom or an argon atom. [Step 7] The compound (VI-a) obtained in the step 3 is tested in a solvent in an amount of from 1 to 10 equivalents (preferably from 2 to 4 equivalents), and from 0.01 to 1 equivalent (preferably 0.05). The compound (XI) is obtained by reacting with 1 to 5 equivalents (preferably 1.1 to 2 equivalents) of the compound (XI) in the presence of 0.22 equivalent of a palladium catalyst. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, DMF, water, or the like, or These are used in combination, and it is preferred to use a mixed solvent of DME and water or 1,4-dioxane and water. As the palladium catalyst, for example, a tetravalent catalyst such as tetrakis(triphenylphosphine)palladium, bis(t-butylphosphine)palladium or tris(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine) φ can be used. A divalent catalyst such as palladium dichloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, of which tetrakis(triphenylphosphine)palladium is preferred. The base may, for example, be a basic salt such as sodium carbonate, potassium carbonate, carbonic acid planer or sodium acetate, and among them, sodium carbonate or potassium carbonate is preferred. 5至24小时。 The reaction temperature is from 0. 5 to 24 hours. [Step 8] The compound (XII) obtained in the step 7 (when L is a hydroxyl group) is dissolved in 40 322543 201121970 and 1 to 10 equivalents (preferably 1 to 3 equivalents) of phosphine, and 1 to 10 equivalents (preferably 1 to 3 equivalents) of an azo compound or a keratin reagent can be obtained by reacting with 1 to 5 equivalents (preferably 1 to 3 equivalents) of the corresponding alcohol derivative. Y is a compound of 〇-〇 (Id). Or the compound (XII) obtained in the step 7 (when L is a hydroxyl group or -NHR8) in a solvent and in the presence of 1 to 10 equivalents (preferably 1 to 3 equivalents) of a base (or in the absence of And reacting with 1 to 5 equivalents (preferably 1 to 3 equivalents) of the corresponding halogen derivative, whereby γ is -〇-, -c〇2_, _c〇NR8_, -NR8-, -C0 (CR8Rg) 0- or -S〇2NR8- compound (id). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, dioxane, DCE, trigas tetrification, stupid, hydrazine. Benzene, xylene, lanthanum, progenitor, NMp, decyl alcohol, ethanol, 1-propanol, 2-propanol, etc., or a mixture of these, in which THF, dioxin, sputum, j) MF Preferably. The phosphine to be used may, for example, be triphenylphosphine, triphosphonium phosphine or tributylphosphine, and among them, triphenylphosphine is preferred. Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, diphenyl decyl azodicarboxylate, and the like. Diethyl dicarboxylate or diisopropyl azodicarboxylate is preferred. As the base, for example, an alkaline salt such as sodium carbonate, potassium carbonate, cesium carbonate or sodium acetate; an aromatic amine such as a bite or H-denier; triethylamine, tripropylamine, butylamine, cyclohexyldiamine, 4 a tertiary amine such as dimethylamine pyridine, N,N-diisopropylethylamine, N'N-dimercaptoaniline, methylpiperidine, N-decylpyrrolidinium or N-hydrazinyl phthalocyanine; Metal hydrides such as sodium hydride, potassium hydride, etc., 41 322543 201121970 Among them, potassium carbonate, carbonic acid planing, pyridine, N,N-diisopropylethylamine or sodium hydride is preferred. The reaction temperature is from room temperature to the boiling point of the solvent to be used, preferably from room temperature to 10 (rc, usually from 5 to 24 hours. Further, a1 is a compound of the formula (B), and A2 is a compound of the formula (A). According to the same production method, the compound (I) wherein A1 is a compound of the formula (A) and A2 is a compound (la) of the formula (B), which can be produced by the production method shown below.

Alk^n10,Afk2)n2 (») NH q2, aii^y, a person (ΧΗΙ) base [Step 9]

Conghua [Step 10]

Hal

(XV)

[]_(NO base [Step 11]

(wherein Q1, Q2, R3, Aik1 to Aik4, X, Y, z, Ar, η1 and η2 are synonymous with the above. Rc represents a substitutable alkyl group, and Hal represents a chlorine atom or a bromine atom). [Step 9] 1 to 10 equivalents (preferably 丨 to 3 equivalents) of the compound (χπι) and the compound (II) in a solvent and 2 to 1 equivalent (preferably 2 to 4 equivalents) of a base The reaction is carried out in the presence of a compound (χιν). The compound (XIII) can be synthesized by a commercially available product or a known method [e.g., Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method therefor. 42 322543 201121970 The solvent used in this reaction can be used as long as it is a reaction, and Yite = limited, I alone used, for example, THF, dioxin, Gu, benzene, toluene, xylene, DMF, DMA, hidden, Methanol, ethanol, propanol, 2-propanol or the like may be used in combination, and methanol or ethanol is preferably used. For the test, various test or soil test metal oxide oxides such as methyl methoxide, sodium ethoxide, and potassium ethoxide may be used, and among them, methanol or ethanol is preferred. The reaction temperature is from room temperature to the boiling point of the solvent used, preferably from π to 100 ° C ', usually from 1 to 60 hours. ® [Step 10] The compound (XIV) obtained in the step 9 is reacted with a halogenating agent in an excess amount (preferably 3 to 10 equivalents) in a solvent (or no solvent), whereby a compound (XV) can be obtained. ). As the halogenating agent, for example, an oxychlorinated dish, a five-gasified dish or an oxygenated scale can be used. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, DCE, THF, 14-dioxane, DME, dichloromethane, benzene, toluene, xylene, and acetic acid. Vinegar, triethylamine, Specific use, such as N, N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylamine, or the like. The reaction temperature is from Ot: to the boiling point of the solvent, preferably from 50 to 140 ° C ', usually from 1 to 24 hours. [Step 11] The compound (xv) obtained in the step 10 is used in a solvent (or no solvent) in the presence of 1 to 10 equivalents (preferably 1 to 3 equivalents) of a base in an amount of from 10 to 10 equivalents. The compound (v) which is preferably 1 to 3 equivalents) is reacted, whereby the compound (la) can be obtained. 43 322543 201121970 The solvent used in this reaction can be used as long as it is inert to the reaction, and the helmet is not limited to 'can be used alone, such as THF, U-di-burn, dirty, benzene: toluene, xylene, DMF, DMA, NMP, methanol. , ethanol, propanol propanol, etc., or the like, which are preferably used. As the base, for example, a salt such as sodium carbonate, potassium carbonate, carbonic acid hammer or sodium acetate; an inorganic base such as sodium hydroxide or potassium hydroxide; an aromatic amine such as pyridine or dipyridylpyridine; and triethylamine, N, N may be used. -diisopropylethylamine, tripropylamine, =

Tertiary amines such as butylamine, cyclohexyldimethylamine, 4-dimethylamine pyridine, N,N-didecylaniline, N-mercaptopiperidine, N-methylpyrrolidine, N-mercaptomorpholine An alkali metal hydride such as sodium hydride or potassium hydride, in which triethylamine or N n diisopropylethylamine is further used. The reaction temperature is preferably from 50 to 1 Torr from room temperature to the point of use of the solvent used. (:, usually carried out for 5 to 24 hours. Further, a compound wherein A is a formula (B) and A2 is a compound of the formula (A) can also be produced by the same production method. . , Production method 5 : Among the compounds (I) 'A1 is a formula (A), A2 is a formula (B), Q2-Alk4-Y-Ar^ Aik4 and Y are single bonds, Q2 is -NR4R5 or a nitrogen-containing saturated heterocyclic ring bonded to Alk4 via a nitrogen atom The compound (Ic) which can be obtained, for example, from the compound (II) by the production method shown below. 322543 44 201121970

Ra〇2Cy(Alk1)n1 〇^AIK2)n2 (ID NH Η3|’Άνη2 _

OH base [Step 12]

Hal* N^Al^n1

Hal halogenation

(XVIII) [Step 13] (XVII) R3, kl〆 Ik3 N Η (V) [Step 14]

X .Q1

Alk1)n1

• Alk2)n2 (XIX) q2~~H (X) coupling reaction [Step 15]

Alk2)n2 (lc) (wherein Q1, Q2, R3, Aik1 to Aik3, X, Z, Ar, n1 and n2 ^ are synonymous with the above, Hal represents a chlorine atom or a bromine atom, and Hal' represents a chlorine atom, bromine An atom or an iodine atom, 1^ represents a hydrogen atom or a substituted alkyl group). [Step 12] 1 to 10 equivalents (preferably 1 to 3 equivalents) of the compound (XVI) and the compound (II) in a solvent and in the presence of 2 to 10 equivalents (preferably 2 to 4 equivalents) of a base The reaction is carried out, whereby the compound (XW) can be obtained. The compound (XVI) can be synthesized by a commercially available product or a known method [e.g., Chemical and Lu Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method therefor. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, DMF, DMA, NMP, hydrazine can be used. Alcohol, ethanol, η-propanol, 2-propanol or the like, or a mixture of these, wherein decyl alcohol or ethanol is preferred. As the base, various alkali or alkaline earth metal alkoxides such as sodium decoxide, sodium ethoxide or potassium t-butoxide can be used, and among them, sodium decoxide or sodium ethoxide is preferable. The reaction temperature is from room temperature to the boiling point of the solvent used, preferably 45 322543 201121970 50 to 100 ° C, usually for 1 to 60 hours. [Step 13] The compound (XW) obtained in the step 12 is reacted with a solvent (or no solvent) in an excess amount (preferably 3 to 10 equivalents) to prepare a compound (XM). . The halogenating agent can be used, for example, by oxychlorination, five gasification or oxybromination. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, 1,2-dioxaethane, THF, 1,4-dioxane, DME, trioxane, or the like can be used alone. Benzene, toluene, diphenylbenzene, ethyl acetate, triethylamine, pyridine, N,N-diisopropylethylamine, hydrazine, hydrazine-dimethylaniline, etc., or these are used in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 50 to 140 ° C, usually from 1 to 24 hours. [Step 14] The compound (XVIII) obtained in the step 13 is used in a solvent (or no solvent) in the presence of 1 to 10 equivalents (preferably 1 to 3 equivalents) of a base in an amount of from 1 to 10 equivalents ( Preferably, 1 to 3 equivalents of the compound (V) are reacted, whereby the compound (XIX) can be obtained. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, diphenyl, DMF, DMA, NMP, A sterol, ethanol, η-propanol, 2-propanol or the like is used, or these are used in combination, and among them, 1,4-dioxane is preferred. For the test, for example, an inorganic salt such as sodium carbonate, carbonic acid oblique, carbonic acid, or sodium acetate; an inorganic base such as sodium hydroxide or potassium argon; an aromatic amine such as pyridine or dipyridin; triethylamine or hydrazine; Ν-diisopropylethylamine, tripropylamine, tris 46 322543 201121970 butanamine, cyclohexyl dimethylamine, 4-dimethylamine pyridine, ν, Ν-dimethylaniline, " piperidine, " Tertiary hydrazines such as pyrrolidine and hydrazine-hydrazinomorpholine; sodium hydride, hydrogenation and other metal hydrides; among them, triethylamine and Νν diisopropylethylamine are preferred. The reaction temperature is from room temperature to the boiling point of the solvent to be used, preferably from 50 to 10 (TC, usually carried out for 5 to 24 hours. [Step 15] The compound (XIX) obtained in the step 14 is in a solvent. And a test of 〇 to 1 (preferably 3 to 5 equivalents), and 1 to 1 equivalent (preferably 0.05 to 0.2 equivalent) of a phosphine ligand, and 〇〇1 to The compound (X) is reacted with 5 equivalents (preferably 1 to 2 equivalents) in the presence of 1 equivalent (preferably 0.05 to 0.2 equivalent) of a palladium catalyst, whereby a compound can be obtained. (Ic) ° The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, methyl bromide, xylene, etc., or These may be used in combination, wherein indene or 1,4-Φ di Df alkane is preferred. The phosphine ligand may be, for example, a triphenylphosphine, a trimethylphosphine, a tridentate unicorn, a second dibutylphosphine, or the like. Coordination phosphine; BI NAP, 2, 2,-bis(xylene squary)-1,1,-binaphthyl, DPE-Phos, XANT-Phos and other two coordination phosphines, of which BINAP Good. Palladium touch For the medium, for example, tetravalent (triphenylphosphine) palladium, bis(t-butylphosphine) palladium, tris(dibenzylideneacetone) dipalladium or the like, or bis(triphenylphosphine) digasification may be used. A divalent catalyst such as palladium, palladium acetate or bis(diphenylphosphinoferrocene) di-palladium dichloride, wherein palladium or palladium acetate is preferably used as tris(dibenzylideneacetone). 322543 47 201121970 For example, sodium chloride, potassium carbonate, carbonic acid, sodium acetate and other mineral salts; sodium decoxide, sodium ethoxide, potassium butoxide, and other alkali or alkaline earth metal alkoxides, among which carbonic acid planing or third 5至24小时。 In addition, the reaction temperature is from room temperature to the boiling point of the solvent used, preferably from 50 to 180 ° C under heating or microwave irradiation, usually carried out 0.5 to 24 hours. B), A2 is a compound of the formula (A) which can also be produced by the same production method. Production method 6: Among the compounds (I), A1 is a formula (A), A2 is a formula (B), and X is a single bond. Q1 is -NR1!?2 or a compound (Ie) in which Aik3 of a nitrogen-containing saturated heterocyclic ring bonded by a nitrogen atom is two or more carbon atoms, which may be, for example, a compound (IV) It is produced by the manufacturing method shown below.

Acid [Step 16] (XXI) [Step 17]

QS^Y, ArB(〇Rb>2 [Step 18] (XXII) (XXIV) rQ1 Rl^^Alk3' N Ν^γ(ΑΙΙ<ι)πΐ (VII) Coupling reaction [Step 19] Q2, Alk4^Y , ArWS)n2 (le) 48 322543 201121970 (wherein Q1, Q2, R3, Aik1, Aik2, Aik4, Y, Z, Ar, η1 and n2 are synonymous with the above. Rc represents a substitutable alkyl group, 鲈And a hydrogen atom or a substitutable alkyl group. Aik3' represents a substituted (^7 alkyl group). [Step 16] The compound (iv) obtained in the step 2 is used in a solvent and is 1 to 5 equivalents. The compound (XXI) can be obtained by reacting with 1 to 5 equivalents (preferably 1.2 to 3 equivalents) of the compound (XX) in the presence of a base (preferably 1.5 to 2 equivalents) of a base. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, 丽 P, Hydroxide, ethanol, propanol, 2-propanol, etc., or a mixture of these, wherein 1,4-dioxane, NMP or 2-propanol is preferred. For example, sodium carbonate or carbonate can be used. , carbonic acid I color, sodium acetate, etc. Salts; inorganic tests such as sodium hydroxide and potassium hydroxide: aromatic amines such as biting, dimethylhydrazine _ bite; triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4~1 a tertiary amine such as methotrexate, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methyl, pyridine, methylpyrrolidine or N-mercaptomorpholine; sodium hydride, An alkali metal hydride such as potassium hydride, wherein triethylamine or N,N-diisopropylethylamine is preferred. The reaction temperature is from room temperature to the point of use of the solvent, preferably from 50 to 180. °C, usually carried out for 0.5 to 24 hours. [Step 17] θ θ The compound (XXI) obtained in Step 16 is used in a solvent and 〇. 1 to 5 (the 乂 乂 is G·1 to 1 equivalent) The acid is reacted, whereby the compound (XXII) can be obtained. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, acetone or methylethyl. a ketone, a diethyl ketone, a cyclohexanone, or the like, or a mixture thereof, wherein acetone is preferred. Examples of the acid include organic compounds such as P-nonylbenzenesulfonic acid, benzenesulfonic acid, and camphorsulfonic acid. Minerals; organic carboxylic acids such as acetic acid and trifluoroacetic acid; mineral acids such as hydrochloric acid and sulfuric acid; lanthanum triflate, indium trifluorosulfonate, etc., among which P-曱Preferably, the reaction temperature is from room temperature to the boiling point of the solvent used, preferably from room temperature to 80 ° C, usually from 0.5 to 24 hours. [Step 18] The compound (XXII) is in a solvent in the presence of 1 to 10 equivalents (preferably 2 to 3 equivalents) of an acid and 1 to 10 equivalents (preferably 2 to 4 equivalents) of a boron hydride compound, and 1 to The compound (XXIV) can be obtained by reacting 10 equivalents (preferably 1.1 to 2 equivalents) of the compound (XXIII). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-diqi B. Alkane, decyl alcohol, ethanol, η-propanol, 2-propanol or the like, or a mixture thereof, wherein 1,2-dioxaethane or methanol is preferred. As the acid, for example, a carboxylic acid such as capric acid, propionic acid, acetic acid or trifluoroacetic acid; a mineral acid such as hydrochloric acid; and acetic acid is preferred. As the boron hydride compound, for example, sodium cyanoborohydride, triethoxyborohydride 50 322543 201121970 sodium hydride, sodium borohydride, and sodium cyanoborohydride or triethoxy hydride can be used. 5至24小时。 The reaction temperature is from room temperature to the boiling point of the solvent, preferably from room temperature to 40 ° C, usually carried out 0.5 to 24 hours. [Step 19] The compound (XXIV) obtained in the step 18 is tested in a solvent in an amount of from 1 to 10 equivalents (preferably from 2 to 4 equivalents), and from 0.01 to 1 equivalent (preferably from 0.05 to 0.2). The compound (I e) can be obtained by reacting 1 to 5 equivalents (more preferably 1.1 to 2 equivalents) of the compound (να) in the presence of a catalyst. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, DMF, water, or the like, or These are used in combination, and it is preferred to use a mixed solvent of DME and water or 1,4-dihydrogen and water. As the palladium catalyst, for example, a tetravalent catalyst such as tetrakis(triphenylphosphine)palladium, bis(t-butylphosphine)-palladium, tris(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine) can be used. A divalent catalyst such as palladium dichloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, of which tetrakis(triphenylphosphine)palladium is preferred. The test may, for example, be an inorganic salt such as sodium carbonate, potassium carbonate, cesium carbonate or sodium acetate, and among them, sodium carbonate or potassium carbonate is preferred. The reaction temperature is usually from 0.5 to 24 hours from the room temperature to the boiling point of the solvent to be used, preferably from 50 to 180 ° C under heating or under microwave irradiation. Further, a compound wherein A1 is a formula (B) and A2 is a formula (A) can also be produced by the same production method. Production Method 7: 51 322543 201121970 Among the compounds (I), A1 is a compound of the formula (A), A2 is a formula (β), Ζ is -N(R1Q)-, and a compound having a wide hydrogen atom (Ig)' and Ri. a compound (Ih) which may be a substituted alkyl group, a substituted cycloalkyl group, a substituted saturated heterocyclic group or a substituted aryl group, which may be -N in the compound (!) The compound (Π) of Pro)- is produced by the production method shown below.

Deprotection [Step 20] 〇 2,

RlK ,, Alk3 N

Aik1)η1 II 'nh reductive amination

Aik4 ^Ar^N^^AI^jn2 [Step 21] dg)

1

(wherein Q1, Q2, R3, Aik1 to Aik4, X, Y, Ar, n1 and η2 are synonymous with the above. Pr〇 represents, for example, the literature (Protective Groups in #0rSanic Synthesis 3rd Edition (John Wiley & Sons,

The general amine protecting group shown by Inc.)), Rll. A cycloalkyl group which may be substituted with a substituted alkyl group, a substituted saturated heterocyclic ring or a substituted aryl group). [Step 20] Deprotecting the protecting group of the compound (If), whereby the compound (Ig) can be obtained, for example, when the protecting group is a benzyl group, in a solvent and at a pressure of 1 to 1 μm (preferably In the presence of a hydrogen atmosphere of 1 to 4 atmospheres, and an amount of 〇. 1 to 1 field (preferably 1 to 3 equivalents) of the acid, using 〇.丨 to 1〇52 322543 201121970 equivalents (preferably The compound (Ig) can be obtained by treating a catalyst such as 0.1 to 1 equivalent of palladium carbon. The compound (If) can be produced in accordance with the production methods 1 to 6. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, THF, 1,4-dioxane, DME, ethyl acetate, decyl alcohol, ethanol, η-propanol, 2 may be used alone. -propanol, water, etc., or a mixture of these, wherein a mixed solvent of decyl alcohol and water is preferred. As the catalyst, for example, a palladium catalyst such as palladium carbon, palladium hydroxide carbon or palladium black; a nickel catalyst such as Reynolds nickel; a platinum catalyst such as platinum oxide, and palladium ® carbon is preferable. As the acid, for example, a carboxylic acid such as acetic acid or trifluoroacetic acid; a mineral acid such as hydrochloric acid; and trifluoroacetic acid or hydrochloric acid is preferred. 5至24小时。 The reaction temperature is from room temperature to the boiling point of the solvent used, preferably from room temperature to 50 ° C, usually 0.5 to 24 hours. [Step 21] The compound (Ig) obtained in the step 20 is used in a solvent in the presence of 1 to 10 equivalents (preferably 2 to 3 equivalents) of an acid and 1 to 10 equivalents (preferably 2 to 4). The compound (Ih) can be obtained by reacting an equivalent of the shed hydrogen compound with 1 to 10 equivalents (preferably 1.1 to 2 equivalents) of the corresponding aldehyde or ketone derivative. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, THF, 1,4-dioxane, DME, dioxane, chloroform, 1,2-dichloro can be used alone. Ethane, decyl alcohol, ethanol, η-propanol, 2-propanol or the like may be used in combination, and among them, 1,2-dichloroethane or decyl alcohol is preferred. As the acid, for example, a carboxylic acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid can be used; 53 322543 201121970 Salt & mineral acid, of which acetic acid is preferred. As the sulphate hydrogen compound, for example, sodium cyanoborohydride, sodium triethyl hydride hydride, sodium hydride, and sodium cyanoborohydride or sodium hexyloxy hydride are preferable. The reaction temperature is from room temperature to the boiling point of the solvent used, preferably from room temperature to 4 (TC, usually carried out for 5 to 24 hours. Further, A is a compound of the formula (B), and a2 is a compound of the formula (A) It can also be obtained by the same manufacturing method. Manufacturing method 8: j is a compound (I), where A1 is a formula (A), A2 is a formula (B), Z is -Ν(ΙΓ)-, and R is a substituted alkyl group, a substituted cycloalkyl group, a substituted compound, a substituted aromatic group or a substituted heteroaryl group, which may be the compound (Ig) by the following The manufacturing method shown is made. Q2· , AIM_ x'Q, RV person k3

(ig)

Alk1)n1 Ha Bu R21. (xxV) .NH---i 'Alk2)n2 Alkali [Step 22] Q2. , Alk4- )TQ1 R3 Person 丨k3 丫, \

Alk1)n1, N-R210 'Alk2)n2 (li), synonymous. Hal represents a chlorine atom, a bromine eyebrow + 4 Chengdun drought p2I〇:::rr group, which can be substituted: = satiety = disubstituted aryl group or a substituted heteroaryl group). The a-equivalent (preferably (1) equivalent) of the product obtained in the step 20 is in the presence of a solvent (in the presence of 1 to 1 〇) in the presence of (or in the absence of) and 1 322543 54 201121970 to The compound (Π) can be obtained by reacting 5 equivalents (preferably 1 to 3 equivalents) of the compound (XXV). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, dioxane, DCE, THF, 1,4-dioxane, DME, DMF, DMA, NMP, or the like, or These are used in combination, with dichloromethane, THF, DMF or NMP being preferred. The test may, for example, be an inorganic salt such as sodium carbonate, potassium carbonate, acid-depleted or sodium acetate; or an alkali metal hydride such as sodium hydride or potassium hydride, and further preferably potassium carbonate, cesium carbonate or sodium hydride. The reaction temperature is from 0 ° C to the boiling point of the solvent used, preferably from room temperature to 100 ° C, usually for 0.5 to 24 hours. Further, a compound wherein A1 is a formula (B) and A2 is a formula (A) can also be produced by the same production method. Production Process 9: Among the compounds (I), A1 is a formula (A), A2 is a formula (B), Z is -N(R1())-, and R1() is a substitutable aryl group or may be substituted. The compound φ (I j) of the heteroaryl group can also be produced from the compound (Ig) by the production method shown below.

Aik1) η1 , N-R310 'Aik2) η2 [Step 23] (wherein Q1, Q2, R3, Aik1 to Aik4, X, Y, Ar, η1 and η2 are synonymous with the above. Hal' represents a chlorine atom, bromine An atom or an iodine atom, R31° represents a substituted aryl group or a substituted heteroaryl group). 55 322543 201121970 [Step 23] The compound (ih) obtained in the production method is prepared in a solvent in an amount of from 1 to 10 equivalents (preferably from 3 to 5 equivalents) of a base, and 〇. 〇1 to 1 equivalent ( Preferably, it is 0. 05 to 〇. 2 equivalents of the phosphine ligand, and 〇. 1 to 1 equivalent (preferably 〇·05 to 〇. 2 equivalent) in the presence of a palladium catalyst and 1 to 1 The compound (Ij) can be obtained by reacting a ruthenium equivalent (preferably 1.1 to 2 equivalents) of the compound (??). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, or the like, or may be used in combination. Among them, indene, (10) E or 1,4-dioxane is preferred. As the phosphine ligand, a single-site coordination type phosphine such as triphenylphosphine, trimethylphosphine, trifuranphosphine or tri-tert-phosphine, or BINAP, 2, 2,-bis(dimethylphosphino)-1 can be used. , Γ-binaphthyl, DPE-Phos, XANT-Phos and other two coordination phosphines, of which BINAP is preferred.

As the palladium catalyst, for example, tetravalent (triphenylphosphine) palladium, bis(t-butylphosphine) palladium, tris(dibenzylideneacetone) dipalladium or the like, or bis (triphenylphosphine) II may be used. A divalent catalyst such as palladium chloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, wherein tris (dibenzylideneacetone) is further quaternary or acetic acid. 'The base can be used, for example, sodium carbonate, potassium carbonate, carbonic acid planing, sodium acetate test salt, sodium decyl alcohol, sodium ethoxide, third butanol unloading, etc. The third butanol reaction temperature is between room temperature and the boiling point of the solvent used, preferably between 180 ° C under heating or under microwave irradiation, usually (10) % ΰ to 24 56 322 S43 2011 21970 hours. Further, a compound wherein A1 is a formula (B) and a2 is a formula (A) can also be produced by a production method. Production Method 10: Among the compounds (1), A1 is a formula (A), A2 is a formula (B), Aik4 is a fluorenylene group, Y is a single bond, and Q2 is -NRY or bonded to Alk4 by a nitrogen atom. A compound containing a nitrogen-containing saturated heterocyclic ring which can be obtained, for example, from a compound (νι) by the production method shown below.

>rQ1 Rl.,.AIk3 Rd V Γ z ) Person Ar*B(0Rb)2 (XXVI) Η3ΐ^ΝΛΆΙΚ2) η2 Coupling reaction (IV-a) [Step 24]

Q2—Η (XXVII) (X) Reductive amination [Step 25]

(Ik)

(wherein Q1, Q2, R3, Alki to Alk3, χ, z, red, 〇1 and y are synonymous with the above. Rb represents a hydrogen atom or a substituted alkyl group, and Rd represents a hydrogen atom or a Cl-3 alkane. Base, Hal represents a chlorine atom or a bromine atom). [Step 24] The compound (Yj_a) obtained in Production Method 1 is used in a solvent in an i to W equivalent (preferably 3 to 5 equivalents) of a base, and 〇. 〇1 to 1 equivalent (preferably 0). 05至〇. 2 equivalents) of a palladium catalyst is reacted with 1 to 5 equivalents (preferably 1.1 to 1.5 equivalents) of the compound (XXVI), whereby a compound can be obtained at 57 322543 201121970 (XXW). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, water, or the like, or may be mixed. It is preferred to use a mixed solvent of DME with water or 1,4-dioxene and water. As the palladium catalyst, for example, a tetravalent catalyst such as tetrakis(triphenylphosphine)palladium, bis(t-butylphosphine) palladium, tris(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine) II may be used. A divalent contact catalyst such as palladium chloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, of which tetrakis(triphenylphosphine)palladium is preferred. The test may, for example, be a sodium salt, a potassium carbonate, an acid etchant, or a sodium acetate, and among them, sodium carbonate or potassium carbonate is preferred. The reaction is carried out at a temperature of from 0.5 to 24 hours. [Step 25] The compound (XXW) obtained in the step 24 is used in a solvent in the presence of 1 to 10 equivalents (preferably 2 to 3 equivalents) of an acid and 1 to 10 equivalents (preferably 2 to 2). The compound (Ik) can be obtained by reacting 3 equivalents of a boron hydride compound and 1 to 10 equivalents (preferably 1.1 to 2 equivalents) of the compound (X). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, THF, 1,4-dioxane, DME, dioxane, trigas tetr, 1,2-di. Ethylene bromide, decyl alcohol, ethanol, n-propanol, 2-propanol, etc., or the like, wherein 1,2-dichloroethane or methanol is preferred. 58 322543 201121970 For the acid, for example, a sour acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid; a mineral acid such as hydrochloric acid; and acetic acid is preferred. As the shed hydrogen compound, for example, cyano hydride, sodium triacetate, sodium hydride or sodium hydride can be used, and among them, sodium cyanohydrin or sodium triethoxy hydride hydride is preferred. The reaction temperature is from room temperature to the boiling point of the solvent used, preferably from room temperature to 40 ° C, usually for 5 to 20 hours. Further, a compound of the formula (B) wherein Αι is of the formula (B) and A2 is a compound of the formula (A) can also be produced by the same production method. Production method 11 : Among the compounds (I), Q2 is _NR4r5, and R4 is a hydrogen atom (II), Q2 is a 4 to 1 member nitrogen-containing saturated heterocyclic ring, and at least one nitrogen atom in the nitrogen-containing saturated heterocyclic ring is -NH-compound (Im), Q2 is a compound of 5% (In) or Q2 is a compound of 4 to 1 member of a nitrogen-containing saturated heterocyclic ring (1〇), which may be compound (VI-a) by the following The manufacturing method shown is made.

322543 59 201121970

"Q1 Ργ〇,Ν,Υ,ΑΚΒ_2 I (XXVIII) R5 or

To protect

X .Q1 R3, M, Alk3 N

Reductive amination X 'Q1 [Step 27]

r\m.aik3 N

X knife 1 R3, N-person 丨 k3

X Chuan

Rl^.Aik3 N

x, q1 RVY, ArWld) n2 R5 (In) [Step 28] or x'q1 R3, n —

(wherein Q1, R3 to r5, Aik1 to Aik3, X, Y, Z, Ar, ni and n are synonymous with the above. γ represents a hydrogen atom or a substituted alkyl group, and 卩(7) represents, for example, a literature (Protective Groups) a general amine protecting group as shown in in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.), Het represents a 4 to 10 membered saturated heterocyclic ring which may be substituted, and Re represents 1 to 5 fluorine atoms. Substituting C^o alkyl, etc.). [Step 26] 322543 60 201121970 The compound 〇Va) prepared in a solvent is in a solvent of 1 to 1 (preferably 3 to 5 equivalents) of a base, and 〇. 1 to 1 equivalent (preferably). a compound (xxvm) or a compound (XXK) in the presence of a palladium catalyst of 0.05 to η οα θ, 当 θ 2 2 2 1 1 1 1 1 1 1 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The reaction is carried out 'by this, the compound (m) or the compound (XXXI) can be obtained. The solvent used for the f reaction may be any one which is inert to the reaction, and is not specifically limited to, for example, THF, 1,4-dioxane, DME, stupid, acetophenone, water, or the like may be used alone or It is preferably used in combination, and it is preferred to use DME with water or a mixed solvent of 1,4-toluene and water. As the palladium catalyst, for example, a zero-valent catalyst such as tetrakis(triphenylphosphine)palladium, bis(t-butylphosphine)palladium-mono(p-benzylidene-propyl)-palladium, or bis(triphenylphosphine) can be used. A divalent catalyst such as palladium chloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride, of which tetrakis(triphenylphosphine)palladium is preferred. The test may, for example, be an inorganic salt such as sodium carbonate, carbonic acid, carbonic acid or sodium acetate, and among them, sodium carbonate or potassium carbonate is preferred. 5至24小时。 The reaction temperature is from 0. 5 to 24 hours from the φ / JBL to the boiling point of the solvent, preferably from 50 to 180 ° C under heating or under microwave irradiation, usually 0.5 to 24 hours. [Step 27] The protecting group of the compound (XXX) or the compound (χχχι) obtained in the step 26 is deprotected, whereby the compound (11) or the compound (1〇1) can be obtained. For example, when the sulfonic acid group is a Boc group, it is reacted with an excess amount (preferably 5 to 10 equivalents) of an acid in a solvent, whereby a compound (11) or a compound (Im) can be obtained. The solvent used in the reaction may be any one which is inert to the reaction, and is not limited to 322543 61 201121970, and may be used alone, for example, THF, 1,4-dioxane, diethyl ether, dioxane, DCE, methanol, ethanol. Alternatively, or in combination, it is preferred to use 1,4-dioxane, dioxane or decyl alcohol. As the acid, for example, a carboxylic acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid; a mineral acid such as hydrochloric acid; and hydrochloric acid or trifluoroacetic acid is preferred. 5至24小时。 The reaction temperature is from room temperature to the boiling point of the solvent, preferably from room temperature to 40 ° C, usually carried out 0.5 to 24 hours. [Step 28] ^ The compound (II) or the compound (Im) obtained in the step 27 is used in a solvent in the presence of 1 to 10 equivalents (preferably 2 to 3 equivalents) of an acid and 1 to 10 equivalents ( Preferably, 2 to 3 equivalents of a boron hydride compound, and 1 to 10 equivalents (preferably 1.1 to 2 equivalents) of the corresponding aldehyde or ketone derivative are reacted, whereby a compound (1〇) can be obtained. ) or compound (Ip). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, THF, 1,4-dioxane, DME, dichloromethane, trichlorodecane, 1,2- can be used alone. Di-ethane, decyl alcohol, ethanol, η-propanol, 2-propanol, etc., or a mixture thereof, wherein 1,2-dichloroethane or decyl alcohol is preferred. As the acid, for example, a carboxylic acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid; a mineral acid such as hydrochloric acid; and acetic acid is preferred. As the boron hydride compound, for example, sodium cyanoborohydride, sodium triethoxy borohydride or sodium borohydride may be used, and among them, sodium cyanoborohydride or sodium triethoxy borohydride is preferred. 5至24小时。 The reaction temperature is from room temperature to the boiling point of the solvent, preferably between room temperature and 40 ° C, usually 0.5 to 24 hours. 62 322543 201121970 Further, a compound wherein A1 is a formula (B) and A2 is a formula (A) can also be produced by the same production method. The compound (IV) which is an intermediate product of the synthesis of the compound (I) can be produced by the production method shown below. ΝΗ

—-esterification (XXXII) η2ν Λ ΝΗ2 [Step 29] OH Η2Ν

Halogenation (XXXIII) [Step 30]

Hal

(XXXIV) Suihua

Hal Sandmeyer Reaction [Step 31]

(In the formula, Aik1, Aik2, Z, η1 and η2 are synonymous with the above. Hal represents a chlorine atom and a bromine atom). [Step 29] The compound (XXXII) is added to the solvent in an amount of 1 to 5 equivalents (preferably 1.1 to 2 equivalents) in the presence of 1 to 5 equivalents (preferably 1.1 to 2 equivalents) of a base. The carbonate or cyanurate is reacted, whereby a compound having an alkoxycarbonyl group introduced into the α-position of the carbonyl group can be obtained. Further, the obtained compound is used in a solvent in the presence of 0 to 5 equivalents (preferably 1 to 2 equivalents) in the presence of (or in the absence of) and 1 to 5 equivalents (preferably 1 to 2 equivalents). The compound (XXXIII) can be obtained by reacting the hydrazine derivative or an acid salt thereof. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction. For the first reaction, for example, an ether solvent such as THF, 1,4-dioxane, ME, 63 322543 201121970 diethyl ether or hexane can be used alone. An aprotic solvent such as heptane, toluene, DMF, DMSO or acetonitrile, or a mixture thereof, wherein THF or diethyl ether is preferred. For the second reaction, for example, an ether solvent such as diethyl ether, THF, 1,4-dioxane or DME, an alcohol solvent such as methanol, ethanol, 2-propanol or butanol; or a halogen such as methane or chlorobenzene; It is a solvent; an aprotic solvent such as benzene, DMF or DMS0, or a mixture thereof, and preferably decyl alcohol or ethanol. The base used in the first reaction may be, for example, a metal amine such as lithium hexamethyldiamine, sodium hexamethyldiamine, potassium hexamethylenediamine or lithium diisopropylamide; a variety of alkali or alkaline earth metal alkoxides such as sodium decoxide, sodium ethoxide, potassium butoxide; metal hydrides such as lithium hydride, sodium hydride or potassium hydride, among which lithium or hexamethylenediamine Isopropyl amination is preferred. For the second reaction, a metal carbonate such as potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; and a hexamethylenediamine amination can be used. Metal amines such as lithium, φ hexamethylenediamide, sodium hexamethyldiamine, etc.; various alkali or alkaline earth metal alkoxides such as sodium decoxide, sodium ethoxide, potassium butoxide; a metal hydride such as sodium hydride or potassium hydride; an organic base such as triethylamine, diisopropylethylamine, pyridine or 4-diguanamine pyridine, etc., which is further used in potassium carbonate or hexamethylenediamine The reaction in the presence or absence of a base is preferred. The hydrazine/acid salt used in the second reaction may be hydrazine/carbonate, hydrazine/hydrochloride, hydrazine/sulfate or the like, with hydrazine/carbonate being preferred. The temperature of the first reaction is from -100 ° C to 50 ° C, preferably 64 322543 201121970 - 80 ° C to 0 ° C, usually for 1 to 10 hours. The temperature of the second reaction is from 0 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C, usually from 1 to 20 hours. _(XXXII) can be, for example, by J. Chem. Soc. Perkin Trans. 2, 1992, 799-803. 'J. Med. Chera. 1993, 36, 295-296., Chem. Ber., 1955, 1053 - 1059., J. Am. Chera. Soc. 1982, 104, 4666-4671., J. Fluorine Chem. 1983, 1 - 18., US Published Patent US 2007/173508 A1, US Published Patent No. 5208259 A1, etc. Synthesize it according to its method, or buy it. L Step 30 The compound (χχχΐνι) obtained in Step 29 is reacted with a toothing agent in a solvent (or no solvent) in excess (preferably 3 to 1 equivalent) to prepare a compound (χχχΐν). ).

The ruthenium-based functionalizing agent may be, for example, a phosphorus oxychloride, a phosphorus pentoxide or an oxygen desertification lining. The stimulating agent is not particularly limited as long as it is inert to the reaction, and may be used alone, for example, hydrazine or THF. , U-diazepam, DME, methylene chloride, stupid, stupid, dimethyl poor χτ τ, ethyl acetate, triethylamine, ° bite, ., '曱 曱 basic amine, Ν, Ν - Diethyl aniline, etc., or 5 Hai special use. The reaction temperature is preferably from 50 to 140 ° C, [Step 31] 〇C is between the boiling point of the solvent or the halogenating agent, usually from 1 to 24 hours. The compound (simplified v) obtained in 3G is used in a solvent and in the presence of a trialkyl hepoxide of 322543 65 201121970 30 $ preferably 5 to 15 equivalents, and 1 to 20 (preferably) The compound (IV) can be obtained by reacting an alkyl nitrite of 3 to 1 Torr equivalent, and a halogenated alkanoyl halide of 1 to 10 (1 to 3 equivalents of the carrier). The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and for example, dichlorosilane, chloroform, 1,2-dichloroethane, tetra-carbonized carbon, or the like can be used alone or It is mixed and used, and it is better to use two gas. • For the trialkyl sulfonium chloride, for example, dimethyl hydrazine chloride, triethyl hydrazine chloride or tripropyl hydrazine chloride can be used, and among them, gasified trimethyl hydrazine is preferred. The nitrite ester can be used, for example, isobutyl phthalate, nitrite, butyl nitrite, isoamyl succinate, neopentyl nitrite, amyl nitrite, etc. Preferably, tert-butyl nitrate or isobutyl nitrite is preferred. As the alkylammonium halide, for example, tetrabutylammonium chloride, triethylammonium chloride, ammonium tetrapropylammonium chloride, tetrabutylammonium bromide or the like can be used, and among them, triethylammonium chloride is preferred. The reaction temperature is from 〇c to the boiling point of the solvent used, preferably from 0 ° C to 30 ° C, usually from 0.5 to 2 Torr. A compound (a compound of an intermediate product of 0) which can be obtained by the production method shown below. 322543 66 201121970 〇RaO^^-(Alk1)n1 Rb〇2C'(Aik2)n2 (XXXV) [Step W32] Ο R3〇,^Y(Alki)ni 0^(Αίκ2)η2 (XXXVI) [Step 33] OHN^Sr(A'2)n1 H2N Person N Person (Al'k2)n2 (XXXIII) Wherein, Aik1, Aik2, and Rb represent a substitutable alkyl group) [Step 32] i to 5 equivalents (preferably, butyl treatment) to thereby obtain a compound (XXXVI). The solvent used in the reaction is as long as the reaction is carried out. In addition, the first reaction can be used alone, for example, ΠΒ..., 1,4-iHF, 1,4-dioxane, DME, monoethyl ether, etc.; hexane, g-burning ^ ^ LL secondary condition, DMF, DMS0 Or a protic solvent, or a mixture of these, wherein THF or diethyl ether is preferred. The n and n2 systems are synonymous with the above. For Ra& hexamethylene two-distribution clock, hexamethyl two a metal amine such as sodium hexahydrate, potassium hexahydrate or diisopropylamine; sodium methoxide/sodium alkoxide, potassium butoxide, etc. , Metal hexamethylTM or diisopropyl amination of sodium or potassium hydride: temperature:: from 100C to 50 C, preferably from -80 to 〇. (;, usually 1 to 10 hours. The diacetate compound (XXXV) can be described by, for example, J. Am. Chem. s〇c. 1960, 82, 2050-2052., J. Am. Chem. Soc. 1997, 119, 4285-4291 'etc. The method and the method thereof are synthesized, or can be purchased as 322543 67 201121970. [Step 33] The compound (XXXVI) is dissolved in a solvent in the presence of 5 equivalents (preferably 1 to 2 equivalents) ( The compound (ΧΧΧΙΠ) can be obtained by reacting with 1 to 5 equivalents (preferably 1 to 2 equivalents) of an anthracene derivative or an acidic salt thereof. The solvent used in the reaction is inert to the reaction. Any one is not particularly limited, and for example, a solvent such as diethyl hydrazine, THF, 1,4-dioxin, DME ® or the like; an alcohol solvent such as decyl alcohol, ethanol, 2-propanol or butanol may be used alone. a halogen-based solvent such as tri-gas methane or chlorobenzene; an aprotic solvent such as toluene, DMF or DMS0, or a mixture thereof, wherein decyl alcohol or B Preferably, the base can use a metal carbonate such as potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; lithium hexamethyldiamine; Metal amines such as sodium methyl sulphonate and hexamethyl bis- sulphide; sodium methoxide, ethanol steel, potassium t-butoxide, etc., various metal or alkane oxides; hydrogenation clock, sodium hydride Or metal weathering compounds such as potassium hydride, diethylamine, monoisopropylethylamine, η than hydrazine, 4-diguanamine, etc., such as potassium carbonate, hexamethylene bisulphate The reaction in the presence or absence of the chemical chain is preferred. As the cerium/acid salt, cerium/carbonate, cerium/hydrochloric acid hydrazine, hydrazine/sulfate, etc. may be used, and among them, hydrazine/carbonate is preferred. The reaction temperature is self-tanning. (From the boiling point of the solvent used, preferably from 50 to 100 ° C, usually for 1 to 2 hours. The compound (χχχκ) of the intermediate product of the compound (I) is synthesized (where z 322543 68 201121970 is an oxygen atom) ), which can be produced by the manufacturing method shown below.

HCT (XXXVII) [Step 34]

(XXXVIII) .Aik2

Ο Aik2 (XXXIX) [Step 35] (In the formula, Aik2 is synonymous with the above). [Step 34] The compound (XXXW) is in a solvent and in an amount of from 1 equivalent to the solvent (preferably, 5 equivalents to the solvent amount) of the acid and 0.2 to 5 equivalents (0.5 to 2 equivalents) of the aldehyde derivative. Alternatively, the ketone derivative is reacted, whereby the compound (XXXW) can be obtained. The acid used in the reaction may be sulfuric acid, nitric acid, hydrochloric acid or the like alone or in combination with water, and an aqueous solution of sulfuric acid and water is preferred. The reaction temperature is from -20 ° C to the boiling point of the solvent used, preferably from 0 to 40 ° C, usually for from 1 to 20 hours. [Step 35] The compound (XXXIX) can be obtained by oxidizing the compound (XXXM) in a solvent with 1 to 10 equivalents (preferably 1 to 5 equivalents) of an oxidizing agent. The solvent used in the reaction is not particularly limited as long as it is inert to the reaction, and an ether solvent such as diethyl ether, THF, 1,4-dioxane or DME can be used alone; dioxane, 1, 2 - a halogen-based solvent such as dichloroethane, trioxane or benzene; an aprotic solvent such as benzene, acetonitrile, DMF or DMS0, or a mixture thereof, wherein chloroformane is used alone or in combination. Or DMS0 is preferred. 69 322543 201121970 The oxidizing agent used in the reaction may be a metal oxide such as chromic acid or a salt thereof; sulfur trioxide ratio biting complex, gas acid, hypochlorous acid or a salt thereof; Swern oxidation reaction or Moffatt oxidation reaction The combination of chloroform or dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride and DMS0, wherein chromic acid or its salt or Swern oxidation reaction is preferred. The reaction temperature is from -20 ° C to the boiling point of the solvent used, preferably from 0 to 40 ° C, usually for from 1 to 20 hours. A compound (VI-a) which synthesizes an intermediate product of the compound (I), which can be produced by the production method shown below. SRa RbS ^^iAIk1)!!1 , (Aik2)n2 [Step 36]

(XXXII)

Halogenation [Step 39]

SRa _. ^V?n1 [Step 38] H2N^N^(Alk2)n2 [Step 37] (XXXXI) X'Q1

1' ;z 2 , N>(Alk2>n2 (XXXXIII) X^1 Rl.rAlk3 N (V)

(Vl-a) .Aik3 base [Step 40] (wherein Aik1, Aik2, Aik3, R3, Q1, X, Z, n1 and n2 are synonymous with the above. Ra and Rb represent a substituted alkyl group, Hal Represents chlorine atoms and desert atoms). [Step 36] The compound (XXXM) is treated with a base of 1 to 10 equivalents (preferably 1 to 5 equivalents) in a solvent, and then reacted with carbon disulfide, followed by alkylation with a halogenated alkane reagent. The compound (χχχχ) was obtained. The solvent used in the reaction may be any one which is inert to the reaction, and is not limited to 70 322543 201121970, and can be used alone, for example, a binary puzzle, TIiF, 丨_

N-u is an ether solvent such as a burnt or DMF; an aprotic solvent such as toluene, acetonitrile, DMF or DMS, or the like, and THF is preferred. For the test used in the reaction, for example, a hexamethylene sulphate, a sulphate, a hexamethyl sulphate metal amine, a sodium methoxide, an ethanol hydride, a third butanol, and the like can be used. Oxygen metal oxides; & Lithium, sodium hydride or potassium hydride and other metal hydrides, among which lithium or hexamethyldiamine is preferred. Oxidized steel

The dentate alkane used in the reaction may, for example, be an iodine oxime reagent such as iodonane, ethyl iodide, odor propylene or bromine toluene or a brominated alkane reagent, and the propylene 1f is also

Alkane is preferred. The T reaction temperature is from -80 C to the point of the solvent used. i is -20 ° C to 50 ° C, usually for 1 to 20 hours. *better [Step 37] The compound (XXXX) is placed in a solvent and in the presence of 5 equivalents (preferably to 2 equivalents) of a base (or in the absence of a base) and 1 to q winter burglary: Preferably, 1 to 2 equivalents of an anthracene derivative or an acidic salt thereof is reacted, whereby a compound (XXXXI) is obtained. The reaction conditions can be the same as those in the step 33 of Production Example 13. [Step 38] Compound (XXXXII) can be produced by treating compound (XXXXI) in a solvent with 1 to 1 equivalent (preferably i to 3 equivalents) of an oxidizing agent. The solvent used in the reaction may be any one which is inert to the reaction, and is not limited to the temple 322543 71 201121970, and an ether solvent such as diethyl ether, THF, 1,4-dioxane or DME, or dichloroguanidine may be used alone. Halogen solvents such as alkane, trichlorodecane, 1,2-dioxaethane, and benzene; alcohols such as decyl alcohol, ethanol, 2-propanol, and butanol; aprotic such as toluene, acetonitrile, and DMF The solvent is used in combination or not, and it is preferred to use dichlorosilane or 1,2-dichloroethane. As the oxidizing agent used in the reaction, for example, a peroxide such as m-chloroperbenzoic acid, peracetic acid or hydrogen peroxide; a metal oxide such as chromic acid, in which m-chloroperbenzoic acid is used. The reaction temperature is between -20 ° C and the boiling point of the solvent used, preferably 0 ° C to 30 ° C, usually for 1 to 20 hours. [Step 39] The compound (XXXXII) is added to the solvent in the presence of 1 to 30 equivalents (preferably 5 to 15 equivalents) of trioxane chloride in an amount of 1 to 20 equivalents (preferably 3 to 10 equivalents). The compound φ (XXXXII I) can be obtained by reacting an alkyl nitrate with 1 to 10 equivalents (preferably 1 to 3 equivalents) of a functional alkylammonium. The reaction conditions can be the same as those in the step 31 of Production Example 12. [Step 40] The compound (XXXXIII) is added to the solvent in an amount of 1 to 5 equivalents (preferably 1.2 to 3 equivalents) in the presence of 1 to 5 equivalents (preferably 1.5 to 2 equivalents) of a base. The compound (V) is reacted, whereby the compound (VI-a) can be obtained. The same conditions as in the step 3 of Production Example 1 can be used as the reaction conditions. By appropriately combining the above production methods, a compound of the present invention having a desired functional group at a desired position can be obtained. 72 322543 201121970 2: The separation and purification of the product and the product can be appropriately synthesized, for example, by hydrazine, extraction, organic crystallization, various color layer analysis, etc., to dry-/concentrate, In particular, the product is supplied to the raw material compound or the intermediate product of the manufacturing method, for example, in the form of a blue salt or the like. When the raw material is used as it is, it is used in the form of a free form of salt, and it is used, for example, in a volumetric agent such as an aqueous solution of sodium hydrogencarbonate.崄4 is neutralized and converted into a free form compound (1) or a pharmacologically acceptable salt thereof such as a tautomer (such as a ketone, an alcohol: oxime, an isomer having a precursor isomer) And the two-position, the structure, the geometric isomer or any of the isomers of -^ are separated by the separation process of light::^^. This evening t = separately known materials such as crystallization method. The optically active substance is used as a starting directly to purify it: when the salt of the compound (1) is obtained, the compound (1) can be dissolved: one (1) is obtained in a free form to form a salt. Further, it is floated in a suitable solvent. Adding an acid or a salt of water, or various, hexa sigma (1) or a pharmacologically acceptable salt thereof, is present in the present invention, but a solvate such as 322543 73 201121970 is also included in the present invention. Permissible ==^_ The active ingredient is mixed with the well-known body in the field of pharmacology. The pharmaceutical carrier can be produced by, for example, lactose or a method. The preparation used is magnesium or glyceric acid vinegar. , injection of sugar alcohol, glucose, temple powder, stearic acid Two kinds of foods such as diol and ethanol, such as physiological saline, propylene glycol, various excipients, lubricating agents, emulsifiers, etc. H-friends, iso-osmotic agents, and those with great effects are better. For intravenous (10) and characteristic eye, etc., the form of administration can be enumerated, for example, _ is: = pulse is more than = =. The amount of administration or the number of times of administration with the cast = shot: =: The range of mg, preferably about ❶, to two: ◦': to about good is about (U to about 500mg range, special circumference: wide one owed mode heart ~ Ming further specific in this particular example The present invention is described below with reference to the following examples and reference examples, but the scope of the present invention is not limited to the physical type of each compound in the following examples. 322543 74 201121970 *HNMR : JEOL JNM-LA300 (300MHz) 'HNMR: Burker AVANCE400 (400MHz) LC/MS : API150EX (measured by API method) The conditions for performing high-speed liquid chromatography analysis of retention time in the following examples and reference examples are As described below. Pipe column: 18-base chemical bonding type Shi Xi (0 DS), aperture 5 // m, particle size 12nm, column length 50mm, column inner diameter 4. 6mm [Product name CAPCELL PAK C18(S-5//m, 12nm) 50x4.6 mm (Shiseido Fine Chemical Ltd.)] Flow rate: 2. 8ml/min (min.) Measurement wavelength: 220nm, 254nm Moving layer: Liquid A; 0.05% trifluoroacetic acid aqueous solution B; 0. 035% trifluoroacetic acid methanol solution Time planning: Stage time ( Sub) Liquid A: B liquid 1 0. 0-0. 5 99 :1 2 0. 5-5. 9 99 • 1 -1 · 99 3 5. 9_6. 4 1 :99 4 6.4-6.5 1 :99 — 99 : 1 5 6. 5-7. 5 99 :1 Reference Example 1 Ν' -(6-Benzyl-2-chloro-5, 6, 7, 8-tetrahydropyrido[4, 3-d] Pyrimidin-4-yl)-N,N-dimercaptopropane-1,3-diamine 75 322543 201121970

(a) 6-Benzenyl-5, 6, 7, 8-tetrahydroxanthrino[4,3-d]pyrimidine-2,4(1H,3H)-dione® in 1-phenylhydrazino- To a solution of 4-oxo-3-piperidinecarboxylate hydrochloride (28. 4 g, 0.1 mol) in ethanol (360 ml) was added 28% sodium methoxide / decyl alcohol solution (204 ml, 1. OOmol) And urea (30. lg, 0.50 mol), and heated to reflux. After 16 hours, the reaction solution was filtered under reduced pressure. Then, the filtrate was added to water and the mixture was combined with aqueous hydrochloric acid, and then filtered under reduced pressure to give the title compound (16.96 g, yield 66%). 'H-NMR (300 MHz, DMSO-de » 5 ppm): 10.92 (1H, s), 10.76 φ (1H, s), 7.29 (5H, m), 3. 60 (2H, s), 2. 98 (2H, s), 2.61 (2H, m), 2.42 (2H, m). (b) 6-Benzenyl-2,4-dichloro-5, 6, 7, 8-tetrahydroacridine [ 4,3-d]pyrimidine was added to the above-prepared compound (8.0 g, 0.031 mol), and phosphorus oxide (80 ml) was added thereto, followed by heating under reflux. After 3 hours, the solvent was evaporated under reduced pressure, and ice was added to the obtained residue, and then neutralized with saturated aqueous sodium hydrogen carbonate. This was extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The title compound (7. 27 g, yield: 79%) was obtained from the title compound (yield: EtOAc, EtOAc: EtOAc). 'H-NMR (300 MHz, CDCh > δ ppm): 7.32 (5H, m), 3.75 (2H, s), 3.65 (2H, s), 3.00 (2H, t, J = 5. 8 Hz), 2.79 (2H, t, J = 5.8 Hz). (c) N -(6-phenylnonyl-2-chloro-5, 6, 7, 8-tetrahydro 0-bit and [4, 3-d] N,N-dimethylpropane-1,3-diamine was added N,N in a solution of the compound (500 mg, 1.70 mmol) obtained in the above-mentioned dioxane (5 ml). _Dimethyl_13-propanediamine (213/^, 1.70 mmol), N,N-diisopropylethylamine (337yL, 187_〇1), and stirred at 80 C. After 3 hours, the reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then evaporated. Then, the obtained residue was purified by ethylamine hexane chromatography chromatography (solvent solvent: hexanes: ethyl acetate) to give the title compound (413 mg, yield: 68%). tNMR (300 MHz, CDC1 in ppm): 7.93 (1H, s), 7 31 (5H, in), 3. 73 (2H, s), 3. 51 (2H, m), 3. 08 (2H, s), 2. 82 (4H, m), 2.42 (2H, m), 1.99 (6H, s), 1.64 (2H, m). Refer to Example 2-16: ', use the corresponding raw material compound, and refer to The same reaction/treatment as the method described in the example was carried out to obtain the compound shown in Table 1. 322543 77 201121970 Table 1

Reference example Structural formula 屮-NMR (MHz, solvent, δ) 2 Me kN, Me Ή-NMR (300 MHz, C0Ci3, 5 ppm): 7. 31 (5H, m), 3. 69 (2H, s), 3.47 (2H. s)f 3.39 (2H. m). 3.00 (3H. s), 2.87 (2H. t, J = 5.8 Hz). 2.76 (2H, t, J = 5.8 Hz), 2.19 (2H. m ), 2.17 (6H. s). 1.69 (2H, m). 3 ον'η j5ct〇Ή-NMR (300MHz, C0CI3. 5 ppm): 7.78 (1H. s), 7.29 (5H. m), 3.71 ( 2H, s). 3.56 (2H, m). 3.25 (2H, s), 2.81 (4H, m). 2.66 (2H, m), 2.50 (4H, m), 1.78 (2H, m), 1.71 (4H , m). 4 Cl Ή-NMR (300MHz, CDCI3, δ ppm): 7.32 (5H. m). 5.54 (1H, t. J = 5.5Hz), 3.72 (2H, s), 3.51 (2H, s) , 3.45 (2H, m), 2.76 (4H, m), 2.53 (2H. m), 2.47 (4H, m)t 1.79 (6H, m). 5 ,λ5ο^ο 'H-NMR (300MHz, CDCI3, <5 ppm): 7.31 (5H, m). 5.31 (1H.m), 3.71 (2H, s). 3.48 (2H, m), 3.23 (2H, s), 2.76 (4H, m), 2.48 ( 6H, m), 1.77 (4H.m)F 1.63 (4H, m). 6 o' ο Ή-NMR (300MHz, C0CI3, 5 ppm): 7.31 (5H, m), 5.31 (1H, m), 3.74 (2H, s), 3.54 (2Ht m), 3.37 (2H, s), 2.72 (4H, m), 2.47 (2H. m), 2.38 (4H. m), 1.74 (2H, m), 1.49 (4H , m), 1.44 (2H, m). 7 o' , 5cr 〇 'H NMR (300 MHz, CDCI 3. δ ppm): 7.36-7.28 (5H, m), 3.74 (2H, s), 3.63 (2H, m)t 3.51 (2Hf m), 3, 20 (2H, m). 2.80 (4H, m), 2.62 (2H, m), 2.47 (2H, m). 1.57 (4H, m). 8 〇0^NH Ή-NMR (300MHz, CDCI3, δ ppm ): 7.31 (5Ht m), 6.56 (1H, m), 3.75 (2H, s), 3.56 (2H, m), 3.28 (2H. s), 2.77 (4H, m), 2.48 (2H. m), 2.41 (4H, m). 1.74 (2H, m). 9 Ή-NMR (300 MHz, CDCI3, δ ppm): 7.33 (5H(m), 5.51 (1Ht m)t 3.71 (6H, m), 3.49 ( 2H, s), 3.42 (2H.m), 2.71 (4H, m), 2.42 (6H, m), 1.73 (2H.m). 10 γ.λ5ο^ο Ή NMR (300 MHzt CDCI3. 5 ppm) : 7.35-7.20 (5H, m), 4.62 (1H, brs), 3.72-3.71 (6H, m), 3.52-3.45 (2H, m), 3.22 (2H, s) ( 2. 78-2. 74 (4H , m), 2.47-2.40 (6H, m), 1.59 (4H. m). 11 Order, λ5〇ν^ο Ή-NMR (300 MHz, C0CI3, δ ppm) : 7. 32 (5H, m) r 4. 44 (1H, m), 3.73 (2H, s), 3.57 (2H, m), 3.28 (1H, m), 3.25 (2H, s), 2.74 (4H, m), 2.49 (4H, q, J = 7.2 Hz), 2.34 (1Hf m)f 2.11 (2H, m), 1.86 (2H, m). 0.97 (6H, t, J = 7.2 Hz). 12 Η 'HNMR (300 MHz, CDCI3t δ ppm ): 7.74 (1H, brs), 7.36-7.22 *(5H, m), 3.70 (2H. s), 3.52 (2H, m), 3.15 (2H, s), 2.78 (4Ht m)( 2.54 (2H, tn), 2.36-2.34 (4H, m), 1.68 (2H, m), 0.88 (6H, m). 13 Μβ, Ν, Μβ ό 'HNMR (300 MHz. CDC13, δ ppm): 7.32-7.24 (5H, m) , 3.92-3.88 (2H, m), 3.67 (2H, s), 3.33 (2H, s) ( 2.90-2.86 (4H, m), 2.80-2.75 (2H. m). 2.42 (1Hf m), 2.30 ( 6H, s), 1.89-1.85 (2H, m), 1.46-1.39 (2Ht m). 78 322543 201121970

1 4 CTT ~ NH 15 16 ~ - Me L NH Human A Ή-NHR (400MHz, CDCI3, δ ppm): 8.09 (1H, s). 4 82 (4H, s), 3.49-3.58 (2H, m), 2.64 (2H, t, J: 5 5 Hz), 2.42-2.53 (4H. m). 1.68-1.78 (6H.m). 'H-NMR (400 mz, CDCI3. <5 ppm) : 5.50 (1H , brs) 3.47-3.42 (2H. m), 2.60 (2H. t. J = 5.9Hz), 2 45 (2H. t, J = 5.7 Hz), 2.22 (2H. t. J = 6.1 Hz) 2.19 ( 6H, s). 1.78-1.72 (4H, in). 'H-NMR (400 MHz, CDCIj. δ ppm): 7.57 OH.^br^· 3.61-2.56 (2H. m). 2.67 (2H, t, J = 5.5Hz), 2 5? (2H. t, J = 5.8Hz), 2.30 (6H, s), 2.21 (2H t 6.1 Hz). 1.88-1.70 (6H, m). 'Reference example 177 benzene Sulfhydryl-N_(3~pyrrolidin-1-ylpropyl)-5,6, 7, 8-tetrahydropyridinium[3,4-d]

(a) 7-Benzyl-5,6,7-tetrahydropyrido[3,4-d]pyrimidin-2,4(1H,3H)-dione in ethanol (200 ml) with a small amount of metal Sodium (7 72g, 〇336mQi), when the sodium metal is dissolved, add the benzyl_3_sideoxy_4_piperidinic acid ethyl ester hydrochloride (l〇g, 0.0336ιπ〇1) and urea (l〇.lg, 0.168m〇1), and heated to reflux. After 25 hours, water was added to the reaction solution, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with water, and then adjusted to pH 5 to 6 with a 5 m? Then, the resulting solid was filtered under reduced pressure and washed with water and diethyl ether to afford the title compound (4. 〇5g, 79 322543 201121970 yield 47%). j-NMROOOMHz, DMSO-de, 5 ppm): 1〇93 (1H, s), 1〇61 (1H's)' 7. 29 (5H, m), 3. 62 (2H, s), 3. 13 (2H, s), 2. 61 (2H, m), 2.22 (2H, m). (b) 7-Benzenyl-2, 4-dioxa-5, 6, 7, 8-tetrahydropyridine And [3, 4_d] pyrimidine was artificially formed in the same manner as in Reference Example 1 (b). MMR (300 MHz, CDCl3, 5 coffee): 7. 34 (5H, m), 3. 72 • (2H, s), 3.65 (2H, s), 2.83 (4H, m). (c) 7-Benzene Methyl-2-chloro-N-(3-pyrrolidinyl-propyl)_5,6,7,8-tetrahydro- 0 is the ratio of [3,4-d]^bit-4-amine to the reference example 1(c) The same method was used for the synthesis. Wherein 1-(3-aminopropyl)pyrrolidine was used as the amine to give the title compound. Legs (300 MHz, CDCh, δ ppm): 7.87 (1H, s), 7.32 (5H, m), 3. 67 (2H, s), 3. 57 (2H, m), 3. 44 (2H, s ), 2. 77 Reference (2H, m), 2. 69 (2H, m), 2. 56 (4H, m), 2. 31 (2H, m), 1. 79 (6H, m). Reference example 18 4-{6-Benzyl-4-[(3-pyrrolidino-p-propyl)amino]_5, 6, 7, 8-tetrahydropyrido[4,3-d]pyrimidine-2~ Benzoquinone

80 322543 201121970 On 6-phenylhydrazino-2-chloro-N_(3-pyrrolidin-1-ylpropyl)-5, 6, 7, 8-tetrahydroindole. Add 4-indene boronic acid (54. lmg, 0.36 mmol) to a solution of [3, 4-d]e, a 4-amine (116 mg, 0.30 mmol) in dioxane (1.2 ml). 3 mol/L aqueous sodium carbonate solution (3 〇〇 yL, 0.90 mmol) and tetrakis (diphosphine) chemistry (34.7 mg, 0.030 mmol) were stirred at 120 ° C under microwave irradiation. After 2 hours, it was subjected to liquid separation extraction with an aqueous solution of ethyl acetate-hydrochloric acid. The aqueous layer was adjusted to pH 1 with aqueous sodium hydroxide. Then, it was subjected to liquid separation extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the obtained residue was purified by a diol-gel layer chromatography method (solvent solvent; trichloropyrene: ethyl acetate) to obtain the title compound (119 2 mg, yield: 87%). . H-NMR (300 MHz, CDCh > δ ppm): 10.07 (1H, s), 8.55 (2H, d, J = 8.3 Hz), 7. 93 (2H, d, J = 8. 3 Hz), 7.26 -7.42 (5H, m), 7.08(1H, m), 3. 76 (2H, s), 3. 72 (2H, m), 3.37 Reference (2H, s), 2.89 (2H, t, J = 5.6 Hz), 2.80 (2H, t, J = 5· 6 Hz), 2. 69 (2H, m), 2. 54 (4H, m), 1. 85 (2H, m), 1. 73 (4H, m). Reference Example 19-21 The same reaction/treatment as in the method described in Reference Example 18 was carried out using the corresponding starting compound, and the compound shown in Table 2 was obtained. 322543 201121970 Table 2 Reference Example Structure M-NMfUMHz, Solvent, δ) 1 9 ΟΛ NH OHC Human Ή-NMR (300 MHz, C0CI3. <S ppm): 9.99 (1H. s), 8.07 (1H. m) , 7.70 (1H, m). 7.62 (1H, m), 7.33 (5H. m). 3.74 (2H, s). 3.61 (2H, m), 3.33 (2H, s), 2.86 (2H, m), 2.79 (2H, m), 2.69 (2H.m). 2.50 (4H, m), 1.79 (2Ht m). 1.71 (4H, m). 2 0 ΟΛ ΝΗ 0HC into 〆Ή-NMR (400 MHz, C0CI3, <5 ppm): 9.98 (1H. s), 8.43 (2H, d, J = 8.3 Hz), 7.85 (2H. d. J = 8. 3 Hz), 7.03 (1H, brs), 5.03 (2H, t, J = 2.6Hz), 4. 91 (2H, t, J = 2. 6 Hz), 3. 74 (2H, dt, J = 5. 6. 6.0Hz)t 3.15-2.91 (4H, m) , 2.98 (2H, t. J = 6.1 Hz), 2.14-1.92 (6H, m). 2 1 ΟΛ oh ohc^qA^C0 Ή-NMR (400 MHz, CDCI3, δ ppm): 10.14 (1H, s) , 8.91 (1H, d, J=1.7Hz), 8.69 (1H, dt, J = 1.3, 7.7 Hz), 7.99 (1H, dt, J = 1.3, 7. 7 Hz). 7.65 (1H, t, J = 7.7 Hz), 7.35 (1H, brs). 5.04 (4H, s). 3.80 (2H, dt, J = 5. 5, 5. 5 Hz), 2. 81 (2H. t, J =· 5. 8 Hz), 2. 74-2. 61 (4H, m), 1. 98-1. 83 (6H, m).

Reference Example 22 4-(4-(3-(° ratio 17 唆-I-yl)propylamino)-7,8-diindole-5H-thioπ-pyrano[4,3-d]pyrimidine- 2-based) benzaldehyde

(a) 7, 8-Dihydro-1H-thiopyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione in tetrahydrothio. Add -7 (TC bis(trimethylhydrazine) hydrazide chain hexane solution to the solution of tetramethyl ketone (5.3 g, 46 mmol) of tetrahydrofuran 82 322543 201121970 (50 ml) (1. Lmol/L, 43 ml, 47 mmol). After 30 minutes, decyl decanoate (4. 67 ml, 47 mmol) was added. After 1.5 hours, a saturated aqueous chloride solution was added and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 6·36g, 33mmol) mixed with urea (1.98g, 33mmol)

In. Then, it was stirred at 6 (TC for 1 hour) and stirred at 70 t for 2 hours. Then, the reaction solution was cooled to room temperature, the resulting suspension was passed through, and the residue was washed with methanol. Then the residue was dissolved in After the water was made acidic with hydrochloric acid, the resulting suspension was filtered, and the residue was washed with water to give the title compound ( 906 mg, yield 22%). H-NMR (400 MHz, DMSO-de > S ppm): 11.1〇(ih, s) 10 69 (1H, s), 3.27 (2H, s), 2.80 (2H, t, J = 5. 8 Hzi, 2.57 (2H, t, J = 5.8 Hz).

(b) 2-Chloro-N-(3-indole ratio n each bite-1*~yl) propyl 0 pyrano[4,3-d]e mp-4-amine 8-dihydro-5 Η- Thio 1,6-. private iugua 丨, Nankai L4,3-d]pyrimidin-2 4 (3H,5H)-^(0 906 N,N--曱 basic amine (10))' and heated 4 times in the boot In addition to the solvent, add the residue to the residual, then re-dissolve the residue in the 4 1 gnach (3 〇 ml), add diisopropylethylamine (2 ml, u. 6 仃 ice cold and cold) Part, bite (l.Gg, 7.8 coffee 1). Slowly raise N'(3-aminopropyl) 『Additional' to room temperature, then carry out (4) 322543 83 201121970. Then the reaction solution is evaporated. After concentrating, the title compound (1. 09 g, yield 71%) was obtained by the purification of the chrome column chromatography (solvent solvent; trichloromethane: decyl alcohol). W-NMR (400) MHz, CDC13, ά 卯m): 8. 19 (1H, s), 3. 56-3. 50 (2H. m), 3. 23 (2H, s), 2· 92 (2H, t, J = 6. 0

Hz), 2.80 (2H, t, J = 6.0 Hz), 2.73-2.48 (6H, m), 1.85-1.69 (6H, m). (c) 4-(4-(3-0) -yl)propylamino)-7,8-dihydro-5H-thioxopyrano[4,3-d]pyrimidin-2-yl)benzaldehyde as a compound prepared above (235 mg, 0. To a solution of 73 mmol) of 1,4-dioxane (2.0 ml) / water (1. 〇ml), 4-methylindole boronic acid (225 mg '1.5 mmol), carbonic acid (415 mg, 3.0 mmol), Tetrakis(triphenylphosphine) red (87 mg '〇. 〇75 minol) was heated and stirred at 125 °C. After 2 hours, the reaction solution was concentrated under reduced pressure. The residue thus obtained was purified by EtOAc (EtOAc:EtOAc:EtOAc) ^-NMR (400 MHz, CDCh > (5 ppm): 10.03 (1H, s), 8.47 (2H, d, J = 8. 3 Hz), 7.86 (2H, d, J = 8. 3 Hz), 7.82 OH, s), 3.71-3.63 (2H, m), 3.36 (2H, s), 3.05 (2H, t, J = 5. 7 Hz), 2.86 (2H, t, J =: 5. 7 Hz) , 2.75 (2H, t, J = 5. 4 Hz), 2. 72-2. 58 (4H, m), 1. 93-1. 77 (6H, m). Reference Example 23: Use of the corresponding raw material compound The same reaction/treatment as in the method described in Reference Example 22 was carried out to obtain the compound shown in Table 3. 84 322543 201121970 Table 3 Reference example Construction formula tlHIUMHz. Solvent, 5) 2 3 ΟΛ NH N^V^S 〇Hcxy^ 'H-Vm (400 MHz, CDCIj, <5 ppm): l〇.〇5 (1H , s), 8.80 (1 H, t. J = 1.6 Hz), 8.59 (1H, dt, J = 7.8, 1.6 Hz), 7.8 7 (1H. dt, J = 7.8. 1.6 Hz), 7.54 (1H. Brs). 7.53 (1H.t. J = 7.8Hz), 3.70-3.63 (2H.m), 3.35 (2H. s), 3.05 (2H, t, J = 5.7 Hz), 2.87 (2H, t, J = 5.7 Hz), 2.68 ( 2H, t. J = 5.8 Hz), 2.58-2.49 (4H. n〇, 1.86-1.73 (6H.m). Reference Example 24 N -(6-stupyl-2-chloro -5, 6, 7, 8-tetrahydro" than biting and [4, 3-d] shouting 0 -4--4-)-N3-isopropylpropanol-1,3-diamine

(a) 6-Benzenyl-2-chloro-N-(3,3-diethoxypropyl)_5, 6,7,8-tetrahydrogen 0 bite and bite [4, 3-d] -4-Amine is added to a solution of the compound (500 mg, 170 mm 〇1) in 1,4-dioxane (5 ml) obtained in Reference Example 1 (b), and the amino- 3,3-diethoxy group is added. Propylene (412.5 / zL, 2.55 mmol) and diisopropylethylamine (613.5 must, 3.40 mm 〇l), then stirred at 5 (TC for 5 hours. The reaction mixture was diluted with ethyl acetate, then water was added The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then concentrated, and then concentrated under reduced pressure. 322543 85 201121970 The residue was then purified by using Shishi rubber column chromatography. The title compound (517. Omg, yield 75%) was obtained. ???H NMR δ (CDCh) 7.34-7.22 (5H, m), 5.53 (1H, brs), 4.58 (1H, m), 3.71- 3.40 (8H, m), 3.22 (2H, s), 2.76 (4H, m), 1.88 (2H, m), 1.15 (6H, t, J=6. 97Hz). (b) 3-(6-benzene Methyl-2-chloro-5, 6, 7, 8-tetrahydroindolepyridinium [4,3-d]pyridin-4-ylamino)propionic acid I The compound obtained in Reference Example 24 (a) I2Q 2mg, 〇. 297mmol) of acetone-water (4··1) mixed The solution (3 mL) was added with p-toluenesulfonic acid (76.7 mg, 〇.446 mmol), and then stirred at room temperature for 3 hours. The reaction mixture was diluted with tris, then added to a saturated aqueous solution of sodium hydrogencarbonate, and then The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chrome column chromatography to give the title compound. (82. 4 mg, yield 84%) Ή NMR (300 MHz, CDCh » δ ppm) 9. 80 (1H, s), 7. 34-7. 24 % (5H, m), 4. 96 (1H , brs), 3. 80-3. 67 (4H, m), 3. 21 (2H, s), 2.83 (2H, t, J = 5.71 Hz), 2.77-2.73 (4H, m). (c) Taking -(6-benzyl-2-chloro-5,6,7-tetrahydron-[4,3-d]pyran-4-yl)-N3-isopropylpropane-1, 3-Diamine In the methanol solution (1.6 ml) of the compound (51.6 mg, 156 mM) obtained in Reference Example 24 (b), isopropylamine (26. 7 / zL,

312. 312 mmol), acetic acid (18.1 / i L, 0. 312 mmol), NaBH3CN (1·6 mg s 〇 312 〇 。 i), and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and then a saturated aqueous sodium hydrogen carbonate solution s. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCla » d ppm) (5 7.39-7.21 (5H, in), 5.93 (1H, brs), 3.73 (2H, s), 3.64 (2H, m), 3.32 (2H, s), 2.92-2.71 (7H,m), 1.87 (2H, m), 0.96 (6H,d, J=6.42Hz). ® Reference Example 25 7-Benzenyl-2-gas-N-{3-(pyrrole Acridine-i-yl)propyl, 6, 7, 8, 9-tetrahydro-5H-pyrimido[4,5d]azepane-4-amine; and 7-phenylhydrazin-4- Gas-N-{3-(®birolidin-1-yl)propyl b, 6, 7, 8, 9-tetrahydro-5H-pyrimido[5,4-d]azepane-2- amine

(a) 1-Benzyl-5-sideoxyazepane_4_oleic acid ethyl ester to benzhydrylpyridin-4-one (25. 〇g, 〇. i3m〇i) In a solution of tetrahydrofuran (150 ml), a boron trifluoride diethyl ether complex (40.8 ml '〇.33 mol) and ethyl diazoacetate (16 7 ml, 〇16m〇1) were simultaneously added dropwise at -25 °C. After the completion of the dropwise addition, the temperature was slowly raised. After 丨 hours, add water to stop the reaction 322543 87 201121970, then dilute with saturated aqueous sodium bicarbonate solution, and then extract with ethyl acetate. The organic layer was dried over anhydrous brine and dried over anhydrous magnesium sulfate. Then, the obtained residue was purified by silica gel column chromatography (solvent solvent: hexane: ethyl acetate) to give the title compound (16.74 g, yield 46%). ^-NMROOO MHz, CDCh > 5 ppm) : 7. 22 (5H, m), 4. 12 (2H, m), 3.53 (2H, in), 2.32-2.92 (6H, m), 2.06 (1H, m). (b) 7-Benzenyl-6, 7, 8, 9-tetrahydro-1H-pyrimido[4,5d]azepine-2,4(3H,5H)- A solution of the above-prepared compound (16.4 g, 060 mol) in ethanol (240 ml) was added 28% sodium methoxide / methanol solution (124 ml, 0.60 mol) and urea (18.3 g, 0.30 mol) And heating and refluxing. After 9 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was neutralized with aqueous hydrochloric acid. Then, it was subjected to liquid separation extraction with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then reduced by φ. Then, the obtained residue was purified by silica gel column chromatography (solvent solvent; chlorobenzene: decyl alcohol) to give the title compound (0. 99 g, yield: 6.2%). ^-NMR (300 MHz, DMSO-de < 5 ppm): 10. 94 (1H, s), 10.67 (1H, s), 7. 26 (5H, m), 3. 58 (2H, s ), 2. 61 (2H, m), 2. 50 (4H, m), 2.41 (2H, m). (c) 7-Benzyl-2, 4-di-6, 7,8, 9 -tetrahydro-5H-pyrimido[4,5-d]azepane was added to the above-prepared compound (960 mg, 3.54 mmol) with oxygen 88 322543 201121970 gasified phosphorus (15 ml) and heated. Reflux. After 5 hours, the solvent was distilled off under reduced pressure, and ice was added to the obtained residue and then neutralized with saturated aqueous sodium hydrogen carbonate. This was subjected to liquid separation extraction with trioxane, and the organic layer was dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: JH-NMR (300 MHz, CDCh > 5 ppm): 7.32 (5H, m), 3.62 (2H, s), 3.10 (4H, m), 2.67 (4H, m). • (d) 7-Benzyl Base-2-gas-N-{3-(n-r-pyridinyl)propyl}-6,7,8 9_tetrahydro-5H-pyrimido[4,5-d]azepane- 4-amine; and 7-phenylhydrazin-4-yl-N-{3-(pyrrolidin-1-yl)propyl}_6, 7, 8, 9-tetrahydro-5H-pyrimidine[5, 4 -d]azetidin-2-amine 3-(pyrrolidin-1-yl)propane was added to a solution of the above-prepared compound (462 mg, 1.50 mmol) in dioxane (8. 1111) - 1-Amine (284 was [, 2·25 mmol), N,N-diisopropylethylamine (541, 3.0 mmol), and stirred at φ 60 ° C. After 5 hours, the reaction solution was subjected to liquid-phase extraction with ethyl acetate-water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue thus obtained was purified by an amine hydrazine gel column chromatography (solvent solvent; hexane: ethyl acetate) to give the title compound 7-phenylhydrazino-2-chloro-N-{3 -(pyrrolidin-1-yl)propyl}-6, 7, 8, 9-tetrahydro-5H-pyrimido[4,5-d]azepane-4-amine (246 mg, yield 41 %) and 7-phenylhydrazino-4-chloro-N-{3-(pyrrolidin-1-yl)propyl}-6, 7, 8, 9-tetrahydro-5H-pyrimidine[5, 4- d] azepan-2-amine (165 mg 'yield 28%). 89 322543 201121970 7-Benzyl-2-oxan-indole-{3-(ο比丁丁-1-yl)propyl}_ 6, 7, 8, 9-tetrahydro-5H-pyrimidine[4 , 5-d]azetidin-4-amine: !H-NMR (300 MHz, CDCh » δ ppm): 8.05 (1Η, m), 7.27 (5H, m), 3. 55 (2H, s ), 3. 46 (2H, m), 2. 82 (2H, m), 2. 62 (2H, m), 2.44-2.57 (10H, m), 1.73 (6H, m). 7-phenylhydrazine 4- gas-N-{3-〇 略 略-1-yl) propyl}-6, 7, 8, 9-tetrahydro-5H-pyrimido[5,4-d]azepane -2-amine: iH-NMR (300 MHz, CDCls' (5 ppm): 7.24 (5H, m), 5.45 (1H, m), 3.54 (2H, s), 3.37 (2H, m), 2.84 ( 4H, m), 2. 39-2. 57 (10H, m), 1. 72 (6H, in). Reference Example 26-33: The same method as described in Reference Example 24 was carried out using the corresponding starting compound. The reaction/treatment was carried out to obtain the compound shown in Table 4. Table 4 Reference Example 1H-NMR (MHz. Solvent, <5) 26 J0XO Ή-NMR (300 MHz. CDCI3 > δ ppm): 7.21 - 7.39 ( 5 H, n〇. 5.98 (1H. in). 3.64-3.72 (8H. m), 3.34 (2H. s). 2.92-3.04 (1H. n〇. 2.81-2.84 (2H. m). 2.72-2.79 (4H. m). 2.34 (3H. s). 1.78-1. 81 (6H. m).7.24-7.31 (5H. n〇. 3.72-3.87 (3H. N〇. 3.56-3.64 (1H. m). 3.32-3.47 (3H. m). 2 .99 (3H, t. J = 8.7 Hz), 2.74 (1H. d. J = 11.4Hz). 2.64 ( 1H. d, J = 12.0 Hz), 2.09-2.18 1.83-1.90 (1H. m), 1.55 (2H, m). 27 'H-NMR (300 MHz, C0CI3. <5 ppm): 7.24-7.34 ( 5 H, m), 3.70-3.72 (2H, m). 3.54-3.58 (2H, n〇, 3.28 (2H. s), 3.02-3.07 (1H, m), 2.70-2.82 (6H, m), 1.58 -1.88 (8H, m), 1.31 (2H, m). 2 8 'J0CTO Ή-NMR (300 MHz. CDCI3, <5 ppm) : 7.24-7.39 (5 H, m). 6.23 (1H, m) 3.72 (2H, s). 3.48-3.56 (4H, m), 3.19 (2H, s), 2.79 (4H. m), 2.50-2 .59 (6H, m), 1.72-1.76 (2H. m) 0.97 (3H, t. J = 7.2 Hz). 90 322543 201121970 2 9

ΜβΟ^ I cn〇 3 0

XT Ή-NMR (300 MHz. C0CI3l < 5 ppm): 7.22-7.38 (5 H. m). 3.62-3.92 (7H, m), 3.72 (2H, s), 3.54 (2H.m), 3.40 ( 2H, m), 3.27 (3H, s). 3.21 ( 2H. n〇. 2.76 (5H, m), 2.58 (2H. n〇, 2.11 (2H .m). 1.72 (2H. m). 1.57 (2H m). 3 1 'H-NIIR (300 11Hz. C0CI3. 6 ppm): 7.24-7.37 (5 H. m). 6.92 (1H. m). 3.74 (3H. m). 3.54-3.56 (2H. m). 3.34 (2H. s). 2.74 (6H. n〇, 2.53 ( 2H, m), 1.77 (2H, m). 1.48-1.60 (6H. m). 3 2 3— σ 'mfflIR (300 MHz COCIj. δ ppm): 7.19-7.38 (5 H. m), 6.74 (1H, n〇, 5.45 (1H. m). 5.31 (1H. m). 3.77 (2H, s). 3.59 (2H. m ), 3.36 (2H, m), 3.09 (1H, m). 2.68-2.74 (6H, m), 2.57 (2H, m). 1.85-2.01 (6H, m). 1.65 (2H, m).

/~ΝΗ:Xxr〇

---- 'H-NMR (300 MHz, C0CI3. δ ppm): 7.20-7.38 (5 H, m), 6.29 (1H, m). 3.65-3.78 (4H, in), 3.25 -3.45 (4H. m), 3.09-3.14 (2H, m), 2.73-2.88 (6H, m). 2.38-2.47 (2H, m), 2.14-2.17 (1H, m ), 1.72-1.83 (4H. m).____ ' H-NMR (300 MHz, C0CI3. δ ppm): 7.20-7.38 (5 H. m). 6.30 (1H, m). 3.66-3.78 (4H.m), 3.26 -3.46 (4H, m), 3.10- 3.15 (2H, m). 2.73-2. (6H. m). 2.39-2.48 (2H, m), 2.15-2.17 (1H. m), 1.74-1.86 (4H, m). _ Reference example 34 N -(2-(6-Benzyl-2-oxo, 5, 6, 7, 8-tetrahydro-o-pyrido[4,3_d]pyrimidin-4-ylamino)ethyl)- 4-indolyl Plough

(a) 2-(6-Benzenyl-2-chloro-5, 6, 7, 8-tetrahydroindole ratio bite [4, 3-d] squeezing _4-ylamino) ethylamine oxime The acid tert-butyl was prepared by using the compound obtained in Reference Example 1 (b) (147. 7 mg, 0.502 mmol), with N-(2-aminoethyl)amine decanoic acid tert-butyl ester and Reference Example 91 322543 201121970 The same reaction/treatment as the method described in 1 (c) gave the title compound (147. 5 mg, yield 70%). 'H-NMR (300 MHz, CDCh » δ ppm): 7.49 (1H, m), 7.23-7.32 (5H, m), 6.63 (1H, m), 3.79 (2H, s), 3.61-3.64 (2H, m), 3.35 (2H, s), 3.01 (2H, m), 2.56-2.64 (4H, m), 1.42 (9H, s). (b) ^-(6-Benzyl-2-chloro-5 , 6, 7, 8-tetrahydroxanthene[4,3_d], butyl-4-yl)ethene-1,2-diamine, the compound obtained above (144. 7 mg, 〇. 346 mmol) 4N-hydrochloric acid/dioxane solution (2 mL) was added to a solution of decyl alcohol (2 mL), and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and then made to be basic with 28% aqueous ammonia, and extracted with a mixture solvent of trichloromethane/ethanol. The title compound (121. 3 mg, yield 1%) was obtained. !H-NMR (300 MHz, CDCh > (5 ppm): 7.24-7.32 (5H, m), Ref. 5.58 (1H, m), 3.78 (2H, s), 3.56-3.58 (2H, m), 3.34 (2H, s), 3.00 (2H, m), 2.71-2.73 (4H, m). (c) N-(2-(6-Benzyl-2-)-5, 6, 7, 8- Hydrogen "•bi-pyrido[4,3-d]pyrimidin-4-ylamino)ethyl)-4-methylpiped-i-carbenamide in the above compound (121. 2mg, 〇 To a solution of 346 mmol) in THF (3 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc ,

0. 692 mmol) and a solution of methicillin (46. 2/zL, 0. 415 mmol) in THF (1 ml). Then, the temperature was naturally raised to room temperature while stirring overnight, and then, after adding 92 322543 201121970, water was added to the reaction solution for extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. Then, the obtained residue was purified by ethylamine hexane-chrome column chromatography (solvent solvent: chloroform:methanol) to give the title compound (9l 3mg, yield: 6%). H-NMR (300 MHz, CDCls > δ ppm). 7. 23-7. 39 (5Η, m), 5.91 (1H, m), 4. 97(1H, m), 3. 74-3. 77 (4H, m), 3. 44 (2H, m), 3.25-3.30 (2H, m), 3.01-3.03 (4H, m), 2.86-2.87 (2H, in), 2. 80-2. 81 ( 2H, m), 2. 33 (3H, s), 1. 98-2. 00 (4H, m). Reference 35 3-(6-Benzenyl-2-chloro-5, 6, 7, 8 -tetrahydropyrido[4,3_d]pyrimidin-4-ylamino)-bu(4-indolyl-1-yl)ethanone NHBoc oxime, oxime ester (a) 2-(4-mercaptopiperidone哄-1-yl)-2-oxoethylamine decanoic acid tertidine

Add 1^-methylpiped (953.7/^, 8.57111111〇1) and Boundary 8 (:1-11) to a solution of N-Boc-glycine (1. 〇g, 5.71 mmol) in DMF (20 ml). (:1 (1. 64g, 8.57mmol), H0Bt (l·16g, 8.57ιμο1), triethylamine (1.20ml, 8.57mmol), and stirred at room temperature overnight. Add saturated carbonic acid to the reaction solution. The sodium hydrogen chloride aqueous solution was extracted with ethyl acetate, and then the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (1. 15 g, yield 78%) was obtained by column chromatography (solvent solvent; tri-hexane: decyl alcohol) to give the title compound (1. 15 g, yield 78%). 93 322543 201121970 H-NMR (300 MHz, CDCh &gt (5 ppm): 5.50 (1H, m), 3. 92-3.94 (2H, m), 3.60-3.64 (2H, m), 3.35-3.38 (2H, m), 2.34-2.39 (4H, m) , 2.28 (3H, s), 1.42 (9H, s). (b) 2-Amino-l-(4-methylpiperidinyl-yl)ethanone. 3. In a solution of 87 mmol) in methanol (10 ml), add 4M hydrochloric acid in dioxane solution (l〇mi) under ice cooling, and stir at room temperature. The reaction mixture was concentrated under reduced pressure, and then the residue was evaporated to dryness, and then evaporated to dryness. 480·7mg, yield 79%) H-Li R (300 MHz, CDCU, 5 ppm): 3. 59-3. 68 (2H, m), 3.42 (2H, s), 3.35-3.38 (2H, In), 2.35-2.38 (4H, m), 2.28 (3H, s). (c) 3-(6-Benzenyl-2- gas-5, 6, 7, 8-tetrahydropyrido[4, 3_d]pyrimidin-4-ylamino)-1-(4-mercaptopiperidin-i-yl)ethanone The compound obtained by the reference example 1 (b) (149. 7 mg, 0. 509 mmol) and the above The obtained compound (148. 〇mg, 0.764 mmol) was subjected to the same reaction/treatment as the method described in Reference Example 1 (c) to give the title compound (163. 7 mg, yield 78%). -NMR (300 MHz, CDCh » (5 ppm): 7.22-7.34 (5H, m), 5.86 (1H, m), 4.97 (1H, m), 4.17-4.18 (2H, m), 3.68-3.72 (4H , m), 3.51-3.52 (2H, m), 3.38 (2H, s), 2.72- 2.78 (4H, m), 2·45 (4H, m), 2.33 (3H, s). Reference 36 94 322543 201121970 Bu (3-(6-phenylmercapto-2-chloro-5, 6, 7, 8-tetrahydropyridine) [4, 3-d] pyrimidine

To a solution of the compound (144. 〇mg, 〇346_〇1) in DMS0 (1.7 ml) obtained in Reference Example 30, diisopropylethylamine (171111) was added at room temperature, and then trioxide was added. Sulfur/pyridine complex (253. 3 mg, 丨.59 mm 〇 1). After stirring at room temperature for 8 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the residue was purified by silica gel column chromatography (solvent solvent: tri-hexane: methanol) to give the title compound (81. 〇mg, yield 57%). !H-NMR (300 MHz, CDCh > δ ppm): 7.24-7.31 (5Η, m), 6.23 (1H, m), 3.69 (2H, s), 3.57-3.58 (2H, m), 3.18 (2H , s), 2. 81 (4H, m), 2. 67 (4H, m), 2. 58 (2H, m), 2. 26 φ (4H, m), 1.77 (2H, m). Reference example 37 2-Chloro-6-isopropyl-4-(3-morpholinylpropylamino)-5H-pyrrolo[3,4-d] ** dimethyl α-7(6H)~ ketone

The same reaction/treatment as that described in Reference Example 1 (b) 95 322543 201121970 is carried out using a commercially available product or a compound obtained by the method described in WO 2008/136756 (180. 〇mg, 0.731 mmol). The title compound (192. 8 mg, yield 75%) was obtained. 'H-NMR (300 MHz, CDCL· > (5 ppm): 7.59 (1H, m), 4.69 (1H, m), 4.11 (2H, s), 3.76-3.77 (4H, m), 3.62-3.68 (2H, m), 2.55-2.62 (6H, m), 1.80-1.84 (2H, m), 1.27 (6H, d, J = 6.6 Hz). Reference 38-44 Using the corresponding starting compounds, with reference The compounds shown in Table 5 were prepared by the same reaction/treatment as described in Example 1. Table 5

Reference example Structure '«NMIUMHz, Solvent.<S) 3 8 Wide N Λ Ή-NMR (300 »«z. C0CI3. 6 ppm): 7.76 (1H. s). 3.55 (2H .td. J = 5.9, 4.2 Hz), 2.65 (4H.m), 2.57-2.52 (4H, m), 2.15 (2H, tn), 1.80-1.73 (10H, m). 3 9 J0〇'H-NMR (300 MHz. CDCI3, 5 ppm): 3.63-3.58 (2H.m), 2.1 3-2.03 (2H, m), 1.92 (6H.m). 40 'H-NMR (300 (Wz, C0CI3, δ ppm): 6.66 ( 1H, brs), 3.82 ( 4H, m), 2.84 (2H, t, J = 7.7 Hz). 2.66-2.62 (8H. m), 2 .16-2.06 (2H, m), 1.56 (2H, in) 4 1 αΛ-U 'H-NMR (300 mz. CDCI„ d ppm): 6.68 (1H. brs), 3.80 ( 4H. n〇. 3.59-3.55 (2H, m), 2.67-2.63 (8H, n 29. 2.29 (2H , m), 1.84-1.80 (6H. m). 42 'H-NMR (300 MHz, C0CI3. δ ppm): 5.59 (1H. brs), 3.55-3 .49 (2H, m) 2.70-2.63 (4H, m). 2.54-2.50 (4H, m). 2.2 7-2.24 (2H, m), 1.80-1.74 (8H. m). 43 , n^nh Ή-NMR (300 MHz. C0CI3. δ ppm): 5.52 (1H, brs), 4.13-4 .06 (4H, m). 3.70-3.49 (2H. m). 2.67-2.57 (4H. m). 2.4 9-2.46 (4H, m ), 2.27-2.23 (2H.m). 1.87-1.68 (4H, n〇. 44 'H-NMR (300 MHz. C0CI3 > δ ppm): 3.95 (2H. m) , 2.89-2.75 (4H, m). 2.4« (2H, m). 2.38-2.28 (7H, m). 1.92-1.78 ( 4H, m), 1.74-1.64 (2H, m), 1.52 (2H, m 96 322543 201121970 Reference 45, 7, 8-tetrahydroisoxanthine 3-(2-(4-(4-mercaptopiperidinyl)phenyl)_5, ~4-ylamino) Pan

OEt

(a) 2-Gas-N-(3,3-di-4-aminoethoxypropyl)-5, 6, 7, 8-tetrahydropurine at 2, 4-di-gas-5, 6 , 7, 4-tetrahydroquinazoline (496. 0 mg, 2 44 mmol) in a solution of 1,4-di-Pf (7.5 ml) was added with amidino-3, methoxypropane (593. 0) y L, 3. 66 mmol) and diisopropylethylamine Φ (881. 0#L, 4. 88 mmol), then stirred at 6 ° C for 3 hours. Saturated brine was added to the mixture, and the mixture was evaporated to ethyl acetate. The residue was purified by hydrazine gel column chromatography to give the title compound (535. Omg, yield 70%). iH-NMR (300 MHz, CDC13, 5 ppm): 5. 73 (1H, brs) 4 61

(1H, t, J = 4. 9 Hz), 3. 75-3. 65 (2H, m), 3.61~3. 45 (4H m), 2.63 (2H, m), 2.20 (2H, m ), 1.94-1.88 (2H 1.79-1.73 (4H, m), 1.63 (3H, s), 1.22 (6.3H t τ II", L, J = 7 1 322543 97 201121970

Hz). (b) N-(3,3-Ethoxypropyl)-2-[4-(4-methyl 〇 -1--1-yl) stupid]-5, 6, 7, 8 - tetrahydroindolyl-4-amine is added to the 1,4-dioxin (3.81111) solution of the compound (300. 〇mg, 〇. 956mm〇l) prepared in Reference Example 46(a). Methyl 4-[4-(4, 4, 5, 5-tetradecyl-1,3,2-dioxaborolan-2-yl)phenyl] piperene (347. Omg, 1. 150mmol), 3mol/L sodium hydroxide solution (956·Ο/zL), tetrakis(triphenylphosphine)palladium (110·0mg, 〇. 〇956mm〇1), under the irradiation of waves at 15 0 C Give a drop. After 30 minutes, the mixture was extracted with ethyl acetate _ water, and the organic layer was washed with saturated brine. After drying with anhydrous magnesium sulfate, the organic layer was evaporated under reduced pressure. Then, the residue was purified by the Shih-Hui-p------------ H-NMR (300 MHz, CDCh » δ ppm): 8.27 (2H, d J = 9 0 Hz), 6.94 (2H, d, J = 9.0 Hz), 5.23 (lH, brs), 4.66 # ΠΗ, t, J = 5.1Hz), 3. 76-3. 69 (4H, m), 3> 54 (2Η>m)>

3· 29 (4H, in), 2.75 (2H, m), 2.58 (4H, m) 2 35 (3H s)> 2.31 (2H, m), 2. 00 (2H, m), 1.85 (4H, In), 1.24(6^ t, J = 7.0 Hz). (c) 3-{2-[4-(4-Hydrylpiperazin-1-yl)phenyl μ5,6 7 8_tetrahydroquine sitting Phenyl-4-ylamino}propanal is added to the compound (47 l. 〇mg, 〇 〇 〇 〇 〇 1) prepared in Reference Example 46 (8) in a mixed solution of propylene-water (4:1) (l 〇 ml). P-toluenesulfonic acid monohydrate (395. Omg, 2.08 mmol) was then stirred at 5 °t for 7 h. The mixture was diluted with water at 322543 98 201121970, and then the aqueous layer was washed with ethyl acetate, and then brought to pH = 1 〇 to 5 with a 5 mol/L aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. EtOAc (EtOAc m. g, H-NMR (300 MHz, CDCh, (5 ppm): 9.87 (1H, s) 8 26 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9 〇 'Hz)', (9ι

(1H, brs), 3.94 (2H, q, J = 5.9 Hz), 3.3" 28 (4H m), 2.93 (2H, t, J ^ 5. 9 Hz), 2.75 (2H, m), 2. 6〇_2 5; (4H,m), 2.36-2.30 (5H,m), 1.84 (4H,m) Reference Example 4 6 2-Chloro-N-(3-morpholinylpropyl)-7, 8 ~Dihydro-511_pyrano[4,3-d]pyrimidin-4-amine

〇0

NH

(a) 2-Amino-7,8-dihydro-5H-t-N-[4,3-d]-penetrate + alcohol in dihydro-2H-pyran-4(3H)--. 〇g, Do not add coffee (4), (15), in -m: add double (three? base aminating clock to burn / gluten (1. lmol / L '46ml '50mmol). After 1 hour, add cyanide Methyl decanoate (3. 96ml, 50mmol). After stirring for 2 hours at -78 Torr, a saturated aqueous solution of ammonium chloride was added, and then extracted with ethyl acetate three times. The organic layer was washed with 99 322543 201121970 saturated brine, then 5小时。 Then the reaction was carried out. The reaction was carried out with a solution of EtOAc (5 ml). The solution was cooled to room temperature, and the resulting suspension was filtered, and the residue was washed with decyl alcohol. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to chromatography on a column chromatography (solvent solvent; trichloromethane) Purification by sterol) gave the title compound (1. 33 g, yield 16° /.). H-NMR (300 MHz, DMSO-de » δ ppm): 10.76 (1 Η, brs), 6. 34 (2H, brs), 4. 23 (2H, s ), 3. 76 (2H, t, J = 5. 7 Hz), 2. 35 (2H, t, J = 5. 7 Hz). (b) 4-gas-7, 8-dihydro-5H- Pyrano[4,3-d]pyrimidin-2-amine was added to the above-prepared compound (1. 5 g, 6.28 minol), and phosphorus (10 ml) was added and heated at ll 〇t for 5 hr. Then, the solvent was distilled off by an evaporator, ice was added to the residue, and saturated aqueous sodium hydrogencarbonate solution was added for neutralization. The aqueous solution was stirred at 5 Torr. After stirring for 1 hour, the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the residue was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssss δ 4 98 (10), brs), 4. 6 〇 (2H, s), 3.97 (2H, t, J = 5.7 Hz), 2.75 (2H, t, J = 5. 7 Hz). (c) 2' 4 - Diqi-7' 8-dihydro-5Hi-[4,3_d]carbanidine was added to the above-prepared compound (72Qmg, 3 88mmQl) in a gas-fired (2〇ml) solution and added under ice cooling. Gasification of trimethyl stone eve (4 birds 322543 100 201121970 38· 8mmo 1). After 15 minutes, succinic acid third butyl vinegar (2. 31 m 1, 19. 4 mmol) and gasified benzoyltriethylammonium (800. 2 mg, 7.76 mmol) were further added. After 20 minutes, the temperature was raised to room temperature and stirred for another 2 hours. A saturated aqueous solution of sodium bismuth carbonate was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc R (300 MHz, CDCh, 5 ppm): 4·69 (2H, s), 4.02 (2H, t, J = 6.0 Hz), -2.97 (2H, t, J = 6. 0 Hz). d) 2-Chloro-N-(3-morpholinopropyl)-7, 8-dihydro-5H-indolo[4,3-d]pyrimidin-4-amine using the compound prepared above ( The title compound (70. 9 mg, yield 74%) was obtained from the titled compound (yield: 74%). • H-NMR (300 MHz, CDCh >< 5 ppm): 6.78 (1H, m), 4.43 φ (2H, s), 3. 96 (2H, t, J = 5. 1 Hz), 3. 74-3. 77 (4H, m), 3.54-3.58 (2H, m), 2.74-2.78 (2H, m), 2.52-2.56 (6H, m), 1.78-1.80 (2H, m). Reference 47 -55 The same reaction and treatment as in the method described in Reference Example 46 were carried out using the corresponding starting compound, and the compound shown in Table 6 was obtained. The dihydro-2H-pyran-4(3H)-one derivative as a raw material can be used in the synthesis of Reference Example 59 or 60 and a commercially available one. 101 322543 201121970 Table 6 Reference example Structural solvent, 5) 4 7 Ή-NMR (300 1 Hz, C0CI 3. 5 ppm): 7.93 (1H. m), 4.32 (2H, s). 3.93 (2H, t. J = 5.7 Hz). 3.54-3.59 (2H. m), 2.68-2.75 (4H, m), 2.58 (4H, m). 1.78-1.84 (6H, m) 48 c丨 human-NMR (300 MHz, CDCI3, 5 ppm): 5.40 (1H, m), 4.45 (2H, s). 3.96 (2H. t, J = 5.4Hz), 3.73 (4H, m). 3.5 3-3.59 (2H, m), 2.77 (2H .t, J = 5.4 Hz). 2.64 (2H, m), 2.52 (4H, m). 4 9 Ή-NMR (300 MHz, C0CI3, <5 ppm): 5.43 (1H, m), 4.39 (2H , s), 3.90 (2H, t. J = 5.7Hz), 3.46-3.51 (2H, m), 2.71 (2H, t. J = 5.7 Hz), 2.65 (2H, t, J = 5. 7 Hz) , 2.46-2.50 (4H.m). 1.72-1.75 (4H.m). 50 ΝΜθ2 ό clANJ〇Ή-NMR (300 MHz. C0CI3. δ ppm): 4.47 (2H. s). 3.96 (2H, t. J = 6.0Hz), 3.81-3.86 (2H, m), 2.81-2.92 (4 H, m). 2.21-2.36 (7H. m). 1.83-1.88 (2H, m), 1.39-1. 53 (2H , n〇. 5 1 k/〇ΝΛγ^-0 'H-WMR (300 mz, C0CI3, <S ppm): 7.17-7.29 (5H, m), 4.72 (1H. m); 4.38 (2H. s ), 3.90 (2H.t. J = 5.7 Hz), 3.57-3.82 (4H, n〇. 3.43 (2H. s), 3.20-3.28 (1H, m) , 2 .70-2.74 (3H, ra), 2.60-2.64 (1H, tn), 2.06-2.15 (1 H. m), 1.82-1.89 (1H, m). 5 2 G NV° αΛΝ^ΛΜβ 'Η-NMR (300 MHz, C0CI3. <5 ppm): 8.02-7.87 (1H, m), 4.42-4.28 (2H, m). 3.81-3.74 (1H, m), 3.58-3.53 (2H, m). 2.71- 2.67 (2H, m). 2.59-2.56 (6H. m), 1.83-1.72 (6H, m), 1.32 (3H. d, J = 6. 3 Hz). 5 3 C into N people乂 Me 'H -NMR (300 MHz, CDCI3, δ ppm): 6.79-6.70 (1H, m). 4.55-4.39 (2H, m). 3.83-3.74 (5H, m). 3.59-3.55 (2H, m), 2.62- 2.50 (8H, m), 1.80-1.76 (2H, m), 1.34 (3H, d, J = 6.0 Hz). 54 NV^O .丨人七 β 'Η-NMR (300 MHz, C0CI3. < 5 ppm): 6.77-6.72 (1H, m), 4.42 (2H, s), 3.75 (4H, t, J = 4.6 Hz), 3.60 -3.55 (2 H, m). 2.61 (2H. s), 2.56-2.52 (6H. n〇, 1.83-1.76 (2 H, m). 1.34 (6H, s). 5 5 N^X^/VΌ c Ή-NMR (300 MHz, C0CI3. δ ppm): 6.70-6.68 (1H, m), 4.40 (2H, s), 3.75 (4H, t, J = 4.6 Hz), 3.60-3.54 (2 H, m ), 2.71 (2H, s), 2.58-2.50 (6H, m). 1.86-1.48 (1 OH, m).

Reference Example 56 ^-(2-Ga-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-N3-(2-methoxyethyl)-N3- Mercaptopropene-1, 3-diamine 102 322543 201121970

(a) 2-Chloro-N-(3, 3-diethoxypropyl)-7, 8-dihydro-5H-°pyrano[4,3-d]pyrimidine-4-amine® Reference The compound (71. 2 mg, 0. 347 匪〇1) obtained in the compound of Example 46 (c) was subjected to the same reaction/treatment as the method described in Reference Example 46 (d), whereby the title compound (90. 6 mg) was obtained. , yield 83%). • H-NMR (300 MHz, CDCh » δ ppm): 5.56 (1Η, ra), 4.62 (1H, t, J = 4.5 Hz), 4.38 (2H, s), 3.94 (2H, t, J = 5. (7H, m), 2. 7. 2 Hz). φ (b) 3-(2-chloro-7, 8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-ylamino)propionic acid The obtained compound (89. 2 mg, 0. 282 mmol) was subjected to the same reaction/treatment as the method described in Reference Example 24 (b), whereby the title compound (70. 9 mg, yield 100%) was obtained. H-NMR (300 MHz, CDCh 5 5 ppm): 9.82 (1H, s), 4. 9〇 (1H, m), 4.38 (2H, s), 3.94 (2H, t, J = 5.7 Hz), 3 77-3. 83 (2H, m), 2. 86 (2H, t, J = 5. 4 Hz), 2. 76 (2H, t, J = 5. 7 Hz), 2. 52-2. 56 (6H, ra). 103 322543 201121970 (c) N -(2-Fluoro-7, 8-dihydro-5Η-° pyrano[4, 3-d] mouth bite-4-yl)-N3- (2-methoxyethyl)-N3-mercaptopropane-; [, 3-diamine using the compound obtained above (69. Omg, 〇. 282 mmol) and carrying out the corresponding raw material with Reference Example 24 ( c) The same reaction/treatment as the method described was used to prepare the title compound (68. 9 mg, yield y 8%). H-NMR (300 MHz, CDCla, 3 ppm): 7.57 (1H, m), 4.40 (2H, s), 3.93 (2H, t, J = 5. 7 Hz), 3.55-3.60 (2H, m), 3.46-3.50 (2H, m), 3.29 (3H, s), 2.73 (2H, t, J = 5. 7 Hz), 2.60 (4H, m), 2.30 (3H, s), 1.74 (2H, m) Reference Example 57 3-(2-(4-(4-methyl)-l-yl)phenyl)-7, 8-dihydro-5H_npyrano[4,3-d]pyrimidine-4- Amino)propionaldehyde OEt

〇hc^.nh

ΜβΌ (a) Ν-(3, 3-diethoxypropyl)-2-(4-(4-methylpy[ΐ井-1-yl)phenyl)-7, 8-dihydro-5Η a solution of the compound (5i3 mg, 1.63 mmol) of 1,4-dioxane (6.5 ml) obtained by the reference of the compound of Example 56 (a). Add 4-(4-methylpiped-1-yl) 104 322543 201121970 Phenylboronic acid pinacol ester (592 mg, 1.96 mmol), 3 mol/L aqueous sodium hydroxide solution (1.6 ml ' 4. 89 mmol) The tetrakis (triphenylphosphine) was stirred under microwave irradiation at (15 g). After 3 minutes, the mixture was extracted with ethyl acetate-water, and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H-NMR (300 MHz, CDCh, (5 ppm): 8. 21 (2H, d, J = 9. 0

Hz), 6. 88 (2H, d, J = 9. 0 Hz), 4. 96 (1H, m), 4. 59 (2H, t, J = 5. 1 Hz), 4. 43 (2H, s), 3. 95 (2H, t, J = 5. 7 Hz), 3.60-3.70 (4H, m), 3.41-3.52 (2H, m), 3.22-3.25 (4H, m), 2.79 (2H, t, J = 5. 7 Hz), 2.50-2.53 (4H, m), 2.29 (3H, s), 1.89-1.95 (2H, m), 1.89 (6H, t, J = 1.2 Hz), (b) 3-(2-(4-(4-mercaptopiperidin D-i-yl)phenyl)-7,8-dihydro-5H_0-pyrano[4,3-d]pyrimidin-4-ylamino Adding a mixture of the above-prepared compound (655 mg, 1.44 mmol) in acetone-water (4:1) (2 mL) to p-toluenesulfonic acid/1 hydrate

Gllmg ' 2.16 mmol), then stirred at 50 ° C for 1 hour and then at 60 °.搅拌 Stir for 1 hour. Further, p_benzenesulfonic acid/hydrazine hydrate (137 mg, 〇·72 ship 〇1) was added, and the mixture was stirred at 60 ° C for 2 hours. After the reaction mixture was allowed to cool at room temperature, then concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added to the residue and then extracted with trichloromethane. The title compound (543 mg, yield 99%) was obtained. 105 322543 201121970 ^-NMR (300 MHz, CDCh » 5 ppm): 9.84 (1H, s), 8.24 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz), 4. 55-4. 57 (1H, m), 4.46 (2H, s), 3.99 (2H, t, J = 5. 7 Hz), 3.88-3.94 (2H, m), 3.28-3.31 ( 4H, m), 2.92 (2H, t, j = 5.7 Hz), 2.84 (2H, t, J = 5. 7 Hz), 2.55-2.59 (4H, m), 2.34 (3H, s). ' Reference example 58 chloro-N_(3_? 吓 propyl propyl)-7,8-diaza^ thio- 0-pyrano[4 g-d] pyrimidine-4-amine

(a) 2,4-diqi-7,8-dihydro-5H-thio-β-pyrano[4,3-d] sprayed to the compound prepared in Reference Example 22(a) (187. 5 mg, 1. 〇 2 mm 〇 1) was added with oxygen chaotic phosphorus (1.9 m 1 ), and heated at 11 ° C for 3 hours. The anti-corridor was concentrated under reduced pressure. Benzene was added to the residue and the solvent was distilled off. Ice was added to the obtained residue and then neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with tri-methane. The organic layer was dried over anhydrous sodium sulfate and evaporated. Then, the residue was purified by a silica gel column chromatography (solvent solvent, hexane, ethyl acetate) to give the title compound (182·3mg, yield 81%). jH-NMR (300 MHz, CDCh > 5 ppm): 3.78 (2H, s), 3.20 (2H, t, J = 5.7 Hz), 2.93 (2H, t, J = 5. 7 Hz). (b) 2- gas-N-(3-morphinylpropyl)-7, g-dihydro-5H-thiopyrano[4,3-d]pyrimidine-4-amine 106 322543 201121970 Add 3-(morpholin-1-yl)propan-1-amine (76. 3//L, 0. 522 mmol) to a solution of the compound (77. Omg, 0. 348 mmol). , N,N-diisopropylethylamine (126/zL, 696 mmol), and stirred at 60 °C. After 3 hours, the reaction solution was extracted with ethyl acetate-water, and then the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) _ !H-NMR (300 MHz, 00013» δ ppm): 6.99 (1H, m), 3.69-3.66 (4H, m), 3.55-3.49 (2H,m), 3.32 (2H, s), 2.94 (2H , t, J = 5.4 Hz), 2.82 (2H, t, J = 5. 4 Hz), 2.46-2.52 (6H, m), 1.71-1.79 (2H, m). Reference 59 2-Mercaptodihydrogen -2H-pyran-4(3H)-one

(a) 2-Mercaptotetrahydro-2-indole-»pyran-4-ol was added to 3-butan-1-ol (27.0 g, 0.374 mol) with acetaldehyde (11. 〇g, 0.25 mol). An 80% aqueous sulfuric acid solution (40 ml) was slowly added dropwise thereto at 0 ° C over 40 minutes, and the mixture was warmed to room temperature and stirred overnight. After the completion of the reaction, ice was added and neutralized with a 1 Torr/L aqueous sodium hydroxide solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was then evaporated under reduced pressure, and the obtained residue was purified using EtOAc EtOAc EtOAc EtOAc EtOAc . ^-NMR (300 MHz, CDCla > (5 ppm): 4.00 (1H, m), 3.82-3.72 (1H, m), 3.42 (2H, m), 1.99-1.84 (2H, m), 1. 56 -1. 42 (1H, m), 1. 20 (3H, d, J = 6. 1 Hz), 1. 18 (1H, in). (b) 2-Methyldihydro-2H-«pyran -4(3H)-one was added to a solution of the above-prepared compound (8. 13 g, 0.070 mol) in dichloromethane (160 ml), molecular sieve 4A (8.13 g), pyridinium dichlorochromate ( 29. 0g' 0 · 077mol), and stirred overnight at room temperature. After the reaction is completed, diethyl ether (320 ml) is added and stirred for 30 minutes, and then filtered with diatomaceous earth. The solvent is then evaporated under reduced pressure to give residue. The title compound (5. 04 g, yield 40%, content 53%) was obtained from the title compound (5. , CDC13, in ppm): 4.28 (1H, m), 3.79-3.63 (2H, m), 2.64-2.53 (1H, m), 2.44-2.24 (3H, φ m), 1.32 (3H, d, J = 6. 1 Hz). Reference Example 60 6-oxaspiro[4. 5]pyrrol-9-one

The title compound (yield 55%, stage) was obtained by the same reaction/treatment as the method described in Reference Example 59, using the corresponding starting compound. ° H-NMR (300 MHz, CDC13, (5 ppro): 3·96 (2H, t,] = 6 322543 108 201121970

Hz), 2.45 rΛ11 m), 1.74 (2H, m), ^ (4H, m), 1.90-1.81 (2H 1.63 (2H ' ' m), 1.53 (2H, m). Reference example 6l~~67 The raw material compound was subjected to the same reaction/treatment as the method described in Reference Example or Reference Example 46 to obtain the compound shown in Table 7. Table 7

Reference example Structural formula 'H-NMROVIHz, solvent, ¢) 61 'H-NMR (300 l«z. CDui3, δ ppm): e.〇8 (i.〇h, brs), 3. 56-3.50 (2H m.. 2.78 (2H. m). 2.70 (2H. m). 2.59-2. 55 (4H. m). 2.40 (2H. m). 1.84-1.75 (8H, m). 1.68-1. 57 (4H.m). 62 'H-NMR (300 MHz, C0CI3, ΰ ppm): 7 〇7 (1H brs) 3 75 (4H, n〇, 3.54 (2H. m). 2.81 (2H, m). Z 57-2.51 (8H. m), 1.88-1.76 (4H. m). 1.70-1.58 (Μ «Λ 63 αΛ-Ο 'H-NMR (300 MHz, C0CI3. «5 ppm): 443 s), 3.95 ( 2H, t, J = 5.6 Hz). 3.55 (2H, m) £.76 (2H, t, J = 5.6 Hz), 2.64 (2H. m). 2.51 (4H, m), 1.65 (4H, m ), 1 .49 (2H. in). 64 Me 6 , N 'h-TBiiK wuo Mhz. UJGI3, δ ppm): 4 45 (2H, s), 3.97 ( 2H, t. J = 6.1 Hz), 3.40 (4H. m), 2.84 (2H, t, J = 6 .1 Hz), 2.44 (4H, m), 2.27 (3H, s). 65 Cl N^Y^O Wide N 'H-NMR (300 fflz , COCI,, δ ppm): 4.53 (2H, s), 3.90 ( 2H, t, J = 5.7 Hz), 3.74 (4H, 〇〇, 2.68 (2H, t, J = 5 .7 Hz), 2.37 ( 4H, m), 2.26 (3H. s). 66 ΟΜθ ύ , N 'H-NMR (300 IWz. C0CI3, δ ppm): 4.57 (2H, s). 3.94 ( 2H, t, J = 5.7 Hz) , 3.80 (4H, m), 3 52 (3⁄4. t, J = 5 .5 Hz), 3. 35 (3H, s), 2.73 (2H, t, J = 5 7 Hz) 2 59 (2H, t. J = 5.5Hz). 2.51 (4H. m). ' ,.^〇67 Cl Μβ〇~Ν” 'H-NMR (300 MHz. CDCI,. 6 ppm): 4.57 (2H s) 3 94 ( 2H, t, J = 5.8 Hz) , 3.80 (4H. m), 3.52 (2H, t, J = 5 .6 Hz), 3.35 (3H. s). 2.72 (2H. t. J = 5.8Hz). 2.59 (2H. t, J = 5.6 Hz), 2.51 (4H.m). Example 1 109 322543 201121970 Ν'-{6-Benzyl-2-[4-(4-methylpiped-bu)phenyl]-5, 6, 7, 8-tetrahydropyrido[4,3-d]pyrimidin-4-yl}-叱N-dimethylpropane-1,3-diaminetris(trifluoroacetate)

Add 4-(4-mercaptopiperazin-1-yl)phenylboronic acid pinacol ester to a solution of Reference Example 1 (50 mg, 0. 139 mmol) in DME (0.8 ml)-water® (0.2 mL) (63.0 mg, 0.208 mmol), sodium carbonate (44.2 mg, 0.417 mmol), tetrakis (diphosphine) Ie (16. lmg, 〇. 〇i 39 mmol), and stirred with heating at ll 〇〇c. After 6 hours, the mixture was extracted with ethyl acetate-water, and dried over anhydrous magnesium sulfate. The resulting residue was purified by high-speed liquid chromatography (solvent solvent; 〇 〇 5% - aqueous trifluoroacetic acid: decyl alcohol) to give the title compound (1.7 mg, yield: 1.4 %). LC/MS; retention time 3.57 min, m/z = 500 (M + 1) Example 2 {' -{6-benzoyl-2-[6-(4-mercapto[alpha]-[alpha]--1 -yl)pyridin-3-yl]-5,6,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl}-yis-difluorenyl-two-sinter-1,3-di Amine 322543 110 201121970

Add 2-(4-mercaptopiperazyl)pyridine _5_boronic acid to a solution of reference example 1 (50 mg, 0.139 mmol) of dioxane (i. 〇mi) and water (0.25 ml). Alcohol ester (63. 2mg, 0. 208mmol), sodium carbonate (44.2mg, 0. 417mmol), tetrakis(triphenylphosphine)palladium (8. 〇mg, 〇. 〇〇7〇mm〇1), The mixture was stirred at 120 ° C under microwave irradiation. 1. After 5 hours, it was subjected to liquid separation extraction with ethyl acetate-water, and then dried over anhydrous magnesium sulfate, and the organic layer was evaporated under reduced pressure. The residue was purified by high-speed liquid chromatography (solvent solvent: EtOAc: EtOAc: EtOAc) 'H-NMR (300 MHz, CDCh > 5 ppm): 9. 19 (1H, d, J = 2. 4

Hz), 8. 40 (1H, dd, J = 8. 8, 2. 4 Hz), 7. 36 (5H, m), 6. 83 • 〇H, s), 6.66 (1H, d, J = 8.8 Hz), 3.75 (2H, s), 3.65 (6H, in), 3.20(2H, s), 2. 87 (4H, m), 2. 54 (4H, m), 2.44 (2H, m), 2.35 (3H, s), 2.06 (6H, s), 1.73 (2H, m). LC/MS; hold time 3.54 minutes ' m/z = 5〇i (M+i) Example 3-42 Use corresponding The starting compound was subjected to the same reaction/treatment as in Example 2 to give the compound shown in Table 8. 111 322543 201121970 Table 8

EXAMPLES Structural formula LC/MS; m/z (M+1) retention time (minutes) 3 ΜβΌ U 488 3.92 4 Me,, Me kN-Me 514 3.38 5 ΜβΌ Me k^.Me W^CTO ΜβΌ 515 3.36 6 ΟΛ NH u Me, N^ 526 3.63 7 ΟΛ NH u Θ MeW 527 3.59 8 ΟΛ NH joy^ 485 3.50 112 322543 201121970 9 ΝΗ 527 3. 48 10 ΟΛ ΝΗ 0 542 3. 57 11 ΟΛ ο#00 〇. 584 3. 62 12 ^ΝΗ Me,NJ 540 3. 64 13 οχ υ 广Ν人^ Me-^ 540 3.71 14 οχ υ 丄θ Me'NJ 541 3.69 15 Ο ^ΝΗ ΜβΌ 528 3.39 16* d N^V^N ^T^i iVvb. υ μ,Νν^ 542 3.43 17 〇〇Χ γ〇570 3. 58 113 322543 201121970

18 〇〇Λη 573 3.44 19 , NH 556 3. 52 2 0 Order XJ Guang M, NJ 554 3.86 2 1 u , NH rNi/X^ 555 3.67 2 2 Eight HN^Y^N^Y^) jy^^O 528 3.53 2 3 Ma, N.Me ό 526 3.37 2 4 526 3.64 2 5 ΟΛ NH ^yiOjO 513 4.31 114 322543 201121970

2 6 Cf\H 〇Νγ〇^Ν Force 0 525 4.51 2 7 ΟΛ , ΝΗ 0^0^° Force 527 3.64 2 8 ΟΛ ΝΗ ΜβΌ 527 3. 62 2 9 ο\Η ox^°nj0 514 3.99 3 0 CTiNH Nyfcj〇广NAJ 528 3:74 3 1 ΟΛ ΝΗ iV^OjO 515 4.44 3 2 , ΝΗ Μβ^ 514 3.57 3 3 Me ό 526 526 3.41 3 4 Μβ 〔:] 1 542 3.30 115 322543 201121970

3 5 ΟΛ , NH 423 3.31 3 6 ΟΛ ΝΗ N^V^S 453 3.51 3 7 ΟΛ , Η Me2U^A^ 412 3.21 3 8 Μβ'Ν^> ^ kNH rNxy^° Μ·^ 409 3. 50 3 9 ΜβΌ Me Lnh Pn human β 410 3.43 4 0 Me M, N\ , NH rNj〇^° 395 3.35 4 1 ΟΛ NH 540 3.40 4 2 ΟΛ NH N^N 540 3.44 : Example 16 can utilize 2-propanol And recrystallize. Example 43 116 322543 201121970 6-Benzenyl-2-{4-[(4-methylpiperidin-1-yl)indolyl]phenyl}-1 (3-indolebiol-1-yl) Propyl)-5, 6, 7, 8-tetrahydro 0 is determined by [4, 3-(1]σ密0定-4-amineΝΗ

曱 Add 1-mercaptopurine (14. 6 // L, 0.132 mmol), acetic acid (37. 7 // L) to a solution of decyl alcohol (1.0 ml) in Reference Example 18 (50 mg, 0.11 mmol) , ® 0· 658 mmol), sodium cyanoborohydride (27. 6 mg, 0.439 mmol), and stirred at room temperature. After the reaction was carried out overnight, the mixture was extracted with ethyl acetate-sodium bicarbonate aqueous solution, and the organic layer was washed with saturated brine and then dried over anhydrous sulphuric acid. Then, the resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) LC/MS; retention time 3.63 min, m/z = 540 (M + 1) φ Example 44-57: The same reaction/treatment as in Example 43 was carried out using the corresponding starting compound, and the yield shown in Table 9 was obtained. Compound. 117 322543 201121970 Table 9 Example Construction LC/MS; m/z (M+1) Hold time (minutes) 4 4 NH Η〇ΌΧ^ U 541 3. 52 4 5 ΟΛ NH 503 3. 46 4 6 ΟΛ NH Ojo^h 545 3. 53 4 7 ΟΛ NH OjD1^0 408 3.35 4 8 ΟΛ NH OjO1^0 424 3. 26 118 322543 201121970 4 9 ΟΛ ΝΗ 410 3.44 50 ΝΗ iV) 〇〇Ί〇ΤΝ 408 3.44 5 1 ΟΛ 424 424 3.34 5 2 ΟΛ ΝΗ 〇NJ〇^ 438 3.37 5 3 ΟΛ ΝΗ N^V^S OjO^ 454 3.28 5 4 ΟΛ 440 440 3.39 5 5 O' N^V^S 438 3.39 5 6 ΟΛ NH N^V ^S 〇cn〇A^ 454 3.30 5 7 ΟΛ NH 440 3.41 Example 582 - {4-(4-Methyl σ 哄 哄-1-yl)phenyl}-Ν-(3_σΛρ唆唆-1-ylpropane 119 322543 201121970 base)-5, 6, 7, 8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

NH

6-Benzenyl-2-[4-(4-methylpiped-1-yl)phenyl]-N-(3-indolyl-1-ylpropyl) obtained in Example 6 -5,6,8-tetrahydropyridinium[4,3-d] benzoate 0--4-amine (800 mg, 1.52 mmol) of decyl alcohol (161111)-water (4. Oml) 10% p-carbon (320 mg, 50%-aqueous), 4 mol/L • hydrochloric acid/dioxane (4.0 ml) was added to the solution under a hydrogen atmosphere (0.4 MPa) and stirred at 4 (TC) for 7 hours. After that, the mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was dissolved in decyl alcohol, neutralized with triethylamine, and the solvent was evaporated under reduced pressure. The title compound (476 mg, yield 72%) was obtained by chromatography on silica gel column chromatography (eluent solvent: hexanes: hexanes). φ LC/MS ; retention time 2.78 minutes, m/z = 436 (M+1). Example 59-61: The same reaction/treatment as in Example 58 was carried out using the corresponding starting compound, and Table 10 was obtained. Compounds shown. 120 322543 201121970 Table ί. Example Construction LC/MS; m/z (M+1) retention time (分) 5 9 ΟΛη Μθ'Ν J 452 1.65 6 0 οΟΛη N人广NH o 483 2.72 6 1 |^0θΗ 436 2. 60 Example 62 6 -Methyl- 2_[4-(4-methyl π卩-1-yl)phenyl]-N-(3_0 to 17 each -1-ylpropyl)-5, 6, 7, 8-tetrahydropyrido[4, 3-d]pyrimidine-4- amine

2-[4-(4-Mercaptopiperidin-1-yl)phenyl]-indole-(3-πΐ^ each α-I-propyl)-5,6 obtained in Example 58 ,7,8-tetrahydrogen 0 is added to the solution of [4, 3-d] ketone 0--4-amine (50 mg, 0.115 mmol) in decyl alcohol (1.0 ml), 35% aqueous solution (27.3) #1^,0.344111111〇1), acetic acid (39.4#[, 0. 689 imnol) and cyano-sodium hydride (28. 9 mg, 0. 459 mmol), and stirred at room temperature. After the reaction was carried out overnight, the mixture was extracted with a solution of trichloromethane-sodium bicarbonate, and then dried over anhydrous magnesium sulfate, and then the organic layer 121 322543 201121970 was evaporated under reduced pressure. The residue thus obtained is purified by an amine-based ruthenium column chromatography (solvent solvent; trioxane: ethyl acetate-trioxane·nonanol) to obtain the title compound (35. 9 mg, yield 70%). LC/MS; retention time 2.61 minutes, m/z = 450 (M + 1). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

122 322543 201121970 Table 11

EXAMPLES Structural Formula LC/MS; m/z (M+1) Hold Time (minutes) 6 3 ΟΛ ΝΗ Ν person, rNi^° Μβ^Ο 478 2. 97 64 ΟΛ ΝΗ Me rNJ〇r^° 478 2.81 6 5 cn NH ΝΛγ^Ν 〇Me rNXX^C 494 2. 94 6 6 «X r〇rNiy^° Me-N^ 520 3.05 6 7 〇〇X { fj^AN^ 494 2. 79 6 8 〇〇X Ν^γ^Ν-Μβ 497 3. 52 69 ΟΊη 525 2. 83 7 0 ΟΛ NH (pY^O'Me 450 2. 87 7 1 ΟΛ NH 广ν0^νΌ 520 3.10 123 ϋ 322543 201121970 Example 72 7- Ethyl-2-[4-(4-mercaptopiperazin-1-yl)phenyl]_^_(3_pyrrolidin-1-ylpropyl)-5' 6, 7, 8-tetrahydrogen Pyrido[3,4-d]pyrimidin-4-amine

2-[4-(4-Methylpiperidin-1-yl)phenyl]-N-(3-0, butyl-1-ylpropyl)-5,6, obtained in Example 61 7, 8-tetrahydrogen is added to the [2, 4-d] oxazolidine-4-amine (40mg, 0. 0918mmol) in a gas-fired (1. 〇mi) solution. (7.8; tzL, 0.11 mmol), and stirred at room temperature. After 2 hours, the solvent was evaporated under reduced pressure, and then the residue obtained was purified by high-speed liquid chromatography (solvent solvent: EtOAc. 14. 4 mg, yield 33%). LC/MS; retention time 3.51 min, m/z = 478 (M + 1) Example 73-74: φ The same reaction/treatment as in Example 71 was carried out using the corresponding starting compound. Compound. 322543 124 201121970 Table 12 Example Construction LC/MS; m/z (M+1) Hold time (minutes) 7 3 ΟΛ NH 521 3.07 7 4 ΟΛ NH —__ Μβ&quot;Ν^ 514 2.81 _Example 75 6- Benzyl-2-[4-(pipen-1-yl)phenyl]-N-[3-(pyrrolidin-1-yl)propyl]-5, 6, 7, 8-tetrahydropyridine [4, 3-d] pyridin-4-amine

hO was added 4-[4-(4, 4,5,5,-tetraindole) to a solution of Reference Example 3 (50 mg, 0.130 mmol) of dibenzoate (1. 〇mi) and water (0.13 ml).一1 3 3 2-monooxa-heterocyclic pentyl-2-yl)phenyl] 卩 well-1--1-acid tert-butyl ester (70. 4 mg, 〇·181 mmol), 3 mol/L sodium carbonate aqueous solution (〇. i3mi, 0.390 mm〇l) and tetrakis(triphenylphosphine)palladium (15.0 mg, 〇〇13〇匪〇1) were stirred at 120 ° C under microwave irradiation. After 2 hours, liquid separation was carried out with an aqueous solution of ethyl acetate-hydrochloric acid, and the aqueous layer was adjusted to pH IO with aqueous sodium hydroxide. The reaction mixture was subjected to liquid-phase extraction with ethyl acetate. The organic layer was washed with saturated brine. Then, the obtained residue is purified by an amine ruthenium column chromatography (solvent 322543 125 201121970; trichloropyrene: ethyl acetate) to obtain a protective body (10). . Then, in the obtained protective body (66·fine), 2m〇1/L hydrochloric acid/sterol (2._' was carried out overnight. The reaction solution and the salty pressure were concentrated and the __ was used in the methanol towel. Among them, triethylamine is added for neutralization and re-concentration under reduced pressure. The residue obtained by (4) is analyzed by chromatography of the amine oxime column column (solution solvent; three gas aeration: methanol is purified, borrowed The title compound (37·3 mg, yield (10) was obtained.

LC/MS; retention time 3.46 min ' m/z = 512 (M + 1) Example 76 6-phenylhydrazinyl 1 (3- </ br> </ br> , 6, 7, 8-tetrahydroacridine [4, 3~d] pyrimidine _4_amine 〇〇Λ ^ ΝΗ

Add 4' 5' 5' synthesized in reference to W0 2006/59778 in the solution of Reference Example 8 (166 mg, 413. 413 mm 〇 1) 嗜 院 (4· 〇ml)_水• (〇.41ml) - Tetramethyl-1' 3,2-dioxazacyclopentan-2-yl)phenoxy + third butoxy (tetra) ° ° ° (2 〇〇 mg, 〇.496 mmol), 3 mol / L Carbonate in water (10). Partial, 丨.23_Gl), tetrakis (triphenylene) genomic (47. 8mg '0. (MUmmol) ' under microwave irradiation at 12〇t: stirring. After 2 hours, with acetic acid The vinegar-hydrochloric acid aqueous solution was subjected to liquid separation extraction, and the aqueous layer was adjusted to ρΗ1〇β with an aqueous solution of nitrogen oxide, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then anhydrous magnesium sulfate. After drying, the mixture was further decompressed. The resulting residue was then subjected to a gum column chromatography method (solvent solvent; trichloromethane: acetic acid purification to obtain a protective body by using an amine shi 126 322543 201121970 hose column chromatography method. Add 2mol/L hydrochloric acid/sterol to the well-known vines (4 〇n into the lamp. The reaction frequency is concentrated under reduced pressure, and the resulting residual carbon k-hydrogen sodium solution will be reversed) The product was subjected to liquid separation extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous sulfur, and then decompressed. Then the residue obtained was used (4) column chromatography. The title compound (32.3 mg, yield 14%) was obtained eluted eluted eluted elute +1) Example 77 6-Benzene m(3-?-like propyl)_2_[4_0_f-based +yloxy)phenyl]-5, 6, 7, 8-tetrahydroindene and [4, ^ illusion Money + amine

6 6-Benzyl hydrazine _ Ν _ (3 吗 淋 propyl propyl) -2- [4-(piperidin-1-yloxy) phenyl] _ 5, 6, prepared in Example 76 7,8, tetrahydroacridino[4,3-d]pyrimidin-4-amine (24.5 mg, 〇. 〇451匪〇1) sterol (1· 〇ml) 35% citric acid added to the solution Aqueous solution (10.7/zL, O.l35inm〇1), acetic acid (l〇.3yL, 〇. 181 赖〇1) and cyanoborohydride (Yi, 〇i35 round 1) ^ and mix at room temperature (four) . After the reaction overnight, the mixture was extracted with ethyl acetate-saturated aqueous solution of the aqueous solution of the aqueous solution, and the organic layer was evaporated under reduced pressure. The resulting residue is purified by the preparative thin 322543 127 201121970 layer chromatography method (amine phthalocyanine, lysing solvent; trioxane: decyl alcohol) to give the title compound (16. 64%). LC/MS; retention time 3.41 min, m/z = 557 (M + 1) Example 78 2-{4-(4-indolepiperidin-1-yl)phenyl}-6-(pyrimidine-2- Base) -N-{3-(port ratio 0-but-1-yl)propyl}-5,6,7,8-tetrahydrogen ratio. And [4, 3-(1]'1 密定-4-amine

2-{4-(4-Mercaptapiperazin-1-yl)phenyl}-^ (3-0 嘻 定-1-ylpropyl)-5, 6, obtained in Example 58 7, 8 - tetrahydro π ratio bite [4, 3-d] ° dimethyl -4-amine (43. 6 mg, 0.1 mmol), Ν-dimercaptoamine (1. 0ml) To the solution was added 2-chloropyroline (13. 8 mg, 0.12 mmol), potassium carbonate (27.7 mg, 0.20 mmol), and stirred at 60 °C. After 3 hours, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue thus obtained is purified by an amine hydrazine column chromatography (solvent solvent; trioxane: ethyl acetate), and then reslurried with diethyl ether to give the title compound ( 12. 7 mg, yield 25 ° / 〇). LC/MS; retention time 3.82 min, m/z = 514 (M + 1) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; . 128 322543 201121970 Table 13

EXAMPLES Structural Formula 'H-NMIUMHz, Solvent, 5) 7 9 广 N八广N人&gt; 'H-NMR (300 MHz, C0CI3. &lt; 5 ppm): 8.27 (2H, d, J = 9.0 Hz) , 6.93 (2H, d, J = 9.0Hz), 5.79 (1H, brs) .3.76-3.67 (6H, m), 3.28 (4H, m). 2.92 (2H. t, J =7.7 Hz). 2.66 ( 2H, t. J = 7.3 Hz), 2.58-2.50 ( 10H, m), 2.33 (3H, s), 2.12 (2_H, m), 1.84 (2H. m ). 8 0 j〇r^ 广N人^ Μβ^ , H4MR (300 ttlz, C0CI3, 5 ppm): 8·27 (2H, d, J = 9.0 Hz). 6.92 (2H. d. J = 9.0Hz). 6.31 (1H. brs) , 3.69 (2H , m). 3.29-3.26 (4H, m), 2.90 (2H, t, J = 7.7 Hz), 2.67-2.53 (12H, m), 2.33 (3Hr s), 2.1 3-2.02 (2H, m), 1.87-1.77 (6H, m). 8 1 wide N^^NH N^V^j 'H-NHR (300 «Hz, CDCI3, 6 ppm): 8.25 (2H, d, J = 9.0 Hz), 6.92 ( 2H. d, J = 9.0 Hz). 5.83 (1H. brs) .3.75-3.65 (6H, m). 3.27 (4H. m), 2.74 (2H. m), 2.58-2.50 (10H, m), 2.33 (5H, m). 1.83 (6H.m). 8 2 broad N^^NH rV^ Me, NJ 'H-NMR (300 MHz, CDCI3, &lt;5 ppm): 9.19 (1H.d, J = 2.2 Hz), 8.41 (1H, dd, J = 9.0, 2.4 Hz), 6.67 (1H , d, J = 9.0 Hz), 5.88 {1H, brs), 3.75 (4H, m), 3 .70-3.63 (6H , m). 2.75 (2H, m), 2.55-2.51 (10H, m), 2.35-2.32 (5H. m), 1.86-1.82 (6H, m). 129 322543 201121970

8 3 'H-NMR (300 MHz, C0CI3f 5 ppm): 8.28 (2Ht d, J = 9.0 Hz). 6.95 (2H. d. J = 9.0 Hz), 5.19 OH, brs) , 3.71 (2H, m) 3.29 (4H. m), 2.76 (4H, m), 2.60-2.56 (8H. m), 2.35 (5H, m), 1.84-1.78 (8H, m). 8 4 〇0NH r^° ^-NMR (300 MHz. CDCI3, 5 ppm): 9.19 OH. d, J = 2.4 Hz), 8.41 (1H, dd, J = 9.0, 2.4 Hz), 6.67 (1H, d. J = 9.0Hz). 5.27 (1H Brs), 3.72-3.63 (6H. m), 2.77 (4H, m) ( 2.59 (4Ht m), 2.55-2.51 (4H, m), 2.35 (5H. m), 1.84-1.80 (8H, m) 8 5 o^NH Guang'H-NMR (300 MHz. CDCI3, &lt;5 ppm): 8.20 (2H. d. J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 5.19 (1H Brs) , 3.76-3.66 (6H. m), 3.29 (4H. m) ( 2.77 (2H. m), 2.59 (2H, m), 2.58 (4H. m), 2.53 (4H, m). 2.34 ( 5 H, m). 1.87-1.85 (4H. m). 8 6 ^Nv^nh Me'NJ Ή-HMR (300 MHz. C0CI3l δ ppm): 9.12 (1H. d, J = 2.4 Hz), 8.34 ( 1H, dd, J = 8.9, 2.4 Hz), 6.60 (1H , d, J = 8.9 Hz), 5.21 (1H, brs), 3.73 (4H, m), 3.67-3.63 (6H, m), 2.75 (2H, m), 2.58 (2H, n〇. 2.5 3 (8H, m). 2.35-2.33 (5H. m). 1.87-1.85 (4H. m). 8 7 NM〇2 ό 1H~NMR (300 C0CI3· &lt;5 pp m): 8.3⁄4) (1H·d, J = 9.0 Hz), 6.88 (1Ht d, J = 9.0Hz), 3.97 (2H, m), 3.30 (4H, m), 2.91-2.85 (4H, m ), 2.60-2.57 (6H, m ), 2.36-2.32 (10H, m), 1.91 (4H. m). 1.74-1.71 (2 H, m). 1.61 (2H( m). 8 8 Wide N people J MeJ 1 H-NMR (300 MHz, CDCI3, δ ppm): 8.25 (2H.d, J = 9.2 Hz). 6.92 (H.d, J = 9.2Hz), 6.62 (1H, m), 3.68 ( 2H, m), 3.26 (4H, m), 2.72 (2H, m). 2.66 (2H , t, J = 6.1 Hz), 2.56 (8H, m), 2.33 (3H, m), 2.2 6 (2H. m). 1.82 (10H, m). 8 9 rr^° 广N人〆Μβ-Ν^ 'H-NMR (300 MHz. C0CI3. $ ppm): 9.18 (1H, d, J = 2.4 Hz), 8.39 (1H, dd, J = 9.0, 2.4 Hz). 6.69 (1H , m). 6.64 (1H. d, J = 9.0Hz), 3.68-3.60 (6H, m) , 2.70 (4H, m). 2.65 ( 4H, m), 2.51 (8H. m), 2.33 (3H. s). 2.25 (2H. m), 1.81 (10H, m). 9 0 . X Xn O^jC^ 1 H-NMR (300 MHz. C0CI3. &lt;S ppm): 8.29 (2H. d. J = 9.0 Hz) t 6.91 (2H, df J = 9.0 Hz). 6.73 (1Hf m) , 4.14 (2H, t, J = 5.8 Hz). 3.70 (6H, m), 2.80 (2H, t, J = 5.8 Hz), 2.72 (2H. m). 2.66 (2H, m), 2.57 (8H, m). 2.26 (2H. m), 1.81 (10H, m). 9 1 /fine, u 'mmR (300 mz. C0CI3, &lt;5 ppm): 8.26 (2H, d, J = 9.0 Hz), 7.21 -7.39 (5H, m), 6.93 (2H, d, J = 9.0 Hz), 5.98 (1H, m), 3.64-3.72 (8H, m), 3.34 (2H, s ).3.25-3.28 (4H. m 2.92-3.04 (1H, m), 2.81-2.8 4 (2H, m), 2.72-2.79 (4H, m), 2.54-2.60 (4H, m). 130 322543 201121970 2.34 (3H, s), 1.78 -1.81 (6H.m). 9 2 NH NMR (300 mz, CDCI3, &lt; 5 ppm): 8.24 (2H, d, J = 9.0 Hz), 7.24-7.39 (5H, m). 6.92 ( 2H, d. J = 9.0 Hz). 6.01 (1H. m). 3.69-3.72 (4H. m). 3.34 (2H, s )t 3.25-3.28 (4H. m). 2.94-3.04 (1Hf m), 2.82-2.8 4 (2H, m)f 2.73-2.77 (4H, m)t 2.54-2.60 (4H? m), 2.33 (3H. s), 1.78-1.79 (6H, m), 1.47-1.60 (2H, m), 1.19-1.28 (2H.m). 9 3 h〇^n^s^nh k^cro rf^ . 1H-NMR (300 iHz, CDCI3, δ ppm): 8.24 (2H, d, J = 8.7 Hz). 7.24-7.4 1 (5Hf m). 6.92 (2H. d, J = 9.0 Hz). 5.20 (1H, m)f 3.74 (2H, s), 3.63-3.65 (2H, m )· 3.52-3.57 (2H. m), 3.26-3.28 (6H, m), 2.86-2.8 8 (2H, m)t 2.81-2.83 (2H. m). 2.55-2.58 (10H, m), 2.34 (3H, s)t 1.81-1.84 (2H, m). 1.01 (3H.d, J = 11.1 Hz). 9 4 MeO, ^N^^NH U 'H-NMR (300 MHz. CDCI3, δ ppm): 8.25 (2H, dt J = 9.0 Hz). 7.25-7.40 (5H, m), 6.91 (2H. d, J = 9.0 Hz), 6.36 (1H, m), 3 73 (2H, s)f 3.65-3.67 (2H, m ), 3.39-3.41 (2H , m), 3.27-3.28 (11H, m), 2.86-2. 88 (2H, m)t 2.80-2.82 (2H, m), 2.55-2.58 (8H, m), 2.34 (3H, s), 2.15 (3H, s), 1.77 Ϊ2Η, m). 9 5 &quot;Ο H ^ΝγΝ^^ΝΗ JO !H-NMR (300 MHz, C0CI3, 5 ppm): 8.18 (2Hf d, J = 8.7 Hz), 7.23 -7.39 (5H, m), 6.92 (2H, d, J = 8.7 Hz), 5.91 (1H, m), 4.97 (1Hf m). 3.74-3.77 (4H, m ), 3.44 (2H, m) , 3.25-3.30 (6H. m). 3.01-3.03 (4H fm). 2.86-2.87 (2H, m), 2.80-2.81 (2H, n〇( 2.54-2.59 (4H, m), 2.33 (3Hf s) , 2.12 (3H, s), 1.98-2. 00 (4H. m). 9 6 ^nY^nh n?&quot; !H-NMR (300 MHz. CDCI3, δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.22-7.34 (5H m), 6.90 (2H, d, J = 9.0 Hz). 5.86 (1H, m), 4.97 (1H, m). 4.17-4.18 (2H, m), 3.68-3.72 (4H, m), 3.51-3.52 (2H, m). 3.38 (2H, s), 3.21-3.25 (4H, m). 2.72-2.78 (4H, m), 2.54-2.58 (4H, m), 2.45. (4H, m), 2.33 ( 3H· s). 9 7 , u 'H-NHR (300 MHz, C0CI3. «5 ppm): 8.20 (2H. d, J = 9.0 Hz), 7.19-7.35 (5H, m). 6.88 (2H. d J = 9.0 Hz), 5.97 (1H, m). 4.21 (2H. s). 3.71 (2H, s), 3. 63 (2H, m), 3.34 (2H. s), 3.21-3.24 (4H, m). 2.74 -2.80 (6H, m), 2.50-2.53 (5H, m), 2.29 (3H, s), 1.81 (2H, m), 1.58 (8H, m). 9 8 wide N^^ NH o^^CTO rf^ /Ό 'H-NMR (300 MHz. CDCI3, &lt;5 ppm): 8.21 (2H. d. J = 9.0 Hz). 7.24-7.31 (5H, m), 6.90 (2H. d, J = 9.0 Hz), 6.23 (1H, m), 3.69 (2H, s), 3.57-3.62 (6H, m ).3.18 (2H. s), 2.81 (4H, m). 2.67 (4H. m ). 2.54 -2.59 (6H. m). 2.26 (4H, m), 1.77 (2H, m). 131 322543 201121970

9 9 广 N八^NH 'H-NMR (300 MHz, C0CI3, &lt; 5 ppm): 8.21 (3⁄4 d. J = 9.0 Hz), 7.19-7.38 (5H, m), 6.93 (2H. d. J = 9.0 Hz), 6.74 (1H, m), 5.45 (1H, ra), 5.31 (1H, m), 3 .77 (2H, s), 3.59 (2H, m), 3.36 (2H, m), 3.22 -3.2 5 (4H, in), 3.09 (1H, m), 2.68-2.74 (6H, m)t 2.50-2.57 (6H, m), 1.85-2.01 (6H. m), 1.65 (2H, m). 10 0 HO—; Λν^^νη (300 MHz. CDCI3, δ ppm): 8.25 (2H, df J = 9.0 Hz), 7.20-7.38 (5H, m), 6.93 (2H, d, J = 9.0 Hz) , 6.29 (1H. m), 3.65-3.78 (4H, m). 3.51-3.57 ( 4H, m). 3.25-3.45 (4H. m), 3.09-3.14 (2H, m). 2.7 3-2.88 (6H m). 2.51-2.56 (4H, m), 2.38-2.47 (2H. m), 2.14-2.17 (1H. m), 1.72-1.83 (4H. m). 10 1 HO-i Λν^-^νη 'H-NMR (300 MHz. CDCI 3. 6 ppm): 8.25 (2H.d, J = 9.0 Hz), 7.20-7.38 (5H, m), 6.93 (2H, d, J = 9.0 Hz), 6.30 (1H , m), 3.66-3.78 (4H, m), 3.51-3.57 ( 4H, m). 3.26-3.46 (4H. m), 3.09-3.15 (2H, m), 2.7 3-2. (6H, m ), 2_ 51-2.55 (4H, m), 2.39-2.48 (2H, m) ( 2.15-2.17 (1H, m), 1.74-1.86 (4H, m). 10 2 U 0 1H-NHR (300 MHz, CDCI3, δ ppn〇: 7.64 (1 H, m), 7.5 4 (1H. m)r 7.24-7.42 (7H, m) ( 3.79-3.86 (4H, m), 3.59 (12H. m), 3.40 (2H. m), 2.82-2.87 (4H , m), 2 .37-2.45 (8H. n〇( 1.77 (2H, m). 10 3 NM〇2 ό N^V^O 'H-NMR (300 MHz, CDCI3, δ ppm): 8.21 (2H , dr J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 4.54 (2H. s). 4.02 (2H. tf J = 6.0Hz), 3.80-3.85 (2H. m). 3.22 -3.26 (4H, m). 2.82-2.92 (4H, m). 2.50-2.53 (4H. m), 2.22-2.36 (10H, m), 1.84-1.88 (2H, m), 1.50-1.64 (2H, m). 1 04 广 N^^NH ^ N-V&quot;〇jQT^ 广N人^J 'H-NMR (300 MHz, CDCI3.5 ppm): 8.27 (2H.d, J = 9.0 Hz), 6.94 (2H.d, J = 9.0Hz), 5.87 (1H.m), 4.51 (2H, s), 4.01 (2H.t, J = 5.4Hz), 3.66-3.77 (6H, m), 3.26-3.30 ( 4H, m), 2.84 (2H, t, J = 5.4 Hz). 2.51-2.58 (1 OH, m), 2.34 (3H. s), 1.81-1.85 (2H, m).. 10 5 ° ,V〇 , u 1 H-NMR (300 MHz, CDCI 3. δ ppcn): 8.26 (2H. d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 6.89 (1H, m). 4.43 (2H .s), 3.99 (2H( t, J = 5.7Hz)t 3.67-3.70 (2H, ra), 3.26-3.29 (4H, m), 2.82 (2H, t, J = 5.4 Hz), 2.70 (2H, m), 2.54-2.58 (8H, m). 2.34 (3H, s), 1.84 (6H, m). 10 6 M®〇N^N^s^NH ^σ°° xj 'H-NMR (300 MHz, CDCI,. &lt;5 ppm): 8.26 (2H, d, J = 9.0 Hz), 6.93 (2H, d. J = 9.0Hz). 6.52 (1H. m), 4.48 (2H, s), 3.99 (2H. t, J = 5.7Hz), 3.69-3.71 (2H, N〇, 3.50 (2H, t. J = 5.4 Hz), 3.26-3.31 (7H 132 322543 201121970

1 07 1 08 10 9 110

112

113

,m)( 2.83 (2Ht t, J=5.7Hz). 2.55-2.62 (8H. m). 2 .34 (3H, s), 2.32 (3H, s), 1.81 (2H, m)._ Ή- NMR (300 MHz. CDCI 3. δ ppm): 9.13 (1H.d, J = 2.1 Hz), 8.34 OH. dd. J = 2.1, 9.0 Hz), 6.60 (1H.d, J = 9.0 Hz), 4.53 ( 2Ht s). 4.01 (2H, t, J = 6.0 Hz). 3.81-3.86 (2Hf m), 3.58-162 (4H, m), 2. 82-2.90 (4H, m), 2.45-2.48 (4H. m)t 2.24-2.35 (10 Ht m), 1.82-1.86 (2H, m), 1.44-1.57 (2Ht m). 'H-NMR (300 MHz, CDCI3, &lt;5 ppm): 8.26 (2H.d) , J = 9.0Hz), 6.93 (2H, d, J = 9.0Hz), 4.91 (1H, m)( 4.52 (2H, s), 4.01 (2H, t, J = 5.7Hz) ( 3.65-3.73 (6H , m), 3.30-3.33 (4H. m), 2.85 (2H, t J = 5.7 Hz), 2.63-2.66 (6H. m). 2.50 (4H, m), 2.37 (3Ht s)._ 'H- NMR (300 MHzTcDCI3 δ ppm): 9.17 (1H.d, J = 2.4 Hz), 8.41 (1H, dd, J = 2.4, 9.0 Hz), 6.66 (1H, dt J = 9.0Hz), 4.98 (1H , m), 4.52 (2H, s), 4.0 1 (2H, t. J = 5.7Hz). 3.65-3.72 (10H, m), 2.83 ( 2H, t, J = 5.7Hz), 2.63-2.65 (6H , m), 2.52 (4H, m), 2.39 (3H, s)._ 'H-NMR (300 MHz. CDCI3. δ ppm): 8.22 (2H.d, J = 9.0Hz), 6.88 (2H(d) , J = 9.0Hz), 4.93 (1H, m), 4. 47 (2H, s). 3.95 (2H. tf J = 5.7 Hz), 3.62-3.67 (2Hr m), 3.22-3.25 (4Ht m), 2.79 {2Ht t, J = 5.7 Hz), 2.70 (2H, t , J = 6.0 Hz), 2.50-2., 53 (8H, m) . 2.29 (3H. s), 1.73-1.76 (4H, m)._ 'H-NMR (300 Hiz, CDCI 3. 5 ppm): 9.13 (1H. d, J = 2.4Hz), 8.35 (1H, dd, J = 2.4, 9.0 Hz), 6.60 (1H .d. J = 9.0Hz), 4.98 (1H. m), 4.47 (2H, s )t 3.9 5 (2H, t, J = 5.7Hz)t 3.58-3.64 (6H. m), 2.77 (2 H, tf J = 5.7 Hz), 2.69 (2H, t, J = 5.7 Hz), 2.45 - 2.51 (8Ht m), 2.28 (3H, s), 1.74 (4H, m). *H-NHR (300 MHz. CDCI3. δ ppm): 9.18 (1Ht d. J = 2.1 Hz), 8.39 (1H, dd , J = 2.1, 9.0 Hz), 6.65 (1H .d, J = 9.0Hz), 5.9Q (1H, m), 4.50 (2Ht s), 4.0 0 (2H, t, 'j = 5.7Hz) ( 3.73 -3.76 (4H.m). 3.62-3. 69 (6H, m), 2.82 (2K t, J = 5.7 Hz). 2.50-2.54 ( 10H, m), 2.33 (3H, s)t 1.77-1.83 ( 2H, m)._ 'H-NMR (300 IHz. CDCI3, δ ppm): 9.13 (1H. d, J = 2.4Hz), 8.34 (1H, dd. J = 2.4. 9.0 Hz), 6.92 (1H , m)t 6.60 (1H.d, J = 9.0Hz) ( 4.37 (2H. s), 3.9 4 (2H. t, J = 5.7 Hz), 3.57-3.63 (6H. m), 2.76 (2 H. t , J = 5.7 Hz), 2.62 (2H, t, J = 5.7 Hz), 2.44 -2.50 (8Hf m), 2.28 (3H, s). 1.76-1.78 (6H. m). 133 322543 201121970

114 (XCCvv 'H-NMR (300 MHz. CDCI3, δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.23-7.30 (5H, m), 6.90 (2H, d, J = 9.0 Hz), 4.51 (3H, m). 4.00 (2H, t, J = 5.7Hz), 3.85 -3.88 (2H, m), 3.64-3.78 (2K m). 3.48 (3H, m), 3 .27-3.30 (4H m), 2.80-2.86 (3H, m), 2.65-2.68 (1 H, m), 2.55-2.59 (4H, m). 2.34 (3H, s), 2.13-2.20 (1Ht m), 1.93-2.03 (1H m). 115 八^nh ^njC^n Me « έ 3 P = , π f 茬i OO C&gt; O) · ? ^ p, g CJ1 ^ to ° ^ - g ° 5 f3 pF G § 'M a: -=:- g SS — •S_c· ^ ^ ω ii O, a 丄:dpg &lt;〇I oo a &quot; 〇〇〆 OO ^ i ·-- c- ◊ · to a ^ II 3 〒 g σ,ϊ0^^· r〇5si co 2 p· S co 〇〇^ *— .= ^ .= π 116 Ν^γ^Ο r&quot;From 1H-«MR (300 MHz, CDCI3. 6 ppm): 9.18 (s. 1H). 8.3 9 (1H. d, J = 9.0 Hz), 6.65 (1H. d, J = 9.0 Hz). 5.95-5.88 (1H, m)f 4.61-4.48 (2H. m). 3.75 (4H, t FJ = 4.6Hz), 3.66-3.56 (7H, m), 2.55-2.48 (12H, m), 2.34 (3H, s)t 1.83-1.79 (2H, m). 1.37 m, d . J = 6.2 Hz). 117 广N八(PY^n人乂他广Μθ^Ν^^ 'H-NMR (300 MHz, CDCI3, δ ppm): 8. 26 (2H. d, J = 9.0 Hz), 6.94-6.89 (3H, m). 4.53-4.40 (2H, m), 3. 87-3.80 (1H, m), 3.70-3.66 (2H, in); 3.27 (4H, tt J = 5.1 Hz). 2.73-2.66 (4H, m), 2.58-2.53 (8H. m), 2.33 (3H, s), 1.86-1.79 (6H, m), 1.35 (3Ht d, J = 6.3 Hz). 118 rNi / from m, nJ 1H-WR (300 MHz, CDCI3, i5 ppm): 9.18 (1H, s). 8.3 9 (1H, d ( J = 9.0Hz), 6.98-^. 95 (1H. s). 6.65 (1 H. d, J = 9.0 Hz), 4.52-4.39 (2H, m), 3.88-3.77 ( 1H, m) ( 3.68-3.55 (6H, m), 2.69-2.63 (4H, m), 2.5 9-2.49 (8Hf m), 2.33 (3H, s), 1.86-1.77 (6H. m), I. 35 (3H, d, J = 6.2 Hz). 119 Γ^ν^ -^νη °^ ν\-0 jfV^Mr 广νλ^ Mb'^ 'Wm (300 MHz, CDCI3, δ ppm): 8.27 (2Ht d, J = 9.0 Hz). 6.93 (2H. d, J = 9.0 Hz), 5.90-5.82 (1H. m), 4.50 (2H, s)? 3.75 (4H, t, J = 4.6Hz), 3.71 -3.67 (2H, m), 3.28 (4H. t, J = 4.9Hz ), 2.70 (2H .s). 2.58-2.49 (10H, m). 2.34 (3H, s)t 1.85-1.79 (2H. (6H. s). 12 0 nV-o Furnace U: (300 »Hz, CDCI3, ό ppm): 9J8 (1H, s), 8.3 9 (1H. d, J = 9.0 Hz), 6.65 (1H, d, J = 9.0 Hz), 5.93-5.88 (1H, s), 4.49 (2H , s), 3.75 (4H, t. J = 4.6 Hz), 3.71-3.62 (6H, n〇, 2.69(2H, s)( 2.55-2.4 7 (10H. m), 2.33 (3H, s), 1.84-1.79 (2H, m), 1.31 (6H. s). 134 322543 201121970

12 1 '\im (300 MHz, CDCI3. δ ppm): 8.26 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0Hz), 5.82-5.78 (1H, m). 4.48 ( 2H, s). 3.76 (4H. t, J = 4.6 Hz). 3.71 -3.69 (2H, m), 3.28 (4H, t, J = 4.8 Hz). 2.81 (2H .s), 2.58-2.51 (10H (m). 2.34 (3H, s), 1.85-1.55 (10H, m). 12 2 N^V^O rJO000 MaO ]Hm (300 MHz. COCI3, δ ppm) : 9.19 (1H. s). 8.3 9 (1Ht d, J = 9.0 Hz), 6.65 (1Ht d, J = 9.0 Hz)t 5.88-5.84 (1H, s). 4.48 (2Ht s)r 3.75 (4Ht t J = 4.6 Hz), 3.69-3.56 ( 6.H (m), 2. CDCI3, δ ppm): 8.20 (2Ht dt J = 9.0Hz), 6.88 (2H. d, J = 9.0Hz), 6.10 (1H. m), 3.61-3.70 (6H, m), 3.40 (2H, s) ( 3.21-3.25 (4H, m ), 3.03 (2H, t. J = 6.0 Hz), 2.86 (2H. t, J = 6.0 Hz) t 2.45-2.53 (10H, m), 2.89 (3H, s). 1.77-1.83 (2H, m). 12 4 , H&quot;NMR (300 ttte. CDCI3, &lt;5 ppm): 8.45 (2H, d, J = 9.0 Hz), 6.93 (2H, d. J = 9.0 Hz) , 6.56 (1H, m), 4.70-4.77 (1H, m), 4.16 (2H, s), 3.75-3.76 (6Ht m ), 3.29-3.32 (4H( m), 2.5 4-2.60 (10H. n〇, 2.34 (3 H, s)t 1.84-1.89 (2H, m), 1.28 (6H, dt J = 6.6Hz). 12 5 NV-0 wide/n human Άμβ γΌ *Η ·Ν»Κ (300 Wk, C0CI3, δ ppm): 8.25 (2H. d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0Hz), 5.60-5.55 (1H , m), 4.55 (2H , dd. J = 14.2, 15.5 Hz), 3.9Q-3.81 (1H, m), 3.76 (4H, t, J = 4.6Hz), 3.73-3.68 (2H , m), 3.28 (4Hf t. J = 4.8 Hz), 2.70-2.65 (7H, m), 2.55-2.50 (6Ht m), 1.84-1.80 (2H, m)f 1.36 (3H. d, J = 6.2 Hz), 1.17 (6Ht d, J = 6.6 Hz) 1 26 ° Λα 广 γ^ί^/'Μ® 广Ύ*0 'H-fMR (300 MHz. CDCI3t δ ppm): 8.25 (2Hr d( J = 9.0 Hz), 6.95-6.91 (3H, m ), 4.46 (2H, dd, J = 11. 7, 14.5 Hz), 3.86-3.80 (1H, m). 3.70-3.62 (2H, m), 3.27 (4H. t. J = 4.8 Hz), 2.72- 2.65 (9H, m), 2. 59-2.51 (4Ht m), 1.85-1.80 (6H, m), 1.35 (3H, d. J = 6.2 Hz). 1.17 (6H, df J = 6.6 Hz). 12 7 广Ν,^^ΝΗ f\\^9 j|^V^N Μββ 1H-NMR (300 MHz, CDCI3, δ ppm): 8.26 (2H, d. J = 9.0 Hz), 6.93 (2H, d. J = 9.0 Hz), 5.90-5.83 (1Ht m), 4.50 (2H, s), 3.76 (4H, t. J = 4.6Hz), 3.72 -3.67 (2H, m), 3.3Q-3.26 (4H, m ) , 2.7 322543 (2011) 12 8 '\Hm (300 MHz. C0CI3. 6 ppm): 8.26 (2H, d, J = 9.0 Hz), 6.93 (2H, d. J = 9.0Hz), 5.85-5.80 (1H, m). 4.48 ( 2H, s). 3.7^-3.67 (6H, m), 3.32-3.27 ( 4H, m)f 2.80 (2Ht s), 2.75-2.67 (5H, m), 2.58-2.4 9 (6H. m), 1.95 -1.53 (10H, m), 1.09 (6Ht d, J = 6 .6 Hz). 12 9 广N^^NH ^jO5'^0 'H-WMR (300 MHz. CDCI3. &lt;5 ppm) :8.22 (2H, d. J = 9.2 Hz), 7.07 (1H, brs), 6.88 (2H, d. J = 9.2 Hz), 3.67 (2H.m), 3.28 (4H.m), 2.90 (2Hf m). 2.69 (2H, t. J = 5.9 Hz). 2.58 (8H. m), 2.48 (2H, m)t 2.35 (3H, s), 1.83 (8H, m), 1.70 (4H. m). 13 0 wide νΛ^ μ.-ν^ 'H-NMR (300 MHz. C0CI3, δ ppm): 8.22 (2H, d, J = 9.0 Hz). 6.88 (2H, d, J = 9.0 Hz). 6.28 (1H· brs ), 3.76 (4H, m), 3.67 (2H, m), 3.29 (4H. m), 2.91 (2H, m), 2.60-2.53 (12H, m), 2.35 (3Ht s), 1.84 ( 4H. m ), 1.68 (4H.m). 13 1 〇'HHWR (300 iHz_ C0CI3· &lt;5 ppm): 8·26 (2H. d_ J = 9.0Hz), 6.93 (2Hf d, J = 9.0Hz), 5.11 (1H, m), 4.51 (2H, s). 4.01 (2H, t J = 5.6Hz), 3.62 (2H, m), 3.28 (4H, m)t 2.84 (2Hf t, J = 5. 6 Hz), 2.57 ( 6H. m)f 2.41 (4H, m)r 2.34 (3H, s)( 1.58 (4H. m ), 1.46 (2Hf m). 13 2 Me ό broad M, nJ 'H-NMR (300 HWz, C0CI3, 5 ppm): 8.26 (2H, d, J = 9.0 Hz), 6.94 (2Hf d, J = 9.0Hz), 4.58 (2H( s). 4.06 (2H, t. J = 6.1 Hz). 3.44 (4H, m), 3.29 (4H. m), 2.95 (2H, t, J = 6.1 Hz), 2.54 (8H, m). 2.34 (3H, s), 2.33 (3H. s). 13 3 Me ή i N^ V^OP人N人^ Μβ&quot;Ν^ 'H-NMR (300 MHz. CDCI3, 6 ppnO: 7.46 (2H. d. J = 9.0 Hz)·6·93 (2H, d, J = 9.0 Hz), 4.70 (2H, s), 4.03 (2H, t, J = 6.0 Hz), 3.85 (4H, m), 3.28 (4H. m), 2.83 (2H. t, J = 6.0 Hz), 2.56 (4H. m ), 2.45 (4H, m), 2.34 (3H, s), 2.32 (3H, s). 1 34 ^ΪΜβ rt Ν' N^V^O rNi^X ]Hm (300 MHz. CDCI3. &lt;5 ppm ): 8.25 (2H. d, J = 9.2 Hz), 6.93 (2H, d, J = 9.2Hz), 4.58 (2H, s), 4.06 (2H. t, J = 6.1 Hz), 3.53 (2H. t , J = 5.5 Hz ), 3.45 (4H. m)t 3.36 (3H, s). 3.29 (4H, m)t 2.94 (2Hf t, J = 6.1 Hz). 2.63-2.54 (10H, m), 2.34 ( 3 H. s). 13 5 Me ή N^ S^O ^nAn^ Me〇~Ό 'H-NMR (300 MHz, CDCI3, 6 ppm): 7.45 (2H, d, J = 9.0Hz)f 6.93 (2H. d, J = 9.0Hz), 4.70 ( 2.H (2H, m), 3.53 (2H. (2H, t, J = 6.0Hz), 2.62-2.51 (10H, m), 2.34 (3 H. s). 13 6 Mo0^^n) rNi/》 Μθ-Ν J 'H-NMR (300 RHz, C0CI3t δ ppm): 9.13 (1H, d, J = 2.4 Hz). 8.34 (1Ht ddf J = 2.4, 9.0 Hz), 6.60 (1H .d, J = 9.0Hz), 6.55 (1H, m), 4.42 ( 2H, s), 3.9 4 (2H, t, J = 5·7 Hz), 3.57-3.64 (6H. m). 3.44 (2 H. t, J = 5.4Hz)f 3.27 (3H, s), 2.76 (2H.t. J = 5.7 Hz), 2.45-2.56 (8H.m). 2.28 (3H, s), 2.24 (3H, s), 1.68-1.76 (2H, m). 136 322543 201121970 Example 137 2 -(4-(4-mercapto-peptidin-1-yl)phenyl)_6_(oxasulfonyl)_ν_(3 (βΛ 咯)-1-yl)propyl)-5, 6, 7, 8- Tetrahydropyrido[4,3_d]pyrimidine_4_amine

Add sulfonium chloride (10. L·, 0.069111111〇1) and three to the solution of the compound (3〇. lmg, 〇. 〇69mm〇1) obtained in Example 58 in THFG. 0ml) under ice cooling. Ethylamine (9.6 from ['0.069111111〇1). After warming to room temperature and stirring for 1 hour, a saturated aqueous solution of sodium carbonate was added to the reaction mixture, followed by extraction with trichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluent solvent: trichloromethane: decyl alcohol) to give the title compound (37. 6 mg, yield 1%) ). ^-NMR (300 MHz, CDCh » δ ppm): 8.25 (2Η, d, J = 8. 7 φ Hz), 6. 93 (2H, d, J = 8. 7 Hz), 4. 15 (2H, s), 3. 75 (2H, m), 3.60 (2H, t, J = 6.0 Hz), 3.27-3.30 (4H, m), 2.86-2.94 (11H, m), 2.55-2.58 (4H, m) , 2.34 (3H, s), 1.97-2.03 (6H, m). Example 138 1-(2-(4-(4-methylpipelin-1-yl)phenyl)-4-(3-( Ethrolidin-1-yl) propylamino)-7, 8-dihydrogen ratio bite [4, 3-d]^°^:-6(5H)-yl)ethanone 137 322543 201121970

To a solution of the compound (29. 1 mg, 0. 068 mmol) of THF (1. 0 ml), EtOAc (5. 3 mg, 068 mmol) and triethylamine 9. 5/iL' 0. 068mmol). After warming to room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and then extracted with tri-methane. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The residue thus obtained was purified by EtOAc (EtOAc) elute !H-NMR (300 MHz, CDCh &gt; ά ppm): 8.25 (2Η, d, J = 8. 7 Hz), 6. 93 (2H, d, J = 9. 0 Hz), 4. 33 (2H , s), 3. 69-3. 73 (4H, m), 3.26-3.30 (4H, m), 2.81-2.88 (2H, in), 2.55-2.73 (8H, m), 2.34 (3H, s) , 2.19 (3H, s), 1.93-2.03 • (8H, m). Example 139 N-isopropyl-2-(4-(4-mercapto-α-indol-1-yl)phenyl)-4 -(3-( 〇 ° ° ° 各 卜 卜 ) )) propylamino)-7, 8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxamide

138 322543 201121970 In a solution of the compound (3〇. 6mg, 〇〇7〇mm〇i) in THF (1.0ml) obtained in Example 58, isopropyl isocyanate was added under ice cooling (6 9# Bu 0.070 wake up 1). Warm up to room temperature and stir! After the hour, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue thus obtained was purified by the title compound (3. 7 mg, yield: 5%). H-NMR (300 MHz, CDCh » δ ppm): 8.25 (2H, d, J = 9. 〇Hz), 6. 93 (2H, d, J = 9. 0 Hz), 6. 80 (1H, m ), 4. 07 (1H, m), 4.20 (2H, s), 4.00-4.06 (1H, m), 3.73-3.74 (2H, m), 3.64-3.67 (2H, m), 3.26-3.29 (4H , m), 2.81-2.84 (6H, m), 2.54-2.58 (4H, m), 2.34 (3H, s), 1.95-2.02 (6H, m), 1.25 (2H, m), 1. ig (gfl , d, J = 6. 6 Hz). Example 140

2-{4-(4-Methylnidonium-Buji) Bub {3 十 洛 _ _ _ _ propyl) propyl}-6, 7, 8, 9-tetrahydro-5H-pyrimidine [4, 5_d]azetane-4-amine

NH

The compound obtained in Example 41 (9 mg. 〇mg, 66·i66 mmol) was subjected to the same reaction/treatment as in the method described in Example 58 to give a solid compound (53.3 mg, yield 71%). JH-NMR (300 MHz, CDCh» ^ ppin); g&gt; 27 (2H, d, J = 9. 0 139 322543 201121970

Hz), 6. 93 (2H, d, J = 9. 0 Hz), 3. 65 (2H, m), 3. 27 (4H, m), 2.91 (2H, ra), 2.68 (2H, m) , 2.57 (l〇H, ra), 2.33 (3. OH, s), 1·81 (6H, ra), 1·66 (4H, m). Example 141 7-isopropyl-2-{4 -(4-methylparphin-i-yl 3-(pyrrolidinyl-l-yl)propyl propyl 6,7,9-tetrahydro-5H-pyrimido[4,5-d]azacyclocycle Heptane-4-amine

The title compound (6. 9 mg, yield) was obtained from the title compound (m. 39%). 'H-NMR (300 MHz, CDCh » δ ppm): 8.22 (2Η, d, J = 9. 〇Hz), 7. 09 (1H, s), 6. 87 (2H, d, J = 9. 0 Hz), 3. 61 (2H, m), 3.20 (4H, m), 2.96-2.84 (3H, m), 2.63 (4H, m), _ 2.59-2.49 (12H, m), 2.28 (3H, s ), 1.77 (6H, m), 0.96 (6. OH, d, J = 6. 6 Hz). Example 142 N (2-methoxyethyl)---methyl-N3-(2-( 4-(4_曱基α底哄~1-yl)phenyl)-5, 6, 7, 8-tetrahydroquinazoline-4-yl)propane-1,3-diamine

140 322543 201121970 : Compound (122·Omg, 0·321mmol) Poic acid (40. 0 &quot; L,0. 706mmol), β L,0. 354mmol), sodium hydride

0小时后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后The reaction was stopped by adding a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with chloroform, and then the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The title compound (33. Omg, yield 22%) was obtained as a solid. </RTI> NMR (300 MHz, CDCh &gt; 5 ppm): 8.20 (2H, d, J = 9. 2 Hz), 6.88 (2H, d, J = 9.2 Hz), 6.11 (1H, brs), 3.69 (2H, m), 3.44 (2H, t, J = 5. 6 Hz), 3.33 (3H, s), 3.29 (4H , m), 2.75 (2H, m), 2.63-2.55 (8H, m), 2.35 (3H, s), 2.31 (5H, m), 1.84-1.78 (6H, m). Examples 143-154 The starting compound was subjected to the same reaction φ / treatment as in Example 142 to obtain the compound shown in Table 4. 141 322543 201121970 Table 14 Example Structural Formula 14 3

14 4

14 5 14 6 14 7

^Η-ΝΜΙ^ΜΗζ, Solvent, g)_ 'H-NMR (300 MHz, C0CI3. &lt; 5 ppm): 8.26 (2H, d. J = 9.0 Hz). 6.93 (2H. d. J = 9.0Hz ), 5.07 (1H. m), 4.50 (2H, s). 3.99 (2H. t. J = 5.4Hz), 3.60-3.69 (4H, m), 3.27-3.30 (4H, m), 2.83 (2H, t. J = 5.4 Hz), 2.55-2.64 (10H, m), 2.34 (3H, s). 1.78-1.87 (2H, m), 1.04 (3H, t, J = 7.2 Hz)._ 'H-NMR (300 MHz. CDCI3. δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.93 (2H, d. J = 9.0Hz), 6.89 (1H, m), 5.31 (1H, n〇, 4.49 ( 2H, s), 4.34-4.36 (1H. m), 4. 00 (2H. t. J = 5.7 Hz). 3.67-3.74 (2H, m). 3.28-3 .31 (4H, m). 3.01 ( 2H. s), 2.84 (2H, t, J = 5.7 H z), 2.51-2.59 (6H, m). 2.34 (3H, s). 2.30 (3H, s) .1.79-1.88 (2H. n〇. _ 'H-NMR (300 JHz. CDCI3, &lt;S ppm): 8.21 (2H, d, J = 9.0 Hz). 6.88 (2H, d, J = 9.0Hz), 5.65-5.68 (1H, m), 4.39 (2Ht s). 3.95 (2H, t, J = 5.4Hz), 3.63 -3.68 (2H, m). 3.22-3.25 (4H. m). 2.84-2.92 (2H, m), 2.78 (2H, t J = 5.4 Hz), 2.70-2.75 (2H.m), 2.59-2.63 (2H, nt), 2.50-2.53 (4H, m), 2.22-2.34 (5H, m), 1.73-1.81 (2H. m )._ 'H-NMR (300 ttlz. CDCIj. δ p Pm) : 8.26 (2H. d, J = 9.0 Hz), 6.93 (2H. d, J = 9.0Hz). 6.17 (1H. m), 4.50 (2H, s), 4.00 (2H. t, J = 5 .7 Hz), 3.74 (1H, m). 3.64-3.70 (2H, m), 3.26-3.29 (4H, m). 2.81-2 .85 (4H, m), 2.49-2.58 (6H, m). 2.33 (3H. s). 2.1 6 (2H, m). 1.92-1.99 (2H, m), 1.77-1.83 (2H. m). 1.56-1.64 (2H, m)._ 'H-NMR (300 MHz C0CI3. δ ppm): 8.26 (2H, d, J = 9.2 Hz), 6.93 (2H. d. J = 9.2Hz), 6.11 (1H. m), 4.51 (2H. s). 4.01 (2H. t , J = 5.7Hz), 3.68 (2H, m), 3.28 (4H, m), 2.84 (2H, t, J = 5.7 Hz), 2.55 (14H, m), 2.34 (3H. s), 2.32 (3H , s), 1.83 (2H, m). 142 322543 201121970

14 8 1 49 1 50 15 1 15 2 15 3 1 54

'H-NMR (300 MHz, C0CI3f 6 ppm): 8.26 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 6.85 (1Ht brs), 4.45 (2H, s). 3.99 (2H, t, J = 5.6 Hz), 3.68 (2H, m). 3.27 (4H. m), 2.82 (2H, t, J = 5.6Hz), 2.61-2.52 (10H, m), 2.33 (3H s). 1.81-1.73 (2H, m), 1.04 (6H.t, J = 7.1 Hz). 1H-NW (300 MHz. CDCI3. δ ppm): 8.26 (2H.d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz ), 6.34 (1H, brs). 4.51 (2Hr s), 3.98 (2H. t. J = 5.5 Hz), 3.69 (2H. m). 3.51 (4H, t, J = 5.9 Hz), 3.43 (4H. q, J = 7.0 Hz) ( 3.27 (4H, m), 2.82 (2H .tr J = 5.4Hz) ( 2.75-2.67 (6H, m), 2.56 (4H. m ), 2.33 (3H. s), 1.77 (2H, m), 1.13 (6H, t. J = 7. 0 Hz)._ 'H-NMR (300 mz, CDCI3. δ ppm): 8.26 (2H. d J = 9.0 Hz). 6.93 (2H, d, J = 9.0 Hz), 6.54 (1H. brs), 4.49 (2H, s), 3.99 (2H. t. J = 5.8 Hz), 3.68 (2H. m ), 3.46 (2H, t, J = 5.6Hz), 3.29- 3.26 OH, m)f 2.82 (2H, m), 2.66-2.55 (10H, m), 2.33 (3H, s), 1.77 (2Hf m) , 1.04 (3H, t, J = 7.2 Hz)._ 'H-NMR (300 ttiz. (X)CI3. δ ppm): 8.26 (2H. d. J = 9.0 Hz). 6.93 (2H, d, J = 9.0 Hz ), 6.34 (1H, brs ), 4.52 (2H, s), 3.99 (2Hr t, J = 5.6 Hz), 3.68 (2H, m), 3.43 (2H. t, J = 5.8Hz), 3.29- 3.26 (7H. dt J = 8.3Hz ), 3.07-2.98 (1H.m), 2.83 (2H(m), 2.61-2.55 (8H, m). 2.33 (3H, s), 1.75 (2H, m), 0.99 (6H, d, J = 6.6 Hz)._ 'H-NHR (300 MHz, CDCI3, δ ppm): 8.25 (2H, d. J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 6.23 (1H, brs), 5.67 (1H, d, J = 7.9 Hz), 4·50 (2H. s), 4.01 (2H, tf J = 5.6Hz), 3.81 OH. m)t 3.66 (2H, m). 3.28 (4H, m) 2.97 (2Hf m). 2.84 ( 2H. t, J = 5.5 Hz), 2.58-2.49 (6H, m), 2.33 (3H, s)f 2.07-1.96 (7H. m). 1.80 (2H, m) , 1.43 (2H, m) 'H-IUR (300 MHz, CDCI3, δ ppm): 8.16 (2H, d( J = 9,0 Hz), 6.83 (2H( d, J = 9.0Hz), 6.68 (1H m). 4.38 (2H, s), 3.90 (2Ht t. J = 5.7 Hz), 3.57-3.62 (2H, m). 3.16-3.19 (4H, m). 2.73 (2H, t, J = 5.7 Hz ), 2.59 (2H, t, J = 5.4 Hz), 2.39-2.48 (6H.m) .2.24-2.29 (5H, m), 1.66-1.70 (2H. m), 1.36-1.44 (2Ht m), 0.78 (3H, t. J = 7.2 Hz). 0.73 (1Ht. m) , 0.37-0.43 (2Ht m), 0.00-0.18 (2H, m)._ 1 H-NMR (300 MHz, CDCI3, δ ppm): 8.26 (2H, d, J = 9.0Hz), 6 .93 (2H, d, J = 9.0Hz), 6.74 (1H. m). 4.48 (2H. s), 3.99 (2H. t. J = 5.7 Hz)t 3.67-3.71 (2H. m), 3.26- 3.29 (4H.m), 3.01-3.10 (1H(m), 2.83 (2H, t, J = 5.7 Hz), 2.48-2.60 (8H, m), 2.33 (3H, s)t 1.76 (2H, m), 1.08 (3H, t, J = 7.2 Hz), 1.00 (6H, d, J = 6.3 Hz). 143 322543 201121970 Example 155 N-(3-morpholinylpropyl)-2-(4~ (piperidinyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine. 〇~

H〇

(a) 4-(4-(4-(3-Morpholinylpropylamino)-7,8-dihydro-5Η_β-pyrano[4,3-d]pyrimidin-2-yl)phenyl) The hydrazine-carboxylic acid tert-butyl ester was subjected to the same reaction/treatment as the method described in Example 75, using the compound (85._, 0·273_) obtained in Reference Example 46, whereby the title compound was obtained. 98. 3 mg, yield 67%). H-NMR (300 MHz, CDCh &gt; δ ppm); 8.27 (2H, d, J = 9. 〇Hz), 6. 92 (2H, d, J = 9. 0 Hz), 5. 87 (1H, m), 4. 52 (2H, s), 4. 01 (2H, t, J = 5. 7 Hz), 3. 79 (4H, m), 3. 70-3. 72 (2H, m), 3.56-3.59 (4H, m), 3.21 (4H, m), 2. 85 (2H, n〇' 2.55 (6H, m), 1.87 (2H, m), 1.47 (9H, s). (b) N -(3-morpholinopropyl)-2-(4-(piperazinyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine 5ml。 The solution of the above-mentioned compound (96. 9mg, 〇. 18〇mm〇1) in decyl alcohol (1.5 ml), 4m〇i / L hydrochloric acid / diterpene solution (1.5 ml) After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. To the residue obtained was added 1% aqueous ammonia solution, and then extracted with trichlorosulfonium. The organic layer was dried over anhydrous sodium sulfate and then reduced. The residue was purified by column chromatography (yield solvent: hexanes: 144 322543, 201121970 methane: methanol) to give the title compound (76 g, yield 97%). W-NMR (300 MHz, CDCL·, d ppm): 8. 27 (2H,d,J = 9.)

Hz), 6. 93 (2H, d, J = 9. 0 Hz), 5. 85 (1H, m), 4. 51 (2H, s), 4. 01 (2H,t, J = 5. 7 Hz), 3.67-3.77 (6H, m), 3.21-3.25 (4H, m), 3.02-3.05 (4H, m), 2.84 (2H, t, j =5.7 Hz), 2.50-2.55 (6H, m) , 1.79-1.87 (2H, m). Example 156 ® 2-[4-(4-ethylpiped-l-yl)phenyl]_n_(3_morpholinylpropyl)_7,8—1· ®α_5Η-βι^η南和[4, 3_d]°密定定_4-amine

(a) 1-(4-(4-(4-(3-morpholinylpropylamino)-7, 8-dihydro-5H-pyrano[4,3-d]) To a solution of the compound (75. 7 mg, 〇. 173 mmol) in THF (1.7 ml) Mg, 0. 173 mmol) and diisopropylethylamine (31.2 / /L, 0. 173 mmol). Naturally, the mixture was stirred to room temperature while stirring for 1 hour, and then a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, followed by extraction with tri-methane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by an amine hydrazine gel column chromatography (solvent solvent; methane methane: methanol) to give the title compound. (74. 6 mg, yield 90%) ^-NMR (300 MHz, CDCh &gt; δ ppm): 8.28 (2 Η, d, J = 9. 〇 145 322543 201121970

Hz), 6. 93 (2H, d, J = 9. 0 Hz), 5. 92 (1H, m), 4. 52 (2H, s), 4.〇l (2H, t, J = 5.7 Hz ), 3.75-3.79 (6H, m), 3.67-3.73 (2H, m), 3.60-3.64 (2H, m), 3.21-3.28 (4H, m), 2. 85 (2H, t, J = 5. 7 Hz), 2. 53-2. 55 (6H, m), 2. 13 (3H, s), 1.85-1.87 (2H, m). (b) 2-(4-(4-ethyl peptin) - phenyl)phenyl)_N_(3_morpholinylpropyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine in the above-obtained compound ( 74. lmg, 154. 154 mmol) in THF (3 mL) EtOAc (EtOAc (EtOAc) Stir in a nitrogen atmosphere at 6 (TC for 1 hour, then let it cool at room temperature. Add water (20/zL), 2N aqueous sodium hydroxide solution (2〇/zL), water (40/L) to the reaction solution. And filtering with diatomaceous earth, and then concentrating the filtrate under reduced pressure. The residue obtained is purified by an amine hydrazine gel column chromatography (solvent solvent; chloroform:methanol) to give the title compound ( 3〇4, yield 42%) H-NMR (300 MHz, CDCh &gt; δ ppm): 8. 21 (2H d J = 9 0 (4), 6.88 (2U, J, HZ), 5.79 (1h^ , 146(2H, s), 3.96 (2H, t, J = 5.7 Hz), 3.61-3.72 (6H, m), 3.23-3.26 (4H, m), 2. 79 (2H, t, J = 5. 7 Hz), 2.53-2.57 (4H, m), 2.38-2.49 (8H, m), 1.75-1.79 (2H, m), 1.07 (2H, t, J = 6. 9 Hz). Example 157 2^ 4-(4-Methyl-methyl)phenyl]_N_(?-yl-methyl)_7,8-dihydro-5Η-σ-pyrano[4,3-d]sodium-4-amine 322543 146 201121970

Ammonium formate (227.〇11^, 3.6〇111111〇1) and 10% palladium carbon (93.) were added to the solution of the compound (185. 2 mg, 0.360 mmol) in decyl alcohol (3.61111) obtained in Example 114. Omg). After stirring at 50 ° C for 4 hours, the reaction mixture was filtered over EtOAc EtOAc. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and the mixture was evaporated to methylene chloride. Then, the obtained residue was purified by aq. EtOAc EtOAc (EtOAc: EtOAc) ^-NMR (300 MHz, CDCh » 5 ppm): 8. 19 (2H, d, J = 9. 0 Hz), 6. 88 (2H, d, J = 9. 0 Hz), 4. 47 (3H , m), 3. 96 (2H, t, J = 5. 7 Hz), 3. 82-3. 90 (2H, m), 3. 51-3. 64 (2H, m), 3.34-3.42 ( 1H, m), 3.22-3.26 (4H, m), 2.78-2.94 (5H, _in), 2.50-2.64 (5H, m), 2.29 (3H, s). Example 158 N-[(4-曱(Methylmorpholin-2-yl)indolyl]-2-[4-(4-indolylpiperidin-1-yl)phenyl]-7, 8-dihydropyrano[4,3_4] 4-amine

A solution of the compound (52. 8 mg, 0. 124 mmol) 147 322543 201121970 in decyl alcohol (1. 6 ml) was added to a solution of 35% aqueous furfural (10.6 mg, 0. 124 mmol). Acetic acid (14.2 / /L, 0.248 mmol), sodium cyanoborohydride (15. 6 mg '0 · 248 mmol) was then stirred overnight at room temperature. The reaction mixture was diluted with trioxane, and then a saturated aqueous solution of sodium hydrogencarbonate was added, and then extracted with chloroform. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Then, the obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) _ !H-NMR (300 MHz, CDCh &gt; δ ppm): 8.19 (2Η, d, J = 9. 0 Hz), 6. 89 (2H, d, J = 9. 0 Hz), 4. 48 ( 3H, m), 3. 96 (2H, t, J = 5. 7 Hz), 3. 83-3. 90 (2H, m), 3. 59-3. 72 (2H, m), 3.41-3.49 (1H, m), 3.23-3.26 (4H, m), 2.80 (2H, t, J = 5.7 Hz), 2.73-2.76 (1H, m), 2.58-2.62 (1H, m), 2.51-2.54 (4H , m), 2.29 (3H, s), 2.22 (3H, s), 2. 03-2. 11 (1H, m), 1. 83-1. 91 (1H, m). _ Example 159 N- [(4-Isopropylmorpholin-2-yl)indolyl]-2-[4-(4-indolylpiperidin-1-yl)phenyl]-7, 8-dihydro-5H-pyran And [4, 3-d]pyrimidine-4-amine

The title compound (39. 6 mg, obtained by the title compound) was obtained from the compound of Example 157 (52. 8 mg ' 0.124mmo 1). The rate is 68%). ^-NMR (300 MHz, CDCh * δ ppm): 8.20 (2Η, d, J = 9. 0 Hz), 6. 88 (2H, d, J = 9. 0 Hz), 4. 47 (3H, in ), 3. 84-3. 97 (4H, m), 3.57-3.73 (2H, m), 3.37-3.45 (1H, m), 3.22-3.25 (4H, m), 2.78-2.81 (3H, m) , 2.50-2.65 (6H, m), 2.19-2.29 (4H, m), 1.98-2.08 (1H, m), 0.98 (6H, d, J = 6. 3 Hz). Example 160-162 ® Correspondence The starting compound was subjected to the same reaction/treatment as in Example 155 to obtain the compound shown in Table 15. Table 15 Example Construction formula ^H^NMIUMHz. Solvent, δ) 1 60 'H-WMR (300 MHz. C0CI3. &lt;5 ppn〇: 8.24 (2H.d, J = 9.0 Hz), 6.93 (2H.d , J = 9.0Hz). 5.84 (1H. m), 4.51 (2H, s). 4.00 (2H, t. J = 5.7Hz). 3.62-3.77 (7H, m). 3.49-3.54 (1H, m) , 2.94-3.00 (1H, m), 2.79-2.88 (3H, m), 2.60-2.67 (1H. m), 2.49-2.55 (6 H, m), 1.91-1.97 (1H, m), 1.79 -1.87 (3H, m), 1.62 -1.73 (1H, m). 1.20-1.31 (1H. m). 16 1 ° nV? 'H-NMR (300 MHz, CDCIj. δ ppm) : 8.23 (2H, d , J = 9.0 Hz), 6.92 (2H. d, J = 9.0Hz), 6.76 (1H. m), 4.44 (2H. s). 3.98 (2H. t. J = 5.7Hz), 3.61-3.69 (3H , in), 3.46-3.54 (1H, m), 2.92-3.01 (1H, m), 2 .80-2.87 (3H. m), 2.73 (2H, t, J = 5.7Hz), 2.59-2.65 (5H , m). 1.77-2.09 (8Hf m), 1.61-1.73 (1H, m ).1.21-1.31 (1H. m). 1 62 C? 'H-NMR (300 MHz. C0CI 3. 6 ppm): 8.23 ( 2H. d. J = 9.0 Hz). 6.94 (2H, d. J = 9.0Hz), 4.58 (2H. s). 4.06(2H.t, J = 5.7Hz), 3.85-3J9(2H,m), 3.65 -3.69 (1H, m), 3.52-3.56 (1H, m), 2.81-3.00 (6H, m), 2.60-2.67 (1H, m), 2.30-2.37 (7H, m), 1.79-1. 93 (4H, m). 1.5M.73 (3H, m). 1.21-1.28 (1H, m).

Example 163 149 322543 201121970 (S)-2-{4-[3-(Diammonium)piperazin-1-yl]phenyl}-N-(3-morpholinylpropyl)-7, 8 -dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

〇C Μθ2Ν/#,^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 0· 750mmol), acetic acid (42. 9 /z L, 0· 750 with 〇1), nitrogen Φ shed sodium hydride (47. lmg, 0. 750mmol) ' then mix at room temperature for 3 $ hours. The reaction mixture was diluted with trioxane, and then a saturated aqueous solution of sodium hydride was added, followed by extraction with trichloromethane. The organic layer was dried over sodium chloride and concentrated under reduced pressure. The residue was purified by the title compound (53.5 mg, yield: 74%). !H-NMR (300 MHz, CDCh » s ppm): 8.24 (2H, d, j ^ g ^ Hz), 6. 92 (2H' d, J = 9. 〇Hz), 5. 84 (1H, m),4. M (2h s)' 4.00 (2H,t,J = 5.7 Hz), 3.89-3. 92 (1H,m) ' 3. 68-3. 77 (7H,m), 2.84 (2H, t, J = 5. 7 Hz), 2. 65~2 75 (2H, m), 2.49-2.55 (7H, m), 2.35 (6H, s), 1.98~2 (1H, m), 1.81-1.85 (3H, m), 1.60-1.66 (1H, m), '1.35-1.40 (1H, m). Examples 164-168 The same raw material compounds were used to carry out the same combination as in Examples 155 and 163. Reaction/treatment, a compound shown in Table 16 was obtained. 322543 150 201121970 Table 16 Example 1H-NMR (MHz, solvent, hydrazine) 16 4 . nV〇'H-NMR (300 mz. C0CI3, &lt;5 ρρηΟ: 8.19 (2Η, d .J = 9.0 Hz), 6.88 (2Η, d, J = 9.0 Hz), 6. 83-6.84 (1H, m 4.38 (2H, s), 3.94 (2H. t. J = 5.7Hz). 3.84-3.87 (1H, m). 3.64-3.67 (3H, m), 2.77 (2H. t. J = 5.7Hz) , 2.60-2.7 0 (4H, m), 2.52 (4H, m), 2.35-2.43 (1H, m). 2.30 (6H, s), 1.93-1.98 (1H. m). 1.78-1.79 (7H, m ), 1.56-1.66 (1H.m). 1.29-1.34 (1H, m). 16 5 'H-NMR (300 MHz, C0CI3, &lt;5 ppm): 8.23 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz). 4. 58 (2H. s), 4.06 (2H, t. J = 5.7 Hz), 3.85-3.93 (3H, m), 3.70-3.74 (1H, m) 2.87-2.96 (4H, m). 2.66-2.76 (2H, m). 2.32-2.48 (8H, m), 2.30 (6H, s). 1.80-2.02 (4H, m). 1.52-1 .68 ( 3H, m), 1.35-1.44 (1H, m). 16 6 ^ΛΝΛ^ΛΜβ 'H-NMft (300 MHz. CDCI3, &lt;S ppm): 8.24 (2H.d, J = 9.0 Hz), 6.92 ( 2H, d, J = 9.0 Hz), 5. 90-5.86 (1H, m), 4.55 (2H, dd. J = 14.1, 15 .8 Hz), 3.93-3.84 (2H, n〇, 3.78-3.67 ( 7H, m ).2.77-2.66 (4H. m), 2.57-2.49 (7H, m). 2. 36 (6H, s). 2.03-1.95 (2H, m), 1.85-1.79 (2 H, m) , 1.73-1.60 On. 2H), 1.37 (3H, d, J = 6.1 Hz). 16 7 N&gt;^^0 υ 1 H-NMR (300 MHz. C0CI3, δ ppm): 8.20 (2H, d, J = 9.0 Hz). 6.86 (2H, d, J = 9.0 Hz) ), 5. 84-5.80 (1H, m), 4.45 (2H, s), 3.89-3.84 (1 H, m), 3.73-3.62 (7H, m), 2.71-2.61 (4H, m), 2.62 2.46 (7H, s). 2.32 (6H, s). 2.02-1.9 6 (2H, m), 1.83-1.75 (2H. m), 1.71-1.57 (in, 2H). 1.26 (6H, s). 16 8 广ΝΗ, ν^ΝΗ 〇ν^ Ν^ι^Ο Μθ2Ν,..^νΛ^ υ 'H-NMR (300 MHz, CDCI3, δ ppm): 8.20 (2H, d , J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 5. 79-5.75 (1H, η), 4.43 (2H. s), 3.89-3.83 (1 H, m), 3.73-3.61 (7H, m), 2.76 ( 2H, s), 2.7 CH2.60 (2H.m), 2.51-2.43 (7H.m). 2.31 (6H, s), 1.93-1.47 (14H, m). Example 169 7-mercapto-2- (1-(1-Mercaptopipridin-4-yl)-1H-indol-5-yl)-N-(3-morpholinylpropyl)-7, 8-dihydro-5H-pyran [4, 3-d]pyrimidine-4-amine 151 322543 201121970

〇~i Add 4-(5-(4, 4, 5, 5-tetramethyl) to the solution of the compound (91.0 mg, 0.29 imn〇l) prepared in Reference Example 53 (2. Base-1,3,2-oxo-purocyclopentan-2-yl)-1Η-α 嗓-1-yl)b bottom α定_ι_ retinoic acid tert-butyl ester (149 mg, 0. 35 mmol ), 2mol/L aqueous sodium hydroxide solution (750 // L ' 1. 50mmol), Ιε (6. 60mg, 〇. 〇3 ugly 1) and S-Phos (24. Omg, 〇. 〇 6mmol), Stir at 8 °C. After 3 hours, the reaction solution was dried over anhydrous magnesium sulfate, and then filtered through Shixiazu soil to remove the sediment, and the reaction solution was decompressed. Then, the obtained residue was purified by an aminophthalocyanine chromatography (solvent solvent; ethyl hexane acetate) to obtain a Boc derivative containing a mixture of the persons obtained in Reference Example 53. Next, a lithium aluminum hydride (11 Å, $. </ RTI> was added to the obtained solution of the hydrogen pentane (5.0 ml) and refluxed at 80 ° C. After 3 hours, 9 lmm 〇 1 was added to the reaction solution. Aqueous sodium solution (3.0 ml), after the end of the reaction, extract with a portion of B: plus hydrazine. Then, the obtained residue was purified by using an amine hydrazine coloring solvent; ethyl acetate: methanol), and the analysis method was used (solution compound (19. 6 mg 'yield 14%). H-NMR (300 MHz, CDCI3 » β ppm): 8 63 Γ (1Η, d, J = 8.8 Hz), 7. 31 (1Η,d,j = 8 8 S)' 8.22 (1H,d,J = 3. 3 Hz), 6. 53 (1H,d,J = 3. 3 H ·, HZ), 7· 17 (1H,m), 4.53 (2H,dd,J = 14.1,16 〇HZ,' 5.87_5.83 4. 21-4. 17 322543 152 201121970 (1H, m), 3.85-3.81 (1H, m), 3.75-3.68 (6H, in), 3.03-2.95 (2H, m), 2.73-2.64 (2H, ra), 2.54-2.44 (8H, m), 2.32 (3H, S), 2.18-2.03 (4H, m), 1.85-1.79 (2H, in), 1. 33 (3H, d, J = 6. 2 Hz). Examples 170-171 The same reaction/treatment as in Example 169 was carried out using the corresponding starting compound to obtain the compound shown in Table 17. Table 17 Example Construction solvent. ά) 17 0 〇^ &gt; 'H-NMR (300 MHz, CDCI3. &lt; 5 ppm): 8.63 (1H. s). 8.22 (1H, d, J = 9.0 Hz). 7.31 (1H, d, J = 9.0 Hz). 7.16 (1H. d. J = 3.3 Hz). 6. 84-6.80 (1H. n〇, 6.52 (1H. d. J = 3.3Hz). 4 .45 (2H. dd, J = 12.7. 14.5 Hz). 4.23-4. 15 (1H, m). 3.88-3.77 (1H, m). 3.72-3.61 ( 2H, οι), 3.00-2.94 (2H. m). 2.74-2.64 (4H.m), 2.59-2.50 (4H.m), 2.31 (3H, s), 2.19-1.95 (6H. in), 1.83-1.77 (6Ht m). 1.32 (3H, d J = 6.2 Hz). 1 7 1 'H-NMR (300 MHz, C0CI3 > 6 ppm): 8.68 (1H. s). 8.26 (1H. d. J = 8.8 Hz). 7.35 (1H, d, J = 8.8 Hz), 7.20 (1H, d. J = 3.3 Hz). 6. 57 (1H, d, J = 3.3 Hz). 5.89-6.85 (1H, m), 4.52 (2H, s), 4.26-4.22 (1H, m), 3.80-3.6 4 (6H. m), 3.08-3.01 (2H. m), 2.75 (2H. s) .2.6Q-2.49 (8H. m). 2.37 (3H, s), 2.25 -2. 08 (4H, m), 1.89-1.83 (2H.m), 1.32 (6H.s). Next, the pharmacological action of the representative compound of the present invention will be specifically described by way of a test example. Test Example 1: Human TLR9 reporter gene assay The HEK293 cell stable human TLR9 expression strain (human TLR9-293 cells) was activated and subcultured until the state of the cells was stable. Cell culture 153 322543 201121970 The line was placed in a c〇2 incubator (37〇c, 5%c〇2). The cells were recovered by trypsin-EDTA to detach the cells, and the pellets after centrifugation were suspended in a proliferation medium. The human heart TLR9-293 cells prepared to be 3xl 〇 5 cells/ml were spread on a 6-well collagen culture plate and cultured overnight. Then, the nf-kB-luciferase gene was introduced into the cells and cultured overnight. The nf-kb luciferin transgene was introduced into the cells for 6.00 weeks to prepare 6.25 x 105 cells/ml, and was spread at a concentration of 80 μL/well on a 96-well black plate (5 x 10 cells/well). After adding the test substance (final concentration: ι 3, 10, 30, 100, 300, ΙΟΟΟηΜ) and CpG2006 (5,-TCGTCGTTT TGT GGT TTT GTC GTT -3') (final concentration 150 nM) each 10//L, culture 6 hours. The Bright-Glo solution was then added at a concentration of 100/iL/well and allowed to stand under light for 1 minute. The luminescence was measured using a luminometer, and the 50% inhibition rate (IC5 〇値) of each test substance was calculated. The results are shown in Table 18.

154 322543 201121970 Table 18

Example NF_/cB inhibition IC50 (nM) Example NF-/cB inhibition IC5〇(nM) Example NF-/cB inhibition IC5〇(nM) Example NF-/cB inhibition ICs〇(nM) 1 73.8 45 27.3 89 8.8 133 65.8 2 30.0 46 92.5 90 18.7 134 227 3 145 47 74.7 91 22.0 135 196 4 12.9 48 808 92 46.5 136 62.3 5 13.0 49 96.8 93 9.4 137 9.9 6 35.9 50 62.3 94 19.2 138 41.5 7 27.1 51 745 95 19.8 139 52.6 8 11.8 52 95.8 96 13.1 140 65.5 9 24.1 53 222 97 9.1 141 7.3 10 21.7 54 77.2 98 17.3 142 4.5 11 15.0 55 68.4 99 36.6 143 13.7 12 16.2 56 249 100 16.3 144 76.3 13 14.8 57 76.5 101 18.0 145 114 14 15.4 58 24.6 102 8.0 146 13.0 15 23.0 59 18.6 103 18.2 147 6.6 16 9.3 60 49.2 104 29.5 148 86.4 17 10.4 61 52.4 105 14.5 149 16.4 18 22.1 62 6.8 106 6.0 150 15.1 19 17.1 63 5.3 107 48.4 151 11.8 20 6.8 64 3.3 108 111 152 20.7 21 8.1 65 15.3 109 244 153 9.0 22 13.0 66 7.4 110 15.2 154 7.2 23 37.0 67 4.2 111 27.3 156 20.0 24 26.4 68 26.0 112 53.4 157 17.5 25 199 69 19.0 113 21.4 158 53.3 26 496 70 8.5 114 53.6 159 15.2 27 66.8 71 10.7 115 31.0 160 16.0 28 29.2 72 46.0 116 75.2 162 11.8 29 196 73 72.0 117 14.0 163 21.8 30 48.7 74 38.2 118 49.8 164 7.7 31 264 75 16.8 119 11.7 165 16.0 32 18.1 76 281 120 70.5 166 7.9 33 19.5 77 60.5 121 21.6 167 8.3 34 18.6 78 7.9 122 51.5 168 9.3 35 55.8 79 20.8 123 15.1 169 6.8 36 8.0 80 7.2 124 68.2 170 9.7 37 62.3 81 12.5 125 6.8 171 84.1 38 11.6 82 10.9 126 6.5 39 20.3 83 7.0 127 8.2 40 20.0 84 10.9 128 8.1 41 6.7 85 16.7 129 5.5 42 22.2 86 28.6 130 4.5 43 19.1 87 16.9 131 7.1 44 14.7 88 7.0 132 23.8 155 322543 201121970 As shown in Table 18, the compounds of the invention are expressed in the nf-kb inhibition test. Strong inhibition. And Examples 16, 20, 21, 36, 41, 62, 63, 64, 66, 67, 70, 78, 80, 83, 88, 89, 93, 97, 102, 106, 125, 126, 127, 128 The compounds of 129, 130, 131, 137, 141, 142, 147, 153, 154, 164, 166, 167, 168, 169 and 170 exhibit particularly strong inhibition. Test Example 2: CpG-induced il-6 production inhibition test using mouse spleen cells • Mouse spleen cells were prepared in the following manner. The spleen removed from C57BL/6 mice (female) was divided with surgical scissors and ground with a sanded portion of the slide. After centrifugation, hemolysis treatment was performed using ACKUmmonium chloride-potassium) hemolysis buffer. The addition of the medium stops the reaction of the ACK hemolysis buffer and is then centrifuged. The cells were conditioned to lxl07 cells/ml' and dispersed in a 96-well plate at a concentration of 100#L/well (lxl06 cells/well). Adding test substances (final concentration: h 3, φ 10, 30, 100, 300, ΙΟΟΟηΜ) and CpG1826 (5,- TCC ATG ACG TTC CTG ACG TT -3') (final concentration ΙΟΟηΜ) 50//L, Incubate for 24 hours in a C〇2 incubator (37 ° C '5% C〇2). The amount of IL-6 produced in the culture supernatant was measured using an ELISA kit, and the 50% inhibition rate (ICs) of each test substance was calculated. The results are shown in Table 19. 156 322543 201121970 Table 19 Example IL-6 produces inhibition IC5. (nM) 16 64. 6 64 22. 1 67 24. 1 88 20. 3 93 24. 8 97 19. 0 106 71. 6 141 27. 0 As shown in Table 19, the compounds of the invention are produced in IL-6. Strong inhibition was shown in the inhibition test. Further, the compounds showing high activity in the NF-/CB inhibition test shown in Table 18 also exhibited strong IL-6 production similarly to the above Examples 16, 64, 67, 88, 93, 97, 106 and 141. Inhibition. Test Example 3: Efficacy evaluation test using CpG1826 administration mode CpG1826 solution was administered intraperitoneally in mice under ether anesthesia. CpG1826 # After 1 to 6 hours of administration, blood collection and peritoneal washing solution were recovered under ether anesthesia. The blood collection system is performed by the heart and recovered into a test tube containing heparin (hepar i η); the peritoneal washing system injects PBS (phosphate buffered sal ine) into the abdominal cavity, and then the soft abdomen is compressed and then recovered. The compound was administered from the tail vein of the mouse before administration of CpG1826. The blood and peritoneal washings were obtained by centrifugation to obtain plasma and peritoneal washing supernatants, and then the cytokines were measured by a commercially available EL ISA kit. The amount of IL-6 produced was measured, and the inhibition rate (%) was calculated by comparison between each test substance and the solvent control. The results are shown in Tables 157 322543 201121970 20 and Table 21. As shown in Table 20 and Table 21, in Example 16, Cp (n826 administered with 1 mg/kg after 2 hours of administration) was confirmed to have significant inhibition of production of inflammatory cytokines compared with the control group. , _ shows that the compound of the present invention can inhibit the production of inflammatory cytokines dependent on TLR 9. Table 20 (Ignition of IL-6 in plasma) IL-6 production---- &quot; ---- Error inhibition rate (% Example 16 975 319 54 Vehicle 2022 L_553 Table 21 (Ignition amount of IL-6 in peritoneal supernatant) IL-6 production amount Standard error inhibition rate (%) Example 16 206 61 69 Vehicle 623 226

Test Example 4: Efficacy evaluation using cecal ligation puncture (CLP) mode The cecal ligation puncture mode is the most widely used animal model in sepsis. It is now the model that best reflects the pathology of human sepsis (Buras) , JA, et al., Nat. Rev. Drug Dscov. 4, 854-865 (2005), Rittirsch, D., et al. J. Leukoc. Biol. 81, 137-143 (2007). Reference Daniel Rittirsch's report (Daniel Rittirsch, et al., Nature Protocols 4, 31-36 (2009)) C57BL/6 mice were treated with CLp. Under ether or isoflurane inhalation anesthesia, scissors were cut along the midline of the abdomen. Centimeters, expose the cecum and surrounding organs. After ligation of the lower part of the cecum, use the i8_23G 158 322543 201121970 needle to puncture and perforate the cecum wall (CLP treatment). Then return the exposed organ to the original part, and then use cyanoacrylate. The surgical infusion is used to close the open incision, and the scope of the operation is disinfected with Isodine cotton. After the operation, the awakening is carried out, and the survival confirmation is performed at least twice a day, and some of them are safely collected after a few hours of surgery. Then, the peritoneal washing liquid and the organ are collected for use in the determination of cytokines or organ damage markers, the number of bacteria, etc. The compounds are administered intravenously before or after the treatment of the CLP, and some of them are combined. The subcutaneous administration of the physiological saline solution at 37 ° C and the intraperitoneal administration of the antibacterial agent were carried out. Test Example 5: Cancer cell proliferation inhibition test The human bone marrow cancer cell line Ramos was confirmed to exhibit TLR9, The report indicates that the TLR9 ligand promotes proliferation (Cellular Immunology 259 (2009) p90-99). The Ramos cell line was prepared to 6.25x104 cel ls/ml and spread in a 96-well plate at a concentration of 80 #L/wel 1 (5xl03cel ls/wel 1) φ Add the test substance (final concentration: 0.01, 0.1, 1, 10//Μ) and

After CpG2006 (final concentration: 3#g/ml), each was 10#L, and cultured for 3 days in a C〇2 incubator (37 ° C, 5% C〇2 concentration). The positive control system was set as a human TLR9-specific inhibitor inhibitory oligonucleotides (iCpG: 5' - TTT AGG GTT AGG GTT AGG GH AGG G -3'). 80 #L of 5-brom〇-2'-deoxy-uridine (BrdU) solution was added to each tank, and culture was carried out for 16 hours. The amount of BrdU uptake in the cells was measured using a luminometer. The proliferation inhibition rates of the respective test substances for promoting cancer cell proliferation by CpG2006 are shown in Table 22 and Table 23. As shown in Tables 22 and 23, 159 322543, 201121970 shows that the compound of the present invention exhibits a strong dose-dependent inhibitory effect on the proliferation of cancer cells. Table 22 Test substance (1 # M) Proliferation inhibition (%) Standard error Example 16 33. 8 12.3 Example 89 65. 1 18. 0 Example 104 Γ 62. 1 h 16.3 iCpG (25 β g/ml) Γ—97. 0 9. 1 Test substance proliferation inhibition (%) Standard error Example 104 0. 01 -6. 8 15.4 ~~0 . 1 β Μ ~ 23.4 11.4 1/ζΜ 62. 1 16. 3 10/ /Μ 85. 8 12.4 φ Table 23 Industrial Applicability As described above, the derivative represented by the formula (I) or the pharmaceutically acceptable salt thereof can be utilized as an anti-immune disease prevention and / or therapeutic drugs, specifically an autoimmune-related disease (inflammation, allergies, asthma, graft rejection, graft versus host disease, infection, cancer), immune system or neurodegenerative disease (Alzheimer Preventives and/or therapeutics for diseases, Parkinson's disease, etc.). Further, the present invention can be utilized as an effective pharmaceutical for the prevention and/or treatment of sepsis, particularly severe sepsis, by identifying a selective TLR inhibitor. ' [Simple description of the diagram] No [Main component symbol description] No 322543 160 201121970 Sequence table &lt;110> Dainippon Sumitomo Pharmaceutical Co., Ltd. &lt;120> Novel condensed pyrimidine derivative &lt;130> 559053 &lt;150〉 JP 2009-264612 &lt;151〉 2009-11-20

&lt;160> 3 &lt;170&gt; Patent In version 3. 2 &lt;210> 1 &lt;211> 24 &lt;212> DNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; CpG2006 &lt;400> 1 tcgtcgtttt Gtggttttgt cgtt 24 &lt;210〉 2 &lt;211> 20 &lt;212> DNA &lt;213>manual&lt;220&gt;&lt;223&gt; CpG1826 &lt;400> 2 tccatgacgt tcctgacgtt 20

&lt;210> 3 &lt;211> 25 &lt;212> DNA &lt;213>manual &lt;220&gt;&lt;223> iCpG &lt;400> 3 tttagggtta gggttagggt taggg 25 l 322543

Claims (1)

201121970 VII. Application for a patent: 1. A compound of the formula: or a pharmaceutically acceptable salt thereof. A1 Ν^γίΑγν αΛν\42 (1) [wherein Α and Α2 represent the following formula (1) or (8); R3 A r!i - Aik3 ~X-Qi (8) Q2-Alk4-Y-Ar__ (β) When A is of formula (A), A2 represents formula (b); when A is formula (B), A2 represents formula ( A); Q1 represents a 4 to 10 membered nitrogen-containing saturated heterocyclic ring or NRR, and R and R are each independently represented by a hydrogen atom, a substituted alkyl group, a substituted Cw cycloalkyl group or Substituted 4 to 1 member saturated saturated heterocyclic group; Aik3 represents a single bond or Cm alkyl group which may be substituted by Cm alkyl group; X represents a single bond, -C0-, -NR6C0---C〇2--- COCO-, -C0NR6-, -0C0NR6-, -NR6C〇2-, -NR6C0NR7-, -(CRY^O- or -NR6-; Here, when Q1 is a 4 to 10 member nitrogen-containing saturated impurity which can be substituted Ring (wherein the carbon atom forming a ring in the ring is bonded to X), and when Aik3 is a single bond or a fluorenylene group which may be substituted by a Cw alkyl group, X represents a single bond, ~c〇_, 1 322543 201121970 • NR6C0 -or-C0C0- when Q1 is a 4 to 10 member nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to X) or _nr1r2, and Alk3 is a C3-alkyl group. When substituted C2-8 alkylene, X represents a single bond, -C0-, -C〇2-, -COCO-, -C0NR6- or -(cr6r7)2〇; When Q1 is a 4 to 10 membered nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to X), &lt;_NRlR2, and Alk3 is a single bond or may be substituted by a Ci-3 alkyl group. In the case of a methylene group, χ represents _c〇 or -coco-; R3 represents a hydrogen atom and a substituted Ch. An alkyl group or a substituted C3-8 cycloalkyl group, which may also form a substituted 4 to 10 membered saturated heterocyclic ring together with a carbon atom of Alk32; Q2 represents a 4 to 1 member which may be substituted A nitrogen-saturated heterocyclic ring, or NR R, R and R are each independently represented by a hydrogen atom, a substituted Ciw alkyl group, a substituted (^8 cycloalkyl group or a substituted 4 to 1 member saturated impurity) a ring group; Aik4 represents a single bond or an alkylene group which may be substituted by a Ch alkyl group; Ar represents a substituted aryl group or a substituted heteroaryl group; Y represents an early bond, -〇- ,—C〇-, -NR8C0_, -C〇2-, -C0C0-, -CONR8---0C0NR8- '-NR8C〇2- '-NR8C0NR9- &gt; -NR8- &gt; -CO(CR8R9)〇- , -NR8S〇2-, -S〇2NR8- or -S-; where 'when Q2 is a 4 to 10 member nitrogen-containing saturated heterocyclic ring which can be substituted (the nitrogen atom forming a ring in the ring is bonded to Aik4) ) or -NR4R5, Aik4 2 322543 201121970 is an alkyl group which can be substituted by Cm alkyl, and red (this trait means pyrolipid, imipenyl, pyrazole, three 4t, sitting, benzopyrene η sitting , porphyrin, tetrahydroquinoline, 3,4-dihydro-2-indole-benzo[b][1,4]oxazine or lHt When the nitrogen atom on the pyrrolo[2,3-b]pyridine) ring is bonded to γ, γ represents a single bond -C0-, -NR8C0-, -COCO- or -NR8S〇2-; when Q2 is replaceable 4 to 10 members of a nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to Aik4) or -NR4R5, Aik4 is a single bond or a methylene group which may be substituted with a hydra-3-alkyl group, and a red ring When the carbon atom is bonded to the Y bond, Y represents a single bond, _co_, _c〇2_, _c〇c〇_, _c〇nr8-, -C0(CR8R9)0- or -S〇2NR8-; when Q2 is Substituted 4 to 1 member nitrogen-containing saturated heterocyclic ring (the nitrogen atom forming a ring in the ring is bonded to Aik4) or -NR4R5, Aik4 is a single bond or a methylene group which may be substituted by Cm alkyl, and red (The red color means pyrrole, imidazole, oxazole, triazole, sulfonium, D-borazole, benzimidazole, porphyrin, tetrahydroquinoline, 3,4-dihydro-2H-benzo[b] When the nitrogen atom on the [l,4]oxazine or in-pyrrolo[2,3-b]pyridine) ring is bonded to γ, γ represents ~C0- or -COCO-; Z represents a single bond, -0- , -S(0)ID2- or -N0O-; Aik and Aik2 are independent, indicating that they can be selected from dentin, hydroxyl, carboxyl, substituted Cl, alkyl (this When two of the alkyl groups are substituted with a methylene group, two of the alkyl groups may also be bonded to each other to form a ring), a substituted Ch alkoxy group, a substituted C3 8 cycloalkyl group, or may be substituted. An aryl group, a substituted heteroaryl group, -NRnR12, -(10)R&quot;R12, a substituted Ci 5 group, and a substituted group 5 322543 3 201121970 in the same or different groups Substituted fluorenylene; or carbonyl; t is independent of each other. An integer of up to 2; = an integer of 'independent'; an integer of ... 丨 丨 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Substituted aryl group, which can be substituted Dream base soil substituted by alkylcarbonyl, ^ substituted Cl_5 alkoxycarbonyl, ~C0NR13R14 or _s〇2R13; RR, R, R11, Rl2, R13 and R14 are independent, the table is atomic or can be substituted Alkyl]. The compound of the formula π, or a pharmaceutically acceptable salt thereof, wherein: a substituted ρ ^ ^, an L1-(1) alkyl group, a substituted G- 5 alkoxy, may, a substituted C1 - ζ, Μ Μ _, such as 疋 疋, a substituted Cl-5 alkoxycarbonyl and a substituted aryl-Cm fluorene group, The alkyl moiety of each group may be substituted with the same or different substituents selected from the group consisting of: (1) lS atom, (2) trans group, (3) cyano group, (4) a carboxyl group, (5) a substituted cycloalkyl group, (6) a substituted aryl group, (7) a substituted heteroaryl group, 4 322543 201121970 (8) (^-5 alkoxy group, (9) Substitutable C3-8 cycloalkoxy, (10) G-5 alkoxycarbonyl, (11) -NR15R16, (12) -CONR15R16, and (13) 4 to 10 members which may be substituted a heterocyclic ring (here, the groups represented by the above (6) and (7) are selected from Substituents substituted by the same or different 1 to 5 substituents in the following groups: (a) hydroxy, (b) halogen, (c) Ch which may be substituted by 1 to 5 fluorine atoms, (d) G-5 alkoxy group substituted by 1 to 5 fluorine atoms, (e) cyano group, (fluorenyl carboxyl group, (g) -NR15R16, (h) -C0NR15R16, and (UCi-S alkoxycarbonyl group The groups represented by (5), (9) and (13) are those which may be substituted by the same or different 1 to 5 substituents selected from the group consisting of: (a) hydroxyl group, (b) a halogen, (c) a C^o alkyl group which may be substituted with 1 to 5 fluorine atoms, (d) an anthracene-5 alkoxy group which may be substituted with 1 to 5 fluorine atoms, (h)-CONR15R16); 322543 201121970 Cycloalkyl and saturated heterocyclic group represent the same or different enthalpy to 5 groups selected from the group consisting of (a), (b), (c), (d) and (h) above. a substituent-substituted group; an aryl moiety of an extended aryl group, a heteroaryl group, an aryl group, a heteroaryl group, and an aryl-Ci 1 alkyl group, which may be grouped by the group selected from the group consisting of (a) to (丨) a group substituted with the same or different 1 to 5 substituents in the group; R and R are each independently and represent a hydrogen atom; 1 to 5 fluorine atoms substituted by Cm. Alkyl or a substituted 4 to 1 member saturated heterocyclic ring' or when R15 and R16 are bonded to the same nitrogen atom, may also form a 4 to 1 member saturated impurity ring. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Q1 represents the same group or groups selected from the group consisting of halogen, hydroxy, -C0NR15R16 and C16 alkyl or 1 to 3 substituents substituted with 4 to 10 members of nitrogen-containing saturated heterocyclic ring, or _NRiR2; Ri&amp; R2 are each independently, represent a hydrogen atom, may be selected from a fluorine atom, a hydroxyl group, and _c〇NRl5Rl6 The Ci-6 alkyl group substituted with the same or different 1 to 3 substituents in the group may be the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and a trans group. a substituted C3-8 cycloalkyl group, or a 4 to 7 membered saturated heterocyclic ring which may be substituted with a Cl-6 leukoyl group; Aik3 represents a single bond or a Cl-6 alkylene group; X represents a single bond, -CO-, -NR6C0- or - (CRWO-; R represents a hydrogen atom, or a Ci-6 alkyl group which may be substituted with the same or different one to three substituents selected from the group consisting of a fluorine atom and a hydroxyl group; 6 322543 201121970 Q2 represents a 4 to 10 member nitrogen-containing saturated heterocyclic ring substituted with the same or different 1 to 3 substituents selected from the group consisting of a trans group, a hydride atom, a Ci-6 alkyl group, and a -c〇NR15R16, or NR4R5; R4 R5 is independently a C atom which may be substituted by the same or a different one to three substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a Cl-5 alkoxy group, -NR15R16 and -C0NR15R16. -6 alkyl or C3-8 cycloalkyl, or a 4- to 7-membered saturated heterocyclic ring which may be substituted by a Cl-6 alkyl group; Aik4 represents a single bond or a Cm-extension group which may be substituted with a fluoren-2-alkyl group; Not a single bond, -〇-, -NR8C0_, -C0NR8-, _NR8C0NR9-, -nr8---C0(CR8R9)0- or -S〇2NR8-; Ar means that it can be selected from dentate, can pass 1 to 3 a phenyl group substituted with a fluorine atom-substituted Ci-e alkyl group and the same or different 1 to 3 substituent groups in a group of 1 to 3 fluorine atoms substituted by Cl-δ alkoxy groups, or 1 or 3 of the same or different groups in the group selected from the group consisting of a 匕-6 alkyl group which may be substituted with 1 to 3 fluorine atoms and a Ci-5 alkoxy group substituted with 1 to 3 fluorine atoms Substituent substituted heteroaryl containing 1 to 2 nitrogen atoms; Z represents a single bond, -〇---S- or -N(R1Q)-; Aik1 and Aik2 are independent, indicating that they can pass through 1 to 2 a calcination group (the Cm alkyl group may be the same or different from the group selected from the group consisting of a hydroxyl group and a Cm alkoxy group) 1 to 2 substituents substituted) substituted methylene &amp; or carbonyl; ml represents 0 or 1; η1 and η2 are each independently, representing 1 or 2; 7 322543 201121970 And R represents a hydrogen atom, Ο 1 which may be substituted with i to 3 substituents which are selected from the group consisting of a fluorine atom and a quinone alkoxy group, and which are the same or different. The alkyl group ' can be substituted with the same or different oxime groups selected from the group consisting of i and the group of 3 groups which are substituted by i to 3 gas atoms to 3 substituents - Cl-6 a group of 4 to 1 member saturated heterocyclic ring which may be substituted with 1 to 3 G-6 alkyl groups, which may be substituted with 〇-6 alkyl groups which may be substituted by 1 to 3 fluorine atoms. The same or different aryl groups substituted with 3 substituents can be selected from the pixels and can be passed! a heteroaryl group substituted into three or more substituents in a group of three fluorine-substituted Cm alkyl groups, which may be the same in the group selected from the group consisting of a fluorine atom and _NR11R12 Substituted 1 to 3 substituents substituted with &amp; oxime, -conr13r14 or -S〇2R13; 立, representing a hydrogen atom or a Ch alkyl group. 4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the coffee is independently represented by a methylene group or a group. 5. 6. For the salt as permitted by the compound of any of the 14th paragraphs of the patent application, wherein X represents a single bond, -C0- or ^~(CR lOi^O-, Aik3 represents a single bond or an alkyl group. = Patent application: to a compound according to any one of the items - or a salt that is allowed in the music, wherein Y is a single bond, -G-, -NR8C〇/, -C0NR8- or -c〇(CR8R9)〇-. 7. The compound of any of the preceding claims, or the pharmaceutically acceptable salt thereof, wherein z represents a single bond or _ The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R1 represents a hydrogen atom, can pass through to 3, a fluorine atom. Substituted C -6 alkyl, which may be substituted by the same or different i to 3 substituents selected from the group consisting of dentate and a Cl-6 alkyl group which may be substituted with 1 to 3 fluorine atoms An aryl-Cl_6 alkyl group, a 4 to 10 membered saturated heterocyclic ring which may be substituted with i to 3 alkyl groups, may be formed by an anthracene-6 alkyl group selected from the group consisting of dentate and substituted with 6 1 to 3 fluorine atoms. 1 to 3 substitutions of the same or different in the group a substituted aryl group, or a heteroaryl group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of _ _ and 匕 6 alkyl groups which may be substituted by 1 to 3 fluorine atoms The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Z represents _0_. Patent Application Nos. 1 to 9 The compound of the above formula, or the salt thereof, wherein R3 represents a hydrogen atom or a Cm alkyl group which may be substituted with a hydroxy group, as described in any one of claims 1 to 1. A compound or a pharmaceutically acceptable salt thereof, wherein Al represents the formula (A) and A2 represents the formula (B). The compound of any one of claims 1 to 1 or a pharmaceutical thereof And a pharmaceutically acceptable salt thereof, wherein A1 represents a formula (B), and A2 represents a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. And a pharmaceutically acceptable compound according to any one of claims 1 to 12, wherein the compound of any one of claims 1 to 12 is exemplified. a salt, wherein Q2 represents a 4 to 10 member nitrogen-containing saturated impurity which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom, a Cm alkyl group, and a _c〇nr15r16 group. A compound according to any one of claims 1 to 5, wherein the Alki and Alk2 represent an anthracene group, and the pharmaceutically acceptable salt thereof, wherein Al6. The compound of any one of the items 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ar represents an anthracene-6 alkyl group which may be deuterated by one or three fluorine atoms selected from halogen A phenyl group substituted with the same or a different one to three substituents in the group of Cl-s alkoxy groups substituted by 1 to 3 fluorine atoms. The compound or the 'pharmaceutically pharmaceutically acceptable salt' according to any one of claims 1 to 15, wherein 'Ar is a selected from a Schane which may be substituted with 1 to 3 fluorine atoms. a group containing 1 to 2 nitrogen atoms substituted by the same or different 1 to 3 substituents in the group of 3 groups of Cl-5 alkoxy groups. base. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 417, wherein Q1 represents _NRiR2. The compound of any one of the above claims, wherein the Q1 represents a group selected from the group consisting of dentin, hydroxyl, -CONR15R16 and Cm alkyl. The same or different J to 3 substituents are substituted for 4 to 1 member of the nitrogen-containing saturated heterocyclic ring. And a medicinal composition comprising the compound of any one of the above-mentioned items of the invention, wherein the compound or the pharmaceutically acceptable salt thereof. A therapeutic agent and/or a prophylactic agent for a Toll-Like receptor-related disease, which comprises the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof As an active ingredient. The therapeutic agent and/or prophylactic agent according to claim 21, wherein the sputum receptor-related disease is sepsis, an autoimmune disease or a neurodegenerative disease. % The therapeutic and/or prophylactic agent according to Item 21 of the patent application, wherein the +' 铎 receptor related disease is cancer. 322543 11 201121970 IV. Designated representative map: There is no schema in this case (1) The representative representative figure in this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: • A1 2 322543