TW201202247A - A new 4, 5-fused pyrimidine derivate - Google Patents

Abstract

The invention relates to a 4, 5-fused pyrimidine derivative useful as a medicament, in more detail, a pyrimidine derivative useful for preventing and/or treating a disease associated with a signaling via Toll-like receptor.

Description

201202247 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a pyridine derivative which can be used as a medicine. More specifically, it relates to disease prevention and phlegm-reducing organisms that are transmitted by the signal transduction of the quinone-receptor (TLR). Specifically, it is effective and/or therapeutically effective (sepsis, inflammation, allergy, asthma, graft-related diseases)

Prophylactic and/or therapeutic drugs for major diseases, infectious diseases, cancers, immune insufficiency or neurodegenerative diseases = susceptibility, Parkinson's disease, etc. (Azi Sea Derivatives, 4, 5) - Circulation sneezing [Prior Art] The stimuli of the immune system in the living body are the physiological and the result of the protection of the host or the opposite toxic physiological results. In recent years, these Z-immunization (innate immunity) institutions In particular, recently discovered TLRs have been reported to be related to natural immunity, identifying receptors for pathogenic microorganisms. TLR is a highly preserved pattern recognition receptor and is attracting attention. As of now, human TLR has been One species was identified and named tlr1 to tlr10. Each TLR identifies the cell wall component of the pathogenic microorganism or the specific molecular structure represented by DNA (Pathogen Associated molecular).

Patterns, PAMPs) induce the host's immune response and act as a living body against purple (Nature Reviews Immunology, 2001, 1, 135-145). For example, TLR2 is a signal that transmits components such as Peptidoglycan and Zymosan of a component of a microbial cell wall, and TLR4 is a lipopolysaccharide (LPS) which constitutes a component of a cell wall of Gram-negative bacteria. The signal of 3 323165 201202247 is delivered from outside the host cell to the cell (Nature Immunology, 2001, 2, 675-680). Furthermore, TLR9, which is expressed in the endosome of the host cell, has been reported to recognize the DNA of the pathogenic microorganism or CpGMA, which is attracting attention (Nature, 2000, 408, 740-745 or Proceedings of the National Academy of Sciences). , 2001, 98, 9237-9242). Therefore, the agent and/or the composition system which is regulated by the natural immunity which can be used for this TLR can be an autoimmune disease-related disease (septicemia, inflammation, allergy, asthma, graft rejection, graft resistance) shown below. Preventive drugs and/or therapeutic drugs for host diseases, infectious diseases, cancers, immunodeficiency or neurodegenerative diseases (Azheimer's disease, Parkinson's disease, etc.). "Autoimmune disease" is a disease in which an antibody or a lymphocyte which reacts with a component of an autologous tissue is continuously produced in the body and reaches a tissue disorder, and is roughly classified into the following (1) organ specific autologous Two types of immune diseases, and (2) non-specific autoimmune diseases (systemic autoimmune diseases). (1) Organ-specific autoimmune diseases: Hashimoto's disease, primary mucinous edema, thyroid poisoning, pernicious anemia, Good-pasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris , water-like pemphigus, insulin-resistant diabetes, young diabetes, type I diabetes, Addison's disease, atrophic gastritis, male infertility, early onset menopause, hydrogenic uvitis, multiple sclerosis Symptoms, cancerous large intestine disease, primary biliary cirrhosis, chronic active hepatitis, autoimmune blood diseases (eg, autoimmune hemolytic anemia, sudden thrombocytopenia, etc.), paroxysmal Hemochromatosis, primary biliary cirrhosis, 4 323165 201202247 Guillain-Barr syndrome, Based〇w disease, sudden thrombocytopenic purpura, interstitial lung Fibrosis and other chronic erythematosus (erythematosus) (2) Organ non-specific autoimmune disease (systemic autoimmune disease): rheumatoid arthritis, systemic lupus Sore, S0gren syndrome, polymyositis, dermatomyositis, systemic skin atherosclerosis, nodular polyarteritis, allergic granulomatous vasculitis, scleroderma, and mixed connective tissue disease. In addition, the 'j6l disease system' is defined as Systemic Inflammatory Response Syndrome (SIRS) (Chest, 1992' 101, 1644-1655). The cause of the disease is caused by the excess of inflammatory mediators induced by pathogenic microorganisms and their toxins. § Forbearance is also associated with inflammatory mediators, septic shock, complications associated with organ failure, and further anti-inflammatory properties. Induction of the medium body. In recent years, based on such a background, agents for inhibiting inflammatory mediators such as carbon monoxide or cytokines have been developed, and their effectiveness is expressed in terms of animal scale, and patients with severe sepsis are treated with inflammatory mediators as the target drug therapy. Clinical trials have been implemented. However, it has not been possible to obtain sufficient therapeutic effects until now, and it has been suggested that only a part of the inflammatory mediator which inhibits the formation of a complex network cannot expect high effects (British Medicai)

Bulletin' 1999, 55, 212-225) » From this result, in recent years, the imbalance between the inflammatory mediators and the anti-inflammatory mediators that are manifested by the immune response is very serious about the severity and sepsis of sepsis. Sexual shock, complications associated with organ failure, and recurrence of sepsis caused by two infections 323165 5 201202247 Post-preventional failure. Therefore, she is expected to become the above-mentioned prevention and/or treatment from the TLR-free historical response of natural immunity. In particular, the selectivity of the inhibitor of W, the second pathogen microorganism, is difficult. #ΓΓτΐΙ2!#^^ ' ^ TLR2^^#J#^ ^ TLR4#flJ#J^ Combined with TLR inhibitors and more like 4

Septicemia - words can be (four) radical treatment. According to the combination obtained by the combination of the existing remedy of the (4) fruit agent 1 liquid coagulant 4, it is also expected to have a further effect on the septicemia. ~ Chloramphenin (a), which has been developed as an anti-dysentery drug, is also used in the treatment of autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, and as an anti-inflammatory drug. Recently The mechanism of action of quinacrine Xb, which has been reported for autoimmune disease, is the result of TLR9 antagonism (European Journal 〇f Immunology, 2〇04, 34, 254/ 2550). '

Others, although TLR9 inhibitors have recently been disclosed, they are structurally different from the compounds of the present invention (Reference 1). Further, a compound having the antagonism of TLR7, TLR8 and TLr9 has also revealed the following representative compound (c), but is structurally different from the compound of the present invention (Reference 2). ~ 323165 6 201202247

[Prior Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2000/076982 [Patent Document 2] International Publication No. 2/8/〇3〇455 [Disclosed] [Problems to be Solved by the Invention] The subject of the present invention provides an autologous Prevention and treatment of immune diseases, specifically providing diseases of the autoimmune side (inflammation, allergy, asthma, graft rejection, graft versus host disease, infection, cancer), immunity = whole disease or phase _ (Azi shipwreck, age-related disease, etc.: prevention, and / or treatment. Also found that selective inhibition of sputum suppression = ancient provide for the failure of A, _ is severe septicemia (four) simple and / also effective drugs Bullying [means to solve the problem] = Ming (4) After the results of intensive research, it was found that the prevention and control of the following blood can be a serious illness. Appreciation of the moon 1 is for a type of ΓΠήί· - ^ (hereinafter, sometimes referred to as "this hair: 4, 5-ring ring syllabus is as follows. The compound of this month") That is, the present invention 323165 7 201202247 [Item 1] A compound represented by the following formula U) or a pharmaceutical preparation thereof And salt,

Ο) [wherein, A1 and A2 represent the following formula (a)

(eight)

Or Z, wherein, when A1 is a formula (A), A2 represents Z, and A is Z. A2 represents a formula (A), and Q and Q2 each independently represent a hydrogen atom and a replaceable CN1. An alkyl group, a substituted C3-8 cycloalkyl group, a cyano group, a substituted Cl-5 alkylcarbonyl group, a substituted Cl-5 alkoxy group, a thiol group, a substituted aryl group a substituted heteroaryl group, or _c〇nr5r6,

Aik represents a substituted alkyl group, and Z represents a hydrogen atom and a substituted Ch. Alkyl, substituted & 8 cycloalkyl, cyano, substituted G-5 alkyl, substituted Ci s alkoxycarbonyl, substituted aryl, may be substituted Heteroaryl, dentate, substituted G-5 alkoxy, -nr5r6, or -conr5r6, X represents -χ1-, -X-NR C0-X2-, -Xi-CONRT-X2-, - Χ1_c〇-x2---X'-NR^ONR^X2---X!-NR7-X2- ' ^-X^o-X2-, X1 represents a substituted Cl-8 alkyl group , where X is _^1_服7 C0-X2---X'-NR7C0NR8-X2---XLNRT-X2-, or -χ^ο-χζ, 323165 8 201202247 X1 is a replaceable C2 -8 alkylene, X2 represents a C,-8 alkyl group which may be substituted, wherein X is _χ1_ c〇NR7-X2 X'-NR'CONR^X2---Χ^ΝΙ^-Χ2- Or, X2 is a substituted C2-8 alkylene group, W represents -W1-, HW1-, -NVCO-W1-, -CONRLw1- or -〇-Wi_, and W1 represents a replaceable Cl_8 alkylene a group, wherein, w is a compound, a -CONf-W1- or -0-W1-, the ore is a substituted Cz 8 alkyl group, and γ represents a substituted aryl group or a Substituted heteroaryl, R, R2, R3 and R4 each independently represent a hydrogen atom and can be taken Replace it with Ch. An alkyl group, a substituted CM cycloalkyl group or a substituted 4 to a saturated heterocyclic ring, and R5, R6, R7, R8 and R9 each independently represent a hydrogen atom or a substituted Cl-1. Burning group, R1 and R2, R丨 and χΐ, Ri and X2, ]^ and r7, χ2, r3, r4, R3 and W1, ❻R9, ❻, respectively, may also be carbon atoms bonded to each other. And forming a nitrogen-containing saturated heterocyclic ring of 4 to 1 member (wherein, the number of nitrogen-containing saturated heterocyclic rings formed is independently 〇 to 2 in _x_NRlR2 and the formula, respectively. Further, the combination of Re is formed. It is said that the saturated heterocyclic morpholine ring is excluded)]. [Claim 2] The compound of Item 1, or a pharmaceutically acceptable salt thereof, wherein the substituted alkyl group, the substituted alkoxy group, and the substituted alkoxy group in the item 1 The bases of the respective bases are independently replaced by the same or different i to 5 substituents selected from the group consisting of 323165 9 201202247 (1) _Atom, (2) a hydroxy group, a (3) cyano group, a (4) carboxy group, (1) a substituted aryl group, (6) a substituted aryl group, (a substituted heteroaryl group,

(8) Cm alkoxy group which may be substituted, (9) Cw cycloalkoxy group which may be substituted, (10) Ci 5 alkoxycarbonyl group which may be substituted, (11) Cl_5 alkylcarbonyl group which may be substituted (12) A saturated impurity (13) which can be substituted by 4, Τ, ^ (14) -CONR10RU, (15) -N(R10)CORn > (16) -S〇2R1(), and 17) -S〇2NR10Rn ; a substituted extendable group may be substituted by the same or different 1 to 5 substituents selected from the group consisting of: (前述) to (Η), and (18) may be substituted by a hydroxyl group, a fluorine atom, a Cl_5 alkoxy group (the group may be substituted by the same or different i to 3 substituents selected from the group consisting of a 〇5 alkoxy group and a fluorine atom) and 4 ClM substituted with the same or different 1 to 3 substituents selected from the group consisting of nitrogen-containing saturated heterocyclic rings. The meaning of the above (wherein the above-mentioned (6) and (in the case of the substituent in the oxime means a group which may be substituted by the same or different 1 to 5 substituents selected from the group consisting of 323165 10 201202247 described below (a) a hydroxy group, (b) a halogen atom, (c) a Cl- gram group which may be substituted by 1 to 5 fluorine atoms, a hydroxy group or a Cn5 alkoxy group, (d) may have 1 to 5 fluorine atoms, a hydroxyl group or Cl-5 alkoxy substituted by Cm alkoxy group,

(e) cyano group, (f) carboxyl group, (g) Cl-5 alkoxy group, (WCm alkylcarbonyl group, (i)-NR10Rn, (D-CONR, 丨, (k) -S〇2R1Q, And (l) -S〇2NR, 0Rn; the bases shown in the months (5), (8), (9), (10), (11), and (12) are meant to be via the aforementioned (a a group substituted with the same or different 1 to 5 substituents selected from the group consisting of (d), (g) to (j); <ιι> The alkyl group and the substituted saturated heterocyclic ring are each independently the same or different one to five substituents selected from the group consisting of the above (a) to (d), (g) to (i). Substituted group; <11 The substituted aryl group, the substituted heteroaryl group, the substituted aryl group and the substituted aryl group independently substituted in the above item 1 are independently (4) The same or different ones selected from the group consisting of (1) are substituted by the group substituted by 11 323165 201202247; Rl^R11 are each independently a hydrogen atom or may be substituted by 1 to 5 fluorine atoms. The Cl-1° filament 'or R. and R11 may also be combined to form a nitrogen-containing saturated heterocyclic ring of 4 to 10 members. Item 3] The compound of Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ', A1 is Formula (A), A2 represents z, A1 is Z, and A2 represents Formula (A), Q and Q. Each represents a hydrogen atom independently; it can be replaced by the same or different ones selected from the group consisting of a base group, a hydrogen atom, and a Cw alkoxy group (which can be selected from a group consisting of Gi5 silk groups and fluorine atoms! ), a Ci 5 alkoxycarbonyl group (which may be substituted by the same or different one to three substituents selected from the group consisting of a Cl s alkoxy group and a fluorine atom) and 4 to 1 employee a heteronuclear group substituted with the same or different 1 to 3 substituents selected from the group consisting of nitrogen-containing saturated heterocyclic rings; may be via a hydroxyl group, a fluorine atom, a Cl 6 alkyl group, and a Ci-5 alkoxy group (this The alkyl group may be substituted by the same or different one to three substituents selected from the group consisting of a Cl_5 alkoxy group and a fluorine atom, and the same or different ones to three selected from the group consisting of a C3·8 cycloalkyl group substituted by a substituent; a cyano group; the same or different one or three selected from the group consisting of a hydroxyl group, a Cl_5 alkoxy group, and a fluorine atom Substituted Cl_5 alkylcarbonyl or hydra-5 alkoxycarbonyl; carboxyl; may be via halogen, Ch alkyl and Cl_5 alkoxy (the alkyl portion of the group may be substituted by 1 to 3 fluorine atoms) An aryl or heteroaryl group substituted with the same or different 1 to 3 substituents selected from the group consisting; or -CONR5R6, 12 323165 201202247

Aik is replaced by a continent selected by a group of towels consisting of: or a substitute of three substituents.

Fluorine atom, Cd oxy group (this group may be substituted by the same or different one to three substituents selected from the group consisting of alkoxy groups and fluorohepatic) and nitrogen-containing saturated impurities of 4 to ί a Cl_1() alkyl group substituted by the same or different 1 to 3 substituents in the ring structure; may be via a base group, a gas atom, a Ch alkyl group, and a G-5 methoxy group (the group The alkyl group is the same or different from the group consisting of the same or different work selected from the group consisting of G 5 alkoxy and gas atoms to three substituents. a C3-8 cycloalkyl group substituted by S3 substituents; a cyano group; the same or different i to 3 substituents selected from the group consisting of a base group, a C a 5 alkoxy group and a gas atom; Substituted Ch Hyunyl or Ci 5 alkoxy group; a suspending group; can be activated via a ruthenium Cl-6 group and a Cl-5 group (the base of the group can be via i to 3 An aryl or heteroaryl group substituted by the same or different 1 to 3 fluorene substituents selected from the group consisting of: an atom may be substituted by the same group selected from the group consisting of a base group and a gas atom Different i to 3 Substituent substituted Ci-5 alkoxy; __NRl 〇 Rll; and - (3) 服 1 () R ll ; is a ruthenium atom, may be via a thiol group, a fluorine atom, a Cl-5 methoxy group (the base system may be oxime Cl-5 alkoxy and one or three substituents which are identical or different in the group consisting of I atoms), Ci5 alkoxy Daichi and 4 to 1 member of a 3 nitrogen saturated heterocyclic ring a selected from the group consisting of the same or different one to three substituents substituted by a, an alkyl group; may be via a base group, a fluorine atom, a ruthenium group, and a G-methoxy group (base group and minus The oxy group may be the same or different from the group consisting of the same or different one or three substitutions selected from the group consisting of a group of oxy groups and a gas atom; 3 substituents, substituted by C3-8 cycloalkyl; t group; may be substituted by the same or different ^ to 3 substituents selected from the group consisting of a group, a ο an alkoxy group and a gas atom a Cl-5 group or a Ci-5 alkoxy group; can be formed by dentate, Cl_6 alkyl and oxy (the base of the base can be substituted by 1 to 3 fluorine atoms) The same or selected from the group a hetero group or a heteroaryl group substituted with i to 3 substituents; halogen; G-5 substituted by the same or different 1 to 3 substituents selected from the group consisting of a base group and a fluorine atom; Alkoxy; -nr5r6; or _c〇nr5r6, X is -X1-, -X1-NR7C0_X2_, _x1_c〇nr7_x2_, -xl_c〇_X2, -X'-NR7C0NR8-X2---X^Nf-X2 -, or -χ^ο-χ2-, X1 is via a hydroxyl group, a fluorine atom, and a Cm alkyl group (this group may be composed of a hydroxyl group, a Cm alkoxy group, a (:η alkoxycarbonyl group, a carboxyl group, and a fluorine atom) Substituting the same or different 1 to 3 substituents selected from the group, the Cm extension φ 基 group substituted by the same or different 1 to 3 substituents selected from the group consisting of -Xi-NfCO-X2-, UlrtONRLx2-, -X-NR-X-, or Κ-χ2- when χ1 is via a thiol group, a fluorine atom, and a Ci-e group (the matrix can be via a thiol group, The same or different one to three substituents selected from the group consisting of Cl-5 alkoxy groups and one or three substituents selected by the same or different ones selected from the group consisting of fluorine atoms are substituted C2-8 stretching base, X2 is via a radical, a fluorine atom and Substituted by the same or different 1 to 3 substituents selected from the group consisting of Ci-6 alkyl groups (: 2-8 alkylene group, W is -W1---NR9-W!---NR ^O-W1---CONf-W1- or -0-W1-, 14 323165 201202247 w is a group which can be formed via a subtractive, fluorine atom and a Ci group (the base system can be via a base, alkoxy group and a fluorine atom) a Cm alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of the same or 1 to 3 substituents selected from the group, wherein w & NR9~ When wl -C0NRH-0 sheep is 'r is the same or different which can be selected via a radical, a fluorine atom and a Ci 6 thiol group which can be via a group consisting of a hydroxyl group, a G-5 alkoxy group and a fluorine atom. a C2-8 alkylene group substituted by the same or different 1 to 3 substituents selected by φ in the group consisting of 1 to 3 substituents, Y being the same or different 1 a heterocyclic group substituted with 3 substituents or a monocyclic or condensed cyclic heteroaryl group having 1 to 2 nitrogen atoms, which is a Ci which may be substituted by 1 to 3 fluorine atoms via a halogen. An alkyl group and a c,-5 alkoxy group which may be substituted by 1 to 3 fluorine atoms Selected from the group, R1, R2, R3 and R4 are each independently a hydrogen atom; can be via a hydroxyl group, an oxygen atom, a Cm alkoxy group, a Cw alkoxycarbonyl group, a Cu alkylcarbonyl group, an aryl group, #-S〇 2NRl°R", -NR%11, can pass 1 to 3 Cm. a heteroaryl group substituted with an alkyl group and a Ci-in alkyl group or a C3-8 cycloalkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of -CONW1; -NR1()CORn Or 4 to be substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom, (V6 alkyl group, Ci-5 alkoxycarbonyl group, and Cm alkyl group) a saturated heterocyclic ring of 1 member, R5, R6, R7, R8 and R9 are each independently a hydrogen atom; or the same or different one selected from the group consisting of fluorine, hydroxyl and Ci-s alkoxy groups Cm.alkyl substituted by 3 substituents; 15 323165 201202247 and R is independently a hydrogen atom or a CM which may be substituted by 1 to 5 fluorine atoms. Acryl group, 戋riq saturated heterocyclic ring; Forming 4 to 10 members of nitrogen-containing R3 2, R1 and X1, R1 and X2, R7, R7 and X2, R4, *, and R9, R9 and W1, and R5 and R6, respectively. And the atomic bond νΌ forms a nitrogen-containing arsenic and a heterocyclic ring of 4 to the member (wherein the number of the 3 nitrogen-saturated heterocyclic rings of the opened ' is in -X-NRiR2 and the formula (A), respectively, is independently 2 to 2 .π ς , the combination of R and R And the pharmaceutically acceptable salt of the compound, wherein A1 is a formula (A), A2 is z, and A is In the case of Z, the A2 formula (a), the Q and the Q knife independently represent a hydrogen atom; and the same group of the group consisting of a radical, a fluorine atom, and an alkoxy group (the money (10) is composed of a Gi5 group and a fluorine group) Or 1 to 3 substituents substituted by different), Cl_5垸oxyf-based groups (the county system can be replaced by the same or different 1 to 3 substituents prepared by Gi s material base and gas) and 4 to 10 = selected from the group consisting of saturated heterocyclic rings = the same t mesh selected from the group consisting of the fluorine atom, or the -conr5r6, AUcf C-3 extended thiol substituted by 1 to 3 substituents of the cloaked synth group: thiophene; 323165 201202247 base, II atom, Cl-5 alkoxy group and nitrogen saturation of 4 to 10 members a Ch substituted with the same or different 1 to 3 substituents selected from the group consisting of heterocycles; the same or different from the group consisting of a hydroxyl group, a Cl a 5 alkoxy group, and a fluorine atom; 1 to 3 a Ch alkylcarbonyl group or a Cm alkoxycarbonyl group substituted by a substituent; a halogen; a Ci-5 oxygenated oxygen which may be substituted with the same or different one to three substituents selected from the group consisting of a hydroxyl group and a fluorine atom; -NR1QRn; and -conrWR"; Φ z is a hydrogen atom; the same or phase selected from the group consisting of a hydroxyl group, a fluorine atom, and a Cl_5 alkoxy group (the group may be composed of a Cm alkoxy group and a fluorine atom) Substituted by the same or different i to 3 substituents selected from the group consisting of 1 to 3 substituents substituted, Cl_5 alkoxycarbonyl and 4 to 1 member nitrogen-containing saturated heterocyclic ring Cl_lD alkyl; may be the same or different via a hydroxyl group, a fluorine atom, a Ci 6 alkyl group, and a Cm alkoxy group (the alkyl group and the alkoxy group may be selected from the group consisting of a Cl a 5 alkoxy group and a fluorine atom) 1 to 3 substituents substituted by the same or different groups selected from the group consisting of 3 substituents substituted by C3-8 ring; Cyanodin; via a base and a fluorine atom a Cl-5 alkoxy group substituted with the same or different 1 to 3 substituents selected from the group; -NR5R6; or -C〇NR5R6, X ~X -, I-NFCO-X2---X'-CONR'-X2---X^NR'CONR8- χ2 Xl~NR7-X2-, or -Χ^ο-Χ2-, x is via hydroxyl a group of fluorine atoms and ci 6 alkyl groups (which may be substituted by the same or different one to three substituents selected from the group consisting of a hydroxyl group Cl 5 alkoxy group and a fluorine atom) The selected Q-8 alkyl group substituted by the same or different substituents, wherein χ is -X1- 17 323165 201202247 NR7-C0-X2---X^NfCONR8-X2---X^ When -fT-X2-, or χ1_〇_χ2_, X1 is a group which can be selected from a group consisting of a hydroxyl group, a fluorine atom and a Cw alkyl group which can be constituted by a via group, a Cm alkoxy group and a fluorine atom. a Cw alkyl group substituted by the same or different 1 to 3 substituents selected from the group consisting of the same or different 1 to 3 substituents, X2 being hydroxy, 1 atom and Ch a Cw alkyl group substituted by the same or different 1 to 3 substituents selected from the group consisting of alkyl groups, W being -W1-, -NR9-W1-, -NR9C〇-r-, -CONRLWL or —〇_wl_, W1 is the same or different one to three selected from the group consisting of a hydroxyl group, a fluorine atom and a Cm alkyl group. a Cl_8 alkyl group substituted by a substituent, wherein, when w is H conr9_w1- or -0-W1-, W1 is the same or different one selected from the group consisting of a hydroxyl group, a fluorine atom and a Ci_6 alkyl group. a C2-8 alkylene group substituted with 3 substituents, Y being a phenyl group substituted by the same or different 1 to 3 substituents or a monocyclic or condensed ring having 1 to 2 nitrogen atoms Heteroaryl group, which is a group consisting of a halogen, a Ci ealkyl 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. Selected, fmR4 is independently a hydrogen atom; it can be selected from the group consisting of a base group, a gas atom, a Ci-5 alkoxy group, a C!-5 alkoxy group, and a _c〇NRl〇R" Or Cm substituted by 1 to 3 substituents. Or a C3-8 cycloalkyl group; or may be substituted by the same or different to three substituents selected from the group consisting of a base, a gas atom, a base group, a base group, and a Cl-5 group. 4 to 10 member _ and heterocyclic ring, 323165 18 201202247 R5, R6, R7Hrs via the group and G ethoxy group = (4) as a hydrogen atom; or can be substituted by l, a substituent in the Cl, ton group The same or different selected 1 to 3 R10 and R11 are independently hydrogen-substituted Cm. Alkyl, or 1^ and RU^ s may be saturated with a heterocyclic ring of 1 to 5 fluorine atoms; may form a nitrogenous K1 of 4 to 10 members and R'R1 with Xi, Rlik

R3 and W1, R3 and R9, R9 and/or, f R7, χ2, R3 and R4, ^^ R and R, respectively, may also be different; t-based slave atoms are bonded to form 4 different The formed money-independent heterocyclic ring is called 丨 / / money saturated heterocyclic ring (which, independently, is .... ==6 in rhyme 2 and formula (1)... heterocycle, except for the lining ring)]. The gas-containing freshness formed by the combination [Item 5] is the salt of any one of the items 1 to 3, and the compound of +$ or the pharmaceutically acceptable Q and Q2 thereof independently represent a hydrogen atom; Substituted by the (four) group, the fluorine atom, the c: alkoxy group (the same or different one to three substituents selected from the composition of the silk (tetra) ei s green base material) and the gas-saturated impurities of 4 to 10 members a "burning group" which is substituted by the same or different i to 3 substituents selected from the group consisting of a ring; may be via (iv), a fluorine atom, a Cl 6 thiol group and a Ch methoxy group (the base portion of the group) It is the same or different 丨 to 3 substitutions of the group caps which can be replaced by the same or different i to 3 substituted oximes selected from the group consisting of Ci 5 alkoxy groups and fluorine atoms. 2 substituted monocyclic alkyl group; cyano group; the same or different oxime selected from the group consisting of a base group, a Ci 5 alkoxy group and a gas atom to 3 substituents 323165 19 201202247 Substituted Ci- a oxycarbonyl group; a thiol group; may be selected from the group consisting of halogen, Ci-6 leucoyl and Ci-5 alkoxy (the alkyl group of which is substituted by 1 to 3 fluorine atoms) The same or different oxime to a phenyl group substituted with 3 substituents and a nitrogen-containing heteroaryl group of 5 or 6 members; or -C0NR5R6. The compound according to any one of items 1 to 5, or A pharmaceutically acceptable salt, wherein w is -W1---NR'-W1---NRtO-W1-, or -0-W1-' ^ R3 and R9, R3 and W1, and each combination of R9 and W1 And a compound of any one of items 1 to 6 or a pharmaceutically acceptable compound thereof, wherein the carbon atom of the respective groups is bonded to form a nitrogen-containing saturated heterocyclic ring of 4 to 10 members. Permissible salts, wherein Q1 and Q2 each independently represent a hydrogen atom; or a group which may be composed of a nitrogen-containing saturated heterocyclic ring via a trans group, a fluorine atom, a Ck alkoxy group, a Ch alkoxycarbonyl group, and a 4 to 1 member. The compound of any one of items 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the same or a different one or three substituents are substituted. z is a hydrogen atom; the same or different 1 to 3 substituents which may be selected from a group consisting of a hydroxyl group, a fluorine atom, and a Ci 5 alkoxy group which may be selected from a group consisting of a Cl-5 alkoxy group and a fluorine atom. Substituted), C, oxygen-based base and nitrogen to 4 to 1 employee a "burning group" which is substituted by the same or different oxime selected from the group consisting of saturated heterocyclic rings, and may be substituted by a group consisting of a base group, a gas atom, a G 6 group and a cw oxy group. The same or different ones selected from the same or different substituents are substituted by the same or different 1 to 3 substituents selected from the group consisting of (4) and cyclone H (4) _ and gas 323165 20 201202247 Ch-alkyl group; _nr5r6; or -c〇NR5R6. [Claim 9] The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof, wherein

R1, R2, R3 and R4 are each independently a hydrogen atom; they may be substituted by the same or different one to three substituents selected from the group consisting of a hydroxyl group, a fluorine atom, a Cm alkoxy group and -coNfR11-. Cw alkyl or c may be via a group consisting of a base group, a fluorine atom, and c, _, a pit group; a base of 4 or 10 substituents substituted with 1 to 3 substituents of the same or phase G, Rings, Rl° and R11 are each independently a germanium atom or may be substituted with 1 to 5 fluorine eyebrows, or may be formed to form 4 2 == saturated heterocyclic ring; R and R and R and R4 Each combination 'may also bond to a carbon atom of a respective group to form a nitrogen-containing saturated heterocyclic ring of 4 to 7 members. The compound of any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R and R are each independently a chlorine atom; or may be composed of fluorine, earth and alkoxy groups. a Ci iq alkyl group substituted with the same or different substituents up to 3 substituents; /, a combination of R' may also bond with a carbon atom of each group to form a 4 saturated heterocyclic ring (its + The nitrogen-containing saturated heterocyclic ring formed by the combination is excluding the morpholine ring). [Item 11] The compound of any one of the items 1 to 1 + or the pharmaceutically acceptable genus thereof, wherein 21 323165 201202247 wherein (A) is the following formula (A'), (A' ') or (A' ' ')

The base ' Y1 shown is = (-) C-Z4 or It atom'

Z1, Z2, Z3 and Z4 are each independently a hydrogen atom, a halogen, a Cl-6 alkyl group which may be substituted by three to three fluorine atoms, or a Ch alkoxy group which may be substituted by one to three gas atoms. The compound of any one of items 1 to 1 or a pharmaceutically acceptable salt thereof, wherein the formula (A) is as follows

The groups shown, Z1, Z2, Z4 and Z5 are each independently substituted by a hydrogen atom or a halogen which can be substituted by three I atoms (: a ton group and an oxy group which can be substituted by a fluorine atom: The three rings or different substituents are constituted, Het is the same or up to 6 members of the I-containing unsaturated heterocyclic ring selected from 5 to 3, and the 3 nitrogen partial saturated heterogeneous [Item 13] is as in items 1 to 12. Any of the salts, of which 5 or its pharmacy

Aik is substituted by the same substituents of the same Gobyl 6 alkyl group and C1-5 alkoxy group selected from the group consisting of a hydroxyl group and a deficient atom. 323165 22 201202247

Ch stretch alkyl. [Claim 14] The compound according to any one of items 1 to 5, wherein the Q1 and Q2 are each a hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 1 to 4, wherein X is -X-, _X^N^CO-X2-. -X^CONR^X2-, or a pharmaceutically acceptable salt thereof -X^NRT-X2-, or -X1 -0-Χ2-,

Any of R, X, R1 and x2, R1 and R7, and each combination of R7 and X2 may be bonded to a carbon atom of a respective group to form an I-containing saturated heterocyclic ring of 4 to 1 Gs. [Claim 16] The compound of any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, wherein X is a C 4 alkyl group and X 2 is a c2-4 alkyl group. The compound of any one of items 1 to 16 or a pharmaceutically acceptable salt thereof, wherein A1 is Z and A2 is formula (A). The compound of any one of items 1 to π, or a pharmaceutically acceptable salt thereof, wherein X is -X _, -X^CONRlx2-, or _χΐ_〇_χ2, R and R Is independently a hydrogen atom; or can be formed via a thiol group, a G-5 alkoxy group, and a -c moiety to form a C!-6 alkyl group which is substituted by the same or different oxime to 3 substituents. ; R1 and X1, R1 and R2 and R1 and the combination of any group, may also be 323165 23 201202247 "Mtton knot to form a nitrogen-containing saturated heterocyclic ring of 4 to 8 members. 葶 and the above - to the material 11 Or a compound according to any one of 13 to 18, wherein the substituent is substituted by the same or different 1s2 substituents, wherein the substituent is Select from the group consisting of (four) and heart-burning groups, w denotes mhe (four), or _〇_r_, ν/w is not arbitrarily, and Cw is extended by one basis group, wherein, w For -NRmw-, I1 is C2—4, and the r-class is not a gas atom, or the same or different ones and 3s can be selected from the base and Ci-5 households. Cm alkyl group substituted by one substituent; any group combined with rr4, = each group The carbon atom is bonded to form a 4 to 8 (4) nitrogen-containing saturated impurity. The compound according to any one of items 1 to 19, wherein the compound is a hydrogen atom, a k-ray, or a Or a pharmaceutically acceptable compound of any one of the above items 1 to 2, or a pharmaceutically acceptable compound thereof. The compound of any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein 323 is a hydrogen atom, and a pharmaceutically acceptable salt thereof, wherein 323165 24 201202247

Aik is 0-3 alkyl. The compound of any one of items 1 to 11 or 13 to 22, or a pharmaceutically acceptable salt thereof, wherein Y is a phenylene group or a stretching ratio, and the formula (Α) is -W- NR3R4 is

a group represented by φ, R and R are independently a non-aerobic atom; or a Cl which may be substituted by the same or different one to three substituents selected from the group consisting of a base and a G-based emulsion base. -6 base. [Claim 24] The compound of Item 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (1) is selected from the group consisting of: 2-[4-(4-fluorenyl) Hexahydropyrene is compared with the well-1-1-yl)phenyl]-7-[3-u ratio p each bite] propyl]_6, dihydropyrrolo[2,3-d]pyrimidine (Example 41 2-[4-(4_ethylhexazone.ββ井_ι_yl)phenyl]_7_[3_β piroxime]propyl]-6,7-dihydro-5Η-pyrrolo[2] , 3-d]pyrimidine (Example 45) 2-[4-(4-Isopropylhexahydropyrazine_丨_yl)phenyl]_7_[3_πpyrrolidino-yl]propyl]-6 , 7-Dihydro-5-pyrido[2,3-d]pyrimidine (Example 46) 2-[3-(4-Mercaptohexahydropyridin-4-yl)phenyl]_7_[3-pyrrolidine Propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Example 48) 4-(3-{2-[4-(4-mercaptohexahydro) 11 哄 卜 卜 ) ) 苯基 5 H H H H H H H 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 (2) [4~(4_isopropylhexahydroindole + base) benzoic acid each [2,3_d]pyrimidin-7(61〇-yl}propyl)morpholine (Example 64) 4 (2 {2 [4-(4-methylhexahydroindolyl)-phenylphenyl 5H_吼[2,3-(1>Bite-7(611)-yl}ethyl)morpholine (Example 69) N,N-Diethyl-3-{2-[4-(4-methylhexa) Hydrogen is called +yl)phenyl],5h_pyrrolo[2,3-(1]pyrimidin-7(61〇-ylpropanepropan-1-amine (Example 7〇) N-(2-decyloxyethyl) )-N-mercapto-3-{2-[4-(4-mercaptohexahydron-p-menthyl)phenyl]-5Η-°piro[2,3-d]pyrimidine-7 ( 61〇-yl}propane-oxime-amine• (Example 72) 2-{4-[4-(2-methoxyethyl)hexahydropyridin-1-yl]phenyl}_7_[3_ ( Pyrrrolidin-1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d] ringing (Example 77) 4-(3-{2-[4-(4- Ethyl hexahydro 0 to 卩 -1-yl)phenyl]_4_methyl-5h-b than arrog[2,3-d]pyrimidin-7(61〇-yl}propyl) morphine Example 78) 4-(3-{4-Ethyl-2-[4-(4-ethylhexahydroindole_ι_yl)phenyl]_ 5H-^ pyrrolo[2,3-d]pyrimidine -7(61〇-yl}propyl) morphine (Example 79) 4-ethyl-2-[4-(4-mercaptohexahydropyridin-1-yl)phenyl]-7-[2 -〇比唆唆-1-yl)ethyl]_6, 7-·-虱-Luo[2,3-d] mouth bite (Example 83) 4-(2-{4-mercapto-2- [4_(4-mercaptohexahydropyridin-1-yl)phenyl]-5H-0 is more than [2, 3-d]e -7 (New)- } 乙基 ) ( (Example 84) 4-mercapto-2-[4-(4-mercaptohexahydropyrylene-1-yl)phenyl]-7-[3-indolepyridine- 1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Example 86) 26 323165 201202247 4-ethyl-2-[4-(4-methyl Hexahydro"birthen-1-yl)phenyl]_7_[3_(0-pyridin-1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine ( Example 87) 4-(3-{4-Ethyl-2-[4-(4-methylhexafluoropyrene: _ι_yl)phenyl]_5H-pyridyl-[2,3-d], ^-7(6H)-*}propyl)lin (Example 91) N,N-dimethyl-l-{4-[4-methyl-7-(3-(N-morpholinyl) Propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl}pyrrolidin-4-amine (Example 95) Spring 2-[4-(1 -methylhexahydrogen. Bipyridin-1-yl)phenyl]-7-[3-indolepyridinyl-1-yl)propyl]-6,7-dihydro-5H-pyrido[2,3-d]pyrimidine ( Example 109) (R)-N,N-Dimethyl-1-(4-{7-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-indole And [2,3-d]pyrimidin-2-yl}phenyl)hexahydropyridin-3-amine (Example 110) (5)-Team 1^-dimercapto-1-(4-{7-[ 3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-indolo[2,3-d]pyrimidin-2-yl}phenyl)hexahydropyridin-3-amine^ (Example 111) N,N-dimercapto-1-(4-(7-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5-indole-pyrrolo[ 2,3-d]pyrimidin-2-yl}phenyl)hexahydropyridin-4-amine (Example 112) 4-[3_(2-{4-[4-(2-decyloxyethyl)-6 Hydroquinone-i-yl]phenyl}-5H-indolo[2,3-d]pyrimidin-7(6H)-yl)propyl]morpholine (Example 114) N,N-monodecyl -1 -{4-[7-(3-(N-Nipyl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl} Hexahydropyridin-4-amine (Example 27 323165 201202247 117) 2-(4-{4-[7-(3-(N-morphinyl)propyl)-6,7-dihydro-5H-α Bilo and [2, 3-d] oxime 11 quinol-2-yl]phenyl}hexahydro.pyridin-1-yl)ethanol (Example 119) (R)-2- ((2-(4-(4-methylhexanitro)-pyridin-1-yl)phenyl)-5Η-° ratio 0 and [2, 3-d] pyridine-7(6Η)-yl) Methyl) morphine (Example 146) (R) -4-mercapto-2-((2-(4-(4-mercaptohexahydropyridin-1-yl)phenyl)_ 5Η-β Bilo[2,3-d]pyrimidine-7(6H)-yl)mercapto)Nanlin (Example 164) ® (S)-4-mercapto-2-((2-(4-( 4-mercaptohexahydroindol-1-yl)phenyl)_5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)indolyl)morpholine (Example 166) (S) -N,N-dimercapto-1-(4-(7-(3-(indolyl) phenyl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine 2-yl]phenyl}pyrrolidine-3-amine (Example 242) 4-(3-(2-Mercapto-4-(4-(4-methylhexahydropyrylene-1-yl)benzene) ))_讪_pyrolo[2,3-d> dense β-den-7(6H)-yl) fluorenyl) (Example 250) φ 2_(4_(4-(2_methyl_7_( 2_(pyrrolidin-1-yl)ethyl)-6,7-dihydro-5H-indolo[2,3-(1]-mouth-4-yl)phenyl)hexahydropyrene Ethyl alcohol (Example 255) and 2-methyl-(4-(4-(4-mercaptohexahydro" 哄-1-yl)phenyl)_7_(2_(〇比唆1) Ethyl)-6,7--虱-5Η-η is more than 嘻[2, 3-d]. (Example 257). [Claim 25] The compound of Item 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (1) is selected from the group consisting of: Ν,Ν-dimethyl-3- {2-[4-(4-Methylhexahydropyridinyl)phenyl]_5Η_ 323165 28 201202247 σ比嘻[2, 3-d]e 密-7 (61〇-基}丙烧1-Amine (Example 39) 2-[4-(4-Methylhexahydropyrrolidin-1-yl)phenyl]-7-[2-pyrrolidin-1-yl]ethyl]-6, 7-Dihydro-5Η-σ ratio ρ and [2, 3-d] bites (Example 40) 4-[4-(4-Indolylhexahydroindol-1-yl)phenyl]-7 -[3-°Byrrolidin-1-yl]propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Example 42) (R) -N,N-di Methyl-1-(4-{7-[3-indolebi-1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl }Phenyl)pyrrolidin-3-amine (Example 49) (S) -N,N-Dimethyl-1-(4-{7-[3-indolepyridin-1-yl)propyl] -6, 7-diindole-5H-° is slightly more than [2, 3-d]°Bite-2-yl}phenylpyrazine-3-amine (Example 50) Bu (4-{7- [3-p-pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-Dpiro[2,3-d]pyrimidin-2-yl}phenyl)pyrrolidine-4- Amine (Example 54) 4-(4-{2-[4-(4) - mercapto hexahydro hydrazine ^ well - phenyl) phenyl]_5H_0 pyro[2,3-d]pyrimidin-7(61〇-yl}butyl)morpholine (Example 63) φ 2-[4 -(4-methylhexahydropyridinium)phenyl]_8_[3_pyrrolidinyl-yl]propyl]-5, 6, 7, 8-tetrahydropyrido[2, 3-d] Pyrimidine (Example 66) 2-[6-(4-Mercaptohexahydropyridinium-!-yl)pyridine-3-yl]_8_[3-pyrrolidin-1-yl]propyl]-5, 6, 7, 8-tetrahydropyrido[2,3-d]pyrimidine (Example 67) 2-[Methyl(3-{2-[4-(4-methylhexahydroindole-1-yl)benzene) -5H-indolo[2,3-d]' bite-7(N)-yl}propyl)amino]acetamide (Example 73) 1-(4-methylhexahydroindole ratio [1,3-(1]pyrimidin-7(61〇-yl}ethanone) (Example 29 323165 201202247 74) 4 啡 曱 曱 六 六 六 ) ) ) ) 苯基 苯基 苯基 苯基 2 2 2 -(3-{2-[4-(4-ethylhexahydropyridinium-indole-yl)phenyl bromide 5H_pyrrolo[2,3-d] mouth bite-7(61〇-yl}} )) (Example π) N,N-Dimethyl-3-H-methyl-2-[4-(4-methylhexahydropyridinium-p-butyl)phenyl]-5H-pyrrole And [2,3-(1]pyrimidin-7(61〇-yl}propan-1-amine (Example 81) 4-methyl-2-[4-(4-methylhexahydroindole Phenyl)phenyl]_7_[2_(indolyl-1-yl)ethyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Examples • 82) 2-[ 4-(4-methylhexahydropyrazole-1-yl)phenyl]_4_propyl_7_[3_(p-pyrrolidin-1-yl)propyl]-6,7-dihydro-5H- Pyrrolo[2,3-d]pyrimidine (Example 88) 4-(3-(4-Mercapto-2-[4-(4-methylhexahydropyridinyl)phenyl]_ 5H_pyrrole And [2,3-(1]pyrimidin-7(61〇-yl}propyl)morpholine (Example 90) 4-(3-{2-[4-(4-isopropylhexamhydroquinone) Phenyl)phenyl]_4_methyl_5H_ • pyrrolo[2,3_d]pyrimidin-7(61〇-yl}propyl)morpholine (Example 92) 4-(3-{4-ethyl- 2-[4-(4-isopropylhexahydro). Phenyl 丨 基 yl) phenyl] -5H-pyrrolo[2,3-d]pyrimidin-7(611)-yl}propyl)morpholine (Example 93) 4-(4-{4-A Base 2-[4-(4-decylhexafluoroindole)phenyl;| _5H_pyrrolo[2,3-(1]pyrimidin-7(61〇-yl}butyl)morpholine ( Example 94) 2-[4-(4-{7-[3-Pyrrolidin-1-yl]propylindole_67_dihydro_5{1_(1-pyrolo[2,3-d]pyrimidine -2-yl] styrene} hexahydropyrone 丨 丨 基) ethanol (Example 125) 2-[4-(4-decyl hexahydro. fluorenyl) phenyl]_7_{2_[2_0 ratio一一卜30 323165 201202247 】]ethoxy}ethyl hydrazine-6, 7-dihydro-5H-b ratio slightly [2, 3-d] ° close bite (Example 127) and 4-(3- {2-[4-(4-Methylhexahydroindole 1-1-yl)phenyl]-6,7-dihydropyridinium[2,3-d]pyrimidine-8 (51〇-yl) And a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof. [Item 27] - Species A therapeutic agent and/or a prophylactic agent for a sputum receptor (T〇li-iike receptors), which is a compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof. [ Item 28] A therapeutic and/or prophylactic agent for a disease associated with a sputum receptor 7 and/or 9 which is effective as a compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof The therapeutic and/or prophylactic agent according to Item 27, wherein the disease associated with the sputum receptor is a sepsis, an autoimmune disease or a neurodegenerative disease. [Item 30] The therapeutic agent according to Item 28 And/or prophylactic agents, wherein the diseases associated with the steroid receptors 7 and #/or 9 are sepsis, autoimmune diseases or neurodegenerative diseases 0 [Item 31] - treatment of diseases associated with sputum receptors and/or Preventive Alchemist's comprising a therapeutically effective amount of a compound of any one of items 1 to 25 or a pharmaceutically acceptable salt thereof for administration to a mammal in need of treatment. ^Item 32] Item 1 to 25 The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and/or prophylactic agent for a disease associated with a terpenoid receptor. [Item 33] - Item i to 25 The use of a compound or a pharmaceutically acceptable salt thereof, 323165 31 201202247, which is used in association with a terpenoid receptor Treatment and/or prevention of the disease. [Effect of the invention] The compound of the present invention can be used for the prevention and/or treatment of an autoimmune disease, specifically, an autoimmune-related disease (inflammation, allergy, asthma) Preventive and/or therapeutic agents for graft rejection, graft versus host disease, infectious disease, cancer, immunodeficiency or neurodegenerative diseases (Azheimer's disease, Parkinson's disease, etc.). Further, it has been found that a TLR inhibitor which selectively inhibits TLR can also be used as a medicament for the prevention and/or treatment of sepsis, special limb syndrome & septicemia. X, found that can selectively inhibit the pore preparation such as tlr, can increase the effect of the fruit and / / "four (four) death material effect, can also be used as a preventive and / or therapeutic treatment of cancer (four) drugs. The present invention will be described in more detail below. In the following description, the compound of the formula (1) is used. (1) The compounds of the other formulae are similarly clarified, and the δ compound or the like may be hydrated or / or solvate: The compound and / or solvate is also included in the present invention (four) =: the two - the palm of the hand - there are several stereoisomers::: two or axial pair 323165 32 201202247 Further, any one or two or more of the compounds (I) converted to 1 h (d) are also included in the compound (〗) of the present invention. Further, in the present specification t, The substituent group in the group is not particularly limited as long as it is replaceable, and is 1 or 2 or more. In the description in the specification, a basis not specifically described means an unsubstituted group. Further, unless otherwise stated, the description of each group is in accordance with the case where the group is a part or a substituent of another group.

(i) "alkyl" means a linear or branched chain saturated hydrocarbon group, for example, "a 6 alkyl" or "Cm. alkyl" means that the number of carbon atoms is from 丨 to 6 or 10 alkyl. Specific examples of the "Ch 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 butyl butyl group, an isopentyl group, and the like. The neopentyl group, the third pentyl group, the hexyl group, the isohexyl group and the like, and the "Cl-ioalkyl group" are in addition to the above, and are also a heptyl group, an octyl group, an isooctyl group, a decyl group, a fluorenyl group or the like. Among them, for example, "Ci 3 burning base" is preferable. (ii) "Cycloalkyl" means a cyclic saturated hydrocarbon group, for example, "c^ fluorenyl means a cyclic saturated hydrocarbon group of 3 to 8 members. Specifically, for example, "two", pentyl, and ring Hexyl, cycloheptyl, cyclooctyl and the like. It is preferable to give two; such as a 5- to 7-membered cycloalkyl group. + (iii) "Aryl" may be, for example, a base of 6 to 12 members. Specific examples thereof include a phenyl group, a decyl group, a benzyl group, and the like. Yico = naphthyl. The "green" = square base may, for example, be a phenyl group and a valence group at the positional bond of any of the above-mentioned positional points, and specific examples thereof include a phenyl group and the like. U2 valence (5) "heteroaryl group" For example, a monocyclic pentoon of a 5 to 7 membered ring of 1 to 4 atoms selected from a heart nitrogen atom, an oxygen atom, and a sulfur atom 323165 33 201202247, a 9-membered 2-ring aromatic heterocyclic ring or 12 to 15 membered cyclic aromatic heterocyclic ring, and specific examples thereof include pyridyl group, pyridyl group, fluorenyl group, benzoimidazolyl group, 2-ketobenzoxazolyl group, benzotriazolyl group, and benzof. Nanji, benzo (tetra), benzyl, benzofluorenyl, benzopyrene = yl, "base 丨 、, iso-yl, fluorenyl, phenyl, porphyrin, pyrazolyl, triazolyl , tetrazolyl, oxazolyl, thiazolyl, iso, yl 1 phenyl, base, and the like. Compared with (4) 5 R Α 6 members of the monocyclicity = aromatic heterozygous 9 (four) 2-ring aromatic ring. Specifically, human pyridyl, imidazolyl, pyrazolyl, thiazolyl, indolyl or tetrazolyl can be exemplified. "knot: a nitrogen-containing partially saturated heterocyclic ring of 5 to 6 S in a stupid ring or a nitrogen-containing non-heterocyclic ring of 5 to 6 members, and a heterocyclic ring" means 5 to 6 selected from the above monocyclic aromatic heterocyclic ring. A ring or a portion thereof that is saturated with a ring. Further, the "heteroaryl group" is a divalent group which can be bonded to any of the above-mentioned positions, and specific examples thereof include a thiazole group and a thiazole group. (v) "Halogen" means each atom of fluorine, gas, bromine or iodine. Preferably, each atom such as fluorine, gas or desert is used. (vi) "Alkoxy" means a group in which a linear or branched chain saturated hydrocarbon group is bonded via an oxygen group, for example, "Cl_3 alkoxy" or "CM alkoxy" means & carbon atom It is an alkoxy group of 1 to 3 or 1 to 5. Specifically, the "Cl_3 alkoxy group" may, for example, be a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and the "Ch alkane group" may, for example, be a butoxy group in addition to the above. A group, an isobutoxy group, a second butoxy group, a third butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a third pentyloxy group or the like. Among them, for example, "Ci 3 alkoxy group" is preferable. 323165 34 201202247 (Vii) "cyclofilament" means a group in which a cyclic saturated hydrocarbon group is bonded via an oxygen atom, and for example, "C3-8 ring alkoxy" means 3 i 8 member (4) (10) and a hydrocarbon group via The base of the oxygen atom and the bond. Specifically, for example, a cyclopropoxy group, a cyclobutoxy 'cyclopentyloxy group or the like can be mentioned, and an oxy group of 5 to 7 Å is preferable, for example. " (viii) "Saturated heterocyclic ring" means a saturated ring containing 1 to 3 hetero atoms other than a carbon atom. For example, "saturated heterocyclic ring of 4 to 8 members" or "saturated heterocyclic ring of 4 to 1 〇 φ 」" means 4 to 8 or 4 to 10 atoms of a hetero atom containing 1 to ^, other than a carbon atom. The saturated ring formed. The atom may, for example, be the same or different I atom, oxygen atom or sulfur atom, more preferably a nitrogen atom or an oxygen atom, more preferably a nitrogen atom. Specific examples thereof include azetidinyl, pyrrolidinyl, pyrrolidinyl, morpholinyl, pyrrrolidinyl, hexahydropyrryl, hexahydropyranyl, tetrahydrofuranyl, tetrahydrogen. A pipenyl group, a tetrahydrothiophenyl group, a tetrahydrothiopyranyl group, a pendant oxytetrahydrothiopyranyl group, a di-oxytetrahydrothiopyranyl group, and the like. It is preferably a saturated or heterocyclic ring of 4 to 7 members, and specific examples thereof include azetidinyl group, pyrrolidinyl group, pyrrolidinyl group, morpholinyl group, pyrrolidinyl group, hexahydropyridinyl group, tetrahydrofuran. Base and tetrahydropyranyl group and the like. "5 to 6 member nitrogen-containing saturated heterocyclic ring" or "4 to 10 member nitrogen-containing saturated heterocyclic ring" is a carbon atom other than a carbon atom, and has 5 to 1 or 4 to 10 atoms containing 1 to 2 nitrogen atoms. The saturated ring (herein, the saturated ring may further be substituted with one carbon atom by an oxygen atom or a sulfur atom). It is preferably a nitrogen-containing saturated heterocyclic ring of 4 to 6 members. (ix) "Extension base" means, unless otherwise defined, a straight-chain hydrocarbon chain which may be substituted with a part of the methylene group to form a cycloalkyl group. For example, "Cm extension 35 323165 201202247 alkyl", "α5 stretching group", "C28 stretching group" or rCi 8 alkyl group means that the number of carbon atoms is 2 to 4 '1 to 5, 2 to 8 or a linear hydrocarbon chain of from i to 8. Specifically, for example, when "(: 2-4) is used, the "Gl_5 stretched wire" such as an ethyl group, a propyl group, a butyl group, a stretching group, and the like may be mentioned, and the above may be exemplified. For example, in the case of a methylene group or a pentamethylene group, the "heart-stretching base" or the "Ci8-extension base" may be mentioned, for example, a hexamethylene group, a heptamethylene group or an octamethyl group. Preferably, for example, a % extended alkyl group is used. X, the above-mentioned alkylene oxide

When the group is a substituted alkyl group, a ring may be formed by binding the same or different two alkyl groups of the same carbon atom. Tributylcarbonyl and the like. Preferably, for example, methylcarbonyl group ======

"Cl_3 炫基基基", more preferably nr-based" pure financials such as ^ silk base, B = base = oxygen diyl, butoxy, different core substituted silk", "peakable substituted silk base ^ ^ 的 的 的 的 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ (4) anthracenyl, a substituted C3-8 cycloalkyl group, (6) a substituted aryl group, (7) a substituted heteroaryl group, (8) a substituted Ci 5 alkoxy group (9) a substituted C3 8 cycloalkoxy group, (10) a substituted Ch alkoxycarbonyl group, (11) a substituted Cl_5 alkylcarbonyl group, (12) a substituted 4 to 10 Saturated heterocyclic ring, (13), 丨. R11, (14) -CONR10R 丨丨, (15) -N(R10)CORn > (16) -S〇2R1D, and (17) -S〇2NR, 0Rn (R1Q and R11 are in the same meaning as described above). The substituents of the "substitutable silk" may be appropriately substituted with, for example, the same or different one to five substituents of the following: (1) to (17), and (18) may be via a hydroxyl group, a fluorine atom, an alkoxy group (which may be substituted by the same or different one to three substituents selected from the group consisting of c, _5 alkoxy groups and fluorine atoms) and nitrogen of 4 to 1 member An alkyl group substituted with the same or different one to three substituents selected from the group consisting of saturated heterocyclic rings. Wherein the 'bases shown in the above (6) and (7) are meant to be via (a) a thiol group, 37 323165 201202247 (b) halogen, (c) may have 1 to 5 fluorine atoms, a hydroxyl group or a Cw alkoxy group. a substituted Cl-Η) group, (d) a Cl-5 alkoxy group which may be substituted by 1 to 5 fluorine atoms, a hydroxyl group or a G-5 alkoxy group, (e) a cyano group, (f) Carboxyl group, (g) Cl-5 alkoxycarbonyl group, (h) Cl-5 alkyl group, (i) -NR10Rn ' (j) -CONR10Rn > (k) -S〇2R1 (1, and (l) -S〇2NR 丨. A group substituted by the same or different 1 to 5 substituents selected from the group consisting of R11; (5), (8), (9), (10), (11) And the group represented by (12) means Cl-ίο which may be substituted by (a) a hydroxyl group, (b) a halogen, (c) may be substituted by 1 to 5 fluorine atoms, a hydroxyl group or a G-5 alkoxy group. a base, (d) a Cl-5 alkoxy group which may be substituted by 1 to 5 fluorine atoms, a hydroxyl group or a G-5 alkoxy group, (g) C!-5 alkoxycarbonyl group, 38 323165 201202247 (h) a CNS alkylcarbonyl group, (i) ~NRlflRn, and (j) 'C〇NR10R 丨丨, a group substituted with the same or different 1 to 5 substituents selected from the group consisting of (1), The substituent of 2), (8), (12), (13) or (14) is preferably, for example, a fluorine atom, (2) or unsubstituted (8). • "Substitutable cycloalkyl group And the substituents of the "supplementable saturated heterocyclic ring" may, for example, be the above-mentioned (3) to (0), (§) to (].), and may be substituted by the same or different one to five of the above. Suitable substituents, wherein the substituents of (a), (b), (c) or (j) are more preferably, for example, a fluorine atom or a substituted aryl group, or a substituted The substituents of the aryl group, the "substituted aryl group" and the "substituted aryl group" may, for example, be the same or different from the above (a) to (1) ' The above substituents are appropriately substituted, and among them, a substituent of (a), (b), (c) or ((1) is preferable, and φ is preferably exemplified by (a), a fluorine atom or (c). The pharmaceutically acceptable salt may, for example, be a mineral acid salt such as a hydrochloride, a hydrogen bromide, a nitrate, a sulfate or a phosphate, a besylate, a benzoate or a citrate. Fumarate, citrate, lactate, horse Acid addition salts such as acid salts, malate salts, oxalates, cesium sulphonates, tartrates and the like, acid salts such as sodium salts and clock salts, alkali metal salts such as magnesium salts and calcium salts 'Metal salts such as aluminum salts and zinc salts, ammonium salts such as ammonium and tetramethylammonium salts, organic acid addition salts such as morpholine addition salts and pyrrolidine addition salts, or glycine 1 addition salts and phenylalanines Addition salt, lysine addition 323165 39 201202247 Salt, aspartic acid methionine addition salt, face glutamate addition salt and other amino acid addition salts. Among the compounds of the present invention which are not in the formula (1), A丨, A2, Q丨, Q2, Alk,

The respective groups of Z, Z1 to Z5, X, X1, X2, W, w1, y, ws β + A γ, R to R" and Het are preferably as follows, but the invention is not limited The compounds listed below. Further, a preferred ring when each of the bases forms a ring with another base will be described later. φ is preferably a compound wherein 'A1 is 2, and A2 is a formula (1) of the formula (A). Q and Q and independently may be exemplified by a hydrogen atom; the same or different ones selected from the group consisting of a hydroxyl group, a fluorine atom, and a Ch alkoxy group (which may be selected from a group consisting of a Cl_s alkoxy group and a deficient atom) a Cl_lQ alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a three substituent substituted with a Ci 5 alkoxycarbonyl group and a 4 to 10 membered nitrogen-containing saturated heterocyclic ring; The same or different phase Φ selected from the group consisting of a hydroxyl group, a fluorine atom, a Ci-6 alkyl group and a Cm alkoxy group (the alkyl moiety of the group can be selected from the group consisting of Cl-5 alkoxy groups and fluorine atoms) a C3-8 cycloalkyl group substituted by the same or different 1 to 3 substituents selected from the group consisting of 1 to 3 substituents; a cyano group; a via group, a Cm alkoxy group And a Ci-5 alkylcarbonyl group and a Cm alkoxy group substituted by the same or different one to three substituents selected from the group consisting of fluorine atoms; a carboxyl group; may be via a halogen, a Ch alkyl group and a Cw alkane An aryl group substituted with the same or different 1 to 3 substituents selected from the group consisting of an oxy group (the base of which is substituted by 1 to 3 fluorine atoms) Heteroaryl; or -conr5r6. Preferably, it is a hydrogen atom; the same or different ones selected from the group consisting of a hydroxyl group, a fluorine atom, a 5 decyloxy group, a Cm alkoxycarbonyl group, and a 4 to 10 membered nitrogen-containing saturated heterocyclic ring; 323165 40 201202247 The substituent is substituted with three substituents, more preferably a ruthenium atom. "10

Aik is preferably a straight chain of the same group which may be substituted by a group consisting of a group consisting of a group consisting of a group consisting of a group consisting of a group consisting of a group of the following: a base group, a fluorine atom, and a Cl_5 alkoxy group (the group) Is the same or different 选 selected from the group consisting of 'oxyl alkoxy groups and fluorine atoms

Substituted by a substituent and substituted by 4 to 1 member of the nitrogen-containing saturated heterocyclic ring to the same or different 1 to 3 substituents selected in 3: a group; , a Cl-6 alkyl group and a Ci_decyloxy group (Κ1. The radical portion of the group can be replaced by a group of siloxanes and fluorine atoms (four) which are substituted by the same or different U3 substituents). A 'cycloalkyl group substituted with the same or different 1 to 3 substituents; selected from the group consisting of a hydroxyl group, a C!-5 alkoxy group, and a fluorine atom: ^ or a phase a Cl_dido group substituted with 1 to 3 substituents and an ei 5 = yl group; a carboxyl group; an alkyl group via a halogen, a Cl_e alkyl group and a Ci 5 group (the alkyl moiety of the group may be a group consisting of 1 to 3 fluorine atoms; a aryl or heteroaryl group substituted with the same or different 1 to 3 substituents; halogen; selected from a group consisting of a hydroxyl group and a fluorine atom C!-5 alkoxy substituted with the same or different 1 to 3 substituents; -nrIQr11; and -C0NR5R6; preferably via a hydroxyl group, a fluorine atom, a Ci ealkyl group and an ο-alkoxy group Group The Ch alkyl group substituted by the same or different one or two substituents selected. More preferably, it is a Ci-3 extension group which may be substituted with the same or different one to two substituents selected from the group consisting of a fluorine atom and a Ci e alkyl group, and most preferably an unsubstituted Cl- group. 3 stretch base. 323165 41 201202247 is preferably a hydrogen atom; the same or different ones selected from the group consisting of a radical, a fluorine atom, a c!-alkoxy group (which can be formed by a group of Cl-S alkoxy groups and atoms). Cm substituted by the same or different 1 to 3 substituents selected from the group consisting of three substituents and 4 to 1 member of the saturated heterocyclic ring. a base group; the same or different from the group consisting of a hydroxyl group, a fluorine atom, a Ci 6 alkyl group, and a Ci 5 alkoxy group (the alkyl moiety of the group may be selected from the group consisting of Ci s alkoxy groups and fluorine atoms) And c3-8 cycloalkyl substituted by the same or different 1 to 3 substituents selected from the group consisting of 3 substituents; dentate; may be composed of a hydroxyl group and a fluorine atom a Cl_5 alkoxy group substituted by the same or different 1 to 3 substituents selected from the group; -nr5r6; or -conr5r6. It is preferably a hydrogen atom, a Cl 6 alkyl group, a halogen, a Ci 3 alkoxy group or —NR 5 R 6 '. More preferably, it is a hydrogen atom or a G 3 alkyl group. Z1 to Z5 are preferably, for example, a hydrogen atom; a halogen; a Ci-6 alkyl group which may be substituted with 1 to 3 fluorine atoms; or a Cm alkoxy group which may be substituted with 1 to 3 fluorine atoms. More preferably, for example, a hydrogen atom, a fluorine atom or a Ci 6 alkane group. X is preferably -X1-, -XLNR7C〇-X2-, -X'-CONF-X2-, or lO-X2-, and more preferably -X1-, _xi_C〇RN7-X2- or -Χ^Ο- Χ2—, more preferably -X1-, or -Χ^Ο-Χ2-. Further, the symbol indicated by "_" of each of the above-mentioned groups indicates that the single bond on the left side of the single bond 'the single bond on the left side of the base and the nitrogen atom bond on the side of the 4, 5-reducted ring bite skeleton side' Indicates binding to the gas atom on the -NR!R2 side. For example, when -Χ^Ο-Χ2-, it means (4, 5-cyclopyrimidine skeleton) OUR2. X is preferably a k-extension group which may be substituted by the same or different i to 3 substituents selected from the group consisting of a base group, an I atom and a Ci-6 alkyl group, preferably 323165 42 201202247, more preferably k. Stretching base, the most suitable for Ci4. Wherein Hco-x2-, -xlnr7(10)r8_x2-, _χ1_Νκ7_χ2_, or , is preferably C2 which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a base group, an I atom and a d group. -8 Stretching base l is more preferably 1 α6 alkylene group, most preferably c2_4 alkylene group. And C2-8 alkylene group substituted by the same or different 1 to 3 substituents selected from the group consisting of a radical, a fluorine atom and a Cl-6 leukox group, more preferably Cw The alkyl group is most preferably a c2_4 alkyl group. W is preferably -W1-, -NR9-W1-, -NR9C0-W1-, -C0NR9-W1- or -0-W1- 'more preferably _w丨---NR9_w·---CONR^W1- or -0-W1-, most preferably -W1-, wisdom-W1-. Further, the symbol indicated by "_" of each of the above-mentioned groups indicates that the single bond on the left side of each group represents a bond with a carbon atom or a nitrogen atom on the Y ring, and the single bond on the right side represents _NR3R4. The nitrogen atoms on the side are combined. For example, when -NR9-W1-, it means y__NR9_w1_nr3r4. The W1 may be, for example, a Cm-extension group which may be substituted with the same or different one to three substituents selected from the group consisting of a hydroxyl group, a fluorine atom and a Cl-6 alkyl group. The substituted Cl_4 alkyl group is preferably a C2-4 alkyl group. Y is preferably, for example, the same or selected from the group consisting of a halogen, a C1-6 substituent which may be substituted by 1 to 3 fluorine atoms, and a Cm alkoxy group which may be substituted by 1 to 3 fluorine atoms. a phenyl group substituted with 1 to 3 substituents, or a Cm alkyl group which may be substituted by 1 to 3 fluorine atoms via a dentate, and a G-5 alkane which may be substituted with 1 to 3 fluorine atoms. a heteroaryl group having 1 to 2 nitrogen atoms substituted by the same or different 1 to 3 substituents selected from the group consisting of oxy groups 43 323165 201202247, further comprising a bicyclic extended aryl group or Heteroaryl. More preferably, the phenyl group may be substituted by the same or different 1 to 3 substituents selected from the group consisting of halogen, C!-6 alkyl and G-5 alkoxy groups. An extended heteroaryl group having 1 to 2 nitrogen atoms, which is substituted by the same or different 1 to 3 substituents selected from the group consisting of a C, an alkyl group and a Cm alkoxy group. Preferably, the phenyl group, the pyridine group or the thiazolyl group may be substituted by the same or different one or two substituents selected from the group consisting of halogen and G-6 alkyl. The above-mentioned aryl group and the heteroaryl group can be exemplified as the preferred structure.

44 323165 201202247

Y-a y-b y-c y-d y«e y-9 y-i y-i y-k y-m y-〇 y-p

V 丨 >,X> 丨 y-q

[wherein R12 is a (c), (g), (8) or hydrogen atom of the item 2]. More preferably, for example, yb, yc, y_d, y_e, y-byi, y_r, ", y~V, yi, y_x, y-y, y_z, y-aa, y-ad, y-ae, y_ah , y al, y-am, y_an, y_a〇, or y ap, more preferably y-bu y_m, y_v, yi, Hd, y-ae, y_a^y_an. ^, R2, R3 and h are preferably each independently, for example, a hydrogen atom; and may be substituted by 1 to 3 substituents of the two: =:: group and - eye, 323J65 45 201202247 ClMO alkyl group Or a C3-8 cycloalkyl group; or the same group selected from the group consisting of a hydroxyl group, a valence ring, a Cl-6 alkyl group, a fluoren-5 alkoxy group, and a C?-5 alkylcarbonyl group. A saturated heterocyclic ring of 4 to 1 Q members substituted with 1 i 3 substituents. More preferably, for example, a hydrogen atom; a Cm alkyl group or a Cm ring which may be substituted with the same or different i 2 3 substituents selected from the group consisting of a hydroxyl group, a gas atom, a c alkoxy group and -CONITR11; An alkyl group; or a 4- to 1Q-membered saturated heterocyclic ring which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a base group, a hydrogen atom and a Ci-e alkyl group. More preferably, it may be, for example, a hydrogen atom; or Ch which may be substituted with the same or different i to 3 substituents selected from the group consisting of a group, a fluorine atom and a Cl_3 alkoxy group. Burning base. More preferably, it is a hydrogen atom or a Cho alkyl group. 70 R, R6, R7, R8 and R9 are each independently, for example, a nitrogen atom or the same or a phase selected from the group consisting of fluorine, a trans group and a Cl-channel oxy group, and 1 to 3 substitutions. The ClM substituted by the base. The alkyl group may, for example, be a hydrogen atom or a Cho alkyl group, and more preferably, for example, a Ci 4 alkyl group. •, ° and RU are preferably, for example, a hydrogen atom; a “hospital base; a nitrogen-containing saturated heterocyclic ring formed by a core of 4 to 1 member, which is substituted by 1 to 5 fluorine atoms. For example, a hydrogen atom or a Ch group may be mentioned. More preferably, for example, a hydrogen atom or a C, 4 alkyl group may be mentioned, and a C group may be mentioned, for example. "R: -R2, Ri-Xi, Ri- Χ2, R1_R' R7_x2, r3 r4, r3_w1, r, 9, 2 w or R-R6, each of which may also be bonded to a carbon atom of a respective group to form a nitrogen-containing saturation of an I-substituted 4 to 1G member. The substituent of the ring is a substituent which directly forms each group of the ring. Further, when each group has a substituent, the carbon atom of the octa substituent is bonded to form a nitrogen-containing saturated heterocyclic ring. The so-called "each 323165 46" 201202247 Charcoal: Sub-bonding? Forming a ring" is bonded to each other as shown below. η = one atom is removed and the respective carbon atoms are bonded, 7 W, and the specific ring is exemplified, but is not limited to the exemplified ring. ^The number of saturated helium-containing heterocyclic rings formed by eight is based on -2 and (1) " knife is independent of G to 2, forming 2 rings, for example, from κ, _χ2 spot r7_x2 to form a 2 ring, also One base (here, 'χ2) can be used in common to both rings.

When R and R, R3 and R5 are combined with each other, or the respective groups of carbon-bonds (4) can be formed into a nitrogen-containing saturated heterocyclic ring of 4 to 1 G M, preferred examples thereof can be exemplified. The configuration is as follows (wherein, when combined with R6, fd is removed). ' °’

_ _ «ΑΛΛΛ r1-a r1-b ^ 1 D r1^c r1-d

More preferably, n-e Π-f r1-g is rl_a, rl_|3, ^-c, rl_d, and rl_f, and more preferably, for example, f-b, f-c, rl-d, and f-f. The combination of R and R7 may be bonded to a carbon atom of a respective group to form a nitrogen-containing saturated heterocyclic ring which is 323165 47 201202247 and substituted with 4 to 1 G oxime, for example, the following structure. The preferred example is R1 R1 .N.

,N〆 *»WV

Rf

r7K R2

R7-d r7-a r7-b

Rf O

R7-e R1

R2 I M

' r?~b' r7~c' r?'d ^ r?'e ^

48 323165 1 More preferably, W - a, xM}, x2_c, x2_d, x2_e, x2 f X / g, and χ 2 are small, and further preferably, for example, x1-a, X1-c, x1-d, and x2_e. Preferred examples of x and x1-i 〇/, x, and each combination of R and x1, or a carbon atom of each group may form a nitrogen-containing saturated heterocyclic ring of 4 to 10 members which may be substituted. For example, the following structure can be mentioned. 201202247 R2 r2' force V^>

R2 M

X1-c x1-b R2

X1-a Rf

X1-h x1-i R?.Ο x1^ x1-e R2 x1-g

X1-k R2

X1-l xi-f

More preferably, for example, 1", χ1 八!

X-g'Vk, and more preferably, for example, χ1+χ, χΐ-two, f, a combination of V and R9' may also be bonded to a carbon atom of each group to form a === member A preferred example of the nitrogen-containing saturated heterocyclic ring is η η R4 r3_e r3-f r3-d , 0_, r3-g, and more preferably, for example, r3-a, r3-b, r3-c, R3-d, r3-P » 3

More preferably, for example, γΊΙ), · 3-^!^. When the combination of S and F1 is also a nitrogen-containing saturated heterocyclic ring in which a carbon atom of each group is bonded to form a star-substituted 4 to 1 member, a preferred example thereof may be, for example, the following structure. . ', 323165 49 201202247 /Na, R4, Λ R4 wl-b •N R wi-c

'R4

人八 /' , N

R4- w1-a

Λ X?

W1-j w1-d w1-e Λ

N

N-R-* w1-k wi-g wi-h

R4-N wl-f

W14

W1-I

W1-m

Pfco t).

/ , R4 ^-N w1-n R4 R4 w1-o w1-p

Λ R4^,

Wl-s w1~q w1-r is better, for example, w^h ' w1-i ' w -a, w1-. , w'-d, w, w, -f, w ~ W - g W -c, w'-e, w^f, W1 - h and i9, W~k and 'further preferred" , W — 1 〇 可 可 /, Ί

R9-b

A rd-a Λ. λ. 〆, r9-h r^-c9 ^ O U Λ』0

R9-d >

Co

R9-e O r9-i UΛ

r^f r9-g O 〆,

O

R9-n r9-k /,. r9-l person r9*m Λ

V r correction

R9-q Λ. r9-o r9-p ίο r9-r Λ. Υ Pic° r9-s r9-t r9-u Λ r9-v r9-w

R9-z r9-x is preferably, for example, r9~yr mc, r9_d, r9_e, r9_f, r ~g 323165 50 201202247 , r9-i, r9, j, r9_j r9_n, r -〇' r9-p and a , r9-c, r9-e, r9-g, r9-h, r9_j, r -hx ^ ' ' ~1 k ' r9 1 g K r , rm rw, and more preferably, for example, n r9-l, And r9-〇.

The Het system may, for example, be a nitrogen-containing partially saturated heterocyclic ring of 5 to 6 members or a nitrogen-containing unsaturated heterocyclic ring of 5 to 6 members, more preferably a fine b butyl group, a dihydropyridyl group, a pyrazolyl group or a tetranitrogen ratio. °Based, four-degree sitting, sneezing, oxazolyl, oxazolyl. Further preferred is a filament, a dihydroindenyl group, a (tetra) group, or a tetrahydrogen group.

Further, in the description of the present invention, the abbreviations of the following examples are sometimes used. 〇-: o-,:: _, p_: _, 卜: third _, s- · second, THF: tetrahydrofuran, DME: ethylene glycol didecyl ether, DMF: N, N-didecyl Brewing amine, DMA: dimercaptoacetamide, NMp: N-methylpyrrolidone, DCE: 1,2-dioxaethane, DMS hydrazine: dimercapto sulfoxide, CDCh: heavy gas imitation, DMS0-ds : heavy dimercapto sulfoxide, hydrazine Ms : methanesulfonyloxy, OTs : pyrene sulfonyloxy, hydrazine Tf : trifluoromethanesulfonyloxy, s: singlet, d: doublet, t: 叁 heavy state, q: quadruple state, m: multiple state, Boc: third butoxycarbonyl, DPPF: 丨, 丨, _bis(diphenylphosphino)ferrocene, DPPE: 1,2-double (diphenylphosphino)ethane, Dppp: hydrazine, 3_bis(diphenylphosphino)propane, DPPB: 1,4-bis(diphenylphosphino)butane, binAP (registered trademark): 2 , 2'-bis(diphenylphosphino X, anthracene, -binaphthyl, 〇pE_ph〇s (registered trademark): bis(2-diphenylphosphino), XANT_ph〇s (registered trademark): 9, 9-Dimethyl- 4, 5-bis(diphenylphosphino)xanthine (xanthine), S-Phos: 2-dicyclohexylphosphino 2',6,2-dioxane Base-1, fluorene-biphenyl (registered trademark), x_ph〇s: 2_dicyclohexylphosphino 2',4' '6' _triisopropyl-1, 丨' _ biphenyl (registered trademark), HATU : 〇_(7_ 51 323165 201202247 azobenzotris-l-yl)-1,1,3,3-tetradecylurea rust hexafluorophosphate, LDA: diisopropyl decylamine, LHMDS : hexamethylenedifluoride, NHMDS: sodium hexamethyldiamine. The method for producing the compound (I) of the present invention is described below. Compounds (la), (lb), (Ic), (Id), (Ie), (If), (lg), (ih), (Ii), (Ij), (Ik), (II), (Im), (In), (I〇), ( Ip) and (Iq) are the compounds contained in the compound (I). The compound (I) is obtained by the method shown in the following Production Methods 1 to 15 or according to the method thereof. In the case of forming a salt, the salt may be, for example, the same as the salt of the compound (I). Production method 1: In the compound (I), 'A2 is a formula (A), A1 is Z, and Z is a gas atom or a bromine. Atom 'Q2 is a compound of a hydrogen atom (la) A1 is a compound of the formula (A), A2 is Z, Z is a gas atom or a bromine atom, Q2 is a hydrogen atom (Ib); A2 is a compound of the formula (A), A is Z, Z and Q2 are hydrogen atoms ( Ic); A2 is a formula (..., ^ is z, Φ Z is a replaceable Cl-!. Alkyl or a substituted C3-8 cycloalkoxy group, Q2 is a gas atom compound (Id); A2 is a formula (A), A1 is Z, Z is -NR5R6, and Q is a hydrogen atom (Ie) And A2 is a formula (A), A1 is Z, Z is a suitable, substituted C-s decyloxy group, and Q2 is a hydrogen atom (if) which can be obtained by the following production method. 52 323165 201202247 Ο Ra02C Q1 Ra02C Can Can 1 (Μ)

Hal8

Oxidative cleavage reaction [Step 3]

(10)*"" (1-5) Reductive amination reaction I step 4J

Hal3

R3, /W, /B(0Rb>2 ^ Y (four) supply reaction [step division

(1-4>

Reduction reaction

HalbZn. (i-8) R1 R2

*· N or z‘^-Zr\, z_ coupling reaction w

, R, N〆, Y

[Step η (W)

H-NRSR6 (1-10) Alkali [Step 1

(In the formula, 'Aik, R, R2, R3, R4, r5, r6, Ql, w, χ and γ are the same as the former'. The IT shot is taken by the wire, and the Rb money can be replaced by 323165 53 201202247 Alkyl 'Hala is a gas atom or a bromine atom, a Halb-based gas atom, a bromine atom or an iodine atom 'Z1 can be substituted Cm. Alkyl or a substituted C3-8 cycloalkyl group, R1 is a substitutable Cl-5 alkyl.) [Step 1] The compound (1-1) is used in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in the solvent, and 1 to 20 equivalents, preferably 2 to 10 equivalents. The urea is reacted to obtain a compound (1-2). The compound (1-1) can be synthesized according to a commercially available product or a known method [e.g., WO2002/066482, Journal of American Chemical Society, 3854 (200)] or a method according thereto. The solvent to be used in the reaction is not particularly limited as long as it is inert in the reaction, but may be, for example, DMF, DMA, NMP, methanol, ethanol, propanol or 2-propanol. It may be used by mixing it or the like, and it is preferably methanol or ethanol. The test system may use, for example, a sodium metal methoxide, an ethoxylate, a third butoxide, or the like, or a calcined oxide of a test group metal, and preferably a sodium methoxy group or a sodium ethoxide. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably from 50 to 1 Torr. Oh, it usually takes 1 to 60 hours. [Step 2] The compound (1-2) obtained in the step 1 is reacted with a solvent or an excess amount, preferably 3 to 1 equivalent of a denture agent, to obtain a compound (1 to 3). For example, an oxygenated dish, a pentachloride structure, an oxybrominated filling or the like can be used. The solvent used in the present reaction may be any one of 323165 54 201202247 as long as it is inert to the reaction, and may be, for example, DCE, THF, 1,4-dioxane, DME, chloroform, stupid or hydrazine. Benzene, xylene, triethylamine, pyridine, N,N-diisopropylethylamine, N,N-didecylaniline, N,N-diethylmethane or n,N-dimethylamino Pyridine or the like is used alone or in combination thereof. The reaction is carried out at a temperature between 〇 ° C and the boiling point of the solvent or halogenating agent, preferably from 50 to 14 ° C, usually for from 1 to 24 hours. [Step 3] I " Compound (1-3) obtained in Step 2 in a solvent with 5 to 1 equivalent of hydrazine, preferably 5 to 0.1 equivalent of cerium tetraoxide or potassium citrate (ιν) 2) water and matter, 1 to 1 equivalent, preferably 1 to 3 equivalents of a base, and 1 to 10 equivalents, preferably 3 to 4 equivalents of a partial sodium perchlorate reaction, to obtain a compound (Bu 4) The solvent used in the reaction may be any one as long as it is inert to the reaction. It is not particularly limited, and for example, THF, 1,4-dioxane, acetone, third butanone, water, or the like can be used alone or in combination, and among them, a mixed solvent of acetone and water is preferable. As the base, an aliphatic tertiary amine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as pyridine, 2,6-dimercaptopyridine, pyridazine, sorghum or pyrimidine may be used. ' Among them, it is preferably 2,6-dimercaptopyridine. 5至24小时。 The reaction is carried out at a temperature of from 0. 5 to 24 hours. Further, the compound (1-4) may be subjected to a flow of oxygen containing ozone in a solvent such as dichloromethane, ethyl acetate or decyl alcohol at room temperature or -78 ° C, and then dimethyl sulfide or the like may be used. Ozone decomposition of the reducing agent reaction is obtained. 55 323165 201202247 [Step 4] The compound (1-4) obtained in the step 3 is used in the presence of 1 to 1 equivalent, preferably 2 to 3 equivalents of the acid, and 1 to 10 equivalents, preferably 1 in the solvent. 2 to 4 equivalents of the boron hydride compound, 1 to 1 equivalent, preferably 1.1 to 2 equivalents of the compound (1-5) are reacted to obtain the compound (1-6). The compound (1-5) can be synthesized according to a commercially available product or a known method [e.g., Chemical Abstract, 1971 (1957); Journal of the Chemical Society, 3096 (1931)] or a method according thereto. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited. For example, THF, 1,4-dioxane, DME, dichlorohydrazine, gas, and 1, 2 - Ethylene bromide, decyl alcohol, ethanol, n-propanol, 2-propanol or the like is used singly or in combination, and it is preferably 1,2-dichloroethane or methanol. As the acid system, for example, a carboxylic acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid, or a mineral acid such as hydrochloric acid can be used, and acetic acid is preferable. As the boron hydride compound, for example, sodium cyanoborohydride, sodium triethoxy borohydride, sodium borohydride or the like can be used, and among them, sodium cyanoborohydride or triethyl hydrazine hydride is preferred. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from room temperature to 40 ° C', usually from 5 to 24 hours. [Step 5] The compound (1-6) obtained in the step 4 is used in the solvent in an amount of from 1 to 1 equivalent, preferably from 2 to 4 equivalents, and from 0.01 to 1 equivalent, preferably 〇. 〇5 To the equivalent of from 1 to 5 equivalents, preferably from 1 to 1. 05 equivalents, in an amount of from 0.01 to 1 equivalent, preferably from 0.05 323 165 56 201202247 to 0.2 equivalents of the phosphine ligand. The compound (1-7) is reacted to obtain a compound (ia) and/or a compound (lb). The compound (1-7) can be synthesized according to a commercially available product or a known method [e.g., WO2008/148867, WO2004/013134] or a method according thereto. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited. For example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, DMF can be used. Water, etc. are used singly or in combination, and preferably DMF and water, DME and water or 1,4-dioxin and water. As the palladium catalyst, a zero-valent catalyst such as ruthenium (triphenylphosphine)palladium, bis(t-butylphosphine)palladium or bis(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine) can be used. A divalent catalyst such as palladium/dihydrate, palladium acetate, bis(diphenylphosphinoferrocene)palladium/dihydrate, and preferably ruthenium (triphenylphosphine) or acetic acid. The phosphine ligand system may be a monodentate coordination type ligand such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos or DPE-Phos, etc. A ligand for a bidentate coordination type, • which should be S-Phos or X-Phos. The base may, for example, be an alkali salt such as sodium carbonate, potassium carbonate, carbonic acid planer, sodium acetate or potassium phosphate, but it is preferably sodium carbonate, potassium carbonate or potassium phosphate. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably under heating of 5 Torr to 180 ° C or under microwave irradiation for 5 to 24 hours. [Step 6] The compound (la) obtained in the step 5 is subjected to a hydrogen atmosphere of 1 to 4 atm in a solvent, preferably 1 to 4 atmospheres, preferably 1 to 3 equivalents. In the presence of an acid, 1 to 10 equivalents, preferably 1 to 57 323165 201202247, 1 equivalent of palladium on carbon or the like is treated to obtain a compound (Ic). Further, the compound (Ic) is treated with a catalyst (la) in the presence of 5 to 1 equivalent of aluminum formate in a solvent in an amount of 0.1 to 10 equivalents, preferably ruthenium to 1 equivalent of palladium carbon. Also available. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxalate, DME, ethyl acetate, decyl alcohol, ethanol, or the like. Propyl alcohol, 2-propanol, water, and the like are used in combination, and it is preferably methanol alone or in a mixed solvent with water. As the catalyst system, for example, a nickel catalyst such as palladium carbon, palladium hydroxide carbon or palladium black, or a nickel catalyst such as Raney Nickel, or a surface catalyst such as platinum oxide, which is preferably palladium carbon, may be used. As the acid system, for example, an acid such as acetic acid or trifluoroacetic acid or a mineral acid such as hydrochloric acid can be used, and among them, acetic acid, trifluoroacetic acid or hydrochloric acid is preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from room temperature to 5 (TC' is generally carried out for 0.5 to 24 hours. Further, by the same manufacturing method, A1 is a formula (A), and A2 is Z. The compound wherein Z is a hydrogen atom can also be obtained from the compound (lb) obtained in the step φ. [Step 7] The compound (la) obtained in the step 5 is subjected to the solvent in 〇. 〇丨 to ! The compound (Id) can be obtained by reacting 1 to 5 equivalents, preferably 1.1 to 2 equivalents of the compound (1-8) or the compound (1-9) in the presence of 0.05 to 0.2 equivalent of a catalyst. Compound (1-8) Or the compound (1-9) can be synthesized according to a commercially available product or a known method [for example, WO2006/024493, WO2008/083070] or a method according to the same. The solvent used in the reaction is as long as it is inert to the reaction. Any one of 58 323165 201202247 may be used without particular limitation, and may be used, for example, THF, 1,4-dioxalate, DME, benzene, toluene, diphenylbenzene, DMF, or the like, alone or in combination, wherein It is preferably THF. Palladium catalysts can be used, for example, palladium (triphenylphosphine) palladium, bis(t-butylphosphine) palladium, ginseng (dibenzylidene) a valence catalyst such as diacetone or a divalent catalyst such as bis(triphenylphosphine)palladium dichloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium/dide; Wherein, it is preferably palladium (triphenylphosphine) palladium or bis(t-butylphosphine) palladium. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, and is preferably heated to a temperature of 20 to 100 ° C. Or microwave irradiation, generally carried out 0.5 to 24 hours. Also, by the same manufacturing method, A1 is a formula (A), A2 is Z, Z is a substituted Cl-1D alkyl or a substituted C3 The compound of the -8 cycloalkoxy group can also be obtained from the compound (lb) obtained in the step 5. [Step 8] The compound (la) obtained in the step 5 is preferably used in the solvent in an amount of from 1 to 10 equivalents, preferably The compound (Ie) can be obtained by reacting 2 to 5 equivalents of the base with 1 to 20 equivalents, preferably 3 to 10 equivalents of the compound (1-10). The compound (1-10) is commercially available. The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxane, DME, benzene or hydrazine. Benzene, xylene, DMF, DMA, NMP, decyl alcohol, ethanol, propanol, 2-propanol, etc. are used singly or in combination, and preferably, it is THF, 1,4-dioxin, NMP or 2-propanol. For example, inorganic salts such as sodium carbonate, potassium carbonate, carbonic acid planer, and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, and aromatics such as pyridine and dimercapto 59 323165 201202247 pyridine can be used. Amines, triethylamine, tripropylamine, tributylamine, cyclohexyldidecylamine, 4-didecylaminopyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methyl hexahydrogen bite, N- thiol ratio slightly bite, N-methyl morphine and other tertiary amines, alkali metal hydrides such as sodium hydroxide, potassium hydroxide, etc., where 'suitably carbonic acid Potassium, triethylamine or hydrazine, hydrazine-diisopropylethylamine. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably under heating of 50 to 180 ° C or under microwave irradiation, generally for 5 to 24 hours. Further, by the same manufacturing method, A1 is a compound of the formula (A), A2 is Z, and Z is -NR5R6. The compound of the stomach can also be obtained from the compound (lb) obtained in the step 5. [Step 9] The compound (If) obtained in the step 5 is reacted with 1 to 2 equivalents, preferably 3 to 10 equivalents of a metal alkoxide (κ) in a solvent to obtain a compound (If). The compound (1-11) can be obtained by a commercially available product or a known method. The solvent used in the reaction may be an alcohol solvent such as methanol or ethanol depending on the type of φ of the metal alkoxide to be used. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably under heating of 50 to 180 ° C or under microwave irradiation, generally for 5 to 24 hours. Further, by the same production method, a compound wherein A1 is a formula (A), A2 is z, and z is a Cm alkoxy group which may be substituted may be obtained from the compound (lb) obtained in the step 5. ° Method 2: In the compound (I), the compound (Ig) wherein 'V is a formula (Α), ζ, ζ is a gas atom or an atom is obtained by the production method shown below. 323165 60 201202247 R1 Factory %2 °t:^ (2-1) Ο Jl RaO>V〇Ra tk {Step 10】 (2-2) R1 R1 Ra〇

Thioamylation O (2-3) /, N'r2 (Step 11)

syS<qi RaO^>^-Aik °2 O (2-4)

[Step 14] Deuteration NH R1'N-R2 1 h2n^nh2 Ί2 ---iii. [Step 12] Η2Ν,>;5γΝ^〇η [Step 13] (2-5)

(wherein, Aik, R1, R2, R3, R4, Ql, w, χ, and γ are the same as defined above. Hala and Halb are each independently a gas atom or a bromine atom, and Ra is a substituted alkyl group. 'Rb is a hydrogen atom or a substituted alkyl group.) [Step 10] A compound synthesized according to a commercially available product or a method such as Bi〇orgamic Chemistry, 34(5), 248-273 (2006) (2-1) A compound can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of an acid anhydride (2-2) in the presence of 1 to 5 equivalents, preferably 1, 5 to 2 equivalents of a base in a solvent. (2-3) Get. The compound (2-2) can be synthesized according to a commercially available product or a known method [e.g., WO2008/001985] or a method according thereto. The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, and any one of 61 323165 201202247 is not particularly limited, but for example, THF, 1,4-dioxane, DME, diethyl ether can be used. Dihalomethane, benzene, toluene, diphenylbenzene, and the like are used singly or in combination, and it is preferably THF, diethyl ether or dichloromethane. For the alkali system, for example, sodium oxide, sodium ethoxide, potassium t-butoxide or the like can be used for various metal or soil-based metal oxides, LDA, LHMDS, NHMDS, etc., sodium hydroxide, hydroxide _ Such as metal hydrides, etc., which are preferably LDA, LHMDS, sodium hydroxide. 5至24小时。 The reaction system -0 ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° °. [Step 11] The compound (2_3) obtained in the step 10 is reacted with a vulcanizing agent such as Lawesson, s reagent or phosphorus pentasulfide in a solvent in an amount of 2 to 10 equivalents, preferably 3 to 5 equivalents. The compound (2_4) was obtained. The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, but for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene can be used. It is used singly or in combination, and it is preferably toluene, THF or 1,4-dioxane. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from room temperature to 10 ° C, usually for 5 to 24 hours. [Step 12] The compound (2-4) obtained in the step 11 is used in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in the solvent, and 1 to 20 equivalents, preferably 2 to 10 The equivalent of guanidine reaction gives compound 62 323165 201202247 (2-5). The solvent to be used in the reaction may be any one which is not particularly limited as long as it is inert to the reaction, and may be, for example, DMF, DMA, NMP, decyl alcohol, ethanol, 1-propanol or 2-propanol. Or use it in combination, and it is preferably sterol or ethanol. As the base, for example, sodium decoxide, sodium ethoxide or potassium t-butoxide can be used for various metals or calcined oxides of a test group metal, and the like, which is preferably 曱 基 或 or ethoxy hydride. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from 50 to 100 ° C, usually for 1 to 6 hours. [Step 13] The compound (2-5) obtained in the step 12 can be reacted in the same manner as in the step 2 to obtain the compound (2-6). [Step 14] A compound (2-) can be obtained by reacting the compound (2-6) obtained in the step 13 with 5 to 10 equivalents of an acid salt and 2 to 5 equivalents of a copper halide in a solvent. 7). Further, the compound (2-7) may also be a compound (2-6) in a solvent with 2 to 10 equivalents of a trimethylformamidine alkyl halide, 5 to 10 equivalents of a nitrite, and 1 to 2 equivalents. It is obtained by reacting triethyl benzalkonium halide. As the nitrite, sodium nitrite, tributyl nitrite or the like can be used. The solvent used in the reaction is mainly a halogen-based solvent such as dichloromethane, chloroform or 1,2-dioxaethane. The reaction is carried out at a temperature between 〇 ° C and the boiling point of the solvent to be used, preferably from 0 ° C to room temperature. 63 323165 201202247 [Step 15] The compound (Ig) can be obtained by reacting the compound (2-7) obtained in the step 14 with the compound (1-7) in the same manner as in the step 5. Further, by the same production method, a compound in which A1 is a formula (A), A2 is Z, and Z is a chlorine or a bromine atom can be obtained. Further, by using the compound (Ig), Hala can be converted into a hydrogen atom, a substituted alkyl group or a substituted & 8 cycloalkyl group, _NR5R6 or by the same production method as in the steps 6 to 9. A compound of various substituents such as an alkoxy group which may be substituted. Manufacturing Method 3:

In the compound (1), Al is Z, Z is a chlorine atom or a bromine atom, and the compound (Ih) wherein W is -NR -W1- is from the compound (2-7) as shown below. Obtained by the manufacturing method.

R3, T, Μ-W1—N—h _ (3-3) Coupling reaction ί Step 17] (lh) κ·, r, q1 (wherein Aik, IT -ww, W, λ, and J J The same as the °R hydrogen atom or the substituted filament, Har, Ha and Xian" are each independently a chlorine atom or a bromine atom. [Step 16] 323165 64 201202247 The compound obtained in step 14 (2-7) The compound (3-2) can be obtained by reacting with the compound (3-1) in the same manner as in the step 5. The compound (3-1) can be obtained by a commercially available product or a known method [for example, Journal of Organometallic Chemistry, 2001, 640, 197-200] or synthesized according to the method thereof. [Step 17] The compound (3-2) obtained in the step 16 is used in a solvent in an amount of from 1 to 1 equivalent, preferably from 3 to 5 equivalents. The base of the palladium catalyst is present in an amount of from 0.1 to 1 equivalent, preferably from 5 to 0.2 equivalents of the phosphine ligand, and from 1 to 1 equivalent, preferably from 〇. The compound (Ih) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 2 equivalents of the compound (3-3). The compound (3-3) can be commercially available or a known method [for example, US200424205, Journal of Medicinal Che Mistry, 1997, 40(13), 2047-2052] or synthesized according to the method thereof. The solvent used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited, and may be, for example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, and the like are used singly or in combination, and among them, it is preferably anthracene or 1,4-dioxane. For example, a phosphine ligand system can be used. Monodentate coordination phosphines such as triphenylphosphine, tris(phenyl)phosphine, trifurylphosphine, tris(tert-butyl)phosphine, or BINAP, 2,2'-bis(xylylphosphino) a 1,1,-binaphthyl, 1)1)5:_1^〇3, a heart-to-heart 1(_1)11〇3, etc., a 2-dentate coordination type phosphine, preferably a Binap. The palladium catalyst system can be used, for example. A ruthenium catalyst such as ruthenium (triphenylphosphine) palladium, bis(t-butylphosphine) palladium, ginseng (dibenzylideneacetone) dipalladium, or bis(triphenylphosphine) 65 323165 201202247 palladium • dichloride A divalent catalyst such as palladium acetate, palladium acetate or bis(diphenylphosphinoferrocene)palladium disulfide, wherein bis(dibenzylideneacetone)dipalladium or ruthenium acetate ε is preferred. Sodium carbonate, potassium carbonate, carbon Alkaline salts such as sodium citrate and sodium acetate, various alkali metals such as sodium methoxide, sodium ethoxide and potassium t-butoxide, or alkoxides of alkaline earth metals, among which cesium carbonate or third butyl carbonate is preferred. Potassium oxyhydroxide. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably from 50 to 180 ° C, under heating or under microwave irradiation, generally for 0.5 to 24 hours. Further, according to the same production method, a compound in which A1 is a formula (A), A2 is Z, and Z is a chlorine atom or a bromine atom can be obtained. Further, by using the same method as in the steps 6 to 9 using the compound (Ih), it is also possible to obtain Ch which can be converted into a hydrogen atom by Hala. A compound of an alkyl group or a substituted C3-8 cycloalkyl group, -NR5R6 or a substituted hydrazine-5 alkoxy group. Production Method 4: Among the compounds (I), A1 is Z, Z is a gas atom or a bromine atom, A2 is a formula (A), and W is a compound of -0-1 (Ii) is a compound (2-7). ) Obtained according to the manufacturing method shown below. 66 323165 201202247

HO—Υ^(. of 2 (4-1)

Mitigation reaction ▲ Alkylation [Step Ί 91 Coupling reaction {Step 18j

R3

I R4 (wherein Aik, R1, R2, R3, R4, Q1, Q2, W1, X and Y have the same meaning as defined above. The Rb hydrogen atom or the alkyl group which may be substituted, Hala and Hale are each independently Chlorine atom or bromine atom) [Step 18] The compound (2-2) can be obtained by the same procedure as in the step 5 using the compound (2-7) obtained in the step 14 and the compound (4-1). The compound (4-1) can be synthesized according to a commercially available product or a known method [e.g., Organic # Letters, 2006, 8(2), 26b 263] or a method according thereto. [Step 19] The compound (4-2) obtained in the step 18 is used in the solvent in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents of phosphine, and 1 to 10 equivalents, preferably 1 to 3 equivalents of azo. The compound (Ii) can be obtained by reacting with an alcohol derivative corresponding to 1 to 5 equivalents, preferably 1 to 3 equivalents, in the presence of a compound or a keratin reagent. The compound (4-2) obtained in the step 18 is used in the presence or absence of 1 to 10 equivalents, preferably 1 to 3 equivalents, and 1 to 5 equivalents, preferably 1 to 3 equivalents, in the solvent. The compound (Ii) can also be obtained by the reaction of the corresponding alkyl halogen derivative, etc., also 67 323165 201202247. The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxane, DME, dichloromethane, DCE, chloroform or benzene. Toluene, dimethyl benzene, DMF, DMA, NMP, methanol, ethanol, propanol, 2-propanol, and the like are used singly or in combination, and among them, THF, dichloromethane, methyl bromide, and DMF are preferable. The phosphine to be used may, for example, be a triphenylphosphine, a tridecylphosphine or a tributylphosphorane, but among them, triphenylphosphine is preferred. The azo compound may, for example, be diethyl azodicarboxylate, azobishydic acid diisopropyl vinegar, azobisdenic acid dicyclohexyl vinegar or diazodicarboxylic acid dibenzyl guanidine. And wherein, it is preferably diethyl azobiscarboxylate or diisopropyl azodicarboxylate. As the base, for example, sodium carbonate, potassium carbonate, carbonic acid planer, sodium acetate, etc. = the current class of aromatic amines such as pyridyl and dimethylpyridine, triethylamine, tripropylamine dibutylamine, and cyclohexyldimethylamine can be used. , 4, dimethylaminopyridine, N,N-.2-isopropylethylamine, N,N-didecylaniline, N-fluorenylhexahydropyridine, ^曱^° than bite, " The third grade _, sodium hydride, potassium hydride, etc. are: hydrides and the like, among which, it is preferably potassium carbonate, cesium carbonate, pyridine, N, N-isopropylethylamine or sodium hydride. The reaction is in the range of (TC to the boiling point of the solvent to be used, preferably from room temperature to 1 Torr, generally 〇 5 to 24 small 2 and 'by the same manufacturing method, and Al is also obtained ( Α), Α2 is ζ, a compound of a gas atom or a filling atom. Further, using the compound (Ii), by the same manufacturing method as in steps 6 to 9, it is also possible to convert Hala into an atom and replace it. a compound having various substituents such as a Ci 1 () alkyl group or a C 3 8 cyclodextyl group which may be substituted, 323165 68 201202247 -NR5R6 or a substituted G-5 alkoxy group. Production method 5: Among the compounds (I) A1 is Z, Z is a chlorine atom or a bromine atom, and A2 is a compound (g) of the formula (A) which can be obtained by the production method shown below.

R4 〇g) Toothing (wherein Aik, R1, R2, R3, R4, Ql, Q2, W, X and Y are the same as defined above. Ra is a substituted alkyl group, and Hala is independently chlorine. Atom or bromine atom) # [Step 20] The compound (2-4) obtained in the step 11 is used in an amount of from 2 to 10 equivalents per 1 to 10 equivalents, preferably from 1 to 3 equivalents, of the compound (5-1) in a solvent. The compound (5-2) can be obtained by reacting in the presence of 2 to 4 equivalents of a base. The compound (5-1) can be synthesized according to a commercially available product or a known method [e.g., Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method according thereto. The solvent used in the present reaction is not particularly limited as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxane, DME, 69 323165 201202247 benzene, toluene, diphenylbenzene. And DMF, DMA, NMP, decyl alcohol, ethanol 2-propanol, etc. are used alone or in combination, and it is preferably methanol or ethanol. As the base, various alkali metals such as sodium methoxide, sodium ethoxide or potassium t-butoxide, or alkoxides of an alkaline earth metal can be used, and among them, sodium decoxide or sodium ethoxide is preferable. The temperature of the reaction between room temperature and the boiling point of the solvent used is preferably from 50 to 1 Torr. (:, generally 1 to 60 hours. [Step 21]

The compound (Ig) can be obtained by reacting the compound (5-2) obtained in the step 20 in the same manner as in the step 2. Production method 6 : Among the compounds (I), A1 is Z, Z is a gas atom or a bromine atom, a2 is a compound of the formula (A), and W is -NF-W1- (ih) is, for example, a compound (2~) 4) Obtained according to the manufacturing method shown below.

NH

Λ ΝΗ, (6-1)

R3, R9 Ν—W1—Ν—Η R4 (3-3) Coupling reaction (Step 23) (6-2) Alkali [Step 22]

W1 (6-3)

In dh) j, the same meaning is stated. Hala and Hald are each independently a chlorine atom or a bromine atom, and a Ra-substituted alkyl group. 323165 70 201202247 [Step 22] Using the compound (2-4) obtained in the step 11 and the compound (6-1) The compound (6-2) can be obtained by the same reaction as in the step 20. The compound (6-1) can be synthesized according to a commercially available product or a known method [e.g., Chemi ca 1 and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method according thereto. [Step 23] Using the compound (6-2) obtained in the step 22 and the compound (3-3), the compound (6-3) can be obtained by the same method as that of the step. [Step 24] The compound (Ih) can be obtained by reacting the compound (6-3) obtained in the step 23 in the same manner as in the step 2. Production Method 7: Among the compounds (I), A1 is Z, Z is a chlorine atom or a bromine atom, A2 is a formula (A), Q2 is a hydrogen atom, and X is a C2-8 alkyl group which may be substituted. (Ij) is obtained, for example, from the compound (1-4) by the production method shown below. 71 323165 201202247

(wherein, Aik, R1, R2, R3, R4, Q1, w, X and Y have the same meaning as defined above. Rb is a hydrogen atom or a substituted alkyl group, and ρ is a substituted alkyl group, X' a substituted alkyl group, a Hala gas atom or a bromine atom) [Step 25] The compound (1-4) obtained in the step 3 is reacted with the compound (7-1) in the same manner as in the step 4, Compound (7_2) can be obtained. Compound (7-1) • can be commercially available or known methods [eg Journal of Heteroycl ic

Chemistry, 1981, 18, 94, 946] or synthesized according to its method. [Step 26] The compound (7-2) obtained in the step 25 is reacted with 酸. 1 to 5, preferably 0.1 to 1 equivalent of an acid in a solvent to obtain a compound (7-3). The solvent to be used in the reaction may be any one which is inert to the reaction, and is not particularly limited, and may be, for example, acetone, T ethyl ketone, diethyl ketone, bad ketone or water, or the like, alone or in combination. Let m be a mixed solvent of acetone and 323165 72 201202247 water. Examples of the acid system include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, and camphorsulfonic acid; organic carboxylic acids such as acetic acid and trifluoroacetic acid; inorganic acids such as hydrochloric acid and sulfuric acid; and lanthanum trifluorosulfonate; A Lewis acid such as indium fluorosulfonate, which is preferably p-toluenesulfonic acid. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from room temperature to 80 ° C, and is usually carried out for 0.5 to 24 hours. [Step 27] ® The compound (7-3) obtained in the step 26 is contained in the solvent in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of the acid, and 1 to 10 equivalents, preferably 2 to 4 equivalents. The borofluorene compound is reacted with 1 to 10 equivalents, preferably 1.1 to 2 equivalents of the compound (7-4) to give the compound (7-5). The compound (7-4) is commercially available. The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxane, DME, φ dioxane, gas, 1 Further, 2-dichloroethane, decyl alcohol, ethanol, n-propanol, 2-propanol or the like is used singly or in combination, and among them, 1,2-dichloroethane or decyl alcohol is preferable. As the acid system, for example, a carboxylic acid such as formic acid, propionic acid, acetic acid or trifluoroacetic acid, or an inorganic acid such as hydrochloric acid may be used, and among them, acetic acid is preferred. As the boron hydride compound, for example, sodium cyanoborohydride, sodium triethoxy borohydride, sodium borohydride or the like can be used, and among them, sodium cyanoborohydride or triethyl decyl hydride is preferred. The temperature of the reaction between room temperature and the boiling point of the solvent used should be 73 323165 201202247

From room temperature to 40 ° C, it is generally carried out for 0.5 to 24 hours. [Step 28J Compound (1)) can be obtained by reacting compound (7-5) obtained in Step 27 with Compound (1-7) in the same manner as in Step 5. Further, according to the same production method, a compound in which A1 is a formula (A), A2 is Z, and Z is a chlorine atom or a desert atom can be obtained. Further, by using the compound (1)), a Cm which can be converted into a hydrogen atom and can be substituted by φ can be obtained by the same production method as in the steps 6 to 9. A compound of an alkyl group or a substituent which may be substituted with a CM cycloalkyl group, _NR5R6 or a substituted Cl' alkoxy group. Manufacturing Method 8:

(2-7) It is obtained by the manufacturing method shown below.

(wherein, Aik, R1, R2, R3, R4, Q1, Q2, X and γ are in the same meaning as defined above. Rb is a hydrogen atom or a substituted alkyl group, an Rd hydrogen atom or a Ci_3 alkyl group 'Ha Γ And the Ha Γ are independently a gas atom or a desert atom. 74 323165 201202247 [Step 29] The compound (2-7) obtained in the step 2 is reacted with the compound (8-1) in the same manner as in the step 5. The compound (8-2) was obtained. The compound (8-1) can be synthesized according to a commercially available product or a known method [e.g., Journal Organicf Organic Chemistry, 1997, 62(19), 6458-6459] or a method therefor. [Step 30] By reacting the compound (8-2) obtained in the step 29 with the compound (8-3) in the same manner as in the step 27, the compound (Ik) compound (8-3) can be obtained. Available from commercial products. Further, according to the same method of description, it is also possible to obtain A1 as the formula (A), A2 as Z, and Z as the chlorine atom or #+. Further, using compound (Ik), by substituting with step 6矣9', it is also possible to obtain Hala transforming a carbon atom, reading a β group or a substituted c3-8 cycloalkyl group, -nr5r6 or a substituted 1 Cl- A compound which is alkoxy groups and various substituents. φ Production method 9 : Among the compounds (I), A1 is Z, 2: is a chloroproton or a bromine atom, A2 is a formula (A), and R4 is a hydrogen atom, and a compound (II) is a compound (Ig). The compound (2-7) can be obtained by the production method shown below. 323165 75 201202247

(wherein, Aik, R1, R2, R3, Q1, Q2, W, X and Y have the same meaning as defined above. R4' is a C^g alkyl group which may be substituted, and is a hydrogen atom or a calcinable group. Base, Pro series has been exemplified in the literature (Protective Groups In Organic

The general amine protecting group of Synthesis 3rd Edition (John Wiley & Sons, Inc.), Hala and Hale are each independently a chlorine atom or a bromine atom) [Step 31] The compound obtained by the production method 2 (2) -7) Compound (9-1) was reacted in the same manner as in Step 5 to give Compound (9-2). The compound (9-1) can be synthesized according to a commercially available product or a known method [for example, WO2007/126957] or a method according thereto. [Step 32] The protecting group of the compound (9-2) obtained in the step 31 is subjected to deprotection to afford the compound (11). For example, when the protecting group is a Boc group, the compound (II) can be obtained by reacting an excess amount with 5 to 10 equivalents of an acid in the solvent. The solvent used in this reaction may be any one of 76 323165 201202247 as long as it is inert to the reaction. It can be used as a base ether, dichloromethane, DCE, methanol, 1-oxane or diethyl ether. Wherein it is preferred to use y ~ alkane, dichloromethane or methanol separately or in combination. For the I system, for example, an inorganic acid such as formic acid Hacetic acid, a chemical such as hydrochloric acid, or the like, a carboxylic acid chamber of the complex I or the like may be used as a salt or a triterpene acetic acid. The reaction system is: to the point of use of each agent. 5至24小时。 The temperature is usually between 0. 5 to 24 hours.

[Step 33] By reacting the compound (1) obtained in the step 32 with the corresponding ketone or ketone derivative in the same manner as in the step 27, the compound (Ig) can be obtained and the same production method can be obtained. Al is a compound of the formula (4), A2 is z, and Z is a gas atom or a bromine atom. Process 10: Among the compounds (I), A2 is a formula (A), A1 is Z, and Z is a substituted Chd alkyl group, a substituted cw cycloalkoxy group, a substituted aryl group or The substituted heteroaryl compound (lm) can also be obtained from the compound (1〇_1) according to the production method shown below. 0

R3, (^W, y 义2 Ra (5-1) (1〇·1) 丨Step.34] (10-3) Alkali I Step 35j

(1CM) Halogenation [Step 36]

(1-5) Coupling reaction (Step 37|

Dm) 323165 77 201202247 (wherein Aik, R1, R2, R3, R4, Q1, Q2, w, X and γ are in the same sense as above. Hala is a chlorine atom or a bromine atom, and Za is a substituted alkyl group. a substituted C3-8 cycloalkyl group, a substituted aryl group or a substituted heteroaryl group.) [Step 34] According to a commercially available product or, for example, Journal of American Chemical Society, 71, 257, 2575 ( The compound (1〇-丨) synthesized by the method described in 1949) is in the solvent in an amount of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base, and 1 to 5 equivalents, preferably 1 to 1 The compound (10-3) can also be obtained by reacting 3 equivalents of the compound (1〇-2). The compound (10-2) can be synthesized according to a commercially available product or a known method [e.g., Journal of Medicinal Chemistry, 24(5), 496 to 499 (1981)] or a method therefor. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited. For example, THF, 1,4-dioxane, DME, diethyl ether, di-methane, benzene can be used. , benzene, xylene, etc. are used singly or in combination with φ or the like, and preferably THF, diethyl ether or benzene. As the base, for example, various alkali metals such as sodium decoxide, sodium ethoxide or potassium t-butoxide, or alkoxides of an alkaline earth metal, a strong base such as LDA, LHMDS or NHMDS, or a base such as sodium hydride or potassium hydride can be used. A metal hydride or the like is preferably LDA, LHMDS, sodium hydride or the like. 5至24小时。 The reaction is carried out at a temperature of from -78 ° C to room temperature, preferably from -78 ° C to room temperature, generally carried out 0.5 to 24 hours. [Step 35] By subjecting the compound (10-3) obtained in the step 34 to a solvent in the range of 2 to 78 323165 201202247 10 equivalents, preferably 2 to 4 equivalents of a base, and 1 to 10 equivalents, preferably The compound (10-4) can be obtained by reacting 1 to 3 equivalents of the compound (5-1). The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxalate, DME, benzene, toluene, xylene, DMF, or the like. DMA, NMP, decyl alcohol, ethanol, propanol, 2-propanol or the like is used singly or in combination, and preferably, it is decyl alcohol or ethanol. As the base, for example, various alkali metals such as sodium decoxide, sodium ethoxide or potassium t-butoxide, or alkoxides of an alkaline earth metal can be used, and among them, sodium decoxide or sodium ethoxide is preferable. 5至60小时。 The reaction is carried out at a temperature of from 50 to 180 ° C. The temperature is generally 0.5 to 60 hours. [Step 36] The compound (10-4) obtained in Step 35 is reacted in the same manner as in Step 2 to give Compound (10-5).至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至至The compound (Im) can be obtained by reacting 1 to 5 equivalents, preferably 1 to 2 equivalents of the compound (1-5) in the presence of 0.5 equivalent of a palladium catalyst. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and may be, for example, THF, 1,4-dioxin, DME, benzene, toluene or diphenyl. Or use it in combination, etc., which should be 曱79 323165 201202247 benzene or 1,4-two ° smoldering. As the phosphine ligand system, a monodentate coordination type phosphine such as triphenylphosphine, tris(tolyl)phosphine, trifurylphosphine or tris(t-butyl)phosphine, or BINAP, 2, 2'-double can be used. (diphenylphosphinyl)-1, quinone-binaphthyl, DPE-Phos, XANT-Phos, S-Phos, etc. 2-dentate coordination phosphine, of which S-Phos is preferred. As the palladium catalyst, for example, a ruthenium catalyst such as ruthenium (triphenylphosphine)palladium, bis(t-butylphosphine)palladium or bis(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine) can be used. A divalent catalyst such as palladium dichloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium dichloride compound, wherein acetic acid is preferably saturated. The temperature between the reaction system and the boiling point of the solvent to be used is preferably from 50 to 180 ° C, usually from 0.5 to 24 hours. Process 11: Among the compounds (I), A1 is a formula (A), A2 is Z, and Z is a substitutable alkyl group, a substituted C3-8 cycloalkoxy group, a substituted aryl group or The compound (In) which may be substituted with a heteroaryl group can be obtained by the production method shown below. 80 323165 201202247

Ο (2-7) RVR2 Halogenation I Step 39]

(11-2)

R3, n 八 Y/B(ORb)2 R-> (1-7)

Coupling reaction I, step 40J (wherein Aik mm, w, X and γ are the same as defined above. Ra is a substituted alkyl group, Rb is a hydrogen atom or a substituted alkyl group, and Za is replaceable. Cl-ι. Alkyl, a substituted C3 8 cycloalkyl group, a substituted aryl group or a substituted heteroaryl group, Hala is a chlorine atom or a desert atom.) [Step 38] By making a manufacturing method The compound (2-7) obtained in 2 and the compound (11-1) are reacted in the same manner as in the step 20 to give the compound (11-2). The compound (11-1) can be used in a commercially available product or a known method [for example,

Chemical and Pharmaceutical Bulletin 55, 372 to 375 (2007)] or synthesized according to its method. [Step 39] The compound (1) can be obtained by reacting the compound (11-2) obtained in the step 38 in the same manner as in the step 2. 81 323165 201202247 [Step 40] The compound (In) can be obtained by reacting the compound (π_3) obtained in the step 39 with the compound (ι_7) in the same manner as in the step 5. Production method 12: In the compound (I), 'V is a formula (A), A2 is Z, and z is a substitutable

The compound (In) of a Chg alkyl group, a substituted C3_8 cycloalkoxy group, a substituted aryl group or a substituted heteroaryl group may also be derived from a compound.

It is obtained by the manufacturing method shown below. 0 Λ Υ· VR3 R4 (12-1) NH I Za NHj (11-1) ohQ1^H Jv.^Alk (10-1) 鲶l step taste R3 <12-2) base (step 411 R4 - R3 <12-3) Halogenation l Step 42]

RVm.R2 N H2N" (1-5) Reflexive reaction [Step 43]

N, R3 R4

(wherein, Aik, R1, R2, R3, R4, Ql, Q2, w, x and γ are of the same meaning as defined above. Z is a substitutable Ci-1(), substituted c3-8 a ring-based group, a substituted aryl group or a substituted heteroaryl group, Hala is a chlorine atom or a bromine atom.) [Step 40] By making compound (10-1) and compound (丨2-1) The compound (12-2) can be obtained by the same reaction as in the step 34. The compound (12-1) can be synthesized in the form of a commercially available product or a known method [e.g., WO2007/099116, WO2005/113494] or a method therefor. 82 323165 201202247 [Step 41] ^ Compound (12_2) obtained by subjecting Hungarian 4G is reacted in the same manner as in Step 35 to obtain Compound (12_3) ί [Step 42] Compound obtained by Step 41 (12-3) The compound (12-4) can be obtained by the same reaction as in the step 36. [Step 43]

The compound (12-4) obtained in the step 42 is reacted with the compound (1-5) in the same manner as in the step 37 to obtain a compound (??). Production Method 13: In the compound (I), 'Α2 is a formula (AhA1 is ruthenium, Ζ and Q2 are hydrogen atoms, and Aik is a fluorenylene compound (ι)), which can be obtained by the production method shown below.

Hal8 Q1 RV2 1 HO (13-2) RVR2 Mitigation reaction xk HaP R\KI.R2 NI rr Hal® N^Hala (13-1) Ha|e (13-3) (13-4} Alkylation 44] R3 B(〇R»)2

N Y r4 (1-7) ----—— Coupling reaction [Step 45]

R4

R4 (13·5) (lo) 83 323165 201202247 (wherein R1, R2, R3, R4, Q1, w, X and Y have the same meaning as defined above. Rb is a hydrogen atom or a substituted alkyl group, Hala Is a chlorine atom or a bromine atom, Hala is a chlorine atom, a bromine atom or an iodine atom.) [Step 44] The compound (13-1) is used in the solvent in 1 to 10 equivalents, preferably 1 to 3 equivalents of the phosphine' and 1 The compound (13-4) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of the compound (13-2) in the presence of 10 equivalents, preferably 1 to 3 equivalents of an azo compound or a keratin reagent. The compound (13-1) ® can be synthesized in accordance with a commercially available product or a known method [e.g., WO2009/026107] or a method therefor. The compound (13-2) can be synthesized in the form of a commercially available product or a known method [e.g., Journal of American Chemical Society, 1936, 58, 1079] or a method therefor. Or 'by using the compound (13_1) in the solvent in an amount of from 1 to 1 equivalent, preferably from 1 to 3, in the presence of hydrazine, and from 1 to 5 equivalents, preferably from 1 to 3 equivalents of the compound (13-3) The reaction gives the compound (13_4). Compound # (13_3) is available on commercial or well-known methods [eg Journal of

Medicinal Chemistry, 1996, 9, 191-195] or synthesized according to its method. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited. For example, THF, u-diwei, hydrazine, methylene chloride, DCE, gas, stupid, toluene may be used. , dimethyl benzene, dmf, awake, NMp, methanol, ethanol, propanol, 2-propanol, etc. are used alone or in combination, and among them, it is preferably THF, di-methane, methane, DMF. The phosphine to be used may, for example, be triphenylphosphine, trimethylsulfonium, tributyl 323165 84 201202247 phosphine or the like, but among them, triphenylphosphine is preferred. Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, and benzhydryl azodicarboxylate. Among them, diethyl azodicarboxylate and diisopropyl azoacetate are preferred. As the base, an alkali metal hydride such as sodium hydride or potassium hydride can be used, and among them, sodium hydride is preferable. The temperature of the reaction between 〇〇C and the boiling point of the solvent used is preferably from 0 ° C to 5 (TC, generally from 0.5 to 24 hours. [Step 45] The compound obtained by the step 44 ( 13-4) Compound (1-7) is reacted in the same manner as in Step 5 to give Compound (13-5). [Step 46] The compound (13-5) obtained in Step 45 is the same as Step 6 By the method reaction, the compound (1〇) can be obtained. Production method 14: • Among the compounds (1), A2 is a formula (A), A1 is Z, Z is a gas atom or a bromine atom, Q1 and Q2 are hydrogen atoms, and Alk is The mercapto compound (Ip) can be obtained by the production method shown below. 323165 85 201202247 (1-5)

Esterification reaction [Step 48] RVR2

I

Ο (14-1) h2n [Step 47]

Thioamylation [Step 49]

R3,

Oh,

NH Λ (5-1) [Step 50]

(wherein, Aik, R1, R2, R3, R4, W, X and anthracene are the same as defined above. Ra is a substitutable alkyl group, and Hala is a gas atom or a bromine atom). [Step 47] 1 to 20 equivalents, preferably 3 to 10 equivalents, of the compound (14-1) in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base, as needed, in a solvent (1-5) The reaction gives the compound (14-2). The compound (14-1) can be synthesized in accordance with a commercially available product or a known method [e.g., Synthetic Communications, 28 (17), 3159-3162 (1998)] or a method therefor. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited. For example, THF, 1,4-dioxane, DME, benzene, toluene, diphenylbenzene, DMF can be used. , DMA, NMP, methanol, ethanol, 1-propanol, 86 323165 201202247 2-propanol or the like is used alone or in combination, and preferably, it is DMF or NMP. As the alkali system, for example, an inorganic salt such as sodium carbonate, potassium carbonate, cesium carbonate or sodium acetate, an inorganic test such as sodium oxyhydroxide or sulphuric acid, or an aromatic amine such as β-denyl or dipyridylpyridine can be used. Ethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-didecylamino group π ratio sigma, hydrazine, hydrazine-diisopropylethylamine, hydrazine, hydrazine-dimethylaniline, hydrazine- A tertiary amine such as mercaptohexahydropyridine, fluorenyl-fluorenylpyrrolidine or fluorenyl-mercaptomorpholine, and the like, and preferably triethylamine or hydrazine, hydrazine-diisopropylethylamine. 5至24小时。 The temperature is between 0. 5 to 24 hours. [Step 48] By reacting the compound (14-2) obtained in the step 47 with a solvent in an amount of 0.1 to 3 equivalents, preferably 0.1 to 1 equivalent of an acid, a compound (14- 3). The solvent used in the reaction may be an alcohol solvent such as decyl alcohol or ethanol depending on the synthesized ester. Examples of the acid system include organic sulfonic acids such as p-nonylbenzene acid, benzoic acid, and camphoric acid, organic carboxylic acids such as acetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. Among them, sulfuric acid is preferred. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent to be used, preferably from room temperature to 80 ° C, usually for 0.5 to 24 hours. [Step 49] Compound (14-4) can be obtained by reacting the compound (14-3) obtained in Step 48 in the same manner as in Step 11. [Step 50] 87 323165 201202247 By reacting the compound (14-4) obtained in the step 49 with the compound (5-1) in the same manner as in the step 20, the compound (14-5) can be obtained. [Step 51] The compound (IP-5) can be obtained by reacting the compound (14-5) obtained in the step 50 in the same manner as in the step 2. Further, using the compound (IP), according to the same production method as in the steps 6 to 9, a Ch which can be converted into a hydrogen atom and substituted with H can be obtained. A compound of an alkyl group or a substituted C3-8 cycloalkyl group, -NR5R6 or a substituted Cm alkoxy group. Production Method 15: Among the compounds (I), the compound (Iq) wherein Y is a divalent heteroaryl group of the saponin, the oxime or the oxime β can be produced from the compound (2-7) as shown below. The method is obtained.

(2-7)

Halogenation

[Step 53J

RfO SnRe3 ^Rg (15-1) coupling reaction (step 52)

(wherein, Aik, R1, R2, R3, R4, Q1, Q2, W, X and Y are the same meaning as defined above. Re& Rf* is independently a substituted alkyl group, and 1^ is a hydrogen atom 88 323165 201202247 or a substituent such as an alkyl group, 'Har and Haie are each independently a gas atom or a bromine atom, and Hale is a chlorine atom, a bromine atom or an iodine atom 'T is a sulfur atom, a nitrogen atom or an oxygen atom) [Step 52] by making 01至1当量,宜为为为1,1,1,1,1,1,1,1,1 The compound (15-2) can be obtained by reacting with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of the compound (15 to 1) in the presence of 2 to 5 equivalents of a phosphine ligand. The compound (15-1) can be synthesized in the form of a commercially available product or a known method [e.g., Journal of the American Chemical Society, 2004, 126, 13614-13615] or a method therefor. The solvent to be 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 can be used. Among them, it should be benzene. As the palladium catalyst, a zero-valent catalyst such as ruthenium (triphenylphosphine), bis(t-butylphosphine) or ginseng (dibenzylideneacetone) dipalladium, or bis(triphenylphosphine) can be used. A divalent catalyst such as palladium dichloride, palladium acetate or bis(diphenylphosphinoferrocene)palladium disulfide, wherein bis(dibenzylideneacetone)dipalladium or acetic acid is preferred. The phosphine ligand system may use a monodentate coordination type ligand such as o-trisylphenylphosphine, S-Ph〇s or X-Phos, DPPF, DPPE, DPPP, DPPB, BINPP, XANT-Phos or A ligand of a bidentate type such as DPE-Phos, which is preferably S-Phos or X-Phos. 5至24小时。 The temperature is between 0. 5 to 24 hours. The temperature is usually between 0.5 and 24 hours. [Step 53] The compound (15-2) can be obtained by reacting the compound (15-2) obtained in the step 52 with i to 5 equivalents, preferably 1.2 to 3 equivalents of a halogenating agent in a solvent. The solvent to be used is not particularly limited as long as it is inert to the reaction, and for example, TJJF or 1,4-di can be used. Oxane i, dmE, benzene, hydrazine, xylene, DMF, water, or the like is used singly or in combination, and is a mixed solvent of THF and water. The halogenating agent may, for example, be an N-gas benzoin, n-bromosuccinimide, N-iodosuccinimide, N-iodoimine or the like, bromine or iodine, but Among them, N-bromosuccinimide is preferred. The reaction is carried out at a temperature between Ot: and the boiling point of the solvent used, preferably from 0 to 40. . ‘Generally carried out. 5 to 24 hours. [Step 54] The compound (15_3) obtained in the step 53 is reacted with (to 5 equivalents, preferably L2 to 3 equivalents of the compound 05-4) in a solvent to obtain the compound (Iq). The compound (15-4) can be synthesized in the form of a commercially available product or a known method [e.g., WO2004/58750 'Journal of Medicinal Chemistry, 2005, 48(24), 7520-7534) or a method therefor. The solvent used in the present reaction may be 'unspecified' as long as it is inert to the reaction, and may be, for example, methanol, ethanol, 1-propanol, 2-323165 90 201202247 propanol, THF, 1,4. - Dioxane, DME, benzene, toluene, diphenylbenzene, DMF, water, etc. are used singly or in combination, and it is preferably ethanol. The temperature between the reaction system and the boiling point of the solvent to be used is preferably from 50 to 100 ° C, usually from 0.5 to 24 hours. Further, using the compound (Iq), according to the same production method as in the steps 6 to 9, a C3o alkyl group which can be substituted into a hydrogen atom, a substituted C^o alkyl group or a substituted C3-8 cycloalkyl group can be obtained. -NR5R6 or a compound of various substituents such as a substituted Ch alkoxy group.

Production Method 16: Among the compounds (I), A1 is Z, Z is a chlorine atom or a bromine atom, and A2 is a compound (la) of the formula (A), which can also be obtained by the production method shown below. R\

Ra02C Q1 Ra02C Human Aik R4 NH -, -1, Yi (5*1) Ύ^ΝΗ2 Alkali [Step 55|

OH

Halogenated R4 (16-1) {Step 5

(1-1) HaP

Oxidative cleavage reaction (16-2)

Hal3

R4 (16*3> [Step 57] V2 H2n" (1-5) Reductive Amination Reaction [Step Qiu]

R4 da) (wherein R1, R2, R3, R4, W, X, Y, Q1 and Aik have the same meaning as defined above. Ra is a substitutable alkyl group, and Hala is a chlorine atom or a bromine atom) 91 323165 201202247 [Step 55] By adding 1 to 10 equivalents, preferably 1 to 3 equivalents of the compound (5-1) and the compound (1-1) in a solvent in the range of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base The reaction is carried out to obtain the compound (16-1). The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and may be, for example, diethyl ether, THF, 1,4-dioxane, DME, benzene or toluene. Diphenylbenzene, DMF, DMA, NMP, methanol, ethanol, propanol, 2-propanol, and the like are used alone or in combination, and preferably, diethyl ether, decyl alcohol or ethanol. As the base, for example, a metal amine such as bis(trimethyldecyl)amino lithium, bis(trimethyldecyl)amino sodium or bis(trimethylmethylalkyl)amino potassium can be used. Alkoxides of various alkali metals or alkaline earth metals, such as sodium sulphate, sodium ethoxide, potassium t-butoxide, etc., preferably bis(trimethyldecyl)amino sodium, sodium decoxide or ethyl Sodium oxygen. The temperature of the reaction between room temperature and the boiling point of the solvent to be used is preferably from 50 to 100 ° C, usually from 1 to 60 φ hours. [Step 5 6] Compound (16-2) can be obtained by reacting the compound (16-1) obtained in Step 55 in the same manner as in Step 2. [Step 57] Compound (16-3) can be obtained by reacting Compound (16-2) obtained in Step 56 in the same manner as in Step 3. [Step 58] Compound (la) can be obtained by reacting compound (16-3) obtained in Step 57 in the same manner as in Step 4, 92 323165 201202247. Production Method 17: The compound (1-3) which synthesizes the intermediate of the compound (I) can also be obtained by the production method shown below.

NH

H2n [Step 59] Halogenated Λ

NH 2

H2N OHM ~ AlkWh. 1 (1-1-1)

Halogenation

Hal8 [Step 60]

Sandmeyer Reaction ίStep 61]

HaP Hal®

(1-3) (wherein Q1 and Aik are the same as defined above. Ra is a substituted alkyl group, Hala is a chlorine atom or a bromine atom, and Halb is independently a gas atom, a bromine atom or a ruthenium atom. 59] reacting the compound (1-1) in a solvent in the presence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base, with 1 to 5 equivalents, preferably 1 to 2 equivalents of hydrazine or an acid salt thereof, The compound (1-1-1) is obtained. The solvent to be used in the reaction may be any one as long as it is inert to the reaction, and is not particularly limited, and may, for example, be diethyl ether, THF or 1,4-di An ether solvent such as methane or DME; an alcohol solvent such as decyl alcohol, ethanol, 2-propanol or butanol; a halogen solvent such as chloroform or benzene; an aprotic solvent such as toluene, DMF or DMS0 alone or in combination. It is preferably used, among which, it is preferably methanol or ethanol. 93 323165 201202247 The system can use metals such as carbonic acid unloading, carbon _, carbon (10), carbonic acid mother, carbonate, sodium hydroxide, potassium hydroxide, etc. Gas oxides, hexamethyl diazepine, hexamethyl diazepine, hexamethyl diazepine and other metal amines, methoxy , Ethylene gas, third butoxy, and other metal oxides of the metal or soil test group, metal halides such as nitriding clock, sodium chloride or potassium hydride, diethylamine, diisopropyl Ethylamine '〇 咬 bite' 4-dimethylamino-based bite and other organic bases, etc., among which is preferably a reaction in methoxy sodium, φ hexamethyldiamide lithium. • Acidic salts can use veins, carbonates, veins, hydrochlorides, sulphates, sulfates, etc., which are preferably strontium carbonates. The reaction temperature is between TC and the boiling point of the solvent used. 50 to i 〇 (rc, generally 1 to 2 hrs. [Step 60] The compound obtained in Step 59 (HD is reacted in the same manner as in Step 2 to obtain Compound 2). % [Step 61] In the step 6. The obtained compound (Bub 2) is in the solvent in the presence of i to when, preferably 5 to 15 equivalents of the three-base 11-base gas and 2 to 20 equivalents, preferably 3 to 10 The compound (I) can be obtained by reacting an equivalent of azonitrite with 1 to 1 equivalent of 1 to 3 equivalents of a halogenated alkyl ammonium halide. Any one may be any one which is inert to the reaction, and may be used without any particular limitation. For example, dioxane, gas, hydrazine, 2-dichloroethane, tetrachlorinated or the like may be used alone or in combination. It is preferably a two-gas methane. 323165 94 201202247 The three-burning base stone gas base system can use, for example, trimethyl sulphur base gas, triethyl sulphur base chlorine or tripropyl sulphur base chlorine, which should be the top three The base stone is sulphur-based chlorine. The sulphate sulphate can be used, for example, as butyric acid, butyl nitrite, butyl nitrite, isoamyl nitrite, neopentyl nitrite, sub Amyl nitrate or the like 'wherein it is preferably butyl nitrite or isoamyl nitrite. As the halogenated alkylammonium group, for example, tetrabutylammonium chloride, vaporized triethylbenzhydrylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium bromide or the like can be used, and among them, triethylbenzene chloride is preferable. Methylammonium. 5至20小时。 The reaction is carried out at a temperature of 0. 5 to 20 hours. Production Method 18: The compound (1-2) which synthesizes the intermediate of the compound (I) can also be obtained by the following production method.

(In the formula, Q1 and Aik are the same meaning as described above. Ra is a substituted alkyl group, and R is a lower alkyl group of C1 to C3.) [Step 62] Compound (1~1) is dissolved in a solvent to The compound (1-1-5) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 2 equivalents of the compound (1-1-4) in the presence of 5 equivalents, preferably 1 to 2 equivalents. 95 323165 201202247 The solvent to be used in the reaction is not particularly limited as long as it is inert to the reaction, and an alcohol solvent such as methanol, ethanol, 2-propanol or butanol, and water alone can be used. Or it may be used by mixing, etc., and it is preferable that it is a sterol or ethanol alone or a mixed solvent with water. As the alkali system, for example, a metal carbonate such as potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate, a metal hydroxide such as an oxidized clock, sodium hydroxide, potassium hydroxide, argon oxide or cesium hydroxide, hexamethyldi Metal amines such as lithium amide, sodium hexyl decylamine, potassium hexamethyldiamine, various alkali metal or alkaline earth metal such as sodium decoxide, sodium ethoxide or potassium third potassium hydride The oxides are preferably sodium decoxide, sodium ethoxide or potassium hydroxide. The acid salt of the 0-alkylisourea used in the present reaction may be 0-mercaptoisourea sulfate, 0-mercaptoisourea 1/2 sulfate, 0-mercaptoisourea, hydrochloric acid. Salt, 0-ethylisourea•sulfate, 0-ethylisourea·1/2 sulfate, 0-ethylisourea•hydrochloride, etc., of which 0-decylisourea·1/2 Sulfate. The temperature between the reaction system o ° c and the boiling point of the solvent used is preferably from room temperature to 100 ° C, and is usually carried out for 1 to 48 hours. [Step 63] The compound (1-2) can be obtained by reacting the compound (1 -1 -5) with a solvent amount of acidic water. For the acidic water system used in the present reaction, for example, an aqueous sulfuric acid solution, an aqueous hydrochloric acid solution, an aqueous hydrogen bromide solution or the like can be used, and among them, an aqueous sulfuric acid solution is preferred. The temperature between the reaction system o ° c and the boiling point of the solvent used is preferably from room temperature to 100 ° C, and is usually carried out for 1 to 48 hours. 96 323165 201202247 By suitably combining the above-described production methods, a compound of the present invention having a desired functional group at a desired position can be obtained. The separation and purification of the intermediates and products in the above production method can be suitably combined with methods generally used for organic synthesis such as filtration, extraction, washing, drying, concentration, crystallization, and various color layer analysis. Further, it is not particularly refined in the intermediate, and can be supplied to the following reaction. The starting compound or intermediate in the above production method may be in the form of a salt such as a hydrochloride or the like, but may be used as it is or in the form of a free ® . The raw material compound or the intermediate is obtained in the form of a salt. When the raw material compound or the intermediate is used in a free form or obtained, it is dissolved or suspended in a suitable solvent, for example, neutralized with an alkali such as an aqueous solution of sodium hydrogencarbonate or the like. Transform into a free form. The compound (I) or a pharmacologically acceptable salt thereof may also exist as a isomer of a keto-enol body, a meta isomer, a positional isomer, a geometric isomer or an optical isomer, but Mixtures of any ratios which may contain all of these isomers and the isomeric φ are also included in the present invention. Further, the optical isomer can be separated by a known separation step such as a method using an optically active column or a stepwise crystallization method in an appropriate step of the above production method. Further, an optically active substance can also be used as a starting material. When the salt of the compound (I) is to be obtained, the salt of the compound (I) can be directly purified, and when the compound (I) is obtained in a free form, the compound (I) is dissolved or suspended in an appropriate manner. The solvent can be formed by adding an acid or a base to form a salt. Further, the compound (I) or a pharmacologically acceptable salt thereof may be present in the form of a solvent or a solvent of water or various solvents, but such a solvent and 97 323165 201202247 are also included in the present invention. The pharmaceutical preparation of the present invention is prepared by mixing the active ingredient with one or more carriers which are pharmacologically acceptable, by any method known in the art of pharmacy. The carrier for the preparation to be used may, for example, be lactose, mannose, glucose, starch, magnesium stearate, glycerate, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol or the like. Further, the pharmaceutical preparation of the present invention may contain other various excipients, a lubricant, a binder, a breaker, an isotonic agent, an emulsifier, and the like. The route of administration should be the most effective when used for treatment, for example, oral, intravenous, application, inhalation, and eye-dropping, etc., but preferably intravenous administration, especially in intravenous injection. . The administration form may, for example, be a tablet, an injection or the like, but is preferably an injection. The amount of music or the number of music in these medical compositions varies depending on the form of the music, the disease or its symptoms of the patient, the age or weight of the patient, etc., and cannot be generally prescribed, but generally for adults, the active ingredient per day The amount of the range of from about 0.0001 to about 2000 mg, preferably from about 0.001 to about 1000 mg, more preferably from about 〇1 to about 500 mg, particularly preferably from about 1 to about 300 mg. Apply once a day or several times. [Examples] Hereinafter, the present invention will be specifically described by way of examples and reference examples, but the scope of the invention is not limited to the examples. The physicochemical data of each compound in the examples are determined by the following apparatus. 1H NMR: JEOL JNM-LA300 The high-speed retention time is described in the following examples and reference examples. 98 323165 201202247 The conditions for carrying out the liquid chromatography analysis are as follows. Column: octacarbon-based chemically bonded cerium oxide (0DS), column length 50 ram, column inner diameter 4.6 mm [trade name CAPCELL PAK C18 ACR S5 50x4. 6mm (stock company Shiseido Fine Chemical)] Flow rate: 3 5ml/min Measurement wavelength: 220nm, 254nm Moving layer: Liquid A; 0. 05% triethylacetic acid aqueous solution B solution; 0. 05% triacetic acid acetonitrile solution time flow chart: Stage time (minutes) A liquid: B liquid 1 〇. 0 to 0. 5 99 : 1 2 〇·5 to 4. 8 99 : 1 — 1 : 99 3 4. 8 to 5.0 1 : 99 4 5.0 to 5. 2 1 : 99 — 99 : 1 5 5 2 to 5. 8 99 : 1 Further, the purification of each compound was carried out using a high-speed tube (Shanxi rubber column or an amine-based Han column) of Shanshan Co., Ltd., or a HPLC method by Gilson Corporation. (Reference Example 1) 3 (2, 4-monox-5H__pyrrolo[2,3_d]pyrimidine_7(611)__yl)-yi N-dimethylpropanol-oxime-amine 323165 99 201202247 O Cl

0 (a) 5-Allylpyrimidine-2,4,6-(111,311,51〇-trione in diethyl 2-allylmalonate (200 g, 1.0 mol) of ethanol ( After adding urea (60 g, 1.0 mol) to a solution of 500 ml), a solution of sodium ethoxylate (68 g, 1.0 mol) in ethanol (500 ml) was added dropwise, and the mixture was heated to reflux. After 3 hours, it was cooled to room temperature and then added. Acetone (500 ml), the precipitated solid was collected by filtration. The obtained solid was suspended in water (1 liter) and concentrated with concentrated hydrochloric acid. The precipitated solid was washed with water and diethyl ether/hexane. The compound lA (lllg, yield 66%) was obtained. Φ ^-NMR (DMS0-d6, (5ppra): 11. 23 (2H, S), 5. 60-5. 74 (1H, m), 4.99 -5.04 (2H, m), 3. 67(1H, m), 2.65 (2H, m). (b) 5-Dil-propyl-2,4,6-trichloro-bite to make phosphorus oxychloride ( 5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The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (solvent solvent: hexane: ethyl acetate) to yield 100 323165 201202247 to compound 1 Β (3.2 g, yield 80%). W-NMR (CDCh, 6 ppm) : 5. 75-5. 88 (1H,m), 5. 07-5. 19 (2H, m), 3. 59-3. 62 (2H, m). (c) 2-(2 , 4, 6-three-gas lanceolate -5-yl)acetic acid, potassium citrate (IV) was added to the above-mentioned compound lB (2.7 g, 12.1 with 〇1) in acetone (30 ml), water (30 ml). 2 Water and the mixture (223 mg, 0· 604 mmol), a little bit of sodium molybdate (1 〇., 48. 3 mmol) was added little by little, and stirred at room temperature. After 4 hours, diatomaceous earth (Ceiite) After filtration, the acetone was evaporated under reduced pressure, and then extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate and saturated brine, and then evaporated to dryness. Column chromatography (solvent solvent; hexanes: ethyl acetate) was purified to give the title compound 1 C (1.5 g, yield 58%). H-NMR (CDCls, δ ppm) · 9. 77 (1H, d, J=〇. β Hz), 4. 11 (2H d, J=0. 6 Hz).

(d) 3-[2,4-Dichloro-5H-n ratio 11 and [2, 3-d] pyridine-7(6H)-yl]-N,N φ-di 1f-propane-1- The amine was added to the above-obtained compound 1C (500 mg, 2.22 mmol) in a solution of decyl alcohol (5.01111) at 0. 0: acetic acid (254 //Bu 4.44111111〇1), N1,N-didecylpropane- 1,3-Diamine (306 /zl, 2 44_〇1), sodium cyanoborohydride (195 mg, 3.10 mmol), stirred at room temperature. After 6 hours, the reaction was stopped with a saturated aqueous solution of sodium hydrogencarbonate and extracted with a portion of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by ethylamine chromatography chromatography chromatography chromatography eluting elut elut elut elut elut ^-NMR (CDCh, 5 ppm): 3. 67-3. 73 (2H, m), 3. 38-3. 43 (2H, m), 2.97-3.03 (2H, m), 2.25-2.30 (2H , m), 2.21 (6H, s), 1.69-1.79 (2H, m). Reference examples 2 to 10: The reaction and treatment were carried out in the same manner as in the method described in Reference Example 1 (d) using the corresponding starting compounds and reagents. The compounds shown in Table 1 were obtained.

102 323165 201202247 [Table 1]

Reference Example Structural Formula H-NMR (solvent, 5) 2 0 〇ΛΧ 'H-NMR (CDCh, δ ppm): 3.78 (2H, t, J = 8.6 Hz), 3.64-3.67 (4H, m), 3.52 ( 2H, t, J = 6.2 Hz), 3.02 (2H, t, J = 8. 6 Hz), 2. 53 (2H, t, J = 6. 2 Hz), 2.45- 2. 48 (4H, m) . 3 CN' N-\ νΛ> c Human Cl 'H-NMR (CDCh, δ ppm): 3.70 (2H, t, J = 8. 6 Hz), 3.44 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 8.6 Hz), 2.42-2.47 (6H, m), 1.73-1.84 (6H, m). 4 Q 'H-NMR (CDCb, δ ppm): 3.78 (2H, t, J = 8.4 Hz), 3.63-3. 67 (4H, m), 3. 50-3. 54 (2H, m), 3. 02 (2H, t, J = 8.4 Hz), 2.47-2.55 (6H, m 5 o' NJ N-\ 〇ΛΧ Ή-NMR (CDCh, δ ppm): 3.67-3.73 (6H, m), 3.45 (2H, t, J = 7.2 Hz), 3.01 (2H, t, J = 8. 6 Hz), 2.39-2.42 (4H, m), 2.35 (2H, t, J = 7.2 Hz), 1.76 (2H, m). 6 Q 'H-NMR (CDCL·, δ ppm): 3.65- 3.71 (6H, m), 3.40 (2H, t, J = 7.1 Hz), 3.00 (2H, t, J = 8. 7 Hz), 2.31-2.41 (6H, m), 1.45-1.63 (4H, m) . 7 〇ΛΧ 'H-NMR (CDCh, δ ppm): 3.70 (2H, t, J = 8.1 Hz), 3.42 (2H, t, J = 7. 2 Hz), 3. 01 (2H, t, J = 8.1 Hz), 2. 40-2. 53 (6H, m), 1.67-1.77 (2H, m), 0.99 (6H, t, J = 7. 2 Hz). 8 h〇c artificial Cl 'H-NMR (CDCh, δ ppm): 3.70 (2H, t, J = 8. 6 Hz), 3.60 ( 4H, t, J = 5.1 Hz), 3. 51 (2H, t, J = 7. 2 Hz), 3. 02 (2H, t, J = 8.6 Hz), 2.62 (4H, t, J = 5.1 Hz ), 2.56 (2H, t, J = 6.6 Hz), 1.70-1.79 (2H, m). 9 O^ry^ C丨人N人Cl 'H-NMR (CDCh, δ ppm): 7.24-7.31 (5H , m), 3.72-3.87 (3H, m), 3. 56-3. 64 (2H, m), 3. 32-3. 47 (2H, m), 2. 99 (2H, t, J = 8.7 Hz), 2.74 (1H, d, J = 11.4 Hz), 2.64 (1H, d, J = 11.4 Hz), 2.09-2.18 (2H, m), 1.87 (2H, m). 10 Me, Q & ' H-NMR (CDCh, δ ppm): 4.21 (2H, s), 3.82 (2H, t, J = 8.4 Hz), 3. 58-3. 61 (2H, m), 3.44-3. 48 (2H, m), 3. 07 (2H, t, J = 8.4 Hz), 2.37-2.45 (4H, m), 2.30 (3H, s). 103 323165 201202247 (Reference example π) 3-(2, 4-two gas -5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-N-(2-decyloxyethyl)-N-mercaptopropenamide

(3) 2,4-Dichloro-7-(3,3-diethoxypropyl)-6,7-dihydro-511-pyrolo[2,3-d] mouth bite in Reference Example 1 (c) The obtained compound 1C (300 mg, 1.33 mmol) in decyl alcohol (6.0 ml) was added with acetic acid (168 /z 1 , 2.97 mmol) and 3,3-diethoxy at 0 °C. Base-1-propylamine (236 " 1, 1.46 mmol), sodium cyanoborohydride (117 mg, 1.86 mmol), was stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 'H-NMR (CDCh, δ ppm): 4. 50-4. 55 (1H, m), 3. 59-3. 75 (4H, m), 3.37-3.54 (4H, m), 2.94-3.30 ( 2H, m), 1.85-1.92 104 323165 201202247 (2H, m), 1. 12-1. 19 (6H, m). (b) 3-(2,4-Dichloro-5H-pyrrole [2, 3 -d]pyrimidine-7(6H)-yl)propanal in acetone of compound 2A (219 mg, 〇. 685 leg 〇 1) obtained above

(6.0 ml)-water (1.5 ml) solution, p-xylenesulfonic acid, 1 water and (177 mg, 1.03 mmol) were added, and the mixture was stirred at room temperature. After 6 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting residue was purified by chromatography eluting elut elut elut elut elut elut eluting H-NMR (CDCh, δ ppm) · 9. 82 (1H, s), 3. 67-3. 78 (4H, m) 3. 00 (2H, t, J=8. 7 Hz), 2. 82 -2. 86 (2H m) (c) 3-(2,4-dichloro-[2, 3-d] bleed _7(6H)-yl)-N-(2-methoxyB -N-mercaptopropen-1-amine in a solution of the above-obtained compound 2B (139 mg, 566. 566 mmol) in methanol (5.7 ml), acetic acid (65. 6 "卜^13面〇1), N-methyl-2-methoxyethylamine (66. 9#卜〇. 623mm〇i), cyanoborohydride (71.0mg, 1.13mmol) 'at room temperature Ingredients. After stirring overnight, the reaction was stopped with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by column chromatography (yield solvent: hexane: ethyl acetate) to give the title compound (100 mg, yield 56%). A-NMRCCD Ch, 5 ppm): 3.70 (2H, t, J = 8. 4 Hz), 3.40-3 46 (4H, m), 3·33 (3H, s), 3.00 (2H, t, J = 8.4 Hz), 2 52_ 323165 105 201202247 2.55 (2H, m), 2.37-2.42 (2H, m), 2. 24 (3H>s)> l n_ 1.81 (2H, m). (Reference 12) 2- {[3-(2, 4-Dichloro-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propyl](indenyl)amino}ethylamine, Ν

Cl N CI 3 Α The title compound 3A (190 mg, yield 49%) was obtained by the same procedure as the compound of Example 11 (c). [H-NMR (CDC13, (5 卯m): 5_ 13 (2H, m), 3. 53-3. 62 (4H, m), 3.00 (2H, t, J = 8. 1 Hz), 2.95 ( 2H, s), 2.47-2.52 (2H, m), 2.24 (3H, s), 1.72-1.83 (2H, ra). ® (Reference 13) 4-(4-(7-[3-(pyrrolidine) -1-yl)propyl]_6,7-dihydro-5H_pyrrolo[2,3-(1]03⁄413⁄4))), hexahydro pi-pyrene-1-butylic acid, tert-butyl vinegar 323165 106 201202247

(a) 2-[4-(Benzyloxy)phenyl]-4-gas-7-[3-(deslidine-1-yl)propyl]-6,7-dihydro-5Η- The ratio of α to p and [2, 3-d] was immersed in a solution of the compound obtained in Reference Example 3 (1.00 g, 3.32 mmol) in 1,4-dioxane (13.28 ml), and 4-(benzoquinone) was added. Benzyl)phenyl benzoic acid (795 mg, 3.49 mmol), hydrazine (triphenylphosphine) (384 mg, 0.3321 111111 〇 1), 3111 〇 1 sodium carbonate aqueous solution (3.321111, 9.96111111 〇 1), Stir at 150 ° C under microwave irradiation. 3. After 5 hours, hydrochloric acid water was added to the reaction solution to stop the reaction, and the reaction was washed with acetic acid. The aqueous layer was brought to pH = 9 with a sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated. The residue thus obtained was purified by chromatography on EtOAc EtOAc (EtOAc: EtOAc) ^-NMR (CDCh, δ ppm): 8. 29 (2H, d, J=8. 8 Hz), 7. 31-7. 44 (5H, m), 6.98 (2H, d, J=8. 8 Hz), 5,10 (2H, s), 3.66 (2H, t, J=8. 5 Hz), 3.54 (2H, t, J=6. 8 Hz), 3.04 (2H, t, J=8.5 Hz ), 2.56 (6H, brs), 1.81-1.92 (6H, m).

107 323165 S 201202247 (b) 4-(7-[3-(pyrrolidinyl)propyl]_6 7_dihydro-5H_pyrrole

[2, 3-d] pyridin-2-yl) W In a solution of the above-obtained compound 4A (705 mg, 1.57 mm 〇l) in methanol (1 〇.〇1111), 1% palladium on carbon ( 5〇% water) (35〇), triacetic acid (55.0 ° / 1), under hydrogen atmosphere (〇. 3MPa), stirring at room temperature. 6. After 5 hours, the reaction solution was filtered through celite, and concentrated under reduced pressure. The obtained residue was diluted with EtOAc. The obtained φ was subjected to a residue (yield: EtOAc, EtOAc: EtOAc). !H-NMR (CDCh, 5 ppm): 8. 21 (2H, d, J=8. 8 Hz), 7. 91 (1H, s), 6.82 (2H, d, J=8.8 Hz), 3, 60 (2H, t, J=8.3 Hz), 3.54(2H, t, J=7. 0 Hz), 3.00 (2H, t, J=8. 3 Hz), 2.58-2-63 (6H, m) , 1.83-1.96 (7H, m). (c) 4-(4-(7-[3-(Pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-pyrrole# and [2 , 3-d]pyrimidin-2-yl)phenoxy)hexahydropyridine-1-carboxylic acid tert-butyl hydrazine to give the compound 4B (44. Omg, 0. 136 mmol) of THF (1. To the solution, tert-butyl 4-hydroxyhexahydropyridine-1-carboxylate (540 mg, 〇.271 mmol), triphenylphosphine (71.0 mg, 0.271 mmol), diisopropyl azodicarboxylate were added. (53. 0// 1, 0. 271 mmol), stirred at room temperature. After 3 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography eluting with EtOAc EtOAc EtOAc Compound 4C (57. Omg, yield 108 323165 201202247 rate 82%). Ή-NMR (CDCh, dppm): 8. 27 (2H, d, J=9. 0 Hz), 7. 92 (1H, s), 6.92 (2H, d, J=9.0 Hz), 4,33 ( 1H, m), 3.52-3.64 (6H, m), 3.30-3.36 (2H, m), 3.01 (2H, t, J=8.4Hz), 2.56 (6H, brs), 1.80-1.89 (10H, m) 1.45 (9H, s). Reference Examples 14 to 21: The compounds shown in Table 2 were obtained by the same reaction and treatment as in the method of Reference Example 13 using the corresponding starting compounds and reagents.

109 323165 201202247 [Table 2 Reference Example Structural Formula H-NMR (solvent, δ) 14 CN' Ν-Λ β. . -O^jO^n Ή-NMR (CDCls, δ ppm): 8.27 (2H, d, J = 8. 8 Hz), 7.94 (1H, s), 6. 88 (2H, d, J = 8 8 Hz), 4. 93 (1H, brs), 4. 44 (1H, brs), 3.46-3.67 (15H, m), 3.03 (2H, t, J = 8.5 Hz), 2.91-1.15 (6H, (m), 1.44 (9H, s). s), 6. 88 (2H, d, J = 8. 8 Hz), 4. 93 (1H, brs), 4. 44 (1H, brs), 3.46-3.67 (15H, m), 3.03 (2H, t, J = 8. 5 Hz), 2.91-1.15 (6H, m), 1.44 (9H, s). 16 Ή-NMR (CDCL·, δ ppm): 8.26 (2H, d, J = 8. 8 Hz ), 7.95 (1H, s), 6.91 (2H, d, J = 8. 8 Hz), 4.11-4.13 (2H, m), 3. 64 (2H, t, J = 8. 4 Hz), 3. 55-3. 59 (4H, m), 3. 33-3. 36 (2H, m), 3.03C2H, t, J = 7. 9 Hz), 1.95 (2H, m), 1.56 (10H, m) , 1.45 (9H, s), 1.12 (3H, t, J = 6.6 Hz). 17 CN' Ή-NMR (CDCh, δ ppm): 8. 24-8. 29 (2H, m), 7. 92 ( 1H, s), 6.89-6. 94 (2H, m), 4. 50-4. 55 (1H, m), 3. 51-3. 72 (10H, m), 3. 29-3. 36 ( 2H, m), 2. 98-3. 04 (2H, m), 2. 39-2. 44 (6H, m), 1.77-1.91 (6H, m), 1.45 (9H, s). 18 CNv Ν -Λ BOC'a0j〇i:J Ή-NMR (CDCh, δ Ppm): 7.95 (1H, s), 7. 73-7. 76 (1H, m), 6. 75-6. 77 (2H, m), 4. 49-4. 50 (1H, m), 3 69-3. 59 (4H, m), 3.47 (2H, t, J = 7.2Hz), 3.28-3.36 (2H, m), 3.02 (2H, t, J = 8.6Hz), 2.46-2.51 (9H , m), 1. 75-1. 88 (10H, m), 1.44 (9H, s). 19 'a. 〆Me Ή-NMR (CDCh, <5 ppm): 8.11-8.13 (2H, m), 7. 92 (1H, s), 6.83-6.86 (1H, m), 4.57 (1H, m), 3.52- 3.63 (6H, m), 3.45-3. 47 (2H, m), 3. 00 (2H, t, J = 8. 3 Hz), 2. 50-2. 52 (6H, m), 2.26 (3H , s), 1. 78-1.87 (10H, m), 1.45 (9H, s). 20 Boc'a0j〇^ Ή-NMR (CDCh, δ ppm): 7.97 (1H, s), 7.7.88-7.94 (1H, in), 6. 63-6. 73 (2H, m), 4. 47 (1H, brs), 3. 59- 3. 65 (4H, m), 3. 50 (2H, t, J = 7.1 Hz), 3. 34-3. 36 (2H, m), 3. 02 (2H, t, J = 7.9Hz), 2. 50-2. 52 (6H, m), 1. 77-1 87 (10H, m), 1.45 (9H, s) 21 CN' N-\ nV , a. Mineral F Ή-NMR (CDCh, δ ppm): 8. 03-8.12 (2H, m), 7. 91 (1H, s), 6.96-7.02 (1H, m), 4.51-4.52 (1H, m), 3.67-3.75 (2H, m), 3. 62 (2H, t, J = 8. 5 Hz), 3. 53 (2H, t, J = 7. 2 Hz), 3, 29-3. 35 (2H , m), 3. 02 (2H, t, J = 8. 5 Hz), 2. 50-2. 51 (6H, m), 1.73-1.94 (10H, m), 1.45 (9H, s).

110 323165 201202247 (Reference Example 22) N-(4-[4-chloro-7-[3-(°Bido-1-yl)propyl]-6,7-diaza-5Η-0 ratio [2, 3-d]pyrimidin-2-yl]phenyl)-2-(didecylamino))acetamide

(a) 4-{4-Ga-7-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-pyridinium[2,3-d]pyrimidine-2 -Based on the solution of the compound obtained in Reference Example 3 (200 mg, 0.646 mmol) in 1,4-dioxane (2. 65 ml), 4-(4,4,5,5-tetradecyl- 1, 3, 2-dioxaborolan-2-yl)phenylamine (153 mg, 0.797 mmol), hydrazine (triphenylphosphine), (77. Omg, 0. 0664 mmol), 3 mol/L sodium carbonate Aqueous solution (664, 1.99 mmol) was stirred at 120 °C. After 7 hours, hydrochloric acid water was added to the reaction solution to terminate the reaction, and the mixture was washed with acetic acid. The aqueous layer was made to have a sodium hydroxide aqueous solution to pH = ll and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by ethylamine chromatography chromatography chromatography chromatography chromatography !H-NMR (CDCh, δ ppm): 8. 16 (2H, dd, J=6. 6 Hz, 2. 0 Hz), 6.67 (2H, dd, J=6. 6 Hz, 2.0 Hz), 3.87 (2H, brs), 3.65 (2H, t, J=8.6 Hz), 3.55 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=8.6 Hz), 2.60-2.71 (4H, m), 1.85-2.00 (6H, m), 1. 55 (2H, brs).

Ill 323165 201202247 (b) N-(4-[4-Ga-7-[3-indole-Butyl-1-yl)propyl]-6,7-dihydro-5Η-»比比和[2, 3-d]pyrimidin-2-yl]phenyl)-2-(dimethylamino))ethinamide in a solution of compound 5A (60.0 mg, 168. Add 1-(3-didecylaminopropyl)-3-ethylcarbonyldiimide hydrochloride (64. Omg, 〇. 335 mmol), 1-hydroxybenzotriazine (4. 50 mg, hydrazine) 〇 335 mmol), N,N-dimethylglycine (35. Omg, 0. 335 mmol), stirred at room temperature. After 24 hours, additional 1-(3-didecylaminopropyl-yl)_3-ethyldiimide hydrochloride (96. Omg, 0. 504mrool), 1-phenylbenzotriazole (6) 75 mg, 0. 〇 504 mmol), N,N-dimercaptoamine (53. Omg, 〇. 504 mmol), stirred for 40 hours. After the saturated saline solution was placed in the reaction solution, ethyl acetate was placed and stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with water and then brine and dried over magnesium sulfate. After concentrating under reduced pressure, the obtained residue was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut . ^-NMR (CDCh, (5 ppm): 9.23 (1H, brs), 8.23 (2H, d, J = 8.6 Hz), 7. 64 (2H, dd, J = 8.6 Hz), 3.70 (2H, t, J=8. 0 Hz), 3.57 (2H, t, J=6.8Hz), 3.03-3.09 (4H, in), 2.74 (2H, brs), 2.38 (6H, s), 1.92-2.02 (6H , m), 1.59 (4H, brs). (Reference Example 23) N-(4-{4-Chloro-7-[3-(σ比洛定定-1-yl)propyl]-6, 7- Dihydro-5Η_σpyrolo[2,3-d]pyrimidin-2-yl}phenyl)-2-(indolyl-morpholinyl)acetamide 112 323165 201202247

On^

In the same manner as in the above-mentioned Example 2 2 (b), the title compound was obtained as a pale yellow oil (yield: 46 mg, yield: 42%). Ή-NMR (CDCh, 5 ppm): 9.17 (1H, brs), 8.32 (2H, dd, J=8.8Hz), 7. 61(2H, d, J=8. 8 Hz), 3.70-3.80 (6H , in), 3.59 (2H, t, J=6.5 Hz), 3.15 (2H, s), 3.08 (2H, t, J=8. 7 Hz), 2.61-2.64 (4H, m), 2.24 (2H, m), 2.02 (2H, m), 1.54 (8H, m). (Reference Example 24) 4 (4-{4-Chloro-7~[3-(pyrrolidin-1-yl)propyl]-6, 7-Dihydro-5H-pyridyl 0 [2'3-d] squeezing '2-yl} stupid) hexahydrodeuterium + tartrate tert-butyl

, 0. 664 mmol) of 1,4-113 323165 201202247 dioxane (2.65 ml) solution, adding 4-(4-(4, 4, 5, 5-tetramethyl-1,3, 2- Oxaborolan-2-yl)phenyl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (270 mg, 0·697 mmol), hydrazine (triphenylphosphine) (77. Omg, 0 0664 mmol), 3 mol/L aqueous sodium carbonate solution (664//1, 1.99 mmol), stirred at 120 °C. 5. After 5 hours, hydrochloric acid water was added to the reaction solution, the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was subjected to an aqueous solution of argon oxide to pH = 11, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography eluting elut elut elut elut elut elut eluting Ή-NMR (CDCh, δ ppm): 8. 24 (2H, d, J=8. 8 Hz), 6. 89 (2H, d, J=8.8 Hz), 3.43-3.72 (12H, m), 3.21 -3.25 (4H, m), 3.03 (2H, d, J=8. 5 Hz), 2.35-2.42 (6H, m), 1.76-1.82 (2Hra), 1.47 (9H, s). References 25 to 36 : The compound shown in Table 3 was obtained by the same reaction and treatment as the method described in Reference Example 24 using the corresponding starting compound and reagent. Ιί:* 114 323165 201202247 [Table 3]

Reference Example Structure j-NMR (solvent, 5) 25 ^ Ν-Λ Boc Ή-NMR (CDCL·, δ ppm): 8.31 (2H, d, J = 8.6 Hz), 7.50 (2H, d, J = 8.6 Hz), 4. 01 (2H, brs), 3. 69 (2H, t, J = 8. 6 Hz), 3. 56 (2H, t, J = 7.1 Hz), 3. 20-3. 28 (2H, m), 3. 06 (2H, t, J = 8. 6 Hz), 2. 63 (6H, brs), 1.85-2.03 C8H, m), 1.64-1.74 (3H, m), 1.42 (9H, s). 26 N-\ BocO n^Y Human Cl Ή-NMR (CDCh, δ ppm): 7.92 (1H, s), 7.86 (1H, d, J = 7.9 Hz), 6. 98-7 . 01 (2H, m), 3. 68 (2H, t, J = 8. 5 Hz), 3. 54-3. 60 (4H, m), 3.18-3.20 (6H, m), 3.06 (2H, t, J = 8.5 Hz), 2.63 (6H, brs), 1. 56-1. 68 (6H, m), 1.47 (9H, s). 27 ^nJ〇^n Cl BocHN-/ ^ Ή-NMR ( CDCb, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz), 6. 53 (2H, d, J = 9. 0 Hz), 4. 69 (1H, brs), 4. 35 (1H, brs), 3. 38-3. 70 (7H, m), 3. 20-3. 22 (1H, m), 3. 01 (2H, t, J = 8. 5 Hz), 2. 47-2. 52 (6H, m), 2. 21-2. 33 (2H, m), 1.76-1.89 (6H, m), 1.43 (9H, s). 28 c~ α BocHN'-Y ^ Ή -NMR (CDCb, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz), 6. 53 (2H, d, J = 9. 0 Hz), 4. 69 (1H, brs), 4. 35 (1H, brs), 3. 38-3 70 (7H, m), 3. 20-3. 22 (1H, m), 3. 01 (2H, t, J = 8. 5 Hz), 2. 47-2. 52 (6H, m), 2. 21-2. 33 (2H, m), 1.76-1.89 (6H, m), 1.43 (9H, s). 29 persons a BocHN^^A^ >U Ή-NMR (CDCL·, δ ppm) : 8. 23 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9.0 Hz), 4.83 (1H, brs), 3.85 (1H, brs), 3.42-3.70 (7H , m), 3.19 (1H, brs), 2.98-3.05 C4H, m), 2.42-2. 52 (8H, m), 1. 76-1. 89 (6H, m), 1.44C9H, s). 30 CN^x N-\ nV ΒοοΗΝ,,^^Λ^1 Ή-NMR (CDCL·, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz), 4. 83 (1H, brs), 3. 85 (1H, brs), 3.42-3.70 (7H, m), 3.19 (1H, brs), 2.98-3.05 (4H, m) , 2.42-2.52 (8H, m), 1. 76-1. 89 (6H, m), 1.44 (9H, s). 115 323165 201202247

31 into Cl BocHN^^^ 'H-NMR (CDCls, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 89 (2H, d, J = 9. 0 Hz), 4.44 (1H, brs), 3. 71-3. 75 (2H, m), 3. 63 (2H, t, J = 8. 6 Hz), 3. 53 (2H, t, J = 7. 0 Hz ), 3. 02 (2H, t, J = 8. 6 Hz), 2. 87-2. 94 (2H, m), 2.47-2.52 (6H, m), 2.01-2.02 (2H, m), 1.79 -1.89 (6H, m), 1.48-1.56 (3H, m), 1.43 (9H, s). 32 c~ rJ〇^N Cl 'H-NMR (CDCh, δ ppm): 8.26 (2H, d, J = 8.4 Hz), 7. 24 (2H, d, J = 8.4 Hz), 4.22 (2H, brs), 3. 66 (2H, t, J = 8. 6 Hz), 3. 54 (2H, t, J = 7.1 Hz), 3. 05 (2H, t, J = 8. 6 Hz), 2. 63-2. 82 (3H, m), 2. 47-2. 52 (6H, m), 1.77- 1.89 (8H, m), 1. 60-1. 68 (2H, m), 1.46 (9H, s)_ 33 c~ rT^V^N^CI Boc'^Sd 'H-NMR (CDCh, δ ppm ): 8. 39 (2H, d, J = 8.8 Hz), 7. 33 (2H, d, J = 8. 8 Hz), 4. 25 (2H, s), 3. 77 (4H, brs), 3. 67 (2H, t, J = 8. 7 Hz), 3. 54 (2H, t, J = 7.1 Hz), 3.05 (2H, t, J = 8.7 Hz), 2.54-2.52 (6H, m) , 1.76-1.89 C6H, m), 1.48 (9H, s). 34 c N<Y αχα O-Boc 'H-NMR (CDCla, δ ppm) :7.55 (1H, d, J = 7.6 Hz), 7.24- 7.29 (1H, m), 6.89-7.04 ( 2H, m), 3.65-3.71 (6H, m), 3. 48 (2H, t, J = 7. 5 Hz), 3. 41-3. 43 (4H, m), 3. 08 (2H, t , J = 8. 5 Hz), 2. 89-2. 92 (4H, m), 2. 34-2.40 (6H, m), 1.76-1.81 (2H, m), 1.43 (9H, s). 35 〇C~N, nV/human Bod 'H-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 6. 89 (2H, d, J = 9.0Hz), 3.43- 3.72 (12H, m), 3.21-3.24 (4H, m), 3.03 (2H, t, J = 8. 3 Hz), 2.32-2.42 (6H, m), 1.75-1.82 (2H, m), 1.46 ( 9H. s). 36 nX> Wide furnace a BocHN^^ Ή-NMR (CDCls, δ ppm): 8.22 (2H, d, J = 9. 0 Hz), 6. 89 (2H, d, J = 9.0 Hz ), 4.45-4.47 (1H, m), 3.56-3.72 (10H, m), 3.53 (2H, t, J = 7. 0 Hz), 3.44-3.47 (1H, m), 3.03 (2H, t, J = 8.6 Hz), 2.87-2.94 (2H, m), 2.37-2.42 (6H, m), 2.00-2.02 (2H, m), 1.77-1.82 (2H, m), 1.43 (9H. s). 116 323165 201202247 (Reference Example 37) l-[2-(2-{4-Chloro-2-[4-(4-mercaptohexahydro). Phenyl-1-yl)phenyl]-5H-pyrrolo[2,3-d]pyrimidin-7(61〇-yl}ethoxy)ethyl]pyrrolidin-2-one

8C (a) 2-(2,4-Dichloro-5H-«pyrolo[2,3-d]pyrimidin-7(6H)-yl)ethanol The compound lC obtained in Reference Example 1 (c) ( In a solution of 310 mg, 1.37 mmol) of decyl alcohol (7.0 ml), acetic acid (173/z 1, 3.01 mmol), 2-aminoethanol (92.0/zl, 1.51 mmol), cyano group were added at 0 °C. The shed hydrogenation (121 mg, 1.92 mmo 1) was stirred at room temperature. After 5 hours, the reaction was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by chromatography on silica gel chromatography (solvent solvent: hexane: ethyl acetate) to give the title compound 8A (236 mg, yield 74%). !H-NMR (CDCh, (5 ppm): 3.79-3.89 (4H, m), 3.55 (2H, t, ϋ:: 117 323165 201202247 J=5. OHz), 3.04 (2H, t, J=8. 6 Hz), 2.32 (1H, t, J=5. 5 Hz). (b) 2-{4-Ga-2-[4-(4-Mercaptohexafluoroindole-bu)phenyl]- 5H-.Bisto[2,3-d]pyrimidin-7(61〇-yl}ethanol in a solution of the compound 8A (218 mg, 0.93 mmol) obtained above in 1,4-dialdehyde (4 ml), Add 1-mercapto-4-[4-(4,4,5,5-tetradecyl-1,3,2-dioxaborolan-2-yl)phenyl]hexahydroindole 296 mg, 0.98 mmol), hydrazine (triphenylphosphine) (108 mg, 0.093 mmol), 3 mol/L sodium carbonate aqueous solution (0.93 ml, 2.79 ramol), and stirred at 110 ° C under microwave irradiation. After the lapse of time, hydrochloric acid water was added to the reaction solution, and the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine. The residue was purified by column chromatography (yield solvent; chloroform: decyl alcohol) to give the title compound 8B (179 mg, yield 51%). H-NMR (CDCh) , δ ppm) : 8. 15 (2H, d , J=9. 0 Hz), 6. 89 (2H, φ d, J=9.0 Hz), 3.86-3.92 (2H, m), 3.72 (2H, t, J=8.4 Hz), 3.53-3.57 (2H , m), 3.26-3.32 (4H, m), 3.05 (2H, t, J=8.4 Hz), 2.52-2.58 (4H, m), 2.33 (3H, s). (c) l-[2-( 2-{4-Chloro-2-[4-(4-mercaptohexahydroindolepyrimidin-1-yl)phenyl]-5H-pyrrole[2,3-d]pyrimidin-7(61〇-yl} Ethyloxy)ethyl]pyrrolidin-2-one A solution of the above-obtained compound 8B (164 mg, 0. 439 mmol) in DMF (4 ml) was cooled to 0 ° C, and sodium hydride (71. 3 mg, 0. 48 After stirring for 15 minutes, 1-(2-ethylethyl)pyrrolidin-2-one was added and stirred at room 118 323165 201202247. After 3 hours, it was extracted with chloroform-water solution to make the organic layer saturated with salt. After washing with water, the residue was evaporated under reduced pressure, and the residue obtained was purified by chromatography eluting with EtOAc EtOAc EtOAc ).

!H-NMR (CDCh, δ ppm) : 8. 23 (2H, d, J-9. 0 Hz), 6. 89 (2H, d, J=9.0 Hz), 4.09 (2H, s), 3.69- 3.83 (6H, m), 3.38-3. 50 (2H, m), 3. 25-3. 33 (6H, m), 3. 02 (2H, t, J=8. 1Hz), 2.52-2.59 ( 4H, m), 2.34 (3H, s), 1.74-1.93 (4H, m). (Reference 38) 2, 4-dioxa-8-[3-(pyrrolidin-1-yl)propyl]- 5, 6, 7, 8-tetrahydropyrido[2,3-d]pyrimidine

(a) 2-(3-butenyl)malonate diethyl ester in a solution of diethyl malonate (22.4 g, 0.014 mol) in ethanol (100 ml), 20% ethoxylate A sodium/ethanol solution (54.9 ml, 0.140 mol) was stirred at 50 ° C for 30 minutes. After cooling to room temperature, 4-bromo-butene (13.5 g, 0.001 mol) was added. After stirring overnight, the reaction solution was concentrated under reduced pressure. The residue obtained by dilution with water was extracted with diethyl ether/hexane (2:1) mixed solvent.

C 119 323165 201202247 Take. The organic layer was washed with brine and concentrated. The residue obtained was concentrated under reduced pressure (6 (TC, lnrnHg) to give the title compound 9A (16.4 g, yield 76%) as a colorless oil. 1 earned (CDChj ppm): 5. 68_5. 82 (1H, m), 4. 97_5 shoulder (10) π〇, 4.13-4.22 (4Η, m), 3.31-3.35 (1H, m), 2.〇1_2.12 (2H, m), 1.94-1.99 (2H, m), 1.20-1.28 (6H, m). (b) 5-(3-butenyl)pyrimidine_2, 4, 6(1H,3H, 5H)-trione _ The compound 9A obtained above (16. Og 〇. 0747m〇1) In a mixture of ethanol (64ml) and propylene (16〇11), add urea (4.49g, 〇.〇747 助.1), 20% sodium ethoxide/ethanol solution ( 29 3ml, 〇〇 747m〇i), stir. After 4 hours, cool to room temperature, take the precipitated solids. Obtain the obtained u body in water (10) concentrated salt (four) as a small pH filter, precipitated solid After that, it was washed with water and a dioxin to give Compound 9B (12. lg, yield: 89%). H-NMR (DMSO-de, <5 ppm): 11.19 (2H, s), 5.67-5.78 ( 1H, • 4.92-5.01 (2H, m), 3.56 (1H, m), 2.01 (4H, m). (c) 5-(3-butenyl)-2, 4, 6-trioxanidine Addition of oxygen to the above-obtained compound 9B (12. 〇g, 〇. 〇 659 mol) Phosphorus (30. lml, 〇. 329mol), N,N-dimethylaniline (4. 17 m Bu 0. 0329m〇l), stirred with 12 (TC superheated. After 5 hours, the reaction solution was added to the ice. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was subjected to chromatography on a chrome column chromatography (solvent solvent) · hexane: ethyl acetate) purified to give compound 9C (3. 15gmg, yield 20%). 120 323165 201202247 Ή-NMR (CDCh, (5 ppm): 5. 78-5. 91 (1H, m ), 5. 01-5. 08 (2H, m), 2.92-2.97 (2H, m), 2.31-2.39 (2H, m). (d) 3-(2,4,6-trichloro-bite -5-yl)propionic acid · In the solution of the compound 9C (3.10g, 0. 0131mmol) obtained above, a solution of hydrazine (IV) 2 water and a mixture of water (30 ml) 240 mg, 0. 653 mmol), a little bit of sodium citrate (8. 37 g, 0. 0392 mmol) was added little by little, and stirred at room temperature. 3. After 5 hours, Celite was filtered, and acetone was evaporated under reduced pressure. The organic layer was washed with a 5% aqueous sodium thiosulfate solution and brine, and then evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) Ή-NMR (CDCh, δ ppm): 9. 84 (1H, s), 3. 14-3. 19 (2H, m), 2.75-2.81 (2H, m). (6) 2,4-Dichloro -8-[3-('1 ratio '1 each bite-1-yl) propyl]-5,6,7,8-tetranitrogen ^ ° ratio is determined [2,3-(1] mouth 11

To a solution of the above-obtained compound 9D (479 mg, 2.0 mmol) in decyl alcohol (9.0 ml), acetic acid (229 #卜 4. 00 mmol), 3-(o ratio p each bite_1) was added at 0 °C. _ base) propane _1_amine (278/z 1, 2. 2Ommo 1), nitrogen-based shed nitride (176 mg, 2.80 mmol), stir-stacked at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by ethylamine EtOAc EtOAc EtOAc (EtOAc:EtOAc W-NMR (CDCh, (5 ppm): 3. 62 (2H, t, J = 7. 2 Ηζ), 3· 36-3. 42 (2H, m), 2.68 (2H, t, J = 6.5 Hz ), 2.41-2.50 (6H, m), 1.85-21.95 (2H, m), 1.73-1.83 (6H, m). (Reference 39) 4-[3-(2, 4-Dichloro-6, 7 -dihydropyrido[2,3-d]pyrimidine-8(5H)-yl)propyl]morpholine

The compound 9D obtained in Reference Example 38 was used to give the title compound (yield: 86%). 'H-NMR (CDCh, δ ppm): 3. 68-3. 71 (4H, [,m), 3. 59-3. 64 (2Η, t, J=6. 4 Hz), 2. 42 1.88 -1.96 (2H, m), • 3.37-3.40 (2H, m), 2.69 (2H, (4H, m), 2.34 (2H, t, J=7. 1 Hz), 1.72-1.82 (2H, m) (Reference Example 40) 4-[3-(2, 4-Dis-7-, 8-dihydro-5H-pyrimido[4,5-b]azepane-9-(6H)-yl) Propyl] 淋 323165 122 201202247

(a) 2-(penta-4-yl)malonate diethyl hydrazine is added to the ethanol solution (60.〇1111) by adding sodium (6.6 舀, 62.4111111〇1), and stirring for 20 minutes until the sodium is completely dissolved. Thereafter, diethyl malonate (10. Og, 62.4 mmol) was added, and the mixture was stirred at 50 ° C for 30 minutes. After the reaction mixture was allowed to react to room temperature, 5-y-pent-1-ene (6.6 g, 44.60 mmol) was added dropwise. After the mixture was stirred for 22 hours, the reaction solution was concentrated under reduced pressure. The residue obtained was diluted with water and extracted with a mixed solvent of diethyl ether / hexane (2:1). The organic layer was washed with brine and dried over magnesium sulfate. The obtained residue was purified by EtOAc EtOAc. 'H-NMR (CDCh, 5 ppm): 5. 69-5. 83 (1H, m), 4. 92-5. 03 (2H, m), 4.12-4.22 (4H, m), 3.27-3.35 ( 1H, m), 2.03-2.15 (2H, m), 1.85-1.92 (2H, m), 1.35-1.45 (2H, m), 1.22-1.29 (6H, m). (b) 5-(pentene- 4-yl)pyrimidine-2, 4, 6(1H, 3H, 5H)-trione

To a mixture of the above-obtained compound 11A (5. lg, 22.3 mol) in ethanol (20 ml) and acetone (10 ml), urea (1.34 g, 22.3 mol), 28% sodium ethoxide was added. / Ethanol solution (4.3 ml, 22.3 mol), stirred at 60 ° C 123 323165 201202247. After 2 hours, it was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was dissolved in water (10 ml), and hydrochloric acid was brought to pH = i. The precipitated solid was filtered, washed with water to give Compound UB (158 g, yield 36%). N.2(2H,s), 5.67_5.8〇(1H,m), 4.91-5.01 (2H, m), 3.5-3.54 (1H, m), 1.94-2.01 (2H, m), 1.83-1.90 (2H, m), 1.26-1.36 (2H, in). ^ (c) 2, 4, 6-trichloro-5-(pentamethylene-4-yl) oxime obtained from the above compound 11B (197 g, 2〇. In the 〇 〇 1), phosphorus oxychloride (10. 1ml, 0 109m〇i), N,N-dimethylaniline (〇. 64 ml, 5.02 mol) was added to 12 〇. 〇 Heat and stir. After 5 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by chromatography (yield solvent: hexanes: ethyl acetate) to give the compound lic (772 mg, yield φ 3 〇%). lH-NMR (CDCh, (5 ppm): 5. 74-5. 85 (1H, m), 5. 〇〇-5. 10 (2H, m), 2.81-2.86 (2H, m), 2. 14 -2. 22 (2H, m), 1. 62-1. 72 (2H, in). (d) 4-(2, 4, 6-tris-pyrimidine-5-yl)butanal obtained in the above To the solution of the compound llC (772 mg, 3.07 bribes) in acetone (60 ml) and water (6.0 ml), potassium ferrite (IV) 2 water and (57 mg, 0.153 mmol) were added. Add sodium metaperiodate (2. 〇g, 9.21 mmol), and stir at room temperature. After 3.5 hours, filter the Celite, 124 323165 201202247, distill off the acetone under reduced pressure, The organic layer was washed with a 5°/〇-sodium thiosulfate aqueous solution and a saturated aqueous sodium chloride solution, and then evaporated under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column chromatography (solvent solvent; The title compound 11D (462 g, yield: 59%). 86-2. 92 (2H, m), 2. 57-2. 61 (2H,m), 1. 88-1. 98(2H,m). (e) 4-[3-(2, 4- Dichloro-6,7-dihydro-5H-pyrimido[4,5-b]aza heterocycle|glycosyl-9(10))]] In the above solution of the compound 11D (139 mg, 0. 549 mmol) in methanol (4.0 ml), acetic acid (69.0 #1, 1.21 mmo 1) and 3-(π ratio 17 bite-1) were added at 0 °C. - ) 丙 -1- 胺 胺 胺 胺 胺 胺 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 胺 胺 -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- The sodium hydrogencarbonate aqueous solution was quenched, and the mixture was extracted with chloroform, and dried over anhydrous magnesium sulfate, and then evaporated to dryness. The obtained residue was subjected to chromatography on an amine-based silica gel column (solvent solvent; hexane: ethyl acetate) The title compound llE (91 mg, yield 48%) was obtained as a white solid. ???H-NMR (CDCh, 5 ppm): 3. 69-3. 72 (4H, m), 3. 53-3. (4H, m), 2.82-2.86 (2H, m), 2.44 (4H, brs), 2.36 (2H, t, J=6.5 Hz), 1.88-1.92 (4H, m), 1.73-1.83 (2H, m (Reference Example 41) 2-(2,4-Dioxa-7-(3-(N-morpholinyl)propyl)-6,7-dihydro-5H-pyrrolo[2, 3-d Pyrimidin-6-yl) decyl acetate 125 323165 201202247

(a) Tetrahydrofuran of (E)-4-(2,4,6-trichloropyrimidin-5-yl)-2-butyric acid decyl ester in 2-(diethoxyphosphonyl)acetate decyl ester The solution (4.5 ml, 2. The tetrahydro-α-propan (3.5 ml). After stirring for 2 hours under cooling, the reaction was quenched with saturated aqueous ammonium sulfate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 'H-NMR (CDCh, 5 ppm): 6. 94-6. 85 (1H, m), 5. 87-5. 81 (1H, m), 3.37-3.71 (5H, m). (b) 2_ (2,4-dichloro-7-(3_(N_)-propyl)propyl)-6,7-diaza-5H-pyrrolo[2,3-d]pyrimidin-6-yl)acetate The ester was added to the above-obtained compound (285 mg, 1.0 mmol) in a 1,4-dis-sigma solution (4. Oml) to give 3-aminopropyl morphine (0.18 ml, 1.21 mmol). It was stirred with N,N-diisopropylethylamine (0.36 ml, 2.02 mmol) at room temperature. After 11 hours, the reaction solution was added to a saturated aqueous solution of sodium chloride, and the mixture was evaporated to ethylamine. The organic layer was dried over magnesium sulfate and dried under reduced pressure. The obtained residue was purified by a silica gel column chromatography (solvent solvent; 126 323165 201202247 hexane: ethyl acetate), and the obtained oil was dissolved in tetrahydrofuran (5.0 ml), and hydrogenated under ice bath. 5小时。 Sodium (46mg, 1 · 04 mmol), stirring at room temperature for 1.5 hours. After the reaction was stopped with water, it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and dried under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H-NMR (CDCh, 5 ppm): 4. 41-4. 31 (1H, m), 3. 78-3. 66 (8H, m), 3.34-3.24 (1H, m), 3.21-3.11 ( 1H, m), 2.90-2.72 (2H, m), 2.55-2.47 (1H, m), 2.40-2.31 (6H, m), 1.85-1.67 (2H, m). (Reference Example 42) 4-(3 -(2,4-dichloro-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)butyl)

Using the compound 1C and the corresponding reagent obtained in Reference Example 1 (c), the title compound (345 mg, yield 78) was obtained. %). 'H-NMR (CDCh, δ ppm): 4. 37-4. 30 (1H, m), 3. 68-3. 57 (6H, m), 3.00 (2H, t, J=8.7Hz), 2.42 -2.26 (6H, m), 1.81-1.56 (5H, m). (Reference Example 43) 127 323165 201202247

2-(4,6-dioxapyridin-5-yl)acetaldehyde OH

(a) 5-Allyl thiophene-4, 6-diol using formamidine hydrochloride (5.20 g, 49.94 mmol) and diethyl allylmalonate (10.Og, 49.94 mmol), 21% sodium ethoxylate / ethanol solution (32. 4 g, 99.88 mmol), the title compound 13A (1.25 g, yield 72) %). ^-NMR (DMS0, (5 ppm): 7. 91 (1H, s), 5. 82-5. 70 (1H, m), 4.96-4.85 (2H, m), 2.98-2.96 (2H, m) (b) 5-Allyl-4,6-dichloromethane was used in the same manner as in Reference Example 1 (b) by using the compound (4.20 g, 27.6 mmol) obtained above. The title compound 13B (4. 74 g, yield 90%), mp.:H-NMR (CDCla, δ ppm): 8. 64 (1H, s), 5. 90-5. 79 (1H, in ), # 5.18-5.08 (1H, m), 3.66-3.63 (2H, m). (c) 2-(4,6-Dichloropyrimidin-5-yl)acetaldehyde in the above compound (500 g, 2. In a solution of 2° 6-didecyl group 0 (0. 62 ml, 5. 30 mmol), add 2,6-diindenyl group to 0 (62 ml, 5. 30 ml), and then add in an ice bath.锇 卸 (IV) 2 water and substances (19. Omg, 0. 0529ramol), slightly added a little bit of sodium molybdate (2.77g, 10.6mmol), stirred at room temperature. After 24 hours After the soil was extracted with ethyl acetate, the organic layer was extracted with 10% sodium thiosulfate aqueous solution and 128 323165 201202247 and brine, and then evaporated under reduced pressure. Shixi rubber column chromatography analysis The title compound (1 g (412 g, yield: 81%)). (1H, s), 4. 14 (2H, s).

[Reference Example 44] 2-(4,6-Dichloro-2-indolylpyrimidin-5-yl)acetaldehyde ΗΝ^

D0 NHZ, 〇〇2曰

14Θ 14Α

(a) 5-Allyl-2-methylpyrimidine-4,6-diol using acetamidine hydrochloride (4.7 g, 49.9 mmol) and diethyl allylmalonate (10. The title compound 14A (4.4 g, yield 53%) was obtained as a white solid. ^-NMR (DMSO-d6, 5 ppm): 11.65 (1H, s), 5.82-5.69 (1H,

m), 4.92-4.82 (2H, m), 2.94-2.92 (2H, m), 2.19 (3H, s). (b) 5-allyl-4,6-dichloro-2-indenylpyrimidine The title compound 14B (4.7 g, yield: 88°) was obtained as a pale yellow oil (yield: EtOAc). /〇). ^-NMR (CDCh, 5 ppm): 5. 91-5. 77 (1H, m), 5. 16-5. 05 (2H, m), 3.61-3.58 (2H, m), 2.65 (3H, s (c) 2-(4, 6-one gas ~2-methyl" sedentate-5-yl) Ethylene is used in the above-obtained compound (丨.〇〇g, 6. 〇2mm〇1) The title compound 14C (535 mg, yield 43%) was obtained as white crystals. ^-NMR (CDCh, (5 ppm): 9. 77 (1H, s), 4. 08 (2H, s), 2. 69 (3H, s). (Ref. 45) (b) 4-Chloro- 7-(2-(«Byrrolidinyl)ethyl)-6,7-dihydro-5H-npyrho[2,3-d]pyrimidine

To a solution of the compound 12C (100 mg, 0.524 mmol) in decyl alcohol (4.0 ml) obtained in the compound of Example 43 (c), acetic acid (57. 0 #1, 1.15 mmol), 2-( 0 to 11 each of 0 -1-yl) ethionamide (73·0 #1, 0. 576 mmol), cyano side hydrogenation (46. Omg, 0.734 mmol), and was stirred at room temperature. After 17 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated evaporated. The obtained residue was purified by ethylamine chromatography chromatography chromatography chromatography chromatography !H-NMR (CDCh, (5 ppm): 8.5 (1H, s), 3.71 (2H, t, J=8. 7 Hz), 3.53 (2H, t, J=6.7 Hz), 3.03 (2H, t , J=8. 7 Hz), 2.66 (2H, t, J=6.7Hz), 2.54-2.51 (4H, in), 1.77-1.73 (4H, m). 130 323165 201202247 Reference Examples 46 to 51 : Correspondence The raw material compound and the reagent were reacted and treated in the same manner as in the method described in Reference Example 45 to obtain the compound shown in Table 4. [Table 4]

Reference Example T1 22 Ή-NMR (CDCla, 6 ppm) 46 \_t Η 'H-NMR: 8.13 (1H, s), 3.74-3.64 (6H, m), 3.52 (2H, t, J = 6. 2 Hz), 3.04 (2H, t, J = 8.8 Hz), 2. 54 (2H, t, J = 6.2 Hz), 2.47 (4H, m). 47 \_/ Η 'H-NMR: 8.14 (1H, s), 3.70-3.62 (6H, m), 3.44 (2H, t, J = 7. 2 Hz), 3. 04 (2H, t, J = 8. 6 Hz), 2. 41-2. 33 ( 6H, in), 1.82-1.74 (2H, m). 48 Me 'H-NMR: 3.68 (2H, t, J = 8.6 Hz), 3.52 (2H, t, J = 6.8 Hz), 2.98 (2H, t , J = 8.6 Hz), 2. 65 (2H, t, J = 6. 8 Hz), 2. 56-2. 51 (4H, m), 2. 42 (3H, s), 1. 77-1 73 (4H, in). 49 \( Me 'H-NMR: 3.71-3.64 (6H, m), 3.52 (2H, t, J = 6.4 Hz), 2. 99 (2H, t, J = 8. 7 Hz), 2. 56-2. 48 (6H, m), 2. 41 (3H, s). 50 CN^ Me 'H-NMR: 3.61 (2H, t, J = 8.6 Hz), 3.43 (2H , t, J = 7. 2 Hz), 2. 98 (2H, t, J = 8. 6 Hz), 2. 48-2. 46 (6H, m), 2.42 (3H, s), 1.79 (6H , t, J = 8.3 Hz). 51 \_1 Me 'H-NMR: 3.71-3.68 (4H, m), 3.61 (2H, t, J = 8.6 Hz), 3. 43 (2H, t, J = 7 2 Hz), 2. 98 (2H, t, J = 8. 6 Hz), 2.48-2.34 (9H, m), 1.82-1.72 (2H, m). 131 323165 201202247 (Reference Example 52) -1- base )phenyl)-5H-bito

OHC

15Β

(a) 4-Chloro-7-(3,3-diethoxypropyl)_2-(4-mono(4-indolylhexahydroindole)-phenyl-1-yl)-6,7-di Hydrogen-5H-pyrrolo[2,3-d]pyrimidine in the solution of the compound 2A (59 mg, 184 mm〇1) obtained in Reference Example 11 (a) in 1,4-dioxane (7.36 ml) Methyl-4_[4-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexahydro was added.哄 (584mg, 1.93nmol), bismuth (triphenylphosphine) palladium (212呃, 〇· 184_〇1),

3-(4-chloro-2-(4-(4-mercaptohexahydro)[2,3-(1]pyrimidin-7(61〇-yl)propanal)

A 3 mol 1 /L aqueous acid solution (1. 84 #1, 5 · 52 mmo 1) was stirred at 110 ° C under microwave irradiation. After 3 hours, water was added to the reaction solution, the reaction was stopped, and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated aqueous solution of sodium chloride, the solvent was evaporated under reduced pressure, and the residue obtained was purified by column chromatography (yield solvent: hexane: ethyl acetate). 14A (401 mg, yield 67%). ^-NMR (CDC13,(5 卯m): 8. 25 (2H,d,J=8. 8 Hz), 6.90 (2H, d, J=8. 8 Hz), 4.57 (1H, t, J=5. 5 Hz), 3.68-3.45 (8H, m), 3.31-3.28 C4H, m), 3.02 (2H, t, J=8.4 Hz), 2.57-2.54 (4H, m), 2.34 (3H, s), 1.98-1.91 (2H, m), 1.19 132 323165 201202247 (10), t, J=7. 1 Hz). text! f "〇 (4 gas 2 (4-(4-methylhexahydro-like well - Phenyl)phenyl)-5H "pyrolo[2,3-d]pyrimidin-7(6H)-yl)propanal is used in the above-mentioned compound 15a (Saki, (1) surgery (4) and hunting" reference example 1 (b) The title compound 15B (340 mg, m.

H NMR (CDCh, δ ppm): 9. 86 (1H, s), 8. 23 (2H, d, J=9. 0 6.90 (2H, d, 1 = 9.0 Hz), 3.79 (2H, t, J =6. 6 Hz), 3.66 (2H, t, J=8. 5 Hz), 3.31-3.28 (4H, m), 3.02 (2H, J=8.5 Hz), 2.86 (2H, t, J=6. 6 Hz), 2.57-2.54 (4H, ^), 2.34 (3H, s). (Ref. 53) 3-(2-(4-(4-Indolylpyridinium)phenyl)_5H_pyrrole And [2,3_d] pyrimidine-7(6H)-yl)propanal

ΜβΌ

OHC

16Β (a) 7-(3,3-Diethoxypropyl)-2-(4-(4-methylhexahydroindole-i-yl) benzyl)-6,7-dihydro-5H -° ratio p and [2, 3-(1] shouting using the compound 15A (965 mg, 2. lOimnol) obtained in Reference Example 53 (a) by the same method as Reference Example 13 (b) The title compound 16A (507 mg, yield 57%) was obtained as a pale yellow solid. 133 323165 201202247 H-NMR (CDCh, δ ppm): 8. 25 (2H, d, J = 9. 2 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.2 Hz), 4. 59 〇H, t, J = 5 6 Hz), 3.71-3.44 (8H, m), 3.30-3.27 (4H, m), 2.99 ( 2H, t, J=8. 1Hz), 2.58-2.54 (4H, m), 2. 34 (3H, s), 1.99-1.92 (2H, m), 1. 19 (6H, t, J=7. 1 Hz). (b) 3-(2-(4-(4-Methylhexahydropyridinium q_yl)phenyl)-5H_pyrrolo[2,3-d]pyrimidin-7(6H)-yl )Propionaldehyde

The title compound 16B (411 mg, yield: 100%) was obtained as a pale yellow amorphous material by the same procedure as the compound of the compound of Example 11 (b). H-NMR (CDCh, (5 ppm): 9.87 (1H, s), 9.23 (2H, d, J = 9. 0 Hz), 7.94 (1H, s), 6.93 (2H, d, J=9. 0 Hz), 3.80 (2H, t, J=6.5 Hz), 3.61 (2H, t, J=8.4Hz), 3. 30-3. 27 (4H, 2.99 (2H, t, J=8.4 Hz), 2.86 (2H, t, J=6.5 Hz), 2. 58-2. 54 (4H, m), 2. 34 (3H, s). (Reference 54) (S)-3-(2, 4- 2 Chloro-5H-°piro[2,3-d]pyrazine-7(61〇-yl)-4-(°rrolidin-1-yl)butyric acid phenyl decyl ester/—/C〇 2Bn ^^NHBoc Ο C02Bn

^C〇2Bn ^ NHBoc

17A 17B (a) (S)-3-(Tertidinoxycarbonylamino)-4-(«pyrrolidine-fluorenyl)butyric acid phenyl phthalate 323165 134 201202247 (S)-3- a solution of (t-butoxycarbonylamino)- 4-keto-(pyrrolidinyl)-butyric acid benzyl ester (2. 〇〇g, 5.31 mmol) in tetrahydrofuran (i5 ml) It was poured into a solution of lm〇l/L borane-tetrahydrofuran (9.75 ml, 1 〇 63 mmol), and stirred at room temperature. After 3 hours, the reaction was stopped by adding a saturated aqueous solution of potassium hydrogensulfate under an ice bath. The solution was made up to a solution of 2N aqueous sodium hydroxide to pH = 9 and extracted with ethyl acetate. After the organic layer was dried over MgSO4, EtOAc was evaporated,jjjjjjj (883 mg, yield 46%). 'H-NMR (CDCh, δ ppm): 7. 34-7. 26 (5H, m), 5. 14-5. 05 (2H, m), 3.99-3.97 (1H, m), 2.77-2.70 ( 1H, m), 2.60-2.46 (8H, m), 1.72-1.68 (4H, in), 1.41 (9H, s). (b) (S)-3-(2, 4-Dichloro-5H-11 Benzene [2,3-d]pyrimidin-7(6H)-yl)-4-(pyrrolidin-1-yl)butyric acid phenyl decyl ester obtained in the above compound l7A (4〇0g, i A solution of 4M hydrochloric acid-dioxane (4.0 ml) was added to .10 mm 〇1) and stirred for 1 hour. After removing the solvent under reduced pressure, it was dissolved in methanol (1 ml). Acetic acid (3), 15 ml, 2.68 imol), the compound lc (3〇lmg, 1.34mmol) obtained in Reference Example i(c), and sodium cyanodecadate (H8mg, 1.) were added to the solution under ice bath. 88 mmol), stirred at room temperature. After 29 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. After the organic layer was dried over sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjjjjjjjj , yield 93%). 323165 135 201202247 W-NMR (CDC13, δ ppm) : 7· 36-7. 25 (5H,m),5 〇8_5 〇〇(10) m), 3.76-3.59 (1H, m), 3.62-3.59 (2H, m), 3.01-2.60 (4H, m), 2.53-2.03 (6H, m), 1.72-1.65 (4H, m) (Reference Example 55) 5 '

(R)-4-Benzyl-2-(4- gas-2-((4-(hexahydro)-pile-i-yl) stupid)-5H-pyrrolo[2,3-d]pyrimidine -7(6H)-yl)hydrazino)morpholine Ph-\

(a) (R)-4-Benzyl-2-((2,4-dichloro-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)methyl)morpholine The compound lc (619 mg, 27 47 mmol) obtained in Reference Example 1 (c) and the corresponding reagent were inverted in the same manner as in the method described in Referential Example i.

The title compound 18A (7. 67, yield 74%) was obtained as white solid. ^-NMR (CDCh, 5 ppm): 7. 31-7. 27 (5H, m), 3. 90-3. 72 (4H, m), 3.63-3.56 (1H, in), 3.47-3.32 (4H , m), 2.99 (2H, t, J=8. 7 Hz), 2.76-2.72 (1H, m), 2.65-2.62 (1H, in), 2.18-2.09 (1H, m), 1.90-1.83 (1H , m). (b) (R)-4-Benzyl-2-((4-chloro-2-(4-(hexahydron) than well _i-yl)phenyl) -5H-« ratio Slightly [2,3-d]pyrimidin-7(6H)-yl)indenyl)morpholine 1,4- 136 323165 201202247 dioxane of 18 compounds (97711^, 2.58111111〇1) obtained above (10.3〇11) Add 4-[4-(4,4,5,5-tetradecyl-1,3,2-dioxaborolan-2-yl)phenyl]hexanindole Pyridinium-indole-carboxylic acid tert-butyl ester (1. 00g, 2.58mmol), hydrazine (triphenylphosphine) palladium (298mg, 0.258mmol), 3mol/L· sodium hydroxide aqueous solution (2. 58/ z 1 , 7. 74 mmol), with 12 (TC stirring. After 30 minutes, water was added to the reaction solution, the reaction was stopped, and the mixture was extracted with ethyl acetate. The transition organic layer was dried with sulfuric acid and then evaporated under reduced pressure. The obtained residue is purified by an amine-based rubber column chromatography layer (solution solvent; hexane: ethyl acetate) to obtain the obtained residue. The oil was dissolved in methanol (3.0 ml), and 2 mol/L hydrochloric acid/methanol (12 ml) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, and the aqueous layer was washed with ethyl acetate. The organic layer was dried over magnesium sulfate, and the residue was evaporated to dryness. Amorphous title compound (663 mg, yield 51%).]H-NMR (CDCh, 5 ppm): 8. 21 (2H, d, J = 9. 2 Hz), 7. 26 (5H, #6· 89 (2H, d, J=9.2Hz), 3. 87-3. 42 (10H, m), 3.26- 2-23 (4H, m), 3.05-2.99 (6H, m), 2.84-2.80 (1H , m), 2.65-2.61 (1H, m), 2.19-2.11 (1H, m), 2.02-1.95 (1H, m). (Ref. 56) (8)-4-Benzenyl-2-(( 2,4-digas-511-吼口[2,3-(1] 咬 -7 (6I〇-yl) fluorenyl) morpholine 323165 137 201202247

Ph^

The title compound (2. 36 g, yield: 69%) was obtained as a white solid.

H-NMR (CDCh, 5: 7. 33_7. 22 (5H, ra), 3. 9G_3 72 (4H m), 3.64 3.56 (1H, m), 3.49-3.32 (4H, m), 2.99 (2H, t, J-8.7Hz), 2. 74(1H, d, J=11.4Hz), 2.64(1H, dd, J-1.8, 11.4Hz), 2. 18-2. 09 (1H, m), 1 91-1. 84(1H, m). (Reference Example 57) 4-(2-(4-Ga-2-((4-(6)))))) , 3-d> dense bite-7(6H)-yl)ethyl)morpholine

Q ν-Λ

The title compound (4〇38, yield 41%) was obtained as a pale-yellow solid. </ br> </ br> </ br> ) : 8. 23 (2H, d, J=9. 0 Hz), 6. 90 (2H, d, J=9.0 Hz), 3.72-3.60 (8H, m), 3.25-3.22 (4H, m), 3.06-3.00 (6H, m), 2.61-2.52 (6H, m). 323165 138 201202247 (Reference 58) 4-[3-(2-(Benzyloxy)-4-chloro-5H-pyrrole [2, 3-d]pyrimidin-7(6H)-yl)propyl]morpholine

To a solution of phenylhydrazinohydrin (180#Bu 1.74 mmol) in THF (10 mL), EtOAc (EtOAc) The reaction solution was cooled to -5 ° C, and a solution of the compound (500 mg, 1.58 mmol) obtained in EtOAc (5 ml) was evaporated. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjj (193 mg, yield 31%). • !H-NMR (CDCh, δ ppm): 7. 45-7. 42 (2H, m), 7. 35-7. 24 (3H, m), 5. 31 (2H, s), 3. 71 -3. 61 (6H, m), 3. 42 (2H, t, J=7. 2 Hz), 2.95 (2H, t, J=8.1 Hz), 2.42-2.33 (6H, m), 1.79 -1.74 (2H, m). Reference Examples 59 to 60: The compounds shown in Table 5 were obtained in the same manner as in the method described in Referential Example 58 using the corresponding starting compound and reagent. 139 323165 201202247 [Table 5]

lH-NMR (CDCI3, δ ppm) 3.84 (3Η, s), 3. 65-3.56 (6Η, m), 3·37 (2. 〇H, t) J = 7. 2 Hz), 2.94- 2.88 ( 2H&gt; ®). 2.40-2.28 (6H, m), 1.76- 1.66 (2H, m), H-NMR: 3.70-3.67 (4H, m), 3.52 (2H, J = 8-4Hz), 3.38C2H, t, J = 7.4 Hz), 3.08 (6H&gt; 2.87 (2H, t, J = 8.4 Hz), 2·43~2.40 (4H, m), 2.35 (2H, t, J = 7.4

Hz), 2.43-2.33 (6H, m), 1.79-1.70 (2H, m). (Example 1) 3-{4-Ga-2-[4-(4-Mercaptohexahydro-ton well + base )phenyl]_5H_d ratio slightly [2,3-(1]pyrimidine-7(61〇-kib 1 succinylpropane-1)

Me2N-^\

To a solution of the compound IDUOOmg, 1.56 mmol) of 1,4-dioxane (6.21111) obtained in Reference Example 1, 1_mercapto_4_[4_(4,4,5,5_tetramethyl_1' was added. 3,2-Dioxaborolan-2-yl)phenyl]hexahydropyridinium (470 mg, 1.56 mmol), hydrazine (triphenylphosphine) palladium (18 〇 mg, 〇·156 mmol), 3 mol /L aqueous sodium carbonate solution (1. 55 ml, 4·67 lflm 〇 1), and stirred at 120 ° C under microwave irradiation. After 2 hours, hydrochloric acid water was added to the reaction solution, and the reaction was stopped and washed with ethyl acetate. The aqueous layer was dissolved in sodium hydroxide with water, 140 323165 201202247, and the mixture was changed to pH = 10, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and evaporated to dryness, and the obtained residue was purified by column chromatography (eluent solvent: hexane: ethyl acetate-ethyl acetate: chloroform). The title compound (167 mg, yield 26%) was obtained as a white solid. W-NMR (CDC13, δ 卯m): 8. 25 (2H, d, J = 9. 0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.63 (2H, t, J = 8.6 Hz ), 3.51 (2H, t, φ J=7.2 Hz), 3.28-3.31 (4H, m), 3.02 (2H, t, J=8. 6 Hz), 2.54-2.57 (4H, m) , 2.29-2.34 (2H, m), 2.33 (3H, s), 2.22 (10), s), 1.74-1.84 (2H, m). Examples 2 to 20 The same raw material compounds and reagents were used, as in Example 1. The reaction and treatment were carried out to obtain the compound shown in Table 6.

141 323165 201202247 [Table 6] Example Structure j-NMR (solvent, 5) 2 0 /Ο Ή-NMR (CDCh, 5 ppm): 8. 25 (2H, d, J = 9. 0 Hz), 6 90 (2H, d, J = 9. 0 Hz), 3. 69 (2H, t, J = 8. 5 Hz), 3. 63 (2H, t, J = 7. 0 Hz), 3. 28 -3. 31 (4H, m), 3. 02 (2H, t, J = 8. 5 Hz), 2. 71 (2H, t, J = 7. 0 Hz), 2. 54-2. 58 ( 8H, m), 2.33 (3H, s), 1.76-1.77 (4H, m). 3 Ν^λ rNJ〇^NCI Ή-NMR (CDCla, &lt;5 ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 60-3. 72 (8H, m), 3. 28-3.31 (4H, m), 3.03 (2H , t, J = 9. 0 Hz), 2.54-2.61 (10H, m), 2.34 (3H, s). 4 CN~ Ν-Λ Ν^? Χ^, Ν Cl Me^ Ή-NMR (CDCL·, δ ppm): 8. 27 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 65 (2H, t, J = 8. 5 Hz ), 3. 55 (2H, t, J = 7. 2 Hz), 3. 30-3. 33 (4H, m), 3. 04 (2H, t, J = 8.5 Hz), 2.49-2.59 (10H , m), 2.35 (3H, s), 1.84-1.91 (2H, m), 1.77-1.81 (4H, m). 5 0,3⁄4. ^N'Me Ή-NMR (CDCh, δ ppm): 7. 76 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz), 3. 65 (2H, t, J = 8.3 Hz), 3. 44-3.48 ( 2H, m), 3. 26-3. 29 (4H, m), 3. 22 (2H, t, J = 8.3 Hz), 2.49-2.56 (10H, m), 2.33 (3H, s), 1.75-1.88 (6H, m). 6 CNv A Human Ή-NMR (CDCh, δ Ppm): 8. 28 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9.0 Hz), 4.14 (2H, t, J = 5.8 Hz), 3. 71-3 74 (4H, m), 3. 66 (2H, t, J = 8. 8 Hz), 3. 54 (2H, t, J = 7. 0 Hz), 3. 04 (2H, t, J = 8.8 Hz), 2. 80 (2H, t,, J = 5. 8 Hz ), 2.56-2.59 (1 OH, m), 1.80-1.91 (6H, m). 7 CN' (ΡγΚΛα Ή-NMR (CDCL ·, δ ppm): 8. 27 (2H, d, J = 8. 8 Hz), 6. 90 (2H, d, J = 8.8 Hz), 4.06 (2H, t, J = 6.2 Hz), 3. 66-3. 72 (6H, in), 3. 57 (2H, t, J = 6. 7 Hz), 3. 05 (2H, t, J = 8.6 Hz), 2.45-2.59 (12H, m), 1.82-2.01 (8H, m).

142 323165 201202247

8 CN' Ν-Λ #人Ή-NMR (CDCL·, δ ppm): 8. 24 (2Η, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz) , 3. 63 (2H, t, J = 8. 3 Hz), 3. 53 (2H, t, J = 7. 3 Hz), 3. 27-3. 31 (4H, m), 3. 02 ( 2H, t, J = 8. 3 Hz), 2. 66-2. 72 (4H, m), 2.48-2. 50 (5H, m), 1.77-1.87 (4H, m), 1.53-1.55 (4H , m), 1.07 (6H, d, J = 6.4 Hz). 9 jO^ Cl Ή-NMR (CDCb, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 69-3. 72 (4H, m), 3. 63 (2H, t, J = 8. 6 Hz), 3. 53 (2H, t, J = 7.1 Hz), 3. 28-3. 31 (4H, m), 3.03 (2H, t, J = 8.6 Hz), 2.54-2.57 (4H, m), 2.33-2.43 (6H, m), 2.33 (3H, s), 1.75-1.84 (2H, m). 10 XT1, Cl Me, NJ Ή-NMR (CDCh, 5 ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 89 (2H, d, J = 9. 0 Hz), 3. 66-3. 69 (4H, m), 3. 61 (2H, t, J = 8. 5 Hz), 3.49 (2H, t, J = 6. 9 Hz), 3. 27-3. 31 (4H, m), 3. 02 (2H, t, J = 8. 5 Hz), 2.53-2. 57 (4H, m), 2.35-2.40 (6H, m), 2.33 (3H, s), 1.50-1.67 (4H, m). 11 c β human (^'NA^ ύΌ Ή-NMR (CDCh, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 69 -3. 72 (4H, m), 3. 63 (2H, t, J = 8. 6 Hz), 3. 53 (2H, t, J = 7. 2 Hz), 3. 28-3. 31 ( 4H, m), 3.03 (2H, t, J = 8.6 Hz), 2.66-2.68 (5H, m), 2.37-2.42 (6H, m), 1.76-1.84 (2H, m), 1.08 (6H, d, J = 6.4 Hz). 12 〆人Μ/” Ή-NMR (CDCh, δ ppm): 8. 25 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz), 3. 63 (2H, t, J = 8.1 Hz), 3.49 (2H, t, J = 7. 2 Hz), 3. 28-3. 31 (4H, m), 3. 02 (2H , t, J = 8.1 Hz), 2.46-2.57 (10H, m), 2.33 (3H, s), 1.76-1.80 (2H, m), 1.00 (6H, t, J = 7.2 Hz). 13 Η〇^ λ /Ν^ Η〇Ν々ΧΤ^Ν Cl Me,N ^ Ή-NMR (CDCh, δ ppm): 8.20 (2H, d, J = 9. 0 Hz), 6.90 (2H, d, J = 9. 0 Hz), 3. 55-3. 63 (8H, m), 3. 28-3. 31 (4H, m), 3.03C2H, t, J = 8. 6 Hz), 2. 53-2. 64 (1 OH, m), 2.33 (3H, s), 1.76-1.85 (2H, m).

C 143 323165 201202247

14 °^〇-η Me'J 'H-NMR (CDCls, δ ppm): 8.21 (2H, d, J = 9. 0 Hz), 7. 24-7. 26 (5H, m), 6. 89 (2H, d, J = 9. 0 Hz), 3. 41-3. 87 (7H, m), 3.28-3.32 (4H, m), 2.99-3.05 (2H, m), 2.79-2.83 (1H, m), 2.55-2.65 (5H, m), 2.34 (3H, s), 1.90-2.15 (4H, m). 15 MeO, N&quot;·*·***\ Nv Wide furnace Cl 'H-NMR (CDCls , 5 ppm): 8. 25 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz), 3. 63 (2H, t, J = 8.4 Hz) , 3.43-3. 52 (4H, m), 3. 32 (3H, s), 3. 27-3. 31 (4H, m), 3. 02 (2H, t, J = 8. 4 Hz), 2. 53-2. 57 (6H, m), 2. 42-2. 47 (2H, m), 2.33 (3H, s), 2.26 (3H, s), 1.76-1.86 (2H, m). 16 H2n Κ^ΝΛ r furnace α 'H-NMR (CDCh, δ ppm): 8.17 (2H, d, J = 9. 0 Hz), 7. 38 (1H, m), 6.92 (2H, d, J = 9.0 Hz), 5.07 (1H, m), 3. 54-3. 62 (4H, m), 3. 28-3. 31 (4H, m), 3. 02 (2H, t, J = 7. 8 Hz ), 2. 95 (2H, s), 2. 55-2.58 (4H, m), 2.47-2.51 (2H, m), 2.34 (3H, s), 2.24 (3H, s), 1.76-1.84 (2H , m). 17 Me, 0? fj^V^N^CI 'H-NMR (CDCL·, δ ppm): 8. 21 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 4. 31 (2H, s), 3. 77 (2H, t , J = 8. 7 Hz), 3. 58-3. 62 (4H, m), 3. 28-3. 31 (4H, m), 3. 09 (2H, t, J = 8. 7 Hz) , 2. 54-2. 57 (4H, m), 2. 39 (4H, m), 2.34 (3H, s) , 2.29 (3H, s). 18 j^XC 广Me&quot;Ns-^ 'H- NMR (CDCL·, δ ppm): 8. 22 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 76 (2H, t, J = 7.1 Hz), 3. 38-3.44 (2H, m), 3. 27-3. 30 (4H, m), 2. 73 (2H, t, J = 6. 3 Hz), 2.71-2.75 (4H , m), 2.46-2. 57 (6H, m), 2.33 C3H, s), 1.84-1.94 (4H, m), 1.74-1.78 (4H, m). 19 Me人Me,NJ 'H-NMR ( CDCb, δ ppm): 9.07 (1H, d, J = 1.8 Hz), 8.30 (1H, d, J = 8.6, 1.8 Hz), 6.58 (1H, d, J = 8. 6 Hz), 3. 69 ( 2H, t, J = 7.1 Hz), 3. 58-3. 61 (4H, m), 3. 33-3. 37 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 2.40- 2.70 (10H, m), 2.28 (3H, s), 1.76-1.92 (4H, m), 1.68-1.72 (4H, m). 20 xy^a 'H-NMR (CDCh, δ ppm): 8.19 ( 2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 76-3. 72 (6H, m), 3.51-3. 54 (2H, m ), 3. 28-3. 31 (4H, m), 2. 86-2. 90 (2H, m), 2. 54-2. 57 (4H, m), 2.39-2.44 (6H, m), 2. 34 (3H, s), 1.84-1.93 (6H, m). 144 323165 20 1202247 (Example 21) 4-chloro-2-[4-(hexahydroindol-1-yl)phenyl]-7-[3-indolepyridin-1-yl)propyl]-6, 7 -Dihydro-5H-° ratio σ and [2, 3-d]°f 唆

4-[4-(4, 4, 5, 5-tetramethyl) was added to a solution of the compound (200 mg, 0.664 mmol) obtained in Reference Example 3 in 1,4-dioxalate (2.65 ml). -1,3,2-dioxaborolan-2-yl)phenyl]hexahydroindole 1-carboxylic acid tert-butyl ester (270 mg, 0.797 mmol), hydrazine (triphenylphosphine) 16 (77. Omg, 0. 0664 mmol), 3 mol/L sodium carbonate aqueous solution (0. 66 &quot; 1, 1.99 mmol), and stirred at 120 °C. After 5 hours, hydrochloric acid water was added to the reaction solution, the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was made to dissolve with sodium hydroxide aqueous solution to pH = ll, and extracted with ethyl acetate. The organic layer was dried and filtered with magnesium sulfate (yield) and evaporated. The residue thus obtained was purified by an amine-based ruthenium column chromatography (dissolving solvent; gas-like: decyl alcohol). The obtained oil was dissolved in decyl alcohol (1.0 ml), and 4M hydrochloric acid / 1,4-dioxane (3.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. Water was added, and the aqueous layer was washed with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue thus obtained was purified by chromatography on an amine oxime column (solvent solvent; methylene chloride: methanol). The title compound (154 mg, yield 56%) was obtained. !H-NMR (CDCh, (5 ppm): 8. 24 (2H, d, J=9. 0 Hz), 6. 90 (2H, 145 323165 201202247 d, J=9.0 Hz), 3. 65 (2H , J=6. 9 Hz), 3. 30-3. 34 (2H, 3. 06 (6H, m), 2.62 (5H, Examples 22 to 32: t, J=8.6 Hz), 3.55 (2H, t, 3.21-3.25 (4H, m), 3.00-brs), 1.84-1.94 (6H, m). Using the corresponding raw material compound and reagent, the reaction and treatment are carried out in the same manner as in the method described in Note 2丨 to obtain a table. Compounds shown in Table 7. [Table 7] _ Example Structure _ l-NMR (solvent, 5) 22 palpitations (CDCh, 5 ppm): 8. 31 (2H, d, J = 8. 6 Hz), 7. 54 (2H, d, J = 8. 6 Hz), 3. 67 (2H, t, J = 8. 6 Hz), 3. 55 (2H, t, J = 7.1 Hz), 3. 03- 3.21 (7H, m), 2.53-2. 58 (8H, m), 2.06-2.15 (2H, m), 1.74-1.94 (7H, m). 23 HO^Sc, 'H-NMR (CDCls, 6 ppm ): 7.93 (1H, s), 7.83 (1H, d, J = 7.5 Hz), 7.28-7.32 (1H, m), 6.99 (1H, dd, J = 7. 5 Hz, 1. 9 Hz), 3 . 68 (2H, t, J = 8. 6 Hz), 3. 56 (2H, t, J = 7. 0 Hz), 3.19-3. 28 (5H, m), 3. 02-3. 09 ( 6H, m), 2.64 (6H, m), 1.85- 1.95 (6H, m). 24 _J〇^N c, HZN \ J 'H-NMR (CDCh, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz), 6. 52 (2H, d, J = 9. 0 Hz), 3.34-3.72 (9H, m), 2. 98-3. 09 (3H, m), 2.48-2.53 (6H, m), 2.15-2.27 (1H, m), 1.74-1.84 (8H, m). 25 h人h2n-(J 'H-NMR (CDCh, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz ), 6. 52 (2H, d, J = 9. 0 Hz), 3.34-3. 72 (9H, m), 2. 98-3. 09 C3H, m), 2.48-2.53 (6H, m), 2.15-2.27 (1H, m), 1.74-1.84 (8H, m). 26 C~N fly h2Noj〇&quot;nci 'H-NMR (CDCb, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9.0 Hz), 3.51-3.69 (6H, m), 2.80-3.05 (4H, m), 2.56-2.67 (1H, m), 2.48-2.53 (6H, m), 1.78-1.98 (6H, m), 1.52 (6H, brs). 146 323165 201202247

27 CN' ν-λ Ν-γ iPT^NC 丨Ή-NMR (CDCls, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9 . 0 Hz), 3. 51-3. 69 (6H, m), 2. 80-3. 05 (4H, m), 2.56-2.67 (1H, m), 2.48-2.53 (6H, m), 1.78 -1.98 (6H, m), 1.52 (6H, brs). 28 CN&quot;^ Ν-λ broadna^ h2n-^^ Ή-NMR (CDCL·, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9.0 Hz), 3.75-3.80 (2H, m), 3.63 (2H, t, J = 8. 5 Hz), 3. 53 (2H, t , J = 7. 2 Hz), 3. 02 (2H, t, J = 8.5 Hz), 2.79-2.88 (3H, m), 2.47-2.52 (6H, m), 1.76-1.92 (8H, m), 1.38-1.51 (4H, in). 29 rr〇r^N c, Ή-NMR (CDCb, δ ppm): 8. 26 (2H, d, J = 8. 4 Hz), 7. 27 (2H, d , J = 8. 4 Hz), 3. 66 (2H, t, J = 8. 5 Hz), 3. 54 (2H, t, J = 7.2 Hz), 3.15-2.19 (2H, m), 3.05 ( 2H, t, J = 8. 5 Hz), 2. 69-2. 73 (2H, m), 2. 48-2. 53 (6H, m), 1.78-1.87 (7H, m), 1.55-1.65 (5H, m). 30 c human Cl ην-.Α〇Ή-NMR (CDCL·, &lt;5 ppm): 8. 38 (2H, dd, J = 6. 8 Hz, 1. 8 Hz), 7.35 (2H, dd, J = 6. 8 Hz, 1.8 Hz), 3.64-3.73 (6H, tn), 3.54 (2H, t, J = 7.1 Hz), 3.22 (2H, t, J = 5.4 Hz), 3 . 05 (2 H, t, J = 8. 5 Hz), 2.47-2. 52 (7H, m), 1.76-1.89 (6H, m) 31 〇GN&quot;^x V-^ Ν-λ (PY^N person Cl HN , /1 Ή-NMR (CDCls, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 69-3 72 (4H, m), 3. 63 (2H, t, J = 8. 6 Hz), 3. 54 (2H, t, J = 7. 0 Hz), 3. 21-3. 25 (4H, m), 3.00-3.06 (6H, m), 2.37-2.42 (6H, m), 1.78-1.85 (2H, m), 1.57 (1H, brs). 32 〇〇N^x N—\ rNX^N c , H Ή-NMR (CDCh, δ ppm): 8. 22 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J = 9. 0 Hz), 3. 69-3 80 (6H, m), 3. 63 (2H, t, J = 8. 6 Hz), 3. 53 (2H, t, J = 7. 2 Hz), 3. 03 (2H, t, J = 8.6 Hz), 2.81-2.88 (3H, m), 2.37-2.42 (6H, m), 1.89-1. 92 (2H, m), 1. 77-1. 82 (2H, m), 1.43-1.51 ( 4H, m). 147 323165 201202247 (Example 33) 4-(4-{4-Chloro-7-[3-(o ratio 17 each α-1-yl)propyl]-6,7-diaza - 5Η-β-pyrolo[2,3-d]pyrimidin-2-yl}phenyl)-1-indenyl hexahydropyridin-4-ol

To the solution (1.5 ml) of the compound (60. Omg, 0. 136 mmol) obtained in Example 22, acetic acid (14/zl, 0-248 mmol), 35% aqueous solution (45/z 1, 1) 22 mmol), sodium cyanophosphate (15 mg, 0.238 mmol), stirred at room temperature. After 1 hour, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc. 67%). φ ^-NMR (CDCh, 5 ppm): 8. 30 (2H, d, J=8. 6 Hz), 7. 55 (2H, d, J=8.6 Hz), 3.70 (2H, t, J=8 6 Hz), 3.57 (2H, t, J=7. 0 Hz), 3.06 (2H, t, J=8. 6 Hz), 2.72-2.86 (8H, m), 2.44 (3H, s), 2.33 (1H, brs), 1.67-1.89 (12H, m). Examples 34 to 37: The compounds shown in Table 8 were obtained in the same manner as in the method described in Example 33 using the corresponding starting compounds and reagents. . 148 323165 201202247 [Table 8] Examples Structural formula _j-NMR (solvent, &lt;5)_ Ή-NMR (CDCh, (5 ppm): 7.92 (1H, s), 34

7.80-7.83 (1H, m), 7.28 (1H, m), 6.99-7.01 (1H, m), 3.70 (2H, t, J = 8. 1 Hz), 3.57(2H, t, J=6.8Hz) , 3.26-3.29 (4H, m), 3. 07 (2H, t, J = 5. 0 Hz), 2. 73 (6H, m), 2.57-2.61 (4H, m), 2.35 (3H, s) , 2. 02 (2H, m), 1. 91 (4H, in). 35

Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6. 52 (2H, d, J = 9. 0 Hz), 3.34-3.73 (9H, m), 2.98-3.09 (3H, m), 2. 49 (6H, m), 2. 16-2. 27 (1H, m), 1.77-1.87 (8H, m). 36 Μβ2Ν(,·

Ή-NMR (CDCh, 6 ppm): 8.24 (2H, d, J -9. 0 Hz), 6. 52 (2H, d, J - 9. 0 Hz), 3.34-3.73 (9H, m), 2.98 -3.09 (3H, m), 2.49 (6H, m), 2.16-2.27 (1H, m), 1.77-1.87 (8H, m). 37

Me2N

Ή-NMR (CDCh, δ ppm): 8.22 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J - 9. 0 Hz), 3.83-3.87 (2H, m), 3.69-3.72 (4H , m), 3.63 (2H, t, J = 8. 4 Hz), 3. 53 (2H, t, J = 7. 1 Hz), 3.03 (2H, t, J=8. 4 Hz), 2.74- 2.83 (2H, in), 2.37- 2.44 (6H, m), 2.26-2.29 (7H, m), 1.89-1.93 (2H, m), 1.75-1.85 (2H, m), 1. 54-1. 67 (2H, m). (Example 38) 4-Gas- 2-[4-(4-ethylhexahydropyran-1-yl)phenyl]-7-[3-(0 than each bite -1-yl)propyl]-6,7-dihydro-5Η-σΛσ each [2, 3-d] mouth bite 149 323165 201202247

To the solution of the compound obtained in Example 21 (64. Omg, 0. 150 mmol) of dichloropurpurin/methanol (2. Oral/O. 50 ml) was added acetic acid _(17. 0 #1, 0. 300 mmol) With triethoxy borohydride (64. Omg, 〇. 300 mmol), it was dropped at room temperature for 2 hours. The reaction was stopped with a saturated aqueous solution of sodium hydride, and extracted with φ gas. The organic layer was washed with saturated brine. The title compound (40. Omg) was obtained as a yellow oil (yield: , yield 58%). H-NMR (CDCL·, &lt;5 ppm): 8. 23 (2H,d,J=8·8 Hz) 6 90 (2H, J=8·6 Hz), 3.56 (2H, t, 3·04 (2H, t, J=8. 6 Hz), q, J=7· 0 Hz), 1. 91-2. 02 d, J=8.8 Hz), 3. 67 (2H, t, J=6. 2 Hz), 3. 01-3. 33 (4H, m), 2. 58-2. 75 (4H, m), 2.47 (2H,

# (6H, m), 1.56 (6H, brs), (Example 39) N, N-dimercapto-N,N-didecyl-3-{2~[4-(4-mercaptohexahydro)呪D well ~ 丄pyrrolo[2,3-d]pyrimidine _7(6H)_*}propane~丨,amine-yl)phenyl]-5H -

323165 150 201202247 Add 10% palladium on carbon (50% aqueous) (30 mg), trifluoroacetic acid (3 drops) to a solution of the compound (10 mg, 0.241 mmol) in methanol (4.0 ml) 'Agitated at 40 ° C under a hydrogen atmosphere (〇. 40 MPa). After 6 hours, the reaction solution was filtered and concentrated under reduced pressure. The residue thus obtained was diluted with methanol, triethylamine was added, neutralized, and concentrated under reduced pressure. The residue obtained was purified by chromatography on an amine-purified column (solvent solvent; hexane: ethyl acetate - chloroform: ethyl acetate). The title compound (53.3 mg, yield 58%) was obtained. Ή-NMR (CDCh, d ppm): 8.24 (2H, d, J = 9. 0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.58 (2H, t, J =8.4 Hz), 3.50 (2H, t, J=7.2 Hz), 3.26-3.29 (4H, m), 2.99 (2H, t, J=8.4 Hz), 2.54-2.57 (4H, m), 2.30 -2.35 (2H, m), 2.33 (3H, s), 2.22 (6H, s), 175_184 (2H, m). Examples 40 to 68: Using the corresponding starting compounds and reagents, the same method as in Example 39 Lufa reacted and processed to obtain Table 9 323165 151 201202247 [Table 9]

EXAMPLES Structural formula j-NMR (solvent, δ) 40 0 .Ο Me〆'H-NMR (CDCh, δ ppm): 8.26 (2H, d, J = 9. 0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3.62-3.67 (4H, m), 3.27-3. 30 (4H, m), 2. 99 (2H, t, J = 8. 2 Hz), 2. 73 (2H, t, J = 7.1 Hz), 2. 54-2. 60 (8H, m), 2.34 (3H, s), 1.77-1.79 (4H, m). 41 Ν-Λ jO^ ' H-NMR (CDCh, δ ppm): 8.20 (2H, d, J = 8. 8 Hz), 7. 85 (1H, s), 6. 87 (2H, d, J = 8. 8 Hz), 3 45-3. 55 (4H, m), 3. 21-3. 24 (4H, m), 2. 93 (2H, t, J = 8. 4 Hz), 2.43-2.52 (1 OH, m) , 2. 28 (3H, s), 1.75-1.85 (2H, m), 1.70-1.75 (4H, m). 42 CN' Ν-Λ N^a ^N'Me 'H-NMR (CDCh, δ ppm ): 8.44 (1H, s), 7.79 (2H, d, J = 9. 0 Hz), 6. 95 (2H, d, J = 9. 0 Hz), 3. 61 (2H, t, J = 8.4 Hz), 3.47(2H, t, J = 7. 2 Hz), 3.23-3.30 (6H, m), 2.47-2.58 (10H, m), 2.34 (3H, s), 1.78-1.89 (2H, m) , 1.74-1.78 (4H, m). 43 ^ N—\ 'H-NMR (CDCh, &lt; 5 ppm): 8.28 (2H, d, J = 8. 8 Hz), 7. 92 (1H, s) , 6. 92 (2H, d, J = 8. 8 Hz), 4.15 (2H, t, J = 5. 8 Hz), 3. 71-3. 74 (4H, m), 3. 61 (2H, t, J = 8. 0 Hz), 3. 54 (2H, t, J = 7. 0 Hz), 3. 00 (2H, t, J = 8.0Hz), 2.80 (2H, t, J = 5. 8 Hz ), 2.51-2.59 (10H, m), 1.78-1.92 (6H, m). 44 x / Ή Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 8. 8 Hz), 7.87 (1H, s), 6.87 (2H, d, J = 8 8 Hz), 4.01 (2H, t, J = 6. 4 Hz), 3. 65-3. 68 (4H, m), 3. 56 C2H, t, J = 8. 3 Hz), 3. 49 C2H, t, J = 7.1 Hz), 2.96 (2H, t, J = 8.3Hz), 2.41-2.49 (12H, m), 1.74-1.95 (8H, m). 152 323165 201202247

45 Ν-Λ Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 8. 8 Hz), 7. 93 (1H, s), 6. 93 (2H, d, J = 8. 8 Hz), 3. 59 (2H, t, J = 8. 6 Hz), 3. 56 C2H, t, J = 6. 8 Hz), 3. 30 (4H, m), 3.01 (2H, t, J = 8.6 Hz), 2.74 (2H.brs), 2. 62-2. 59 (4H, m), 2. 46 (2H, q, J = 7. 2 Hz), 1. 91 (4H, brs), 1.58C6H, brs), 1.12C3H, t, J = 7. 2 Hz). 46 Ν-Λ Ύο^ Ή-NMR (CDCL·, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3.59 (2H, t, J = 8. 5 Hz), 3. 53 C2H, t, J = 7.1 Hz), 3. 26-3. 30 (4H, m), 2. 99 (2H, t, J = 8. 5 Hz), 2. 65-2. 72 (5H, m), 2.50-2.52 (6H, m), 1.83 -1.88 (2H, m), 1.76-1.78 (4H, m), 1.08 (6H, d, J = 6.4 Hz). 47 CN-^ ~ N-^\ Me&quot; Ή-NMR (CDCh, δ ppm): 8.25 (2H, d, J = 8.4 Hz), 7.91 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 3.61 (2H, t, J = 8. 4Hz), 3. 52 (2H, t, J = 6. 7 Hz), 2. 99 (2H, t, J = 8.4Hz), 2.77C4H, m), 2. 58 (2H, brs), 2.28 (1H, brs), 2.10 (3H, s), 1.63-1.97 (14H, m). 48 Ν-Λ Μθ'Ν^ N^Y ^n15AnJ Ή-NMR (CDCh, δ ppm): 7.95 (1H, s), 7.88-7.89 (1H, m) , 7.7 5-7.76 (1H, m), 7.23-7.29 (1H, m), 6. 93-6. 97 (1H, m) 3. 64 (2H, t, J = 8. 3 Hz), 3. 56 ( 2H, t, J = 6. 5 Hz), 3. 24-3. 28 (4H, m), 3. 01 (2H, t, J = 8. 3 Hz), 2. 58-2. 60 (4H , m), 2. 33 (3H, s), 2.21-2.27 (2H, m), 2.01 (4H, m), 1.51 (6H, m). 49 Cn' Ν-Λ jO^ Me2N^N^ Ή- NMR (CDCb, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 90(1H, s), 6.55 (2H, d, J = 9. 0 Hz), 3.47-3.61 (7H , m), 3.35-3.41 (1H, m), 3.15-3.21 (1H, m), 2.98 (2H, t, J = 8.3 Hz), 2.80-2.84 (1H, m), 2.49-2.51 (6H, m ), 2.31 (6H, s), 2.10-2.14 (1H, m), 1.77-1.94 (6H, m). 50 CN' Ν-Λ Me2N&gt;'&lt;(^y Ή-NMR (CDCL·, δ ppm ): 8.24 (2H, d, J = 9. 0 Hz), 7. 90 (1H, s), 6. 55 (2H, d, J = 9. 0 Hz), 3. 47-3. 61 (7H , m), 3.35-3.41 (1H, m), 3.15-3.21 C1H, m), 2. 98 (2H, t, J = 8. 3 Hz), 2. 98 (2H, t, J = 8. 3 Hz), 2. 80-2. 84 (1H, m), 2. 49-2. 51 (6H, m), 2. 31 (6H, s), 2.10-2.14 (1H, m), 1.77-1.94 (6H, m). 153 323165 s 201202247

51 ~ Ν-λ 'H-NMR (CDCh, δ ppm): 8.25 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 93 (2H, d, J = 9 . 0 Hz), 3. 50-3. 62 (4H, m), 3.20-3.23 (4H, m), 2.96-3.04 (6H, m), 2.49-2.54 (6H, m), 1.78-1.90 (2H , m), 1.74-1.76 (4H, m), 1.23 (1H, brs). 52 CN' Ν-Λ jY? H2N<^ Human^ Ή-NMR (CDCla, 5 ppm): 8.22 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 51-3. 69 (7H, m), 2.93-3.01 (3H , m), 2.79-2.88 (1H, m), 2.59-2.66 (1H, m), 2.50-2.55 (6H, m), 1.76-1.97 (8H, m), 1.53-1.72 (3H, m). 53 CN~ Ν-Λ jQ^ 'H-NMR (CDCh, δ ppm): 8.22 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 51-3. 69 (7H, m), 2.93-3.01 (3H, m), 2.79-2.88 (1H, m), 2.59-2.66 (1H, m), 2.50-2.55 (6H, m), 1.76-1.97 (8H, m), 1.53-1.72 (3H, m). 54 o*·^ Wide N" H2N^^ 'H-NMR CCDCh, &lt;5 ppm): 8.23 (2H , d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 74-3. 78 (2H, m), 3 51-3. 62 (4H, m), 2. 99 (2H, t, J = 7. 8 Hz), 2.79-2.87 (3H, m), 2.45-2.54 (6H, m), 1.77-1.92 ( 8H, m), 1.45-1.53 (4H, m). 55 CN~ α0^ 'H-NMR (CDCh, δ ppm): 8.26 C2H, d, J = 8.4 Hz), 7.94 (1H, s), 7.26 (2H, d, J = 8. 4 Hz), 3.61 (2H, t, J = 8. 3 Hz), 3. 54 (2H, t, J = 7. 2 Hz), 3.15-3.19 (2H, m), 3. 01 (2H, t , J = 8. 3 Hz), 2. 65-2. 77 (3H, m), 2.49-2.54 (6H, m), 1.77-1.86 (8H, m), 1.62-1.67 (3H, m). 56 ~ ν-λ 0 Μβ2Ν^ΛΝΛ^ Η 'H-NMR (CDCh, δ ppm): 9.20 (1H, s), 8.31 (2H, d, J = 8.8 Hz), 7.95 (1H, s), 7.64 (2H , d, J = 8. 8 Hz), 3.67 (2H, t, J = 8.4 Hz), 3. 57 (2H, t, J = 7. 0 Hz), 3. 00-3. 07 (4H, m ), 2. 76 (4H, m), 2. 37 (6H, s), 2.04(2H, m), 1.91 (2H, m), 1.59C4H, in). 57 CN' ^ N-\ H 'H -NMR (CDCh, δ ppm): 9.15 (1H, brs), 8.32 (2H, d, J = 8. 8 Hz), 7. 97 (1H, s), 7. 62 (2H, d, J = 8 8 Hz), 3.77-3.80 (4H, m), 3.67 (2H, t, J = 8.4 Hz), 3. 58 (2H, t, J = 6. 5 Hz), 3.15 C2H, s), 3. 05 (2H, t, J = 8.4 Hz), 2.61-2.64 (4H, in), 2.15 (2H, m), 1.98 (2H, m), 1.55 (8H, m). 154 323165 201202247

58 59 60 61 62 63

Ή-NMR CCDCh, &lt;5 ppm): 8.37 (2H, m), 7.94 (lH, s), 7. 35 (2H, m), 3. 69-3.73 (4H, m), 3. 62 (2H , t, J = 8.4 Hz), 3. 54 (2H, t, J = 7.1 Hz), 3. 22 (2H, t, J = 5.4 Hz), 3. 02 (2H, t, J = 8.4 Hz) , 2.48-2. 54 (6H, m), 1.68-1.90 (6H, m), 1.69 (1H, brs). Ή-NMR (CDCls, &lt;5 ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 92 (1H, s), 6. 92 (2H, d, J = 9. 0 Hz), 3. 70-3. 72 (4H, m), 3.59 (2H, t, J = 8.5 Hz), 3.54 (2H, t, J = 7. 6 Hz), 3. 20-3. 24 (4H, m), 2. 97-3. 04 (6H, m), 2.39-2.44 (6H, m), 1.77-1.86 (2H, m), 1.60 (1H, brs). Ή-NMR (CDCla, δ ppm): 8.37 (2H, d, J = 8. 6 Hz), 7.95 (1H, s), 7.35 (2H, d, J = 8. 6 Hz), 3.79-3.73 (8H, m), 3.62 (2H, t, J = 8.5 Hz), 3.54 (2H, t, J = 7.1 Hz), 3. 22 (2H, t, J = 5.4 Hz), 3.03 (2H, t, J = 8. 5 Hz), 2. 39-2.44 (6H, m), 1. 77-1.87 (2H, m), 1.58 (1H , brs). Ή-NMR (CDCb, δ ppm): 8.22 (2H, d, J = 9. 0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3.71 -3.73 (6H, m), 3. 51-3. 62 (4H, m), 2. 99 (2H, t, J = 8. 3 Hz), 2.79-2.88 (3H, m), 2.38-2.44 ( 6H, m), 1.76-1.92 (4H , m), 1.40-1.53 (4H, m). Ή-NMR (CDCla, δ ppm): 8.23 (2H, d, J = 9. 2 Hz), 7. 91 (1H, s), 6. 92 ( 2H, d, J = 9. 2 Hz), 3. 69-3. 72 (4H, m), 3.51-3.61 (4H, m), 3.26-3.30 (4H, m), 2. 96-3. 02 (2H, m), 2. 54-2. 57 (4H, m), 2. 38-2. 43 (6H, m), 2.33 (3H, s), 1.76-1.85 (2H, m). NMR (CDCb, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 92 (2H, d, J = 9. 0 Hz), 3. 66 -3. 69 (4H, m), 3.57 (2H, t, J = 8.4 Hz), 3.49 (2H, t, J = 7. 0 Hz), 3. 26-3. 30 (4H, m), 2 . 99 (2H, t, J = 8.4 Hz), 2. 54-2. 58 (4H, m), 2. 36-2. 41 (6H, m), 2.33 (3H, s), 1.52-1.66 C4H , m). 155 323165 201202247

64 NΝ—ν Ή-NMR (CDCh, 5 ppm): 8. 23 (2H, d, J = 9. 0), 7. 91 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 67-3. 73 (4H, m), 3. 51-3. 62 (4H, m), 3. 3. 27-3. 30 (4H, m), 3. 00 (2H , t, J = 8. 5 Hz), 2. 66-2. 73 (5H, m), 2. 39-2. 44 (6H, m), 1.79-1.86 (2H, m), 1.08 (6H, d, J = 6.4 Hz). 65 H〇'^, /N^ H〇々j〇V 广N人〆Me&quot;N^ Ή-NMR (CDCb, δ ppm): 8.19 (2H, d, J = 9 . 0 Hz), 7.94(1H, s), 6.93 (2H, d, J = 9.0Hz), 3.52-3.60 (8H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.5 Hz), 2.53-2.64 (1 OH, m), 2.33 (3H, s), 1.76-1.85 (2H, m). °^9 Ή-NMR (CDCL·, δ ppm): 8.18 (2H, d, J = 9. 0 Hz), 7.82 (1H, s), 6.88 (2H, d, J = 9. 0 Hz), 3.71 (2H, t, J = 7. 2 Hz), 3. 34-3. 38 (2H, m), 3. 22-3. 25 (4H, 66 fj N m), 2.59 (2H, t, J = 6.1 Hz), 2.44-2.53 (10H, m), 2.29 (3H, s), 1.81-1.88 (4H, m), 1.69-1.74 (4H, m). Ή-NMR (CDCL·, δ ppm): 9.10 (1H, d, J = 2.4 Hz), 8.32 (1H, dd, J = 9 0, 2. 4 Hz), 7.81 (1H, s), 6.61 (1H, d, J = 9. 0 Hz), 3.69 (2H, t, J = 7.1 Hz), 67 fjN Me, NJ 3.57-3.61(4H, m), 3.34-3.38 (2H, m), 2.59 C2H, t, J = 6.1 Hz), 2.42-2.48 (10H, m), 2.28 (3H, s), 1.77-1.89 (4H, m) , 1.71 (4H, m). Ή-NMR (CDCb, δ ppm): 8.21 (2H, d, J = 9. 0 Hz), 〇fV 7. 93 (1H, s), 6. 93 (2H, d , J = 9. 0 Hz), 3. 67-3. 72 68 xy^N 广N人〆Me,NJ (6H, m), 3.51-3.54 (2H, m), 3.27-3.30 (4H, m) , 2. 69-2. 73 (2H, m), 2. 55-2. 58 (4H, m), 2. 39-2. 46 (6H, m), 2.34 (3H, s), 1.86-1.92 (6H, m). (Example 69) 4-(2-{2-[4-(4-Methylhexahydron-rhen-1-yl)phenyl]-5H-indole[2, 3 -d]pyrimidine-7-(61〇-1-yl}ethyl)morpholine 156 323165 201202247

To a solution of the compound (131 mg, 0.2296 mmol) obtained in Example 3 (5. Trifluoroacetic acid (3 drops) was stirred at 50 °C. After 2 small φ, after cooling to room temperature, the reaction solution was filtered through celite and concentrated under reduced pressure. The residue thus obtained was diluted with ethyl acetate, and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue thus obtained was purified by chromatography on an amine-purified gel column (solvent solvent; hexane: ethyl acetate-chloroform: ethyl acetate). The title compound (64. 6 mg, yield 53%) was obtained. !H-NMR (CDCh, (5 ppm): 8. 24 (2H, d, J=8. 7 Hz), 7. 92 (1H, s), 6.93 (2H, d, J=8. 7 Hz) , 3.61-3.68 (8H, m), 3.27-# 3.30 (4H, m), 3. 00 (2H, t, J=8. 4 Hz), 2. 54-2. 63 (10H, m), 2.34 (3H, s). Examples 70 to 74: The compounds shown in Table 10 were obtained in the same manner as in Example 69 using the corresponding starting compounds and reagents. 157 323165 201202247

[Table 10 - Example Structure j-NMR (solvent, &lt;5) 70 MeO Ή-NMR (CDCh, 5 ppm): 8.21 (2H, d, J = 9. 0 Hz), 7.87 (1H, s), 6.89 (2H, d, J = 9. 0 Hz), 3.54 (2H, t, J = 8.4 Hz), 3.45 (2H, t, J = 7.2Hz), 3.22-3.26 (4H, m), 2.95 (2H , t, J = 8.4 Hz), 2. 44-2. 53 (10H, m), 2. 29 C3H, s), 1. 73-1.78 (2H, m), 0. 97 (6H, t, J = 7. 2Hz). 71 Η^π Me&quot;Ns^ Ή-NMR (CDCh, &lt;5 ppm) : 8. 24 (2H, d, J = 9. 0 Hz), 7. 93 (1H, s) , 6. 93 (2H, d, J = 9. 0Hz), 3.88 (1H, m), 3.55-3.75 (5H, m), 3.38-3.45 (1H, m), 3.27-3.33 (4H, m), 2.96-3.03 (2H, m), 2.77-2.91 (2H, m), 2.54-2.58 (5H, m), 2.35 (3H, s). 72 MeO, N^s 广N人^ Me'J Ή-NMR (CDCh, δ ppm): 8.25 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 58 ( 2H, t, J = 8. 4 Hz), 3. 44-3. 52 (4H, m), 3.27-3.32 (7H, m), 2.96-3.01 (2H, m), 2. 54-2. 57 (6H, m), 2. 44-2. 49 (2H, m), 2.34 (3H, s), 2.27 (3H, s), 1.77-1.87 (2H, m). 73 H2N Kr^H^ Ή- NMR (CDCh, δ ppm): 8. 17 (2H, d, J = 9. 0 Hz), 7.93C1H, s), 7.35(1H, brs), 6. 92 (2H, d, J = 9.0 Hz), 5.09 (1H, brs), 3.54-3.62 (4H, m), 3.28-3.31 (4H, m), 3.02 (2H, t, J = 7. 8 Hz), 2.95(2H, s) , 2. 55-2. 58 (4H, id), 2.47-2.51 (2H, m), 2.34 (3H, s), 2.24 (3H, s), 1.76-1.84 (2H, m). 74 Me, Qw ^Y) J〇^ 广 N人〆Me&quot;N^ Ή-NMR (CDCh, δ ppm): 8.21 (2H, d, J = 9. 0 Hz), 7.99(1H, s), 6.93(2H, d , J = 9. 0 Hz), 4. 32 (2H, s), 3. 73 C2H, t, J = 8. 4 Hz), 3.61-3.63 (4H, m), 3.27-3.31 (4H, m) , 3.06 (2H, t, J = 8.4 Hz), 2.55-2.58 (4H, m), 2.36-2.39 (4H, m), 2.34 (3H, s), 2.28 (3H, s). 158 323165 201202247 (implementation Example 75) 4-(3-{2-[2-(4-Mercaptohexahydroport)-indol-1-yl)phenyl]-5Η-»pyrolo[2,3-d]pyrimidin-7- (61〇-1-yl}propyl)morpholine

(a) 4-(2-(4-Chloro-7-(3-(N-morpholinyl)propyl)-6,7-di-argon-5H-pyrrolo[2,3-d]pyrimidine-2 - phenyl) hexafluoropyrazine-1-carboxylic acid tert-butyl hydrazine in a solution of the compound obtained in Reference Example 5 (10Omg, 0. 315mmo 1) in 1,4-dioxane (1.26 ml) 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl]hexahydro was added.哄··〗-Repulsive acid third • Butyl ester (128mg, 0.331mmol), bismuth (triphenylphosphine)! Bar (36 mg, 0.032 mmol), a 3 mol/L aqueous sodium carbonate solution (0.32 mg, 993 mmol) was stirred at 110 ° C under microwave irradiation. After 1 hour, hydrochloric acid water was added to the reaction solution, the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was made to have a sodium hydroxide aqueous solution of pH = 9 and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography eluting elut elut elut elut elut elut eluting 159 323165 201202247

H-NMR (CDCla, δ ppm): 7. 54-7. 59 (2H, m), 7. 35-7. 29 (1H m), 6. 96~7.04 (2H, m), 3.65-3 . 71 (6H, m) 3 48 (2H t, J=7· 5 Hz), 3.41-3.44 (4H, m), 3.08 (2H, t, J=8. 5

Hz), 2.89-2.92 (4H, m), 2.34-2.40 (6H, m), 1.76-1 81 C2H, m), 1.43 (9H, s). (b) 4-(2-( 7-(3) -(N-morpholinyl)propyldihydro-5H_opyrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridinium-i-carboxylic acid tert-butyl vinegar (a) Adding formic acid (87. 0mS, 1.38mmol) and 1% by weight of carbon (5〇% aqueous) (127mg) to the methanol solution of the obtained compound (i50rag, 〇. 276mm〇1) The mixture was stirred for 5 hours at 50 C. After the reaction solution was allowed to cool to room temperature, the mixture was filtered, and the residue was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (extracted with 1 mol/L aqueous hydrochloric acid solution) and washed with ethyl acetate. The water layer was separated, and the aqueous layer was extracted with ethyl acetate aqueous solution to pH = ll., and extracted with ethyl acetate. The mixture was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was analyzed by chromatography. The title compound (65. Omg, yield 46%) was obtained as a white crystals of the title compound (CDH, δ ppm): 7.97 (1H, s), 7. 47-7. 50 (1H, m), 7.30-7.25 (1H, m), 6.95-7.04 (2H, m), 3.61-3.69 (6H, m), 3.48 (2H , t, J = 7.2 Hz), 3.36-3.40 (4H, m), 3.04 (2H, t, &gt; 8.3 Hz), 2.87-2.90 (4H, m), 2.35-2.40 (6H, m), 1.77- 1.82 (2H, m), 1.43 (9H, s). (c) 4-(3-{2-[2-(4-Mercaptohexahydroindol-1-yl)phenyl]-5H-indole And [2,3-d]pyrimidin-7-(6H)-byl}propyl)morpholine The compound obtained in the above (b) (65. 〇mg, 〇. i28mmol) was dissolved in 160 323165 201202247 in THF ( 2.0小时), adding hydrogenated Zhong Ming (14. 〇mg, 0 383mm 〇 1), stirred at 80 ° C under reflux with heating for 2.5 hours. Allow the reaction solution to cool to room temperature, add water (14 / z 1 2, 2mol / L aqueous sodium hydroxide solution (14 with hydrazine, water (28 / 1). Celite (Celite) filtered, the solution was extracted with ethyl acetate. After drying with sulfuric acid, filtered and concentrated under reduced pressure The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) 'H-NMR (CDCh, δ ppm): 7. 98 (1H, s), 7. 47 (1H, dd, J=7 9 Hz, 1. 7 Hz), 7. 28 (1H, m), 6 98 (2H, m), 3. 60-3. 69 (6H, m), 3.49 (2H, t, J=7.2 Hz), 3.04 (2H, t, J=8.3 Hz) 2.95-2.98 (4H, m), 2.36-2.41 (10H, m), 2.26 (3H, s) 1.79-1.86 (2H, m). (Example 76) 4-(3-{2-[4-(4-ethylhexahydro)吼耕-卜基)phenyl]_5H_B than arden[2,3-d]pyrimidin-7-(61〇-1-yl}propyl)morpholine

(a) 1-(4-{4-[7-(3-(indolyl) phenyl)propyl)-6,7-dihydro-5-indole-[2,3-d]pyrimidine- 2-Based] hexyl} hexahydropyridinium iodo ketone was added to the compound (78 〇mg, 〇191 mm 〇1) of methylene chloride (2.0 ml) obtained in Example 59 under ice cooling. Acetyl chloride (15 from 1, 〇. 210 mmo 1) was disturbed for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added under ice-cooling, and 161 323 165. Dry over magnesium sulfate and concentrate under reduced pressure. The resulting residue was purified by chromatography on EtOAc (EtOAc: EtOAc). !H-NMR (CDCh, 6 ppm): 8. 25 (2H, d, J=9. 0 Hz), 7. 92 (1H, s), 6.92 (2H, d, J=9.0 Hz), 3.75- 3.78 (2H, m), 3.70-3.73 (4H, m), 3.52-3.63 (6H, m), 3.22-3.29 (4H, m), 3.01 (2H, t, J=8.1 Hz), 2.39- 2.44 (6H, m), 2.13 (3H, s), 1.77-1.86 (2H, in). (b) 4-(3-{2-[4-(4-ethylhexa-argon) The phenyl]-5H-n-pyrolo[2,3-d]pyrimidin-7-(6H)-buyl}propyl)morpholine compound obtained by the above (a) (49. Omg, 0 5小时。 After stirring in THF (2. 0ml), adding hydrogenated ming (12. Omg, 0. 326mmol), heated at 80 ° C under reflux for 2.5 hours. The reaction solution was allowed to cool to room temperature, and water (12 / / 1), 2N aqueous sodium hydroxide (12 v 1), water (24 #1) was added. After filtering through Celite, the solution was extracted with ethyl acetate. After drying over magnesium sulphate, the mixture was concentrated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) ). !H-NMR (CDCh, δ ppm) : 8. 23 (2H, d, J=9. 0 Hz), 7. 91 (1H, s), 6.93 (2H, d, J=9.0 Hz), 3.70- 3.72 (4H, in), 3.51-3.59 (4H, m), 3.28-3.31 (4H, in), 3.00 (2H, t, J=7.2 Hz), 2.58-2.61 (4H, m), 2.39-2.50 ( 8H, m), 1.79-1.83 (2H, m), 1. 12 (3H, t, J=7.2 Hz). (Example 77) 162 323165 201202247 2-{4-[4-(2-曱oxy Ethyl)hexahydro-fyphthyl+yl]phenyl}_7_[3-decapyridin-1-yl)propyl]-6,7-dihydro-5H~pyrrolo[2,3_d]pyrimidine

(a) 2-decyloxy-1-[4-(4-{7-[3-indolylpyridinyl]propyl]-6,7-dihydro-5H-pyrrolo[2,3- (1) pyrimidin-2-yl}phenyl)hexahydropyridin-1-yl] ethyl ketone The compound of Example 51 was used with 2-methoxyethyl hydrazine chloride (丨5.0//1, 163 mmol). The title compound (53. 〇mg, yield 77%) was obtained as a pale yellow oil. Ή-NMR (CDCla, δ ppm): 8. 27 (2H, d, J=9. 〇Hz), 7. 92 (1H, s), 6.93 (2H, d, J=9. 0 Hz), 4.14 (2H, s), 3.75-3.78 (2H, m), 3.51-3.66 (6H, m), 3.43 (3H, s), 3.26-3.28 (4H, m), 3.00 (2H, t, J=8.6 Hz ), 2.50-2.54 (6H, m), 1.78-1.91 (6H, m). (b) 2-{4-[4-(2-methoxyethyl) hexahydromorphinyl] stupid}_7_ [3-0-Byrrolidin-1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine using the above compound (a) (53. Omg, 0.115 mmol The title compound (21.Omg, yield 40%) was obtained as a pale yellow solid. !H-NMR (CDCh, δ ppm) : 8. 19 (2H, d, J=9. 〇Hz), 7. 86 (1H, 163 323165 201202247 s), 6. 87 (2H, d, J-9 . 0 Hz) , 3. 46-3. 54 (6H, m), 3. 31 (3H, s), 3.24-3.27 (4H, m), 2.94 (2H, t, J=8.0 Hz), 2.56- 2.62 (6H, m), 2.44-2.49 (4H, m), 1.70-1.85 (6H, m), 1.12-1.28 (2H, m). (Example 78)

4-(3-{2-[4-(4-ethylhexahydropyrimidin-1-yl)phenyl]_4_fluorenyl-neu-pyrrolo[2,3-d]pyrimidine_7(61〇- 1-yl}propyl)morpholine

(a) 1-(4-{4-[4-Ga-7-(3-(N-)yl)propyl)_6,7-dihydroφ_5H_pyrrolo[2,3-d] _2-yl]phenyl}hexahydropyridinium-diyl&gt; Ethyl ketone The compound of Example 31 (124#1, 〇.248mmol) was used, whereby the same method as in Example 76 (a) gave a pale yellow color. Amorphous title compound (123 mg, yield 90%). *H-NMR (CDCh, (5 ppm): 8.26 (2H, d, J = 9. 0 Hz), 6. 90 (2H, d, J=9.0 Hz), 3.60-3.78 (10H, m), 3.54 (2H, t, J=7. 0 Hz), 3.23-3.30 (4H, m), 3.04 (2H, t, J=8.5 Hz), 2.38-2.42 (6H, m), 2.13 (3H, s), 1.78-1.83 (2H, m)! (b) l-(4-{4-[4-methyl-7-(3一(N_) Morpholinyl)propyl)_6,7-dihydrogen 323165 164 201202247 -5H-pyrrolo[2,3-(1]pyrimidin-2-yl]phenyl}hexahydropyridin-1-yl)ethanone To a solution of the compound (6 mg, 〇141匪〇1) obtained in the above (a) in THF (1.2 ml), bis(tris-tert-butylphosphine) dipalladium (〇) (13 mg, 0. 0247mmol), 2M cerium chloride-THF solution (〇. 31m Bu 0. 620 mmo 1) 'After stirring to the temperature. After 3 hours, add hydrochloric acid water to the reaction solution' to stop the reaction, to acetic acid The ester was washed, and the aqueous layer was adjusted to pH = ll with aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The title compound (51. Omg 'yield: 89%) was obtained as a pale yellow oil. (H-NMR (CDCh, δ ppm): 8.26 ( 2H, d, J=8. 8 Hz), 6. 92 (2H, d, J=8.8 Hz), 3.75-3.78 (2H, m), 3.70-3.73 (4H, m), 3.49-3.63 (6H, Ra), 3.20-3.27 (4H, in), 2.95 (2H, t, J=8.2Hz), 2.38-2.43 (6H, m), 2.27 (3H, s), 2. 13 (3H, s), 1 76-1. 85 (2H, m). (c) 4-(3-{2-[4-(4-ethylhexahydroindole-l-yl)phenyl]-4-mercapto-5H -pyrrolo[2,3-(1]pyrimidin-7(61〇-1-ylmercaptopropyl)morpholine using the compound of the above (b) (46. Omg, 0. 0990 mmol) by using Example 76 (b) The title compound (12. Omg, yield: 28%) 'H-NMR (CDCls, δ ppm): 8. 24 (2H, d, J=8. 8 Hz), 6. 92 (2H, d, J=8.8 Hz), 3.70-3.72 (4H, m), 3.49-3.60 (4H, m), 3.27-3.30 (4H, m), 2.94 (2H, t, J=8.3 Hz), 2.60-2.61 (4H, m), 2.38-2.50 (8H, m), 2.26 (3H, s), 1.78-1.82 165 323165 201202247 (2H, m), 1.12 (3H, t, J = 7.2 Hz). (Example 79) 4-(3-{4-ethyl-2-[ 4-(4-ethylhexahydro-yl)phenyl]_5H_e is more than [2,34]pyrimidin-7(61〇-yl}propyl)

(a) 1-(4-丨4-[4-(N-morpholinyl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d Pyrimidine-2-yl]phenyl}hexahydropyridinyl-yl) ethyl ketone The THF of the compound obtained in Example 78 (a) (6〇·〇mg, 〇.丨24_〇i) In a solution of 1.5 ml), bis(tris-tert-butylphosphine) dipalladium (〇) (19. Omg, 0·0362 mmol), 1 mol/L diethyl-hexane solution (〇. 62 ml, 0.620) was added. Inmol) 'Agitate for 丨 hours under microwave irradiation. Hydrochloric acid water was added to the reaction solution to stop the reaction, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = ll with aqueous sodium sulfate and extracted with ethyl acetate. The organic layer was filtered and evaporated under reduced pressure. The residue obtained was purified by column chromatography (eluent solvent; ethyl acetate: hexane- chloroform) to give a pale yellow oil. The title compound (45. 〇mg, yield 75 / /). !H-NMR (CDCh, δ ppm) : 8. 24 (2H, d, J=8. 8 Hz), 6. 87 (2H, d, J=8.8 Hz), 3.71-3.74 (2H, m), 3.65-3.68 (4H, m), 3.45-3.59 (6H, m), 3.15-3.22 (4H, in), 2.92 (2H, t, J=8.3Hz), 2.50(2H, q, J=7. 6 Hz), 2.34-2.39 (6H, m), 2.08 (3H, s), 1.71-1.81 (2H, m), 1.21 (3H, t, J=7.6 166 323165 201202247 (b) 4-(3-{4 -ethyl-2-[4-(4-ethylhexahydro.bine-1-yl)phenyl]-5H-pyrrolo[2,3-(1]pyrimidin-7(61〇-ylpropionate The title compound of the title compound (16. Omg' yield 36 was obtained from the title compound (45 mg). %) NMR (CDCh, δ ppm): 8. 27 (2H, d, J=8. 8 Hz), 6. 93 (2H, d, J=8. 8 Hz), 3.70-3.73 (4H , m), 3.49-3.59 (4H, ra), φ 3.26-3.30 (4H, m), 2.96 (2H, t, J=8. 6 Hz), 2.39-2.62 (14H, m), 1.76-1.85 ( 2H, in), 1.25 (3H, t, J=7. 5 Hz), 1. 12 (3H, t, J=7.2 Hz). (Example 80) 4-(3-{2-[3 -(4-mercaptohexahydropyrrol-1-yl)phenyl]-5H-pyrrolo[2,3-d]pyrimidin-7(61〇-yl}propyl)morpholine

4-[3-(4, 4,5,5-tetradecyl-1) was added to a solution of the compound (127 mg, 0.400 mmol) obtained in Reference Example 5 in 1,4-dioxazole (1.6 ml). , 3,2-dioxaborolan-2-yl)phenyl]hexahydroindole tiller-1-carboxylic acid tert-butyl ester (12111^, 0.40〇111111〇1), hydrazine (triphenyl) Phosphine) (46.3111, 0. 0400 mmol), 3 mol/L sodium carbonate aqueous solution (400 μl, 1.20 mmol), and stirred at 110 °C. After 1 hour, water was added to the reaction solution to stop the reaction, and 167 323165 201202247 was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over EtOAc. The resulting residue was purified by chromatography on an amine sulfasole column (solution solvent, hexane: ethyl acetate). The B〇c protectant (1) 5 mg) was obtained as a mixture. To the obtained mixture (1) (4)), (2. 〇 1111) solution was added with lithium hydride (16.1, (.), 212 face 1), and heated under reflux. After 2 hours, additional hydrogenation (16. 峋, 〇. 2 ΐ 2 υ) was added and the mixture was heated to reflux. After 3 hours, aqueous sodium hydroxide solution was added to stop the reaction, and the mixture was filtered over Celite, and concentrated under reduced pressure. Dissolved in ethanol (3. 〇ml) 'Add 1 〇% to carbon (50% aqueous, 4 〇mg), formic acid (200 mg) 'heated under reflux. After 1 hour, the reaction solution was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by ethylamine chromatography chromatography chromatography eluting elut elut elut elut elut - NMR (DMS0, δ ppm) : γ. 90 (2Η, m), 7. 78 (1H, dd, J=8 0 Hz), 7. 25(1H, dd, J=8.0, 8.0 Hz), 6.93 (1H, dd, J=8 〇2. 2 Hz), 3. 63-3. 66 (4H, m), 3. 56 (2H, t, J=8· 5 Hz) 3.49 (2H, t, J =7. 1 Hz), 3.21-3.25 (4H, m), 2.96 (2H t, J=8.5 Hz), 2.51-2.55 (4H, m), 2.34-2.39 (6H, m) 2.29 (3H, s) , 1.72-1.82 (2H, m). ' (Example 81) N, N-dimercapto-3-{4-mercapto-2-[4-(4-methylhexahydro- 0-indenyl) stupid Base]-5Η-σ is more than [2, 3-d] shouting -7(611)-base} _ι一胺 323165 168 201202247

Me2N

Μβ^Ό

To a solution of the compound (10 mg, 〇. 241 mmol) obtained in Example 1 in THF (2.0 ml), bis(tri-tert-butylphosphine) dipalladium (〇)

(24.6 mg, 0.0482 mmol), 1 mol/L dimethyl zinc-THF solution (1. 20 ml, 1.20 mmol), and stirred at room temperature. After 8 hours. Add bis(tris-tert-butylphosphine) dipalladium (0) (24.6 mg, 0. 0482 mmol), 1 mol/L bis-indenyl zinc _THF solution (0. 602 ml, 0· 602 mmol) at room temperature Scrambled. After 2 Torr, hydrochloric acid water was added to the reaction solution, the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was made into a NaOH solution by aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and evaporated to dryness, and the obtained residue was purified by chromatography on an amine column (purification solvent; ethyl acetate:methanol). The hexanes were washed with EtOAc (EtOAc) (EtOAc) φ Ή-NMR (CDCh, (5 ppm): 8. 25 (2H, d, J=9. 〇Hz)&gt; 6. 92 (2H d, J=9.0 Hz), 3.57 (2H, t, J= 8.4 Hz), 3 49 (2H, t J-7. 2 Hz), 3.25-3.28 (4H, m), 2.94 (2H, t, J=8. 4 Hz) 2.54-2.57 (4H, ra), 2.30 -2.35 (2H, m), 2.33 (3H s) 2.22 (3H, s), 2.18 (6H, s), 1.74-1.84 (2H m) Examples 82 to 95: Using the corresponding starting compounds and reagents Example 81 was reacted and treated in the same manner to obtain the compound shown in Table 11. 323165 169 201202247 [Table 11]

EXAMPLES Structural NMR (solvent, 5) 82 0 Νγ μθ Ή-NMR (CDCls, 5 ppm): 8. 21 (2H, d, J = 9. 0 Hz), 6. 88 (2H, d, J = 9. 0 Hz), 3. 55-3. 60 (4H, m), 3.21-3. 24 (4H, m), 2. 90 (2H, t, J = 8. 3 Hz), 2. 67 ( 2H, t, J = 7. 2 Hz), 2. 50-2. 55 (8H, m), 2. 29 (3H, s), 2. 21 (3H, s), 1.73 (4H, m). 83 0 mV Ή-NMR (CDCh, 5 ppm): 8. 29 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 59-3 . 65 (4H, m), 3. 25-3. 29 (4H, m), 2.96 (2H, t, J = 8.1 Hz), 2.69-2.74 (2H, m), 2.51-2.61 (10H, m) , 2. 34 (3H, s), 1.78 (4H, m), 1.25 (3H, t, J = 7. 5 Hz). 84 rNJ〇^ Me Ή-NMR (CDCla, δ ppm): 8. 24 ( 2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 59-3. 68 (8H, m), 3. 26-3. 29 (4H , m), 2.95 C2H, t, J = 8. 6 Hz), 2.54-2.62 (10H, m), 2.33 (3H, s), 2.27 (3H, s). 85 Q ^Ν-Λ Me-H^ Ή-NMR (CDCh, δ ppm): 8. 26 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 66-3. 69 ( 4H, m), 3. 59-3. 63 (4H, m), 3.26-3.29 (4H, m), 2.96 (2H, t, J = 8.3 Hz), 2.54-2.63 (12H, m), 2.34 ( 3H, s), 1.25 (3H, t, J = 7. 5 Hz) 86 c~ Furnace Me Ή-NMR (CDCls, δ ppm): 8. 27 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz), 3. 51-3. 62 (4H, m), 3. 27-3. 31 (4H, m), 2.93-2.99 (2H, m), 2.51-2.60 (10H, m), 2.35 (3H, s), 2.28 (3H, s), 1.79-1.92 (6H, m). 170 323165 201202247

87 CN' N—\ Ή-NMR (CDCh, δ ppm): 8. 27 (2Η, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3.49- 3. 59 (4H, m), 3. 25-3. 28 (4H, m), 2.95 (2H, t, J = 8. 5 Hz), 2.51-2.58 (12H, m), 2.34C3H, s) , 1.77-1.87 (6H, m), 1.25 (3H, t, J = 7. 6 Hz). 88 Cr^ Me, NJ Ή-NMR (CDCls, δ ppm): 8. 26 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 48-3. 58 (4H, m), 3. 25-3. 28 (4H, m), 2.94 ( 2H, t, J = 8. 3 Hz), 2.47-2. 58 (12H, m), 2.33 (3H, s), 1.71-1.87 (8H, m), 0. 96 (3H, t, J = 7 . 3 Hz). 89 Cn*^n Ή-NMR (CDCh, δ ppm): 8. 26 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz ), 3. 51-3. 61 (6H, m), 3. 25-3. 29 (4H, m), 2.97 (2H, t, J = 8. 5 Hz), 2. 50-2. 57 ( 10H, m), 2.33 (3H, s), 1.77-1.87 (6H, m), 1.44 (9H, s). 90 rNJ〇^ Μθ Me,NJ Ή-NMR (CDCL·, δ ppm): 8. 24 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 69-3. 72 (4H, in), 3. 49-3. 60 ( 4H, m), 3.25-3.29 (4H, m), 2.94 (2H, t, J = 8.4 Hz), 2.54-2.58 (4H, m), 2.41-2.45 (6H, m), 2.33 (3H, s) , 2.26 (3H, s), 1.75-1.85 (2H, ra). 91 N&qu Ot;^\ 〇ν^^ΝΛ nV ΓΥ^νΛ^ Μθ&quot;Νν^ Ή-NMR (CDCL·, δ ppm): 8. 27 (2H, d, J = 9. 0 Hz), 6. 92 (2H , d, J = 9. 0 Hz), 3. 70-3. 73 (4H, m), 3. 49-3. 60 C4H, m), 3.26-3.30 (4H, m), 2.96 (2H, t , J = 8.3 Hz), 2. 51-2. 59 (6H, m), 2. 39-2. 44 (6H, m), 2. 35 (3H, s), 1.79-1.83 (2H, m) , 1.25 (3H, t, J = 7. 6 Hz). 92 Ν-\ Ή-NMR (CDCL·, &lt;5 ppm): 8. 23 C2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3. 70-3. 73 (4H, m), 3. 57 (2H, d, J = 8. 5 Hz), 3. 51 (2H, d, J = 7. 9 Hz), 3.25-3. 29 (4H, m), 2.94 (2H, t, J = 8.5 Hz), 2.66-2.72 (5H, m), 2.38-2.43 (6H, m), 2.26 (3H, s), 1.78-1.82 (2H, m), 1.08 (6H, d, J = 6.4 Hz). 171 323165 201202247

Ή-NMR (CDCh, δ ppm): 8. 26 (2H, d, J = 9 &gt; 〇Hz) g ^ (2H, d, J = 9. 0 Hz), 3. 70-3. 73 (4H, m), 3.49_3 59 (4H m), 3.26-3.28 (4H, m), 2.95 (2H, t, J = 8 5 Hz) 2.68-2. 70 (5H, m), 2.54 (2H, q, J = 7. 6 Hz), 2.39-2 41 (6H, m), 1. 78-1. 83 (2H, m), 1. 25 (3H, t, J = 7 6 Hz) 1. 08 (6H, d, J = 6. 4 Hz). 'H-NMR (CDCk δ ppm): 8. 24 (2H, d, J = 9· 〇j^) 6 92 (2H, d, J = 9. 0 Hz) , 3. 69-3. 66 (4H, m), 3 55 (2jj ^ J = 8.5 Hz), 3.48 (2H, t, J = 6. 9 Hz), 3.28_3 25 m), 2.93 (2H, t , J = 8.5 Hz), 2.57-2.54 (4H m) 2.40-2.35 (6H, m), 2.33 (3H, s), 2.26 (3H s) 1.66-1.51 (4H, m). H-NMR (CDCU ό Ppm): 8. 23 (2H, d, J = 9· 〇Hz) 6 93 (2H, d, J = 9.0 Hz), 3.81-3.85 (2H, m), 3· 7〇_3 73 (4H m ), 3.54 (4H, m), 2.94 (2H, t, J = 8. 5 Hz), 2 73-2 80 (2H, m), 2.38-2.43 (6H, m), 2.26-2.31 (12H ❸ 1.89 -1.93 (2H,ra), 1.78-1.83 (2H,m)· [Example 96] =hexa-nitrogen:called +base gas)phenyl]_7_[3_(feeding base)dioxo, kiss each [2, 3_d]Do

4 mol 1 / L hydrochloric acid / 1,4-dioxin solution (2. Oml) was added to the compound 4C (57. Omg, 〇. 112mm〇1:) obtained in Reference Example 13 5 hours. After adding water, the aqueous layer was washed with ethyl acetate, and then aq. After drying over MgSO.sub. 172 323165 201202247, filtered. The obtained residue was purified to give the title compound (23··················· ^-NMR (CDCh, (5 ppm): 8. 26 (2H, d, J = 9. 0 Hz), 7. 92 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 4.39-4.47 (1H, m), 3.61 (2H, t, J=8. 2 Hz), 3.54 (2H, t, J=7.2 Hz), 3.10-3.17 (2H, m), 3.00 (2H, t, J=8.2 Hz), 2.68-2.77 (2H, m), 2.52-2.57 (6H, m), 2.00-2.03 (2H, m), 1.65-1.93 (9H, reference m). Examples 97 to l 〇2 : The compound shown in Table 12 was obtained by the same reaction and the same procedure as in Example 96 using the corresponding raw material compound and reagent.

173 323165 201202247 [Table 12]

EXAMPLES Structural Formula j-NMl? (Solvent, &lt;5) 97 Ή-NMR (CDCh, δ ppm): 8.26 (2H, d, J = 8. 8 Hz), 7.93 (1H, s), 6. 88 (2H, d, J = 8. 8 Hz), 4. 86-4. 89 (1H, m), 3.62 (2H, t, J = 8.3 Hz), 3. 55 (2H, t, J = 7. 0 Hz), 3.13-3. 22 (2H, m), 2. 98-3. 04 (3H, m), 2. 85-2. 94 (1H, m), 2.55-2.60 (6H, m), 2.04-2.16 (1H, m), 1.92-2.00 (4H, m), 1.84 (4H, m). 98 hearts.,, furnace-NMR (CDCh, δ ppm): 8. 26 (2H, d, J = 8. 8 Hz), 7. 93 (1H, s), 6.88 (2H, d, J = 8.8 Hz), 4.86-4.89 (1H, m), 3. 62 (2H, t, J = 8.3 Hz) , 3. 55 (2H, t, J = 7. 0 Hz), 3.13-3. 22 (2H, m), 2. 98-3. 04 (3H, m), 2.85-2.94 (1H, m), 2.55-2.60 (6H, m), 2.04-2.16 (1H, m), 1.92-2.00 (4H, m), 1.84 (4H, m). 99 CN^ Ν-Λ H Ή-NMR (CDCla, δ ppm) : 8.27 (2H, dd, J = 6. 9 Hz, 2.1 Hz), 7. 93 (1H, s), 6. 93 (2H, dd, J = 6. 9 Hz, 2.1 Hz), 4.21 (1H, Brs), 4.10-4.13 (2H, m), 3.61 (2H, t, J = 8. 5 Hz), 3. 55 (2H, t, J = 7.1 Hz), 2. 98-3. 03 (4H, m), 2.72 (2H, q, J = 7. 2 Hz), 2.61 (6H, m), 1.91-1.95 (2H, m), 1.82 (4H, m), 1.14 (3H, t, J = 7.2 Hz ). 100 CN' ~, Ν-Λ NJy Ηα°Χ7^Ν Ή-NMR (CDCh, &lt;5 ppm): 7.91-7.95 (3H, m), 7.30 (1H, dd, J = 8.2, 8.2 Hz), 6.93- 6.97 (1H, m), 4.44-4.50 (1H, m), 3.62 (2H, t, J = 8.5 Hz), 3.54 (2H, t, J = 7. 2 Hz), 3.10-3.17 (2H, m) , 3. 02 (2H, t, J = 8. 5 Hz), 2. 68-2. 76 (2H, m), 2. 47-2. 54 (6H, m), 2. 01-2. 04 (2H, m), 1.81-1.91 (2H, m), 1.75-1.79 (4H, m), 1.64-1.72 (2H, m). 101 c~ Ha0i/N Me Ή-NMR (CDCb, δ ppm): 8.10-8.13 (2H, m), 7.92 (1H, s), 6.85 (1H, d, J = 9.5Hz), 4.43-4. 48 (1H, m), 3.60 (2H, t, J = 8.4 Hz) , 3.54 (2H, t, J = 7.2 Hz), 3. 08-3.16 (2H, m), 3. 00 (2H, t, J = 8. 4 Hz), 2. 70-2. 77 (2H, m), 2.50-2.55 (6H, m), 2.27 (3H, s), 1.95-2.15 (2H, m), 1.65-1.91 (9H, m). 102 CN, Ν-Λ NV hncx〇Cn Ή-NMR (CDCh, δ ppm): 7.97 (1H, s), 7.91 (1H, t, J = 8. 9 Hz), 6. 63-6. 74 (2H, m), 4. 35-4. 39 (1H , m), 3. 61 (2H, t, J = 8.4 Hz), 3.50 (2H, t, J = 7.2 Hz), 3. 08-3.16 (2H, m), 3. 02 (2H, t, J = 8.4 Hz), 2. 67-2. 75 (2H, m), 2.47-2.52 (5H, m), 1.99-2.02 (2H, m), 1.82-1.90 (6H, m), 1.60-1 .71 (4H, m). 174 323165 201202247 (Example 103) 2-[4-(l-methylhexahydropyran-4-yloxy)phenyl]-7-[3-indole ratio p唆-l-yl)propyl]-6,7-dihydro_5Η-° ratio slightly [2, 3-d] mouth bite

A solution of the compound obtained in Example 96 (23.0 mg, 0. 〇 570 mmol) in methanol / dioxane (2:5) (1. 〇ml) was added to a 35% aqueous solution (20. 0// 1), triethylphosphonium oxyborohydride (24·〇mg, 〇. !i4inm〇i), and stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous sodium hydrogencarbonate solution and extracted with methylene chloride. The organic layer was washed with saturated brine. It was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified to give crystals crystals eluted eluted eluted eluted eluted eluted eluted j-NMR (CDCh, d 卯m) : 8. 26 (2H,d,J=8. 8 Hz), 7. 93 (1H, φ s), 6.92 (2H, d, J=8. 8 Hz) , 4. 39(1H, brs), 3.62 (2H, t, J=8.4 Hz), 3.55 (2H, t, J=6.8 Hz), 3.01 (2H, t, J=8.4Hz), 2.67(8H, m), 2.30-2. 32 (5H, in), 1.85-1.99 (10H, m). Examples 104 to 10: The reaction and treatment were carried out in the same manner as in Example 103 using the corresponding starting compound and reagent. The compounds shown in Table 13 were obtained. 175 323165 201202247 EXAMPLES Structural W-NMR (solvent, 5) 104 Cn^n Ή-NMR (CDCh, 5 ppm): 8.24 (2H, d, J = 8. 8 Hz), 7.94 (1H, s), 6.87 C2H, d, J = 8. 8 Hz), 4.85-4.89 (1H, m), 3.64 (2H, t, J = 8.4 Hz), 3.56 (2H, t, J = 6. 4 Hz), 3. 02 (2H, t, J = 8. 4 Hz), 2. 83-2. 84 (4H, m), 2. 39-2.41 (5H, m), 1.95-2.02 (6H, m), 1.59 (6H , m). 105 CN, Ν-Λ Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 8.8 Hz), 7.94 (1H, s), 6.87 C2H, d, J = 8. 8 Hz ), 4.85-4.89 (1H, m), 3. 64 (2H, t, J = 8.4 Hz), 3. 56 (2H, t, J = 6. 4 Hz), 3. 02 (2H, t, J = 8. 4 Hz), 2.83-2.84 (4H, m), 2. 39-2.41 (5H, m), 1.95-2.02 (6H, m), 1.59 (6H, m).

[Table 13] (Example 106) 2-[3-(1-Methylhexahydrogen ratio 11 Well-4-yloxy)phenyl]-7-[3-(indolyl-1-yl) Propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

To a solution of the compound (38.6 mg, 947. 0947 mmol) obtained in Example 1 (MeOH (1.1111)), 35% aqueous solution of Formalin (15.()//1, 0. 189 mmol), acetic acid (16 Di.284_〇1), sodium cyanoborohydride

Cll·9 mg, 〇· i89 mmol), stirred at room temperature. After 5 hours, the reaction was quenched with a saturated aqueous sodium hydrogen carbonate mixture and extracted with ethyl acetate. The organic layer was washed with brine, and the mixture was filtered under reduced pressure, and the obtained product (4) was purified by column chromatography (eluent solvent; hexane: ethyl acetate chloroform: decyl alcohol). The title compound 〇〇. 4 mg, yield 26%) was obtained as a white solid. H-NMR (CDC13, (5 卯m): 7. 89-7. 93 (3H, m), 7.29 (1H, this 'J=8.2, 8_2Hz), 6. 92-6. 95 (1H, m), 4. 41 (1h, m), 3. 6〇 (2H, t, J=8. 4 Hz), 3.53 (2H, t, J=7.2 Hz), 3.00 (2H' t, &gt ;8.4 Hz), 2.67 (2H, m), 2.48-2.53 (6H, m), 2.27 (3H, s), 2.25 (2H, m), 1.99 (2H, in), 1.75-1-89 ^8H, m). Examples 107 to in: The compounds shown in Table 14 were obtained by the same reaction and treatment as in Example 106 using the corresponding starting materials and reagents.

177 323165 201202247 [Table 14]

EXAMPLES Structural Formulas] H-NMR (solvent, (5) 107 ^ Ν-λ Me, 〇L. Mine Me 'H-NMR (CDCh, δ ppm): 8.11-8.13 (2H, m), 7.92 (1H, s), 6.84 (1H, d, J = 9.4 Hz), 4.43 (1H, brs), 3. 52-3. 63 (4H, m), 3. 00 (2H, t, J = 8. 9 Hz) , 2.51-2.62 (8H, m), 2.27-2.29 (8H, m), 1.78-1.97 (10H, m). 108 ~ N-V Me, aQjcCN 'H-NMR (CDCL·, δ ppm): 7.88- 7.96 C2H, m), 6.62-6.73 (2H, m), 4.33 (1H, m), 3.61 (2H, t, J = 8. 5 Hz), 3.50 (2H, t, J = 7. 2Hz), 3.02 (2H, t, J = 8.4 Hz), 2.66 (2H, m), 2.48-2.53 (6H, m), 2.26-2.29 (5H, m), 1.96-2.01 (2H, m), 1.74-1.87 (8H , m). 109 CNv 'H-NMR (CDCL·, &lt; 5 ppm): 8. 25 (2H, d, J = 8. 3 Hz), 7. 94 (1H, s), 7.27 (2H, d , J = 8.3 Hz), 3.61 (2H, t, J = 8. 5 Hz), 3. 54 (2H, t, J = 7. 2 Hz), 2. 94-3. 04 (5H, m), 2. 50-2. 54 (6H, m), 2. 31 (3H, s), 1. 99-2. 04 (2H, m), 1.77-1.88 (10H, m). 110 CN' Ν-Λ Μ6ζΝ(^人^ 'H-NMR (CDCh, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6.92C2H, d, J = 9. 0 Hz), 3.89-3.93 (1H, m), 3. 69-3. 73 (1H, m), 3. 51-3. 62 (4H, m), 2. 99 (2H, t, J = 8.0 Hz), 2.64-2.75 (2H, m), 2.41-2.54 (7H, m), 2.35 (6H, s), 1.97-2.01 (1H, m), 1.77-1.89 (8H , m), 1.31-1.43 (1H, m). 111 Ν-λ Μβ2ΝΛ.^ΝΛ^ 'H-NMR (CDCh, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 7 91 (1H, s), 6.92C2H, d, J = 9. 0 Hz), 3.89-3. 93 (1H, m), 3.69-3.73 (1H, m), 3.51-3.62 (4H, m), 2.99 (2H, t, J = 8.0 Hz), 2.64-2.75 (2H, m), 2.41-2.54 (7H, m), 2.35 (6H, s), 1.97-2.01 (1H, m), 1.77-1.89 ( 8H, m), 1.31-1.43 (1H, m). 112 CN' Ν-Λ 'H-NMR (CDCh, δ ppm): 8. 23 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6.93C2H, d, J = 9. 0 Hz), 3. 82-3. 86 (2H, m), 3. 51-3. 62 (4H, m), 2. 99 (2H , t, J = 8.1 Hz), 2. 72-2. 80 (2H, m), 2.49-2.51 (6H, m), 2.28-2.30 (7H, m), 1.77-1.88 (8H, m), 1.58 -1.63 (2H, m). 178 323165 201202247 Ή-NMR (CDCL·, δ ppm): 8. 37 (2H, d, J = 8. 8 Hz), 7. 94 (1H, s), 7.34 (2H , d, J = 8.8 Hz), 3.73 (2H, t, J = 113 Μθ.ν^^〇5. 4 Hz), 3. 62 (2H, t, J = 8. 4 Hz), 3. 54 ( 2H, t, J = 7.1 Hz), 3. 28 (2H, s), 3. 02 (2H, t, J = 8.4 Hz), 2. 78 (2H, t, J = 5.4Hz) , 2.49-2.54 (6H, m), 2.39 (3H, s), 1.84-1.91 (2H, m), 1.76-1.78 (4H, m). Ή-NMR (CDCL·, δ ppm): 8. 23 ( 2H, d, J = 9. 0 Hz), 7. 91 ΝΝ—\ (1H, s), 6. 92 (2H, d, J = 9. 0 Hz), 3. 70-3. 73 (4H, m), 114 3. 51-3. 62 (4H, m), 3. 36 (3H, s), 3. 29-3. 32 (4H, m), Meo~o 3.00(2H, t, J = 8.7 Hz), 2. 61-2. 67 (6H, m), 2.39-2.44 C6H, m), 1.79-1.84 (2H, m), 1.52-1.55 (2H, m). Ή-NMR (CDCL·, δ ppm): 8. 36 (2H, d, J = 8. 4 Hz), 7. 95 Ν-\ ΝΧ&gt; (1H, s), 7.34(2H, d, J = 8.4Hz), 3. 69- 3. 75 (6H, m), 115 ifVv^ 3. 62 (2H, t, J = 8. 3 Hz), 3. 54 (2H, t, J = 7. 4 Hz), r/7 3. 28 (3H, s), 3. 03 (2H, t, J = 8. 3 Hz), 2. 78 (2H, t, J = 5.4 Hz), 2.39-2.44 (8H, m), 1.77-1.87 (2H , m). 〇Gn^n Ή-NMR (CDCls, &lt;5 ppm): 8. 36 (2H, d, J = 8. 8 Hz), 7. 94 Ν^J Ν—\ ΝΧ&gt; (1H, s), 7.34 (2H, d, J = 8.8 Hz), 3.51-3.77 (11H, 116 fyV m), 3. 37-3. 39 (6H, m), 3. 03 (2H, t, J = 8 3 Hz), 2. 89 Me〇~Νν^Λ〇(2H, t, J = 5.2 Hz), 2.70 (2H, t, J = 5.2 Hz), 2.39-2.44 (6H, m), 1.80-1.84 (2H, m). f\ Ή-NMR (CDCls, δ ppm): 8. 22 (2H, d, J = 9. 0 Hz), 7. 91 ~X) (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3. 82-3.87 (2H, m), 117 χ/ί 广Ν&quot; Me2N^^ 3. 70-3. 73 C4H, m), 3. 51- 3. 62 (4H, m), 3. 00 (2H, t, J = 8. 3 Hz), 2. 72-2. 81 (2H, m), 2. 39-2. 44 (6H, m) , 2.29-2.31 (7H, s), 1. 79-1. 93 (4H, m), 1. 55-1. 67 (2H, m).

(Example 118) 4-mercapto-2-({2-[4-(4-mercaptohexahydroindol-1-yl)phenyl]-5H-pyrolo[2,3-d]pyrimidine -7(61〇-yl}fluorenyl)morpholine 179 323165 201202247

The compound obtained in Example 71 (79. lmg, 〇. 2〇1_〇1) was dissolved in a solution of methanol (2. 1111). (: adding acetic acid (23. () private 1, (). 4 〇 2 mmol), formaldehyde (35% aqueous solution) (16. 6 &quot; 丨, 〇 2 〇 lmm 〇 1), sodium cyanoborohydride (25.3 mg The mixture was stirred at room temperature. After 5 hours, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc: EtOAc) , δ ppm) : 8. 24 (2H, d, J=8. 7 Hz), 7. 94 (1H, s), 6.93 (2H, d, J=8.7Hz), 3.88-3.92 (1H, m) , 3.62-3.74 (5H, m), 3.46-3.50 (1H, in), 3.30 (4H, m), 2.98-3.03 (2H, m), 2.79-2.82 (1H, m), 2.57-2.66 (5H, m), 2.34 (3H, s), 2.27 (3H, s). (Example 119) 2-(4-{4-[7-(3-(1^-morpholinyl)propyl)-6, 7_Dinitro-511_11 is more than [2, 3-d], e-di-2-yl]phenyl}hexahydron-p-i-yl)ethanol 180 323165 201202247

f 4 = (2-(4-{4~[2_(T-butyldimethyl oxaxo)ethyl]hexafluoride:yl}phenyl)~5H-D is 17 and [2,3 - (1) -7 (61 〇-bu) propyl) 淋 广 广;; 59 known compound (189 mg, 0.461 mmol) of the solution of the yeast (5.0 ml), flat. τ at 0 0 added acetic acid (105/U, 1.84mm〇l), Α Γ monomethyl oxa oxy) jun (2) 0&quot; 1, Lniol), sodium cyanide bismuth (6lGmg, 1 () lmmQl), in the room temperature_. Spoil down! After a small time, the reaction was stopped with fresh sodium bicarbonate water, and q was extracted by liquid separation. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by ethylamine EtOAc EtOAc (EtOAc:EtOAc:

^-NMR (CDCI3, 6 ppra): 8. 25 (2H,d, J=9. 〇 Hz) 7 93 (1H

s), 6.94 (2H, d, J=9.0 Hz), 3.80 (2H, t, J=6 2 Hz) 3.72-3.78 (4H, m), 3.51-3.64 (4H, m), 3.27-3.31 (4H m), 3.02 (2H, t, J=8.4 Hz), 2. 68-2.71 (4JJ,m) 2 59 (2H, t, J=6.4Hz), 2.41-2.46 (6H, m), 1. 78 -1.88 (2H, 323165 181 201202247 m), 0.90 (9H, s), 0.07 (6H, s). (b) 2-(4-{4-[7-(3-(N-)-based) Base,-6,7-dihydro-5H-0, each of the [2,3-d]D dimethyl-2-yl]phenyl}hexahydro η than 哄_ι_yl)ethanol in the above (a A solution of the obtained compound (184 mg, 0. 325 mmol) in THF (3.0 ml) was added to a lmol/L solution of tetrabutyl fluorene/THF (0. 70 ml, 0·700 mmol). After stirring at room temperature for 1 hour, water was added to stop the reaction. The mixture was extracted with chloroform (yield, dried over magnesium sulfate), and filtered. The obtained residue was purified by chromatography on an amine-based rubber column (dissolving solvent; gas-like: decyl alcohol). The title compound (82 mg, yield 56 〇 / 〇) was obtained as a pale yellow solid. • H-NMR (CDCh, δ ppm): 8. 24 (2H, d, J=9. 0 Hz), 7. 92 (1H, s), 6.93 (2H, d, J=9.0 Hz), 3.70- 3.73 (4H, m), 3.51-3. 67 (6H, m) 3. 27-3. 30 (4H, m), 3. 00 (2H, t, J=8. 0 Hz), 2.65-2.68 ( 4H, m), 2.60 (2H, t, J=5. 3 Hz), 2.39-2.44 (6H, ra), 1.76-1.86 (2H, ra), 1.57 (1H, m). (Example 120) 4 -(3-{2-[4-(l-fluorenylhexahydron-bipyridin-4-yloxy))phenyl]_5Η_σpyrolo[2,3-d]pyrimidin-7(61〇-yl }propyl)morpholine

To a solution of 182 323165 201202247 THF (5.0 ml) obtained from the title compound (229 mg, y. 437 mmol) was added to the title compound (49.8 mg, 1.31 mmol). After 2 hours, the aqueous sodium hydroxide solution was added to stop the reaction. After filtration through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to chromatography on an amine-based gel column chromatography (solvent solvent; hexane: The title compound (90. 1 mg, yield 47%) was obtained eluted elute • H-NMR (CDC13, (5 卯m): 8. 23-8. 28 (2H, m), 7. 92 (1H, s),

6.89-6.94 (2H, m), 4.38 (1H, m), 3.69-3.72 (4H, m), 3.60 (2H, t, J=8. 4 Hz), 3.54 (2H, m, J=7. 2 Hz), 3.01 (2H, t, J=8.4 Hz), 2.68 (1H, m), 2.41-2.44 (6H, m), 2.29 (3H, s), 2.25 (2H, m), 1.97-2.04 (2H m), 1.77-1.90 (4H, m). Examples 121 to 122: In the same manner as in Example 120, using the corresponding raw material compound and reagent

The reaction shown in Table 15 was obtained by the reaction and treatment. [Table 15]

121 'H-NMR (CDCb, &lt;5 ppm): 7.95 (1H, s), 7.67 (1H, d, J = 9.4 Hz), 6.74-6.77 (2H, m), 4.34 (1H, m), 3.61 (2H, t, J = 8.4 Hz), 3.47 (2H, t, J = 7.2 Hz), 3. 02 (2H, t, J = 8.4 Hz), 2.66 (2H, m), 2.46-2.51 (10H, m), 2.26-2.28 (6H, m), 1.99-2.01 (2H, m), 1.76-1.85 (6H, m).

Me,

CN' 122

Me,

'H-NMR (CDCh, δ ppm): 8.03-8.10 (2H, m), 7.91 (1H, s), 6.96-7.02 (1H, m), 4.37 (1H, m), 3.62 (2H, t, J = 8.5 Hz), 3.53 (2H, t, J = 7. 3 Hz), 3.01 (2H, t, J = 8.5 Hz), 2.69 (2H, m), 2.51-2.54 C6H, m), 2.27-2.30 ( 5H, m), 1.78-1.90 0〇H, m). 183 323165 201202247 (Example 123) 4-decyloxy-2-[4-(4-methylhexahydropyridinyl q-yl)phenyl] _7_[3_(〇比罗ridin-1-yl)propyl]-6, 7-dihydro-5H-pyrolo[2,3-d]

The compound obtained in Example 4 (50. 〇mg, 〇. 113 mmol) was dissolved in methanol (2.0 ml), and a solution of 28% sodium decoxide/decyl alcohol (i 〇 9 mg, 0. 565 mmol) was added. The mixture was stirred at 120 ° C for 5 hours under microwave irradiation. Ethyl acetate was added to the reaction solution, and then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, The residue obtained was purified by chromatography on EtOAc EtOAc (EtOAc:EtOAc) φ ^-NMR (CDCh, δ ppm) : 8. 21 (2H, d, J=8. 8 Hz), 6. 88 (2H, d, J=8. 8 Hz), 3.96 (3H, s), 3.46-3.55 (4H, m), 3.23- 3.26 (4H, m), 2.88 (2H, t, J=8. 2 Hz), 2.51-2.56 (4H, m), 2.30 (3H, s), 1.98 ( 2H, m), 1.51 (10H, m). (Example 124) N,N-dimercapto--2-[4-(4-decylhexahydropyridin-1-yl)phenyl]indole嘻-1-yl) propyl]-6, 7-dihydro-5H-° piroxi[2, 3-d] carcinoma 唆4 amine 184 323165 201202247

Me. The compound obtained in Example 4 (60. Omg, 0. 136 mmol) was dissolved in N-methylpyrrolidone (i. 5 ml), and 2 mol/L dimethylamine/THF solution (1.5 ml, 3) was added. OOminol), stirred at 180 ° C for 2 hours under microwave irradiation. Saturated brine was added to the reaction solution, and the mixture was separated with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by chromatography on an amine-tane tube column (solvent solvent; gas; oxime). The title compound was yellow amorphous (43. Omg, yield 70%). ^-NMR (CDCh, δ ppm): 8. 27 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9.0 Hz), 3.46 (2H, t, J = 7.2 Hz ), 3.42 (2H, t, J=8. 6 Hz), 3. 24-3. 28 (4H, m), 3. 15-3. 21 (8H, m), 2. 54- 2.58 (4H, m), 2.49-2.51 (6H, m), 2.33 (3H, s), 1.^5-1.87 (6H, m). (Example 125) 2-[4-(4M7-[3 ten bite bite _ 基 ) 丙基 丙基 ] ] ] ] ] ] 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323

(a) 2-(4-{4-[2-(Butyryloxy)ethyl]hexahydroindolyl 丨-yl}phenyl)-4- gas-7-[3-(pyrrolidine- Propyl] propyl]_6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine The compound obtained in Example 51 (9 〇.〇, 〇.2HmmC)i) and 2-( The title compound (65. Omg, yield 55%) was obtained as a pale yellow oil (yield: 5%). . !H-NMR (CDCh, δ ppm): 8. 23 (2H, d, J=8. 8 Hz), 7. 27-7. 36 (5H, m), 6.89 (2H, d, J=8. 8 Hz), 4.54 (2H, s), 3.54-3.69 (6H, m), 3.28-3.32 (4H, m), 3.04 (2H, t, J=8. 3

Hz), 2.63-2.68 (10H' m), 1.89-1.99 (6H, m), 156 (2H, in). (b) 2-(4-{4-[2-(benzoyloxy)B ]] hexahydrola D well-buki}phenyl)-7-[3-(pyrrolidinyl)propyl]-6,7-dihydro-5H-pyrrolo[2,3_d]pyrimidine (a) The obtained compound (65. Omg, 〇. u6mmc &gt; i), 323165 186 201202247 (23·mg, yield 37%) by the same method as Example 39. The title compound H-indole (CDC13, 5 ppm): 8.23 (2H, d, 1 = 9 _, 7 % (10) s), 7.27-7.34 (5H, m), 6.89 (2H, d, J = 9.0) Hz), 4.55 (10)' s), 3.54-3.65 (6H, ra), 3.28-3.31 (4H, m), 3.01 (2H, t, J 8.1Hz), 2. 63-2. 69 (l〇H, m), 1. 92-2. 06 (6H, m), 1. 57 (2H, m). '

(c) 2-[4-(4-{7-[3-(Pyrrolidinyl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl }phenyl)hexahydropyrazine_丨_yl]ethanol was added to the compound (23mg, 〇〇43mm〇1) obtained in the above (b), in Erqiyuan/Guoye (0.90ml), and added under ice cooling. Im 〇 / / / / / / / / / / / / / / / / / / / / / / / / / / / The reaction solution was poured into ice water to stop the reaction, and the mixture was extracted with ethyl acetate. The title compound (8 mg, yield 42%) was obtained as a white solid (yield: EtOAc) ). !H-NMR (CDCh, δ ppm): 8. 25 (2H, d, J=9. 0 Hz), 7. 92 (1H, s), 6.93 (2H, d, J=9.0 Hz), 3.30- 3.66 (8H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J=8.11 Hz), 2.51-2.68 (9H, m), 1.78-1.86 (6H, m), 1. 17-1. 23 (2H, ra). (Example 126) 2-{Ethyl[2-(4-{7-[3_(0-Butyl-1-yl)propyl]-6,7- Dihydro-511-pyrrolo[2,3-d]pyrimidin-2-yl}phenoxy)ethyl]amino}ethanol 187 323165 201202247

(a) 2-(Tertiary butyl dimethyl methoxy)-N-ethyl-N-(2-(4-(7-(3-(pyrrolidin-1-yl)propyl)-6) , 7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenoxy)ethyl)ethinamide The compound obtained in Example 99 was used (50. 〇mg, 〇. 127 mmol) and 2-(t-butyl bis-decyl fluorenyloxy) oxime (48//1, 0.254 mmol) were obtained in the same manner as in Example 119 (a). The title compound (70 mg, yield 100%). • H-NMR (CDCh, δ ppm): 8. 29 (2H, d, J=8. 8 Hz), 7. 94 (1H, s), 6.93 (2H, d, J=8.8 Hz), 4.08 ( 2H, t, J=6.3 Hz), φ 3.72 (2H, t, J=6.6 Hz), 3.62 (2H, t, J=8.4 Hz), 3.56 (2H, t, J=7. 1 Hz), 3.02 (2H, t, J=8.4 Hz), 2.96 (2H, t, J=6.3 Hz), 2.66-2.74 (4H, m), 2.52-2.54 (6H, m), 1.80-1.93 (6H, m), 1.07 (3H, t, J=1.2 Hz), 0.90 (9H, s), 0.06 (6H, s). 〇3)2-{ethyl[2-(4-{7-[3-(吼) 1-yl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl}phenoxy)ethyl]amino}ethanol in the above (a) The obtained compound (70 mg, 0. 126 mmol) in THF (1. 5 ml) was added with 1 mol/L of tetrabutylammonium fluoride/THF 188 323165 201202247 (0.30 ml, 0.30 mmol) under ice cooling to room temperature. After 2 hours of stirring, the reaction was stopped by adding water, and the mixture was extracted with chloroform. The title compound (31 mg, yield 55) was obtained as a pale yellow solid (yield: %). !H-NMR (CDCh, (5 ppm): 8. 28 (2H, d, J=9. 0 Hz), 7. 92 (1H, s), 6.92 (2H, d, J=9.0 Hz), 4.04 -4.08 (2H, m), 3.51-3.63 (7H, m), 3.00 (2H, t, J=8.3 Hz), 2.92 (2H, t, JJ=5.8 Hz), 2.66-2.72 (4H, m) , 2.48-2.52 (6H, m), 1.78-1.89 (6H, m), 1.60 (3H, t, J=7.1 Hz). (Example 127) 2-[4-(4-methylhexahydro)哄-1-yl)phenyl]-7-{2-[2-(«pyrrolidin-1-yl)ethoxy]ethyl b 6,7-dihydro-5H-pyrrolo[2 , 3-d]pyrimidine

To a solution of the compound (131 mg, 0.27 mmol), THF-diethyl ether (1.0 ml to 1.0 ml), . After 3 hours, it was extracted with aq. chloroform-sodium hydroxide aqueous solution, and the organic layer was washed with saturated brine and evaporated. The residue obtained was dissolved in decyl alcohol (2.0 ml), and ammonium formic acid (239 mg, 3.79 mmol) and 10% palladium carbon (58 mg) were added and stirred at 60 °C. After 7 hours, the palladium carbon was filtered, and the filtrate was extracted with a gas-water-liquid mixture, and the organic layer was washed with saturated salt 189 323165 201202247, and then evaporated under reduced pressure. The obtained residue was subjected to EtOAc EtOAc (EtOAc) elute Ή-NMR (CDCh, δ ppm): 8. 23 (2H, d, J=9. 0 Hz), 7. 92 (1H, m), 6.92 (2H, d, J=9.0 Hz), 3.66-3.73 (6H, m), 3.61 (2H, t, J=6.0 Hz), 3.25-3.31 (4H, m), 2.99 (2H, t, J=7. 8 Hz), 2.64 (2H, t, J=6 . 0 Hz), 2.53-2.58 (4H, ra), 2.46-2.52 (4H, m), 2.33 (3H, s), 1.68-1.77 (4H, m). • (Embodiment 128) (S)-l -(3-{2-[4-(4-mercaptohexahydro)&quot;tough-i-yl)phenyl]-5H_0-pyrolo[2,3-d]-bite-7(611)-yl }propyl)°Bilobital-2-sodium decyl decyl ester

(a) (S)-l-(3-{4-Ga-2-[4-(4-mercaptohexahydropyrani-l-yl)phenyl]-5Η-indole[2,3- (1) pyrimidine-7 (61〇-ylmercaptopropyl)pyrrolidine-2-carboxylic acid decyl ester Compound 2A (500 mg, 1.56 mmol) of 1,4-dioxane obtained in Reference Example 11 ( 8.21111) Add 'detyl-4-[4-(4,4,5,5-tetradecyl-1,3,2-dioxaborolan-2-yl)phenyl]hexahydro-β in solution Specific tillage (296mg, 0.98mmol), hydrazine (triphenylphosphine) palladium (i〇8mg, 〇. 〇93mmol), 3mol/L sodium carbonate aqueous solution (〇.93ml, 2.79mmol), water (0.5ml) The mixture was stirred at 120 ° C under microwave irradiation. After 2.5 hours, 190 323165 201202247 hydrochloric acid water was added to the reaction solution, and the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with acetic acid aqueous solution. Ethyl acetate was separated and extracted. The organic layer was washed with saturated brine and concentrated under reduced pressure. Toluene (14.sup.1. Hydrochloride (260 mg, 1.57 mmol), sodium cyanoborohydride (125 mg, 2.0 mmol), stirred at room temperature. The sodium hydrogen chloride aqueous solution was stopped and the mixture was extracted with a gas-like fraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was analyzed by chromatography on an amine-based gel column (solvent solvent; hexane: acetic acid The title compound (130 mg, yield 17%) was obtained as a pale yellow oil. NMR (CDCh, (5 ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H) , d, J=9.0 Hz), 3.68 (3H, s), 3.63 (2H, t, J=8.5 Hz), 3.45-3.57 (2H, m), 3.28-3.31 (4H, m), 3.13-3.22 ( 2H, m), 3.02 (2H, t, J=8.4 Hz), 2.69-2.78 (1H, m), 2.54-2.59 (4H, m), 2.42-2.51 (1H, m), 2.30-2.38 (4H, m), 2.07-2.15 (1H, m), 1.81-1.97 (5H, in). (b) (S)-l-(3-{2-[4-(4-Mercaptohexahydroindole) a compound obtained by the above (a) (67), a phenyl]-5H-pyrrolo[2,3-d]pyrimidin-7(61〇-yl}propyl)pyrrolidine-2-carboxylic acid decyl ester Omg, 0. 246 mmol) of methanol (4.5 ml) was added 10% palladium on carbon (50% aqueous) (150 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (0. 40 MPa). 5. After 5 hours, the reaction solution was filtered through Shixia, and concentrated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Yield 68%).

Ή-NMR (CDCh, (5ppm): 8. 24 (2H, d, J=9. 0 Hz) 7 91 (1H s), 6.93 (2H, d, J = 9.0 Hz), 3.68 (3H, s) , 3.58 (2H, t, J=8.4 Hz), 3.48-3.54 (2H, m), 3.27-3.30 (4H, m), 3. 13_3. 23 (2H,m), 2.99 (2H, t, j=8 i Hz) 2 70_2 80 (1H, m), 2.55-2.58 (4H, m), 2.44-2.50 (1H, m), 2.31-2.39 (4H, m), 2.06-2.15 (1H, m) , 1.79-1.98 (5H, in). (Example 129) Spring (3) 4-(3-(244-(4-mercaptohexahydropterin 11-yl)phenyl]-5Η-» ratio咯[2, 3-d] bite -7 (61〇-yl} propyl) "&gt; than η each bite_2_ slow acid

A solution of the compound (65.0 mg, 0.14 mmol) in MeOH (20 mL) After stirring overnight, a 1 M aqueous hydrochloric acid solution was added to pH = 8 and extracted with chloroform/ethanol (3/1). The organic layer was dried (MgSO4), evaporated !H-NMR (DMS〇3, (5 ppm): 8. 18 (2H, d, J=9. 0 Hz), 7. 91 (1H, s), 6.94 (2H, d, J=9.0 Hz) , 3.53-3.67 (4H, m), 3.36-3.46 (4H, m), 3.19-3.22 (4H, m), 2.88-3.00 (3H, m), 2.72-2.82 (1H, m), 2.42-2.45 ( 4H, m), 2.18-2.25 (3H, s), 2.08-2.18 (1H, in), 1.79-1.93 (4H, m), 1.56-1.69 323165 192 201202247 (1H, m). (Example 130) 4 -(3-{2-[4-(4-methylhexahydropyrone-i-yl)phenyl]_6,7-dihydro 0-pyrido[2,3-d]pyrimidine-8(5H) -propyl propyl)morpholine

A mixture of the couplings (77. 1 mg) was obtained in the same manner as in Example 1 using the compound 10A (100 mg, 0.302 mmol). This mixture was reacted in the same manner as Example 69 to give the title compound (5. H-NMR (CDCh, δ ppm): 8. 21 (2H, d, J=9. 0Hz), 7. 87 (1H, s)' 6.92 (2H,d,J=9.0 Hz), 3.68-3.76 ( 6H,m), 3.40 (2H, t, J=5.5 Hz), 3.26-3.29 (4H, m), 2.64 (2H, t, J=6.1 Hz), 2.54-2.57 (4H, m), 2.38-2.42 (6H, m), 2.33 φ (3H, s), 1.79-1.93 (4H, m). (Example 131) N-ethyl-2-(4-{7-[3-(pyrrolidine-丨-) Base) propyl]_6, 7_ dihydrogen

Compound 4B (5G. Gmg, G. 154mmol) obtained in Reference Example 13 DMF of 193 323165 201202247 (2.N solution added 2|N,N-diethylamineamine hydrochloride (28 mg, 0) 162 Curry 1), Potassium Carbonate (45·0mg, 〇323〇1). After 7 hours of stirring at room temperature, add ethyl acetate and 7% ammonia solution. Extract with ethyl acetate. After the rhythm is biased, _concentrated. The residue obtained is purified by chromatography on an amine hydrazine column (solvent solvent; chloroform: decyl alcohol) to give the title compound (14 〇11^, yield 22%) 'H-NMR (CDCh, 5 ppm): 8. 27 (2H, d, J=9. 〇Hz), 7. 93 (1H s), 6.92 (2H, d, J=9.〇Hz) , 4.09 (2H, t J=6 4 Hz) 3*61 ^ ^ ^ 3 Hz), ,55 (2H, t, J=6:9Hz), ,〇; (2H, t, J=8.3Hz), 2.88 (2H, t, J=6. 3 Hz), 2.60-2.67 (10H, ra), 1.83-1.94 (6H, m), 1.60 (6H, t, 1 = 7.2 Hz). (Example 132) ( S)-1-(3-(2-(4-(4-methylhexahydroindole-bu)phenyl)_5H_〇tt-[2, 3-d] bite-7(6H) -yl)propyl)π 洛洛 bite_2-isopropyl acid isopropyl ester

To a solution of the compound (50 mg, 〇154 mm〇1) in isopropyl alcohol (2.0 ml) obtained in Example 129, was added 4 mol/L hydrochloric acid/1,4-dioxalate solution (0.55 ml). After stirring for 7 hours at room temperature, it was stirred for 6 hours at 6 Torr. After the reaction was stopped with a saturated aqueous sodium hydrogencarbonate solution, the mixture was extracted with ethanol/methanol (1/3). The organic layer was dried over sodium sulfate, and the residue was evaporated to dryness, and the residue of 323165 194 201202247 was purified by column chromatography (solvent solvent; hexane: ethyl acetate-ethyl acetate: decyl alcohol). The title compound (9. 85 mg, yield 23%). ^-NMR (CDCh, δ ppm): 8. 26 (2H, d, J=g. 〇Hz), 7. 92 (1H s), 6.94 (2H, d, 1=9.0 Hz), 5.08-4.99 ( 1H, in), 3.64-3.47 (4H, m), 3.32-3.29 (4H, m), 3.23-3.19 (1H, m), 3. 14-3. 10 (1H, m), 3. 00 (2H , t, J=8. 3 Hz), 2. 80- 2. 73 OH, m), 2.60-2.56 (4H, m), 2.53-2.47 (1H, m), 2.38-• 2.36 (4H, m) , 2.14-2.09 (1H, m), 1.93-1.80 (5H, m), 1.22 (6H, d, J=6.4 Hz).

[Example 133] (2S,4R)-4-carbyl-1-(3-(2-(4-(4-methylhexahydroindole-i-yl)phenyl)-5H-pyrrolo[ 2, 3-d]pyrimidin-7(6H)-yl)propyl)pyrrolidine-2-carboxylic acid decyl ester

To a solution of the compound 15B (50.0 mg, 0. 142 mmol) obtained in Reference Example 53 (1.5 ml), acetic acid (19.0/z 1, 0.312 mmol), (2S, 4R)-4-hydroxyl Pyrrolidine-2-carboxylic acid decyl ester (28. Omg, 0. 156 _ 〇 1), sodium cyanoborohydride (10.2 mg, 1.99 mmol). After stirring at room temperature for 16 hours, the reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate and extracted with chloroform 195 323165 201202247. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The residue obtained was purified by chromatography on EtOAc EtOAc (EtOAc: EtOAc) 'H-NMR (CDCh, δ ppm) : 8. 23 (2H, d, J=9. 0 Hz), 7. 91 (ijj s), 6.93 (2H, d, J=9.0 Hz), 4.46 (1H , m), 3.65 (3H, s), 3.61-3.47 (5H, in), 3.44-3.39 (1H, m), 3.30- 2.67 (4H, in), 2.99 (2H, t, J=8.4 Hz), 2.80-2.76 (1H, m), # 2.62-2.48 (7H, m), 2.34 (3H, s), 2.23-2.16 (1H, m), 2.09-2.06 (1H, m), 1.85-1.80 (2H, m). (Example 134) 2-(4-(4-(4-methyl-7-(3-(pyrrolidin-1-yl)propyl)-6,7-dihydro-5Η-πΛπ each [2, 3-d] Mouth. Benz-2-yl)phenyl) hexahydro η: -1-yl)ethanol

(a) 2-(4-(4-(2-(Tertiary dimethyl dimethyloxy)ethyl)hexahydro phthalate-1-yl)phenyl)-4-chloro-7-( 3-(°-pyrrolidin-1-yl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine Compound obtained in Example 21 (10 mg, 〇 · 234 mmol) in methanol (3.0 ml) under ice cooling, adding acetic acid (54. 〇&quot; 1, 936. 936 mmol), 2-(t-butyldimethyl methoxy) acetaldehyde (lllmg, 585.585 mmol), cyano-sodium hydride (32. Omg, 0.515 mmol). After 4 hrs of stirring at 196 323 165 201202247 at room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to stop the reaction, and the mixture was extracted with a gas-like fraction. The organic layer was dried over sodium sulfate (MgSO4). , yield 88%). ^-NMR (CDCh, (5 ppm): 8. 23 (2H, d, J = 8.6 Hz), 6. 89 (2H, d, J = 8.6 Hz), 3.78 (2H , t, J=6. 2 Hz), 3.63 (2H, t, J=8.6Hz), 3.53 (2H, t, J=7. 2 Hz), 3.29-3.26 (4H, m), # 3.02 (2H , t, J=8. 6 Hz), 2.68-2.65 (4H, in), 2.57 (2H, t, J=6.2 Hz), 2.51-2.47 (6H, m), 1.88-1.77 (6H, ra), 0.88 (9H, m), 0.05 (6H, in). (b) 2-(4-(4-(4-pyridyl-7-(3-(°-pyrrolidinyl)propyl)-6,7-dihydro-5H-indole[2, 3-d]pyrimidin-2-yl)phenyl)hexahydroindol-1-yl)ethanol in a solution of the above-obtained compound (120 mg, 0. 205 mmol) in tetrahydrocarbomate (2.0 ml) Add bis(tri-tert-butylphosphine)palladium (21. Omg, 0.0410 mmol), 2 mol/L decyl zinc chloride-tetrahydro 0 von 0 South solution (0.50 ml, 1.03 mmol), in the chamber After 7 hours, a 1 M aqueous solution of hydrochloric acid was added and the mixture was stirred for 1 hour. After washing the solution with ethyl acetate, the mixture was extracted with a 5M aqueous sodium hydroxide solution to pH = 10, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography on an amine-purified gel column (solvent solvent; chloroform: decyl alcohol), and then washed with diethyl ether. The title compound (36. O mg, yield 39%) was obtained. 197 323165 201202247 ^-NMR (CDCh, δ ppm): 8. 25 (2H, d, J=8. 6Hz), 6. 92 (2H d, J=8.6 Hz), 3.65-3.49 (6H, m), 3.28-3.35 (4H, m), 2. 94 (2H, t, J=8. 3 Hz), 2.77(1H, brs), 2. 68-2. 65 (4H, in), 2.59 (2H, t , J-5.2 Hz), 2.53-2.48 (6H, m), 2 26 (3H, s), 1.87-1.77 (6H, m). (Example 135) (R)-2-(4-(4- (7-(morpholin-2-ylmethyl)-6,7-dihydro-5H-n is more than [2,3-d] oxime-2-yl)phenyl)hexahydro. Ethanol

(a) (R)-4-Benzyl-2-((2-(4-(4-(2-(t-butyldimethyl methoxy)))) ()) 笨 基 ) -4 -4 -4 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用The title compound (1. 46 mg, yield 76%) was obtained. 'H-NMR (CDCh, dppm): 8.20 (2H, d, J=9. 〇Hz), 1. 27-7.22 (5H, s), 6.88 (2H, d, J=9. 0 Hz), 3.87 -3 41 (11H, m), 3.30-3.26 (4H, m), 3.01 (2H, t, J=8. 6 Hz), 2.83-2.79 (1H, m), 2.69-2.66 (4H, m), 2.61-2.55 (3H, ra), 2.18-2.10 (1H, m), 2.02-1.94 (1H, m), 〇. 88 (9H, m)), 0.05 (6H, m). (b) (R) -2-((2-(4-(4-(2-(t-butyldidecyloxy)ethyl)) 198 323165 201202247 hexachloro-p-mental~1_yl)phenyl)-5H- Labromo[2,3-d]pyrimidin-7(6H)-yl)methyl)linine was obtained using the compound obtained above (146 mg, 2.20 〇1) by using the same procedure as in Example 69. The title compound was obtained as a pale yellow gum (1.06 mg, yield 88%). !H-NMR (CDCh, δ ppm) : 8. 22 (2H, d, J=9. 0 Hz), 7. 82 (1H, s)? 6.91 (2H, d, J=9.0 Hz), 3.89- 3.86 (1H, m), 3.80- 3.55 (8H, m), 3.45-3.38 (1H, m), 3.28-3.25 (4H, m), ® 3.02 (3H, m), 2.91-2.76 (2H, ra) , 2.69-2.65 (4H, m), 2.61-2.54 (2H, in), 0.88 (9H, m)), 〇. 05 (6H, in). (c)(R)-2-(4-(4 -(7-(morpholin-2-ylindenyl)-6,7-dihydro-5H-°pyrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridinium-i- The title compound (520 mg, yield 80%) was obtained as a pale yellow solid (yield: 420 mg). φ 'H-NMR (CDCh, δ ppm) : 8. 24 (2H, d, J=9. 0 Hz), 7. 93 (1H, s), 6.92 (2H, d, J=9.0Hz), 3.90 -3.86 (lH,m), 3.75-3.55 (8H, in), 3.47-3.39 (1H, m), 3.36-3.27 (4H, m), 3. 03-2. 97 (3H, t, J=8 . 5 Hz), 2. 91-2. 77 (2H, m), 2.69-2.65 (4H, m), 2.61-2.57 (2H, m). (Example 136) (R)-2-((2 -(4-(4-(2-decyloxyethyl)hexahydron-p-mentyl)phenyl) -5Η_ο than 17 each [2, 3-(1] mouth change-7 (61〇-yl) Methyl) linlin 323165 199 201202247

(a) (R)-l-(4-(4-(7-((4-Benzylmethylmorpholin-2-yl)indolyl)-4~chloro-6,7-dihydro-511-° Ratio [2, 3-d] shouting-2-yl)phenyl)hexahydro-β ratio η well-1-yl)-2-decyloxyethyl ketone obtained using Reference Example 55(b) Compound 18B (1.60 mg, 3.16 mmol), m. ^-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 7. 3 Hz), 7.27-7.23 (5H, s), 6.89 (2H, d, J = 7.3 Hz), 4.14 (2H, m ), 3. 87-3.46 (13H, m), 3. 43-3. 42 (3H, in), 3.29-3.26 (4H, m), 3.02 (2H, t, J=8. 6 Hz), 2.83 -2.79 (1H, in), 2.65-2.61 (1H, m), 2.20-2.11 (1H, m), 2.03-1.95 (1H, m). (b) (R)-2-methoxy-1- (4-(4-(7-(morpholin-2-yl)indolyl)-6,7- • dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydro Pyridin-1-yl)ethanone The title compound (911 mg, m.p. Yield 77%). !H-NMR (CDCh, (5 ppm): 8. 25 (2H, d, J=9. 0 Hz), 7. 93 (1H, s), 6.92 (2H, d, J=9.〇Hz) , 4.14 (2H, s), 3.96-3.86 (1H, m), 3.79-3.55 (l〇H, m), 3.46-3.39 (4H, m), 3.27- 200 323165 201202247 3.24 (4H, m), 3.03 -2.96 (3H, m), 2.91-2.78 (2H, m), 2. 69-2. 62 (1H, m). ' (c) (R)-2-((2-(4-(4- (2-methoxyethyl) hexahydroindole 丨 丨 基 基))-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)methyl)morpholine using the above The title compound (169 mg, yield 40%) was obtained as a yellow solid.

Ή-NMR (CDCh, d ppm): 8. 23 (2H, d, J=9. 0 Hz), 7. 92 (1H • s), 6.92 (2H, d, J=9.0 Hz), 3. 89 -3. 86 (1H, m), 3.75- 3.52 (8H, m), 3.45-3.36 (4H, ra), 3.32-3.28 (4H, m), 3.02-2.96 (3H, m), 2.91-2.77 ( 2H, m), 2.69-2.61 (7H, m). (Example 137) (R)-N-indolyl-bu (4-(7-(3-(N-morpholinyl)propyl)), 7_Dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridinium_3_amine

The title compound (70. Omg, yield: 18%) was obtained as a pale yellow oil (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 'H-NMR (CDCh, 5 ppm): 8. 21 (2H,d,J=9. 0 Hz), 7· 91 (1H, 323165 201 201202247 s), 6.93 (2H, d, J=9.0 Hz) , 3.73-3.70 (5H, t, J=4. 7 Hz), 3.62-3.51 (5H, m), 2.99 (2H, t, J=8. 4 Hz), 2.96-2.84 (1H, m), 2.76 -2.63 (2H, m), 2.49 (3H, s), 2.44-2.35 (6H, m), 1.96-1.93 (1H, m), 1.86-1.77 (3H, in), 1.71-1.59 (1H, m) , 1.38-1.26 (1H, m). (Example 138) 4-Benzyl-2-(4-(4-chloro-7-(3-(N-morpholinyl)propyl)-6, 7 -dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)morpholine

(a) 2-(phenylhydrazinylamino)-1-(4-bromophenyl)ethanol in a suspension of sodium hydride (55%, 872 mg, 20.8 mmol) in THF (40 mL) at 0 ° C A solution of tridecyl sulfide (4.16 g, 20.0 mmol) in DMSO (40 ml) was added dropwise. After 10 minutes, a solution of 4-bromobenzaldehyde (3.70 g, 20. Ommol) in THF (10 mL) was evaporated. After 30 minutes, the temperature was raised to room temperature. After 1 hour, it was poured into ice water. The reaction was stopped and extracted with hexane. The organic layer was washed with 323165 202 201202247 brine, and then concentrated to give a mixture (4·78 g). To the obtained mixture (2. 〇g, 1 〇· 〇mm〇i), benzylamine (1. 32 ml, 12.1 mmol), perchloric acid (214 mg, 2.0 mmol), at room temperature Stir the whole night. Water was added to the reaction solution, the reaction was stopped, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by silica gel column chromatography (yield solvent:methanol:methanol) to give the title compound (1.48 mg, yield 33%). H! NMR (DMS0, 5 ppm): 7.45 (2H, m), 7.20-7.35 (7H, m), 4. 65 (1H, dd, j=8. 9, 3. 7 Hz), 3.84 ( 1H, d, J=13. 2 Hz), 3. 78 C1H, d, J=i3. 2 Hz), 2. 90 (1H, dd, J=12. 3, 3. 7 Hz), 2. 66 (1H, dd, J=1. 3, 8. 9 Hz). (b) 4-Benzyl-6-(4-bromophenyl)morpholin-3-one as the compound obtained above (1. 48g, 4. 83mmol) of a two-gas azepine (2〇ml) solution, adding 1mol / L sodium bismuth oxide aqueous solution (6. 28ml, _ 6. 28mmol), acetyl chloride gas (5 〇〇 to 1) , 6. 28mmol). The aqueous sodium hydroxide solution was dropped until the reaction solution became pH = 8. After 2 hours, it was extracted with an air-mesh fraction. The organic layer was washed with brine and concentrated under reduced pressure to give a mixture. Potassium hydroxide (542 mg, 9.67 mm oi) was added to a solution of the obtained mixture in isopropyl alcohol (10 ml), and stirred at room temperature overnight. Water was added to the reaction solution, the reaction was stopped, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent elution 323165 203 201202247 Ή-NMR (CDCh, d ppm): 7. 45 (2H, m), 7. 24-7. 35 (5H, „i) 7. 18 (2H, m), 4. 72 (1H, Dd, J=10. 3, 3. 7 Hz), 4. 70 (lH d, J=14.3 Hz), 4.57 (1H, d, J=14.3 Hz), 4.46 (1H, d J=16.7 Hz ), 4.36 (1H, d, J = 16.7 Hz), 3.34 (1H, dd J = 12.3, 10.3 Hz), 3.24 (1H, dd, J = 12.3, 3.7 Hz). (c) 4-Benzyl- 6-(4-(4, 4, 5, 5_tetramethyl 3,2-dioxaborolan-2-yl)phenyl) linyl-3-one is a compound obtained above (1) 70g, 4.91mmol) of 1,4~2-r-dioxane (3〇m〇 solution, adding [1, bis-bis(diphenylphosphonium)ferrocene] 二 (Π) di-vapor Dioxane complex (4〇〇mg, 〇491mm〇1), bis(pinacol)-deletion (2. 49g, 9.82mmol), acetic acid unloading (1.93g, 19 6mmol) '9 (TC is stirred. After 2 hours, water is added to the reaction solution to stop the reaction. The mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and then concentrated under reduced pressure. The residue obtained is obtained by column chromatography. After layer analysis (solution solvent; hexane: ethyl acetate), the title product was obtained as a pale yellow solid. φ Compound (2.08 mg, yield 1 〇〇./0). ^-NMR (CDCla, (5 ppm): 7.76 (2H, d, J=7.9 Hz), 7. 24-7. (7H, m), 4. 76(1H, dd, J=10.5, 3. 5 Hz), 4. 69(1H, d, J=14.5Hz), 4. 35-4. 58 (3H, m) , 3. 36(1H, d, J=12. 3, 10.5 Hz), 3.26 (1H, dd, J=12.3, 3.5 Hz). (d) 4-Benzyl-6-(4-(4- Chloro-l-(3-(N-heptyl)propyl). A compound obtained by the above-mentioned compound (1. 〇g, 2.54 mmol). In the solution of 1,4-bis" (20 ml), the compound obtained in Reference Example 5 (8〇7n]g, 323165 204 201202247 2. 54ramol), 肆(triphenylphosphine) was added (294mg, 0. 254 mmol), 2M aqueous solution of hydrogen chloride (5. lml, 10.2 mmol), and 12 (TC). After 2 hours, water was added to the reaction solution, the reaction was stopped, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by ethylamine chromatography chromatography chromatography chromatography chromatography 'H-NMR (CDCh, 5 ppm): 8.30 (2H, d, J=8. 3 Hz), 7.24-7. 35 (1H, m), 4. 80 (1H, dd, J=10. 4, 3. 5 Hz), 4. 72 (1H, • d, 1=14.7 Hz), 4.55 (1H, d, 1=14.7 Hz), 4.52 (1H, d, J=16.7 Hz), 4.39 (1H, d , J=16.7Hz), 3.66-3.71 (6H, m), 3.53 (2H, t, J=7. 1 Hz), 3.40 (1H, dd, J=12.3, 10.3 Hz), 3.28 (1H, dd, J = 12.3, 3.5 Hz), 3.05 (2H, m), 2.36-2.41 (6H, m), 1.80 (2H, m). (e) 4-phenylmercapto-2-(4-(4-chloro-) 7-(3-(N-morphinyl)propyl)_6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)morpholine ^ obtained in the above To a solution of the compound ( 534 mg, EtOAc, m. After 2 hours, water and a 2 M aqueous sodium hydroxide solution were added to the reaction solution to terminate the reaction. The reaction solution was filtered with EtOAc (EtOAc)EtOAc. (Example 139) 4-(3-(2-(4-((3S,5R)-3,5-didecylhexahydropyrene-diyl)phenyl)-5H-pyrrolo[2,3 -d]pyrimidine-7(6H)-yl)propyl) 琳琳323165 205 201202247

(a) 4-(3-(4-Ga-2-(4-((3S,5R)-3, 5-dimethylhexahydropyranyl)-phenyl)-5H-° [2,3-d]°i-yt-7(6H)-yl)propyl) phenanthrene The compound obtained in Reference Example 5 (274 mg, 0.864 mmol) in 1,4-dioxalate (3.51111) Add (23,61〇-2,6-dimethyl Φ -4-(4-(4, 4, 5, 5-tetradecyl-1,3,2-dioxaborolan)- 2-yl) stupid) hexahydropyrazine-polycarboxylic acid tert-butyl ester (377 mg, 0.91 mmol), hydrazine (triphenylphosphine) (l〇〇mg, 0. 086 mmol), 3 mol/L The aqueous sodium hydroxide solution (0.86 ml, 2.59 mmol) was stirred at 120 ° C under microwave irradiation. After 30 minutes, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and then reduced. The residue was purified by column chromatography (eluent solvent; hexane: ethyl acetate). The obtained oil was added to a solution of decyl alcohol (3-0 ml) with 4 mol/L hydrochloric acid. /1.4-Di® oxane (6. 〇ml) and stirred at room temperature. After stirring for π hours, the solvent was removed under reduced pressure. Water was added to the residue and washed with ethyl acetate. The sodium hydroxide aqueous solution was adjusted to pH = 10, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Analysis (solvent solvent; hexanes: ethyl acetate) was purified to give the title compound (yield: 33%).

!H-NMR (CDCh, 5 ppm): 8. 22 (2H, d, J=9. 0 Hz), 6. 88 (2H 323165 206 201202247 d, J=9. 0 Hz), 3. 72-3.70 (4H,m), 3.66-3. 60 (4H,m), 3.53 (2H, t, J=7.1 Hz), 3.05-2.98 (4H, m), 2.43-2.30 (8H,m), 1.85 -1.75 (2H, m), 115 (3H, s), 113 (3H, s). (b) 4-(3-(2-(4-((3S,5R)-3, 5-dimethyl) Hexahydronaphthalenyl)phenyl)-5H-pirop[2,3-(1]pyridin-7(611)-yl)propyl)morpholine using the compound obtained above (136 mg, 〇289 The title compound Lu (71. Omg, yield: 56%) was obtained as a white solid. </RTI> NMR NMR Ch, 5 ppm): 8.22 (2H, d, J=8) . 8 z), 7.91 (iH, s), 6.91 (2H, d, J=8.8Hz), 4.11-4.09 (4H, m), 3.73-3.51 (6H, m), 3.06-2.97 (4H, m) , 2.44-2.30 (8H, m), 1.86-1.76 (2H, m), 1.15 (3H, s), 1·13 (3H, s). (Example 140) 5 ' 4-(3-(2- (2-(4-methylhexahydropyrazine_丨_yl)pyrimidinyl)_5H-pyrrolo[2,3-d]t-dec-7(6H)-yl)propyl)morpholine

Using the compound obtained in Reference Example 5 (1 mg, 〇 315 mm 〇i) and the corresponding reagent, the title compound (16) 〇lng, yield 13%). !H-NMR (DMS0, (5 ppm): 9,18 (2H, s), 7.88 (1H s) 323165 207 201202247 3.93-3.91 (4H, m), 3.71-3.68 (4H, m), 3.61 (2H , t, J=8. 6 Hz), 3.49 (2H, t, J=7. 1 Hz), 3.01 (2H, t, J=8. 6 Hz), 2.48-2.36 (10H, m), 2.33 ( 3H, s), 1.85-1.75 (2H, m). (Example 141) 4-(2-(2-(4-(4-ethylhexahydroindol-1-yl)phenyl)-5H- Npirodi[2,3-d]pyrimidin-7(6H)-yl)ethyl)morpholine

Using the title compound (33. , yield 31%). φ Ή-NMR (CDCh, (5 ppm): 8. 22 (2H, d, J=9. 2 Hz), 7. 92 (1H, s), 6. 93 (2H, d, J=9. 2 Hz), 3. 68-3. 61 (8H, m), 3. 31- 3.28 (4H, m), 3.00 (2H, t, J=8. 0Hz), 2. 63-2. 58 (5H, m), 2.55-2.54 (3H, m), 2.46 (2H, q, J=7.2 Hz), 1.62-1.60 (2H, m), 1. 12 (3H, t, J=7.2 Hz). ( Example 142) (S)-3-(2-(4-(4-ethylhexahydro- 0-哄-i-yl)phenyl)-5Η-&gt;»Bilo[2,3-d] Pyrimidine-7(6H)-yl)-4-pyrrolidin-1-yl)butyric acid methyl ester 208 323165 201202247

Using the compound of Example 54B of Reference Example 54 (24 () mg, and borrowed

In the same manner as in Example 1 and Example 39, the obtained residue was dissolved in methanol (2. Gml) and added with 4 mGl/L of hydrochloric acid μ 4_bilaterally a〇ml under ice cooling. Stir at room temperature. After 4 hours, it was concentrated under reduced pressure, and then added with NaHCOs, and extracted with ethanol/chloroform (3/1). After the organic sound is dried by sodium sulphate, the pressure is removed, and the ampere is found!丨 , , , , , , , , , , 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg , yield 91%). Color s), 6.89 (2H, d, J=9.〇Hz), 4.68-4.61 (lH m) 3 βη (2H, t, J=8.5 Hz) ^ 40 rQu λ 〇' )' 3· 60 ΗΖλ 3 ·49 (3Η, s), 3.26^3.23 (4Η 2.93 (2H, t, J=8.5 Hz) 2 ' 5 nz; 5 (s 2.65 (3H, m), 2.53-2 (8H, m), 2.29 ( 4H, s), 165 (4H, m)·. Examples 143 to 248: The compounds shown in Table 16 were carried out using a hearing compound and a lysate. Further, the synthesis method and the implementation 2: A, and implementation In the same manner as in the case of the example 69, it is B, and when it is the same as the embodiment 69, it is D, and when it is the same as the embodiment 78, it is E, and the example 81 is the same as the case of the embodiment (10). g is the same as the embodiment 323165 209 201202247, and is I in the same manner as in the embodiment 129, J in the same manner as in the embodiment 133, and K in the same manner as in the embodiment 134, and the same as in the embodiment 139 (a). For L, combine this and so on.

210 323165 201202247 [Table 16]

Example T2 • j«3 U Method analysis 値143 Me Me-lsT^N- \/ H CH AC Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 94 (2H, d, J = 9. 0 Hz), 4.57-4.50 (1H, m), 3.72-3.69 (4H, in), 3.64-3.50 (2H, m), 3. 32-3. 29 (4H, m), 3. 00 (2H, t, J = 8.4 Hz), 2.60-2.56 (4H, m), 2.43-2.35 (9H, m), 1.89-1.80 (1H , m), 1.73-1.62 (1H, in), 1.24 (3H, d, J = 6. 8 Hz). 144 0 ~ Me Plant Me~N N+ \__( H CH J Ή-NMR (CDCh, δ ppm ): 8.23 (2H, d, J = 8.4 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 70-3. 50 C6H, m), 3.30-3.26 C4H, m), 2. 99 (2H, t, J = 8.3 Hz), 2.75-2.72 C2H, m), 2.58-2.54 (4H, m), 2.40-2.33 (5H, m), 1.86-1.76 C2H, m), 1.71-1.68 (2H, m), 1.14 (3H, s), 1.12 (3H, s). 145 Me2N-(^N- H CH AC Ή-NMR (CDCh, δ ppm): 8.21 (2H, d, J = 9. 0 Hz), 7. 92 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 86-3. 82 (2H, m), 3.68- 3.61 (8H, m), 3.00 (2H, t, J = 8.4 Hz), 2.76 (2H, t, J = 11.3 Hz), 2. 61 (2H, t, J = 6. 6 Hz), 2. 54 (4H, m), 2.29 (6H, s), 1.93-1.89 (2H, m), 1.61-1.54 C3H, m). 146 HN ' Me~NN* \__/ H CH C Ή-NMR (CDCL·, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9 . 0 Hz), 3. 89-3. 85 (1H, m), 3.79-3.55 (5H, m), 3.45-3.38 (1H, m), 3.30-3.26 (4H, m), 3.02-2.96 (3H , m), 2.91-2.77 (2H, m), 2.69-2.61 (1H, m), 2.57-2.54 (4H, m), 2.33 (3H, s). 211 323165 201202247

147 .νΟ Η CH C Ή-NMR CCDCh, δ ppm): 8.21 (2Η, d, J = 9.0 Hz), 7.92 (1H, s), 7.28-7.24 (5H, m), 6.92 C2H, d, J = 9.0 Hz), 3.88-3.84 (2H, m), 3.73-3.41 (7H, m), 3. 31-3. 27 (4H, m), 2. 99 C2H, t, J = 8.1 Hz), 2.84 ( 1H, d, J = 11.4 Hz), 2.63 (1H, d, J = 11. 4 Hz), 2.59-2.55 C4H, m), 2.34 (3H, s), 2.18-2.12 (1H, m), 2.04- 1.91 (1H, m). 148 Η〇λ m®'nCn* Η CH C Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 7. 92 (1H, s ), 6. 92 (2H, d, J = 9.0 Hz), 3.89-3.85 (1H, m), 3.79-3.55 (5H, m), 3.45-3.38 (1H, m), 3.30-3.26 (4H, m ), 3.02-2.96 (3H, m), 2.91-2.77 (2H, m), 2.69-2.61 (1H, m), 2.57-2.54 (4H, m), 2.33 (3H, s). 149 〇ο Me- CN* Η CH C Ή-NMR (CDCh, &lt;5 ppm): 8.21 (2H, d, J = 9. 0 Hz), 7. 92 C1H, s), 7. 28-7. 24 (5H, m ), 6.92 (2H, d, J = 9.0 Hz), 3.88-3.84 (2H, m), 3.73-3.41 (7H, m), 3. 31-3. 27 (4H, m), 2. 99 (2H , t, J = 8.1 Hz), 2.84 (1H, d, J = 11.4 Hz), 2.63 (1H, d, J = 11.4 Hz), 2.59-2.55 (4H, m), 2.34 (3H, s), 2.18 -2.12 (1H, m), 2.04-1.91 (1H, m). 150 〇3^ Η CH C Ή-NMR (CDCla, δ ppm): 8.29 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 7.38 (2H, d, J = 8.4 Hz), 4.52 (1H, dd, J = 10.2, 2.3 Hz), 4.04 (1H, dd, J = 11.4, 2.2 Hz), 3.67-3.81 (5H, m), 3.51-3.64 (4H, m), 2.93-3.08 (4H, m), 2.85- 3.92 (1H, m), 2.73-2.81 (1H, m), 2.36-2.48 (6H, m), 1.76-1.86 (2H, m). 212 323165 201202247

151 Μθ2Ν^ Cn* Η CH LGC Ή-NMR (CDCls, δ ppm): 8.21 (2Η, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9. 0 Hz) , 3.93-3.89 (1H, m), 3.73-3.61 (10H, m), 3.00 (2H, t, J = 8.8 Hz), 2.72-2.54 (7H, m), 2.48-2.40 (1H, m), 2.35 (6H, s), 2.03-1.97 (1H, m), 1.85-1.80 (1H, m), 1.67-1.55 (1H, m), 1.44-1.35 (1H, m). 152 iQ...., Η 〇-\ /~\ Η* \»_! Η CH D Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.94-6.91 (2H, m), 3.88-3.84 (2H, m), 3.71-3.64 (6H, m), 3.47 (1H, dd, J = 14.4, 6.3 Hz), 3.29-3.28 (4H, m), 3.00 C2H, t, J = 8.3 Hz), 2.80 (1H, d, J = 11.6 Hz), 2.67-2.66 (5H, m), 2.60-2.59 (3H, m), 2.26 (3H, s), 2.11 (1H, td, J = 11.6, 3.5 Hz), 1.92 (1H, t, J = 10. 7 Hz). 153 I}, Η CH D Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 92-3. 60 (6H, m), 3.56-3.44 (3H, m), 3.36 (3H, s), 3 32-3. 29 (4H, m), 3. 00 (2H, t, J = 8.3 Hz), 2.91-2.87 (1H, m), 2.75-2.71 (1H, m), 2.67-2.61 (6H, m), 2.38 (2H, q, J = 7. 2 Hz), 2.13-2.05 (1H, m), 1.95-1.87 (1H, m), 1.06 (3H, t, J = 7.2 Hz). 155 \__/ Et〇-\ /—\ Η CH D Ή-NMR (CDCh, δ ppm) : 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 73-3. 70 (4H, m), 3.62-3.47 (8H, m), 3.31-3.27 (4H, m), 2. 99 (2H, t, J = 8.1 Hz), 2. 68-2.61 (6H, m), 2.43-2.39 (6H, m), 1.86 -1.76 (2H, m), 1.20 (3H, t, J = 7. 2 Hz). 213 323165 201202247

156 HcT^r^N* H CH D 'H-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.91 (2H, d, J = 9. 0 Hz), 3. 82 (2H, t, J = 5.4 Hz), 3.72-3.70 (4H, m), 3.62-3.51 (4H, m), 3.29-3.26 (4H, m), 3.00 (2H, t , J = 8. 4 Hz), 2. 69-2. 65 (6H, m), 2.44-2.39 (6H, m), 1.86-1.74 (4H, m). 157 MecT^r^N* H CH D 'H-NMR (CDCb, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 C1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 73-3. 70 (4H, m), 3. 62-3. 51 C4H, m), 3. 43 (2H, t, J = 6.3 Hz), 3.33 (3H, s), 3.29-3.26 (4H, m), 2.99 ( 2H, t, J = 8.1 Hz), 2.61-2.58 (4H, m), 2.49-2.39 (8H, m), 1.86-1.75 (4H, m). 158 E 卜N门N* \_· Me CH E 'H-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9. 2 Hz), 6. 92 (2H, d, J = 9. 2 Hz), 3. 54 (4H, m), 3. 28 (4H, m), 2. 94 (2H, t, J = 8.3 Hz), 2. 60 (4H, m), 2.48 (8H, m), 2.26 C3H, s), 1.82 (6H, in ), 1.11 C3H, t, J = 7.2 Hz). 159 Cn^ ΜθΟ^. /—\ VN N· Me CH E Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9. 0 Hz ), 6. 91 (2H, d, J = 9. 0 Hz), 3.59-3.49 (6H, m), 3.36 (3H, s), 3. 30-3. 27 (4H, m), 2 94 (2H, t, J = 8.6 Hz), 2.67-2.60 (6H, m), 2.55-2.50 (6H, m), 2.26 (3H, s), 1.88-1.83 (2H, m), 1.78 (4H , m). 160 ΜθΟTM\ /\ Me CH E 'H-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 6. 91 (2H, d, J = 9. 0 Hz), 3.72-3.70 (4H, m), 3.59-3.49 (6H, m), 3. 36 (3H, s), 3. 29-3. 28 (4H, id), 2. 94 (2H, t, J = 8. 3 Hz), 2. 66-2. 60 (6H, in), 2.42-2.39 (6H, m), 2.26 (3H, s), 1.81-1.79 (2H, m). 214 323165 201202247

161 CN^ )-N^N- Me CH F 'H-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3.60-3.48 (4H, m), 3.27-3.26 (4H, m), 2. 94 (2H, t, J = 8. 3 Hz), 2. 68-2.66 C5H, m), 2.52-2.49 (6H, m), 2.26 (3H, s), 1.82-1.78 (6H, m), 1.07 (6H, d, J = 6.4 Hz). 162 Me Me-N^N- Mr H CH G Ή-NMR ( CDCh, δ ppm): 8.22 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 90 (2H, d, J = 9. 0 Hz), 3. 72-3 . 71 (4H, m), 3.62-3.51 C6H, m), 3.00 (2H, t, J = 8.1 Hz), 2.64-2.60 (2H, m), 2.44-2.30 (11H, m), 1.82-1.80 ( 2H, m), 1.17 (6H, d, J = 6.2 Hz). 163 mn〇^ H CH G Ή-NMR (CDCh, δ ppm): 8.33 (2H, d, J = 8.6 Hz), 7.94 (1H, s), 7.25 (2H, d, J = 8. 6 Hz), 3. 88-3.86 (2H, m), 3. 71-3. 70 (4H, m), 3. 62 (2H, t, J = 8. 4 Hz), 3. 54 (2H, t, J = 7.1 Hz), 3. 02 (2H, t, J = 8. 4 Hz), 2. 87-2. 85 (2H, in), 2. 73-2. 70 (4H, brs), 2. 42-2.40 (9H, m), 1.87-1.77 (2H, m). 164 Me Q.., Me-CN* H CH G Ή-NMR ( CDCh, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 93 (1H, s), 6. 93 (2H, d, J = 9.0 Hz), 3.91-3.80 (2H, m ), 3.73-3 .60 (4H, m), 3.50-3.43 (1H, m), 3. 30-3. 27 (4H, m), 3. 00 (2H, t, J = 7.8 Hz), 2.79 (1H, d, J = 11.4 Hz), 2.63C1H, d, J = 11.4Hz), 2.58-2. 54 (4H, m), 2. 33 (3H, s), 2. 26 (3H, s), 2.15-2.07 ( 1H, m), 1.95-1.88 (1H, m)· 215 323165 201202247

165 Q.' Me-N^N* H CH G Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3.92-3.89 (1H, m), 3.82-3.77 (1H, m), 3.74-3.60 (4H, m), 3.49-3.42 (1H, m), 3.30-3.27 (4H, m) , 3.00 (2H, t, J = 8.1 Hz), 2.85 (1H, d, J = 11.4 Hz), 2.67 (1H, d, J = 11.4 Hz), 2.62-2.55 C5H, m), 2.33 (3H, s ), 2.32-2.24 (1H, m), 2.14-2.06 C1H, m), 1.02 (6H, d, J = 6.6 Hz). 166 Me Me-N Gate N* \__! H CH G Ή-NMR (CDCh , δ ppm): 8. 24 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3. 91-3. 80 (2H, m), 3.73-3.60 (4H, m), 3.50-3.43 (1H, m), 3. 30-3. 27 (4H, m), 3. 00 C2H, t, J = 7.8 Hz), 2.79 (1H , d, J = 11.4 Hz), 2.63C1H, d, J = 11.4Hz), 2.58-2. 54 (4H, m), 2. 33 C3H, s), 2. 26 C3H, s), 2.15-2.07 C1H, m), 1.95-1.88 (1H, m). 167 Μθ-Ν^N* \_! H CH G Ή-NMR (CDCb, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.93 C1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.92-3.89 (1H, m), 3.82-3.77 (1H, m), 3.74-3.60 (4H, m), 3.49-3.42 (1H, m), 3.30-3.27 (4H, m), 3.00 C2H, t, J = 8.1 Hz), 2.85 (1H, d, J = 11.4 Hz), 2.67 (1H, d, J = 11.4 Hz), 2.62-2.55 (5H, m), 2.33 (3H, s), 2.32-2.24 (1H, m), 2.14-2.06 (1H , m), 1.02 (6H, d, J = 6. 6 Hz). 168 Me Q.' H〇-\ /~\ N- N_! H CH G Ή-NMR (CDCh, δ ppm): 8.24 (2H , d, J = 9.0 Hz), 7.93 (1H, s), 6.93 (2H, d, J = 9. 0 Hz), 3. 88-3. 84 (2H, m), 3.71-3.64 (6H, m ), 3.49-3.45 (1H, m), 3. 29-3. 28 (4H, m), 3. 00 (2H, t, J = 8. 3 Hz), 2.82-2. 78 (2H, m) , 2. 67-2.66 C4H, m), 2.60-2.59 (2H, m), 2.26 (3H, s), 2.13-2.09 (1H, m), 1.93-1.90 (1H, m). 216 323165 201202247

169 々0' ΗΟλ /~\ \_t H CH G Ή-NMR CCDC13, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.93-3.89 (1H, m), 3.80-3.60 (9H, m), 3.48-3.44 (1H, m), 3. 29-3. 28 (4H, m), 3. 00 (2H , t, J = 8.3 Hz), 2.87-2.83 (1H, m), 2.67-2.66 (5H, m), 2.60-2.56 (2H, m), 2.30-2.27 (1H, m), 2.08 (1H, m ), 1.02 (6H, d, J = 6.6 Hz). 170 Me Μθ〇-\ /~~\ VN N- H CH G Ή-NMR (CDCla, δ ppm): 8.23 (2H, d, J = 9.0 Hz) ), 7.93 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 89-3. 82 (2H, m), 3.70-3.63 (4H, m), 3.55-3.53 (2H , m), 3.50-3.43 (1H, m), 3.36 (3H, s), 3. 30 (4H, t, J = 5. 0 Hz), 3. 00 (2H, t, J = 8. 0 Hz ), 2.82-2.78 (1H, m), 2.65-2.62 (7H, m), 2.26 (3H, s), 2.16-2.07 (1H, m), 1.93-1.90 (1H, m). 171 Μθ〇-\ /—λ \t H CH G Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9. 0 Hz) , 3.92-3.88 (1H, m), 3.77-3.65 (5H, m), 3.55-3.53 (2H, m), 3.48-3.43 (1H, m), 3.36 (3H, s), 3. 31-3. 29 (4H, m), 3. 00 (2H, t, J = 8.3 Hz), 2.86-2.82 (1H, m), 2.63-2.59 ( 8H, m), 2.30-2.26 (1H, m), 2.12-2.04 (1H, m), 1.02 (6H, d, J = 6. 6 Hz). 217 323165 201202247

172 \„t Me 0* H CH G 'H-NMR (CDCls, δ ppm): 8.29 (2H, d, J = 8.4 Hz), 7.95 C1H, s), 7.39 (2H, d, J = 8.4 Hz) , 4.59 (1H, dd, J = 10.2, 2.1 Hz), 4.04 (1H, d, J = 11.9 Hz), 3.87-3.80 (1H, m), 3.72-3.70 (4H, m), 3.62 (2H, t , J = 8.3 Hz), 3. 55 (2H, t, J = 7.1 Hz), 3. 02 (2H, t, J = 8.3Hz), 2.89(1H, d, J = 11.7 Hz), 2.73 (1H , d, J = 11.0 Hz), 2.43-2.40 (6H, m), 2.31 (3H, s), 2.25-2.20 (1H, m), 2.03 (1H, t, J = 10.8 Hz), 1.87-1.78 ( 2H, m). 173 \__t H CH G 'H-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3. 96-3.89 (2H, m), 3.81-3.71 (1H, m), 3.70-3.51 (9H, m), 3.30-3.26 (4H, m), 3.03-3.00 (4H, m), 2.69-2.67 (2H, m), 2.58-2.56 (2H, m), 2.43-2.39 (6H, m), 2.09-2.05 (1H, m), 1.83-1.79 (2H, m). 174 Μθ2Ν__ CN* Me CH GF Ή-NMR (CDCh, &lt;5 ppm): 8.23 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3.91-3.86 C1H, m ), 3.72-3.67 (1H, m), 3.59-3. 49 (4H, m), 2. 93 (2H, t, J = 8.2 Hz), 2.74-2.63 (2H, m), 2.51-2.46 (6H , m), 2.34 (6H, s), 2.26 (3H, s), 2.01-1.97 (1H, m), 1.87-1.76 (6H, m), 1.60-1.56 (3. OH, m), 1.41-1.35 (1H, m). 175 CN^ Me2M. CN* Me CH GF 'H -NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 6. 92 (2H, d, J = 9. 0 Hz), 3.91-3.86 (1H, m), 3.72- 3.67 (1H, m), 3. 59-3. 49 (4H, m), 2. 93 (2H, t, J = 8.2 Hz), 2.74-2.63 (2H, m), 2.51-2.46 (6H, m ), 2.34 (6H, s), 2.26 (3H, s), 2.01-1.97 (1H, m), 1.87-1.76 (6H, m), 1.60-1.56 (3. OH, m), 1.41-1.35 (1H , m). 218 323165

S 201202247

177 Η〇2〇—, Me-N Plant&quot;W \_t H CH I 'H-NMR (DMSO-de, δ ppm): 8.13 (2H, d, J = 9.0 Hz), 7.84 (1H, s) , 6.95 (2H, d, J = 9.0 Hz), 4.67-4.63 (1H, m), 3.62-3.53 (2H, m), 3.23-3.22 (4H, in), 2.95-2.89 (2H, m), 2.79 -2. 72 (4H, m), 2. 57-2. 49 (4H, m), 2. 26 (2H, m), 2.22 (3H, s), 1.59 (6H, m). 178 Ηα. Ν^Λ Med^. \_/ H CH J Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.46 (1H , m), 3.65 (3H, s), 3.61-3.47 (5H, m), 3.44-3.39 (1H, m), 3.30-2.67 (4H, m), 2. 99 (2H, t, J = 8.4 Hz ), 2. 80-2. 76 (1H, m), 2.62-2.48 (7H, m), 2.34 (3H, s), 2.23-2.16 (1H, in), 2.09-2.06 (1H, m), 1.85 -1.80 (2H, m). 179 Me H〇-\ /~\ N- \__! H CH J Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H , s), 6.93 (2H, d, J = 9.0 Hz), 4.46 (1H, m), 3.65 (3H, s), 3.61-3.47 (5H, m), 3.44-3.39 C1H, m), 3.30-2.67 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.80-2.76 (1H, m), 2.62-2.48 (7H, in), 2.34 (3H, s), 2.23-2.16 (1H, m ), 2.09-2.06 (1H, m), 1.85-1.80 (2H, m). 180 HO~\ t~\ N* \t H CH J Ή-NMR (CDCls, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 92 (1H, s), 6. 93 (2H, d, J = 9. 0 Hz), 3. 65-3. 59 (4H, m), 3.51-3.47 ( 4H, m), 3.31-3.29 (8H, m), 2.99 (2H, t, J = 8.5 Hz), 2.68-2.66 (4H, m), 2.61-2.59 (4H, m), 2.50 (2H, t, J = 6. 8 Hz), 2.30 (3H, s), 1.85-1.83 (2H, m). 219 323165 201202247

181 Me Μθ〇-ν /-^ VN hK \__/ H CH J Ή-NMR (CDCh, δ ppm): 8.24 (2H, d, J = 9. 0 Hz), 7. 91 (1H, s), 6. 92 (2H, d, J = 9.0 Hz), 3.62-3.48 (6H, m), 3.36 (3H, s), 3.31-3.29 (4H, m), 2. 99 (2H, t, J = 8 . 0 Hz), 2. 65-2. 62 C6H, m), 2.45-2.38 (4H, m), 2.22 (3H, s), 1.86-1.77 (2H, m), 1.04 (3H, t, J = 7.2 Hz). 182 MecT^ Me Μθ〇-\ /~v VN N* \_! H CH j Ή-NMR (CDCh, δ ppm): 8.23 (2H, d, J = 9. 0 Hz), 7.91 〇 H, s), 6.92 (2H, d, J = 9.0 Hz), 3.56-3.50 (9H, m), 3.36 (3H, s), 3.31-3.29 (5H, m), 2. 99 (2H, t, J = 8. 4 Hz), 2. 64-2. 58 (9H, m), 2.47 (2H, t, J = 7.8 Hz), 2.28 (3H, s), 1.84-1.81 (2H, m). 183 O-^ Me-N^H* \—( H CH J m/z =437(M+ 1), 2_10 (minutes) 184 CONMe2 Μθ~Ν \^! H CH J m/z =478(M+ 1), 2.13 (minutes) 185 CONHEt Cn^ Me-NT^N. V__! H CH J m/z =478(M+ 1), 2.16 (minutes) 186 CONHMe Me-lsT^N· \__( H CH J m/z =464(M+ 1), 2.11 (minutes) 187 Cn-^ AcHN~ Me-N~^N- \! H CH J m/ z =464(M + 1 ) * 2· 09 (minutes) 188 Ηα.〇 ^ Me-N Gate N* \__1 H CH J m/z = 423(M+ 1), 2.07 (minutes) 189 Fo^ Me-N^N* \( H CH J m/z =425(M+ 1), 2.09 (minutes) 190 Ft&gt;^ Me-N —^N* \_! H CH J m/z =425 (M+ 1), 2.10 (minutes) 191 #-OMe Μθ*Ν^N* _! H CH J m/ z =451(M + 1), 2.16 (minutes) 192 MeC^N^ x Μθ-Ν N- * _! H CH J m/z = 469 (M+ 1), 2.18 (minutes) 193 Me*N^N* ! H CH J m/z = 439 (M+ 1), 2.14 (minutes) 194 ΗαςΝ^Λ Μθ ~Ν N* _! H CH J m/z = 423(M+ 1), 2.08 (minutes) 195 ^OH Me-N^N* _! H CH jm/z =437(M+ 1), 2.09 (minutes) 196 .-OH c:^ Me-hT^N, __! H CH J m/z =437(M+ 1),2.09 (min) 220 323165 201202247

197 ΗΟ'Ν^&quot;^ \t H CH J m/z=425(M+l), 2. 09 (minutes) 198 ,OMe ^ΟΜθ Me-N factory\_/ H CH J m/z =495 (M+ 1), 2.24 (minutes) 199 Me Me-N Plant W \_/ H CH J m/z =478(M+ 1), 2.11 (minutes) 200 ΜΒ2Ν-〇,^λ Μθ-Ν~^N* N! H CH J m/z = 450(M+ 1), 2.07 (minutes) 201 Hb^ Me-rD* \__/ H CH J m/z =437(M+ 1), 2.10 (minutes) 202 ΗΟ-ζ ;Ν-/ΛΛ' Me-N^M* \^t H CH J m/z =409(M+ 1),2.06 (minutes) 203 MeO ΙίΝ^ Me-N Factory\_I H CH J m/z=411 (M+l), 2.10 (minutes) 204 PrO ΙίΝ^ Me-N N* \__/ H CH J m/z = 439 (M+ 1), 2.25 (minutes) 205 Etq Μθ-Ν^N* sl H CH J m/z =425 (M+ 1), 2.16 (minutes) 206 ΡγΟ ΊΪν^ Me-hT^N. \_/ H CH J m/z =439(M+ 1 ), 2.22 (minutes) 207 Me-N N **· \_! H CH J m/z=463(M+l), 2·13 (minutes) 208 Cn-^ N* \__t H CH J m/z =393(M+ 1),2.07 (minutes 209 Μθ-Ν^N* \__! H CH J m/z=439(M+l), 2.15 (minutes) 210 Λ Me-N plant \_r H CH J m/z = 439 (M+ 1), 2.11 (minutes) 211 AcHN,'(^nV^ Me-N N— \__! H CH J m/z =464(M+ 1), 2.09 (minutes) 212 Μβ2Ν^Νν^ \/ H CH jm/z = 450 (M+ 1), 2_06 (minutes) 213 Me Μθ_Ν N— _t H CH jm/z=451(M+l), 2·12 (minutes) 214 〇=CN^ Me-N factory&quot; _· H CH J m/z =435 ( M+ 1), 2.06 (minutes) 215 Me~NN* __/ H CH J m/z =437(M+ 1), 2. 08 (minutes) 216 cr0^ ΗΝ"\ Me-hT^N* _t H CH J m/z =437(M+ 1), 2.13 (minutes) 217 〇-\ Μθ~Ν N··* __1 H CH J m/z =437(M+ 1), 2.11 (minutes) 221 323165 201202247

218 Μβ〇-(3^~^ Me-hT^N* H CH J m/z=451(M+l), 2.10 (minutes) 219 ΜβΟ/ Μβ-Ν^N- \· H CH J m/z =425(M+ 1), 2.13 (minutes) 220 Me Me-N gate N* \! H CH J m/z =437(M+ 1), 2.07 (minutes) 221 NMe2 Μθ~Ν N,· \! H CH Jm/z = 464(M+ 1), 2.03 (minutes) 222 Me-N^N* \__/ H CH J m/z =478(M+ 1), 2.07 (minutes) 223 HQ Me-N^N* \ __t H CH J m/z =437(M+ 1),2.06 (minutes) 224 Ma2N_ 妄0 Me-N gate N* v_t H CH J m/z =488(M+ 1),2· 19 (minutes) 225 Me -N plant, N- \«_·&lt;t H CH J m/z =462(M+ 1), 2.02 (minutes) 226 Me〇-\ Me-N plant, N* \! H CH J m/z =453(M+ 1), 2.29 (minutes) 227 Μβα〇^\ Μθ~Ν N* \&gt;_«( H CH J m/z =437(M+ 1), 2_09 (minutes) 228 Me-hT^N * \_f H CH J m/z =437(M+ 1), 2.09 (minutes) 229 vOO^ Me-hT^N* \_f H CH J m/z =476(M+ 1), 2.04 (minutes) 230 Μθ2Ν Me-hT^N* \_/ H CH J m/z =466(M+ 1 ), 2.09 (minutes) 231 HC^Va HN"\ Μθ-Ν^N- H CH J m/z =423 (M+ 1 ), 2.11 (minutes) 232 Me-N gate N-_r H CH jm/z =464 (M+ 1), 2.21 (minutes) 233 MeHN Μθ*Ν^N-__! H CH jm/z =452 (M+ 1 ), 2.08 (minutes) ) 234 Me5- Μθ-ν&quot;^n* __( H CH J m/z =451(M+ 1), 2.12 (minutes) 235 Me Me-N^N-_/ H CH J m/z =463 (M+ 1), 2.30 (minutes) 236 Η (\ίΝ^Λ Me-hT^N* __/ H CH J m/z = 398 (M+ 1), 2.10 (minutes) 237 Me-hT^N* ! H CH J m/z=382(M+l), 2.11 (minutes) 238 Me-N N* \_»! H CH jm/z =493(M + 1 ), 2.16 (minutes) 222 323165 201202247

239 ΗΟλ /~~, Me CH K Ή-NMR (CDCla, &lt;5 ppm): 8.24 (2H, d, J = 8. 8 Hz), 6. 92 (2H, d, J = 8. 8 Hz) , 3.72-3.70 (4H, m), 3.66-3.63 (2H, m), 3.60-3.49 (4H, m), 3.28-3.26 (4H, in), 2.95 (2H, t, J = 8.3 Hz), 2.76 (1H, br s), 2.67-2.66 (4H, m), 2.60-2.59 (2H, m), 2.42-2.39 (6H, m), 2.27 (3H, s), 1.82-1.79 (2H, in). 240 Μθ~ν\^ν—H CH LB Ή-NMR (CDCh, &lt;5 ppm): 8.15 (2H, d, J = 9.0 Hz), 7.84 C1H, s), 6.51 (2H, d, J = 9.0 Hz), 4.20 (1H, s), 3.68-3.65 (4H, m), 3.54-3.43 (5H, m), 3.33 (2H, s), 2.95-2.89 (3H, m), 2.59-2.55 (1H, m), 2.38-2.33 (6H, m), 2.30 (3H, s), 1.94-1.82 (2H, m), 1.78-1.73 C2H, m). 241 hnCn* H CH LC Ή-NMR (CDCh, δ ppm ): 8.23 (2H, d, J = 8.8 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 8.8 Hz), 3. 66-3. 63 (8H, m), 3.23-3.21 ( 4H, m), 3.04-2.98 (6H, in), 2.60-2.57 (6H, m). 242 〇Cn^ \TMt Me^l, 〇H CH LCG Ή-NMR (CDCla, δ ppm): 8.21 ( 2H, d, J = 9.4 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.4 Hz), 3.93-3.89 (1H, m), 3.72-3.70 (4H, m), 3.62-3.51 (4H, m), 2. 99 (2H, t , J = 8. 0 Hz), 2. 75-2.65 (2H, m), 2.48-2.39 (6H, m), 2.35 C3H, s), 2.01-1.97 (1H, m), 1.86-1.77 (2H, m), 1.68-1.63 (6H, m), 1.41-1.33 (1H, m). 243 cT^N-^^ Me# H CH LGC Ή-NMR (CDCh, δ ppm): 8.21 (2H, d, J = 9.4 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.4 Hz), 3.93-3.89 (1H, m), 3.72-3.70 (4H, m), 3.62-3.51 (4H, m) , 2. 99 (2H, t, J = 8. 0 Hz), 2. 75-2.65 (2H, m), 2.48-2.39 (6H, m), 2.35 (3H, s), 2.01-1.97 (1H, m), 1.86-1.77 (2H, m), 1.68-1.63 (6H, in), 1.41-1.33 (1H, m). 223 323165 201202247

244 Ο, Μθ2Ν, Ο* Η CH LGC Ή-NMR (CDCh, δ ppm): 8.21 (2Η, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3.93-3.89 (1H, m), 3.73-3.61 (10H, m), 3.00 (2H, t, J = 8.8 Hz), 2. 72-2. 54 (7H, m), 2.48-2.40 ( 1H, m), 2.35 (6H, s), 2.03-1.97 (1H, id), 1.85-1.80 (1H, m), 1.67-1.55 (1H, m), 1.44-1.35 (1H, m). 245 Me -N0 Η CH MC Ή-NMR (CDCla, δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.38 (1H, Brs), 4.01 (1H, d, J = 8.1 Hz), 3.59-3.55 (5H, m), 3.47 (1H, brs), 3.29-3.28 (4H, m), 2. 99 (2H, t, J = 7. 9 Hz), 2. 94-2.91 (1H, m), 2.71-2.48 (7H, m), 2.34 (3H, s), 1.86-1.69 (4H, m). 246 )~NWN* Η CH MC Ή-NMR (CDCL·, &lt;5 ppm): 8.22 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9. 0 Hz), 3. 66- 3. 63 (8H, m), 3. 29-3.28 (4H, m), 3. 00 (2H, t, J = 8.6 Hz), 2.73-2.67 (5H, m), 2.61 C2H, t, J = 6. 7 Hz), 2. 55-2. 54 (4H, m), 1.08 (6H, d, J = 6.4 Hz). 247 Μβ_Ν〇Η Ν MC Ή-NMR (CDCh, δ ppm): 9.19 (1H , d, J = 2. 4 Hz), 8. 39 (1H, dd, J = 9 0, 2.4 Hz), 7.91 (1H, s), 6.67 (1H, d, J = 9. 0 Hz), 3. 68-3. 59 (6H, m), 3. 53 (2H, t, J = 7. 0 Hz), 3. 02 (2H, t, J = 8.4 Hz), 2.54-2.52 (10H, m), 2.35 C3H, s), 1.88-1.81 (6H, m). 248 〇Cn^ hC - Η CH LC Ή-NMR (CDCh, δ ppm): 8.34 (2H, d, J = 8.6 Hz), 7.94 (1H, s), 7.24 (2H, d, J = 8. 6 Hz), 3.85-3 . 83 (2H, m), 3. 71-3. 70 (4H, m), 3. 62 (2H, t, J = 8.4 Hz), 3. 54 (2H, t, J = 7.1 Hz), 3.13 -3.10 (4H, m), 3. 02 (2H, t, J = 8. 5 Hz), 2. 84 (2H, t, J = 5. 0 Hz), 2.42-2.40 (6H, m), 1.84 -1.82 (2H, m). 224 323165 201202247 (Example 249) 4-(3-(2-(Benzyloxy)-4-(4-(4-mercapto)-yl-l-yl Phenyl)-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-propyl)morpholine

To a solution of the compound (191 mg, 0.491 mmol) in 1,4-dioxane (2 ml) obtained in the compound of Example 58 was added 1-meryl-4-[4-(4, 4, 5, 5- Mercapto-1,3,2-dioxazacyclopentan-2-yl)phenyl]hexahydro-11 hydrazine (178 mg, 0. 589 mmol), hydrazine (triphenylphosphine) le (56.8 mg, 0. 049 mmol), 3 mol/L aqueous sodium hydroxide solution (500 ml, 2·50 mmol), and stirred at 150 ° C under microwave irradiation. After 30 minutes, hydrochloric acid water was added to the reaction solution, the reaction was stopped, and the mixture was washed with ethyl acetate. The aqueous layer was extracted with an aqueous solution of sodium hydroxide to pH = 10, and extracted by gas-mesh separation. The organic layer was washed with φ with a saturated aqueous solution of sodium chloride, and then evaporated to dryness, and the residue obtained was purified by chromatography on an amine-purified gel column (solvent solvent; hexane: ethyl acetate-ethyl acetate:methanol). The title compound was obtained as a white solid ( 236 mg, yield: ^-NMR (CDCh, δ ppm): 7. 83 (2H, d, J=9. 0Hz), 7. 49-7. 47 (2H, m), 7.34-7.22 (3H, m), 6.94 (2H , d, J=9. 0 Hz), 5.43 (2H, s), 3.70-3.67 (4H, m), 3.61 (2H, t, J=8. 1 Hz), 3.46 (2H, t, J=7 2 Hz), 3.31-3.28 (4H, ra), 3.20 (2H, t, J=8.11 Hz), 2.60-2.57 (4H, m), 2.42-2.35 (9H, m), 1.83-1.74 ( 2H, m). 225 323165 201202247 Examples 250 to 264: Reaction and treatment were carried out using the corresponding starting compounds and reagents, and the method for forming the compound n shown in Table 17 was obtained in the same manner as in Example 1 = upper and example 76 is the same at the same time, and is the same as in the embodiment 119 ==) is L at the same time, and is the same as the embodiment: [Table 17]

250 251 Μθ-Ν Ν-

Me-N Ν'·*

Me-N NMej 〇Me H-NMR CCDCh, δ ppm): 7. 79 (2H, d, j = 7 Hz), 6. 97 (2H, d, J = 9. 2 Hz), 3. ?2- 3 6g (4H, m), 3.58 (2H, t, J = 8.3 Hz), 3 48 (2H, t, J = 7.2 Hz), 3.28-3.25 (4H, m) 3. 22 (2H, t, J = 8.3 Hz), 2. 57-2. 54 (4H' m), 2. 50 (3H, s), 2.45-2.37 (6H, m), 2 ^ (3H, s), 1.84-1.75 (2H, m). ' --------- Ή-NMR (CDCIj, δ ppm): 7.84 (2H, d, j = g 〇Hz), 6.93 (2H, d, J = 9.0 Hz), 3. 71-3 69 (4H, m), 3.50 (2H, t, J = 8.1 Hz), 3 43 (2H, t, J = 7.1 Hz), 3.26-3. 25 (4H, m) 3.19-3.13 (8H ,m),2.57-2.55 (4H,n)' 2.45-2.37 (6H,m),2.33 (3H,s), l 83^ 1.73 (2H, m)._ : ------ Ή-NMR (CDCh, &lt;5 ppm): 7. 88 (2H, d, j = 9 〇Hz), 6.96 (2H, d, J = 9. 0 Hz), 3, 98 (3jj s), 3.71-3.70 ( 4H, m), 3.64 (2H, t, j 1 8.3 Hz), 3.48 (2H, t, J = 7. 2 Hz), 3 3l_ 3.29 (4H, m), 3.23 (2H, t, J = 8. 3 hz) 2.59-2.57 (4H, m), 2.45-2.38 (6H, m)' 2.36 (3H, s), 1.86-1.76 (2H, m). ' 323165 226 252 201202247

253 MeO-\ /~s Me D 'H-NMR (CDCh, δ ppm): 7. 75 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz ), 3. 65-3. 52 (6H, m), 3. 36 (3H, s), 3. 29-3. 27 (4H, m), 3.19 (2H, t, J = 8. 3 Hz) , 2. 68-2. 61 (12H, m), 2.50 (3H, s), 1.78-1.75 (4H, m). 254 HN gate N* \t Me L Ή-NMR (CDCh, &lt;5 ppm) : 7. 76 (2H, d, J = 8.8 Hz), 6. 94 (2H, d, J = 8.8 Hz), 3. 63-3. 57 (4H, m), 3.21-3.17 (6H, m) , 3.03-3.01 C4H, m), 2. 69 (2H, t, J = 7. 0 Hz), 2. 59-2. 55 (4H, m), 2. 51 (3H, s), 1. 77 -1. 76 (4H, m). 255 ΗΟ-λ. /~\ Me H Ή-NMR (CDCh, δ ppm): 7. 76 (2H, d, J = 8. 8 Hz), 6. 94 ( 2H, d, J = 8. 8 Hz), 3. 63-3.57 (6H, m), 3.27-3.26 (4H, m), 3.19 (2H, t, J = 8. 5 Hz), 2. 72- 2. 65 (7H, m), 2. 61-2. 59 (6H, m), 2.51 (3H, s), 1. 78-1. 75 (4H, m). 256 CN^ Me~NN* \ _t Me M Ή-NMR (CDCh, δ ppm): 7. 76 (2H, d, J = 9. 0 Hz), 6. 95 (2H, d, J = 9. 0 Hz), 3. 56 (2H , t, J = 8.4 Hz), 3.46 (2H, t, J = 7. 2 Hz), 3.28-3.26 (4H, m), 3.19 (2H, t, J = 8.4 Hz), 2.56-2.52 (13H, m), 2.34 (3H, s), 1.85-1.80 (6H, m). 257 Me-hT^N * \_! Me M Ή-NMR (CDCh, δ ppm): 7. 76 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz), 3. 66-3. 55 (4H, m), 3.27-3.26 (4H, m), 3.19 (2H, t, J = 8. 3 Hz), 2. 74-2. 70 C2H, m), 2. 59- 2. 55 (8H, m), 2.51 (3H, s), 2.34 (3H, s), 1.79-1.76 (4H, m). 258 Cn, Me-N^N- __I Me M Ή-NMR (CDCh, δ ppm): 7. 79 (2H, d, J = 9. 0 Hz), 6. 97 (2H, d, J = 9. 0 Hz), 3. 71-3. 63 (6H, m), 3.58 (2H, t, J = 6.6 Hz), 3. 30-3. 28 (4H, m), 3. 23 (2H, t, J = 8. 3 Hz), 2.60-2.54 (13H, m), 2.36 (3H, s). 259 Cn^* Me-lsT^N* _t HM Ή-NMR (CDCls, δ ppm): 8.44 (1H, s), 7.78 (2H, d, J = 9. 0 Hz), 6 . 95 (2H, d, J = 9. 0 Hz), 3. 67 (2H, t, J = 8. 3 Hz), 3. 57 (2H, t, J = 6.8 Hz), 3. 29-3 . 25 (6H, m), 2. 70 C2H, t, J = 6.8 Hz), 2. 57-2.55 (8H, m), 2.34 (3H, s), 1.77-1.76 (4H, m). 227 323165 201202247 260 Me-lsT^N. HM Ή-NMR (CDCh, δ ppm): 8.43 (1H, s), 7.79 (2H, d, J = 8. 8 Hz), 6. 96 (2H, d, J = 8. 8 Hz), 3.71-3. 65 (6H, m), 3. 57 (2H, t, J = 6.7 Hz), 3.29-3.25 C6H, m), 2.60-2.56 (6H, m), 2. 52-2. 49 (4H, m), 2. 34 (3H, s). 261 Μθ-ν&quot;^n- v__t HM Ή-NMR (CDCh, δ ppm): 8.43 (1H, s), 7.78 (2H, d, J = 9. 0 Hz), 6. 96 (2H, d, J = 9. 0 Hz), 3.70-3.69 (4H, m), 3. 61 (2H, t, J = 8. 3 Hz), 3.46 (2H, t, J = 7. 2 Hz), 3. 29-3.25 (6H, m), 2.57-2.55 (4H, m), 2.43-2.38 (6H, t, J = 7. 5 Hz), 2. 34 (3H, s), 1.82- 1.79 (2H, m). 262 〇Cn-^ t~\ HN N- \t Me M Ή-NMR (CDCb, δ ppm): 7. 77 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz), 3. 71-3. 70 (4H, m), 3.56 (2H, t, J = 8.4 Hz), 3.46 (2H, t, J = 7.1 Hz) , 3.21-3.19 (6H, m), 3.03-3.01 (4H, m), 2.51 (3H, s), 2.43-2.38 (6H, m), 1.81-1.78 (2H, m). 263 〇Cn^ H〇 -\ t~v Me H Ή-NMR (CDCh, δ ppm): 7. 77 (2H, d, J = 9. 0 Hz), 6. 95 C2H, d, J = 9. 0 Hz), 3. 72-3. 65 (6H, m), 3.59-3.54 (2H, m), 3.49-3.44 (2H, m), 3.28-3.17 (6H, m), 2.80-2.77 (1H, m), 2.68-2.66 (4H, m), 2.65-2.62 (2H, m), 2. 60-2. 58 (2H, m), 2. 51 (3H, s), 2.44-2.37 (6H, m), 1.82-1.77 ( 2H, m). 264 MeO*\ /·—\ Me D Ή-NMR CCDCL·, δ ppm): 7. 76 (2H, d, J = 9. 0 Hz), 6. 94 (2H, d, J = 9. 0 Hz), 3. 72-3. 69 (4H, m), 3.58-3.52 (4H, m), 3.48-3.43 (2H, m), 3. 36 (3H, s), 3. 30- 3. 26 (4H, m), 3.22-3.17 (2H, m), 2.66-2.60 (6H, m), 2.50 (3H, s), 2.44-2.37 (6H, m), 1.81-1.77 (2H, m ).

(Example 265) 2-(2_(4_(4_Mercaptohexanitro) 哄 ·_1.yl)phenyl)_7-(3_(N_?), propyl)_6,7-diaza_ 5H_ ° ratio σ and [2,3-d ] mouth bite _6_ base) decyl acetate 228 323165 201202247

Me. The title compound (6· 〇mg) was obtained as a pale yellow oil (yield of the title compound of Example 11). , yield 6%). Ή-NMR (CDC13, (5 ppm): 8. 22 (2H, d, J=9. 0 Hz), 7. 93 (1Η, s), 6.92 (2H, d, J=9. OHz), 4.27 -4.21 (1H, m), 3.89-3.79 (1H, m), 3.71-3.70 (8H, m), 3.30-3.16 (6H, ra), 2. 89-2. 84 (1H, m), 2. 77-2. 72 (1H, m), 2. 58-2. 34 (13H, in), 1.88-1.75 (2H, in). (Example 266) 2-(4-(4-(7-( 2-(N-morpholinyl)ethyl)-6,7-dihydro-5H_0-pyrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridinium)ethanol

H0-O Using the compound obtained in Reference Example 57 (i </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 233 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Example 134 (a), Example 69 and Example 126 (b) Compound (56.0 mg, yield 55%). !H-NMR (CDCh, δ ppm) : 8. 23 (2H, d, J=9. 2 Hz), 7. 92 (1H, s), 6.92 (2H, d, J=9.2Hz), 3.68- 3.61 (10H, m), 3.29- 229 323165 201202247 3.28 (4H, m), 3.01 (2H, t, J=8. 3 Hz), 2.74 (1H, brs), 2.65-2.57 (12H, in). ( Example 267) 2-(1-(1-Methylhexafluoropyridin-4-yl)-1Η-indol-5-yl)-7-(3-(pyrrolidine-1-yl)propane Base)-6,7-dihydro-5H-° ratio σ and [2, 3-d] shouting

The title compound (28. Omg, yield 20%) was obtained as white crystals.

^-NMR (DMSO, 5ppm): 8. 66 (1H, s), 8. 24 (1H, d J = 9 0 Hz), 7. 96 (1H, s), 7.36 (1H, d, J = 9.0 Hz),6 57 (1H d, J=3.1 Hz), 4.22 (1H, brs), 3.62-3.57 (4H, m) φ 3.04-3.01 (4H, m), 2.56-2.53 (6H, m) , 2.35 (3H, s\ 2.20-2.17 (2H,m), 2. 10-2.06 (4H,m), 1.88 (2H,t, J=7.2 Hz), 1.80-1.77 (4H, m). ' ' (Example 268) 4-(3-(2-(2-(4-cyclopropylhexahydro-)-yl) is a syllabic ratio of [2,3-d]pyrimidin-7(6H) -base) propyl) linlin 323165 230 201202247

The compound obtained in Reference Example 59 (4〇·〇mg, 〇. 〇98mm〇1) and (1-ethoxycyclopropoxy)trimethyl sulphate as a ketone equivalent were used at 5 degrees. The title compound (27. Omg, yield 61%) was obtained as a yellow solid. 'H-NMR (CDCh, &lt;5 ppm) : 8. 22 (2H, d, J=9. 0 Hz), 7. 91 (1H, s), 6.92 (2H, d, J=9. 0 Hz ), 3.72-3.70 (4H, m), 3.62-3·51 (4H, m), 3.25-3.23 (4H, m), 3.00 (2H, t, J=8. 3 Hz), 2.77-2.75 (4H , in), -2. 42-2. 40 (6H, m), 1.82-1.80 (2H, m), 1.65-1.60 (1H, m), 0.48-0.45 (4H, m). (Example 269) 4-(3-(2-(4-(4-Mercaptohexahydropylinyl)-l-yl)phenyl)-5H-pyrrolo[2,3-d]pyrimidine synthesized in Example 62 The 7(6H)-yl)propyl)morpholine can also be synthesized by the following method. 231 323165 201202247

OH

(a) 4-(4-cyanophenyl)hexahydropyranylpyridinium-1-decanoate ethyl hydrazine is added to a solution of 4-fluorobenzonitrile (121 g, 1.0 mol) in DMF (100 ml), Hydrogen σ ratio D well-1-acidified ethyl vinegar (176 ml, 1.2 mol), carbonic acid planer (456 g, 1.4 mol), and stirred at 90 ° C. After 21 hours, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with 5% aqueous citric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride (yield: EtOAc (yield: 66%). ^-NMR (CDCh, (5 ppm): 7. 49 (2H, d, J = 9. 0 Hz), 6. 84 (2H, d, J = 9.0 Hz), 4.15 (2H, q, J=7 . 2 Hz), 3.61 (4H, m), 3.29 (4H, m), 1.26 (3H, t, J=7.2 Hz). (b) (4-(4-(5-allyl-4) , 6-dihydroxypyrimidin-2-yl)phenyl)hexahydro 232 323165 201202247 Pyridin-1-carboxylic acid ethyl ester in lithium hexamethyldiamine (74. 0g, 0.40mol) of diethyl The above obtained compound (52. Og, 0.20 mol) was added to the ether solution (500 ml), and stirred at 55 ° C for 6 hours. After the reaction solution was cooled to 0 ° C, methanol (500 ml) was sequentially added. The mixture was stirred with diethyl isopropyl malonate (72. 9 ml, 0.40 mol) at 65 ° C for 3 hours, and the reaction solution was concentrated under reduced pressure to crystallize the obtained yellow solid from acetonitrile. The aqueous solution of hydrochloric acid was taken to pH = 3 to give the title compound (yield: 82%) (yield: 82%). H-NMR (CDCh, (5 ppm): 8. 00 (2H, d, J=9. 0 Hz), 7. 01 (2H, d, J=9.0 Hz), 5.86-5.75 (1H, m), 4.99-4.87 (2H, m), 4.09-4.02 (2H, m), 3.51-3.47 (4H , in), 3.36-3.28 (4H, m), 3.05-3.01 (2H, m), 1.21-1.17 (7H, m). (c) (4-(4-(5- Propyl-4,6-dichloropyrimidin-2-yl)phenyl)hexahydroindole-1-ethyl carboxylate φ was added to the phosphonium chloride (298 ml, 3.2 mol) at 0 ° C. The dimercaptoamine group 0 is more than the bite (19.5 g, 159 mol) and the compound obtained above (61.4 g, 159 mol). The reaction solution is heated at 90 ° C and stirred for 3 hours, and then the reaction solution is concentrated under reduced pressure. After the reaction was stopped by adding ice, the solution was extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The title compound (48. 5 mg, yield 71%) was obtained as a pale yellow solid. 233 323165 201202247 Ή-NMR (CDCh, δ ppm): 8. 28 (2H, d, J=9. 0 Hz), 6. 92 (2H, d, J=9.0 Hz), 5.92-5.81 (1H, m ), 5.15-5.09 (2H, m), 4.20-4.12 (2H, in), 3.65-3.61 (6H, m), 3.33-3.29 (4H, m), 1.29-1.25 (3H, m). (d) (4-(4-(4-Chloro-7-[3-(N-morpholinyl)propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2- a mixture of phenyl)hexahydropyrazine-1-carboxylic acid ethyl ester in the above-obtained compound (70. 〇g, 166 mmol) of 1,4-dioxalate (1.51) and water (500 ml) Potassium tetraoxide (1. 22g, 3.3 〇1), sodium perchlorate (i42g, 664mmol), 2,6-lutidine (38. 5ml, 332mmol) were added to the solution at 〇 °c. . After stirring at room temperature for 12 hours, the solid was removed by filtration over celite, and the mixture was concentrated under reduced pressure. Ethyl acetate and 10% sodium thiosulfate were added to the residue for 1 hour, and then the mixture was extracted. Thereafter, the organic layer was washed with brine, dried over magnesium sulfate and evaporated. Then, 3 -(pyrrolidinyl-p-yl)propane-1-amine φ (49 ml, 332 mmol) and acetic acid (57 ml, l.) were added to a mixed solvent of methanol (700 ml) and tetrahydrofuran (700 ml). Onmol), stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. ethyl acetate and saturated sodium hydrogen carbonate were added to the residue, and the mixture was stirred for 1 hour. Thereafter, the organic layer was washed with brine, dried over magnesium sulfate and evaporated. The title compound (35. 9 mg, yield 42 «. , (e) 4-(3-) was purified by chromatography on EtOAc (methanol): (2-(4-(4-mercaptohexahydroindol) well) phenyl)_5H_ npyrolo[2,3-d]pyrimidin-7(6H)-yl)propyl)morpholine 323165 234 201202247 The above obtained compound (22·Og, 38.8 mmol) of a mixture solvent of decyl alcohol (250 ml) and tetrahydrofuran (125 ml) was added with decanoic acid (17. Og, 272 mol) and carbon (50% aqueous) at room temperature. (4. Og) 'The mixture was stirred at 7 ° C for 5 hours. After cooling to room temperature, it was filtered through Shixiazao soil and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium carbonate solution were added to extract. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sulphuric acid, and then the solvent was evaporated to give a mixture. Then, THF (4. 4 g, 116 mmol) of tetrahydronaphthol (27 〇ml) / gluten solution was added to the above-obtained mixture of the tetrahydro-alpha-propanol (2 〇〇mi) solution at 0 C. After 2 hours of ageing, a sodium hydroxide aqueous solution was added under ice cooling to become pH=10. The mixture was extracted with ethyl acetate in an aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue obtained was purified by chromatography on the amine sulfite column chromatography (solvent solvent; acetic acid ethyl acetate: methanol). Recrystallized from a mixed solvent of water and isopropyl alcohol to give the title compound (17. lmg, yield 96%) as a white solid. j-NMR (CDCh, 5 ppm) : 8. 25 (2H d TQ η η, η' d, J-9· ϋ Ηζ), 7· 90 (1Η, s), 6.92C2H, d, &gt; 9.0 Hz), 3. 72-3. 69 (4Η, ra) 3 60- 3.50(4H,m), 3.29-3.24 (4η,哟,3 〇卜 2 96 (four, ' 2. 58-2. 52 (4H, m), 2. 44-2. 37 (6H, m), 2. 33 (3H) l 82-1.77 (2H, m). * (Example 270) 4-(3-[6-Methyl-2-{4-(4-mercaptohexahydro)) } 笨 基]Pylpyr[2'3-d]pyrimidin-7(6H)-yl]propyl)morpholine, and (Example 271) 323165 235 201202247 4-(3-[6-mercapto-2 -{4-(hexahydropyranin-1-yl)phenyl}-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl]propyl)morpholine (Example 271)

φ (a) 4-(4-(4,6-dioxa-5-(2-ketopropyl)pyrimidin-2-yl)phenyl)hexahydropyrazine-1-carboxylic acid ethyl ester Example 269 (c) of the compound (136 mg, 0.323 mmol) in DMF (6 ml), water (1 ml), gasification (11) (5.7 mg, 0.020 mmol), vaporized copper (1) (52. 2 mg, 0. 388 mmol), stir at room temperature. After stirring overnight, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered and evaporated. The obtained residue was purified by chromatography (yield: hexane: ethyl acetate) to afford 236 323 165. ^-NMR (CDCb, δ ppm): 8. 26 (2H, d, J=9. 〇Hz), 6. 91 (2H, d, J=9.0Hz), 4. 16 (2H,q, J= 7.2 Hz), 4·〇3 (2H, s), 3.65-3.61 (4H, m), 3.33-3.30 (4H, m), 2.31 (3H, s), 1.27 (3H, t, J=7.2 Hz) (b) (4-(4-(4-Gas-6-methyl-7-(3-ketopropyl)-6,7-dihydro_5H_ 0) and [2, 3-d] E-Bist-2-yl)phenyl)hexahydro-e-pyrene-i-resorcinic acid ethyl acetate (45. 5 mg, 〇·i〇4 mmol) of THF ^ (1 ml) In a solution of sterol (1 ml), acetic acid (13.1/bu 0.229 111111〇1) and 3,3-diethoxy-1-propylamine (25.2; ^1, 0.156 111111〇) were added at 0 °C. 1), sodium cyanoborohydride (13. lmg, 〇. 208 mmol), stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. After washing with water, the mixture was dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated, evaporated, evaporated, The product was added to the solution of ketone (1.0 ml)-water (0.25 ml). Acid 1 water and 2 (22.4 mg, 0.11 mmol) were stirred at room temperature for 3 hours, then heated and stirred at 55 ° C for 1 hour. After cooling to room temperature, the solution was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained residue was subjected to chromatography on a gel column chromatography (solvent solvent; The title compound (20. 3 mg, yield 56%) was obtained as a pale yellow gum. </RTI> H-NMR (CDCh, δ ppm): 9. 81 (1H, s), 8. 19 (2H, d, J=9. 0 Hz), 6.85 (2H, d, J=9. 0 Hz), 4.11 (2H, q, J=6. 9 Hz), 237 323165 201202247

3.99-3.80 (2H, m), 3.63-3.54 (5H, m), 3.22-3.08 (5H m), 2.93-2.73 (2H, m), 2. 60-2. 52 (1H, m), 1.30 ( 3H, d, J=6.3 Hz), 1.22 (3H, t, J=6. 9 Hz). (c) (4-(4-(4-chloro-6-mercapto-7-(3-(N) -Merlinyl)propyl)-6,7-dihydro-oxo[2,3-d]-pyrene-2-yl)phenyl)hexahydro-n-than In the methanol_(lml) solution of the above-obtained compound (20.3 mg, 0. 〇44 mm〇l), acetic acid (5.1/z 1, 〇.〇89mm〇i), 琳琳 was added at 〇 °c. (5·7 μl, 〇·〇67ramol), sodium cyano hydride (5.6 mg, 〇〇89 ιηιηο 1) 'Stop at room temperature. After 3 hours' stop the reaction with saturated aqueous solution of sodium bicarbonate The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained residue was analyzed by chromatography (yield solvent; chloroform: decyl alcohol) The title compound (22. 6 mg, yield: 96%) was obtained as a pale yellow gum. NMR (CDCh, (5 ppm): 8.19 (2H, d, J = 9.0 Hz), 6. 85 ( 2H, d, J=9.〇Hz), 4.11 (2H, q, J=6. 9 Hz), 4.02-3.90 (1H, m), 3.76-3.65 (5H, m), 3.59-3.56 (4H, m), 3.30-3. 12 (6H, m)' 2.59-2.51 (1H, ra), 2.42-2.33 (6H,ro),l.85__ ^70 C2H, m), 1.28 (3H, d, J=6. 3 Hz), 1.22 (3H + J=6.9 Hz). , ' (d) (4 -{4-[6-Methyl-7_(3-(N-morpholinyl)propyl)_6,7-dihydro 5H ° ratio of [2,3-d]pyrimidin-2-yl]phenyl} Hexammonium hexanoate (24 g, 0.37 mol) was added to a solution of the above-obtained compound (19.8 g, 0.037_〇1) in sterol 323165 238 201202247 (1.0 ml). 10% palladium on carbon (50% aqueous) (10 mg), stirred at 50 ° C. After 2.5 hours, after cooling to room temperature, the reaction solution was filtered through Celite, and concentrated under reduced pressure. The aqueous solution of sodium hydrogencarbonate was extracted with chloroform, and the organic layer was washed with EtOAc. ). ^-NMR (CDCh, δ ppm): 8. 19 (2H, d, J=9. 0 Hz), 7. 85 (1H, s), 6.88 (2H, d, J=9.0 Hz), 4.11 (2H , q, J=7. 2 Hz), Lu 3.95-3.88 (1H, m), 3.76-3.65 (5H, m), 3.60-3.56 (4H, m), 3.30-3.08 (6H, m), 2.56- 2.48 (1H, m), 2.39-2.34 (6H, m), 1.84-1.71 (2H, m), 1.26 (3H, d, J=6. 3 Hz), 1.22 (3H, t, J=7.2 Hz) (e) 4-(3-[6-Methyl-2-{4-(4-methylhexahydropyrene)-1-yl}phenyl]-511-pyrrolo[2,3-( 1] pyrimidine-7(61〇-yl)propyl)morpholine, and 4-(3-[6-methyl_2_{4-(hexahydro 0-pyrid-1-yl)phenyl ratio p And [2, 3-d] mouth bite -7(6H)-yl]propyl), the compound obtained above (15.3 mg, 〇.〇31 mmol) was dissolved in THF (2.0 ml) °C After adding hydrogenated Zhongming (3.5 mg, 〇. 〇93mm〇l), at 60° (: stirring for 1 hour, the reaction solution was cooled to 0. (:, adding water (3.5 y 1), 2 mol/L) An aqueous solution of sodium argonoxide (3.5/z 1) and water (7·0/z 1) were stirred at room temperature for 1 hour. After filtration of the celite, the filtrate was concentrated under reduced pressure. Tube chromatography (dissolved solvent; gas imitation: sterol) refined, obtained The title compound (Example 270: colorless gum material, 3.6 mg, yield 27%, Example 271: pale yellow gum material, 5.8 mg, yield 323165 239 201202247 44%). Example 271: W- NMR (CDCh, 5 ppm): 8. 18 (2H, d, J = 9. 0 Hz), 7.84 (1H, s), 6.88 (2H, d, J = 9. 0 Hz), 3.94-3.87 (1H, m), 3.75-3.65 (5H, m), 3.30-3.07 (6H, m), 2.55-2.48 (5H, m), 2.39-2.34 (6H, m), 2.29 (3H, s), 1.83-1.71 ( 2H, m), 1.26 (3H, d, J = 6.0 Hz). (Example 272) 2-(2-(4-(4-methylhexahydropyridin)-1-yl)phenyl)-7 -((N-morpholinyl)propyl)-6, diazin-5Η-σ is more than [2, 3-d] mouth bite-6-yl) ethanol

Ο (a) (4-(4-(4, 6-Dichloro-5-(2-ketoethyl)pyrimidin-2-yl)phenyl) hexahydropyridin-1 - eucalyptyl ethyl vinegar The compound obtained in Example 269 (c) (1. 〇g, 2.21 mmol) in a mixed solution of 1,4-dioxane (24 ml) and water (8 ml) was added as a hydrazine. 16g, 0·〇4mmol), sodium periodate (1. 89g, 8.85_〇1), 2,6-lutidine (0·54ml, 4.43mmol). After stirring at room temperature for 12 hours 'The solid was removed by filtration through celite, and the reaction solution was concentrated under reduced pressure. Ethyl acetate and 10% sodium thiosulfate were added to the residue, and the mixture was stirred for 1 hour, and then the mixture was extracted 240 323 165 201202247. Thereafter, the organic layer was saturated. The mixture was washed with brine, dried over magnesium sulfate, and evaporated, evaporated, evaporated, evaporated, (0. 9lmg, yield 91%) ^MRCCDCh^ppra) : 9.71 (1H, s), 8. 23 (2H, d, J=9. 0 Hz), 6.85 (2H, d, J=9.0 Hz ), 4.14-4.07 (2H, m), 4.01 (2H, s), 3.59-3.56 (4H, m), 3.29-3.25 (4H, m), 1.24-Φ 1· 19 (3H, ra). (b) 4-(4-(4-Ga-6-(2-methoxy-2-ketoethyl)-7-(3_(N_morphinyl)propyl) -6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl) hexahydropyridin-1-carboxylic acid ethyl ester in the above compound 〇〇g, 2. 37_〇1) hydrazine hydrazine ml) carboxymethoxymethylenetriphenylphosphane (1.03g, 3. 08imnol) was added to the solution at room temperature, and mixed for 1 hour at 〇 ° °c . Saturated salt water was added under ice cooling, and the solution was extracted with chloroform. Thereafter, it was dried over magnesium sulfate, decompressed ® widened. Then, in the 1,4-dioxin-burning solution of the residue obtained as follows, 3-indenebine-based propyl-propanol- _ι-amine (352//1, 2.39 mmol) and carbonic acid unloading (〇) 9g, 6. 51mmol), stirred at 11 (TC for 1 hour. Thereafter, sodium hydride (10 mg, 4.35 mmol) was added under ice cooling and stirred at room temperature. After stirring for 1 hour, saturated ammonium sulfate was obtained. The aqueous solution was stopped and the reaction was carried out. After adding a saturated aqueous solution of sodium hydrogencarbonate to pH=8, it was extracted with a gas-like liquid separation. After drying with anhydrous magnesium sulfate, the pressure was reduced. The obtained residue was analyzed by chromatography of an amine stone. (Solution solvent, hexane: acetic acid) To purify 'a yellow oily title compound (651 mg, yield 47%). 241 323165 201202247 ^-NMR (CDCh, δ ppm) : 8. 24 ( 2H, d, J=9. 0 Hz), 6. 90 (2H, d, J=9.0 Hz), 4.32-4.29 (1H, m), 4.19-4.12 (2H, in), 3. 86-3. 81 (1H, m), 3. 71-3. 60 (11H, m), 3. 36-3. 19 (6H, m), 2.91-2.73 (2H, m), 2.55-2.35 (7H, m) , 1.83-1.78 (2H, m), 1.27-1.24 (3H, m). (c) (4-(4-(6-(2-decyloxy-2-ylethyl)-7-) -(N-morphinyl)propyl)-6,7-dihydro-5H-pyridyl Butyl [2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridin-1-carboxylic acid ethyl ester The sterol (10 ml) of the compound (650 g, 1.10 mmol) obtained above. In the solution, formic acid (1.5 g, 23.8 mmol) and le carbon (50% aqueous) (300 mg) were added at room temperature, and the mixture was stirred at 70 ° C for 5 hours. After cooling to room temperature, it was carried out using diatomaceous earth. After filtration, the mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title compound (550 mg, yield: 90%) was obtained as a yellow oil (yield: hexanes: hexanes: δ ppm) : 8. 18 (2H, d, J=9.0Hz), 7.88 (1H, s), 6.87 (2H, d, J=9.0 Hz), 4.22-4.06 (3H, m), 3. 84- 3. 74 (1H, m), 3. 66-3. 55 (11H, m), 3.27-3.11 (6H, m), 2.84-2.66 (2H, m), 2.47-2.31 (7H, m), 1.81 -1.74 (2H, m), 1.24-1.19 (3H, m). (d) 2-(2-(4-(4-decylhexahydro). Specific plough-based)phenyl)_7-(3_(Bulylinylpropyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanol obtained as described above The compound (55 〇 mg, 1. 〇〇mm〇i) in tetrahydrocarbamate 242 323165 201202247 (10ml) solution, adding lithium aluminum hydride (189mg, 4.98mmol) at 〇 ° C, disturbed at 70 ° C Mix for 2 hours. After adding an aqueous sodium hydroxide solution under ice cooling to pH = 10, the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced vacuo. The obtained residue was purified to give crystals eluted eluted elut elut elut elut elut elut elut elut elut elut ^-NMR (CDCh, (5 ppm): Ή-NMR (CDCh, &lt;5 ppm): 8.20 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.90 (2H, d, J = 9.0 Hz), 3.99-3.96 (1H, m), 3.80-3.67 (6H, m), 3.28-3.25 (4H, m), 3.14-3.05 (1H, m), 2.80-2.64 (2H, m), 2.56 -2.52 (4H, m), 2.41-2.31 (8H, in), 2.10-2.05 (1H, m), 1.83-1.67 (3H, m). (Example 2 7 3) 2-(7-((R )-4-indolyl-2-yl)methyl)-2-(4-(4-mercaptohexahydro- 0-indol-1-yl)phenyl)-6,7-dihydrocarbazino[ 2, 3-d] Xiao Bing-6-base) 243 323165 201202247

(a) 4-(4-(7-((R)-4-Benzyl morpholin-2-yl)indolyl)-4-indolyl-methoxy-2-ketoethyl)-6 , 7-Diar-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)hexahydropyridin-1-carboxylic acid ethyl ester The compound obtained in Example 272 (a) was used ( The title compound (900 mg, yield 59%) was obtained as a yellow oil.

Ή-NMR (CDCh, δ ppm): 8. 22-8. 18 (2H, m), 7. 29-7. 24 (5H, m), 6.90-6.86 (2H, m), 4.45-4.35 (1H , m), 4.19-4.12 (2H, m), 3.80-3.23 (19H, m), 3.00-2.92 (1H, m), 2.82-2.73 (2H, m), 2.64-2.48 (2H, m), 2.16 -2.08 (1H, m), 1.97-1.94 (1H, m), 1.29-1.25 (3H, m). (b) 4-(4-(7-((R)-4-phenylmethylmorpholine- 2-yl) fluorenyl)-6-(2~methoxy-2-ketoethyl)_6,7-dihydro-5H-° ratio [2, 3-(1] cancer bite~2~ )) phenyl) hexahydropyridin-1-carboxylic acid ethyl ester in the above-obtained compound (9〇0mg, 1.39_〇1) of methanol 244

To the solution of 32316S 201202247 (15 ml), formic acid (3. g, 46.9 mmol) was added at room temperature, and carbon (50% aqueous) (450 mg) was stirred at 80 ° C for 5 hours. After cooling to room temperature, the solution was decompressed with a solution of sputum. Then, in the mixed solution of the obtained residue in methanol (10 ml) and acetic acid (500 /zl), furfural (120 a 1, 4.17 mmol), sodium cyanoborohydride (262 mg, 4.17 mmo 1) was added. After the mixture was stirred at room temperature for 5 hours, the reaction was stopped with a saturated aqueous solution of sodium hydrogencarbonate and extracted with a mixture of methylene chloride. After the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) . ^-NMR (CDCh, δ ppm): 8. 20-8. 17 (2H, m), 7. 90-7. 88 (1H, m), 6.88-6.85 (2H, m), 4.40-4.30 (1H , m), 4.16-4.06 (2H, m), 3.80-3.77 (2H, m), 3.61-3.57 (9H, m), 3.43~ 3.18 (6H, m), 2.93-2.87 (1H, m), 2.79 -2.69 (2H, m), 2.60-2.56 (1H, in), 2.48-2.41 (1H, m), 2.21 (3H, s), φ 2.08-2.01 (1H, m), 1.87-1.80 (1H, m ), 1.23-1.19 (3HS m). (c) 2-(7-((R)-4-indolylmorpholin-2-yl)methyl)-2-(4-(4-methylhexahydro) Pyridin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidinyl)ethanol was prepared by using the compound (340 g, 0.63 mmol) obtained above. The title compound (140 mg, yield 49%) of m. !H-NMR (CDCh, 5 ppm) : 8. 25-8. 21 (2H, ra), 7. 90-7. 89 (1H, 245 323165 201202247 ^ 6\93—6. 9〇(2H,m ), 4.17—4. 08 (1H,ra)' 3.90-3.58 ^ 2·84^·59 (7H, m), 2.35- 1 Qfi 1 8R r * '25~2*24 (3H,m), 2 -11-2.02 (2H, m), 1.96-1.86 (1H, m), 1.78-1.76 (1H, (Example 274) m * N,N-monodecyl-2-(2-(4-(4) -甲其·_ I曱-based pyridin-1_yl)phenyl)-7-

(=Merlinyl) propyl adeno[2,3_d]p close bite-6-yl) acetamidine

(4) 2 CHC2_(4_(:4~methylhexahydro-[well]))phenyl)_7_(3_(N-Marinyl)propyl)_6,7-diaza each [2, 3_&amp; _6_ base) -N,N-dimercaptoacetamide The compound 12B (33 mg, 〇.85 mm 〇1) obtained in Reference 41 was mixed with 1,4-dioxane (16 ml) and water (4.0 ml). In the solution, add sulfonium-4-4-(4,4,5,5-tetramethyl&lt;,3,2-dioxaborolan-2-yl) base) (256 mg, 〇. 85 mmol), hydrazine (triphenylphosphine) (98 mg, 〇. 090 mmol), lithium hydroxide (8 lna, 3.40 mmol), and stirred at 120 C. After 1 hour, the reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The obtained oil was dissolved in gas (3. 〇mi), and 1-ethyl-3-(3-didecylaminopropyl)carbonyldiimide (325 mg, 1.70 mmol) was added. -Hydroxybenzotriazole (229 mg, 1.70 mmol), 2 mol/L dimethylamine tetrahydro 246 323165 201202247 The solution was stirred (2. lmi), stirred at room temperature for 8 hours, and the reaction solution was evaporated under reduced pressure. The obtained residue was purified by chromatography on EtOAc EtOAc EtOAc (EtOAc) 'H-NMR (CDCh, 5 ppm): 8. 17 (2H, d, J=9. 0Hz), 6. 84 (2H, d, J=9.0Hz), 4.40-4.37 (1H, m), 3.93 -3.80 (1H, m), 3.66-3.62 (4H, m), 3.39-3.09 (6H, m), 2.94-2.91 (6H, m), 2.81-2.74 (1H, m), 2.63-2.49 (5H, In), 2.44-2.29 (12H, m), 1. 77-1.72 (2H, m). (b) N,N-Dimethyl-2-(2-(4-(4-mercaptohexahydron n) Phenyl-i-yl)phenyl)-7-(3-(N-morpholinyl)propyl)-6,7-dihydro-5H-pyrrolo[2 3_d]pyrimidin-6-yl)acetamidine The title compound (74 mg, yield 39%) (yield: 39%) • 'H-NMR (CDCh, 5 ppm): 8. 33 (2H, m), 7. 91 (1H, m), 6. 92 (2H, m), 4.55-4.50 (1H, m), 3.90- 3.80 (6H, in), 3 58- 3.37 (7H, m), 3.03-2.87 (8H, m), 2.79-2.51 (12H, in), 2.11-1.96 (2H, m). ' ' (Example 275 N, N-Dimethyl-2-(7-((R)-4-methyl-arachnid-2-yl)indolyl)_2-(4-(4-methylhexahydro-tonin-1- Base) stupid base)_6, 7_dihydro_5H_ 〇 咯 并 [2, 3-d] -6-yl) acetamamine 323165 247 201202247

(a) 2-(7-((R)-4-Benzylmethylpyran-2-yl)indolyl)~4-chloro-2-(4-(4-mercaptohexahydropyrazole-1- Compound 12A obtained from Reference Example 41, phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-yl)-N,N-dimercaptoacetamide (1. lg, 5.35 mmol) (1. lg, 5.35 mmol) was added to a solution of (1. lg, 5.35 mmol). With potassium carbonate (1.5 g, 10.7 mm〇l), stir for 2 hours. Thereafter, sodium hydride (104 mg, 4.35 mmol) was added under ice cooling and stirred at room temperature. After 1 hour of stirring, the reaction was stopped with a saturated aqueous solution of chlorinated sodium chloride, and saturated aqueous sodium hydrogen carbonate solution was added to pH = 8 and then extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced vacuo. The residue thus obtained was simply purified by chromatography on an amine base rubber column (solution solvent; gas: methanol). The obtained residue was dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and thiol_4_(4,4,5,5-tetradecyl_1 was added. , 3,2-dioxaborolan-2-yl)phenyl)hexahydropyridinium (39 〇mg, 1.29 mm 〇l), hydrazine (diphenylphosphine) (123 mg, 0.11 mmol) , Hydroxide clock (iQ2 ml, 4.3 〇 mmol), stirred at 12 Torr. After 1 hour, the reaction solution was cooled to a temperature of vacuo to distill off the solvent. The obtained oil was dissolved in chloroform (5.0 ml). Add i-ethyl_3_(3-didecylaminopropyl)carbodiimide (4 l mg, 2.14 mmol), hydroxybenzene. The triazole (289 rog, 2. Umm〇i), 2 mol/L monomethylamine tetrahydrofuran solution (2. imi) was stirred at room temperature for 8 hours 323165 248 201202247, and the reaction solution was depressurized. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc) ). !H-NMR (CDCh, δ ppm) : 8. 22-8. 19 (2H, m), 7. 31-2. 70 (5H, m), 6.90-6.86 (2H, m), 4.50-4.44 ( 1H, m), 3.81-3.68 (4H, m), 3.49-3.34 (9H, m), 3.07-2.95 (8H, m), 2.87-2.65 (5H, m), 2.49-2.33 (4H, m), 2.12-1.97 (2H, m). (b) N,N-Dimercapto-2-(7-((R)-4-methylmorpholin-2-yl)methyl)-2- • (4 -(4-mercaptohexahydro-α-specific cultivating 丨_yl)phenyl)_6,7-dihydro-5Η_β-pyrolo[2,3-d]pyrimidin-6-yl)acetamidamine using the above The title compound (71 mg, yield 30%) was obtained. • H-NMR (CDCh, (5 ppm): 8. 33-8. 28 (2H, ra), 7. 95-7. 94 (ιΗ in), 6.94-6.92 (2H, m), 4.50-4.44 ( 1H, m), 3.89-3.74 φ (4H, m), 3.56-3.35 (7H, m), 3.05-2.95 (10H, m), 2.85^ 2.64 (5H, m), 2.54-2.36 (5H, m) , 2.27-2.10 (2H, m) (Example 276) (2-(4-(4-Methylhexahydroindole)-1-yl)phenyl)-7-(3-(n-?-linyl) ) propyl)-6,7-dihydro-5H-0 to 17 and [2, 3-d] lanceolate-5-yl)methanol 323165 249 201202247

(a) (4-(4-(4,6-Dichloro-5-(2-decyloxy-2-ketoethyl)pyrimidin-2-yl)phenyl)hexahydropyridin-1-carboxylate Acid ethyl ester In a mixed solution of the compound (2.2 mg, 4.73111111〇1) of the third butanol (15 ml) and water (15 ml) obtained in Example 272 (3), sodium chlorite was added at 0 ° C ( 1. 28g, 14·2mmol), sodium hydride (3.2 g, 23.6 mmol), 2-mercapto-2-butene (5.0 ml, 47.3 mmol), stirred at room temperature for 3 hours. Saturated brine was added thereto, and the solution was extracted with a gas-like fraction. The mixture was dried over sulfuric acid # magnesium, and the solvent was concentrated under reduced pressure. Then, the obtained residue of the decyl alcohol solution was added at a temperature of 0 ° C to 2 mol / L of tridecyl decyl group. A solution of diazoxane in hexane (9.47 ml) was stirred at 0 ° C for 10 hours. Thereafter, acetic acid (5.0 ml) was added under ice cooling to stop the reaction. After adding saturated aqueous sodium hydrogencarbonate solution to pH = 8, The mixture was extracted with ethyl acetate. After dried over anhydrous magnesium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by chromatography chromatography (solvent solvent: hexane: ethyl acetate) The title compound of the crystal form (1.7 mg, Rate 80%). H-NMR (CDCla, ^ ppm): 8. 29 (2H, d, J=9. 0 Hz), 6. 91 (2H, 250 323165 201202247 d, J=9.0 Hz), 4.19 -4.13 (2H, m), 3.94 (2H, s), 3.74 (3H, s), 3.65-3.59 (4H, m), 3.34-3.30 (4H, m), 1.30-1.25 (3H, m). ( b) 4-chloro-2-(4-(4-(ethoxycarbonyl)hexahydroindole) phenyl)-7-(3-(N-morpholinyl)propyl)_6,7_2 Hydrogen-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid decyl ester was added to a solution of the above-obtained compound (1 25 g, 2.76 mmol) in hydrazine (20 ml) (223 #1, 7.70). Methyl), tetrabutylammonium iodine (40 mg, 0.11 mmol), potassium carbonate d. 14 g, 8·28 mraol), stirred at 6 (rc for 2 days). Thereafter, after removing the precipitate by filtration through Shixiazao soil The solvent was removed under reduced pressure. The residue obtained was 1,4-di. In the methane solution, each of the bite-diyl-propan-1-amine (378//1, 2.76 mmol) and potassium carbonate (〇. 9〇g, 6.51mm〇i), stir 2曰 at ll〇°C. Thereafter, it was filtered through celite, and after removing the precipitate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 'H-NMR (CDCh, δ ppm): 8. 21 (2H, d, J=9. 0 Hz), 6. 87 (2H d, J=9. 0 Hz), 4.15-4.06 (3H, m) , 3.80-3.76 (2H, m) 3. 71-3. 57 (12H, in), 3. 46-3. 41 (1H, in), 3. 23-3. 17 (4H&gt; m), 2. 37-2. 32 (6H, in), 1. 78-1. 74 (2H, m), 1. 25-1 2〇(3H, m). ' (c) (2-(4-(4- Methylhexahydroindole)-i-yl)phenyl)propyl)-6,-flavored [2,3-d]-bist-5-yl)methanol (75 mg, 1. 32 mmol) of methanol 323165 251 201202247 (10 ml) was added to a solution of ammonium formate (3.0 g, 46.9 mmol) and Ιε (50% aqueous) (350 mg) at room temperature, and stirred at 80 ° C for 5 hours. After cooling to room temperature, it was filtered through celite, and concentrated under reduced pressure to give a mixture. To a solution of the obtained mixture in tetrahydrofuran (10 ml) was added to THF (176 mg, 4.64 mmol) at 0 ° C and stirred at 70 ° C for 2 hours. Under ice cooling, an aqueous solution of argon oxide was added to obtain a pH = 10, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) , (5 ppm) : 8. 22 (2H, d, J=9. 0 Hz), 7. 91 (1H, s), 6.91 (2H, d, J=9.0Hz), 3.77-3.65 (7H, m ), 3.59-3.41 (4H, m), 3.35-3.25 (4H, m), 2.60-2.55 (4H, m), 2.48-2.30 (10H, m), 1.85-1.78 (2H, m). (Example) 277) (7-((R)-4-indolylmorpholin-2-yl)indolyl)-2-(4-(4-mercaptohexahydro.p.p.-1-yl)phenyl)- 6, 7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-yl)nonanol 252 323165 丨1:; H,·1 201202247

Ο

(a) (7-((R)-4-Benzyl morpholin-2-yl)indolyl)-2- gas-2-(4-(4-(ethoxy) hexahydro-β ratio哄-1-yl)phenyl)-6,7-dihydro-5H-°tb嘻[2,3-d]pyrimidine-5-carboxylic acid decyl ester The compound obtained in Example 276 (a) was used. The title compound (720 mg, yield 41%) was obtained. Lu 'H-NMR (CDCh, δ ppm) : 8. 23 (2H, d, J=9. 0 Hz), 7. 28-7. 23 C5H, m), 6.88 (2H, d, J=9.0 Hz ), 4.19-4.10 (3H, m), 4.06-3.82 (4H, m), 3. 74-3. 48 (12H, m), 3.28-3.24 (4H, m), 2.83-2.80 (1H, m) , 2.67-2.65 (1H, m), 2.16-2.12 OH, m), 2.00-1.96 (1H, m), 1.29-1.24 (3H, in). (b) 2-(4-(4-(ethoxy) Alkylcarbonyl)hexahydroindole_丨-yl)phenyl-4-benzylmorpholin-2-yl)indenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine -5-carboxylic acid methyl vinegar using the compound obtained above (720 g, 1. i3 mmol) by the same method as in 323165 253 201202247 Example 2 7 3 (b) to give a diastereomeric yellow oil The title compound (281 mg, yield 74%). !H-NMR (CDCh, δ ppm): 8. 27-8. 24 (2H, in), 8. 16-8. 15 (1H, m), 6. 93-6. 90 (2H, m), 4. 18-4. 04 (4H, m), 3. 92-3. 84 (3H, m), 3.77-3. 52 (10H, m), 3.30-3.23 (4H, m), 2.87-2.83 ( 1H, in), 2.73-2.69 (1H, ra), 2.34-2.30 (3H, m). 2.18-2.14 (1H, in), 2.02-1.97 (1H, m), 1.28-1.24 (2H, m). ® (c) (7-((R)-4-indolylmorpholin-2-yl)methyl)-2-(4-(4-methylhexaazinium-1-yl)phenyl) -6,7-Dihydrofuro[2,3-d] shouting-6-yl) decyl alcohol using the compound obtained above (281 g, 0.54 mmol) by the same method as Example 273 (d) The title compound (132 mg, yield 56%) was obtained. ^-NMR (CDCh, δ ppm): 8. 26-8. 22 (2H, m), 7. 98-7. 96 (1H, φ m), 6.93-6.90 (2H, m), 3.86-3.50 ( 11H, m), 3.35-3.32 (4H, m), 2.83-2.79 (1H, m), 2.62-2.59 (5H, in), 2.39-2.36 (3H, m), 2.28-2.26 (3H, m), 2.19-2.15 (1H, m). 1.98-1.91 (1H, m). (Example 278) 4-(3-(6-(2-decyloxyethyl)-2-(4-(4-) Oxy hexahydro. 〇 ~ ~ 1__ base) Stupid than argon [2, 3-d] pyrimidine-7(6H)-yl) propyl) morpholine 323165 254 201202247

OMe was dissolved in methylene chloride (5 ml) in EtOAc (m.). (: tetrafluoroboric acid (53 mg, 0.25 匪〇 1), 2 mol/L tridecyl decyl azocyclohexane hexane solution φ (〇. 25 ml, 0.550 mmol) was added in sequence. Stirring at 〇 ° C After 1 hour, the mixture was added with water and water, and the mixture was stirred for 1 hour, and then the mixture was separated and extracted. Then, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Column chromatography (solvent solvent; ethyl acetate: decyl alcohol) to give the title compound (9. <RTIgt; (2H, d, J=9. 0 Hz), 7. 85 (1H, s), 6.88 (2H, d, J=9.0 Hz), 3.95-3.92 (1H, m), 3.81-3.65 (5H, m ), 3.42-3.38 (2H, m), 3.26-3.17 (8H, m), Lu 3.13-3.04 (1H, m), 2.72-2.64 (1H, m), 2.53-2.50 (4H, in), 2.39- 2.29 (9H, m), 2.12-2.06 (1H, m), 1.81-1.63 (3H, m). (Example 279) (2R)-2-((6-(2-methoxyethyl)- 2-(4-(4-methoxyhexahydro-n-n-n-yl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)indolyl Morpholine 255 323165 201202247 ΟΜθ

The title compound (11 mg, yield: 14%) was obtained. φ • H-NMR (CDC13, δ ppm): 8. 20 (2H, d, J=9. 0 Hz), 7. 87 (1H, s), 6.88 (2H, d, J=9.0 Hz), 4.09 -3.96 (1H, m), 3.84-3.80 (2H, m), 3.66-3.54 (2H, m), 3.42-3.38 (3H, m), 3.36-3.23 (7H, m), 3.18-3.05 (1H, m), 2.78-2.66 (2H, m), 2.58-2.50 (5H, in), 2.29 (3H, s), 2.20-2.01 (5H, m), 1.92-1.80 (1H, m), 1.73-1.65 ( 1H, m). (Example 280) 4-(3-(5-(Methoxycarbonyl)-2-(4-(4-methylhexahydroindole-l-yl)phenyl)- 5H -pyrrolo[2,3-(1]pyrimidin-7(61〇-yl)propyl)morpholine

The title compound (8 mg, yield 8%) (yield: 8%) 323165 256 201202247 Ή-NMR (CDC13, (5 ppm): 8. 19 (2H, d, J=9. 0 Hz), 7. 90 (1H, s), 6.88 (2H, d, J=9.0 Hz) , 3.68-3.60 (5H, m), 3.52-3.42 (4H, m), 3.39-3.32 (5H, m), 3.26-3.23 (4H, m), 2.53-2.50 (4H, m), 2.37-2.33 ( 6H, m), 2.29 (3H, m), 1.78-1.74 (2H, m). (Example 281)

(2R)-2-((5-(methoxyindolyl)-2-(4-(4-decyloxyhexahydron-p-an-yl)phenyl)-5H-indole[2] , 3-d]pyrimidin-7(6H)-yl)methyl)-4-methyl

The title compound (3 mg, yield 6%) was obtained from m. 'H-NMR (CDCh, δ ppm) : 8. 20 (2H, d, J=9. 〇Hz), 7. 94-7. 93 (1H, m), 6.88 (2H, d, J=9.0 Hz ), 3.86-3.70 (3H, m), 3.63-3.35 (7H, m), 3.32 (3H, s), 3.27-3.23 (4H, m), 2.75-2.72 (1H, ra), 2.60-2.50 (5H , m), 2.29 (3H, s), 2.21 (3H, s), 2.10-1.98 (1H, m), 1.90-1.74 (1H, m). (Example 282) 2-(2-(4-( 7-(3-(N-morpholinyl)propyl)_6,7-dihydro_5H_n ratio 323165 257 201202247 [2, 3-d] shouting bit-2-yl) stupid)-n~•琳琳基)ethanol

The title compound (yield: 72%) was obtained as a yellow amorphous compound. . !H-NMR (CDCb, δ ppm): 8. 30 (2H, d, J=8. 4 Hz), 7. 95 (1H, s), 7.40 (2H, d, J=8.4Hz), 4. 59(1H, dd, J=10.5, 2.2 Hz), 4. 06 (1H, dd, J=ll. 6, 5. 8 Hz), 3. 86-3. 79 (1H, m), 3.72-3.70 (4H, m), 3.63-3.61 (4H, m), 3.55 (2H, t, J=7.2 Hz), 3.03 (2H, t, J=8. 6Hz), 2.93 (1H, d, J= 11.6 Hz), 2.80 (1H, d, J=10.5 Hz), 2.71 (1H, brs), 2.58-2.57 (2H, m), 2.44-2.33 (7H, m), 2.19 (1H, t, J=10 6 • Hz), 1.83-1.81 (2H, m). (Example 283) 4-(2-decyloxyethyl)-2-(4-(7-(3-(N-)-) Propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)morpholine

323165 258 201202247 The title compound (69. Omg, obtained from the title compound (69. The rate is 57%). 'H-NMR (CDCh, δ ppm) ·* 8. 29 (2H, d, J=8. 4 Hz), 7. 95 (1H, s), 7.39 (2H, d, J=8.4Hz), 4 . 65 (1H, dd, J = 10.4, 2.5 Hz), 4 (1H, dd, J = 11.6, 2.1 Hz), 3.90-3.86 (1H, m), 3.72-3.70 (4H, m), 3.61-3.53 (6H, m), 3.35 (3H, s), 3.03-2.97 (3H, in), 2.85 (1H, d, J=11.6Hz), 2.60 (2H, _ t, J=5.5 Hz), 2.43-2.40 (6H, m), 2.31-2.27 (1H, m), 2.09 (1H, t, J = 10.8 Hz), 1.87-1.77 (2H, m). Next, the representative compounds of the present invention will be specifically described by way of test examples. Pharmacological effects. Test Example 1: Human TLR9 reporter gene assay The HEK293 cell stable human TLR9 expression strain (human TLR9-293 cells) was activated, and the state of stability was repeated to the cells. The culture of the cells was placed in a C〇2 incubator (37 ° C, 5% C 〇 2). The cells were recovered by using trypsin-EDTA to detach the cells, and the pellets after centrifugation were suspended in the proliferation culture. Human TLR9-293 cells prepared at 3 x 105 cells/mL were seeded in a 6-well collagen plate and cultured overnight. The NF-/c B-luciferase gene was introduced into the cells and cultured overnight. The NF-/c B-luciferase gene was introduced into the cells to prepare 6.25 x 105 cells/mL, and seeded at 80 μl/well on a 96-well black disk (5 x 10 cells/well). The test substance (final concentration: 1, 3, 10, 30, 100, 300, ΙΟΟΟηΜ) and CpG 2006 (5'-TCG TCG TTT TGT GGT TTT GTC GTT-3,) (final concentration 259 323165 201202247 degree 300nM) After each 10/8 L addition, culture for 6 hours. Bright-Glo solution was added at 100 μL/well and placed under light-shielded for 2 minutes. The luminescence was measured using a luminometer, and the 50% inhibition rate (ICsd value) of each test substance was calculated and shown in Table 18. [Table 18]

EXAMPLE NF-kB inhibition of ICs〇(nM) Example NF-kB inhibition Ι〇5〇(nM) Example NF-kB inhibition ICso (nM) Example NF-kB inhibition IC5〇(nM) 4 84.4 86* 3.7 , 3.3 156 8.5 218 9.2 6 327 87* 15.3, 10.7 157 18.7 219 7.5 7 166 88 18.7 158 5.9 220 17.1 8 87.6 89 16.7 159 8.5 221 2.7 9 151 90 8.3 160 27.9 222 20.4 18 82.1 91 7.9 161 3.1 223 6.9 19 107 92 9.5 162 9.2 224 9.6 24 168 93 7.0 163 762 225 2.8 25 150 94 3.5 164 14.7 226 9.9 33 180 95 3.1 165 9.1 227 10.8 34 172 99 11.8 166 13.9 228 9.9 35 90.9 100 71.3 167 8.1 229 1.8 36 97.5 103 * 9.2, 19.2 168 35.2 230 10.6 38 71.0 104* 6.6, 8.8 169 17.5 231 10.9 39 7.7 105. 9.6, 18.2 170 35.1 232 13.3 40 9.8 106 17.7 171 18.6 233 19.8 41* 5.3, 2.4 107 8.9 173 88.8 234 20.8 42 8.6 108 16.9 174 4.4 235 9.1 43 25.7 109* 15.0, 11.0 175 4.5 236 46.0 44* 7.5, 18.2 110 12.3 178 22.6 237 9.1 45* 6.5, 7.9 111· 13.0, 5.6 179 9.7 238 9.8 46 8.7 112 8.0 180 14.3 239 13.1 47 128 113 965 181 14.6 240 8.3 48· 21.9, 19.4 114 21.3 182 19.5 241 48.6 49 10.5 117· 6.4, 5.6 183 9.3 242 8.1 50 8.5 118 17.9 184 21.3 243 6.2 51 6.1 119* 11.3, 13.8 185 52.4 244 42.5 260 323165 201202247

52 24.4 120 12.7 186 33.7 245 6.9 53 19.7 121 32.6 187 18.9 246 65.9 54 36.4 122 13.7 188 38.1 247 16.7 55 48.8 123 125 189 12.2 248 252 56* 16· 3,64· 3 124 73.3 190 22.7 249 18.8 57 186 125 11.8 191 16.4 250 9.7 58 959 126 16.2 192 25.7 251 2.7 59 9.6 127 20.3 193 17.1 252 15.2 62* 8.5, 7.2 128 13.2 194 47.6 253 8.1 63 4.0 130 10.2 195 26.5 254 7.0 64 8.9 131* 10.3, 12.4 196 36.1 255 9.8 65 13.5 132 17.7 197 25.2 256 6.7 66* 6.1, 14.0 133 29.4 198 37.3 257 9.4 67* 13.7, 20.1 134 5.9 199 21.6 258 112 68 15.0 135 29.3 200 15.4 259 17.5 69 42.9 136 13.5 201 13.1 260 271 70 10.7 137 9.4 202 58.1 261 65.5 71 12.6 139 10.0 203 22.1 262 44.3 72 14.8 140 89.1 204 25.2 263 56.7 73 18.4 141 54.4 205 15.4 264 69.0 74 25.4 142 18.7 206 24.1 265 16.4 75 55.8 143 6.2 207 6.1 266 243 76 7.3 144 15.4 208 5.9 267 3.3 77* 4.3, 3.0 145 23.4 209 11.1 268 33.7 78 4.2 146 6.2 210 7.7 270 22.2 79 5.2 147 27.3 211 12.2 271 18.9 80 55.7 148 5.4 212 2.6 272 19.6 81 8.4 149 27.3 213 6.6 273 23.3 82 6.2 151 7.2 214 8.6 274 6.5 83 13.1 152 21.6 215 9.8 276 21.3 84 22.3 153 19.7 216 8.6 277 31.2 85 31.4 155 23.3 217 9.9 * : The results of the two tests were carried out. 261 323165 201202247 As shown in Table 18, the compound of the present invention showed a strong inhibitory effect in the NF-kB inhibition test. Examples 39, 40, 41, 42, 44, 45, 46, 50, 51, 59, 63, 64, 66, 76, 77, 78, 79, 81, 82, 86, 90, 91, 92, 93, 94, 95, 103, 104, 105, 107, 112, 117, 134, 137, 143, 146, 148, 151, 156, 158, 159, 161, 162, 165, 167, 174, 175, 179, 183, Compounds of 207, 208, 210, 212 to 219, 221, 223 to 226, 228, 229, 235, 237, 238, 240, 242, 243, 245, 250, 251, 253 to 257, 267 ® and 274 Particularly strong inhibition. Test Example 2: CpG-induced IL-6 production inhibition test using mouse spleen cells Mouse spleen cells were prepared as follows. The spleen removed from the G57BL/6 mouse (half) was divided with surgical scissors and shattered by the set of slides. After centrifugation, hemolysis treatment was performed using ACK. The medium was added to stop the reaction of ACK. The cells were prepared at 5xl 〇 6 cells/mL, and seeded on a 96-well plate (5xl 〇 5ceiis/well) in l〇〇#L/well. The test substances were added separately (final concentration: 1, 3, 10, 30, 100, 300, 1000 nM) each from L and CpG 1826 (5' -TCC ATG ACG TTC CTG ACG ΤΤ-3,) ((final concentration ΙΟΟηΜ) Each 80/zL was cultured for 24 hours in a C〇2 incubator (37. (:, 5% C〇2). The amount of il-6 produced in the culture supernatant was measured using an ELISA kit, and each test was calculated. The 5〇% inhibition rate (IC5. value) of the substance is shown in Table 19. 262 323165 201202247 [Table 19]

EXAMPLE IL-6 Production Inhibition ICso (nM) Example IL-6 Production Inhibition ICso (nM) Example IL-6 Production Inhibition ICso (ηΜ) 41 65.0 130 64.1 199 90.2 45 51.4 131 122 200 25.2 46 22.6 139 25.3 201 18.4 48 90.1 142 135 203 68.9 62 80.0 143 52.7 204 23.6 64 72.2 146 30.29 205 45.0 69 176 147 45.6 206 25.3 70 60.2 148 22.6 240 21.9 72 69.7 161 &lt;10 241 32.1 78 21.8 162 38.6 242 14.7 83 36.8 164 83.2 243 &lt;10 84 52.8 165 &lt;10 244 <10 86 25.3 166 71.0 245 26.8 87 28.9 167 &lt;10 246 81.4 91 13.3 183 25.4 247 61.2 95 20.1 185 50.3 249 90.1 109 135 186 92.6 250 69.9 110 28.7 187 190 252 120 111 32.7 189 22.6 256 24.2 112 72.6 190 78.9 257 19.8 114 135 191 30.5 259 182 117 22.6 192 85.4 262 69.2 119 66.7 193 28.7 263 96.6 120 81.6 195 80.7 264 70.4 121 141 196 149 267 &lt;10 122 82.3 197 83.5 268 126 127 63.9 198 124 263 323165 201202247 As shown in Table 19, the compound of the present invention showed a repressive action in the IL-6 production inhibition test. Examples 46, 78, 86, 87, 91, 95, 110, 117, 139, 148, 16 165, 167, 183, 189, 193, 200, 201, 2〇4, 2〇6, 240, 242 to Compounds of 245, 256, 257 and 267 showed particularly potent IL-6 production inhibition. Test Example 3: Efficacy evaluation using CpG 1826 administration mode (peritoneal administration)

The CpG 1826 solution was administered to the peritoneal cavity of the mice under ether anesthesia. After 6 hours of CpG 1826 administration, blood collection and peritoneal washings were recovered under ether anesthesia. The collection system was performed from the heart, and the tube to which heparin was added was recovered. The abdominal cavity was washed by injecting PBS (Pho_ate buffered saline) into the abdominal cavity. The compound was administered from the tail vein of the mouse prior to administration of CpG1826. The blood is formed by centrifugation to form plasma, and the cytokine is measured by a commercially available ELISA kit. The amount of IL_6 produced was measured, and the inhibition rate (%) was calculated by comparison of the solvent control of each test substance, and is shown in Table 2 and Table 21. As shown in Table 20 and Table 21, Examples 41, 45, 48, 62, 77, 84 Winter 1 () 9, Out, 117, 118, 119, and the drug were administered 2 hours after CpG Na Le Le. The inhibition of significant inflammatory cytokine production was confirmed in comparison with the solvent control group, and the inflammatory cytokine production of the compound of the present invention was shown. 323165 264 201202247 [Table 20] (Inhibition of IL-6 production in plasma) Example IL-6 production inhibition ED50 (mg/kg) Example IL-6 produced inhibition of EDs. (mg/kg) 41 3.6 111 0.9 45 0.9 117 0.5 48 0.1 118 &lt; 0.1 77 2.2 119 0.6 84 2.6 250 7.1 86 1.7 255 3.4 109 2.6 [Table 21] Example dosage (mg/kg) IL-6 production Inhibition rate (%) 62 1 79 10 86

Test Example 4: Efficacy evaluation using cecal ligation puncture (CLP) mode The cecal knot purple puncture mode is the most commonly used animal model in the study of sepsis (Buras, j A). ., etal., Nat. Rev. Drug Discov. 4, 854-865 (2005),

Rittirsch, D., et al. J. Loukoc. Biol, 81, 137-143 (2007)). Daniel Rittirsch et al. (Daniel Rittirsch, et al., Nature Protocols 4, 31-36 (2009)) for reference, CLP treatment was performed on C57 BL/6 mice. Under inhalation of ether or isoflurane anesthesia, the midline of the abdomen was cut with scissors to expose a few 265 323165 201202247 minutes to expose the cecum and nearby organs. After ligation of the lower part of the cecum, the 18 to 23G needle was used to puncture and perforate the cecal wall (CLP treatment). After the exposed organs were returned to their original places, the open wounds were closed with a cyanoacrylate surgical adhesive, and the surgical area was sterilized with Isodine. After the operation, the awakening and breeding were carried out, and the survival confirmation was performed at least twice a day. In some cases, after a total of blood collection and euthanasia after a few hours of surgery, the abdominal cavity washing liquid or organ is used, and the cytokines or organ disorder markers and the number of bacteria are measured. The compound is administered intravenously before or after treatment with CLP. Part of the implementation and heating to 37. (: Subcutaneous administration of physiological saline and intraperitoneal administration of an antibacterial agent. As shown in Fig. 1 and Fig. 2, Examples 62 and 86 were administered at i〇mg/Kg after 6 hours of CLP treatment, Compared with the solvent control group, it showed a significant survival rate. Further, it was confirmed that the inflammatory cytokines and organ marker markers were also significantly improved, and it was revealed that the compound of the present invention can also be used in the clinic. Test Example 5: Cancer cells Proliferation inhibition assay The human myeloma cell line Ramos was able to recognize TLR9 expression and has a proliferation promotion report of TLR9 ligand (Cellular Immunology 259 (2009) p. 90-99).

The Ramos cell line was modulated to 6.25xl04cells/mL, and a 96-well plate (5xl03 cells/well) was seeded at 8〇eL/well. On the next day, add the test substance (final concentration: 0.01, 0.1, 1, ΙΟ / zm) and CpG 2006 (final concentration: 3; ag / mL) each 10 / / L, in the (: 〇 2 incubator Internal (371, 5% C〇2 excitability) culture for 1 day. For the positive control, the human TLR9 specific inhibitor was defined as inhibitor olig〇nucleotides (iCpG: 5'-TTT AGG 266 323165 201202247 GTT AGG GTT AGG G -3'). A solution of 5-bromo-2'-deoxy-uridine (BrdU) was added to each well for further incubation for 1 hour. The exposure of BrdU to the cells was measured by a luminometer. The proliferation inhibition rate of the cell proliferation promotion by the substance f to the (four) fiber is shown in Table 22 and Table 23. The compound of the present invention is a pair, as shown in Table 22 ^ ^ Λ ηΖ. 1Λ. The inhibition of the amount dependence is strong: Produced by hedgehog

Growth of cancer cells, showing [Table 22] Example (1/zM) Proliferation inhibition (%) Standard error 62 101.4 6.4 111 162.5 15.0 Example (10 Μ) Proliferation inhibition (%) Standard error 119 100.1 42.8 iCpG ( 25^g/ml) 143.7 20.2 [Table 23]

[Industrial Applicability] As described above, the salt allowed by the following formula (1) can be used for autoimmune &lt;bamboo organisms or their treatments. Intimidating for autoimmune diseases~π 惹 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药 制药Prophylactic and/or therapeutic agents for infectious diseases, cancer, immunodeficiency or neurodegenerative diseases (Azheimer's disease, Parkinson's disease, etc.). It has also been found that the selective inhibition of TLR t TLR inhibitors can also be used as a medicament for the treatment of sepsis, which is particularly severe in sepsis. In particular, the TLR9 inhibitor system can also be used in combination with inhibitors, TIT inhibitors or TLRs, and TLR2 can be used in a more advanced step, the new defeat and TLR4

treatment. In the case of the festival, the following is a diagram showing the survival rate after the treatment of the spurs (CLP) of the intravenously administered group of 10 mg/kg of the composition and the solvent of the compound according to the test example 4 described later. (n=8), survival &lt; cecal ligation through 1% means an improvement from the pathology of sepsis. The value of the value of the second image is based on the test example 4 described later, which shows the survival rate of the compound after administration of the 10 mg/kg intravenous group and the solvent control (CLP) treatment. (n=8), survival &lt; cecal ligation 100% means an improvement from the pathology of sepsis. ;;The value is reversed. [Main component symbol description] None. 268 201202247 Sequence Listing &lt;110> Dainippon Sumitomo Pharmaceutical Co., Ltd. &lt;120&gt; Novel 4,5-Cyclopyrimidine Derivative &lt;130&gt; 560346 &lt;150&gt; JP 2010-127353 &lt;151> 2010-06- 02 &lt;160&gt; 3

&lt;170&gt; Patentln version 3.2 &lt;210> 1 &lt;211&gt; 24 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; CpG2006 &lt;400&gt; 1 24 20 tcgtcgtttt gtggttttgt cgtt &lt;210&gt ; 2 &lt;211&gt; 20 &lt;212&gt; DNA &lt;213> artificial sequence

&lt;220&gt;&lt;223&gt; CpG1826 &lt;400&gt; 2 tccatgacgt tcctgacgtt &lt;210&gt; 3 &lt;211&gt; 25 &lt;212&gt; DNA &lt;213>Artificial sequence &lt;220&gt;&lt;223&gt; iCpG &lt;400&gt; 3 tttagggtta gggttagggt taggg 25 1 323165

Claims (1)

201202247 The compound shown or its pharmaceutically acceptable VII. Patent scope: 1. A salt of the following formula (1), 0) [In the formula, A1 and a2 It is represented by the following formula (A) or Z, wherein, when A is a formula (A), a2 represents z, and when A is Z, 'A2 represents a formula (A), and Q and Q2 each independently represent a hydrogen atom and can be substituted Ci-io, C3-8 cycloalkyl, cyano, substituted 0-5 alkylcarbonyl, substituted C1-5 alkoxycarbonyl, carboxyl, substituted aryl, a substituted heteroaryl group, or _C0NR5R6, Aik represents a substituted C 5 alkyl group, Z represents a hydrogen atom, a substituted group, a substituted C 3-8 cycloalkyl group, a cyano group, Substituted Cm alkylcarbonyl, substituted Cl.5 succinyl, substituted aryl, substituted heteroaryl, halogen, substituted Ci-S alkoxy, - NR5R6, or -conr5r6, X means -X1---X'-NR^O-X2---X^CONR^X2---χ»_ CO-X2---X^NR^ONR8-!2- --Χ1-^7]2-, or lOf I, 323165 1 201202247 x represents a substituted Cl-8 alkyl group, wherein X is -X!-NR CO-X2-. -Xl-NR7C〇 When NR8_X2_ ^ _x*_NR7_X2_ x _χ1_〇_ X -, X is a Cz 8 alkyl group which may be substituted, and X2 represents a CH alkyl group which may be substituted Where X is -Xi_c〇NR_X_, ~X1~Nr7C〇NR8-X2-, H-X2-, or -χΐ_〇_χ2·, X2 is a substitutable α_8 alkylene group, and W is -W1 ---nF-W1---NR9C0-W*---C0NR9-r- or -0-W1-, ^ w1 represents a substitutable Cl_8 alkylene group, wherein w is _NR9_w], -C0NR9 When -W1- or -ο-r-, r is a substituted C2 8 alkylene group, 'Table 1 may be substituted aryl or substituted heteroaryl, and RRR and R are independently represented. A hydrogen atom, a Ch which can be substituted. An alkyl group, a substituted C3 8 cycloalkyl group or a substituted 4 to 10 membered saturated heterocyclic ring, and R5, R6, R7, R8 and R9 each independently represent a hydrogen atom or a substituted Chg alkyl group, R and R, R and X1, R1 and X2, R1 and r7, r7 and χ2, r3 and R4, R3 and W1, each combination of R3 and R9, ❹r and r6 may also be bonded to a carbon atom of the other group. Forming a nitrogen-containing saturated impurity of 4 to 1G members (wherein the number of nitrogen-containing saturated heterocyclic rings formed is in _乂_嶋2 and formula (4), respectively, independently from 〇 to 2; in addition, r^r6 Except for the nitrogen-containing saturated heterocyclic morpholine ring formed by the combination)]. • For example, the compound described in claim 1 or its pharmaceutically acceptable salt, 323165 2 201202247 Application for full-time (4) 可 之 之 可 可 、 、 、 、 、 、 、 、 、 、 、 The burnt soil portions of the respective bases of the listening base are independently independent of (1) halogen atoms, U) hydroxyl groups, (3) cyano groups, (4) carboxyl groups, (5) Substitutable C3-8 cycloalkyl, (6) Substitutable aryl, (7) Substitutable heteroaryl, (8) Substitutable Cm alkoxy, (9) Substitutable C3-8 cycloalkoxy, (10) substituted Cl_5 alkoxycarbonyl, (U) substituted G-5 alkylcarbonyl, d2) 4 to 10 member which may be substituted Selected from the group consisting of saturated heterocycles, ^3)~NR10Ru &gt; (HkCONRWR11, (15), ri〇)c〇r丨1, (16), S〇2R1Q, and (17) -S〇2NR10R11 Substituted by the same or different 1 to 5 substituents; the substituted alkylene group may be substituted by the same or different 1 to 5 substituents selected from the group consisting of: (1) ) to 3 323165 201202247 (17); and (18) may be the same or different from the group consisting of a hydroxyl group, a fluorine atom, and a G 5 alkoxy group (the group may be formed by a group of Cl-S alkoxy groups and fluorine atoms) a Cmo alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of 1 to 3 substituents) and 4 to 10 members of the nitrogen-containing saturated heterocyclic ring (where 'the foregoing ( Substituents in 6) and (7) are meant to be via (a) a hydroxy group, (b) a halogen atom, a fluorene group which may be substituted by 1 to 5 fluorine atoms, a hydroxyl group or a G-5 alkoxy group, (d) may have 1 to 5 fluorine atoms, a hydroxyl group or Ch alkoxy substituted by Cm alkoxy, (e) cyano, (indenyl, k)Ci-5 alkoxycarbonyl, (h) Ci-5 alkylcarbonyl, Ci)~NR10Ru &gt; ( j) -CONI^R 丨丨, (k) -S〇2R1 (&gt;, and (l) a group substituted by the same or different 1 to 5 substituents selected from the group consisting of 'S〇2NR10Rn , (1), the bases shown in the above (5), (8), (9), Π〇), (11), and (12) are meant to be via (a) to (d), (S) to (j) Among the groups consisting of 323165 4 201202247, the same or different i to 5 substituents are substituted;) &lt;_ιι&gt;υ:^ surrounding the substituted t-ring in item t The saturated and heterocyclic groups which may be substituted with the left and the other are each independently substituted by the same or different 1 to 5 substituents selected from the group consisting of the above (a) to (4), (g) to (j). (11) The aryl group which can be substituted in the first item of the patent scope, the heteroaryl group which can be taken = The substituted extended aryl group and the substituted heteroaryl group are independently independently substituted by one or five substituents selected from the group consisting of the above (a) to (丨). And R is a Cl-1° alkyl group, or R1, which is independently a hydrogen atom or may be substituted with 1 to 5 fluorine atoms. It can also be combined with R11 to form a nitrogen-containing saturated heterocyclic ring of 4 to 1 member. 3. The compound of claim 2 or 2, wherein A1 is a formula (A), A2 represents Z, #A1 is Z, and A2 represents a formula ( a), Q and Q each independently represent a hydrogen atom; the same or different ones selected from the group consisting of a trans group, a fluorine atom, and a Ch alkoxy group (the group may be via a G_5 alkoxy group and a fluorine atom) Substituted to 3 substituents), Ci-5 alkoxycarbonyl group (this group may be substituted by the same or different 1 to 3 substituents selected from the group consisting of 5 alkoxy groups and fluorine atoms) And a Cl_lfl alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10 members of a nitrogen-containing saturated heterocyclic ring; may be via a hydroxyl group, a fluorine atom, a Cm alkyl group, and a Ci 5 alkane The same or phase of the selected phase of the group consisting of an oxy group (the alkyl moiety of the group 323165 5 201202247 can be substituted by one or three substituents which are the same or different in the group consisting of an oxy group and a fluorine atom) The C3 8 ring substituted by 1 to 3 substituents may be the same or different from the constituents of the oxy group and the fluorine atom. a CM carbonyl or a C 5 alkoxy group substituted with 3 substituents; a carboxyl group; may be via dentate, Cl 6 = 2 and a C alkoxy group (the alkyl moiety of the group may be cleaved to 3 a quaternary group substituted with the same or different oxime selected from the group consisting of three substituents substituted by three substituents; Aik is the same selected from the group consisting of the following Or a heterocyclic 1 to 3 substituent substituted with a Ci 5 alkyl group: a hydroxyl group; a group which may be via a hydroxyl group, a fluorine atom, or a Cm alkoxy group (the group may be via a Ci 5 alkoxy group and a fluorine atom) Substituted from the same or different 丨 to 3 substituents) and 4 to 1 member of the nitrogen-containing saturated heterocyclic ring selected from the same or different 丨 to 3 substituents Ci i. An alkyl group; may be the same or different one selected from the group consisting of a Cm alkoxy group and a fluorine atom via a hydroxyl group, a fluorine atom, a Cl 6 alkyl group, and a Ci 5 alkoxy group (the alkyl portion of the group) a C3-8 cycloalkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of 3 substituents; a cyano group; a hydroxyl group, a Cl a 5 alkoxy group, and a fluorine atom a Cl-5 alkyl group and a C!-5 alkoxycarbonyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of; a carboxyl group; may be via a hydroxyl group or a Ci-e alkyl group. And the same or different ones selected from the group consisting of Cl-5 alkoxy groups (the base of which is substituted by 1 to 3 fluorine atoms) are selected to be 1 to 6 323165 201202247 3 substitute secrets Or a heteroaryl group; _; a C-5 alkoxy group which may be substituted with the same or different oxime selected from the group consisting of a base group and a fluorine atom to 3 substituents; _NRH)Ru; 〇NRl()Rll; Z is a hydrogen atom; may be selected from a group consisting of a hydroxyl group and a fluorine atom via a hydroxyl group, a fluorine atom, or a G group; J is the same or different from 1 to 3 substituents. Replace) a C! cardinyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a Ci5 alkoxy group and a 4 to 10 member nitrogen-containing saturated heterocyclic ring; may be via a hydroxyl group, a fluorine group An atom, a Ci-e alkyl group, and a Ci-5 alkoxy group (the alkyl group and the alkoxy group may be the same or different from the group consisting of a Ci-s methoxy group and a fluorine atom) a C3 8 cycloalkyl group substituted by the same or different 1 to 3 substituents selected from the group consisting of a substituent; a cyano group via a trans group, a Cl.5 alkoxy group and a fluorine atom a Cl_5 alkylcarbonyl group or a C-5 alkoxycarbonyl group substituted with the same or different 1 to 3 substituents selected from the group; may be via a halogen, a Cl_5 alkyl group and a Cl_5 alkoxycarbonyl group (the group) The alkyl moiety is an aryl or heteroaryl group substituted by the same or different 1 to 3 substituents selected from the group consisting of 1 to 3 fluorine atoms; halogen; And a Ci 5 compound having the same or different 1 to 3 substituents selected from the group consisting of fluorine atoms; -NR5R6; or _c〇NR5R6, X being -X1-, UFTCO-X2-, ΚΟΝΙ -Χ2-, -χΐ一c〇-X2 X^NR'CONR^X2---X^NR'-X2-, or -X^O-X2-, χ1 is via hydroxyl group, fluorine atom and Ci-6 An alkyl group (this group may be substituted by the same or different oxime selected from the group consisting of a group, a Cw alkoxy group, a Cl_5 alkoxycarbonyl group, a carboxyl group, and a fluorine atom; 323165 201202247) to 3 substituents) The same or different selected from the group consisting of G-8 alkyl groups substituted by 3 substituents, wherein X is a χ1_Νβ7(:〇_χ2_, -X-NR7C0NR8-X2---f -NR'-X2-, or -χΐ-〇_χ2_, χ1 is pharmaceutically acceptable, 'foot-based, fluorine atom and Ci_6 alkyl group (this group can be via a base group, a fluorene alkoxy group and a fluorine atom) a Cm extension base substituted by the same or different 1 to 3 substituents selected from the group consisting of the same or different ones selected from the group consisting of 1 to 3 substituents, X is a C2 8 alkyl group, -0-W丨-, which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a base, a gas atom and a c, 6 alkyl group. It may be constituted by a hydroxyl group, a fluorine atom and a C16 alkyl group which may be substituted by the same or different one to three substituents selected from the group consisting of a hydroxyl group, a Cm alkoxy group and a fluorine atom. a group of the same or different i to 3 substituents selected in the group, wherein 'W is n, _(10) heart _ or _winter, can be via a group: a fluorine atom and a Cl_6 group ( The base system may be replaced by the same or different i to 3 of the group by the same or different i^ substituents selected from the group consisting of a group of Cl 5 and oxygen atoms. a G 8 alkyl group substituted by a substituent, H may be a monocyclic or condensed cyclic heteroaryl group having 1 to 2 nitrogen atoms, which may be substituted with the same or different oxime to 3 substituents. 323165 8 201202247 The substituent is selected from the group consisting of a cyano group, a Ci 6 alkyl group which may be substituted by three fluorine atoms, and a Ci 5 alkoxy group which may be substituted by 1 to 3 fluorine atoms. P, R 2, R3 and R4 are each independently a hydrogen atom; can pass through a hydroxyl group, a fluorine atom, a Cw alkoxy group, a Cl_s alkoxycarbonyl group, a Ci 5 alkylcarbonyl group, an aryl group, -SOAPV, _NR&quot;Rn, a "alkyl or c&quot; cycloalkyl group, -NiTCOR11 substituted by three heteroaryl groups substituted by a Ci 1Q alkyl group and one or three substituents selected from the same group selected from -C0NR1GRn; Or 4 or 4 substituents which may be substituted by the same or different substituents selected from the group consisting of a radical, a fluorine atom, a hexa group, a Cl-s alkoxy group and a Ch group. To a saturated heterocyclic ring of 1 member, RR, R, R and R are each independently a hydrogen atom; or the same or different ones selected from the group consisting of oxygen, a meridine and a C,-dooxy group; Cl_1() alkyl substituted to 3 substituents; • R1. and Ru are each independently a hydrogen atom or a Ch which may be substituted by i to 5 fluorine atoms. The alkyl group or R^Rn may also form a bucket together. Nitrogen-saturated heterocyclic ring to 1 member; r丨 and r2, r丨 and x, R丨 and r, Ri and R, R7 disk m r4, r3 and ww and r, r9 and rmR6 Other carbon atoms are bonded a nitrogen-containing saturated heterocyclic ring of 4 to 1G members (wherein the number of nitrogen-containing saturated heterocyclic rings formed is in _x_nr1r2 and fine, respectively, to 〇 to 2; respectively, in combination with r and r6 And a pharmaceutically acceptable salt thereof, wherein A1 is In the formula (A), A2 is Z, and when A is Z, A2 is a formula (A), and Q and Q are each independently a hydrogen atom; and may be via a hydroxyl group, a fluorine atom, or a Cl_5 alkoxy group (the group may be via Cm) a group selected from the group consisting of an alkoxy group and a fluorine atom, or the same (4) to 3 substituents, and a Cm alkoxycarbonyl group (the group may be composed of a &lt; 5 alkoxy group and a fluorine atom) Ci substituted by the same or different 1 to 3 substituents selected from the group consisting of the same or different substituents selected from the group) and 4 to 1 member of the nitrogen-containing saturated heterocyclic ring a G substituted by the same or a different one or three substituents selected from the group consisting of a hydroxyl group, a Cl—5 alkoxy group, and a fluorine atom; -5 alkylcarbonyl or Cl 5 alkoxy group; or _C〇nr5r6, Aik is Ci-substitutable by the same or different 1 to 3 substituents selected from the group consisting of 5 alkyl group: a hydroxyl group; may be, the same or different 1 to 3 selected from the group consisting of a base group, a gas atom, a C15 alkoxy group, and a 4 to 1 member nitrogen-containing saturated heterocyclic ring. C^ substituted by a substituent. An alkyl group; a C alkylcarbonyl group or a Cn5 alkoxycarbonyl group which may be substituted with the same or different one to three substituents selected from the group consisting of a hydroxyl group, a Ci-5 alkoxy group and a fluorine atom; An anthracene-5 alkoxy group which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; -NRUR11; and -CONR1%11; Z is a hydrogen atom; The same or different 1 to 3 substituents selected from the group consisting of a thiol atom and a C1-5 alkoxy group (the 10 323 165 201202247 base system may be formed by a Ci-5 saponin group and a fluorine atom) a substituted or substituted Cl-1D alkyl group substituted by the same or different one to three substituents selected from the group consisting of a Ci-5 hospitalized oxygen base and a 4 to 10 member nitrogen-containing saturated heterocyclic ring; The same or a phase selected from the group consisting of a peroxy group, a fluorine atom, a Cl-S succinyl group, and a Cl-s alkoxy group (the alkyl group and the alkoxy group which may be formed by a group of Cl-5 alkoxy groups and fluorine atoms) a c3_8 cyclodextrin group substituted with the same or different 1 to 3 substituents selected from the group consisting of 1 to 3 substituents; the halogen; a Ci-5 alkoxy group substituted by the same or different 1 to 3 substituents selected from the group consisting of atoms; -nr5r6; or -conr5r6, X is -X1-, -X^NI^CO-X2 -, -乂丨-.0 service 7-乂2-, -χ1-^7 C0NR8-Xz---X'-NR^X2- ' ^cX^O-X2- » X1 is via hydroxyl, fluorine atom And a group of G-6 alkyl groups (which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a benzyl alkoxy group and a fluorine atom) Cm alkyl group substituted by the same or different 1 to 3 substituents, wherein 'X is -t-NfftO-X2-, -Χ^ΝΙΛΟΝΙ^-Χ2-, -XHxL, or -Χ^Ο- In the case of Χ2-, X1 is the same or different one to three selected from the group consisting of a hydroxyl group, a fluorine atom and a Cu alkyl group which can be selected from a group consisting of a base group, a Cl-5 alkoxy group and a fluorine atom. Substituted by a substituent consisting of the same or different 1 to 3 substituents selected from the group consisting of (2 to 8 alkylene groups, X2 being groupable via a hydroxyl group, a fluorine atom and a G-6 alkyl group) C2-8 substituted by the same or different 1 to 3 substituents selected in the group 323165 11 201202247 a base group, W is -w1-, -Nf-W1-, -NRtO-W1-, -CONR^W1- or -0-W1-, and W1 is formed by a hydroxyl group, a fluorine atom, and a Cl-6 group. a Ci-8 alkyl group substituted by the same or different 1 to 3 substituents selected from the group, wherein W is -Nf-W1-, -C0NR9-W1- or -0-W1-, W1 is a C2-8 alkyl group which may be substituted with one or three substituents selected from the group consisting of a group consisting of a fluorine atom and a Ci-e alkyl group, and Y may be the same or a phase a phenyl group substituted with 1 to 3 substituents or a monocyclic or condensed ring-extended heteroaryl group having 1 to 2 nitrogen atoms, the substituent being a functional element, capable of passing 1 to 3 fluorine atoms The substituted Cm alkyl group and the Ch alkoxy group which may be substituted by 1 to 3 fluorine atoms are selected, and R'R^R3 and R4 are each independently a hydrogen atom; and may be via a hydroxyl group or a fluorine atom. a Cl-io or C3-8 cyclosyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of G-5 alkoxy, Cm alkoxycarbonyl and -CONRl11, or It may be constituted by a trans group, a fluorine atom, a Cl-6 alkyl group, a Cw alkoxycarbonyl group and a C!-5 alkylcarbonyl group. a 4 to 10 membered saturated heterocyclic ring substituted by the same or different 1 to 3 substituents selected from the group, and R5, RB, R7, R8 and R9 are each independently a hydrogen atom; or may be via fluorine, hydroxyl and Ch substituted with the same or different 1 to 3 substituents selected from the group consisting of Cl-5 alkoxy groups. Alkyl; 12 323165 201202247 and R are each independently a hydrogen atom or a Cm which can be substituted by up to 5 fluorine atoms. Alkyl groups, or γ and Rn may also form a nitrogen-containing saturated heterocyclic ring of 4 to 1 member; R1 and R2, R1 and xi, r1 and X2, and R?, ruler 7 and χ2, ^ and R4, Each of the combination of the ruler 3 and wl, R3 and R9, R9 and W1, and R5 and R6 may be bonded to a carbon atom of a respective group to form a nitrogen-containing saturated heterocyclic ring of 4 to 1 member (wherein formed The number of gas-saturated heterocycles is in URlR2 and (A), which are independently 〇 to 2; in addition, the nitrogen-saturated heterocyclic ring formed by the combination of R and R6 is excluding the morphine ring)] . 5. The compound of any one of claims 1 to 3, wherein the Q1 and Q2 are each independently a hydrogen atom; and may be via a hydroxyl group, a fluorine atom, or a Cl-5, or a pharmaceutically acceptable salt thereof. Alkoxy group (this group may be substituted by the same or different one to three substituents selected from the group consisting of C!-5 alkoxy groups and fluorine atoms) and nitrogen-containing saturated impurities of 4 to 10 members a Cl_1Q alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a ring; may be via a hydroxyl group, a fluorine atom, a Cw alkyl group, and a Ci-5 alkoxy group (the alkyl group of the group) The same or different one to three substituents selected from the group consisting of the same or different one to three substituents selected from the group consisting of a silk group and a fluorine atom) Substituted cw cycloalkyl; cyano; Ci oxy group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a C!-5 alkoxy group and a fluorine atom Base; ruthenium; can be converted into 323165 via dentate, Cl-6 alkyl and Cl oxy (the alkyl group of the sinter group can be substituted by 1 to 3 fluorine atoms) 13 selected from the group of 201202247, the benzene group substituted with the same or different 1 to 3 substituents and the nitrogen-containing heteroaryl group of 5 or 6 members; or -C0NR5R6. 6. The compound of any one of claims 1 to 5, wherein the W is -w1---NRLw1-, -NPCO-W1-, or -0-, or a pharmaceutically acceptable salt thereof. Any one of W1-, R3 and R9, R3 and w1, and each combination of R9 and W1 may be bonded to a carbon atom of a respective group to form a nitrogen-containing saturated heterocyclic ring of 4 to 1 member. 7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Q and Q are each independently a hydrogen atom; or may be via a trans group, a fluorine atom, or a Cl. A G-6 alkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of -5 alkoxy, Cl-5 alkoxycarbonyl and 4 to 1 member of a nitrogen-containing saturated heterocyclic ring. 8. A pharmaceutically acceptable salt as claimed in claims 1 to 7, wherein hydrazine is a hydrogen atom; may be via a transradical, a fluorine atom, or a Ci oxy group (the thiol group is via Gl_5 pure radical and fluorine) The composition of the composition of the material is selected from the group consisting of H (the substitution of three substituents), the G(tetra)oxy group and the four-membered nitrogen-containing saturated heterocyclic ring, and the same or the same is selected from the group of 3 to 3 a K group substituted by a substituent; which may be substituted by the same or different 1 to 3 substituents of a group, a fluorine atom, a Cw alkyl group and a Cl_5 alkoxy group; The same or 323165 14 201202247 different 1 to 3 substituents substituted by Cu alkoxy; or -C〇NR5R6. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein RR and R are each independently a nitrogen atom; may be via a trans group, a fluorine atom, C, - a fluorinated 6-alkyl or fluorenyl 8-cycloalkyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of 5 alkoxy groups and _CONRl 〇Rn; or via a hydroxyl group, a fluorine atom and Ge a 4 to 10 membered saturated heterocyclic ring substituted by the same or different 1 to 3 substituents in the group consisting of an alkyl group, and R10 and R11 are each independently a hydrogen atom or may have 1 to 5 fluorine atoms. Substituted Cl-1G alkyl, or R1. And Rn may also form a nitrogen-containing saturated heterocyclic ring of 4 to 1 member; each combination of R and ^ and R3 and R4 may also bond with carbon atoms of the respective groups to form a nitrogen-containing saturation of 4 to 7 members. Heterocyclic. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R, R6, f, R8 and R9 are each independently a hydrogen atom; And Cm substituted by the same or different 15 to 3 substituents selected from the group consisting of a radical and a Cm alkoxy group. An alkyl group; a combination of R and R' may also be bonded to a carbon atom of a respective group to form a nitrogen-containing saturated heterocyclic ring of 4 to 8 members (wherein a nitrogen-containing saturated heterocyclic ring formed by a combination of R5 and R6) Except for morpholine ring). The pharmaceutically acceptable salt of the compound according to any one of the items 1 to 10 of the U.S. Patent No. 1 to 10, wherein the formula (A) is represented by the following formula (A,), (A''). Or (A''') The group shown, Y1 is =(-)C-Z4 or a nitrogen atom, and Z1, Z2, Z3 and Z4 are each independently a hydrogen atom, a halogen, a Cw alkyl group which may be substituted by 1 to 3 fluorine atoms, Or a 0-5 alkoxy group which may be substituted by 1 to 3 fluorine atoms. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the formula (A) is a group represented by the following formula: Z1, Z2, Z4 and Z5 are each independently a hydrogen atom, a halogen, a Ch alkyl group which may be substituted by 1 to 3 fluorine atoms, and a C!-5 alkoxy group which may be substituted by 1 to 3 fluorine atoms. The same or a different substituent selected from the group consisting of a group, Het is a nitrogen-containing partially saturated heterocyclic ring of 5 to 6 members or a nitrogen-containing unsaturated heterocyclic ring of 5 to 6 members. The compound according to any one of claims 1 to 12, wherein the Aik is via a hydroxyl group, a fluorine atom, a Ci-6 alkyl group and a G-5 alkoxy group, or a pharmaceutically acceptable salt thereof. The same or different generations of Cl-3 extension groups selected by the group consisting of 16 323165 201202247. 1 to 2 substituents are taken as a pharmaceutically acceptable salt of any of claims 1 to 13, wherein Q1 and Q2 are each a hydrogen atom. 15. A pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein the compound or one of the compounds or X is -X1-, _χι-NR7C0_x2_, , or -X'-O-X2-, 'X'-CONR^X2- -X^NR7- a RM, R1 and x2m7, and a combination of R7 and X2 Alternatively, the carbon atoms of the respective groups may be bonded to form a nitrogen-containing saturated heterocyclic ring of 4 to 10 members. A compound or a pharmaceutically acceptable salt thereof according to any one of the items of the invention, wherein X is a Cl-4 stretching group and X2 is a C2-4 stretching group. 17. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein A1 is Z and A2 is formula (A). 18. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein X is -Χ1_, _X1_C0NR7-X2-, or -χ'-ο-χ2-, R1 and R2 are each independently a hydrogen atom; or a C-alkyl group which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a base, a Ci-5 alkoxy group, and -CONH2; 323165 17 201202247 R and any combination of X, R and R and R and the combination of the ruler 7 may also be bonded to the carbon atom of the respective group (d) to form a nitrogen-containing saturated heterocyclic ring of 4 i 8 . And a pharmaceutically acceptable salt thereof, wherein Υ indicates that the same can be the same as the pharmaceutically acceptable salt of any one of the above items, or the pharmaceutically acceptable salt thereof. Or replaced by 42 different substituents a phenyl group, a hydrazine group, a stretching group, the substituent is selected from the group consisting of (4) and Cl-6 alkyl groups, and w represents -w1-, n, _nr9c〇_w, one, or one good , w represents a Ci 4 stretching group which may be substituted by one impurity, wherein W is wisdom winter, or Ή1, w1 is c2-4 stretching group, and R and R4 systems respectively represent hydrogen atoms; a Cl-6 alkyl group substituted with the same or different i to 3 substituents selected from the group consisting of a hydroxyl group and a Cl-channel oxy group; R3 and R9, R3 and only 9 and ¥, and ❻r4 Any one of the combinations, and may also be bonded to a carbon atom of a respective group to form a gas residue and a hetero ring of 4 to 8 members. 20. A compound according to any one of claims -19 to 19, or a pharmaceutically acceptable salt thereof, wherein the % is a hydrogen atom, a G group, a 素素, a Ci• hydroxy group or a _nr5r6 , divided into the atomic atom or ei 6 burning base. The compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein Z is a hydrogen atom or a Cl-3 alkyl group. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Aik is a Ci-3 alkylene group. 23. The compound of any one of the preceding claims, wherein the Y is a phenyl group or a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof. ratio. Fixed base, type (Α)-W-NR3R4 is The groups shown, R3 and R4 are each independently a hydrogen atom; or a C16 alkyl group which may be substituted with the same or different one to three substituents selected from the group consisting of a hydroxyl group and a Ci_5 alkoxy group. The compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (1) is selected from the group consisting of: 2-[4-( 4-mercaptohexahydropyridinium-diphenyl)phenyl]_7_[3_pyrrolidinyl]propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine Example 41) 2-[4-(4-Ethylhexahydropyran-l-yl)phenyl]_7-[3_pyrrolidinium&amp;yl]propyl]-6,7-dihydro-5Η -πΛ洛和[2, 3-d&gt; close bite (Example 45) 19 323165 201202247 2-[4-(4-Isopropylhexahydron-p-phenyl)phenyl]_7_[3_βpyrrolidine-基]propyl]-6,7-dihydro-5Η-pyrrolo[2,3-d]pyrimidine (Example 46) 2-[3-(4-methylhexahydropyridin-1-yl) Phenyl]-7-[3-0-pyridyl-1-yl]propyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Example 48) 4-(3-{ 2-[4-(4-methylhexahydropyridinium-indoleyl)phenyl]-5H_pyrrolo[2,3-d]pyrimidin-7(61〇-yl}propyl)morpholine (Example 62) 隹4-3-{2-[4-(4-isopropylhexahydro"pyrimidin-1-yl)phenyl][2,3-d]pyrimidin-7(611)-yl}C Morpholine (Example 64) 4-(2-{2 -[4-(4-methylhexahydroindol-1-yl)phenyl]-5H-pyrrolo[2,3-d]°Bite-7(6H)-ylhydrazineethyl) Example 69) * «ν N,N-Diethyl-3-{2-Ί4-(4-methylhexahydron-indol-1-yl)phenyl]-5Η-pyrrolo[2, 3- d]pyrimidin-7(61〇-yl}propan-1-amine (Example 70) φ N-(2-decyloxyethyl)-N-indolyl-3-{2-[4-(4- Methylhexahydroindole phenyl phenyl]-5H-b pirodi[2,3-d]pyrimidine-7(611)-yl}propanol-1' amine (Example 72) 2- {4-[4-(2-decyloxyethyl)hexahydropyranyl-1-yl]phenyl}- -7-b b-bityl-propyl]propyl]_6,7-dihydrolopabend [2, 3-d] '^ pyridine (Example 77) 3-{2-[ 4-(4-ethylhexahydroindol-1-yl)phenyl]-4-indolyl~pyrrolo[2 , 3-d]pyrimidin-7(6-yl}propyl) morphine (Example 78) 20 323165 201202247 4~(3~{4-ethyl-2-[4-(4-ethylhexahydro)哄1_yl)phenyl]_ 5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl}propyl)morpholine (Example 79) 4-ethyl-2-[ 4-(4-Methylhexahydro 0 to D well-1 -yl)phenyl]_7_[2_(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-. Bisolo[2,3-d]pyrimidine (Example 83) 4~(2~{4-mercapto-2-[4-(4-mercaptohexahydrol)-p-phenyl-1-yl)phenyl ]_pyrrolo[2,3-d]pyrimidine_7(61〇-yl}ethyl)morpholine (Example • 84) 4-methyl-2-[4-(4-methylhexahydro-n-well -1-yl)phenyl]_7_[3 〇 〇 η 唆 唆 ι ι ι ι ι ) ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 86) 4-ethyl-2-[4-(4-methylhexahydro 0-indol-1-yl)phenyl]-7-[3-Ob- each π-1,4-yl)propyl]-6, 7-Dihydro-5H-° ratio slightly [2, 3-d] pyridine (Example 87) φ 4~(3~U-ethyl^244-(4-mercaptohexahydro'» Phenyl]phenyl]_ 5H-pyrolo[2,3-(1]pyrimidin-7(61〇-yl}propyl)morpholine (Example 91) Ν' N-dimercapto-i-{ 4-[4-mercapto-7-(3-(N-morphinyl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl }pyrrolidine-4-amine (Example 95) 2~~[4-(1-methylhexahydropyridin-1-yl)phenyl]-7-[3-(. 〇 〇 唆 -1- Propyl]-6,7-dihydro-5H-° ratio p and [2, 3-d] ringing (Example 109) 21 323165 201202247 (foot)-1^dimethyl-1-( 4-{7-[3-indolepyrrolidine-diyl]propyl]-6, 7- Hydrogen_5H-° ratio of [2,3-d]pyrimidin-2-yl}phenyl)hexahydropyridin-3-amine (Example 11〇) (S)-N,N-dimethyl-1 -(4-{7-[3-(pyrrolidinyl)propyl]-6,7-dihydro-511-indolo[2,34]pyrimidin-2-yl}phenyl)hexahydropyridine 3-Amine (Example 111) N,N-Dimethyl-1-(4-{7-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-pyrrole [2,3-d]pyrimidin-2-yl}phenyl)hexahydropyridin-4-amine (Example 112) 4-[3-(2-{4-[4-(2-methoxyethyl) Hexahydropyranyl-p-phenyl]phenyl}-5H-pyrrolo[2,3-(1]pyrimidin-7(61〇-yl)propyl]morpholine (Example 114) N,N-dimethyl -l-{4-[7-(3-(N-morpholinyl)propyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl] Hexahydropyridine 4-amine (Example 117) (4 {4 [7 (3-(N-Nylinyl)propyl)-6,7-dihydro-5Η-α piroxi[2, 3- d]pyrimidin-2-yl]phenyl}hexahydropyridinium-fluorenyl)ethanol (Example 119). 25. The compound of the first aspect of the patent application or the pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (1) is selected from the group consisting of: methyl group ~3~{ 2-[4-(4-methylhexahydropyrazine-i-yl)phenyl]pyrolo[2,3_d]pyrimidine_7(61〇_ylpropanepropane-p-amine (Example 323165 22 201202247 2 -[4~(4-methylhexahydropyridinium-phenyl)phenyl]_7-[2_pyrrolidinyl]ethyl]-6,7--虱-511-°Biluo[2 , 3-d] continued bite (Example 40) 4-[4-(4-mercaptohexahydropyridinium pi-pyridyl)phenyl]_7_[3_pyrrolidinyl]propyl]-6, 7-Dihydro-5H-*»Biloze[2,3-d] mouth bite (Example 42) (R) -N,N-Dimethyl-1-(4-{7-[3-( &gt;Byrrolidine-Bulk)propyl]-6' 7-hydrogen-5H-吼洛和[2, 3-d] mouth bite-2-yl} stupid base) "Bilo bite• -3~· Amine (Example 49) (S) -N,N-Dimercapto-1-(4-{7-[3-indolepyridin-1-yl)propyl]_ 6, 7-dihydro-5H -pyrrolo[2,3-d]pyrimidin-2-yl}phenyl)pyrrolidin-3-amine (Example 50) 1-(4-{7-[3-indolepyridin-1-yl) Propyl]_6,7-dihydro-511-pyrrolo[2,3-d]pyrimidin-2-yl}phenyl Pyrrolidine-4-amine (Example 54) 4-(4-{2-[4-(4-Methylhexahydropyridin-1-yl)phenyl]_5H_pyrrolo φ [2, 3-d Pyrimidine-7(611)-yl}butyl)morpholine (Example 63) 2-[4-(4-Methylhexahydropyridin-1-yl)phenyl;|_8_[3_σpyrrolidine- Propyl]propyl]-5, 6, 7, 8-tetrahydropyrido[2,3-d]pyrimidine (Example 66) 2-[6-(4-methylhexahydropyridyl α--1- Pyridyl-3-yl]-8-[3-pyrrolidin-1-yl]propyl]-5,6,7-tetrahydropyrido[2,3-d]pyrimidine (Example 67) 2-[Methyl(3-{2-[4-(4-mercaptohexahydropyridin-1-yl)phenyl]-5H-°pyrho[2,3-(1]pyrimidine-7 ( 〇 基 基 ) ) ( Phenyl]-5H-pyrrolo[2,3-d]pyrimidin-7(610-yl}ethanone (Example 74) 4 -(3 - {2-[4-(4-ethylhexahydro, Phenyl]phenyl]_5H_n is more than [2,3-d]pyrimidine-7(6"-yl}propyl} (Example 76) N,N-dimercapto-3-{4 -mercapto-2-[4-(4-mercaptohexahydropyridin-1-yl)phenyl]-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-ylpropanepropane-1 -amine # (Example 81) 4-Methyl-2-[4-(4-decylhexahydropyrrole)phenyl]_7_[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro_5H -pyrrolo[2,3_uracil (Example 82) 2-[4_(4-methylhexahydron-indenyl)phenyl]-4-propyl-7_[3_(pyrrolidine-1 -yl)propyl]_6,7-dihydro-5H_pyrrolo[2,3(1]pyrimidine (Example 88) φ 4—(3_{4_methyl- 2-[4-(4 曱) Hexahydro-pyridyl-1-yl)phenyl]-5H-pyrrolo[2,3-(1]pyrimidin-7(61〇_yl}propyl)morpholine (Example 90) 4-(3 -{2-[4-(4-isopropylhexahydroindole-bu)phenyl]_4_methyl-5H-pyrrolo[2,3-&lt;1]pyrimidin-7(611)-yl }propyl)morpholine (Example 92) 4-(3-{4-Ethyl-2-[4-(4-isopropylhexahydro-tonyl-indole-yl)phenyl]-5H-pyrrole [2,3-(1]pyrimidin-7(611)-yl}propyl)morpholine (Example 93) 24 323165 201202247 4-(4-{4-methyl-2-[4-(4-A Base hexahydrogen ratio 卩 well_1_yl)phenyl]-5H-indolo[2,3-(1]pyrimidin-7(61〇-ylindole butyl)morpholine (Example 94) 2-[ 4-(4-{7-[3-(&gt; each bite-1-yl)propyl]-6,7-dihydro-5Η-σ ratio 11 and [2, 3-(1]唆Di-2-yl]phenyl}hexahydro卩井_1_基)ethanol (Example 125) 2-[4-(4-methylhexamethylene-1-yl)phenyl;|_7_{2_[2_ηpyrrolidin-1-yl] Ethoxy}ethyl}-6,7-dihydro-5Η-»Biloze[2,3-d] pentidine (Example 127) and 4_(3-{2-[4-(4- Methylhexahydroindole (Phenyl) phenyl]_6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-ylmercaptopropyl)morpholine (Example 130) 〇26 A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof. 2 7. - Species receptor (Tq丨丨_丨丨) Ke (a sipping s) related to the treatment of a disease and/or a preventive agent, which is effective as a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof And a therapeutic agent and/or a prophylactic agent according to any one of claims 1 to 25, or a pharmaceutical preparation thereof, according to any one of claims 1 to 25. The permissible salt is used as an active ingredient. The therapeutic and/or prophylactic agents described in the scope of patent application 帛27 are related to steroids and related bodies. The disease is sepsis, autoimmune grade degenerative disease. 323165 25 201202247 3〇. The therapeutic agent and/or prophylactic agent according to claim 28, wherein the sputum receptor 7 and/or 9 associated disease is sepsis And an autoimmune disease or a neurodegenerative disease. 31. A method for treating and/or preventing a disease associated with a sputum receptor, which comprises the method of claiming any one of items i to 25; The therapeutically effective amount of the pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof is administered to a mammal which is in need of treatment. The compound of any one of the inventions of claim 25 or a pharmaceutically acceptable The use of a salt for the manufacture of a therapeutic or/and prophylactic agent for a disease associated with a sputum-like receptor. 33. A compound according to any one of claims 1 to 25, or a pharmaceutical thereof The above-mentioned salt material is used for the treatment and/or prevention of diseases associated with the release of the receptor. 323165 26